THE BEHAVIORAL AND BRAIN SCIENCES (1982)5, 89-137

Printed in the United States of America

Depression: The predisposing influence of stress

Hymie Anisman
Department of Psychology, Carleton University, Ottawa, Ontario, Canada K1S 586

Robert M. Zacharko
Department of Psychology, Carleton University, Ottawa, Ontario, Canada K1S 586

Abstract: Aversive experiences have been thought to provoke or exacerbate clinical depression. The present review provides a brief survey of the stress-depression literature and suggests that the effects of stressful experiences on affective state may be related to depletion of several neurotransmitters, including norepinephrine, dopamine, and serotonin. A major element in determining the neuroehemical changes is the organism's ability to cope with the aversive stimuli through behavioral means. Aversive experiences give rise to behavioral attempts to cope with the stressor, coupled with increased utilization and synthesis of brain amines to contend with environmental demands. When behavioral coping is possible, neuroehemical systems are not overly taxed, and behavioral pathology will not ensue. However, when there can be no behavioral control over the stressful stimuli, or when the aversive experience is perceived as uncontrollable, increased emphasis is placed on coping through endogenous neuroehemical mechanisms. Amine utilization increases appreciably and may exceed synthesis, resulting in a net reduction of amine stores, which in turn promotes or exacerbates affective disorder. The processes governing the depletions may be subject to sensitization or conditioning, such that exposure to traumatic experiences may have long-term repercussions when the organism subsequently encounters related stressful stimuli. With continued uncontrollable stimulation, adaptation occurs in the form of increased activity of synthetic enzymes, and levels of amines approach basal values. It is suggested that either the initial amine depletion provoked by aversive experiences or a dysfunction of the adaptive processes, resulting in persistent amine depletion, contributes to behavioral depression. Aside from the contribution of behavioral coping, several organismic, experiential, and environmental variables will influence the effects of aversive experiences on neuroehemical activity, and may thus influence vulnerability to depression. Keywords: depression; loss; norepinephrine; separation; serotonin; stress; suicide

Considerable interest has focused on the contribution of aversive life events to both physiological and psychological pathologies (Selye 1973). Indeed, there is good reason to believe that stressful events participate in the induction of pathologies such as ulceration (Weiss 1971a; 1971b; 1971c), heart disease (see Glass 1977), and affective disorders (see reviews in Depue 1979), and may be a salient factor in modifying neoplastic disease (Sklar & Anisman 1981). The finding that stress has such a broad range of effects suggests two possibilities. First, one or more of the physiological changes engendered by stress may represent a common feature for disparate forms of pathology. Second, stress may provoke dysfunction in any number of physiological systems, and the nature of the pathology observed will depend on the particular system adversely influenced by the stress experience. The effectiveness of stressors in provoking pathology is dependent on the organism's ability to cope with these aversive experiences (henceforth "insults"). In this respect a great number of mechanisms are available to the organism in order to diminish the impact of the stressor. Not only will the organism rely on behavioral and psychological responses and on buffering the stress effect using socioenvironmental resources, but several
7982 Cambridge University Press

physiological changes will also occur whose function is primarily one of meeting environmental demands. Some of the physiological changes act to blunt the immediate physical and psychological attributes of the stressor, whereas others will protect the organism from potential health threats. At the same time, the directed mobilization of resources may leave the organism disposed toward, or at least unprotected from, the impact of other physical or psychological insults. Moreover, if the stress is sufficiently protracted, exhaustion of the resources necessary to contend with it may render the organism relatively unable to deal with further environmental insults. Although the term "stress" is widely used, we are not aware of any adequate definition of it (see, for example, the panel discussion on stress theory in Usdin, Kvetnansky, & Kopin 1980). Some investigators have considered stress as the organism's response to aversive events (Rabkin & Streuning 1976). Others have been more concerned with the controllability of the aversive event. For present purposes, stress will be considered the behavioral and physiological response to actual or impending aversive stimuli. In some instances, these responses represent adaptive changes that allow the organism to cope with the events; in others, they are physiological changes (e.g., immunological alterations)
89

0140-525XI82l010089-49l$06.00l0

Anisman & Zacharko: Depression and stress that protect the health of the organism. Stressors include personal life changes and physical or psychological traumas, both actual and threatened. Terms such as "helplessness" will be reserved for hypothetical cognitive changes resulting from uncontrollable aversive events. The present paper will assess the contribution of stress to the precipitation of clinical depression and will evaluate the involvement of stress-related neurochemical changes in affective illness.
Stress as a precipitant of depression

Although stress has been implicated as a factor in the precipitation of depression in a subset of individuals (see review in Akiskal & McKinney 1973; 1975), support for this proposition has not been unanimous. For instance, some theorists have argued that the depressive reaction to stressors may be symptomatic of an already existent depression (Slater & Roth 1969) or that stressors precipitate hospitalization in already depressed individuals (Hudgens, Morrison, & Barchha 1967; Morrison, Hudgens, & Barchha 1968). Still others (e.g., Hinkle 1974) have ascribed a secondary role to stress in the promotion of illness. Unfortunately, disentangling the stress-depression relationship is complicated by the experimental techniques that are available and by the very nature of the illness. Depression is clearly not a unitary illness but appears to be best described in terms of subgroups of affective illnesses differing in symptomatology, therapeutic prognosis, familial history, and so forth (see the descriptions in Depue & Monroe 1979; Fowles & Gersh 1979). Indeed, even within a single "category" of depression interindividual differences in symptomatology are frequent. And, as will be seen later, available evidence points to the possibility that neurochemical substrates for depression are likewise complex and may differ among individuals. The response of individuals to natural or man-made catastrophes provides an opportunity to examine the incidence of affective illness. However, catastrophic events such as war, fire, and earthquake (Eitinger 1964; 1973; Star 1949; Swank 1949) are fortunately not frequent, so detailed analysis is not possible. Besides, many catastrophic events involve a host of variables with stressful components (including anxiety, fear and physical trauma, financial loss etc.) and as a result, their investigation provides little information concerning the potential impact of the more common life stresses. Furthermore, under such drastic conditions many social and cognitive factors, such as reliance on others, shared grief, social pressures, and modelling behaviors, may influence affective outcome. In addition, as will be seen in later sections of this paper, it is important to distinguish between transient and sustained stressors, since these may provoke very different physiological changes and could induce different behavioral outcomes. A second approach is that of retrospective analysis, in which stress history is assessed in depressed and nondepressed populations. It seems, however, that the individual's recollection of past events is not particularly impressive (Jenkins, Hurst, & Rose 1979). Furthermore, the perception of past events in depressed patients may be colored by their current affective state. An event that 90
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

might ordinarily be considered a minor inconvenience could assume undue import for the depressed individual, whereas an apparently minor inconvenience from the perspective of the experimental protocol might, in fact, have been a significant event to the individual at the time it occurred. The utility of scaling procedures in the analysis of previous major changes in life-events has been seriously challenged. Rabkin and Streuning (1976) have questioned the reliability and validity of life-event scales, and have indicated that these procedures account for only a small portion of the variance associated with illness. Cross-cultural differences, as well as community lifestyle, also appear to be determinants of the subjective impact of stress. Furthermore, the time between a stressor and the depression may be a major constraint on whether one can conclude that a causal relationship exists between the two (for a detailed discussion of these and other related issues see Dohrenwend & Dohrenwend 1979; Rabkin & Streuning 1976). A third approach is that of the prospective study in which the instances of stress are monitored and related to the occurrence of later psychopathology. Here, as in the case of the retrospective studies, it is difficult to gauge the severity of a given event. The interpretation of an event depends not only on the various variables mentioned earlier, but also on the individual's previous history with similar types of stress. Furthermore, in both the retrospective and prospective analyses it is virtually impossible to assess individually (at least in quantitative terms) the potential impact of a series of apparently inconsequential events. By the same token, the elimination of environmental stimulation, as in the case of the individual who retires from a job or completes a longterm project, might be considered stressful. Finally (and again this applies to the retrospective studies as well), the impact of a stressor must be considered in the context of the various buffers that are available to the individual, such as familial support systems (Brown 1979; Clayton, Halikas, & Maurice 1972; Rabkin & Streuning 1976). A fourth approach has been to simulate "depression" by imposing relatively minor stresses in a laboratory situation (e.g., see reviews in Garber, Miller, & Seaman 1979). As indicated by Costello (1978), this approach is of dubious value. A performance change in a problemsolving task following induction of frustration or failure in college students in a contrived laboratory situation seems far removed from the emotional, motivational, affective, and somatic dysfunctions that characterize depressive syndromes. It should be mentioned, however, that a number of studies have evaluated the response to aversive uncontrollable events among depressed individuals (see review in Abramson, Garber, & Seligman 1980). Such studies have certainly provided essential information concerning attributional style in depressed populations. To analyze stress-depression relations, several additional issues must be considered. Apparently equivalent amounts of stress may have appreciably different affective consequences for different individuals. Likewise, depending on environmental circumstances (including previous history), profound intraindividual differences may occur in response to aversive events (see later discussion). Moreover, other things being equal,

Anisman & Zacharko: Depression and stress the particular pathology engendered by a stressor may also differ from one individual to another. It may be the case that a variety of experiential and environmental factors, acting singly or interacting with genetically based physiological processes, are responsible for the individual differences. In light of these caveats, it should be clear that conclusions concerning the relationship between stressful life events and depression must be considered cautiously. It is not our intention to adopt a narrow position concerning the validity of the conclusions derived from human experiments. However, despite the various shortcomings associated with the approaches described so far, it is significant that most studies have revealed depression to be associated with a high frequency of antecedent stressful life events (Lloyd 1980a; 1980b). Of course, these studies do not in themselves imply that all instances of depression are associated with stressful events, or that the relationship between stress and depression is a causal one. Life changes requiring social adjustment - as measured by the Holmes and Rahe (1967) life-change scale or modifications of this scale - in the 6-month to 1-year period preceding illness have been found to be predictive of depression and of suicide attempts (Briscoe & Smith 1975; Paykel 1979; Paykel, Myers, Dienelt, Klerman, Lindenthal, & Pepper 1969; Paykel, DiMascio, Haskell, & Prusoff 1975; Thomson & Hendrie 1972). In addition, recurrence of depression following remission is more frequent among individuals who have experienced significant life event changes (Paykel & Tanner 1976). Moreover, although stressful experiences were found to precede both depression and schizophrenia, the incidence of undesirable or hazardous events was greater in depressed populations (Beck & Worthen 1972; Jacobs, Prusoff & Paykel 1974). Several experiments (Jacobs et al. 1974; Lewinsohn & Amenson 1978; Paykel 1974; Vinokur & Selzer 1975) have indicated that the "unpleasantness" of the life event, rather than social adjustment per se, was more closely aligned with depression. Significantly, consistent with some of the earlier reports, stress of personal loss (death in the family, divorce, separation) yielded the greatest frequency of depression and attempted suicides (Clayton et al. 1972; Levi, Fales, Stein, & Sharp 1966; Parkes 1964; Paykel et al. 1969; Paykel, Prusoff, & Uhlenhuth 1971; Paykel et al. 1975; Sethi 1964), although other investigators have failed to find such a relationship (Forrest, Fraser, & Priest 1965; Hudgens et al. 1967). One additional factor should be emphasized at this point concerning the contribution of stress to endogenous and reactive types of depression. Thomson and Hendrie (1972) reported that increased life-change scores were associated with both reactive and endogenous depression, although somewhat higher life-change scores were evident in the former condition. In a similar fashion, Goodwin and Bunney (1973) reported that upon hospitalization, endogenously depressed patients did not always disclose stressful events that preceded illness onset; however, in some patients stress experiences that preceded hospitalization by as little as 1-2 months were disclosed after patients had been in hospital for several weeks. Similarly, Leff, Roatch, and Bunney (1970) and Paykel (1974) found a marked incidence of precipitating stress in patients diagnosed as endogenously depressed, although symptom manifestation did not appear to be highly related to their stress experiences. Taken together, these data suggest that despite the differences in symptomatology associated with endogenous and reactive or neurotic depression (Fowles & Gersh 1979), stressful events are not restricted to a single form of affective illness.
Early experience and coping factors

In addition to recent life-event changes precipitating depression, considerable data suggest that early life trauma (e.g., bereavement and separation) may increase vulnerability to later depression (see reviews in Lloyd 1980a; Heinicke 1973). Indeed, several investigators have reported that the death of a parent before a child is seventeen results in a substantial increase in the incidence of adult depression (Beck, Sethi & Tuthill 1963; Brown 1961; Forrest et al. 1965; Greer 1964; Dennehy 1966; Hill 1969; Hill & Price 1967; Caplan & Douglas 1969; Munro 1966; Munro & Griffiths 1969; Roy 1978; see reviews in Brown 1979; Lloyd 1980a). In contrast, bereavement under similar conditions is not associated with increased occurrence of bipolar illness (Hopkinson & Reed 1966). In a particularly interesting series of studies (see Brown 1979) it was reported that women who had lost a parent early in life were more vulnerable to depression as adults. This effect, however, was manifest only if these women encountered a further trauma in adulthood. In effect, the early stress sensitized the subjects to later stress, thereby increasing the probability of affective illness. The second interesting feature reported by Brown was that the presence of a confidant in adulthood counteracted the negative consequences of stressful experience. It seems that the effect of stress on depression may depend on the subject's early life history and on the individual's ability to cope with or buffer the impact of the stress through either behavioral or psychological means. Brown's studies not only underscore some of the salient variables that alter the individual's vulnerability to stress effects, but they also point to the fact that analyses of stress-related pathology should also consider life events beyond those that were immediate antecedents of illness onset. Although most studies have found a relation between early life trauma and vulnerability to depression, Crook and Eliot (1980) have indicated that many of these studies were methodologically flawed (i.e., not controlled for age, sex, and psychiatric history of the deceased parent) and consequently conclusions concerning the early stress-depression relationship should be held in abeyance. On the other hand, Lloyd (1980b) has suggested that despite the procedural weaknesses, the data do, in fact, imply a relationship between early-life stress and depression. Of course, it is not certain that the relationship between bereavement and depression is a causal one. It is possible that repercussions of the early loss, rather than bereavement per se, are actually responsible for the affective illness seen in adulthood. For example, as indicated by Lloyd (1980a), distress on the part of the surviving parent or financial difficulties resulting from the death of a family member may be
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

91

Anisman & Zacharko: Depression and stress responsible for the psychological-behavioral changes. Alternatively, the stressful experience may result in loss of self-esteem or a sense of inability to control events, which in turn may predispose the individual to depression. One final point should be considered. It has been the view of several investigators that early-life trauma increases vulnerability to depression, not that it necessarily provokes depression. Accordingly, it would be expected that variables such as bereavement should increase the probability of depression in the face of a later pathogenic stimulus. Indeed, the literature survey conducted by Lloyd (1980a) reveals that only 20-40% of adult depressives had encountered early parental loss, suggesting that life stress probably interacts with other variables in determining affective changes (see Brown 1979). In effect, it may not be sufficient to consider the contribution of early-life trauma to depression in the absence of data concerning stresses that occur in adulthood (see later discussion concerning stress-induced neurochemical changes).
Cognitive models of stress-induced depression

While most theorists will probably accept the contention that coping factors are fundamental in determining behavioral or emotional consequences of stress, divergent views have been expressed concerning the mechanisms underlying stress-related pathology. One view that has received considerable attention of late deals with the cognitive changes induced by stress. For example, Beck (1976) has indicated that a cognitive triad of negative conceptions (negative perception of the self, negative views of past experiences, and negative expectations of the future) are associated with depression. In a similar fashion, Seligman and his associates (Klein & Seligman 1976; Miller & Seligman 1976; Seligman 1975; Seligman, Klein, & Miller 1976) have proposed that from experiences with uncontrollable events or events perceived as being uncontrollable the individual learns that he is "helpless" in determining outcomes, and consequently stops trying to influence his own destiny. The "helplessness" and the accompanying decline in motivation are responsible for the negative perceptions and negative affect characteristic of depression. Recently, Abramson, Seligman, and Teasdale (1978) have reformulated the "helplessness" hypothesis in terms of attributions formed in the face of uncontrollable events, and expectancies about later performance based on these attributions. The reformulated hypothesis attempts to account both for individual differences in response to uncontrollable events and for the conditions under which helplessness is generalized across environmental situations. According to this hypothesis, the immediate consequence of noncontingency or failure is a tendency to attribute the helplessness to a particular cause. The individual may assume that neither he nor anyone else could have altered the course of events (universal helplessness), or that he alone was unable to alter events (personal helplessness). The former represents an "external" attribution, the latter an "internal" one. The attribution will influence self-perceptions and will also determine expectancies of future performance.
92
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

That is, personal helplessness may be accompanied by a loss of self-esteem, whereas "universal helplessness" may not have the same result. A second important dimension concerns the range of situations covered by attributions. That is, the helplessness may apply to a broad range of conditions (global) or to a narrow range (specific). It may be persistent (chronic) or brief (transient). The attribution may further be stable (recurrent or continuous) or unstable (shortlived or intermittent). In effect, pronounced individual differences may occur in response to a stressor, and variation can be expected in the generality and time course of the helplessness effect. Expectancy of performance is still seen as fundamental to the development of helplessness, but the expectancy is formed on the basis of attributions. Despite the apparent advantages of the reformulated helplessness hypothesis over the initial proposal, it is not without shortcomings. Its suitability as a model of depression has been challenged by several investigators (Costello 1978; Depue & Monroe 1978; Wortman & Dintzer 1978) and consequently these criticisms need not be reiterated. Suffice it to say that although depressed subjects do, in fact, report feelings of helplessness and hopelessness (Beck 1976), it is not clear that these features provoke depression rather than merely constituting symptoms of depressed affect. Moreover, as will be seen in the next section, considerable evidence exists suggesting that depression may result from neurochemical abnormalities, and hence that the feelings of helplessness may simply be a manifestation of these central changes.

Neurochemical concomitants of depression

A number of theorists have argued that depression is associated with dysfunction of neurochemical activity. Since numerous excellent papers are available on this topic (Murphy, Campbell, & Costa 1978; Post & Goodwin 1978; Schildkraut 1978; van Praag 1978a), only a limited review of this literature will be provided here. Two principal hypotheses have been advanced. One of these attributes depression to a functional deficiency in norepinephrine activity (NE) (Schildkraut 1970; 1978), while the other assigns a primary role to serotonin (5-HT deficiency) (Murphy et al. 1978). Mania, in contrast, is thought to be a result of increased amine activity or receptor supersensitivity secondary to a deficiency of central amines (Bunney, van Kammen, Post, & Garland 1979). As indicated by Schildkraut (1978), the NE and 5-HT hypotheses need not be considered mutually exclusive. Moreover, other central transmitters such as acetylcholine (ACh) and dopamine (DA) may also be associated with the depressive symptomatology (Bunney et al. 1979; Janowsky, El-Yousef, Davis, & Sekerke 1972). Several lines of research have supported the basic contention that one or more transmitters underlie the depressive symptomatology. These studies typically include analyzing brain tissue of suicide victims, examining amine and metabolites in blood, urine and cerebrospinal fluid (CSF), and determining the therapeutic effi-

Anisman & Zacharko: Depression and stress cacy of pharmacological treatments with demonstrated effects on central neurotransmission. To be sure, the available data are not conclusive and the experimental procedures are not without shortcomings; nevertheless, these diverse sources of data have converged on NE and 5-HT as two possible candidates prominent in affective illness. Post-mortem studies. The analysis of the biochemical concomitants of depression is hampered (as are other types of research dealing with depression) by the potential for misdiagnosis, and by the fact that the various forms of depression may differ not only in behavioral symptomatology but also with respect to the biochemical mechanisms underlying the illnesses. The analysis of post-mortem brain tissue is further hampered by the fact that the subject population is typically that of suicide victims and it is not clear whether such subjects are representative of the depressed population at large, nor is it clear what effects the cognitive processes preceding suicide have on brain neurochemical activity. Furthermore, the interval between death and tissue extraction varies considerably between subjects, contributing to the variance of the neurochemical levels observed. Finally, the drug history of the individual will alter brain amine levels, adding yet another source of confusion (see review in van Praag 1978a). Inconsistent results have been reported concerning NE concentrations in the brains of depressed subjects. Whereas some investigators (Bourne, Bunney, Colburn, Davis, Davis, Shaw, & Coppen 1968; Pare, Yeung, Price, & Stacey 1969) have found that NE levels do not differ between depressed suicides and controls, others (Birkmayer & Rederer 1975) have found reduced NE concentrations in the brain among depressives who died of causes other than suicide. More consistent results are available concerning 5-HT levels in the brains of depressed suicides. Several investigators, for example, have found decreases of 5-HT (Beskow, Gottfries, Roos, & Winoblad 1976; Bourne et al. 1968; Pare et al. 1969; Shaw, Kemps, & Ecclestone 1967), and analyses of discrete brain regions have revealed that the reductions were localized mainly in the raphe nuclei (Lloyd, Farley, Deck, & Hornykiewicz 1974). Several of these studies also indicated that the reduced 5-HT levels were accompanied by decreases in the concentration of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) (Bourne et al. 1968; Beskow et al. 1976). Cerebrospinal fluid. Consistent with the post-mortem analyses, indications of amine dysfunction have been derived through analyses of cerebrospinal fluid (CSF). It should be noted, however, that since metabolites of 5-HT are determined from CSF taken from the lumbar spinal region, the 5-HT is of mixed spinal and cerebral origin. Thus it is not particularly surprising that some inconsistencies are observed. When the probenecid technique is used to inhibit transport of 5-HIAA from the CNS (central nervous system) the observed results are more uniform. In the absence of probenecid, some investigators report a small decline in 5-HIAA production (Bowers, Heninger, & Gerbode 1969; Papeschi & McLure 1971), whereas others find no appreciable differences (Goodwin & Post 1974). However, Asberg, Thoren, Traskman, Bertilsson., and Ringberger (1976) have found reduced 5-HIAA concentrations in a subgroup of patients with unipolar depression. As indicated earlier, the mixed cerebral and spinal 5-HIAA in these studies may have contributed to the variable results. In addition, it has been reported (see van Praag 1980) that the nature of the depressive symptomatology may also be an essential element in determining whether 5-HIAA changes will be seen in CSF. In studies employing probenecid, the accumulation of 5-HIAA was reduced among individuals who exhibited symptoms characteristic of endogenous depression (Bowers 1969; van Praag, Korf, & Puite 1970). Van Praag and Korf (1971) have suggested that there are two subgroups of depressives, homogenous in symptomatology but biochemically heterogeneous. These investigators observed a bimodal distribution in 5-HIAA accumulation, with about 40% of depressives exhibiting reduced metabolite concentrations. In addition, it was found that the bipolar type of depression was associated with lower metabolite concentrations than the unipolar type (Roos & Sjostrom 1969; van Praag 1978b). It is of interest that van Praag and deHaan (1980) have recently reported that although 5-HTP alleviates depression in a subgroup of patients, the 5-HT deficiency seems to persist. These investigators posit that 5-HT depletion may not cause depression directly but may be a predisposing factor for the illness. Indeed, continued medication with 5-HTP seems to have a prophylactic effect on recurrent depression. With regard to the catecholamines, variable results have been reported concerning NE metabolites in depressed individuals. For example, several investigators found reduced levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) (Gordon & Oliver 1971; Post & Goodwin 1978; Post, Gordon, Goodwin, & Bunney 1973) but others found no such effect (Shopsin, Wilk, Gershon, Davis, & Suhl 1973). The latter investigators, however, did report increased MHPG levels associated with mania. In contrast to NE metabolites, decreased concentrations of the DA metabolite, homovanillic acid (HVA), have been reported in lumbar CSF of depressed patients (Bowers et al. 1969; Brodie, Sack, & Siever 1973; McLure 1973; Mendels, Fraser, Fitzgerald, Ramsay, & Stokes 1972; Nordin, Ottosson, & Roos 1971). These differences in HVA concentrations were most pronounced in retarded forms of depression, that is, where motor deficits were apparent (Mendels et al. 1972). In addition, the reductions in HVA concentration were less pronounced in unipolar than in bipolar depression (Ashcroft, Blackburn, Eccleston, Glen, Hartley, Kinloch, Lonergen, Murray, & Pullar 1973; van Praag & Korf 1975), although such a finding has not been consistently observed (Papeschi & McLure 1971). Using the probenicid technique, Berger, Faull, Davis, and Barchas (1979) found that accumulation of HVA concentrations was decreased in depressed subjects relative to controls, but neither 5-HIAA nor MHPG accumulation differed in these two groups. Likewise, van Praag and Korf (1975) reported reduced HVA concentrations in unipolar "vital" depression, and, as indicated by others, the reduced amine metabolite was accompanied by motor retardaTHE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

93

Anisman & Zacharko: Depression and stress tion. Inasmuch as HVA concentrations are not correlated with the severity of the depression, it is possible that the amine metabolite variations were secondary to motor changes associated with the affective state (Goodwin & Post 1975; Post, Kotin, Goodwin, & Gordon 1973; Sachar & Coppen 1975). Urinary metabolites. In contrast to metabolites of 5-HT in CSF, urinary metabolites have not been found to differ between depressed and nondepressed subjects (Fraser, Pandy, & Mendels 1973). With respect to NE, renal excretion of the metabolite normetanephrine was reduced during depressed periods relative to nondepressed periods in these same subjects (Greenspan, Schildkraut, Gordon, Levy, & Durell 1969). However, since normetanephrine reflects peripheral as well as central NE activity, these data must be considered cautiously. In the case of MHPG, it was reported that more than 60% of this urinary metabolite originates in the brain (Maas, Dekirmenjian, Garver, Redman, & Landis 1973), and that this consequently represents an adequate index of central NE activity (Maas, Greene, Hattox, & Landis 1979). In contrast, when MHPG conjugates and vanillylmandelic acid were considered in the analysis of urinary MHPG, it was concluded that only 20% of the metabolite was actually derived from brain norepinephrine (Blomberg, Kopin, Gordon, Markey, & Ebert 1980). Accordingly, it may be premature to accept MHPG concentrations as genuinely reflective of central NE activity. Consistent with a catecholamine hypothesis of depression, it has been reported that MHPG concentrations were lower in depressed than in nondepressed patients (Fawcett, Maas, & Dekirmenjian 1972) and were associated with anxiety in depressed subjects (Beckman & Goodwin 1975). However, other investigations (Coppen, Rama Rao, Ruthven, Goodwin, & Sandier 1979) have been unable to detect differences in urinary excretion of MHPG between depressive and control populations. Furthermore, in a within-subject design, greater MHPG excretion rates have been reported to occur during manic than depressed phases (see review in Goodwin & Potter 1979) although there exist contradictory data in this regard (cf. Bond, Jenner, & Sampson 1972; Bunney, Goodwin, & Murphy 1972; Edwards, Spiker, Kupfer, & Neill 1979; Greenspan, Schildkraut, Gordon, Baer, Aranoff, & Durrell 1970). Several investigators have provided evidence suggesting that there may be biochemically and pharmacologically distinct subgroups of depressives (Goodwin, Cowdry, & Webster 1978; Maas 1975). Specifically, patients with primary affective disorders who excrete relatively small quantities of MHPG respond more favourably to imipramine, desipramine (Maas, Fawcett, & Dekermenjian 1972), and nortriptyline (Hollister, Davis, & Berger 1980) than do patients with high MHPG excretion rates. Conversely, a more favourable therapeutic response to amitriptyline has been observed among patients who exhibit high levels of MHPG excretion (Schildkraut 1973; Beckman & Goodwin 1975). Thus, in cases where depression is associated with reduced NE activity, tricyclic agents that preferentially influence NE uptake are most efficacious, whereas in the presence of adequate NE activity but possibly reduced 5-HT neuronal functioning, drugs with greater effects on 5-HT reuptake are most beneficial. In addition to these subclassifications, lower concentrations of MHPG have been reported in bipolar patients than in other depressions (Goodwin & Potter 1979; Maas, Dekermenjian, & Jones 1973; Schildkraut, Keeler, Grob, Kantrowich, & Hartmann 1973). Moreover, Schildkraut, Orsulak, Schatzberg, Gudeman, Cole, LaBrie, and Rohde (1979) were able to distinguish biochemically among several subgroups of depression. That is, bipolar depression and schizo-affective depression were found to be associated with low urinary MHPG, lowered NE excretion, and low platelet MAO activity. Schizophrenia-related depressions were also characterized by low MHPG excretion, low epinephrine and metanephrine excretion, and high platelet MAO activity. The unipolar nonendogenous depressions were characterized by high MHPG levels, while heterogeneous biochemical results were seen among unipolar endogenous patients. In summary, it appears that the contribution of norepinephrine may vary with different forms of depression. In addition, consistent with the data discussed earlier concerning amine metabolites in CSF, the data derived from studies dealing with urinary amine metabolites suggest that even within a single subtype of depression, heterogeneity may exist with respect to the relative contributions of NE and 5-HT. Therapeutics. Strong evidence supporting the amine hypotheses of depression is derived from clinical studies showing that drugs with known catecholamine or 5-HT action have predictable effects on affective disorders. Before describing these data, however, we must interject one important caveat: In assessing the effects of pharmacological treatments on depression, it should be understood that the drugs may influence the affective symptomatology without necessarily altering the substrate (i.e., the etiology) of depression. The amine uptake inhibitors, imipramine, desmethylimipramine, chlorimipramine, and amitriptyline, have been shown to alleviate depression, although the effects of these agents vary among individuals. For example, as indicated in the preceding section, imipramine and desmethylimipramine, which have strong effects on NE reuptake, are most effective in patients exhibiting low urinary MHPG excretion rates, while amitriptyline is effective in other instances (Beckman & Goodwin 1975; Maas et al. 1972; see the review in Kupfer & Detre 1978, concerning the preferential therapeutic action for different types of depression; Schildkraut 1978). Furthermore, the selective 5-HT reuptake inhibitor, zimelidine, also appears to have potent antidepressant prbperties (Aberg & Holmberg 1979). A number of studies have evaluated the effects of the 5-HT precursors, tryptophan and 5-hydroxytryptophan, alone or in combination with MAO (monoamine oxidase) inhibitors on depression. These studies are based on the proposition that depression is associated with reduced 5-HT at postsynaptic receptor sites, and hence that precursor loading should have a positive therapeutic

94

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Anisman & Zacharko: Depression and stress effect. It should be understood, however, that the deficiency may reflect a receptor dysfunction, rather than deficits in levels of the monoamine. In the case of tryptophan the data are inconclusive. Coppen, Shaw, Hersberg, and Maggs (1967) have reported that tryptophan alleviates depressive symptoms. However, Dunner and Goodwin (1972) and Bunney, Murphy, and Goodwin (1970) did not observe 1-tryptophan to effectively reduce the depressive symptomatology. As with tryptophan, variable results have been reported with 5-HTP, although precursor loading was found effective in a subgroup of unipolar depressives (Brodie et al. 1973; Takahashi, Gondo, & Keto 1975; van Praag, Korf, Dols, & Shute 1972). Van Praag and Korf (1971) found 5-HTP to be most effective in patients with indications of central 5-HT deficiency, and the therapeutic effectiveness of 5-HTP was not found to differ from that of other antidepressants (Angst, Waggon, & Schopef 1977; van Praag 1978a; 1978b). Finally, when administered in combination with chlorimipramine, 5-HTP was found effective in alleviating depression (van Praag 1978b; van Praag et al. 1972; Walinder, Scott, Nagy, Carlson, and Roos, 1975). In the case of catecholamine precursor loading through tyrosine, only weak evidence has been provided concerning catecholamine involvement in depression. However, it has been reported that in a subgroup of depressives particularly marked elevations of plasma tyrosine levels occurred after oral administration of the compound, possibly suggesting retarded production of NE from its precursor (Takahashi, Utina, Mashiyama, Kurihama, Otsuka, Nakamura, & Konamura 1968). Despite the similarly inconclusive results obtained with tryptophan loading, van Praag (1980) has indicated that the tryptophan studies to date have not been conducted in patients classified on the basis of biochemical dysfunction. Moreover, a critical range of tryptophan concentrations may be necessary in order for any therapeutic efficacy to be evident. It is likewise possible that tyrosine loading will only be effective in a subgroup of depressives, and that studies will require classification of subjects on the basis of biochemical characteristics. Although a number of agents that stimulate catecholamine neurons (e.g., monoamine oxidase [MAOJ inhibitors and tricyclics) alleviate depression, drugs such as 1-dopa, which increase DA levels, are effective exclusively in reducing motor effects associated with retarded depression (Weiss, Kupfer, Foster, & Delgado 1974). More recent experiments, however, have shown that a subgroup of depressives characterized by low levels of homovanillic acid in CSF responded favorably to DA agonists, such as peribedil, nomifensine, and 1-dopa (see Post 1978; Post, Jimersom, Reus, Goodwin, Silberman, & Bunney 1979; van Scheijen, van Praag, & Korf 1977). Such findings led Post (1978) to suggest that DA, possibly in conjunction with several other neurotransmitters, may be fundamental in determining the affective symptomatology, at least in a subgroup of depressives. With regard to the contribution of ACh to affective disorders, it has been suggested that depression and mania may reflect an imbalance in cholinergic and noradrenergic functioning. Depression is thought to result from cholinergic dominance and mania from noradrenergic dominance (Davis & Janowsky 1975; Shopsin, Janowsky, Davis, & Gershon 1975). Indeed, the anticholinesterase, physostigmine, has been shown to reduce mania and elicit depression (Janowsky, ElYousef, Davis, & Sekerke 1972; Janowsky, El-Yousef, Davis, Hubbard, & Sekerke 1972; Janowsky, El-Yousef, Davis, & Sekerke 1973a; 1973b). It is interesting that Shopsin et al. (1975) have found the treatment of manic patients with physostigmine initially to result in attenuation of manic symptoms, followed several hours later by intensification of the manic behavior. It is suggested that a compensatory rebound reflecting noradrenergic dominance may be responsible for the heightened mania. Although the data are intriguing and lend themselves to an interactive chemical model of affective disorder, difficulties in analyzing endogenous ACh activity have prevented a more complete exploration of this proposition. Although the NE and 5-HT hypotheses of depression have received considerable attention, it is important to indicate at this juncture that recent reviews of the NE involvement in depression have taken a different tack. In particular, it has been suggested that depression may not be associated with reduced NE levels, but rather may actually be a reflection of hypersensitive postsynaptic NE receptors (Sulser, Vetulani, & Mobley 1978). The heightened NE receptor activity may, for example, result in exaggeration of a negative affect and may exacerbate the response to environmental stimuli with negative valence. Maas and Huang (1980) have recently reviewed some of the literature in support of such a proposition. Much of the support derives from the finding that the effects of antidepressants, such as desmethylimipramine, are not apparent until 2-4 weeks after commencement of the treatment. Yet the effects of desmethylimipramine on NE reuptake are seen both after acute and chronic treatment with the drug (Schildkraut, Winokur, & Applegate 1970). Moreover, contrary to the view that depression is associated with reduced NE, chronic treatment with desmethylimipramine has been shown to result in decreased brain NE and tyrosine hydroxylase activity (Segal, Kuczenski, & Mandell 1974; Schildkraut et al. 1970), reduced firing rates in cells in the locus coeruleus (Svensson & Usdin 1978) and increased firing rates in hippocampal neurons normally inhibited by NE input from the locus coeruleus (Huang 1979). Finally, chronic treatment with desmethylimipramine has also been shown to decrease the sensitivity of presynaptic autoreceptors (Crews & Smith 1978) and postsynaptic /3-adrenergic receptors (Banerjee, Kung, Riggi, & Chanda 1977; Sulser et al. 1978). On the basis of these findings, Maas and Huang (1980) have suggested that depression is associated with increased postsynaptic NE receptor sensitivity. The heightened postsynaptic receptor sensitivity is accompanied by an increase in the sensitivity of autoreceptors, which in turn decreases impulse flow, thus accounting for the reduced MHPG associated with depression. The efficacy of desmethylimipramine treatment, according to this formulation, is derived from a decrease in postsynaptic receptor sensitivity, which occurs after repeated treatment with the drug.

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

95

Anisman & Zacharko: Depression and stress

Neurochemical concomitants of stress

We have on several occasions reviewed the neurochemical as well as the hormonal consequences of stress (Anisman 1978; Anisman, Kokkinidis, & Sklar 1981; Sklar & Anisman 1981). Accordingly, only a synopsis of this literature will be presented here, with an emphasis on the relationship between neurochemical consequences of stress and neurochemical concomitants of depression. As indicated earlier, a fundamental feature of our hypothesis is that stress influences neurochemical activity and that the nature and extent of the neurochemical changes are dependent on a series of organismic, environmental, and experiential factors. When an organism encounters aversive stimuli, it adopts defensive behaviors to avoid or terminate these stimuli. Concurrently, several neurochemical changes occur whose function appears to be to facilitate the organism's behavioral response as well as to maintain the biological integrity of the organism. Specifically, soon after stress inception, synthesis and utilization of NE is increased in a wide variety of brain regions (see reviews in Anisman et al. 1981; Stone 1975; Welch & Welch 1970). Such effects are not restricted to any single stressor, but have been shown to occur following a number of physical stressors. When the organism is able to terminate stress through behavioral means, amine utilization is not excessive and synthesis keeps pace with release (see discussion in Anisman et al. 1981). However, when behavioral control over stress is not possible, the utilization of brain amines increases and exceeds synthesis, consequently resulting in reduced levels of NE. Indeed, two groups of investigators (Anisman, Pizzino & Sklar 1980; Weiss, Glazer, & Pohorecky 1976) have shown that depletion of NE will not occur after escapable shock; however, application of an identical amount of uncontrollable shock in a yoked paradigm (i.e., where shock offset is contingent upon the responses of the animal receiving escapable shock), resulted in depletion of NE in the hypothalamus, hippocampus, and cortex. It has similarly been reported that if rats are shocked in pairs and permitted to fight - a response that may serve as a coping response (see Weiss, Pohorecky, Salman, & Gruenthal 1976) - the NE depletion otherwise produced by stress will not occur (Stolk, Conner, Levine, & Barchas 1974). Like NE neurons, DA neurons become more active following stress; however, these variations are restricted to certain specific brain regions, notably the nucleus accumbens (Thierry, Tassin, Blanc and Glowinski, 1976), the mesolimbic frontal cortex (Blanc, Herve, Simon, Lisoprawski, Glowinski, & Tassin 1980), and the arcuate nucleus of the hypothalamus (Kobayashi, Palkovits, Kizer, Jacobowitz, & Kopin 1976; Kvetnansky, Mitro, Palkovits, Brownstein, Torda, Vigas, & Mikulaj 1976). When DA activity is measured in other regions, such as the substantia nigra or the whole hypothalamus, changes in neuronal activity are typically not evident (Thierry et al. 1976; Kobayashi et al. 1976). Although depletion of whole-brain DA is not evident after uncontrollable stress, DA depletions are observed in more discrete brain areas such as the frontal cortex (Blanc et al. 1980) and the arcuate nucleus (Kvetnansky et al. 1976). There are as yet no data directly evaluating the effects of stress 96
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

controllability on DA levels in discrete brain regions. However, Cherek, Lane, Freeman, and Smith (1980) have reported that in the frontal mesolimbic cortex, where DA utilization is increased, DA receptor sites are less available in rats that have received uncontrollable shock than rats that have received escapable shock. As in the case of DA and NE, exposure to aversive stimuli was shown to increase the turnover of 5-HT (Thierry, Javoy, Glowinski, & Kety 1968; Thierry, Fekete, & Glowinski 1968). It seems, however, that the stress severity necessary to provoke 5-HT utilization differs from that needed to elicit NE utilization. Specifically, it seems that moderate stress increases the release of NE from the functional storage pools, whereas severe stress results in release from the main storage area. Release of 5-HT from the functional pools, in contrast, requires exposure to a relatively severe stressor (see Thierry 1973). Several investigators have shown that stress of sufficient severity will result in reductions in 5-HT levels (Telegdy & Vermes 1976). However, such an effect is dependent on the brain region examined and the time after aversive stimulation at which tissue is extracted. For example, within 10 min. of stress, 5-HT reductions are seen in the dorsal raphe nucleus, but within 30 min., control levels are attained, and an increase of 5-HT is evident 2 hr. after stress. In the median eminence and forebrain bundle, the depletion at the 10-min. interval is less pronounced, and increased 5-HT concentrations are evident 30 min. after exposure to a stressor (Palkovits, Brownstein, Kizer, Saavedra, & Kopin 1976). Finally, with respect to ACh it has been found that stress will increase levels of this amine, but unlike the rapid catecholamine changes, increased ACh does not occur until about 1 hr after stress termination (Zajaczkowska 1975). Moreover, decreased ACh turnover has been observed in the frontal cortex after 1 hr. of restraint plus cold, but turnover rates approach control values after 4 or 24 hr. of restraint plus cold. In the hypothalamus, the reduced turnover is evident after 1, 4, or 24 hr. of stress (Costa, Tagliamonte, Brunello, & Cheney 1980). These investigators postulate that the ACh changes in the frontal cortex may be secondary to reduced DA levels provoked by stress, while the hypothalamic alterations represent changes in neurons intrinsic to this region. Finally, only limited data are available concerning the effects of stress controllability on ACh levels or turnover. It has been reported that compared to controllable stress, the availability of ACh receptor sites is increased by uncontrollable stress (Cherek et al. 1980) and there are data provisionally suggesting that the changes in ACh levels are dependent on stress controllability (Karczmar, Scudder, & Richardson 1973). It seems that an organism is able to deal with aversive events through both behavioral and neurochemical means. Although neurochemical systems function effectively under most conditions, when the stress is uncontrollable and sufficiently protracted, excessive neurochemical utilization may ensue. Such neurochemical changes may be manifested behaviorally as affective disorders. It should be emphasized that there is no reason to expect that all individuals will respond to a given stressor in a like manner. Experiments with

Anisman & Zacharko: Depression and stress infrahuman animals have shown wide differences in neurochemical change across strains (Ray & Barrett 1975; Winner, Norman, & Eleftheriou 1974). Accordingly, it is theoretically possible that in humans uncontrollable stress will result in an excessive utilization and consequent depletion of NE or 5-HT or both, as well as a depletion of DA and increases in ACh. In effect, a dramatic change in a particular system would represent inadequate ability to adapt to environmental demands. Just as neurochemical variations occur across strains, it has been shown that the depletion of NE in the face of uncontrollable stress is detectably more pronounced in older rats than in younger ones (Ritter & Pelzer 1978). If this were true in humans as well, older people would be more disposed to affective consequences of stress. It should be noted here that in the aged the loss of buffering systems - the result, for instance, of the death of a spouse or of isolation from family members - may not only represent a stressor in its own right, but may also dispose the individual to greater neurochemical lability owing to lesser coping ability. Finally, animal experiments have revealed that social housing conditions influence neurochemical activity and also determine the nature and magnitude of stressrelated neurochemical lability (Blanc et al. 1980). Furthermore, neurochemical lability ordinarily induced by uncontrollable stress are modifiable if animals engage in coping attempts through fighting (Modigh 1976; Stolk et al. 1974; Welch & Welch 1970). Fighting, incidentally, has also been shown to modify the effects of stressors and the development and growth of carcinogen-induced tumors (Sklar & Anisman 1980). In addition to the organismic and environmental variables just discussed, it appears that the neurochemical consequences of stress are dependent in great measure on the organism's prior history. We have shown, for example, that although the NE depletion provoked by uncontrollable stress persists for only a few hours, the amine depletion is reinduced if animals are subsequently exposed to a relatively mild stress that ordinarily has little effect (Anisman & Sklar 1979). Likewise, Cassens, Roffman, Kuruc, Orsulak, and Schildkraut (1980) have reported that a CS (conditioned stimulus) that has previously been paired with shock will increase NE utilization; and Hingtgen, Smith, Shea, Aprison, and Gaff (1976) have found that a CS will increase ACh levels. Exposure to traumatic stress may sensitize the organism to a similar stress or cues associated with the stress. In human studies, it will be recalled that stress applied early in life, particularly in the form of separation, is associated with later depression. As indicated by Brown (1979), these affective changes are most prominent if the individual has suffered parental loss as a child and is subsequently exposed to stress as an adult. In assessing stress-related pathology, it is important to consider that the chronicity of the stress is an important feature in determining neurochemical lability. Although a single session of uncontrollable stress may result in NE depletion, such an effect is absent if animals are exposed to either repeated stress sessions or a single protracted session of uncontrollable stress (Kvetnansky et al. 1976; Weiss et al. 1976). Likewise, the depletion of 5-HT induced by uncontrollable stress will not be evident if the stress session is of protracted duration (Palkovits et al. 1976). It seems that with chronic stress, tyrosine hydroxylase, dopamine-/3-hydroxylase, and tryptophan hydroxylase activity are increased, thereby assuring adequate supplies of brain NE and 5-HT. Such adaptive changes have been seen not only in the central nervous system, but also in peripheral neurotransmitters, and in their synthetic enzymes (Kvetnansky 1980). Moreover, changes in immune functioning, in hormonal activity as well as in the development and growth of transplanted, carcinogen-induced, and spontaneous tumors in animals vary with stress chronicity (see review in Sklar and Anisman 1981). It is conceivable, however, that the neurochemical adaptation that occurs with chronic stress is not equally efficient among all individuals. While adaptive changes in the form of increased enzyme activity may occur in most individuals, thereby preventing psychopathology, a deficit in one or the other of the enzymes may result in insufficient storage of an amine following chronic stress, eventually culminating in affective illness. This proposal, although highly provisional, warrants consideration. The neuronal changes following chronic stress are not restricted to increased activity and levels of brain NE and 5-HT. It will be recognized that equivalent levels of NE in nonstressed and chronically stressed animals do not imply equivalent neuronal activity. On the contrary, the return to normal amine levels in chronically stressed animals is a consequence of a compensatory increase in amine synthesis, but utilization continues at an enhanced rate. In addition, Weiss et al. (1976) have found that NE reuptake diminishes following chronic stress. Thus the increased NE may act at the postsynaptic site for a longer duration. Accordingly, the organism may become over-stimulated, at least in neuronal terms. Stone (1979a) has provided data concerning the presence of yet another adaptive change. Following chronic stress it was found that NE-sensitive cyclic AMP was reduced, possibly suggesting NE receptor subsensitivity. Either as a result of the excessive stimulation or as a direct consequence of the chronic stress the sensitivity of the postsynaptic neuron is reduced, thereby deterring excessive stimulation. As indicated earlier, after treatment with tricyclic antidepressants, receptor subsensitivity ensued. Stone (1979b) is one worker who has suggested that some of the symptoms of depression (e.g., insomnia, anorexia, anxiety) may arise owing to variations in neurochemical activity (e.g., increased sensitivity of NE neurons or changes in a nonnoradrenergic system). It is thought that emotional-laden stimuli may provoke some of the symptoms associated with depression. Depression, according to this view, reflects neurochemical alterations which may heighten the emotional response of depressed individuals to acutely stressful stimuli. Treatment with desmethylimipramine or exposure to chronic stress do not necessarily affect the immediate causal factors in depression, but will result in the blunting of the exaggerated emotional response to incoming stimuli.

Overview

As indicated earlier, there is reason to believe that aversive events may precipitate or exacerbate clinical
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

97

Anisman & Zacharko: Depression and stress depression. To be sure, this view has not been unanimously endorsed, and serious shortcomings in the human experimental data have been documented. However, if there is truth to the contention that stressful events provoke or increase vulnerability to depression, it may be fruitful to consider the neurochemical events induced by stress as a fundamental feature in the stress-depression relationship. It is our view that in the face of aversive experiences, a series of neurochemical changes occur which may be essential in behavioral attempts to cope with stress and instrumental in preventing various forms of pathology (see Sklar and Anisman 1981). When the aversive events are sufficiently severe, and behavioral coping mechanisms fail, depletion of transmitters may culminate in depression. It should be emphasized that we are not proposing that any one neurotransmitter is principally involved in depression, but rather that biochemically distinct subgroups of depression may exist, each involving dysfunction of one or more transmitters. The contribution of stress to these subgroups of depression has yet to be determined; however, as a working hypothesis we have considered that stress may differentially influence neurochemical activity across individuals, possibly reflecting the ability of the synthesis rates of various transmitters to keep pace with utilization. Figure 1 is a schematic representation of the changes in NE that occur under various stress conditions. Following acute uncontrollable stress, NE synthesis and utilization increase to a comparable extent. Welch and Welch (1970) have also suggested that MAO may be transiently inhibited, thereby increasing NE levels and ensuring adequate stores of the transmitter, at least over the short run. Stressors with such an effect would not be expected to lead to depression. Indeed, quite to the contrary, heightened arousal (or vigilance) may ensue. If the stress is uncontrollable, a further increase of NE utilization occurs in order to compensate for the lack of behavioral coping. As a result, synthesis may not keep pace with utilization, and depletion will be observed. Recall that uncontrollable stress will also result in 5-HT depletion, reduction of DA in some brain regions, and an increase of ACh. One, or probably more than one, of these changes may result in behavioral depression. At this point we cannot specify the relationship between the various symptoms of depression and the corresponding neurochemical alterations. For example, as depicted in Figure 1, depression may be a result of brain NE depletion. Alternatively, depression may be a reflection of postsynaptic receptor effects (vis-a-vis excessive stimulation resulting from increased amine release or hypersensitivity owing to the depletion itself). Furthermore, 5-HT, DA, and ACh changes may all provoke different symptomatologies. Indeed, the various subtypes of depression may reflect dysfunction of a single transmitter or the interaction of several neurochemical events. We would expect that individual differences in response to stresses of equivalent severity would reflect the adaptability of the neurochemical system. Those organismic or experiential factors that lend themselves to heightened utilization, together with the rapid and pronounced amine depletion, would likewise render the organism more vulnerable to affective illness. Thus, for

NO STRESS

BRIEF STRESS

ACUTE CONTROLLABLE STRESS

ACUTE UNCONTROLLABLE STRESS

CHRONIC UNCONTROLLABLE STRESS

Figure 1. A schematic representation of changes in NE levels, synthesis, utilization, and reuptake as well as MAO activity after various stress conditions. In the face of mild, brief stress, NE levels rise, possibly owing to a transient inhibition of MAO activity. If the stress is more prolonged the inhibition is no longer present. In the case of escapable stress, the amine level remains stable since increased utilization is accompanied by increased synthesis. When the stress is uncontrollable, NE utilization rates exceed synthesis, resulting in the reduction of the amine level. Following chronic stress a further increase in synthesis results in adequate levels of NE. In addition, NE reuptake is blocked, and hence the released NE may activate receptors for a longer duration. Not shown in the figure is the finding that chronic stress may reduce NE-sensitive cAMP (cyclic AMP).

example, organismic variables such as age or genetically determined dysfunction of catecholamine turnover would be most likely to provoke stress-induced affective disorders. It should be underscored, however, that the availability of behavioral or social coping mechanisms may reduce demands on neurochemical compensatory systems, thereby minimizing instances of depression. Under normal conditions the NE, DA, and 5-HT depletions which occur after acute uncontrollable stress are not evident following chronic stress exposure. It seems that following chronic stress a compensatory increase in tyrosine hydroxylase and tryptophan hydroxylase reinstates adequate amine levels. In addition, blocked reuptake maximizes the efficiency of released amine substances. The integrity of such adaptive systems may be essential in order to deal with severe, traumatic life events and even with the sustained presence of moderate life stressors. The failure of such an adaptive

98

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentan//Anisman & Zacharko: Depression and stress system and the resultant diminished supply of amines may lead to depression. At the outset of this paper, it was indicated that there were interindividual differences in the affective consequences of a given stressor and in the nature of the pathology engendered by stress. Considering the second of these issues first, it should be recognized that a variety of changes, aside from neurochemical alterations, may be provoked by stress - immunological, hormonal, or steroidal changes, for example. Dysfunction in any one of these adaptive systems could provoke pathology. Furthermore, a change in one system with apparent beneficial consequences for affective processes could have detrimental effects on other attributes of the organism. For example, the excessive utilization of amines to cope with stress may result in ACTH secretion from the pituitary and hence increased release of adrenocorticosteroids. The corticosterone may in turn inhibit /3-lymphocytes, thereby increasing the probability of immunologically-related illness. With respect to the differences in the affective response to a stress of a particular severity, it should be considered that any number of adaptive failures (e.g., rapidity and duration of initial amine depletion, failure of tyrosine hydroxylase or tryptophan hydroxylase activity with chronic stress) would increase the probability of stress-induced depression. Genetic factors could theoretically determine the adaptability of neurochemical systems to stress, as could other organismic variables, such as age. In addition, environmental factors associated with social conditions will affect neurochemical lability. Finally, among individuals that have previously encountered traumatic stress, reexposure to even moderate stress could provoke the amine changes and hence result in the depressive symptomatology. Ultimately, however, the most pragmatic approach to the relation between stress and depression is to consider the organism's ability to cope with acute stress through behavioral means in conjunction with its endogenous adaptability to stress. As indicated earlier, some investigators have assumed that alterations in NE may influence reactivity to environmental events (e.g., Maas & Huang 1980). It is also possible that DA reductions reduce motivation or the rewarding properties of particular stimuli (Wise 1978), or are related to the motor retardation associated with depression. Moreover, cognitive changes (i.e., helplessness) may be associated with alterations of 5-HT or NE (Sherman & Petty 1980; but see Weiss, Glazer, Pohorecky, Bailey, & Schneider 1979). Whatever the correspondence between neurochemical changes and specific behavioral events, it is likely that the composite of symptoms comprising clinical depression involves the direct effects of several neurotransmitters and their interactions.

Open Peer Commentary

Commentaries submitted by the qualified professional readership of this journal will be considered for publication in a later issue as Continuing Commentary on this article. Among the forthcoming contributions, received too late for copublication, is a commentary by J. Weiss.

Is stress a predisposing or precipitating factor in clinical depression?

Hagop S. Akiskal
Affective Disorders Program, Departments of Psychiatry and Pharmacology, University of Tennessee College of Medicine, Memphis, Tenn. 38163

ACKNOWLEDGMENTS Preparation of this article was supported by Grants A9845 and MA6486 to Hymie Anisman from the Natural Science and Engineering Research Council of Canada and the Medical Research Council. Robert M. Zacharko is an NSERC Research Fellow.

Genuine psychobiologic understanding of psychiatric disorders has been hampered by philosophic dilemmas about the mindbody interface, by professional rivalries among psychoanalysts, behaviorists, and biologically oriented investigators, and by the relative absence of suitable experimental methods. Anisman and Zacharko's (A & Z's) paper is a contribution to the meager literature on attempts to unite insights gained from brain and behavioral sciences in elucidating the pathogenesis of depressive disorders. The authors review animal experimental paradigms developed by themselves and others to shed light on the neurochemical mechanisms linking stressful events to depressive phenomena. Although their approach is not original, it provides a valuable theoretical elaboration of previous work (Goodwin & Bunney 1973; Akiskal & McKinney 1973; 1975; Whybrow & Parlatore 1973; Kraemer & McKinney 1979; Depue 1979). The review's major strength is its discussion of the neurochemical consequences of stressful events in animals. The thrust of the argument is that maladaptive neurotransmitter changes induced by uncontrollable aversive stimulation in animals are similar to those reported in human depressions. A & Z distinguish the impact of acute versus chronic stress and controllable versus uncontrollable stress. They further point to the influence of early stress and of old age in sensitizing the organism to maladaptive neurochemical responses to current stresses. Appropriate parallels are drawn to human depressions, which are more common in the elderly, and which in some studies have been associated with childhood losses. However, other than brief mention of behavioral sensitization by early stress, the focus is primarily on stress as a precipitant of depression, rather than a predisposition, as indicated in the title. A & Z seem to imply that clinical depression is largely the psychobehavioral consequence of stress-induced neurotransmitter dysfunction. Little attention is given to research indicating that psychosocial stress and related mediating mechanisms (e.g., lack of social support) are limited to precipitant roles (Paykel 1976; Warheit 1979). Such studies have suggested that formative (predisposing) influences are to be found in more remote factors, such as developmental experiences and heredity (Akiskal 1979; 1981). There is also limited mention of factors that can increase the depressionengendering influence of current stress (Akiskal 1979) - the nature of the stressful event, concurrent life events, use of depressant antihypertensives, contraceptives, or alcohol, borderline hypothyroidism, and genetic predisposition. Further, there are a host of pharmacologic, hormonal, metabolic, infectious, and neurologic stresses which are established causes of clinical depression (reviewed in Hendrie 1978 and Akiskal 1981). A review of such specific biologic insults as precipitant stresses would have bolstered A & Z's central argument. A & Z pose the question: Since stress appears relevant to a large number of unrelated illnesses, both psychiatric and

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

99

Commentary/Anisman & Zacharko: Depression and stress nonpsychiatric, what determines illness specificity (i.e., the organism's specific response)? Although this question is discussed in terms of individual variation, only brief mention is made of specific genetic factors in depressive illness. Thus, the contribution of heredity in the causation of depressive illness is more firmly established than that of stressful events (Akiskal 1979). Furthermore, the amount of variance contributed by heredity is considerably greater and, at least in recurrent and bipolar forms, appears to be the dominant causative factor (Gershon, Dunner, & Goodwin 1971; Akiskal 1979). A & Z propose that insomnia, anorexia, and anxiety are psychobehavioral consequences of altered central noradrenergic function secondary to stress. However, these symptoms are common to many psychiatric and nonpsychiatric disorders, and it is unclear how the proposed model specifically accounts for such core characteristics of depressive illness as anhedonia, lowered self-esteem, guilty ruminations, and suicidal ideation (DSM-III, 1980). Furthermore, many depressed subjects experience /ii/persomnia and increased food intake. Thus a major shortcoming of A & Z's review is the limited attention given to clinical considerations. The authors do mention the clinical heterogeneity of depressive conditions, citing the largely undemonstrated but plausible hypothesis that differences in neurotransmitter pathologies may account for the heterogeneity. More crucial to their central thesis, however, would be a discussion of the clinical symptoms common to all types of depression, and a demonstration of the relevance of stress-induced synaptic dysfunction to these depressive manifestations. The general tone of the paper is integrative and holistic in that, at various junctures, the joint contribution of experiential and somatic factors in determining depressive behavior is given careful consideration. Yet the paper ends with a reductionistic statement to the effect that depressive experience and behavior are "directly' derived from chemical events. In summary, while they have provided a cogent review of the neurochemical bridge of the stress-depression relationship, A & Z have overlooked major parameters of stress and depression that could have provided the opportunity to build a conceptually sturdier construct. Yet the attempt to construct such a hypothetical bridge is in itself meritorious.
Clinical depression (specify type) Present metabolites or levels ofNE, DA, 5-HT higher cortical functions exposure to, impact of, past stressors Current degree of stress attributional variables Absent Time

High

Low or nil

Figure 1 (Bauer). Multivariate assessment model for research on the stress-depression relationship. It should be noted that "depression" and "stress" are conceived as continuous variables, presented here in binary fashion only for purposes of discussion. Independent variables in the approach are represented by marginal headings; dependent variables are outlined within the upper left cell. Cells A and B are discussed in detail in the text. Dotted arrows representing time emphasize the suitability of the model for use in longitudinal research. a "multilevel" model, encompassing historical (e.g., past learning), neurochemical, "experiential" (e.g., coping) and behavioral components, attempts at validation seem especially prone to tautology (where constructs such as "stress" and "neurotransmitter depletion" are defined in terms of their effects on other systems). In this commentary, I wish to argue that validation must proceed by using dependent measures that are simultaneously (a) reflective of neurotransmitter dysfunction, and (b) correlated with, but not necessarily constitutive of, stress and depression. I will argue for a neuropsychological approach to validation. I begin with the likely assumption that the brain is functionally characterized by neurochemical (transmitter) systems just as it is characterized by neuroanatomical systems (cf. Luria 1973), and that many such systems are localized within specific brain regions. This assumption suggests that specific transmitter dysfunction may lead to localized deficits in higher cortical function. If such deficits can be measured by neuropsychological assessment, and subsequently related to depression or stress in the individual, then strong correlative evidence would exist for the stress-depression model. An example of the application of this approach is sketched below. A & Z suggest that discrete depletion of DA may occur in frontal cortex following uncontrollable stress. If so, individuals exposed to such stress should display convergent evidence of frontal-lobe dysfunction as measured, for example, by formal neuropsychological evaluation. Similarly, if DA deficiency subsequently characterizes some subtypes of depression, these patients should also show maximal neuropsychological impairment localized to brain regions rich in DA neurons (e.g., basal ganglia and frontal cortex). To my knowledge, such predictions have not been systematically tested but would, if confirmed, support the A & Z model. Specific

Depression, neurotransmitters, and stress: some neuropsychological implications

Russell M. Bauer
Department of Clinical Psychology, University of Florida, Gainesville, Fl.

32610

Anisman and Zacharko's (A & Z's) paper presents problems and prospects for the interdisciplinary study of the relationship between stress and depression. First, stipulating a stressneurotransmitter relationship as an etiological factor in depressive illness may serve to complicate the already difficult business of constructing causal chains between neurochemistry and behavior. It is clear that specifying the biological effects of stress does not shed light on how specific neurochemical changes lead to the cognitive and behavioral effects constituting depression in the individual. We are still left with the difficult task of understanding the relationship between physical and chemical events on the one hand, and psychological/mental events on the other. In another sense, however, A & Z have created an integrative model that is internally consistent, generates scores of testable hypotheses, and accounts for much extant data. This is all that could be asked of a scientific hypothesis. Attempts to validate their model must verify the stress-depression relationship by using other correlates of behavior in addition to transmitter metabolites or clinical therapeutics. Because their approach is

100

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary/Anisman & Zacharko: Depression and stress

predictions, of course, could be made for other transmitters as well. In our clinic, we frequently evaluate patients with demonstrable CNS pathology as well as hospitalized psychiatric patients who show varying degrees of "soft CNS signs. ' It is our experience that many clinically depressed patients (particularly those with endogenous depressions and bipolar affective disorders) show striking resemblances to patients with verified frontal-lobe disturbance. Such patients frequently perform poorly on tasks of abstract-concept formation, repetitive motor sequencing, and motor speed. They are often impaired in their ability to form and maintain cognitive sets, are perseverative and rigid in their thinking, and find it difficult to initiate and maintain self-regulated plans of action (e.g., adaptation). Such observations have been made in other clinics as well (E. F. Kaplan, personal communication, 1980). In particularly severe cases of depression, it may be difficult blindly to differentiate the patient's neuropsychological profile from that of a patient with veridical frontal-lobe pathology. A review of the functional effects of frontal-lobe lesions, as well as afferent and efferent connections of frontal cortex, is available in Damasio (1979). There1 is, of course, a "chicken-and-egg" problem here; we do not yet know whether such neuropsychological impairments result as part of depressive ideation, or whether they contribute etiologically to the spectrum of depressive disorders. Longitudinal analysis of the emergence of depressive symptomatology and neuropsychological impairment should shed light on this issue. We know little about whether these impairments render the individual more vulnerable to stress effects, thus exacerbating an already emergent depression. Nonetheless, it is intriguing to speculate that the "failures of behavioral coping" so important to the A & Z model are largely related to impairment in neuropsychological functioning in the frontal lobe. For example, stressors may be functionally "uncontrollable" not only because of a cognitive appraisal of response noncontingency ("learned helplessness") but also because the patient cannot behaviorally initiate or execute a plan that is effective in dealing with stress. The neuropsychological effects of stress are largely unknown but should, if evaluated in light of the neurochemical substrate and its regional localization, provide convergent evidence for or against its proposed relationship with depression. Figure 1 sketches one method of analysis that could be conducted on an interdisciplinary basis. The assessment model includes two groups essential for demonstrating the construct validity of the proposed stressdepression relationship. The first group, located in Cell A, is comprised of patients who display depressive symptomatology but who do not have a history or self-report of significant psychosocial stress. This is a group for which A & Z's model cannot easily account. The group may include some "functional" psychiatric patients who become depressed without apparent precipitants, as well as neurological patients with depression or psychomotor retardation as a prominent feature of their illness (see Albert, Feldman, & Willis 1974; Valenstein & Heilman 1979). In particular, patients with Huntington's chorea and Parkinson's disease, in whom depression of marked proportions is frequently associated with obvious neurochemical abnormality, would be included here. Assessment of historical, neuropsychological, and neurochemical factors in these patients may help elucidate which forms of depression result from cause's other than stress, and may thus provide additional information regarding the stress-depression mechanism. In Cell B are patients with an evident history of significant psychosocial stress who do not show signs of clinical depression. Although A & Z define these individuals as "effective copers," the adaptive response to stress may represent only one way in which these individuals differ from their stressed counterparts who eventually become depressed. They may also differ in terms of basic neurochemical or neuropsychological characteristics that contribute to the risk of psychopathology. This issue may also be addressed by an interdisciplinary model. Implications. (1) By including these two groups in a systematic fashion, it is possible to assess the separate and interacting effects of stress and depression on the neurochemical and cognitive substrate presumed to lie at the basis of depression in A & Z's model. (2) Employing the multivariate approach in a longitudinal manner may permit a better understanding of the temporal relationship between stress, depression, and the neurochemical substrate. (3) Functional assessment of the cognitive and behavioral capabilities of patients with subtypes of depression, and subsequent correlation of these capabilities with neurotransmitter dysfunction, may provide a more operational view of the nature and impact of "stress' and its vicissitudes.

Stress, neurochemical substrates, and depression: Concomitants are not necessarily causes
Aaron T. Beck and Raymond P. Harrison
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pa. 19104

Anisman and Zacharko (A & Z) have provided a scholarly and wide-ranging review of possible relations between stress responses and depression. The basic thrust of their paper seems to be that when behavioral attempts to cope with stress become inadequate, the increased emphasis on neurochemical coping mechanisms may lead to neurochemical abnormalities that in turn lead to depression. Our own feeling is that the above formulation may be premature, based on the inadequacy of the data currently available. At several points in the paper A & Z acknowledge some of these inadequacies, but they have not emphasized them. Moreover, we believe that it may be counterproductive to speak of the "cause " of depression. There are a multitude of possible predisposing and precipitating factors for depression. What we label as depression is the final common pathway of perhaps many converging variables, and it may be futile to look for an underlying cause. Even the notion that depressed individuals have experienced significantly more stress than others may prove unfounded. Lloyd (1980b) has suggested an alternative explanation based on state-dependent learning. Individuals who are depressed will undoubtedly have a negative set for recollection and will be more likely to recall a preponderance of negative events in their life. Another possibility is that many stressors are a result, rather than a cause, of depression. The lethargy, lack of drive, avoidance, and withdrawal manifested by depressed individuals may often contribute to the creation of additional problems which may then further fuel the depression but not precipitate it. Based on our own research with depressed individuals, we would also say that the reports of stress prior to and during depression may be greatly exaggerated. Magnification, overgeneralization, and selective abstraction are frequently seen in the cognitive processes of depressives. The memories and ongoing reports of depressed individuals must then be suspect. It is interesting to note that despite the voluminous amount of research on stress and its relation to depression, no prospective studies exist that have reliably predicted depression. Early parental loss, for instance, has been proposed as one of the most powerful predisposing factors for depression. However, most depressives have not experienced this kind of early loss, and many individuals who have experienced it never become

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

101

Commentary/Anisman & Zacharko: Depression and stress depressed. The research does seem to indicate a positive correlation, but a direct connection, let alone causality, has not been established. In confining themselves to a restricted definition of stress as a behavioral or physiological event, A & Z have paid scant attention to important data derived from cognitive studies of depression. They have touched only briefly on our work (Beck, Rush, Shaw, & Emery 1979) and have dismissed Seligman's work in favor of a neurochemical explanation. They suggest that the cognitive changes in depression, which are well documented, may simply be the manifestation of more central changes occurring in neurochemical substrates. But why is it any more implausible that neurochemical abnormalities may reflect cognitive changes? There is also a substantial literature that would confirm the latter hypothesis. We will cite only a few studies here. Teasdale and Bancroft (1977) found that instructions to "think sad thoughts" led to increased dysphoric mood and physiological concomitants in subjects. Cognitive inductions appear to be related to physiological changes, which are consistent with the relevant mood state. Changes in physiological process have been found following covert rehearsal of affectively valenced self-referential statements (May & Johnson 1973; Rimm & Litvak 1969; Russell & Brandsma 1974). Even more interesting is a study by Rogers and Craighead (1977) which found that physiological as well as affective measures were associated not only with the specific act of ideating, but the belief in the validity of the thoughts. From studies like this it would not be hard to make the interpretative leap into concluding that depression is caused by cognitions. If one can chart physiological changes so readily in the laboratory, imagine the effect of a lifetime of chronic negative thinking on the neurochemistry of the body. However, we would not make this interpretative leap. We would prefer to think of the cognitive changes, physiological abnormalities, behavioral deficits, and affective symptoms as all part of the whole of depression. To pick out one cluster of factors and posit it as the cause is shortsighted and misguided. positions, coping stategies, and subjective perceptions. In general, stress is the overall transactional process between an organism and a stressor. The stressor is anything that the organism perceives as a threat to self-esteem (Lazarus & Launier 1978). This threat - and possible loss of self-esteem or, at least, of momentary psychological homeostasis - presumably results in the activation of a psychological homeostatic regulatory mechanism (Burchfield 1979; Falek & Britton 1974; Klinger 1975). This mechanism, previously described as the grief cycle (Lindemann 1944), consists of the five stages of denial, anxiety, anger, depression, and acceptance. During the first stage, denial of the threat, homeostasis is maintained. Denial is an adaptive short-term defense, although, if it persists for a long period of time in the face of disconfirming evidence, it is maladaptive. Cognitive awareness of the loss results in fear and anxiety with concomitant attempts to reestablish the status quo. When these efforts fail, the stage of anger begins. In this stage, the psychological integrity of the individual is maintained by externalizing the responsibility for and the source of the threat. When the individual finally achieves both cognitive and emotional recognition of the threat/loss, sadness/depression results because the person realizes that the status quo cannot be regained. At this point the cause of the loss and the associated anger are internalized. As depression subsides, acceptance is initiated as the individual incorporates the meaning of the loss into his self concept. After this growth process is completed, a new level of homeostasis is reached. This entire process may occur within a few minutes, as in the form of thoughts an individual has while waiting for a friend who is late (Breznitz 1971), or it may take several years, as when a family member has died. The psychological homeostatic reaction to stress is one means by which stress is linked to depression. This type of depression, referred to as sadness by Arieti and Bemporad (1978), is normal, although the biochemical process involved is probably similar to that of a depressive disorder. Jacobs and Douglas (1979) have suggested that two antagonistic systems, the ergotropic and the trophotropic, mediate the psychological reaction to a threat/loss. These subcortical systems include the reticular formation, the limbic system, and the hypothalamus (Kiely 1975). The ergotropic system integrates functions that prepare the individual for possible action and, hence, may underlie the stages of denial, anxiety, and anger. The trophotropic system integrates functions that promote withdrawal and energy conservation and may underlie the stage of depression. This activationinactivation sequence is also alluded to by A & Z in their description of biochemical changes after acute stress. Immediately after acute uncontrollable stressor exposure, NE is increased, while after a prolonged period, it is decreased. The time frame within which these alterations occur presumably correlates with changes in the individual's psychological reaction to the stressor. During the inactivation phase, individuals are more susceptible to many health alterations, including depression (Engel 1961; Schmale 1958). Hence, one possible mechanism of stress-induced depression is that the individual does not successfully complete the depressive stage of the psychological regulatory process. Those individuals for whom a normal emotional process precipitates an affective disorder may be identified by their predisposition to depression, their failure to cope adaptively with the stressor, and their lack of social supports. Certain types of reactions to stress - those that result in depletion of NE - are likely to precipitate depression, especially in people whose basal NE level has been lowered by other factors. A & Z briefly review the research on these moderator variables and succinctly show the complexity of the relationship between stress and depression. In their target article, one possible mechanism linking depression with stress was examined. Given that depression/sadness is a normal

The psychological homeostatic response to stress and its relation to depression

Susan R. Burchfield
Department of Psychology, University of Washington, Seattle, Wash. 98195

Anisman and Zacharko (A & Z) have tied together several disparate lines of research concerning stress and depression. Their premise is that the biochemical changes induced by stress (e.g., norepinephrine and serotonin depletion) are the same as those postulated to underlie depression and, hence, that these changes are one mechanism of stress-induced depression. It is the purpose of this commentary to offer further support for A & Z's thesis by describing mild depression as a homeostatic response to stress and discussing its biological concomitants and relation to depressive illness. Theoretically, stress has been implicated as a predisposing factor in any health alteration, ranging from pregnancy (Schuster & Schuster 1969; Williams, Williams, Griswold, & Holmes 1975) to accidents (Griswold 1970). Given the homeostatic changes that occur when an organism is exposed to a stressor, it is quite reasonable to assume that these biochemical changes could strain the system and result in the activation of other regulatory mechanisms. Together, these alterations could precipitate various health changes depending on the interaction between the organism's past and present biological and psychosocial history. One of the great difficulties of stress research is that the stress construct is broad and encompasses a variety of behaviors that are confounded with individuals' biological predis102
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary/Amsman & Zacharko: Depression and stress

reaction to stress, it is reasonable to assume that the biochemical concomitants of this stage would predispose certain individuals to depressive illness. More research is needed before this association can be better understood. amine levels have some therapeutic benefits. The evidence is problematical in many respects, however. For example, time courses don't jibe, and drugs with considerable amine effect, such as MAO inhibitors, are clinically dubious. Most antidepressants produce a number of side effects which could "amplify" a cognitive expectancy or placebo response. For example, on the basis of the 84 placebo-controlled doubleblind studies of tricyclic antidepressants reviewed by Morris and Beck (1974), when inert placebo controls are used the antidepressant appears significantly more efficacious than when "active " placebos with perceptible effects (e.g., atropine) are used (x2 = 4.42 with Yates correction p < .05). I might (somewhat facetiously) suggest that stress, because of a commonality of neurochemical mechanisms, might best be dealt with using placebos which produce anticholinergic side effects. The central point I would make, then, is that the observed commonality of neurochemical sequelae of depression and stress does not necessarily imply any relationship between them. Nevertheless, A & Z's observations may have heuristic value. If for the moment their argument is accepted, does it not imply that some of the known hormonal consequences of stress may predispose an individual to depression? Such speculation could conceivably integrate much recent work on neuropeptides and psychopathology.

Does a commonality of neurochemical sequelae imply a relationship between stress and depression?
Douglas L. Chute
Division of Life Sciences, University of Toronto, Scarborough, Ontario, Canada M1C 1A4; Department ot Psychiatry, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Anisnian and Zacharko (A & Z) present the speculative notion that stress, in particular its neurochemical sequelae, may predispose an individual to depression. The evidence for such a proposition is quite conditional, however, as the authors themselves note appropriately in some circumstances. With the intent of being constructive and not simply critical I would raise additional reservations about the proposition. A & Z point out quite correctly in the initial section the tenuous nature of any conclusion that relates stress to depression either causally or correlationally on the basis of existing studies with human beings. Without putting such differences altogether aside, the A & Z proposal is that stress (neglecting for the moment problems of definition, chronicity, and differences in individual response) causes a measurable change in some CNS neurotransmitters; and, since depression is (arguably) correlated with similar changes in CNS transmitters, this observation may supply new evidence of a relationship between stress and depression. There is no logical reason to assume a relationship, however. If A causes B and C causes B there is not necessarily any causal or even correlational relationship between A and C. For example, if breaking a leg causes you to miss a flight and an air-traffic controllers' strike causes you to miss a flight, not even a correlational relationship need exist between broken legs and controller strikes. The opportunity to demonstrate the presence or absence of a relationship between stress and depression is not readily available. There are no adequate definitions of either concept. There are no suitable animal models of depression. Levels of stress cannot be easily equated without resorting to a circular argument by comparing physiological effects. Individual differences in both stress and depression are such that there is virtually no possibility of predicting whether there is a relationship. Although being depressed may be stressful if such a relationship can be empirically demonstrated, that would in no way logically support a hypothesis that stress may cause depression. For example, "if smoking then cancer' does not necessitate "if cancer then smoking. ' (Not incidentally, suppose depression is a stressor: could this not explain many of the observations without at all implying that stress predisposes one toward depression?) Depression is certainly the "common cold " of psychopathology, as has often been pointed out. Any insight into prevention or treatment that could be gained would be worthwhile. I am unsure, however, about the capacity of the now-traditional neurotransmitter analysis to provide such insight. A & Z's own review illustrates many of the difficulties and contradictory findings relating neurotransmitters and depression. In fact, it seems that the catecholamines and indolamines have been related to just about everything. I suspect that this occurs as much because of their ubiquitous nature as because of their reasonably discrete synthetic pathways and their comparatively old and straightforward methods of assay. The bulk of the evidence suggesting a role for CNS amines in depression comes from the observation that drugs which alter

Biological fitness and affective variation

Denys de Catanzaro
Department of Psychology, McMaster University, Hamilton, Ontario, Canada L8S 4K1

Anisman and Zacharko's (A & Z's) unique contribution is the juxtaposition of data relating depression and stress, neurochemistry and depression, and the neurochemistry of stress in laboratory animals. I have few quarrels with the main themes of the article, especially the physiological aspects, but I believe that the relationship of stress and depression is better construed as a relationship of biological fitness and affective variation. Constructs such as "stress" seem useful only insofar as they are clearly defined in terms of consistent relationships among concrete, measurable events. A & Z's definition of stress makes reference to "aversive stimuli" and "traumas," which have commonsense meaning but themselves require definition, and to "personal life changes,' which could include almost any environmental or developmental change. Selye (1973) and others have referred to demands upon the organism and stereotyped nonspecific physiological responses accompanying such demands. The term "demand," however, is used only figuratively, except where social demands exist. Also, almost all behavior can be viewed as a response to some environmental "demand," and hence the concept of stress in its broadest sense may have little meaning. We could conceivably define stress in terms of patterns of autonomic or pituitary-adrenal arousal; the question is then whether neurochemical variations and other factors consistently covary with these such that we have a unitary phenomenon. A & Z discuss qualitative differences between acute and chronic stress, and between stress that can and cannot be coped with; these distinctions may help to undermine this unitary notion. The antecedents of depression and various pathologies may be more clearly conceptualized in terms of coping difficulties. Coping status could be defined through parameters of biological fitness relative to the species' behavioral repertoire and ecological history (see de Catanzaro 1981). Any impairment of an organism's capacity to survive, reproduce, and advance the welfare of kin can constitute a coping difficulty. Accordingly, we might define "stressors" or "aversive'stimuli" as events
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

103

Commentary/Anisman & Zacharko: Depression and stress threatening an organism's health and reproduction, and of course organisms tend actively to avoid perceptible events of this sort. In humans, strategies for promoting fitness are complex and structured by culture, and there may exist several alternative strategies for maximizing fitness at various phases in the life cycle. Various threats to an individual's capacity to promote his fitness (i.e., "stressors') differ qualitatively and quantitatively. Acute stressors such as physical insults or especially demanding social situations may be transitory and hence of little consequence for fitness. Such events may recur, however, taxing the resources of the individual and hence diminishing his capacity to promote his fitness. A large variety of chronic situations, such as illness, old age, low social status, unemployment, andfinancialdifficulty, may render effective coping difficult for many individuals. Such situations may impair the ability to develop reproductive relationships, to bear and raise children, to behave toward the welfare of other kin, and so on. A failure in or loss of reproductive relationship (divorce, widowhood, separation) is often very damaging to an individual's residual fitness; some individuals are entirely excluded from reproduction because they fail to compete effectively for mates (Daly & Wilson 1978; Symons 1980). A lack of contact with kin is often especially damaging to fitness, particularly for those that are postreproductive or young but excluded from direct reproductive relationships (see de Catanzaro 1981). Consideration of residual inclusive fitness may allow a relatively objective and conceptually clear scaling of individuals in terms of coping status, clarifying many currently muddled definitions in the area of abnormal psychology. The construct "depression" has also been used with insufficient precision in the literature, being applied to a rather heterogeneous set of phenomena. Much of human affective variation probably derives from variation in fitness, with genetics also involved in individual differences (Gershon 1978). Transitory euphoria in times of success and dysphoria in times of failure are surely normal, universal features of human behavior. Indeed, the pharmacological manipulability of such conditions and other evidence of a neurochemical substrate (see A & Z's target article), taken with ethological evidence on stereotyped facial expressions associated with positive/negative affect in humans and other primates (Ewer 1968; Harlow 1974), suggest that the capacity to vary on this affective dimension is innate. Long-lasting (but usually transitory) states of mourning, bereavement, or dysphoria after a major loss are also surely a normal aspect of human affect. In other cases a dysphoric state may be associated with the cumulation of a large number of experiences that collectively preclude an individual from effectively behaving to promote his inclusive fitness; this may explain many cases of so-called endogenous depression that cannot be attributed to a single adverse event. Where such natural affective variation becomes "pathological" is difficult to define and perhaps is partly a matter of semantics. I do not like the term "depressive illness," because it involves an evaluative rather than a more descriptive and scientific view. Another important distinction is between "depression " and "hopelessness" (see also Beck, Kovacs, & Weissman 1975). A person may experience chronic negative affect due to prolonged adversity but nevertheless anticipate future improvement. Others, due to permanent infirmity, senescence, or a long history of negative experience, may view all conceivable future prospects as negative. The latter condition is the one more commonly associated with suicidal behavior (see Beck et al. 1975; de Catanzaro 1980; 1981; Farber 1968). A breakdown in the life-preserving orientation of behavior with low residual fitness is consistent with evolutionary pressures; there is no conceivable pressure of natural selection supporting lifepreserving behavioral predispositions and gene expression when future reproductive and kin-solicitous behavior are both precluded (see de Catanzaro 1981). It is similarly not surprising that basic patterns of self-maintenance, including eating, sleeping, grooming, and working, break down in some individuals classified as depressed (Beck 1976). Neurochemical and cognitive explanations of these phenomena do not seem entirely contradictory; both involve proximate mechanisms subserving processes attributable to evolutionary pressures. We need to know more about the interaction of cognitive/cortical and neurochemical/hormonal activity accompanying coping difficulty. Perception of social status, achievement or failure in social roles, and many other fitness changes must initially occur on a cognitive level. Such perception may in turn induce affective changes mediated at the physiological level by processes like those discussed in the target article. Much of subsequent behavioral change, for example in general activity level, may indeed be induced more by neurochemistry than by purely cognitive processes. There are limits, however, to analogies between stress-induced behavioral and neurochemical conditions in nonhumans and humans. I doubt that laboratory rats and mice show the richness in affective variation found in humans; the human cognitive structure is undoubtedly much inore developed. Nevertheless, the consistency of the animal data on monoamines and stress with data on monoamines and human depression is notable.

Appraising psychobiological approaches to the influence of stress on depression

Joel E. Dimsdale
Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, Mass. 02114

With the advent of highly sensitive neuroscience techniques and a spirit of interdisciplinary collaboration has come a burgeoning literature about the psychobiological concomitants of stress and depression. It is important, however, to emphasize that vastly different explanatory models are being used and that a truly synthetic approach may well be impossible. Can one tie together the following key links? 1. Is there a predisposition to depression? Can one seek this predisposition in genetic terms? Can one seek it in terms of the individual's previous life experience? 2. What is the role of painful life events in precipitating depression? Is there a "threshold" effect, either in terms of immediate difficult events or in terms of an accumulation over time of difficult life events? Can one quantify across all subjects a rating for the severity of difficult events? 3. What are the pathophysiological manifestations of depression? How may these manifestations be studied in humans? 4. What are "depression" and "stress"? There is an immense body of literature on each of the four preceding questions. Investigators have examined meticulously the possible genetic correlates of depression and attempted to tease apart the thorny issue of "nature" versus "nurture" (Allen 1976). Others have developed techniques for monitoring life-change events, examining such issues as the common ranking of distress associated with various life events, the ability of individuals to report accurately in retrospect about the occurrence of life events, and the role of the individual's interpretation of life events as a modifying influence (Dohrenwend & Dowrenwend 1974; Benner, Roskies, & Lazarus 1980). As Anisman and Zacharko (A & Z) have summarized, an impressive literature has accumulated regarding neurochemical concomitants of depression. This literature reflects post-mortem studies in humans, studies of eerebrospinal fluid, blood, and urinary metabolites in humans (Schildkraut 1978) and animals, and studies of brain tissue obtained from animals exposed to various stressful circum-

104

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary/Anisman & Zacharko: Depression and stress stances. Major strides have also been made regarding the phenomenological description of depressions (Spitzer & Endicott 1978). The attempt to integrate the above divergent research strategies is a laudable one, but it is an attempt that requires restraint because such an integration faces major obstacles. To apply such different investigative approaches to the study of depression is not quite the same as studying tuberculosis in terms of its social setting in poverty, its racial vulnerabilities, or its bacteriology, histology, and clinical signs and symptoms. Would that depression were so homogeneous! Instead, we may ultimately find ourselves with two or more accurate but incompatible theories of depression, similar to theories of light transmission as wave form or particulate. One of the crucial difficulties in studying the psychobiology of depression is the lack of clarity regarding the definition of depression itself. As commonly used, a diagnosis of depression conveys little more information than a diagnosis of fever. We do not know whether a diagnosis of "fever" reflects bacterial or viral infection or pulmonary atalectasis, for example. The physiology and the therapeutics for any of the above causes of fever are quite different. Similarly, for depression, some use the term to reflect a normal continuum of sad feelings, whereas others reserve it for mood states that seem somehow distinct from normal mood states. Phenomenological psychiatry, however, has derived consistent guidelines for reliably diagnosing various forms of depression (Spitzer et al. 1978), guidelines that are crucial for use in psychological studies of depression. As if agreement about depression were not hard enough, agreement about "stress" is more difficult. All investigators are aware of the imprecision of stress. In reaction, some have suggested newer terms such as "negative environmental contingencies" or "aversive events" as an alternative framework; however, it is not clear that such newer terminology helps. It is extraordinarily difficult to find an adequate animal model of depression. The current literature on learned helplessness may be a step in the right direction (Seligman 1975). However, much of the animal literature has assumed that stressing the animal is the same thing as depressing the animal. This is a difficult proposition to defend. To begin with, many of the stresses referred to in this stress-depression neurochemistry literature refer to physical stresses such as imposition of heat or cold. Presumably, the animals are uncomfortable and do not "like" such "stress"; however, I do not believe that anyone has seriously suggested that thermal stress is a good model for depression. The animal studies that have focused on a stress that is more behavioral than environmental would appear to be closer to the mark in terms of modelling depression. However, again, it is not clear whether stressing the animal by the yoked imposition of electrical shock triggers anxiety or rage or frustration or depression. One could perhaps make more progress in the animal modelling of depression if the stresses imposed seemed more consistently related to the stresses associated with human depression. Applying histological and neurochemical analyses to animals that have experienced bereavement or sudden loss of social prestige may be a better long-term strategy for modelling depression (Harlow & Harlow 1965; Henry & Stephens 1977). One way or another, depression must be neurochemically expressed. Research has accumulated regarding the classical neurotransmitters (norepinephrine, dopamine, serotonin, and acetylcholine), but the information is so contradictory that one is hard pressed to accept a paradigmatic view regarding these neurotransmitter abnormalities (Baldessarini 1981). This neurotransmitter-based research may ultimately provide a psychobiological key to understanding this complicated area; in the meantime, replicated studies and studies of some of the newer neurotransmitters' roles in depression would appear to be a profitable research strategy. In recent years, a more modest focus for psychobiological concomitants of depression has been developed. Given that the animal behavioral models of depression are uncertain and that the brain neurochemical changes are also uncertain, some investigators have looked for consistent peripheral biological markers of depression. This research strategy has had a high yield in detecting physiological markers that can be readily studied in a patient population, appearing and disappearing as the depression waxes and wanes. Two promising peripheral biological markers of depression relate to changes in sleep REM activity (Kupfer & Foster 1972; Gillin, Duncan, & Pettigrew 1979) and changes in peripheral cortisol levels. The latter in particular has had wide confirmation. Depressed patients manifest a higher and more frequent pulsatile spiking of cortisol; furthermore, the normal diurnal rhythm with a cortisol nadir in the late afternoon is diminished (Sachar, Hellman, Roflwarg et al. 1973). In normal subjects, a one-time dose of dexamethasone at bedtime is sufficient to inhibit ACTH release for one to two days, and thus the peripheral cortisol levels are diminished. However, in depressed patients, the cortisol is not suppressed. The dexamethasone suppression test has both high sensitivity and specificity (Carroll, Feinberg, Greden et al. 1981). Its ease of administration and its low cost make it a to"ol that will be used increasingly in routine settings. I have highlighted the cortisol changes in depressed patients because there is a consistent literature on this topic, a literature that is soundly grounded in human depression, and a literature with a clearly pathophysiological orientation. Detailed study of the mechanism of these changes may provide vital information about the psychobiology of depression. Human depression has a lifetime prevalence of between 5 and 10 percent. The treatment of depression has made remarkable strides in the past 20 years. The concomitant advances in neurosciences and the willingness of investigators from different areas to collaborate in this complex area offer great promise both for understanding the psychobiological mechanism of depression and for improving the treatment for this major medical problem.
ACKNOWLEDGMENTS This work was supported by a Clinician Scientist Award from the American Heart Association with funds contributed in part by the AHA Massachusetts affiliate.

A cognitive/information-processing approach to the relationship between stress and depression

Vernon Hamilton
Department of Psychology, University of Reading, Reading RG6 2AL, England

My comments on this very readable paper are restricted to three questions. (1) What is the conceptual status of the terms "depression" and "stress"? (2) If cognitive events participate in the stress-depression interaction, what form do they take? (3) What is the nature of the dispositions that mediate such interaction? The issues involved here do not appear to be clearly conceptualized by Anisman & Zacharko (A & Z), partly, no doubt, because they reflect our fairly general problems in relating biological and behavioral processes to unobservable cognitive events. Depression is not a unitary category. Apart from differences between the so-called reactive variant without evidence of incongruous (psychotic) thought processes and depressions with evidence of bizarre logic, depression occurs with schizophrenic reactions, in mental retardation, and in combination with severe anxiety. Lader (1975), for example, has demonstrated that so-called agitated depressions are very common.
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

105

Commentary/Anisman & Zacharko: Depression and stress

More significant is the large number of individuals who display transient depressive moods that lead to equally transient bouts of unhappy and behavioral inefficiency without any evidence that they were preceded by insult, distant trauma, or recent aversive life-event changes. Thus, depression as well as anxiety can be a normal response that is more closely related to the individual's evaluation of his personal and social integrity and role-playing capacity at any given point in time than to the neurochemical reactions that evaluation processes may induce. If inefficency due to depression has cognitive mediators, what is commonly and imprecisely termed stress requires reinterpretations of the kind that have been offered recently (Hamilton & Warburton 1979). First, a distinction is required between stress-as-an-agent and stress-as-an-effect, although in combination they may loosely be called the stress reaction. Without a distinction, however, between agent and effect, dispositions cannot be argued when stress has the traditional response connotation because dispositions relate more to types and levels of effect rather than to agents. To overcome this problem, it has been argued (Hamilton 1979a) that the agents are stressors and the effects are strain. Stressors and strain are then interpreted as the load on the adaptive system and its energizing, coping, or defensive capabilities. There is general agreement that cognitive processes play an important role in depressive moods or dysfunctions, whether we prefer somewhat general conceptualizations concerning conscious or unconscious negative self-evaluations and socialization experiences or limit the focus to learned helplessness and an identification of attributed causes. The important question is why these internal events are stressors. A term derived from physical science deserves a quantitative indexing analogue appropriate to behavioral science. Limitedcognitive-processing-capacity theory provides this analogue in the form of information, Stressors may be defined, therefore, by the amount of information which stimuli generate in the cognitive analysing system and in its response-generating components. This definition seems to be equally useful whether we are considering the work load of air-traffic controllers, studying the effects of learning a long list of nonsense syllables with or without an additional task, trying to account for the interfering effect of high levels of anxiety on complex problem solving, or attempting to define the stressors which mediate depression. The first two examples lend themselves easily to an informational analysis of stressor-strain-load effects. Anxiety and depression and other personality and motivational variables require additional specification. For anxiety this task has been attempted in some detail already. Hamilton (1979b) proposed that anxiety can be defined as conceptual long-term memory structures encoding a personal history of aversive experience. These structures possess low thresholds for available and retrievable informational data which encode finely elaborated representations of unfavorable or threatening expectancies of behavior outcomes. Low thresholds are a function of the subjective importance of avoiding probabilistic uncertainty as well as uncertainty of behavior outcome. Furthermore, low thresholds for the retrieval of aversive data are a function of the degree of aversiveness and differential elaboration which conceptual structures have encoded with respect to competence, family and social acceptance, "defects" and injuries, etc. These structures, organized in schemata, provide the dispositions towards overt or covert anxiety by operating as "top-down" data resources (Bobrow & Norman 1975). The informational-cognitive structures of depression remain to be identified with a greater degree of precision than is available at present. Beck's cognitive triad (Beck 1976), Bowlby's qualitative analysis of sadness (Bowlby 1980), and the clinically observable cognitive changes in the therapy of depressed patients discussed by Horowitz (1979) will help in this task. What we can say at this stage is that, just as questionnaires assessing levels of anxiety, anger, or dominance provide an estimate (albeit a gross one) of the extent and hierarchical order of response dispositions organized in concept-bearing schemata of the so-labeled characteristics, so do well-designed depression questionnaires provide a comparable estimate. We can plausibly predict that the greater the elaboration of negative self-evaluations of actual or phantasied loss, of guilt and anxiety about actual or phantasied damage or injury caused to others, of the importance of socially transmitted and internalized ideal goals and evaluations and anticipations concerning failure to achieve them, the higher the score on a reliable and validated questionnaire. There is already some evidence (Averill, DeWitt, & Zimmer 1978) that self-attribution of an emotion is more likely when behavior has undesirable rather than desirable consequences. There is other evidence that the relationship between mood and cognition is at least one of concurrence, if not one yielding precedence to cognition (Isen, Shalker, Clark, & Karp 1978; Bower 1981). If depression, like anxiety, can be defined by its intrusive cognitive content, much of it verbally labeled (i.e., in terms of amount of information processed in task settings that do not require it but that simultaneously require their own quantum of attention and working memory space and time), we obtain an updated view of depression as a stressor. In this context coping, by utilizing neurochemical as well as cognitive mechanisms and processes, is not a strain- and load-reducing event, but cognitively (and probably neurochemically) loadincreasing in the first instance. In that case, the therapeutic effects of pharmacological intervention reside in the shifting of load-bearing resources to cognitive restructuring efforts. Changes in norepinephrine metabolism, however, cannot alter the content of cognitive structures encoding the representations of dispositional concepts; they can only raise their retrieval thresholds. Since the thresholds of nondepressive cognitive schemata are likely to be raised simultaneously, lasting change in cognitive bias can be achieved only by stimulating cognitive structures encoding events, situations, objects, and relationships which have favorable meaning for the individual.

A tripartite physiology of depression

L D. Hankoff
Department of Psychiatry, Elizabeth General Hospital and Dispensary, Elizabeth, N.J. 07201

Schopenhauer, referring to the question of mind's relationship to matter, called it the "world knot," his wonderfully evocative term for the vortex of philosophical and biological entanglements. In addressing the problem of the effect of stress on the disorder of depression, Anisman and Zacharko (A & Z) have confronted a fundamental issue in the behavioral sciences. The effort of A & Z to provide an integrated framework for psychosocial input (aversive life events) and the physiological correlates of depression focuses on the impact of stress on biogenic amine-level changes. Their main biochemical link to stress effects is the demonstration of a laboratory finding that bodily utilization of biogenic amines is increased under the impact of acute stress. Correlations, however, are not causal relationships. Such a correlation of an external event with a change in brain milieu (and it is often a highly imperfect correlation) does not offer a theoretical framework in which to integrate brain event and environmental influence. I suggest that an approach to integrating the brain and behavioral levels in the condition called depression be approached through a study of the biological aspects of the phenomenology of depression. (My hope would be that the phenomenological study of depression would provide the

106

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

CommentaryVAnisman & Zacharko: Depression and stress necessary links to the psychosocial sphere wherein stress is defined.) The phenomenology of affective disorders has long been studied in terms of three different components. Might these correspond to three different neurophysiological subsystems? Kraepelin, in the last decade of the nineteenth century, delineated in the depressed patient three areas: mood or emotional disorder, motor activity, and cognition. All are altered in depression, or may be so but in varying directions. The depressed patient may manifest motor activity over a range from extreme agitation to catatonia-like stupor. Cognitive changes of a wide range from a minimal apathetic reflection of depression to an elaborate delusional system may occur. These phenomenological changes do not all occur in a uniformly orchestrated fashion. For example, the depressed patient may be agitated or retarded in his motor activity. The development of delusional thinking may accompany a manic mood or a depressed mood. Hallucinations may accompany depression or mania. There are suggestions that these three areas of phenomenology reflect different physiological systems. It is likely that the mood-modulating system is most involved with the biogenic amines discussed by A & Z. Most recently the studies with brain polypeptides have demonstrated their function as neurotransmitters. The threshold for pain, which correlates positively with the level of endorphins generally, is increased in depressed patients. The distress calls of guinea pigs elicited by social isolation have been found to be inhibited by an endorphin-medicated forebrain action (Herman & Panskepp 1981). The inability to experience pleasure, which is an accompaniment of depression, may reflect the malfunctioning of the pain, pleasure, and self-stimulating centers of the hypothalamus and may be related to the diminished ability to experience pleasure which accompanies depression. I would suggest that the mood-change aspect of affective illness is particularly related to this neurophysiological subsystem. Motor disorders are common in affective disorders. In the experimental setting, amphetamines typically produce stereotyped behavior, which may be antagonized by the use of antipsychotic medication. Laboratory studies indicate that the hippocampus and septum are important links in this form of behavior. For example, the stereotyped behavior produced by both amphetamine intoxication and hippocampal damage is antagonized in both cases by use of the antipsychotic haloperidol (Devenport, Devenport, & Holloway 1981). The disorders of volition or motor activity may be related to involvement of the hippocampus and septum, accounting for phenomenological changes which are not always well correlated with mood changes. The third area, cognitive functioning, has in recent years been explored in terms of the characteristic thought structure and content of the depressed patient. The work of A. T. Beck (1967) and others has demonstrated characteristic changes in thinking in depression that may respond to direct treatment (i.e., cognitive therapy), as well as to indirect treatment (biological intervention). The research demonstrating involvement of the nondominant hemisphere of the brain in affective disorders suggests that these higher cortical areas reflect the significant correlates of the cognitive changes in depression (summarized by P. Flor-Henry 1976). In experimental studies with amphetamine intoxication, a dissociation of motor stimulation and delusional thinking has been observed (Angrist & Gershon 1970). When a patient intoxicated with amphetamines is given reserpine, the psychotogenic effect is blocked, whereas behavioral stimulation is retained. There is thus an observable dissociation between these two areas in the phenomenology of affective disorders. The further dissection of brain subsystems along lines suggested by phenomenological findings should lead to a more complete picture of the brain mechanisms underlying the symptomatology. The elucidation of brain mechanisms in relation to the phenomenology of depression should also shed light on the poorly understood area of the relationship of mood, activity, and cognition to each other in affective disorders. Flor-Henry, for example, has tried to explain through lateralization studies why a transition from a chronic manicdepressive psychosis to schizophrenia is possible, but not the reverse. The phenomenological changes of depression are the natural screen on which stressful events are projected. The social and cultural influences on the patient are the sources of the depressive cognitions. The motor activity, agitated or retarded, is gauged by its immediate human environment, which provides the measure for its deviance. If a fully mature brain description of phenomenological changes were to emerge, the aversive life event might be viewed in its phenomenological context and integrated into the physiological understanding of the phenomenological.

Monoamine receptor sensitivity and antidepressants

George R. Heninger
Yale University and Connecticut Mental Health Center, New Haven, Conn. 06508

I would like to compliment Anisman and Zacharko (A & Z) on an interesting and useful presentation and discussion of an important, long-standing problem. It is unfortunate that they revert to unnecessary dualism in their summary when they view behavioral attempts to cope with stress as being coupled in some parallel fashion with alterations in neurochemical activity. The more parsimonious view is that behavior is a consequence of nervous activity; thus, behavioral attempts to cope with stress are only one visible aspect of a large number of adaptive mechanisms occurring in the nervous system in response to stress. Successful behavioral coping would be viewed as an indication that at least some part of the neurochemical system is not overly taxed. There are certainly instances where neurochemical systems decompensate without behavioral decompensation and vice versa. A nondualistic formulation would better focus attention on the critical question -i.e., what are the specific mechanisms involved when the nervous system fails to adapt adequately to stress? A & Z have suggested that one of these mechanisms may be a depletion of the monoamines norepinephrine (NE) and serotonin (5-HT). Neuroactive peptides should also have been considered, since recent evidence indicates that they are at least as important in the regulation of stress reactions as monoamines. Another important mechanism that was not thoroughly discussed involves changes in monoamine-receptor sensitivity. There is considerable evidence that antidepressant treatment (ADT) may act by inducing changes in monoamine-receptor sensitivity independent of changes in synaptic concentrations of monoamines (Charney, Menkes, & Heninger 1981). The "receptor-sensitivity hypothesis," which is an alternative to the "monoamine-deficiency hypothesis," is supported by the evidence that clinically effective antidepressant drugs such as iprindole and mianserin do not inhibit uptake or metabolism (Rosloff & Davis 1974; Goodlet, Mireylees, and Sugrue 1977) and that good uptake inhibitors such as amphetamine, phemoxetine, or cocaine are not effective antidepressant treatments (Post, Kopin, & Goodwin 1974; Overall, Hollister, Pokorny, Casey, & Katz 1962; Ghose, Gupta, Coppen, & Lund 1977). There is the obvious temporal discrepancy between the effects of MAO inhibitors or uptake-blocking drugs on amine concentrations and the delayed clinical response observed when these drugs are used in patients (Oswald, Brezinova, & Dunleavy 1972). Recent research into the mechanism of action

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

107

Commentary/Anisman & Zacharko: Depression and stress

of ADTs indicates that all effective ADTs produce changes in monoamine-receptor sensitivity with a time course that is similar to the 7- to 14-day delay in the antidepressant effects observed in patients (Charney, Menkes, & Heninger 1981). This has made it necessary to reevaluate the hypothesis that the therapeutic effects of antidepressant drugs are a consequence of their ability to increase acutely the availability of synaptic NE or 5-HT. Since there do not appear to be any specific changes in NE or 5-HT turnover that can account for the therapeutic mechanism of most ADTs (Sugrue 1981), current research on this problem has shifted from effects on amine turnover to adaptive changes occurring in monoamine-receptor systems. Major advances elucidating the complex effects of long-term ADT on NE- and 5-HT-receptor function have been facilitated by the development and application of new techniques, such as radioligand-receptor binding, single-unit electrophysiological recordings, pharmacologic characterization of adenylcyclase (cAMP) production, and neurotransmitter behavioral paradigms, all of which are capable of assessing receptor regulation and function. It has been found that changes in sensitivity of monoamine receptors are produced by all effective ADTs. Following long-term ADTs, there is reduced beta-adrenergic sensitivity, while responses to alphaadrenergic and serotonergic stimulation appear to be increased. This suggests that alterations in receptor sensitivity may be a common mechanism of action of a variety of different ADTs, including tricyclic antidepressants, "atypical drugs," monoamine oxidase inhibitors, and electroconvulsive therapy. Clinical studies are now being conducted to assess whether receptor abnormalities exist in depression, and the initial results indicate that some receptor systems are indeed subsensitive in depression (Checkley, Slade, & Shur 1981). Thus, stress-induced changes in receptor sensitivity provide another mechanism by which environmental events could predispose to depression. As appropriate and sensitive measures of neural function are increasingly applied to the study of human depressive illness, we should be able to better understand the most important question brought to mind by this review - i.e., what neurobiologic mechanisms account for the extremely wide variation between individuals in the susceptibility to stressinduced depression. We may eventually better understand why bipolar patients have depression that is not precipitated by stress, why parental deprivation and stressful life events precipitate depression in some individuals, and, most importantly, why in other individuals depression never occurs despite massive stressful experiences in early life or following recent life events. hypothesis in the attempt to understand the chemistry of affective disorders. No doubt because of their previous work with the noradrenergic system, A & Z tend to emphasize the role of the catecholamines in the etiology of depression. Much of our own research since 1960 has led us to similar conclusions regarding the influence of stress on the serotonergic system and depression. Although not cited by them, these studies lend additional empirical support to A & Z's general theoretical position. Our work with animal models of depression has yielded an extensive series of experiments in which we have demonstrated that periods of behavioral depression (defined as a significant reduction of baseline learned behavior on foodreinforced operant schedules) following the administration of the serotonin precursor (5-hydroxytryptophan; 5-HTP), as well as certain other compounds, are associated with an increase release of serotonin (5-HT) into the synaptic cleft of specific areas of rat and pigeon brains (for reviews see Aprison & Hingtgen 1970; 1972; Aprison, Hingtgen, & McBride 1975). These data of Aprison, Hingtgen, and co-workers, when viewed with two very important sets of clinical data (i.e., first, probenecid-induced accumulation of 5-hydroxyindoleacetic acid [5-HIAA] in the cerebrospinal fluid [CSF] of depressed patients is lower than that of appropriate controls, and, second, the probenecid-induced accumulation of 5-HIAA in the CSF of depressed patients is significantly decreased during the one- to three-week treatment with amitriptyline or imipramine when compared with the pretreatment value for these patients) led to the formulation of the hypersensitive-postsynapticserotonergic-receptor theory of depression (Aprison et al. 1978; Aprison & Hingtgen 1981). This theory, simply stated, postulates that the amount of 5-HT released from serotonergic nerve endings is reduced in individuals predisposed to depression. We have suggested, as do A & Z, that this could be due to some psychiatric precipitating factor such as chronic stress, resulting in rapid utilization and perhaps lowered synthesis of the neurotransmitter. The net effect of this reduction is the development of a supersensitive receptor in the postsynaptic membrane which reacts to a "subjective" excess of released 5-HT during periods of stress, resulting in some forms of depression. Additional support for the plausibility of this hypothesis has come from two recent series of studies with animals in our laboratories. The first employed parachlorophenylalanine (PCPA), a drug which inhibits tryptophan hydroxylase, to reduce the amount of 5-HT released at serotonergic synapses. In rats pretreated with PCPA a significantly increased behavioral depression followed the administration of low and previously ineffective doses of 5-HTP. Similarily treated rats also provided receptor-binding data which indicated that the serotonergic receptors were indeed made hypersensitive to 5-HT release (Fleisher, Simon, & Aprison 1979). A second series of studies showed that several of the currently used antidepressive drugs (amitriptyline, mianserin, imipramine, and iprindole) blocked the 5-HTP-induced depression in a way similar to that seen after methysergide, an established postsynaptic-receptor blocker, rather than fluoxetine, a presynaptic-receptor blocker of 5-HT (Nagayama, Hingtgen, & Aprison 1980; 1981). In one sense, our new hypersensitive-serotonin-receptor theory of depression might be considered an extension of the serotonin-deficiency theory with the levels of 5-HT in depressed patients still assumed to be low. However, in our new theory a suggestion is made that a hypersensitive postsynaptic receptor develops in these individuals due to a prolonged decreased release of 5-HT (as in the A & Z model). Space does not permit a discussion of a number of biochemical mechanisms that might cause the decreased release of the neurotransmitter. Since the postsynaptic receptors in this state

Hypersensitive serotonergic receptors and depression

J. N. Hingtgen and M. H. Aprison
Section of Applied and Theoretical Neurobiology, Institute of Psychiatric Research and Departments of Psychiatry and Biochemistry, Indiana University School of Medicine, Indianapolis, Ind. 46223

The hypothesis that stress may provoke psychotic depression through neurotransmitter depletion has been suggested for a number of years. It is gaining even wider acceptance since being coupled with the newer concept of hypersensitive postsynaptic receptors, especially with regard to the serotonergic system (Aprison, Takahashi, & Tachiki 1978; Aprison & Hingtgen 1981). Anisman and Zacharko (A & Z) give an overview of the neurochemical aspects of stress and depression and present a strong case for seriously considering this

108

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary/Anisman & Zacharko: Depression and stress can compensate for the decreased release of 5-HT, the serotonin synapses in this subgroup of individuals are functioning at close-to-normal levels postsynaptically under most conditions. At some later date, a stress factor causes an increased release of 5-HT, which now interacts with the supersensitive postsynaptic receptors, resulting in behavioral depression. Although there is an excess of 5-HT in the now depressed patients when compared to the previous release, their overall levels of 5-HT are still lower than those of the normal population. Thus, we refer to this hypothesized increased release of 5-HT in the subgroup of depressed patients as a "subjective" excess of free 5-HT acting at postsynaptic receptors. Hence these patients, no doubt, still have lower levels of 5-HIAA, even during the recovery period following treatment (van Praag 1979; 1981). This theory predicts that, in at least one subgroup of human depression, the major action of the clinically effective drugs may be a blocking of the serotonergic receptors in the postsynaptic membrane (although some blockade of the presynaptic uptake of 5-HT may also be involved). One of the critical elements of our theory would necessitate the demonstration that one or more types of stress could produce significant changes in neurotransmitter levels - in the case of our theory, serotonin levels. A & Z cite some studies in which this has been shown. In preliminary studies from our own laboratories we have also found significant depletions of 5-HT in specific brain areas of rats following activity-wheel stress or shock-avoidance stress, sufficient to produce gastric erosions and elevated levels of corticosteroids (Hellhammer, Hingtgen, Wade, Shea & Aprison 1982). The interaction between stress and depression appears to be a fruitful area to search for underlying behavioral and neurochemical mechanisms of depression. As A & Z have noted, physical illness itself could provide sufficient stress for depression to result (see also Hendrie 1981). Perhaps a number of distinct subgroups of depression will be delineated in this way. One or more groups may involve mainly serotonergic mechanisms, whereas others could involve catecholaminergic, cholinergic (Hingtgen, Smith, Shea, Aprison, & Gaff 1976), or ami no acid neurotransmitters (Aprison 1977). Thus, neurotransmitter involvement in the interaction of stress and depression is likely to be extremely complex, but it offers an exciting new approach to the whole field of psychosomatics. helpful, at least briefly? One possible resolution to this confused state of affairs, to which A & Z briefly allude, involves catecholamine autoreceptors, a special class of catecholamine synapse that inhibits catecholamine neurons. If the problem in depression is specifically excess sensitivity of autoreceptors, there could be both a deficit in overall catecholamine release and excess sensitivity of one kind of catecholamine receptor - and both problems might be alleviated by antidepressant drugs. It takes a little handwaving to make this hypothesis seem tofitall the data, but it does gain support from recent evidence that autoreceptors have drug sensitivity different from that of other catecholamine receptors (Skirboll, Grace, & Bunney 1979) and that electroconvulsive shock and the antidepressant drug mianserin both selectively antagonize autoreceptors (Chiodo & Antelman 1980; Dresse & Scuvee-Moreau 1980). At the rate things are going, the autoreceptor hypothesis too may be dead before the ink is dry. A & Z, meanwhile, offer a novel approach to the problem of the biochemistry of depression: Try to make sense out of its relationship to precipitating or predisposing events, such as stress. That is, as when working a complex jigsaw puzzle, it might become easier to deal with one difficult section if we consider its relationship to another section. In a nutshell, A & Z propose that acute, severe, uncontrollable stress depletes amine reserves by utilizing amines faster than they can be resynthesized. Well aware of the complexities of the situation, they add the qualification that a variety of circumstances, including genetics, hormones, previous stress experiences, chronicity of the stressor, and available coping methods, determine which amine transmitter is depleted and to what extent. Further, they do not insist that stress is involved in all cases of depression, but merely that it is involved in some. Their carefully understated proposal does seem to fit a large quantity of data. The question at this point, given the nature of this field, should not be whether A & Z's proposal is right or wrong, but how useful it might be as a working hypothesis to organize future research. Some of the key research questions are obvious: What kinds of stress are effective, what predisposing factors modify this effect, and which types of depressive syndromes are involved? In addition, one could add, what are the differential effects of stress on autoreceptors and conventional synaptic receptors? Another, possibly less obvious, question should be of serious concern: If depression is related to transmitter depletion caused by acute stress, why is depression so persistent? If we deplete a transmitter by reserpine or other drugs, the brain ordinarily resynthesizes the transmitter, and behavior soon returns to normal. But human clinical depression often persists, seriously and unremittingly, for years. There can also be an oscillation between depression and mania that does not relate to anything we can identify in the environment. It is easy to see how stress could precipitate a brief, abating depression. If stress can precipitate persisting or oscillating depressions, however, we will need a concept of "triggering," in which the neurotransmitter abnormality, once triggered, becomes selfperpetuating. Perhaps there is a failure of normal resynthesis processes; perhaps there is a persisting hypersensitivity of autoreceptors; or perhaps other processes are involved. Perhaps depression has something in common with other self-perpetuating processes, such as puberty, or drug addiction, or anorexia nervosa. At any rate, the question of persistence would seem to be critical in the relationship between depression and any precipitating conditions, including stress. The great jigsaw puzzle of depression has seemingly become more complex, the longer we have tried to work it. A & Z, by emphasizing possible links between different parts, may lead us toward a valuable restructuring of the puzzle, and to increased attention to some new questions.

Triggering stimuli and the problem of persistence

James W. Kalat
Department of Psychology, North Carolina State University, Raleigh, N.C. 27650

Since Larry Stein's (1962) suggestion that depression was due to a deficit of norepinephrine, a consensus has gradually grown that depression is indeed due to some sort of neurotransmitter abnormality, involving especially the amines. However, hypotheses have proliferated abundantly about the exact nature of that abnormality. As Anisman and Zacharko (A & Z) have amply reviewed, there is evidence suggesting deficits of norepinephrine, dopamine, and serotonin and a possibility that other transmitters are also involved. However, the common therapeutic drugs both increase transmitter levels (rapidly) and decrease receptor sensitivity (slowly). The time course of the drugs' therapeutic value is consistent with an effect primarily on receptor sensitivity. But if the main problem in depression is excess receptor sensitivity to the amines, then why are MAOIs and tricyclics merely neutral at first, instead of harmful? And why are amine depletors, such as reserpine, not

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

109

Commentary/Anisman & Zacharko: Depression and stress Neurochemical correlates of stress and depression: Depletion or disorganization?
Gary W. Kraemer
Department of Psychiatry and Primate Laboratory, University of Wisconsin, Madison, Wis. 53706

Stress may be a predisposing factor in the precipitation of depression. Anisman and Zacharko (A & Z) propose that stressful experiences engage behavioral and neurochemical coping mechanisms. However, if behavioral control of the stress is not achieved then the emphasis on neurochemical coping mechanisms causes the depletion of brain biogenic amines, resulting in affective disorders. The topic of A & Z's paper is relevant because of the intuitive relationship between untoward life events and subsequent depression, and because of the now long-standing hypothesis that affective disorders in humans are somehow related to altered function in brain biogenic amine systems. There may be a link between stress and the function of brain biogenic amine systems. If stress and depression are linked with each other in terms of involvement with the same brain mechanisms, then defining the characteristics of this interaction would be important in understanding the etiology of depression from a neurobiological standpoint. Unfortunately, the premises of this argument are themselves not well established. For both ethical and practical reasons it is either difficult or impossible to test neurobiological-behavioral hypotheses rigorously with human subjects. The role of life events, or "stress," in predisposing humans to depression is not well defined, and this is an area of controversy. Also, the experimental record has not supported the simplistic hypothesis that human depression is the result of depletions of brain biogenic amines; and it is now appreciated that a variety of neurobiological changes probably play a role in affective disorders (Schildkraut 1978). Fortunately, some aspects of hypotheses about life events and the neurobiological basis of depression can be addressed in the context of animal models. A & Z seem to agree, since their review depends heavily on tests conducted in animals. Kraemer and McKinney (1979) examined some of the interrelationships between a psychosocial stressor (social separation) and the response to agents that alter function in biogenic amine systems in the context of a primate model of depression, i.e., the despair response of rhesus monkeys to separation from their peer group. It was found that the severity of the despair response in groups of monkeys was dependent on early rearing conditions and the number of previous separations sustained by the monkeys. Furthermore, the monkeys were differentially susceptible to the depressant effects of catecholamine- (CA) but not indoleamine-depleting drugs, based on these same factors. These results suggest that: (1) social separation early in life, or repeated separations during development, can predispose monkeys to more severe depression-like responses in subsequent tests; and (2) the separation responses are particularly susceptible to alteration by drugs that affect CA metabolism. Viewing social separation as a "stressor" that is unavoidable as long as it persists, the results of this study conform to the analysis presented by A & Z. However, the interaction of the despair response to social separation .with concurrent pharmacological challenges is not a simple one. It was found that extremely low doses of alpha-methyl-para-tyrosine (AMPT, 25 mg/kg/day), known to deplete norepinephrine (NE) and dopamine (DA), exacerbated the despair response. On the other hand, fusaric acid, which depletes NE by inhibition of dopamine-beta-hydroxylase,'ameliorated the despair response and had effects that were opposite to those produced by

AMPT. Ostensibly, it appeared that depletions of both NE and DA augmented the despair response, while depletions of NE alone ameliorated it. However, the results of another study complicate the interpretation of these results. Kraemer et al. (1981) examined the separation response of monkeys following intracerebral administration of 6-hydroxydopamine (neurotoxin) and subsequent reduction of brain NE and DA to about 30% of control values. This treatment had no effect on the separation response in monkeys that had previously been shown to display adverse separation responses when treated with AMPT, although the level of depletion of brain catecholamines produced by 6-hydroxydopamine was much greater. Taken together, these studies indicate that the magnitude of depletion of biogenic amines may not be nearly as important as the particular way in which the functional organization of the system taken as a whole is altered by pharmacological intervention. These findings emphasize the problems with the "overtaxing" or "depletion" neurochemical hypotheses presented as the neurobiological concomitant of the response to stress that leads to depression. Depletions in brain neurotransmitter content, at least as we are able to produce them experimentally, are not necessarily associated with behavioral changes in the predicted direction or of the expected magnitude. Depression, on the other hand, has not been associated with predictable and reliable reductions in neurobiological measures of function. Rather, as A & Z note in their review of the literature, a wide spectrum of changes can be found in depressed patients, there appear to be subgroups, and the sorts of differences found vary from study to study. In humans, and in many cases in animal models, it is not clear that changes in measures of either content or turnover of a given brain neurotransmitter system are interpretable without a further understanding of the dynamic interrelationships that must exist between several of the neurotransmitter systems which we now have the technological capacity to study. While the authors state that a number of systems must be studied, they remain focused only on NE and serotonin and set forth a "bathtub" model of neurotransmitter metabolism to account for behavioral change. However, theories that account for the modulatory influences of one system on another in terms of both excitation and inhibition of function (e.g., that proposed by Antelman & Caggiula 1977) may be more appropriate. The implication that tricyclic antidepressants act by altering postsynaptic-receptor sensitivity is discussed by A & Z. However, this finding points more to the concept of a "mismatch" of interdependent excitation and inhibition in a number of different systems rather than metabolic exhaustion as a neurobiological basis of depression. The "life events" which are thought by some to be possible etiologic factors in depression are not nonspecific "stressors." Rather, they appear to be events that interfere with future performance, or coping, in conceptually similar circumstances. If stressful situations engage a neurochemical coping mechanism, as A & Z suggest, then it may be that this system is organized to mediate complex patterns of coping behavior, and its own organization reflects this. However, repeated or longterm exposure to uncontrollable and inescapable events may leave this mechanism as disorganized as the coping behavior that it is supposed to mediate. Empirically, this could be manifested by a somewhat unitary behavioral syndrome (depression) because the coping mechanism does not work. The associated neurochemical dysfunction might be characterized by a wide spectrum of neurobiological symptoms which are not the primary cause of the disorder, but which are indicative of loss of organized interaction and regulation among a variety of normally interdependent neurochemical systems. This might be true for human depression.

110

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary/Anisman & Zacharko: Depression and stress

Depression and the action inhibitory system (AIS)

Henri Laborit
Laboratolre d'Eutonologie, HOpltal Boucicaut, Paris 75015, France

I would like to thank H. Anisman and R. M. Zacharko (A & Z) for their contribution, including, in their definition, precise details on various senses of the term "stress." I agree to consider it "the organism's response to aversive insults. ' But my own work has convinced me that, except in the case of acute insults and shock, such a response is pathological only if the organism's active behaviour (flight or fight) is unable to bring the situation under control, the situation then becoming chronic. In such a case the peripheral neuroendocrinal response (NE and glucocorticoids) induces an inhibition of immunological defenses with consequent susceptibility to infectious or tumoral disease. Along with this goes hydrosaline retention, which, combined with vasoconstriction, provokes both a hypertensive syndrome and a perturbation of protein synthesis and catabolism; these last participate strongly in many disorders, including sleep dysfunctions. I regret that the authors did not indicate some of the relations between depressive states and the hypercortisolemia, which very frequently accompanies them and seems to be an important factor in all so-called psychosomatic pathology (Laborit 1974; 1979). For us, depression appears to be the syndrome that accompanies "inhibition of action" (Laborit 1974; 1979). But A & Z are right to insist that there is no "single" isolated cause of this syndrome; every subject possesses the memory of his experiences since birth, conscious and, especially, unconscious. The "vecu" of each individual is practically impenetrable to everyone, beginning with the individual himself. Action inhibition appears at a moment of one's life when memorized automatisms prohibit gratifying action; that is, a stimulus may be aversive for one individual but gratifying for another. One of my criticisms of this work is that it leaves out one whole level of organisation - the neurophysiological - and passes directly from the event level to the behavioural to the biochemical. For us, however, there is a relation on the level of cerebral organisation between that area which controls consummatory reinforced behaviour (MFB), fight or flight behaviour (PVS), and inhibitory behaviour (action inhibitory system - AIS). Most authors consider the first to use catecholaminergic neuromediators (NE, DA) and the latter cholinergic and serotonergic neuromediators. We believe that it is these same mediators which control the appearance of the depressive state. A molecule, minaprine, synthesized and studied by our group (Laborit et al. 1972; Laborit 1981) and recently available on the market, gives some indirect pharmacological and therapeutic evidence for this. It does not belong to any known antidepressant family. It limits ACh (Garattini 1981) and 5-HT release without influencing the concentration and turnover of CA. It increases brain protein synthesis and memory retention. In short, this pyridazine acts as an "inhibitor of behavioural inhibition." We greatly appreciate the care with which A & Z interpret the published results of their studies of the biochemical basis of depression. The level of neuromediators in the whole brain compared to that in specific areas, the difficulty in determining their turnover, the variable sensitivity of postsynaptic and autoreceptors, the as yet unclear role of brain neuropeptides, the feedback action of various hormones on the brain - all these are difficult to interpret. Nevertheless, it seems to us that, roughly and globally speaking, an increase in the level of neuromediator will generally favor a decrease in its release and vice versa (Laborit et al. 1980). If such were the case we would

expect to find, and indeed do find, that after daily, inescapable electric shock, rats show an increase in the level of CA and a decrease in the level of 5-HT in the brain. This fact suggests that in an inhibitory state (depression), the central catecholaminergic system is inhibited while the serotonergic system is stimulated (Laborit 1981). In conclusion, when we observe a depressive state, it might be interesting not to think solely of the exhaustion of one activational system (the catecholaminergic) but rather to consider that the environment is activating an inhibitory system (cholinergic and serotonergic) in the organism. Many experimental facts show that when this system's activity is long and repeated it triggers the set of biological and physiological perturbations which accompany depressive and chronic states of stress.

An alternative hypothesis of depression

Alan I. Leshner
Office of Special Projects, National Science Foundation, Washington, D.C. 20550

This very interesting article by Anisman and Zacharko (A & Z) introduces a new twist into traditional theories of the biochemistry of depression. The more traditional views have argued that depression is the result of some biochemical abnormality in the central nervous system; A & Z's article proposes that reaction to stress, and perhaps hyperreactivity to it, can be one of the sources of that biochemical abnormality. However, both this new hypothesis and the more traditional theories that preceded it posit a particular series of events in depression that, I shall argue here, is not necessarily supported by the extant data. I propose here an alternative sequence to account for the role of biochemical alterations in depressive states. The A & Z hypothesis is that certain individuals respond to stressful events with a particular biochemical alteration that then leads to the onset of depression. Thus, the sequence they propose is: environmental stressor-* biochemical stress response - depression. Most of the data called upon in support of this hypothesis are the same as those used to argue for one or another of the more traditional views: (1) Depressed individuals have certain biochemical traits that are different from those of nondepressed individuals. (2) "Reversing" those biochemical abnormalities via pharmacological interventions results in a decrease in the depressive symptoms. The data reviewed by A & Z, then, are consistent with the view that stress exposure can lead to the biochemical abnormalities associated with depression. The data called upon to support this view, as well as to support more traditional theories, however, are all either correlational or post hoc, and where this theory and those which have come before it break down is in their inability to account fully for the facts that (1) individuals prone to depression but not actively depressed have perfectly normal biochemical characteristics, and (2) inducing the biochemical abnormality in the absence of depression-causing events or stimuli has never been shown to result in true depression. In the first case, A & Z argue that it is the stress response of the depressive that is critical, rather than its baseline biochemical state. Thus, within the A & Z framework, in nondepressed states the depressive would appear normal but would become biochemically abnormal when exposed to stress. This is an advance over earlier theories, which could not account for the normal biochemical profiles of nondepressed depressives. However, neither the A & Z hypothesis nor the older ones

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

111

Commentary/Anisman & Zacharko: Depression and stress

can account for the fact (no. 2 above) that inducing the biochemical alteration first does not lead to depression; and demonstrating that phenomenon would be critical to all of those theories, since they posit biochemical causation for depression. There have been numerous attempts to cause emotional states with purely physiological manipulations, beginning with such workers as Maranon (1924) and Cantril and Hunt (1932) and continuing until today (see reviews in Leshner 1977; 1978). Those attempts have always failed. In the early days, this failure led Cannon (1915) to propose an opposite sequence of events; namely, that emotion causes physiological alterations rather than the reverse. That failure has led me to propose another sequence of events in the relationship between physiological events and emotional states (e.g., Leshner 1977), which I extend here to the case of depression. What I propose is that the relevant biochemical abnormality does not directly cause the depressed state. Rather, I argue that it merely maintains or prolongs depression. My position is that an environmental event, perhaps a stressor, first causes the emotional response typical of depression. That emotion normally subsides relatively quickly. However, there are some individuals who react to emotion with an unusual series of biochemical changes, and suffering those biochemical abnormalities then prolongs the emotional state, in a way involving positive feedback. Thus, the sequence I propose is: environmental stimulus* emotional state* biochemical response* prolonging of the emotional state. This sequence differs from that proposed by A & Z, using their conceptualization involving stress, as follows: Whereas A & Z propose that a stressor first leads to a biochemical change, which in turn leads to depression, I argue that the same environmental stressor first leads to an emotional state, the concomitant of which, in some individuals, is to suffer a biochemical alteration; this in turn prolongs and perhaps exaggerates the initial emotional response, with positive feedback. The first, and critical, question then becomes whether my notion fits the extant data better than does the more traditional view. Both sequences are consistent with the data usually cited when one is considering the role of biochemical events in depression: First, in both cases depressives would be expected to have unusual biochemical characteristics when depressed. Second, drug treatment would be expected to be effective in both cases, although in A & Z's model, drug treatment works because it prevents or reverses the biochemical state causing the depression, whereas in my view, drug treatment is effective because it breaks the positive feedback loop maintaining the depression. However, whereas neither A & Z's nor more traditional views can deal with the fact that physiological manipulations alone are totally ineffective in causing depression, the view proposed here can. One would not expect purely physiological manipulations to induce depression because the causal factor in depression is not a biochemical change - it is an environment event, and the biochemical change, with its behavioral consequences, occurs only after the onset of the emotional state. It should be emphasized that I am not simply resurrecting here the long-dead James-Cannon controversy about the physiology of emotion (cf. Leshner 1977). I am not suggesting that those who believe that a physiological abnormality leads to depression are wrong, whereas those who argue that physiological changes only follow, and do not contribute to, emotional activation are right. What I am suggesting is that neither simple sequence is correct; the correct sequence is probably much more complex than either view would have it. I have argued this kind of view elsewhere for the general cases of emotion (Leshner 1977) and as a general principle of the complex relationship between hormones and behavior (Leshner 1978; 1979). There is not enough space here to present the relevant data yet again. What I would hope is that some investigators actively studying the question of the role of physiological factors in depression would entertain this alternative hypothesis as a workable one, and begin to test it empirically. NOTE The views in this paper are those of the author and should not be construed as representing the official position of the National Science Foundation.

On the utility of stress as an explanatory concept

David Lester
Department of Psychology, Richard Stockton State College, Pomona, N.J.

08240

The argument proposed by Anisman and Zacharko (A & Z) may be summarized as follows: (1) stress is a precipitant of depression, (2) depression has particular neurochemical concomitants, (3) stress has similar neurochemical concomitants, and (4) therefore, stress provokes depression by means of these neurochemical mechanisms. Stress as a precipitant of depression. A & Z note that stress has been shown to lead to ulceration, heart disease, affective disorders, the development of neoplastic diseases, and other disorders. They note that life-stress events, in particular, have been found to precede both depression and schizophrenia (though the incidence of such events was higher in depressed persons), and that life-stress events precede both reactive and endogenous depressions. It becomes critical, therefore, to ascertain the conditions under which stress leads to each kind of disorder. A & Z mention in passing several explanations of this plethora of stress-related disorders. First, these different disorders may be related physiologically. Second, individual responses to stress may differ depending upon previous experiences or present environment. But a passing reference is hardly sufficient. It is critical to identify which stresses lead to which disorders in which individuals in which circumstances. It is critical to do this, for unless we do so, stress loses its explanatory power. We are left with statements of the form "Stress precedes disorders," which by itself is not a very powerful proposition. We might well replace the word "stress" by a word like "experience," particularly since Selye has distinguished between good stresses (eustress) and bad stresses (distress), leaving only neutral stresses unmentioned. All events are stressful. It is interesting to rephrase several well-known theories using the concept of stress. Henry and Short's (1954) proposition that experience of physical punishment leads to assaultive life-styles whereas experience of love-oriented punishment leads to self-destructive life-styles could be rephrased as: Stress leads to assaultive life-styles and stress leads to self-destructive life-styles - a rephrasing that loses most of the original theory. Or the double-bind theory of schizophrenia may be rephrased as: Stress leads to schizophrenia. This comment becomes more pointed since A & Z state that stress of separation is most salient for depression. We can question the usefulness of the word "stress" here. What does its use add to the conclusion? A statement that experience of separation is found more often in depressed people than in nondepressed people says as much, and avoids the use of the word "stress." Since the different disorders may be caused by different stresses, one way out of this dilemma may be to define which experiences lead to which disorders, and, when we do so, we can clearly dispense with the word "stress."

112

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

CommentaryI'Anisman & Zacharko: Depression and stress

The neurochemical concomitants of depression and stress.

A & Z note that depression has been associated with a norepinephrine deficiency, a serotonin deficiency, and deficiencies in other central neurotransmitters such as acetylcholine and dopamine. Similarly, uncontrollable acute stress has been found to lead to deficiencies in norepinephrine, dopamine (in some regions of the brain), and serotonin, but to increases in the levels of acetylcholine. This proposed physiological basis for the stress-depression relationship raises several problems. First, some biochemical theories of schizophrenia (for example, Snyder 1974) are based on the neurochemical concomitants of increased levels of norepinephrine and dopamine. Thus, schizophrenia and depression are contrasting behaviors. It would be difficult (neurochemically) for both to occur at the same time in the same individual. However, diagnoses of schizoaffective disorders imply an inability to distinguish between the two major syndromes of schizophrenia and psychotic depression. Furthermore, surveys of untreated psychotic depressed patients often report a high incidence of typically schizophrenic symptoms (for example, Rennie 1942). However, leaving this problem aside, if life-stress events are found to precede both depression and schizophrenia (Beck & Worthen 1972; Jacobs, Prusoff, & Paykel 1974), how do we explain the stressschizophrenia association neurochemically? Finally, the neurochemical concomitants of stress that are necessary for the stress-neurotransmitter-depression association to be supported are found only for acute uncontrollable stress. At this stage of research, can it be demonstrated that the stresses found to precede depression are acute and uncontrollable? For example, experience of early separation is found to be frequent in depressed patients. Is early separation an acute uncontrollable stress? Possibly yes. Could the reason that double-bind communications may precede schizophrenia but not depression be that double-bind messages are chronic stresses rather than acute stresses? Stress as a distal variable. Stress is an easy variable to measure at a distal level of analysis. That is to say, we can subject a laboratory organism to an objectively defined stress, such as electric shock of a given duration and intensity. We can quantify the recent life-event stresses with a scale. But the intensity of a stress is clearly subject to individual perceptions and evaluation. The death of a spouse is not 100 points of stress for all widows and widowers. To measure the subjective level of stress (a proximal variable) is more difficult, but it would be more meaningful. At this proximal level of analysis, the intensity of the stress and the type of stress as well as a knowledge of the type of individual, are critical. The stress of a promotion, for example, will be different in intensity and type for a person low in self-confidence than for a person high in self-confidence. As long as research into stress stays at a distal level of analysis, it is likely that its incorporation into propositions will remain less than fully informative.

Schizophrenia, not depression, as a result of depleted brain norepinephrine

Stephen T. Mason
Department of Physiology, The University, Sheffield S10 2TN, England

Anisman and Zacharko (A & Z) suggest that stress may challenge brain norepinephrine (NE) systems to the point that they fail, causing what Ritter, Pelzer, & Ritter (1978) have elsewhere termed a "functional lesion." The question then is what sort of mental pathology would result. A & Z suggest that "depression may be a result of brain NE depletion." I have elsewhere suggested that a more likely result is a subset of some of the symptoms seen in schizophrenia (Mason 1979a; 1981).

One way to decide what mental pathology would occur after loss of brain NE function is to examine the behavioral effects of NE depletion caused in experimental animals by the neurotoxin 6-hydroxydopamine (6-OHDA). Rats injected bilaterally in the dorsal NE bundle with 4 fig of 6-OHDA dissolved in 2 /ul of saline-ascorbate solution show depletions of more than 95% in the NE content of the cortex, hippocampus, and other forebrain areas (see Mason & Iversen 1979). These animals, when examined behaviorally, show unimpaired learning of many simple tasks (Mason 1979b) but are resistant to extinction (Mason & Iversen 1975) so that they continue responding in the face of contrary environmental influences. Such NEdepleted rats are only impaired in learning complex tasks, such as a multiple choice-point maze (Leconte & Hennevin 1981) or visual-discrimination tasks and their reversals (Mason & Iversen 1977). Similar alterations in complex cognitive processing without global learning deficit have also been seen in primates following alpha-receptor blockade with aceperone (Ridley, Haystead, Baker, & Crow 1981). One analysis which accounts for these behavioral deficits suggests that NE depleted rats are deficient in filtering out irrelevant environmental stimuli. This is the attentional model (Mason 1980) based on the notions of a Broadbent selective attention filter (Broadbent 1958) and its detailed application to rodent discrimination behavior (Mackintosh 1965; Sutherland 1964). Rather than attempt to review here the extensive evidence implicating NE in selective attention, I refer the reader to Mason (1980; 1981) for a rigorous treatment. A pathology of attentional processes has often been suggested in the history of theory of schizophrenia. Kraepelin (1923) noted that patients "let their thoughts wander without voluntary control in the most varied directions" and showed "an irresistible attraction of the attention to casual external impressions." Failure to filter out irrelevant stimuli leads schizophrenics to show overinclusive thinking and an inability to preserve the conceptual boundaries which normally act to exclude distantly related material (Cameron, 1938a; 1938b; 1939a; 1939b). On object-sorting tasks schizophrenics include more attributes of the objects than normals (Payne & Friedlander 1962; Payne, Ancevich, & Laverty 1963). NE-depleted rats are more distractable by external stimuli than normals (Roberts, Price, & Fibiger 1976; Mason & Fibiger 1978a), and this parallels similar reports on enhanced distractability in human schizophrenic patients (Chapman 1956; Salzinger, Portnoy, & Feldman 1966). NE systems project to many sensory relay stations and play a direct role in reducing transmission along these pathways. Thus, NE projections to, and alteration in transmission across, the lateral geniculate nucleus in the visual system (Nakai & Takaori 1974), the dorsal cochlear nucleus in the auditory system (Chikamori, Sasa, Fujimoto, Takaori, & Matsuoka 1980) and the trigeminal nucleus in the somatosensory system (Sasa & Takaori 1973) have been reported, as well as changes in olfactory (Sobrian & Cornwell-Jones 1977) and pain processing (Segal & Sandberg 1977). This raises the possibility that the hallucinations of schizophrenics may be due to the penetration into sensory systems of random noise which would normally have been filtered out by NE systems. The resistance to extinction seen in rats after forebrain NE depletion (Mason & Iversen 1975) parallels the behavioral inflexibility of schizophrenic patients and is truly a cardinal feature of the NE-depleted rat (as shown by Thornton, Goudie, & Bithell 1975; Tremmel, Morris, & Gebhart 1977; Owens, Boader, & Gray 1977; Plaznik & Kostowski 1980; and Ashford & Jones 1976). This generally consists of continued responding when reward is withdrawn (but see Mason & Fibiger 1978b; 1979). While the analogy with schizophrenia is clear, such inappropriate overresponding would not be thought to be a sign of depression.

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

113

Commentary/Anisman & Zacharko: Depression and stress

Space prevents a more inclusive exposition of the parallels between human schizophrenia and the behavior of NEdepleted rodents, but reference may be made to Mason (1979a; 1981). Despite the many dangers of extrapolating from animal to human behavior, it does not appear that NE depletion gives rise to a "depressed" rat. Lest the motor depression, failure of grooming, rearing, and, forward motion seen in early reports of 6-OHDA treatment (Everts, Uretsky, Iversen, & Iversen 1970) be invoked, let it be stated that these effects are now acknowledged to be due to dopamine, not NE, loss (Smith, Cooper, & Breese 1973). Surely, it has been argued, the fact that classical antidepressants, such as the tricyclics, block NE reuptake and hence increase the availability of NE in the synapse indicates that the basic pathology in depression is a deficit in NE function. Recent work has suggested that additional effects of these drugs may correlate more closely with the time course of clinical action. Thus, a downward regulation of postsynaptic beta receptors has emerged as a common effect of many antidepressants (see review by Maas & Huang 1980). The net effect of the opposed processes of a block of NE inactivation by reuptake and fewer NE receptors postsynaptically is less transmission through the NE system. This has been shown electrophysiologically by Huang (1979) and Huang & Maas (1980) for the final effect on the postsynaptic activity of hippocampal cells; the behavioral effect has been demonstrated in Sue Iversen's laboratory by Wilner & Montgomery (1980) for a behavior known to be under the control of the final output from NE systems, the rate of runway extinction. In this view depression results from an overactivity of NE systems. On the selective-attention model of NE function this would be exactly what might be expected from such an overactivity of NE systems. The patient is actively filtering out most environmental stimuli, including those which by previous association with reward have acquired secondary reinforcing value. Thus, a decrease in well-being will occur as a result of "secondary-conditioned anhedonia" - that is, a failure of the pleasurable stimuli of life to get through. A & Z suggest that mild stress may increase NE function and that perhaps this would be a suitable stimulus to precipitate depression; but more severe or inescapable acute stress, which depletes NE causing a "functional lesion," would seem on the above data more likely to give us a schizophrenic, rather than a depressed, patient. major. There are some strong points which I will also highlight. There is by now considerable evidence linking certain kinds of life events and depression in humans. The studies are not entirely consistent and there are some methodological problems, but the trend is clear. Obviously this does not mean that all persons experiencing such events will develop clinical depression or that all patients with depression have a history of such events. Also, it is not a matter of "stress" in a general sense, and hence the use of this word in the title is unfortunate. Certain classes of events, i.e., separation or exit-type events are particularly high-risk events. A & Z do acknowledge this in the target article. These aversive events probably act to precipitate depression in vulnerable individuals. Vulnerability can be defined on a number of grounds including genetic, developmental, neurobiological, and environmental. We need much more data to further define the relative contributions of each of these factors (and others) in determining vulnerability. There is an unfortunate tendency in some quarters to view major depressions as largely unrelated to environmental or interpersonal events. Dogmatic assertions are made that there is no connection between (for example) separation and depression. Such statements are made in the context of genetic and neurobiological theories of affective disorders, and of the fact that most people, when subjected to aversive life events, develop grief reactions but not clinical depression. The latter is true but does not mean that certain life events cannot be major precipitating events when interacting with vulnerability factors. One such factor may be the inability to cope, i.e., the feeling of helplessness. Another may be a genetic predisposition, but I will not focus on this aspect in this commentary. To supplement A & Z's article, one could ask what makes people unable to cope. Theoretically, if people could cope the subsequent neurochemical changes and resultant depression would not occur. In rare instances, the event itself may be so overwhelming that coping is impossible for anyone, (e.g., widespread slaughter). However, in most instances, feelings of helplessness and hopelessness in the face of "stress" are developmental in origin. I use "developmental" here in a psychodynamic sense. It is not a negative criticism of A & Z's article to say that this wasn't covered, because that was not its stated purpose. However, to understand more fully the "stress-failure-to-cope-neurobiology-depression" linkages, one should also understand some psychodynamics. To oversimplify, feelings of inability to control events and feelings of helplessness in the face of stress arise from failure to develop adequate ego identity or self-esteem in the process of development, i.e., an adequate appreciation of one's self and confidence in one's ability to cope. Without this, one is more vulnerable to certain stressors. One of A & Z's important points is that depressions should no longer be classified in terms of the presence or absence of environmental precipitants. I agree. In integrating theories which we and others have presented elsewhere, depression(s) can be viewed as the final common pathway(s) involving interactions among many different kinds of variables. In this context, the contribution of life events is independent of the kind of depression. They do or do not occur in any kind of depression. A heavily "endogenomorphic" depression can (or cannot) be precipitated by aversive events as much as a milder "neurotic" one. An emerging body of literature, some of which is reviewed in A & Z's article, is beginning to identify in animal models neurochemical sequelae of certain stresses that may also serve as important substrates in depression. There is nothing new in the part of this paper that deals with the neurochemical concomitants of depression. This is by far the weakest section of the paper, but, on the other hand, it is not intended as the paper's major contribution. This article, like too many other reviews, focuses excessively on norepinephrine and serotonin and gives only lip service to other neurotransmitter systems. For example, newer developments in the

Coping, depression, and neurotransmitters

William T. McKinney, Jr.
Department of Psychiatry, University of Wisconsin Medical School, Madison, Wis. 53706

In their target article, Anisman and Zacharko (A & Z) attempt to review the stress-depression literature in humans, the learned-helplessness controversies, the neurochemical concomitants of depression in humans, and the neurochemical concomitants of stress in animals. As they state in their abstract, they are proposing that stress, especially uncontrollable stress, increases the demand on coping mechanisms and specifically leads to depletion of norepinephrine and serotonin and that these changes may be the mechanism whereby stress provokes depression in humans. Each of these represents large and complex research areas, and it would be impossible in one article comprehensively to review any one of them, let alone all of them. A & Z's attempt is to bridge research areas. I consider this a worthy goal and a particularly important one with illnesses as complex as depressive illnesses. The task of bridging these areas is particularly difficult because of the shifting foundations available for the bridges. Each of the basic areas is still in considerable flux. It is, therefore, not surprising that there are omissions, and I will mention only those I consider 114

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary/Anisman & Zacharko: Depression and stress

field, such as sleep studies, neurophysiological data, neuroendocriiK- challenge tests, and circadian rhythm studies, are not even mentioned. The concept that 5-HT depletion may not directly cause depression but may be a predisposing factor for the illness is credited to van Praag and deHaan (1980). Prange et al. (1974) were major contributors to the development of this "permissive hypothesis." The most interesting aspects of A & Z's paper concern the neurochemical concomitants of stress. A & Z highlight the variable of uncontrollability and show how a variety of animal studies suggest that uncontrollable stress in animals can deplete NE, 5-HT, and DA and increase ACh. However, A & Z frequently fail to make clear which species of animal is being discussed. Interestingly, these effects are age-related, being more pronounced in older animals. Likewise, the fact that prior experience with uncontrollable stress can sensitize neuroehemical systems to subsequent stress provides corroborative evidence for our clinical experience and data with depressed patients. Behavioral coping mechanisms in humans can fail if the stress is severe enough, but they will fail more frequently for personality-developmental reasons at stress levels which don't affect others. Neurobiological changes seen in depression could be viewed as derivative or secondary phenomena in this context. This does not mean that they are unimportant as substrates, but it does mean that their etiologic significance is that of mediating mechanisms. In other situations it is likely that the status of the neurotransmitter systems at the time the stress is encountered may influence one's ability to cope rather than the lack of coping driving the neurotransmitter systems. In other words, the arrows can go both ways. The status of neurotransmitter systems may, in turn, be determined by a combination of genetic and developmental events. We do not yet comprehend, and certainly do not have adequate data, about these various theoretical possibilities. From a therapeutic standpoint, the implication is that both pharmacotherapy (or electroconvulsive therapy) combined with some kind of psychotherapy focused on personality/developmental/ interpersonal coping strategies is critical. It is interesting to wonder how much of the differential neurochemical reactivity to different kinds of stress could be altered by attention to how the person behaviorally/cognitively/intrapsychically deals with stress. Adaptive failures can occur for behavioral or neurochemical reasons and could potentially be reversed by either means. We all need to continue to struggle with the development of conceptual models that will help integrate multiple levels of explanation for illnesses as serious as depressions and serve as a basis for future research. Closed-system or deterministic explanations are no longer sufficient to explain such a complex set of illnesses. that "stress will be considered the behavioral and physiological response to actual or impending stimuli." Throughout the body of the paper, however, the term is clearly used to refer to the stimulus situation rather than to the response elicited. This inconsistency is particularly surprising in view of the authors' stated awareness of the problems of definition. A & Z write that they know of no adequate definition of stress. A major problem here is that the word has acquired negative attributions, which are also implicit in the way these authors use the concept. The assumption that stress is bad for you, an assumption which is implied in modern workenvironment legislation, leads inevitably to several paradoxical situations. Most, if not all, individuals seek stress in some way, whether it be by climbing mountains or by visiting amusement parks. More constructive discussion might be encouraged by disposing of the word altogether. Stress as described by Selye (1936) is a nonspecific response of the organism to diverse novel or threatening stimuli. This classical definition demands a nervous substrate which receives inputs from all peripheral sensory systems and from central processes. The general-activation theory of Moruzzi and Magoun (1949) describes just such a system. The brain stem reticular formation receives inputs from peripheral and central sources and produces EEG activation as well as muscular, autonomic, and behavioural changes. From our point of view, the response aspect of the term "stress" may be replaced by the concept of general activation. Similarly, the stimulus aspects of stress may be described as any stimulus that produces general activation in the organism. In general, activation is the response to any stimulus that has properties of novelty, threat or conflict, or homeostatic imbalance. Whenever the actual value differs from the set value of any variable controlled by the central nervous system, activation will occur (see Ursin 1978 for an expansion of this argument). The general-activation concept has fallen into some disrepute because of the lack of correlation between different psychophysiological indices commonly used. This lack of correlation between classical psychophysiological indices should hardly be surprising in view of the fact that most are dually innervated, by the sympathetic and parasympathetic nervous systems. However, the endocrine system is also involved in activation, and the relatively recent development of inexpensive and reliable assay techniques for various hormones may present us with a new opportunity in this area. It follows simply from general-activation theory that the stress response is general and nonspecific, and that there is a wide choice of somatic and endocrine indices that could be used as a measure of "stress." The simplest operational definition of stress, therefore, is that it is the process which produces a change in your own favorite physiological parameter. However, confusion will be avoided if it is realized that, whichever measure is chosen on practical and theoretical grounds, it is only one of many possible indicators, and not necessarily the most interesting from the pathogenic point of view. This process will also affect brain neurochemistry, and it is these changes which A & Z refer to as the stress response. The problem, however, is to be able to describe precisely when this process is healthy and when psychological or physiological damage may occur. The physiological response (activation) provides the animal with the motivation or drive to cope with its environment appropriately. The stress response is therefore as important to the individual's well-being as is the ability to perceive pain, although in acute situations it might be associated with a strong negative affect. At the same time, data from sensorydeprivation studies and the common phenomenon of sensation-seeking behaviours indicate the rpere positive aspects of the stress response. There are, however, such things as stress-induced diseases, and many psychosomaticists would argue that there are few disorders which are not precipitated
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Stress as activation
Robert Murison and Holger Ursin
Institute of Physiological Psychology, University of Bergen, 5000 Bergen, Norway

Anisman and Zacharko (A & Z) have provided us with a useful and long overdue review of the putative relationship between changes in brain chemistry and clinical depression, and also with a comprehensive summary of the animal literature on the neurochemical effects of aversive stimulation. In bringing these two areas together, they have also emphasized the importance of the subject's previous history and experiences as factors which may determine the response to later aversive situations. This seems to us to be a praiseworthy extension of a basic psychosomatic concept into the field of neurochemistry. With regard to the definition and use of the term "stress," however, A & Z seem to have added to the general confusion rather than resolving the issue. In their definition, they state

115

Commentary/Anisman & Zacharko: Depression and stress by the stress response, or affected by earlier stressful experiences. Stress-induced disease will occur when the activation is sustained, i.e., when activation-dampening mechanisms fail to come into play. We believe that sustained activation is also the important variable for the A & Z model of depression, and we also agree with them that coping is one way to avoid the pathological effects of stressful situations. The question is why coping should protect the individual. Coping may be operationally defined in terms of the subject's endocrine response (activation) to repeated exposure to the stress stimulus. It is important, therefore, that the individual not only master the situation, but that he also perceive his own mastery. When animals or humans have learned that they have mastered the situation, they exhibit a decline in their endocrine response to subsequent exposure, this decline being not necessarily correlated with improved performance (Coover, Ursin, & Levine 1973; Berger, Starzec, & Mason 1981: Ursin 1978). On the other hand, if an animal learns that there is no way to control aversive stimulation, subsequent exposures lead to sensitization of the adrenocortical response, not only to the aversive stimulus but also to novel environments (Levine, Madden, Conner, Moskal, & Anderson 1973). This may have consequences for the somatic effects of later stress stimuli (Murison & Isaksen 1980). As an alternative to coping, the human subject may employ psychological defense mechanisms. Whereas coping occurs over several trials, defense mechanisms operate at first exposure to the stress stimulus and involve perceptual distortion of the situation. Whereas coping leads to stable performance with minimal activation, the operation of psychological defenses has its own hazards in terms of reliability and safety. High scores on defense tests (Kragh 1960) are predictive of poor and unsafe performance in parachutists (Ursin, Baade, & Levine 1978) and divers (Vaernes 1981). High scores on the Kragh test also correlate with the cortisol factor in the subjects' endocrine activation response to stress stimuli (Ellertsen, Johnsen, & Ursin 1978). Other studies have suggested a relationship between cortisol and depression (Carrol, Curtis, & Mendels 1976). There is therefore some evidence for a connection between psychological defense and depression via the cortisol response. However, the widespread use of one-hormone/onesymptom studies should make us proceed with caution. The sustained-activation hypothesis for psychosomatic disease (Ursin 1980) and the model for depression described by A & Z are clear in their predictions of no pathology when the stress stimulus either is short-lasting or can be coped with. Danger occurs when the aversive situation is chronic and no coping occurs. The symptoms displayed will be a function of the predominant factor in the individual's activation pattern. If the predominant factor in the individual's activation response is catecholamine as measured in urine, one might expect the main effect to be on the cardiovascular system. If, on the other hand, the main factor is that of NE (norepinephrine) utilization in the brain, one might expect the main effect to be one of clinical depression. The important point is that the common process for depression and psychosomatic diseases is sustained activation, and it is this process which needs to be described and used instead of the misleading and unclear "stress." factors for illness, and with the biology of psychiatric disorders, often make merely token gestures toward a synthesis of research findings from these three fields. Confronted with the wealth of publications in each area, this course is only prudent. Consequently, Anisman and Zacharko's (A & Z's) attempt to link stress with depressive illness by means of catecholamine hypotheses of depression is laudable for its courage and is a most welcome stimulus to debate and future research. Unfortunately, the authors' daring is not always matched by their rigor. Their exposition suffers, at times, from ambiguous and inconsistent terminology and from incompletely elaborated causal sequences. In addition, they never satisfactorily argue that stress is strongly implicated as a risk factor for clinical depression. The causal sequence proposed by A & Z begins with stress and concludes with depression. But what is "stress"? A & Z's definition advises us that "stress" represents "the behavioral and physiological response to actual or impending aversive stimuli, ' whereas "stressors" refer to "personal life changes." In other words, "stressors" constitute phenomena occurring outside the organism; "stresses" constitute internal organismic changes. While this distinction seems serviceable enough, it is promptly ignored in the text proper. Thus, retrospective life-event studies in which depressed patients and nondepressed controls are interviewed regarding stressful occurrences in the period preceding the onset of the illness or the date of interview are said to assess "stress history" in the two groups of subjects. No. They measure "stressor history." A similar misnomer appears in the remarks on prospective studies. Implicitly equating stressors with stress while explicitly distinguishing between them misrepresents the true causal mechanisms examined in these studies and thereby obscures their potential contribution to an understanding of the psychosocial origins of psychiatric illness. In general, these nonexperimental investigations look for an association between recent routine life events and depression. Let's assume for the moment that their findings of a direct association are valid. Then, if A & Z elect to enlist these studies in the service of their argument, they must first address the question of how stressors, such as life events, are related to stress. Do stressors produce stress always, usually, or only sometimes? If only sometimes, the authors' model, to be compelling, should include personality or social characteristics that attenuate or augment the ability of given stressors to provoke stress. A & Z aim at a behavioral and neurochemical model that explains the demonstrated association between stress (or stressors) and depressive illness. Readers are left in grave doubt, however, as to where, when, and by whom this relationship has been demonstrated. A & Z assemble some supportive citations, only to demolish them with considerable acumen. Four types of studies are noted: (1) reports on the incidence of affective states in the aftermath of catastrophic occurrences; (2) studies of exposure to stressful life events among depressed patients and nondepressed controls, with data on patient exposure obtained after illness onset; (3) prospective studies of illness experience among previously depressed patients experiencing varying levels of stress (really stressors); (4) experimental work involving the administration of minor contrived stressors in an effort to simulate depression. No sooner are these studies summoned than they are dismissed for conceptual or methodological shortcomings. The value of the first and fourth types of studies is properly challenged because they provide only meagre information on the possible impact of mundane stressors experienced in normal nonlaboratory settings. The validity of retrospective studies is sensibly questioned because of the inadequacies and possible distortions in life-event recall; a caution about prospective investigations is also introduced. Given these shortcomings, A & Z fail to clarify why their synthesis and model-building efforts have been launched at this time. Invoking a familiar arithmetic, they

Documenting the association of stress (or stressors) with depressive illness

Richard Neugebauer
Gertrude H. Sergievsky Center, Faculty of Medicine, Columbia University; Epidemiology of Brain Disorders Department, New York State Psychiatric Institute, New York, N.Y. 10032

Investigators concerned with physiological (and, specifically, neurochemical) consequences of stress, with psychosocial risk 116
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary IAnisman & Zacharko: Depression and stress

suggest that the replication of a positive association across numerous studies, however imperfect, sums to a persuasive finding. But it is well to remember that the consistency of such results may represent merely extended repetition of the same errors of design or measurement. While A & Z dwell on problems of validity in retrospective studies, the reliability of life-event checklists is a psychometrically prior question and deserves some discussion. At least fourteen reliability studies of life-event inventories have been conducted (Brown & Birley 1968; Casey, Masuda, & Holmes 1967; Horowitz, Schaefer, Hiroto, et al. 1977; Hudgens, Robins, & Delong 1970; Jenkins, Hurst, & Rose 1979; McDonald, Pugh, Gunderson, & Rahe 1972; Rahe, Romo, Bennett, & Siltanen 1974; Schless & Mendels 1978; Steele, Henderson, & Duncan-Jones 1980; Thurlow 1971; Yager, Grant, Sweetwood, & Gerst 1981), with five using depressed psychiatric patients as subjects. The median reliability level for these studies was.43; only one result was above.60. (Among the nine other studies, only three reported levels above .70; the median level for the remainder was around .40.) This very low reliability of stressor measurement, combined with the consistently positive findings of a link between stressors and illness episodes in retrospective studies, suggests that this link is an illusion produced by recall artifacts or some other source of bias. At the very least, these reliability investigations preclude, at present, any simple presumption that stressors increase the risk of depressive illness. Prospective studies involving recall of quite recent events, using event interviews conducted prior to an illness episode, overcome many of the methodological hazards that plague retrospective investigations. Unfortunately, few prospective studies have been conducted to date. A & Z cite the work of Paykel and Tanner (1976) in support of the association of stressors and depressive illness. However, the results of another prospective study with Bipolar I patients produced largely negative results (Hall, Dunner, Zeller, & Fieve 1977). In the absence of a persuasively argued and documented case for an association between stress (or stressors) and risk of depressive illness, readers may wish to postpone judgment on the merits of the intriguing neurochemical and behavioral model proffered by these authors. As the sage John Selden remarked not long ago, "The reason of a thing is not to be enquired after, till you are sure the thing itself is so. We commonly are at what's the reason of it? before we are sure of the thing" (Reynolds 1892, p. 161). 1979; Ferster 1973; Lewinsohn, Youngren, & Grosscup 1979) might appear to have further muddied the picture. A & Z have not mentioned one attempt to integrate some of the apparently contradictory evidence, the "permissive" hypothesis of Prange, Wilson, Lynn, Alltop, & Stikeleather (1974), which postulated that depression and mania arose from fluctuations in functional catecholamine utilization superimposed on a chronic deficit in serotonergic function. Nevertheless, their attempt to coordinate a number of lines of reasoning and evidence and to show that biochemical and psychological events can be interrelated ranks with the contribution of Depue and Monroe (1978; Depue, 1979) as a landmark. They have made a good argument for the possibility that experience can effect neurochemistry. However, they have ignored the reciprocal effect that altered neurochemistry may have on the individual's perception of his experience, a sometimes circular interaction which makes cause and effect difficult to untangle. They have also failed to comment on how neurochemical alterations might interact with each other, and how these might be related to other symptoms and symptom patterns seen in depression; nor have they commented on the issue of differential diagnosis within the affective disorders. We would like to propose some ways in which some of these effects might take place. Behavioral (and, to some extent cognitive) theories of depression have been based on the individual's experience of rewarding (pleasurable) or punishing (aversive) events. Electrode studies of animal brain have suggested that brain stimulation which has positive or negative reinforcing properties (suggesting that it is experienced as pleasurable or aversive) can be localized to anatomically distinct brain regions (Olds & Olds 1962) and is subserved by particular excitatory and inhibitory neurotransmitters (Aprison, Hingtgen, & McBride 1975; Carlton 1963; Crow 1971; Poschel & Ninteman 1971; Stein 1974), the same transmitters which have been discussed in relation to depression. The relationships between the parameters of reinforcement and these neurotransmitters might be summarized as diagrammed in Figure 1. This pattern of relationships suggests that there are biochemical equilibria which could affect the individual's perception of "motivating" events. These equilibria - between excitatory and inhibitory inputs on the one hand and between the relative "saliences" of reward and punishment on the other - might well be disturbed by stress-induced transmitter alterations such as those which A & Z have described. In addition, preexisting imbalances - such as those which might be left over from earlier experiences or produced by genetic influences could also alter the individual's affective perception of environmental events. Examples that suggest these preexisting imbalances even in currently euthymic individuals are Sitaram, Nurnberger, Gershon, & Gillin's (1980) finding of cholinergic supersensitivity in depressed and formerly depressed patients, and the finding by several researchers that many patients who have recovered from depression still show abnormally low levels of 5-HT metabolites in CSF (Coppen, Prange, Whybrow, & Nogura 1972; van Praag 1977). Reward
o *S

Stress, learning, and neurochemistry in affective disorder

Katherine M. Noll" and John M. Davis"
'Psychology Department, Bmhurst College, Elmhurst, III. 60126 and "Research Department, Illinois State Psychiatric Institute, Chicago, III. 60612

Before the advent of somatic treatments for depression and mania in the 1940s and 1950s, the vast majority of theoretical approaches to the etiology of the affective disorders involved the individual's psychological reaction to various kinds of stressors. The success of somatic treatments, however, led to the postulation of biological factors in these disorders. The simultaneous elucidation of the catecholamine hypothesis of depression by Bunney and Davis (1965) and by Schildkraut (1965) was followed by the indoleamine hypothesis (Lapin & Oxenkrug 1969), and later by substantial evidence for the involvement of ACh (Janowsky, El-Yousef, Davis, & Sekerke 1972). As implied by Anisman and Zacharko (A & Z), these approaches have been seen as being in conflict with each other, and the recent contributions of the behavioral and cognitive theorists (Abramson, Seligman, & Teasdale 1978; Beck, Rush, Shaw, & Emery

Punishment

S S

Catecholamines

Acetylcholine

11

Serotonin

Serotonin

Figure 1 (Noll and Davis). Neurotransmitter relationships in the brain motivational systems.
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

117

Commentary/Anisman & Zacharko: Depression and stress

Reward Punishment ACh t Reward CAsl Punishment Inhibitory Excitatory ACh Reward CAs | Punishment Inhibitory Excitatory ACh t Reward CAs i Punishment ACh t

CAs

" I
W

5-HT 5-HT
2

5-HT

5-HT

5-HTi

5-HTi

5-HTi

5-HTi

Unipolar I Reward o Punishment AChf

Unipolar II

Hypomania

Depression

CAs |

Figure 4 (Noll and Davis). Patterns of altered transmitter functioning in Bipolar II affective disorder. \ = Functionally elevated; | = Functionally reduced; = Functionally unchanged. sion (Carlton 1963). Cholinergic agonists produce crying spells in affective patients (Janowsky & Davis 1979). Changes in these behaviors and functions in patients might be expected to parallel the particular neurochemical changes that underlie these patients' depression and could even be used diagnostically. The particular patterns of transmitter alterations, and their relation to various diagnostic subgroups, are proposed in Figures 2, 3, and 4. Thus, in all depressed groups, patients would be experiencing an excess of aversive experience over pleasurable experience, and thus would probably experience a great deal of stress even if there were not a large number of stressful events happening to them. Furthermore, these individuals would (correctly) perceive that these changes in their experience were internal, global, and stable, the characteristics of the learned-helplessness-generating cognitions proposed by Abramson et al. (1978). Their reward-maintained behaviors would extinguish (as noted by Ferster 1973; and Lewinsohn et al. 1979). Patients in the Bipolar II group, whose transmitter profile is postulated to be the most abnormal, have been observed by Dunner, Gershon, & Goodwin (1976) to have the highest probability of attempting suicide; this may be the same apparently unipolar, low-5-HIAA group observed by Asberg, Traskman, & Thoren (1976) to have a higher risk of attempted and completed suicide than other depressed patients. This paradigm shows how preexisting changes in nervoussystem chemistry might lead to a patient's experiencing of excessive levels of stress even in the absence of clearly stressful environmental events; combined with stress-induced further alterations in transmitters such as those proposed by A & Z, symptoms would be expected to grow progressively worse, and this is in fact what is frequently observed. A & Z have mentioned several possibilities for how an individual might be genetically predisposed to these neurohumoral disruptions, but have been vague as to what specific enzymes might be involved, or how these changes might produce the transmitter alterations. One possibility is a change in the calcium- and magnesium-dependent contractile protein responsible for the exocytosis of vesicles containing certain of the neurotransmitters. While NE, DA, and ACh are released by this calcium-dependent process (Berl, Puszkin, & Nicklas 1973), 5-HT and GABA are not (Katz, Chase, & Kopin 1969); and GABA and 5-HT have been found to be deficient in depressed patients (Gold, Bowers, Roth, & Sweeney, 1980). This might be the site of action of lithium ion; Birch (1973) observed that lithium binds to many calcium and magnesium binding sites in various enzymes, and has varying effects on their function. Another likely candidate is the enzyme choline acetyltransferase (choline acetylase), the activity of which is the rate-limiting step in the production of ACh. An individual who had more of this enzyme available (perhaps by inheriting more gene segments containing the DNA sequence for the enzyme) might show more elevated cholinergic function in response to

5-HT

5-HT

Unipolar III Figure 2 (Noll and Davis). Three patterns of altered neurotransmitter functioning in unipolar affective disorders, t = Functionally elevated; j = Functionally reduced; = Functionally unchanged. This also shows how changes in the functional activity of these neurotransmitters could lead to symptoms that in some cases differ between patients and in some cases are puzzlingly similar. For example, either depletion of catecholamines or an excess of ACh would lead to aversive events' becoming more salient to the individual than pleasurable events, while at the same time other functions controlled by these transmitters would show differences; a reduction in 5-HT in the absence of changes in the others might produce an individual generally more emotionally responsive (or labile, to use the clinical term) under normal circumstances and much more affected by stress-induced alterations in catecholamines or ACh. Alterations in various behaviors related to transmitter changes have been reported in the literature; for example, catecholamines appear to affect activity level (Seiden 1976), eating behavior (Booth 1968; Ungerstedt 1971), and sexual behavior (Brown, Brown, Kofman, & Quarrington 1978), among other things. Serotonin affects arousal (Hollister, Breese, Kuhn, Cooper, & Schanberg 1976), sleep (Koella 1974), and pain sensitivity (Lints & Harvey 1969; Lytle, Messing, Fisher & Phebus, 1975); ACh is significantly involved in memory (Davis, Mohs, & Tinklenberg 1979; Davis, Mohs, Tinklenberg, Pfefferbaum, Hollister, & Kopell 1978; Sitaram, Weingartner, & Gillin 1978), dreaming (Sitaram et al. 1980), and behavioral suppresReward citatory CAs| Punishment Reward Punishment ACh

ACh o CAsf

5-HTi
Mania

ibitory

5-HTi

5-HTj

5-HTi

Depression

Figure 3 (Noll and Davis). Patterns of altered transmitter functioning in Bipolar I affective disorder (the "Permissive Hypothesis"). | = Functionally elevated; I = Functionally reduced; = Functionally unchanged.

118

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary/Anisman & Zacharko: Depression and stress

stress (and on the other side of the coin, might also have a better memory). Treatments that brought the activity of this enzyme into the normal range might produce a subjective memory deficit for that individual, concomitant with recovery - and in fact many successful treatments for depression are accompanied by memory complaints by the patient. A final interesting possibility is presented by the evidence that neurons which will become part of the autonomic nervous system go through a period - parts of which last significantly beyond birth - during which the neuron can become either noradrenergic or cholinergic, and a variety of factors affect which neurotransmitter the cell will in fact "choose" (Bunge, Johnson, & Ross 1978). If this is true of the neurons that later affect the cholinergic-adrenergic balance proposed here, and if this period lasts into childhood in humans (and there is evidence of considerable neuronal plasticity in humans during the first several years of life), this might also be one of the ways in which childhood stress could produce adult predisposition to depression. Whether one emphasizes - as do A & Z - potential neurochemical determinants or the burdens on cognitive-phenomenological events (see Bandura 1981), such ruminations are the source of much human misery and may create or invite depletion of brain chemicals as well as altering the person's vulnerability to developing affective or physical illness. Hence, therapeutics that combine pharmacological interventions and guidance to change cognitive and life-style patterns will often surpass either approach used alone. For instance, despite thymoleptics, depressed persons usually need much clinical persuasion to resume social and recreational activities that have lain fallow. Third, an aspect of subjective stress nowhere discussed by A & Z involves perfectionism. In social-learning terms, this entails having set "acceptable" standards for oneself (and others) that are so high that the distribution of "acceptable" performances becomes thin. In a statistical sense, as compared to normative achievements of peers, the person's "failures" are clumped high, and there is a low-amplitude wide skew in the "success" direction. Even upon recovery from an acute affective episode (or reduction in objectively high external stress) it is no mean clinical feat to teach,' urge, model, and nag the patient to adopt personal performance standards that are more realistically in line with human fallibility. If this is not done, "B+" and "A" performances may remain subjective failures and hence stressors for the patient. (See Rosenthal & Bandura 1978 for a discussion of cognitive standards for self-regulation.) In early and preliminary data, derived from the self-report devices we are refining (in collaboration with Professor Bandura at Standord), we have been struck by the empirical concordance among the following: (1) diminution of leisure activities and interests (especially in physical exercise), (2) inability to resist complying with others' "urgent" demands, (3) inability to take breaks or slow down, lest one "waste" time, (4) inability to relax (without the aid of alcohol or drugs) after a long, hard day and (5) inability to concentrate attention on just one high-priority task without worrying about others not yet begun or checking on how much time has elapsed on the task (nominally) at hand.

Stress: Chicken or egg?

Ted L. Rosenthal
Department of Psychiatry, University of Tennessee College of Medicine and Memphis Mental Health Institute, Memphis, Tenn. 38105

Anisman and Zacharko (A & Z) present a good review of the growing knowledge and remaining ambiguities concerning the relations between stress and depression. Let me say at the outset that some major role for neurochemical (see Akiskal 1979) and genetic (e.g., Akiskal, Rosenthal, Haykal,.Lemmi, Rosenthal, & Scott-Strauss 1980; Rosenthal, Akiskal, ScottStrauss, Rosenthal, & David 1981) determination now appears beyond dispute in both the full syndromal and subsyndromal forms of affective disease. Likewise, the role of stress as at least a modulator and perhaps a cause of depression keeps gaining plausibility. Given such substantial agreement with A & Z's key views, I shall confine further comment to issues left unraised, and I shall examine them from the standpoint of a working clinician (with a few technical citations given to the scientific literature). In our experience at the University of Tennessee Department of Psychiatry's Stress Management Clinic, extant lifeevent scales do not allow sufficiently for the role of personal perceptions and values in assigning subjective weights to a (potential) stressor. For this reason, we are collaborating with Professor Albert Bandura to develop self-efficacy scales that can better index common sources of stress as subjectively weighted by the patient. Our reasoning is based on social learning theory (Bandura 1981; Rosenthal, in press) plus considerable clinical exposure, and it leads me to raise three matters from that vantage point which are ignored in A & Z's discussion. First, the effective impact of a stressor will hinge heavily on how well or poorly the patient deploys attention. For instance, endorphins may enter into somatosensory (and perhaps also visual and auditory) attentional mechanisms (see Davis, Buchsbaum, & Bunney, in press), likewise, clinically, when under duress and time pressures, patients typically surrender the leisure interests and other distracting activities, which they misperceive as "low-priority." These life events serve essential buffer functions and, when deleted, can hasten the development of an exacerbation cycle which may result in an affective episode, in cardiovascular strain, in gastrointestinal illness, etc. (For a discussion of attention, distraction, and depression see Rosenthal 1980.) Second, once the person's attention becomes "stuck" on stressful cues, a pattern of self-referent brooding, worrying, and negative self-evaluation is often observed clinically.

Is chronic stress better than acute stress?

Douglas K. Rush
Psychologisches Institut II, University DOsseldort, 4 DQsseldort, West Germany

In the first and second parts of their article, Anisman and Zarchako (A & Z) present evidence that (1) stress is a predisposing factor in the development of at least some cases of depressive illness and (2) depression is characterized by dysfunction of neurotransmitter systems. In developing an integrated position relating stress, depression, and neurotransmitter dysfunction in humans, A & Z in a third section examine studies of stress-induced neurochemical changes in animals. Their review indicates that acute uncontrollable stress (e.g., one hour of cold swimming or footshock) often results in maladaptive behavior, such as failure to escape from shock, whereas chronic stress (e.g., several hours of stress in a single session or several days of one-hour sessions) does not have this effect. Likewise, acute-stress treatment has been shown to result in depletions of NE, DA, and 5-HT and an increase in ACh, whereas changes in the levels of neurotransmitters are no longer observed following chronic treatment. Rather, an increase in synthesis and a reduction of reuptake occurs, changes which apparently act to normalize both escape/avoidance behavior and the levels of transmitters available at the synapse. Presumably because of the differential effects of acute and chronic stress on behavior and neurotransmitter levels, A & Z rely on the effects of acute uncontrollable stress to provide an
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

119

CommentaryI'Anisman & Zacharko: Depression and stress appropriate model for understanding the changes in neurotransmitter functioning that occur in human depression. An animal model based on chronic-stress effects is seen as less appropriate, although A & Z do suggest that some individuals may be unable, due to constitutional, environmental, or experiential factors, to compensate for the increased utilization of transmitters via increased synthesis, etc., and may thus show a depressive reaction when chronically stressed. An emphasis on the effects of acute stress as a model implies that less stress (acute) is more likely to result in the neurochemical changes leading to depression than is more (chronic) stress. In fact, at the end of the section on neurochemical concomitants of stress, A & Z suggest that chronic stress may reduce the symptoms of depression in the same way that certain tricyclic antidepressants do. Should one conclude that chronic stress might be an effective treatment for depression? An emphasis on the effects of acute stress as a model is at variance with the evidence that stressful life events are a precipitating factor in the development of depression. Such evidence implies that depression is more likely to occur with increasing stress - i.e., more likely with chronic than with acute stress. Experimental treatments and their effects in an animal model should reflect as closely as possible the etiological factors and symptomatology of the human psychopathology being modelled. Although presumed behavioral analogues of the symptoms of human depression in animals, such as impaired escape/avoidance, are not always found following chronic stress (Weiss, Glazer, & Pohorecky 1976 vs. Seligman & Groves 1970), few studies comparing the behavioral effects of acute and chronic stress have been conducted, and there is no clear consensus as to what forms of stress leading to behavioral impairment likewise induce changes in neurotransmitter systems (for a discussion of these issues, see Seligman, Weiss, Weinraub, & Schulman 1980). In terms of neurochemical disturbances in human depression, the physiological effects of chronic stress in animals may provide a better model than the effects of acute stress. For example, the study of the effects of chronic stress on neurotransmitter function could aid the search for variables predicting which individuals are predisposed to depression. A & Z suggested that not all humans suffering chronic stress may be able to compensate for increased utilization of neurotransmitters, and that those who cannot consequently become depressed. If there were a greater emphasis in animal studies on the effects of chronic stress, attention could be focused on those animal subjects who do not show the compensatory changes. A search for variables that predicted which subjects do not show these adaptive changes might also have some import for understanding which humans are unable to adapt neurochemically to stressful life events. (Such an approach would assume, of course, that it is changes in neurotransmitter levels that are responsible for depression.) In depressed humans, the only direct evidence for changes in the levels of neurotransmitters comes from post-mortem analysis of brain tissue. The only consistent result, according to A & Z, is that the level of 5-HT is reduced in depressed suicides. Most of the evidence indicating dysfunction of neurotransmitter systems in depressed humans stems from the analysis of metabolites in cerebrospinal fluid and urine and from knowledge of the biochemical effects of antidepressant drugs. Neither area provides unequivocal evidence for changes in transmitter levels. The failure to find changes in levels following chronic stress in animals should thus not rule out the possibility that chronic-stress effects may aid our understanding of human depression. Two areas of human depression research reviewed by A & Z suggest that more than changes in levels are involved. The first concerns the subpopulations of depressives who differ both in 3-methoxy-4-hydroxy-phenylglycol (MHPG) excretion rate and in which drug treatment has the best therapeutic effect. The second area of research centers on the effects of desmethylimipramine. Based in part on the finding that this antidepressant may exert its therapeutic effect by reducing NE, both Sulser, Vetulani, and Mobley (1978) and Maas and Huang (1980) have suggested that depression might be the result of postsynaptic receptor hypersensitivity. We can no longer rely on the notion that only changes in levels of neurotransmitters are correlated with or cause depression. Changes can occur in synthesis, reuptake, and degradation rates, in receptor sensitivity, and probably in other processes not yet understood. After having reviewed both human and animal studies, A & Z present an integrated theory relating depression, stress, and neurotransmitters. They conclude that depletion of amines under acute uncontrollable stress and the failure of adaptive compensatory mechanisms to maintain normal levels under chronic stress conditions may lead to depression. Certainly such a viewpoint is an advance in conceptualizing the relationships between stress, neurotransmitters, and depression. With increasing knowledge of the complexity of changes occurring in human depressive illness, a further extension of the theory proposed by A & Z is warranted. A more thorough examination of the neurochemical effects of chronic stress in animals may aid this extension.

Problems with a stress-depression model

William P. Sacco
Department of Psychology, University of South Florida, Tampa, Fla. 33620

Anisman and Zacharko (A & Z) have presented a comprehensive review and integration of findings in the area of stress and depression with special attention to neurochemical mediators. They have delineated some problems faced by a stressdepression model. However, the shortcomings of a view that focuses on the role of stress in causing depression warrant further attention. Specifically, the utility of such an approach is limited by problems of inconsistent use of terms, lack of consensus regarding measurement and quantification, and weak empirical relationships between life events and depression or other pathological states. Though in the abstract stress would seem to be related to depression, the relationship appears extremely complex and mediated by such a large number of variables as to render it a construct of limited explanatory value. A & Z indicate that they are not aware of any adequate definition of the term "stress." They define "stress" and "stressor"; yet their use of these and other terms (e.g., "aversive experiences," "aversive events," "stresses") is often far from distinct, and it is often difficult to discern conceptual and operational differences among terms. Take, for example, their statement that "aversive experiences give rise to behavioral attempts to cope with stress." Their definition of stress as "the behavioral and physiological response to actual or impending aversive stimuli" suggests that aversive experiences lead to behavioral attempts to cope with the response to the aversive stimuli rather than to attempts to cope with the aversive stimuli itself. A & Z's reference to uncontrollable stress is similarly confusing. Do they mean to refer to an uncontrollable response or an uncontrollable aversive event or are the terms meant to be interchangeable? "Uncontrollability" is another term that plays an important role in A & Z's conceptualization. They imply that uncontrollability is a function of the severity of the aversive insult and the success of behavioral coping mechanisms, terms that resemble Lazarus's concepts of primary and secondary appraisal (Lazarus & Launier 1978). But is severity and success at coping determined subjectively by the victim or by more objective means?

120

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Commentary/Anisman & Zacharko: Depression and stress

According to A & Z, individual differences "in response to stresses of equivalent severity would reflect the adaptability of the neurochemical system." The authors also state that cognitions of helplessness may be manifestations of the more central neurochemical changes they hypothesize. Sufficient evidence suggests that depressed individuals are likely to differ from nondepressed ones in their subjective appraisal of severity and success at coping (e.g., Garber, Miller, & Seaman 1979; Hammen & Cochran 1981; Hollon & Beck 1979). Thus, it would appear that A & Z must demonstrate that differences in subjective appraisals of severity of stressor and success at coping follow and reflect individual differences in neurochemical responding rather than preexisting differences in cognitive style. Perhaps because of problems in defining terms, stress researchers have found it difficult to decide how to measure "stressful" life events. Stress researchers still seek to determine which sample of stressful events is most important to examine and what level of stressfulness is associated with each event (Dohrenwend & Dohrenwend 1979). Events ranging in severity from loss of parent to daily hassles (Delongis, Coyne, Dakoff, Folkman, & Lazarus, in press) have been implicated in the stress-pathology relationship. Stress models must also contend with the fact that the evidence establishing a relationship between stressful events and depression or other disorders is weak. The following conclusions underscore this problem: "the general point remains that most stressful events are not followed by psychiatrically treated depression. Some are followed by other psychiatric disorders . . . or by somatic disorders, but many do not lead to any disorder at all" (Paykel 1979, p. 257); "it is by no means clear that research has demonstrated their [life events'] importance either in the etiology of psychiatric disorders or of physical illnesses" (Dohrenwend & Dohrenwend 1979, p. 119). In addition, most studies examining life events and depression suffer from various methodological flaws, one of the more important being the failure to use psychiatric or medical control groups to establish the specificity of a stress-depression relationship (Crook & Eliot 1980; Lloyd 1980a; 1980b). Further evidence damaging to a stress-depression model is provided by Warheit (1979), who examined the role of life events, coping resources, and depressive symptoms by interviewing a random sample of 517 community residents three years apart. By far the best predictor of depression scores at Time-2 was Time-1 depression scores. Availability of coping resources and occurrence of loss-related life events (Paykel Inventory: Paykel 1971) were significantly related to depression scores, but accounted for a much smaller amount of variance. Whereas Time-1 depression scores accounted for 44.57% of variance in Time-2 scores (24.95% unique contribution), losses contributed 9.83% (2.86% unique). Warheit's findings are not surprising in light of research demonstrating that clinically depressed states in depression-prone individuals often recur (e.g., Beck 1976). In an effort to deal with the weak relationship between life events and depression, a host of interrelated personal and environmental variables that may mediate the stressdepression effect have been postulated (e.g., Brown 1979; Paykel 1979). However, despite their heuristic value, the number of variables and the complexity of their relationships are formidable. Most would agree that easily identified severe stressful events such as the loss of a loved one often lead to grief reactions which are symptomatically quite similar to depression (DSM-III, 1980). However, in most cases, even such powerful events as object loss do not lead to depression (Clayton, Halikas, & Maurice 1972). Rather, it seems more plausible to conclude that in most cases various life events merely provide the context in which depression-prone individuals become depressed.

Stress, depression, and helplessness

Arnold D. Sherman and Frederick Petty
Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242

In attempting to assess the relationship between stress and depression, the commentator is invariably faced with one monumental problem - that the effects of stress on neurotransmitter systems in the human brain are essentially undefined. This problem can be circumvented by relying on studies of the neurochemical effects of well-defined stressors in animals. If the rat brain can be taken as an acceptable model for the human, one wonders why studies of the effects of chronic stress on rat behavior have been omitted from Anisman 6c Zacharko's (A & Z's) review, especially considering the substantial contribution that Dr. Anisman s lab has made to this area. Exposure to aversive stimulation does produce a transient escape deficit in rats which is not evident after chronic exposure to stress. Chronic stress, in the form of 20 days of alternating shock, food deprivation, swimming in cold water, water deprivation, tail pinches, being shaken, switching of cage mates, increased housing density, or isolation (Katz, Roth, & Carroll 1981) also produces only transient behavioral changes. In addition, nonbehavioral stressors (i.e., ether anesthesia) which result in a hypothalmic norepinephrine depletion which outlasts the anesthesia (Vellucci 1977) are without behavioral consequences. In light of this, one must conclude either that the rat is an unacceptable model for studies on stress and depression or that during some "stressful" situations some other factor is also present, and that this second factor may, in fact, be the one related to the precipitation of depression. Another indication that a second factor, actually related to depression, may be involved can be obtained from literature reviews. For example, at one point A & Z propose that sufficiently protracted and uncontrollable stress may result in neurochemical changes which are manifested as affective disorders. Later, they note that chronic stress has actions similar to those produced by antidepressants, and thus would eliminate some depressive symptoms. Thus, unless stress is both the cause and the cure of depression, a second factor might be present. Some of the reluctance to admit the possibility of a second factor's being present in some stress situations may derive from the assumption that "controllable stress" is really not very stressful, while "uncontrollable stress" is. Just the opposite is the case. More of the classical signs of the general adaptation syndrome (i.e., gastric lesions, changes in adrenal weight, thymus involution, and elevated 17-hydroxy-corticosteroids) were observed in the 1950s in the animals performing an avoidance task than in their yoked counterparts, who received identical shock that was uncontrollable by them. We performed a neurochemical study which differentiates between these two factors (Petty & Sherman 1980b). Animals were either stressed by being forced to acquire and perform an escape response ("executives") or received an equal amount of shock in a "yoked" paradigm. The "yoked" animals are thus exposed to equivalent shock, but a much reduced level of stress. In assaying the crude synaptosomal pellets derived from several brain regions for serotonin, two distinct patterns were clear. "Executive" (stressed) animals showed a slight elevation of serotonin similar to that seen after restraint stress (Curzon and Green, 1971). These changes dissipated in 24 hours. "Yoked" animals had decreased levels of serotonin in pellets derived from the septum and anterior neocortex. These decreases were returning to normal in five days, but were still significantly lower when compared either to unshocked controls or to "executives." Since no other neurotransmitter systems were measured, there is no evidence that this effect was specific to serotonin. This "second factor," neurochemically and behaviorally differentiated from "stress," was suggested almost 15 years ago

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

121

CommentaryVAnisman & Zacharko: Depression and stress (Seligman & Maier 1967). It is the separation of reinforcement from behavior leading to "helplessness." This state, although dismissed by A & Z as a "hypothetical cognitive change," is easily defined and measured in animals, who are the source of all of the neurochemical data on stress. Animals exposed to "uncontrollable stress" have a long-lasting behavioral deficit which can be reversed by chronic treatment with tricyclic antidepressants (Petty & Sherman 1980a), atypical antidepressants, or MAO inhibitors, but not major or minor tranquilizers or stimulants. Although one may argue about the cognitive aspects of helplessness in humans, failing to include this important theory (which has immense predictive utility) in a review involving studies on animals represents a considerable oversight. 1978). We observed no effect of chronic footshock on the concentration of NE required to elicit a half-maximal cAMP response (EC5o) in the cortex or hypothalamus; it is known that a reduced reuptake will markedly shift the NE-cAMP doseresponse curve to the left to produce a smaller EC30 (Kalisker, Rutledge, & Perkins 1973). The above findings have led us to conceptualize stress, depression, and central neurochemical changes in the following way (Stone, 1979b): When animals are first exposed to stress there is an excessive release of catecholamines as well as of other neurotransmitters and hormones. The release of these substances causes a variety of behavioral, emotional, and physiological reactions. A subset of these responses, involving changes in motivation and mood, comprises the phenomenon that we call depression. It should be noted that in this scheme NE depletion is held to be an index of high release and not, as A & Z propose, a deficit leading to impaired transmission. As animals are subjected to repeated stress a number of adaptive changes occur which reduce the impact of stress. One of these changes is a reduction in the function of adrenergic receptors. Others may include subsensitivity to endorphins and alterations in responsiveness to brain dopamine and serotonin. As these receptor changes develop, the animals show fewer adverse reactions to stress, and there is a corresponding reduction of depressive symptoms. We think that our theory has a number of advantages over the one presented by A & Z. First, our hypothesis offers a unified conceptual framework which fits together many diverse findings on stress, adaptation, depression, and antidepressant therapy. According to our view the various antidepressant agents, all of which are known to induce subsensitivity to NE in the brain, work by mimicking the biochemical effects of adaptation to stress at brain NE (and possibly other) receptors. By inducing subsensitivity, these agents may increase resistance to emotional stress in patients, and this process may facilitate recovery from depression. Antidepressant therapy can therefore be viewed as a unique form of adaptation to stress in which adaptive changes are produced without actually subjecting patients to stress. Second, our theory appears to agree more closely with the physiological actions of catecholamines. These substances are extremely potent, they are generally liberated in emergency situations, and when released excessively or for prolonged periods they are known to produce deleterious effects. Subsensitivity to catecholamines would therefore be expected to reduce adverse consequences of stress. Third, our view, like A & Z's, is in accordance with the time course of the relationship between stress and depression and also agrees with the time course of antidepressant therapy. When there is clear evidence of precipitation by stress - e.g., after object loss or loss of function - depression is usually an acute reaction which gradually diminishes with time. Although many cases of depression coexist with chronic stress, this may reflect a failure of adaptive processes rather than an etiological effect of the chronicity of the stress. Likewise, antidepressant therapy is generally effective only after several weeks of treatment, an interval similar to the time needed for adaptation and receptor changes to occur. Finally, our hypothesis is unique in that it predicts the effectiveness of antidepressants in a nondepressive disorder involving a high degree of stress - i.e., panic and phobic states such as agoraphobia.

Noradrenergic function during stress and depression: An alternative view

Eric A. Stone
Millhauser Laboratories, Department of Psychiatry, New York University School of Medicine, New York, N. Y. 10016

Anisman and Zacharko (A & Z) attempt a major synthesis of stress and depression based on central neurochemical changes known to occur after stress. Although they consider a number of mechanisms involving multiple transmitters, it appears that the central aspect of their argument concerns changes in brain noradrenergic function. Specifically, the depletion of brain norepinephrine (NE) after acute stress is held to be a sign of impaired neurotransmission that contributes to the etiology of depression, while adaptive changes of enhanced noradrenergic function after chronic stress are held to be restitutive processes leading to remission. We think that a good case can be made for the reverse series of changes - i.e., an excessive noradrenergic activity after acute stress followed by an adaptive decrease after chronic exposure. First, in the acute situation, the evidence indicates that the depletion of brain NE by stress does not lead to a decrease of NE release but rather to an increase. We have demonstrated this point in studies with forced running stress in rats involving measures of hypothalamic NE turnover based on the utilization of tritiated NE and the decline of endogenous NE after synthesis blockade (Stone 1971; 1973). The same effect (increased release during depletion) was found by Weiss, Glazer, and Pohorecky (1976) in the hypothalamus, brain stem, and telencephalon of rats subjected to uncontrollable shock stress. Similar findings were also reported in the rat brain stem during acute hindlimb ischemia (Stoner & Elson 1971; Stoner & Hunt 1976). Second, in the chronic-stress situation our evidence supports the occurrence of decreased noradrenergic function. We and others have found that chronic footshock or restraint stress leads to reduced postsynaptic sensitivity to NE in the rat cortex, hypothalamus, and brain stem (Stone 1978; 1979a; U'Prichard & Kvetnansky 1980; Torda, Yamaguchi, Hirata, Kopin, & Axelrod 1981). The chronic situation is made more complex because changes indicative of increased presynaptic function (elevated tyrosine hydroxylase [TH] activity and reduced reuptake) are known to occur. Our data suggest that these changes may be misleading, however. The increase in brain TH should lead to an increase in the amount of NE released by stress. We have not found this to be the case (unpublished experiments). Rats subjected to chronic footshock and having a higher brain TH activity do show increased resting-brain NE release but do not show augmented stressinduced release. If anything, these animals show diminished NE release in the brain stem and possibly the hypothalamus. The other presynaptic change, a decrease in reuptake, should prolong and enhance the action of NE at receptors. However, this action was not evident in our studies of the cAMP (cyclic AMP) response to NE in brain slices from stressed rats (Stone

Stress (whatever that is) and depression

Earl Usdin
Department of Health & Human Services, National Institute of Mental Health, Rockville, Md. 20857

The terminology in the Stress field is enough to cause depression. That which we are sure is stress (e.g., personal life

122

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Response/Anisman & Zacharko: Depression and stress

changes and physical or psychological trauma) is defined in this paper as "stressors," and that which we are sure is the response to stress (e.g., the physiological or psychological reactions to aversive insults) is defined here as "stress." If one were particularly sensitive, one might also become depressed by the fact that no simple correlation is proposed between changes in level of one neurotransmitter or other, but rather there seems to be the suggestion of some interaction(s) between levels of several neurotransmitters and various depression-related phenomena. It might be hoped that even if there are problems in the "softer" aspects, when we get to the neurochemistry of depression we will hit hard ground. But this just isn't so. Superimposed on the NE and 5-HT hypotheses are some involving ACh and DA; surely peptides would have been included if Anisman & Zacharko (A & Z) had waited but a short time in the preparation of their review. To confound the CNS results, differences are cited between results obtained from different tapping sites as well as with or without probenecid pretreatment. And should we look at HVA, 5-HIAA, or MHPG (or HMPG)? Ah, but if you decide that CSF studies are just too confusing, you may decide that urinary metabolite levels are your preferred variable. One cited report even concludes that there are no differences in urinary metabolites between depressed and nondepressed subjects. Of course, the A & Z review then goes on to cite a paper which shows that urinary MHPG levels are lower in depressed patients than in controls. But fear not: citations are then given to even later work in which no differences could be found, and even to other work indicating that it may require subclassification of depressive patients to reveal differences. Not only do different types of stress (again: whatever that is) produce different neurochemical sequelae, but so too (according to this review) do different lengths of time of stress, different numbers of stress applications (or should I write "stressor applications"?), and even differences in time of tissue sampling after stress. And, of course, there is a lack of consistency among cited reports. About the only conclusion I can draw is that we are not yet ready to reach definitive conclusions on the predisposing influence of stress.

interactions contributing to symptom profiles, it is not surprising that disentangling the relationship between stressful life events, neurochemical lability, and depression would not be simple. It is even less surprising that considerable disagreement and different focuses of attention would exist between the views we expressed and those of several commentators. Despite the shortcomings and inconsistencies in the stress-depression literature there is reason to believe that stressors contribute to depression through their actions on neurochemical processes. Although one might choose to offer alternatives or elaborations of our working hypothesis (Beck & Harrison, Hingtgen & Aprison, Stone), it is inappropriate to assume that provisional working models cannot be derived on the basis of available data (Usdin). Many of the commentators provided insightful and provocative suggestions that required modifying our working model and that certainly point to the need for multidisciplinary research. We have directed our response primarily to those issues which either appeared most frequently in the commentaries or appeared to us as most challenging. Limitations of space and time prevented a detailed discussion of several other issues. Stress as an elusive concept. The intention of our definition of stress was twofold. First, we wished to indicate that the concept is a vague one and that it is understandably difficult to provide a definition to which some investigators will not take exception. Second, we wanted to emphasize that stressful experiences should be considered, inter alia, in terms of the organism's ability to cope with those experiences. That an aversive event can be coped with through behavioral means does not rule out the fact that it is a stressor. An individual can certainly consider an aversive experience stressful regardless of whether or not control over that stimulus is possible. Likewise if one chooses to consider stress a physiological response to aversive stimulation then either controllable or uncontrollable stressors can be assumed to produce stress, even though these treatments may induce quantitatively (and perhaps qualitatively) different physiological effects. We had hoped that we could bypass semantic arguments and get to the gist of the problem, namely, the conditions that provoke or exacerbate clinical depression. If our expectation was not met, we suppose this might be considered a stressor hopefully depression will not ensue. Several commentators (de Catanzaro, Hamilton, Lester, Murison & Ursin, Neugebauer, Rosenthal, Sacco) took exception to our definition of stress and offered alternatives. De Catanzaro, for example, finds the term "stress" vague, and chooses instead to define "stressors" as "events threatening an organism's health and reproduction." Murison & Ursin suggest that the simplest operational definition of stress would be "the process which produces a change in your own [the experimenter's] favorite physiological parameter." Hamilton differentiates between stress as an agent and stress as an effect and suggests that agents be termed stressors and effects be termed strain. The combination of stressor and strain represents the load on an adaptive system. Sacco correctly indicates that stress should be considered in terms of subjective appraisal of environmental events.
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

Authors' Response
Stressing our points
Hymie Anisman and Robert M. Zacharko
Department of Psychology, Carleton University, Ottawa, Ontario, Canada K1S 586

The purpose of our target article was to sketch a mechanism whereby aversive events might increase vulnerability to clinical depression. As indicated by several commentators (Akiskal, Dimsdale, Lester, McKinney, Noll & Davis), the symptoms that characterize depression vary widely among individuals, and it might be more appropriate to consider the illness in terms of subtypes with some common underlying features. The pharmacological and biochemical evidence lends support to the contention that different neurochemical and hormonal factors subserve or are associated with these different subtypes of depression. In view of the diversity of symptoms which characterize depression and the potential for complex neurochemical

123

Response/Anisman & Zacharko: Depression and stress He also notes that we frequently interchange the terms stress and stressor, while Neugebauer appears to delight in this revelation again (and again). It is certainly essential to define operationally what is meant by stress; however, it appears that Neugebauer had little difficulty in recognizing those occasions in which we inappropriately used the term stress (or stressor). We were sorry that Usdin found the stress terminology depressing. He no doubt recalls the "Panel Discussion on Stress Theory" in the volume edited by Usdin, Kvetnansky, and Kopin (1980), in which the participants of the symposium were apparently likewise unable to reach agreement on an appropriate definition. Indeed, the proposal was made there that "we be as specific as we can when we use the word and that the definition of stress awaits the next Symposium on Catecholamines and Stress" (p. 586) (whatever that is). In general, it seems that some researchers prefer to consider stress in terms of physiological responses whereas others consider it in terms of subjective appraisal. Evidently, we all have an intuitive appreciation for the term stress although formulating a precise definition is difficult. Most investigators appreciate that by stress or stress reaction we mean the response to aversive events or stimuli associated with those events. To be sure, as indicated by Sacco, Rosenthal, and Lester, what is perceived as stressful by one individual may not be perceived as stressful by another. For instance, divorce or marital separation, which rate highly on most lifechange scales, may be viewed as aversive by some individuals but as a blessing by others. By the same token, occupational disengagement or, for that matter, dramatic changes in life style may be differentially construed by individuals. The experimental analysis of the contribution of stressors to pathology must consider the context in which the stressor occurs as well as the subjective response to it (Sacco, Rosenthal, Lester, Murison & Ursin). In this respect, it is significant that Seligman and his associates (e.g. Abramson, Seligman & Teasdale) have proposed several variables which may govern the cognitive changes brought about by aversive events and have emphasized that an individual's performance expectancy is an essential element in determining behavioral outcome. We are not in disagreement with this view and are surprised that several of the commentators perceived our view of stressors as being a narrow one (e.g., Rosenthal). Omission of potential stressors such as perfectionism (Rosenthal) and daily hassles (Sacco) stemmed from our reluctance to attempt an exhaustive list. Coping processes. In the study of coping processes, animal experimentation has chiefly involved comparing the behavioral and neurochemical consequences of controllable and uncontrollable stressors. In their discussion, Sherman and Petty reported that escapable shock produced an increase in 5-HT whereas yoked, inescapable shock produced a relatively persistent reduction in the concentration of this amine. This finding is reminiscent of the differential effects of escapable and yoked inescapable shock on central NE levels reported by Anisman, Pizzino & Sklar (1980) and by Weiss, Glazer & Pohorecky (1976). Sherman and Petty suggested that the independence of reinforcement from outcomes lead to a 124
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

state of "helplessness" that characterized or provoked the alterations of 5-HT levels. We have consistently maintained, as have Weiss et al. (1976), that control over aversive stimuli is an essential factor in determining neurochemical lability and behavioral outcome. However, we question whether it is necessary to invoke a concept such as "helplessness" to account for the differential outcomes induced by the two stress paradigms. It should be added that Sherman and Petty have provided impressive data showing that repeated treatment with tricyclic antidepressants eliminates the escape deficits ordinarily introduced by prior exposure to uncontrollable shock. However, such data can neither be taken to indicate that uncontrollable shock induces "helplessness" nor that the behavior of rats in a shuttle-box after exposure to uncontrollable shock represents a valid animal analogue of human depression. As with tricyclic antidepressants, L-dopa treatment, which is relatively ineffective in combating depression, has also been shown to counteract the performance deficits engendered by uncontrollable shock (Anisman, Remington & Sklar 1979; Anisman & Sklar 1979). We would like to believe that the behavior of rats or mice in a shuttle-box could be taken as representative of clinical depression in humans. Indeed, we have expended considerable effort in the past assessing the effects of controllable and uncontrollable events on neurochemical functioning and its relation to escape behavior. It seems, however, that, without resorting to cognitive interpretations, one can interpret the data derived from infrahuman studies comfortably on the basis of changes in response initiation and maintenance induced by uncontrollable shock (Anisman, Kokkinidis & Sklar 1981; Weiss et al. 1976). Moreover, as indicated by Dimsdale and by de Catanzaro, it is difficult to equate the consequences of shock applied to rats or mice with the complex stressors (including the antecedent events and subjective interpretations) encountered by humans. In considering coping styles, much of our discussion centered around the effects of controllable and uncontrollable shock in infrahuman subjects, with occasional reference to aggressive behavior as a means of coping. Of course, a great number of coping strategies are possible in humans. As we indicated in the target article, prior history in dealing with stressors will determine coping style; the availability of a buffer such as a close friend or confidant may diminish the impact of a stressor; even belief in God may represent a coping strategy. One of us, being airplane-phobic, makes (financial) deals with God before every flight. Thus far, God has religiously kept His side of the bargain, while the phobic renegotiates the terms of the contract at the termination of each flight (double or nothing?). Just as a given stressor may be variously perceived by different individuals, surely coping strategies are equally individualistic. Accordingly, it is commendable to develop a scale that allows one to assign subjective weights to a (potential) stressor and that considers whether behavioral coping methods are available to the individual (see Rosenthal). In their discussion, Murison & Ursin indicate that aversive stimulation increases endocrine secretion, but that once the animal learns (perceives) its mastery over the situation, the endocrine response declines. If animals learn they cannot control aversive stimulation,

Response/Anisman & Zacharko: Depression and stress further increases occur in the endocrine response. This raises an interesting issue bearing on the relationship between coping factors and amine depletion. (We have discussed this point elsewhere [Anisman & Lapierre 1981] but it warrants repeating.) What, specifically, provokes the catecholamine depletion provoked by an uncontrollable stressor? On the one hand, it can be argued that depletion only occurs when animals perceive that they have no control over environmental events. Alternatively, it may be argued that any aversive stimuli, if sufficiently severe and protracted, will provoke amine depletion, but that learning that behavioral control over the stressor is possible reduces the burden on neurochemical systems, thereby reducing the likelihood of depletion. The fact that Anisman et al. (1980) and Weiss et al. (1976) found that only uncontrollable shock provoked NE depletion does not imply that controllable shock will not produce such an effect, only that it is less likely to do so. Similarly, escape deficits are more pronounced after uncontrollable shock than controllable shock; but among some naive animals and some animals that received controllable shock, performance deficits may nonetheless be observed. The parameters of the test task, of course, determine to a great extent the frequency of escape failures. The point is that control over a given stressor does not assure that amine depletion and behavioral deficits will not occur. In a similar fashion, one can imagine that sustained aversive stimulation, or a series of "minor" stressors, whether controllable or not, could potentially influence affective state. Cognitive aspects of depression. If it appeared to the commentators that we overstated the case for neurochemical contributions to affective illnesses this stems from the fact that the major thrust of the target article was to describe the course of neurochemical changes provoked by stressors and some of the conditions that maximize these neurochemical events. Obviously any multidisciplinary approach to the analysis of conditions leading to depression should not ignore the potential contribution of cognitive processes to depression. In fact, we have indicated in several papers (Anisman 1978, 1982; Anisman & Sklar 1979) that cognitive processes or stimuli associated with a stressor may influence neurochemical state. There seems to be a belief (de Catanzaro, Beck & Harrison, Leshner) that we have adopted the view that neurochemical lability - and only neurochemical lability - determines whether or not depression will occur. This is simply not the case. Leshner proposes that stressors cause neurochemical depletions, which provoke depression. Therefore, it follows that drug-induced neurochemical depletion should provoke a similar depression. In effect, the equation here is that a stressor plus the ensuing neurochemical depletion should have effects comparable to that of neurochemical depletion alone (e.g. as induced by drug treatment). Although this may be applicable to the effects seen in a shuttle-box using rats or mice, it can also be argued that the neurochemical events associated with the stressor may provoke emotional repercussions that sustain or enhance neurochemical lability, which ultimately leads to depression. Certainly, the effects of the neurochemical depletion must be considered with respect to the background conditions in which they occur. For example, one could imagine that a catecholamine-depleting agent would have somewhat different quantitative and qualitative consequences under ideal versus unattractive environmental conditions. Both Burchfield and Rosentha! comment that the impact of a stressor not only involves an immediate cognitive reaction, but also the rumination and selfreferential brooding that may continue for some time after termination of the stressor. We have no quarrel with such an hypothesis. On the contrary, Anisman (1978, 1982) indicated that cognitive consequences associated with a stressful experience may exacerbate or invite further alteration of brain NE activity. As Bauer suggests, the alterations in neurochemical lability could create difficulties in initiating or executing a plan that is effective in dealing with environmental demands. Furthermore, it is conceivable that neurochemical status at any given time may also determine the individual's behavioral coping ability or perception of stressful events
(Kalat, McKinney, Noll & Davis, Sacco).

Although we assume interplay between neurochemical and cognitive events, caution must be exercised in describing the dynamics of such interactions. Leshner, for example, feels that our approach is too restricted. Rather than supposing that environmental stimuli biochemical change > depression, he suggests that environmental stimuli emotional state * biochemical response prolonging of the emotional state. But surely some neuronal events must have occurred when the environmental stimuli initially provoked the emotional state. As indicated earlier, we accept that an emotional state can exacerbate extant neurochemical aberrations. Perhaps the initial emotional state would not be clinically diagnosed as depression, and that only once rumination and its associated neurochemical states come into play would the full-blown depressive symptomatology be exhibited. Any way one looks at it, though, the initial stressor must be viewed as having neuronal consequences (whatever they may be) that ultimately lead to depression (Kalat). In addition to cognitive appraisal of stressful stimuli there exists a host of other factors that probably governs vulnerability to affective illnesses. Characteristics of the individual such as those described by Abramson, Seligman & Teasdale (1978) may be one set of factors that determine the way individuals perceive aversive experiences; and they may be determinants of the emotional state as well as the neurochemical consequences of an aversive experience. As we indicated in the target article, a great number of variables, including social factors, early life events, age of the individual and so forth, may all determine vulnerability to illness. Akiskal notes several additional factors which may act similarly. Moreover, as briefly indicated in the target article, and emphasized further by both McKinney and Akiskal, genetic factors should be considered when one assesses the contribution of stressors to the induction of depression. From our perspective, genetic predispositions might be viewed as greater vulnerability to neurochemical dysfunction given an appropriate set of environmental events. That is, inherited characteristics, including nongenetic factors such as in utero environment (see
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

125

Response/Anisman & Zacharko: Depression and stress Wahlsten, 1979), while not necessarily influencing basal neurochemical levels and activity, may under some circumstances affect the course of the neurochemical alterations that follow aversive experiences. Dimsdale, Laborit, and Noll & Davis suggest that the rate of cortisol secretion and the activity of enzymes involved in synthesis and degradation of transmitters are associated with depression and may serve as genetic markers for such illnesses. At any rate, as indicated by McKinney and explicitly stated in the target article, there is no reason to assume that stressful experiences will always lead to depression, nor that depression is in all individuals necessarily a consequence of the stressful experience. Contrary to the assertion of Beck & Harrison, we argued that stressful life experience in some individuals may represent a predisposing factor for the illness, but certainly not the sole factor. One final remark concerning the stress-depression relationship seems appropriate. If the cycle of neurochemical dysfunction and cognitive disturbance is self-perpetuating, adaptation might be expected to occur, as it does in infrahuman animals that receive repeated exposures to shock. Our model predicts that considerable interindividual variability should exist with respect to the adaptability of neurochemical systems. This is not to imply that chronic physical or psychological insults act as antidepressants, but that depression following chronic stressors occurs because of failure of neurochemical adaptation (see Rush). Wide-ranging differences in neurochemical activity occur in different strains of mice exposed to stressors of equivalent severity. We are unaware whether differential rates of adaptation occur with repeated exposure to a stressor. It would be difficult to assess the contribution of rumination to changes in catecholamine activity in humans, much less to determine when rats or mice are ruminating over stressful experiences. Perhaps some indication can be derived from the "despair response" of rhesus monkeys (Kraemer), although the validity of this procedure would be questionable. Life stressors and relation to depression. The validity of studies showing a relationship between life stressors and depression was questioned by several commentators
(Beck & Harrison, Chute, Neugebauer, Sacco). We

Although not indicated in the target article, it has been our feeling that most life-event inventories may not be tapping essential life stressors. The procedure described by Rosenthal considers important issues in this respect, and we look forward to hearing the results of his work. Subgroupings of depression. There is a good deal of data indicating a relationship between NE activity and depression, but there is equally good evidence pointing to a role for 5-HT. Furthermore, DA and ACh have also been implicated in affective illness. On the one hand, one can conclude that all of this is just too complex to disentangle and that we are not yet ready to reach definitive conclusions (Usdin). A more optimistic view, on the other hand, is that at least we are rid of a monistic approach to the analysis of depression. As Akiskal indicates, the questions that the optimistic view now encounters are, among others: What forms do these complex interactions take? Do some neurotransmitters play a permissive role in the induction of depression, while others are responsible for expression of the symptomatology? What is the correspondence between specific neurochemical changes and specific symptoms characterizing depression? How do stressors come to provoke particular symptoms? We would like to be able to make definitive statements concerning these questions. Unfortunately, the data are still too sparse, the techniques too limited, and the research approaches too restrictive to permit valid conclusions to be drawn. The very fact that depression is characterized by dramatic individual differences in symptom profile tells us, as indicated by Dimsdale, that analysis of the illness will not be simple. It also raises the possibility that depression may represent several illnesses characterized not only by different experiential and environmental premorbid factors, but also by different neurochemical substrates. Studies of oncology indicate that the cancer process should not be considered a singular illness: tumors can either be spontaneous or induced by carcinogens or viruses; they may be hormonally dependent or independent; immune factors may or may not play a role; treatments that are effective for one form of cancer may be ineffective for another form. Does this mean that no definitive conclusions can be reached? Clearly not! It means that therapies must consider the nature of the processes subserving the particular form of cancer and the factors that lead initially to the presence of those particular neoplastic cells. So, too, in the case of depression. Acknowledging the importance of subtypes of depression has not only been instrumental in determining more effective choice of treatment, but it seems to have been beneficial in discerning, at least to some extent, neurochemical correlates of depression that might otherwise have been obscured.
Correspondence between neurochemical lability and

presented a brief overview of this literature followed by a series of caveats questioning the conclusions derived from these experiments. Moreover, we stated explicitly that relationship between these variables may not be causal but secondary to the initial life stressors encountered by the individual (e.g., the financial difficulty which may follow parental loss). Neugebauer actually wonders why we bothered reviewing this literature when immediately afterward we called its value into question. This particular literature is so fraught with problems one would be foolhardy to accept it uncritically; yet its pervasiveness makes it equally foolhardy to dismiss it entirely. McKinney addressed this issue exceptionally well, and we refer the reader to his commentary. We agree with Beck & Harrison that there is a need for prospective studies evaluating whether a relationship exists between life stressors and depression, although such studies may not be without their own shortcomings.
126
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

behavior. The problem of the relation between specific neurochemical dysfunctions and corresponding behavioral pathologies is brought up by both Lester and Murison & Ursin. Sklar and Anisman (1981) suggest that aversive stimuli not only influence the activity of central neurotransmitters, but also affect hormonal secretion and peripheral transmitters release and influence immune functioning. The way in which a particular

Response/Anisman & Zacharko: Depression and stress stressor provokes a specific pathology would depend, according to Murison and Ursin, on the specific process (e.g., central or peripheral) activated by the physical or psychological insult. Yet the fact that such insults may have parallel and serial effects on numerous endogenous substrates makes it difficult to discern which of these is primarily involved in the emergence of the pathology. It has been our contention that many of the endogenous chemical actions induced by stressors serve in an adaptive capacity, and the specific pathology witnessed reflects the weak link among these systems (e.g., reduced central NE may increase vulnerability to depression; altered epinephrine functioning could lead to cardiovascular problems). In addition, as indicated in the target article and emphasized by Laborit, endogenous chemical change induced by a stressor with assumed positive affects may also have secondary consequences which are detrimental to the organism's welfare (e.g. the immunosuppressive effects of corticoid release). Noll & Davis describe several of the neurochemical factors that are associated with depression and suggest several symptoms of the illness that may correspond to variations in these endogenous substrates. As we indicated in the target article, and as is further emphasized by Noll & Davis, DA depletion may be responsible for the anhedonia frequently seen in depression. While this is certainly a viable hypothesis (see Wise 1978), it has been our contention that the available data are not sufficiently compelling to permit such a conclusion (see the accompanying target article by Wise and commentary by Anisman, this issue). In the case of 5-HT, Noll and Davis suggest that reduction of this amine may be responsible for heightened emotional responsiveness. Indeed, in their review of the literature Peters, Anisman, and Pappas (1978) indicated that considerable data point to 5-HT involvement in reactivity to environmental stimuli. Mason suggests that reductions in forebrain NE may provoke attentional deficits, while Kokkinidis and Anisman (1980) expressed the view that reduced NE coupled with increased DA neuronal activity provoke disorganized patterns of responding. Although both explanations merit consideration, they may be overstating the case. The difficulty in specifying a one-to-one correspondence between a neurochemical event and a particular behavior is revealed in a statement made by Karczmar (1975) in his review of cholinergic influence on behavior. He states "I do not know of any behavioral paradigm which is not affected by the cholinergic agonists and antagonists or which does not affect acetylcholine (ACh), cholinesterase (ChE) or their turnover" (p. 501). To a great extent, a similar statement could also be applicable when one is considering the catecholamines. The problem, as we see it, is specifying the conditions that lead to particular neurochemical events in specialized brain regions and then determining the precise behavioral expression induced by a restricted neurochemical effect. A phenomenological approach, as suggested by Hankoff, or a longitudinal-multivariate approach, as described by Bauer, represent potentially useful strategies in determining the relation between life stressors, neurochemical activity, and depression. At this time, however, any attempt on our part to provide anything more than a rudimentary analysis could be counterproductive and misleading. Neurochemical interactions. As if determining the relationship between neurochemical events and behavior were not sufficiently difficult, we are also faced with the problem of deciphering the contribution of fairly complex neurochemical interactions to behavioral output. Moreover, the joint effects of two or more neurotransmitters in one brain region may not be the same as in another brain region. In the case of some behaviors, (e.g., stereotypy, locomotor activity) considerable information is available pointing to dopaminergic-cholinergic interactions (see Butcher 1978), as well as noradrenergic-dopaminergic interactions (Antelman & Caggiula 1977). Analyzing such interactions has not been easy, and it will be considerably more difficult to determine the nature of the interactions that govern more complex behaviors such as avoidance-escape performance, let alone syndromes such as human depression. Kraemer, for example, documents work conducted in his own laboratory demonstrating the complexity encountered in attempting to decipher the effects of reductions of DA and NE on depression-like behaviors in monkeys. In our studies of escape performance in mice, we have likewise found several complex interactions between these transmitters (Anisman, Irwin & Sklar 1979; Anisman, Ritch & Sklar 1981). Kraemer suggests that stressors may result in the disorganization, as opposed to the depletion, of interdependent neurochemical systems, which in turn results in coping failure and the emergence of a behavioral syndrome that can be characterized as depression. This view is not inconsistent with our hypothesis and differs only in that we assert neurochemical depletion to be fundamental to the disorganization. We make our arguments simply on the basis that in several species uncontrollable shock has reliably been shown to result in reductions of NE as well as region-specific changes of DA. We should add that we are in total agreement with the comments made by Laborit. One should not only consider inhibition of an activating system, but also excitation of an inhibitory system. We also note that our failure to discuss peripheral neuroendocrine responses should not be taken to imply that we view these substrates as unimportant in depressive symptomatology. Rather, it reflects our limited familiarity with this line of research. Alternative neurochemical models. The argument presented by Stone and by Heninger (see also Rush and Mason) is intriguing and certainly accounts for a great deal of data. In fact, this position is not one which we would wish to dismiss. Accordingly, the ensuing remarks should only be considered as cautionary notes. While the proposition advanced by Stone would appear to be in direct opposition to our hypothesis, there does appear to be common ground. For example, Stone suggests that depression may result from the increased release and postsynaptic..receptor stimulation that occur following exposure to a stressor. We suggest that depression is associated with the reduced amine levels and release after the initial amine efflux. Perhaps depression will only occur if amine release is sufficiently great for the depletion to occur. It is even conceivable that the initial amine release sets the stage for the adverse consequences that occur once amine levels and activity are reduced. Increased amine activity may be essential for behavioral
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

127

Response/Anisman & Zacharko: Depression and stress coping responses to be manifested or may be involved in the subjective appraisal of the stressor's impact (see discussion in Redmond & Huang 1979; see also Burchfield). So long as heightened amine activity persists, the organism is prepared to engage in coping attempts. Only when levels of the amine are reduced will depression be manifested. (A cognitively oriented theorist might wish to rephrase this description to read that the initial amine release is responsible for cognitive coping strategies, but continued failure to gain control over the stressor results in amine depletion and hence the cognitive changes associated with depression.) Upon exposure to chronic shock, tyrosine-hydroxylase activity increases and amine concentrations return to control levels. We have assumed that the resultant increased postsynaptic NE activity should counteract the depressive symptomatology or lead to further behavioral-cognitive coping attempts. In contrast, Stone posits that receptor subsensitivity is responsible for the reduction of the depressive symptoms. We accept that the subsensitivity reflects an essential adaptive change, but suggest that it represents a compensatory response to deal with the sustained increase of amine utilization. Stone reports that rats subjected to chronic foot-shock show increased levels of NE and tyrosine hydroxylase activity, but not augmented release of the amine. As yet unpublished data collected in our laboratory indicate similar effects 24 hours after fourteen sessions of stress applied on consecutive days. Measurements taken immediately after the last stress session, however, revealed increased utilization of NE in the hypothalamus, cortex, hippocampus, and locus coeruleus. A major source of support for Stone's position comes from the fact that antidepressant therapy requires several weeks of administration before it is effective. As indicated by Huang (1979) and Maas and Huang (1980), there is good reason to believe that the beneficial effects of this drug treatment are derived from the receptor subsensitivity following repeated drug treatment. It is unclear, however, whether the subsensitivity is responsible for the antidepressant effects of the chronic drug treatment or the subsensitivity simply follows, and is an index of, the sustained NE postsynaptic stimulation (Tang, Seeman & Kwan 1981; Crews, Paul & Goodwin 1981) that might be necessary to antagonize the depressed symptomatology. Furthermore, the fact that the receptor subsensitivity and therapeutic effects of desmethylimipramine are not evident for several days following drug administration may be due to the passage of time rather than repeated treatment with the drug (Chiodo & Antelman 1980). Alternatively, repeated drug treatments may be necessary for sufficient drug to accumulate in some brain regions before the treatment is therapeutically efficacious. Finally, it should be noted that if /3-NE receptor subsensitivity alone is responsible for the therapeutic effects of chronic desmethyiimipramine treatment, then any direct-acting /3-NE antagonists should have a beneficial effect on the depressive symptomatology. One final note should be added before concluding this section. Although several investigators have reported decreased NE postsynaptic receptor activity (Huang 1979; Olpe & Schellenberg 1980; Korf, Sebens, & Postema 1979; Sulser 1978; Sulser, Vetulani & Mobley 128
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

1978) or decreased sensitivity of DA autoreceptor (Serra, Argiolas, Fadda & Gessa, 1980) after repeated treatment with tricyclics, others have reported either no effect or apparent increases in NE postsynaptic receptor activity (Wang & Aghajanian 1980; DeMontigny & Aghajanian 1978). As indicated by Wang and Aghajanian (1980), the discrepant results following repeated treatment with tricyclic antidepressants may reflect differential action of the drug on different types of receptors in various brain regions. It should also be noted, as discussed by Korf et al. (1979), that the dosage of tricyclic antidepressants employed in rat studies considerably exceeds the therapeutic dose used in humans. Thus, caution must be exercised in extrapolating the data from infrahuman experiments to the clinical setting. Finally, in the rat studies, the effects of tricyclic antidepressants are presumably evaluated under conditions in which the interplay between neurons is functionally undisturbed, whereas the therapeutic effectiveness of such drugs in humans is examined in a system that may already be out of kilter. Somewhat related to the NE receptor subsensitivity model is the view of Hingtgen & Aprison. They suggest that reductions of 5-HT may result in supersensitive 5-HT receptors (see, for example, Wang & Aghajanian 1980), such that environmental stimuli that provoke 5-HT release produce exaggerated postsynaptic receptor activity. Antidepressants, according to this view, might be clinically effective because of a blocking action (or reduced sensitivity) at receptor sites. As suggested by Olpe and Schellenberg (1980), depression may in fact reflect the joint effects of hypersensitive 5-HT receptors and hyposensitive NE receptors. The beneficial effect of antidepressants results from alterations in the imbalance between these systems. The view expressed by Hingtgen and Aprison is not inconsistent with our proposition, and raises the possibility that stressors could provoke different subtypes of depression depending on the relative adaptability of NE and 5-HT systems in response to environmental stimuli (see Laborit). Mason raises the possibility that reductions of NE may result in schizophrenic-like symptoms, rather than symptoms associated with depression (see also Lester). Specifically, he indicates that depletion of forebrain NE by 95% in 6-hydroxydopamine-treated rats results in behavioral changes reminiscent of the inability to filter irrelevant environmental stimuli. Although schizophrenia has been associated with apparent deficits in filtering environmental stimuli, or stimulus "overload" (see Hamilton), the reductions of NE necessary to induce the assumed attentional deficit in rats (95%) is probably considerably greater than the NE reductions that are actually present in schizophrenic brains. Moreover, it remains to be determined whether reductions of NE actually do affect attentional processes (Pisa & Fibiger 1980). These caveats notwithstanding, Kokkinidis and Anisman (1980) proposed that some schizophrenic-like symptoms, at least those related to chronic amphetamine abuse, may be due to reduced NE activity coupled with hypersensitive DA receptors. The heightened motor activity associated with increased DA receptor activity may not be sufficient to provoke schizophrenic-like behavior. When accompanied by deficits in stimulus filtering, presumably related to NE reductions induced by

References/Anisman & Zacharko: Depression and stress chronic amphetamine treatment, the nondirected, hyperactive responding may be more closely related to the schizophrenic symptomatology. It should be noted, however, that in Kokkinidis and Anisman's model, chronic amphetamine treatment no doubt produced wide-spread neurochemical alterations beyond that of modifying NE and DA activity. Concluding remarks. Even a cursory overview of the various commentaries reveals a broad spectrum of opinions concerning both the target article and the strategies that should be employed in assessing the processes responsible for depression. Some investigators have placed greater emphasis on cognitive processes and the effects of stressors on these, while others have been more concerned with neurochemical mechanisms (and interactions) and their relation to the various symptoms and subtypes of depression. It will be clear from our response that each of these issues is considered essential for a comprehensive understanding of depression. Our contention that neurochemical lability induced by stressful experiences is one factor determining vulnerability to depression does not exclude the possibility that cognitive changes are essential in sustaining the affective state. Together, neurochemical and cognitive factors may be part of a dynamic process which culminates in the progressive exacerbation of the depressive symptomatology. The nature of the neurochemical events associated with depression has yet to be fully elucidated. The diverse symptomatology which characterizes the illness suggests the involvement of more than a single neurotransmitter. Even when one considers the involvement of any given transmitter, it remains to be demonstrated whether it is dysfunction of this substrate directly that influences the illness or whether serial effects associated with the dysfunction are more closely related to the depressive symptomatology. In addition, it seems that dysfunction of a given neurotransmitter system may consist of reduced levels or activity, or it may reflect alterations of pre- and postsynaptic receptors. Stressful experiences may influence vulnerability to affective illnesses by altering the unique balance that exists within a neurochemical system as well as between several such systems.
Akiskal, H. S., & McKinney, W. T. (1973) Depressive disorders: Toward a unified hypothesis. Science 182:20-29. [HSA, taHA] (1975) Overview of recent research in depression: Integration often conceptual models into a comprehensive clinical frame. Archives of General Psychiatry 32:285-305. [HSA, taHA] Akiskal, H. S., Rosenthal.T. L., Haykal, R. F., Lemmi, H., Rosenthal, R. H., & Scott-Strauss, A. (1980) Characterological depressions: Clinical and sleep EEC findings separating "subaffective dysthymias" from "characterspectrum disorders." Archives of General Psychiatry 37:777-83. [TLR] Albert, M. D., Feldman, R. G., & Willis, A. L. (1974) The subcortical dementia of progressive supranuclear palsy. Journal of Neurology, Neurosurgery, and Psychiatry 37:121-30. [RMB] Allen, M. C. (1976) Twin studies of affective illness. Archives of General Psychiatry 33:1476-78. [JED] Angrist, B. M. & Gershon, S. (1970) The phenomenology of experimentally induced amphetamine psychosis: Preliminary observations. Biological Psychiatry 2:95-107. [LDH] Angst, J., Waggon, B., & Schoepf, J. (1977) The treatment of depression with 1-5-hydroxytryptophan versus imipramine. Archives Psychiatrica Ncrvcnkrankheit 224:175-86. [taHA] Anisman, H. (1978) Neurochemical changes elicited by stress: Behavioral correlates. In: Psychopharmacology of aversively motivated behavior, ed. H. Anisman & G. Bignami, pp. 119-72. New York: Plenum Press. [tarHA] (1982 in press) Vulnerability to depression. In: Neurobiology of mood disorders, ed. R. M. Post & J. C. Ballenger. Baltimore: Williams & Wilkins. [rHA] Anisman, H., Irwin, J., & Sklar, L. S. (1979) Deficits of escape performance following catecholamine depletion: Implications for behavioral deficits induced by uncontrollable stress. Psychopharmacology 64:163-70. [rHA] Anisman, H., Kokkinidis, L., & Sklar, L. S. (1981) Neuroehemical consequences of stress: Contributions of adaptive processes. In: Physiological and psychological interactions in response to stress, ed. S. Burchfield. New York: Hemisphere. [tarHA] (1981, in press) Contribution of neurochemical change to stress-induced behavioral deficits. In: Psychopharmacology Vol. 1., ed. S. J. Cooper. London: Academic Press. [rHA] Anisman, H. & Lapierre, Y. (1981 in press) Stress and depression: Formulations and caveats. In: Psychological stress and psychopathology, ed. W. J. M. Neufeld. New York: McCraw Hill. [rHA] Anisman, H., Pizzino, A., & Sklar, L. S. (1980) Coping with stress, norepinephrine depletion and escape performance. Brain Research 191:58388. [tarHA] Anisman, H., Remington, G., & Sklar, L. S. (1979). Effects of inescapable shock on subsequent escape performance: Catecholaminergic and cholinergic mediation of response initiation and maintenance. Psychopharmacology 61:107-24. [rHA] Anisman, H., Ritch, M., & Sklar, L. S. (1981) Noradrenergic and dopaminergic interactions in escape behavior: Analysis of uncontrollable stress effects. Psychopharmacology 74:263-68. [rHA] Anisman, H. & Sklar, L. S. (1979) Catecholamine depletion upon reexposure to stress: Mediation of the escape deficits produced by inescapable shock. Journal of Comparative and Physiological Psychology 93:610-25. [tarHA]. Antelman, S. M. & Caggiula, A. R. (1977) Norepinephrine-dopamine interactions and behavior. Science 195:646-53. irHA, GWK] Aprison, M. H. (1977) Are some amino acid neurotransmitters involved in psychiatric disorders? In: Neitroregulators and psychiatric disorders, ed. E. Usdin, D. A. Hamburg, & J. D. Barchas, pp. 381-90. New York: Oxford University Press. [JNH] Aprison, M. H., & Hingtgen, J. N. (1970) Neurochemical correlates of behavior. International Review of Neurobiology 13:325-341. [JNH] (1972) Serotonin and behavior: A brief summary. Federation Proceedings 31:121-29. [JNH] (1981) Hypersensitive serotonergic receptors: A new hypothesis for one subgroup of unipolar depression derived from an animal model. In: Serotonin: Current aspects of neurochemistry and function, ed. B. Haber, S. Gabay, S. Alivisatos, & M. Issidorides, pp. 627-56. New York: Plenum Press. [JNH] Aprison, M. H., Hingtgen, J. N., & McBride, W. J. (1975) Serotonergic and cholinergic mechanisms during disruption of approach and avoidance behavior. Federation Proceedings 34:1813-1822. [JNH, KMN] Aprison, M. H., Takahashi, R., &Tachiki, K. (1978) Hypersensitive serotonergic receptors involved in clinical depression: A theory. In: Neuropharniacology and behavior, ed. B. Haber & M. H. Aprison, pp. 23-53. New York: Plenum Press. [JNH] Arieti, S. & Bemporad, J. (1978) Severe and mild depression. New York: Basic Books. [SRB] Asberg, M., Thoren P., Traskman, L., Bertilsson, L., & Ringberger, V. (1976)

References
Aberg, A., & Holmberg, C. (1979) Preliminary clinical testing of zimelidine (H 102/09) a new reuptake inhibitor. Ada Psychiatrica Scandinavica 59:4558. [taHA] Abramson, L. Y., Garber, J., & Seligman, M. E. P. Learned helplessness in humans: An attributional analysis. In: Human helplessness, ed. J. Garber & M. E. P. Seligman, pp. 3-39. New York: Academic Press. [taHA] Abramson, L. Y., Seligman, M. E. P., & Teasdale, J. D. (1978) Learned helplessness in humans: Critique and reformulation. Journal of Abnormal Psychology 87:49-74. [tarHA, KMN] Akiskal, H. S. (1979) A biobehavioral approach to depression. In: The psychobiology of depressive disorders: Implications for the effects of stress, ed. R. Depue, pp. 409-37. New York: Academic Press. [HSA] (1981) Clinical overview of depressive disorders and their pharmacological management. In: Neuropharmaeotogy of central and behavioral disorders, ed. G. C. Palmer, pp. 37-72. New York: Academic Press. [HSA] ed. (1979) Affective disorders: Special clinical forms. Psychiatric Clinics of North America 2(3). [TLR]

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

129

References!Anisman & Zacharko: Depression and stress

Serotonin depression: A biochemical subgroup within the affective disorders? Science 191:478-80. [taHA] Asberg, M., Traskman, L., & Thoren, P. (1976) 5-HIAA in the cerebrospinal fluid: A biochemical suicide predictor? Archives of General Psychiatry 33:1193-97. [KMN] Ashcroft, G. W., Blackburn, I. M., Eccleston, D., Glen, A. I. M., Hartley, W., Kinloch, N. E., Lonergen, M., Murray, L. G., & Pullar, I. A. (1973) Changes on recovery in the concentrations of tryptophan and the biogenic amine metabolites in the cerebrospinal fluid of patients with affective illness. Psychological Medicine 3:319-25. [taHA] Ashford, J. & Jones, B. J. (1976) The effects of intra-amygdaloid injections of 6-hydroxydonamine on avoidance responding in rats. British Journal of Pharmacology 56:255-61. [STM] Averill, J. R., DeWitt, G. W., & Zimmer, M. (1978). The self-attribution of emotion as a function of success and failure. Journal of Personality 46:32347. [VH] Baldessarini, R. (1981) A summary of biomedical aspects of mood disorders. McLean Hospital Journal 6:1 -34. [JED] Bandura, A. (1981) Self-referent thought: A developmental analysis of selfeffieacy. In: Social cognitive development: Frontiers and possible futures, ed. J. H. Flavell & L. Ross, pp. 200-39. Cambridge: Cambridge University Press. [TLR] Banerjee, S. P., Kung, L. S., Riggi, J. S., & Chanda, S. K. (1977) Development of/3-adrenergic receptor subsensitivity by antidepressants. Nature (London) 268:455-56. [taHA] Beck, A. (1976) Depression: Clinical, experimental and theoretical aspects. New York: Harper and Row. [taHA, DdeC, VH, WPS] Beck, A., Sethi, B., & Tuthill, R. (1963) Childhood bereavement and adult depression. Archives of General Psychiatry 9:295-302. [taHA] Beck, A. T. (1967) Depression: Causes and treatment. Philadelphia: University of Pennsylvania Press. [LDH] Beck, A. T., Rush, A. J., Shaw, B. F. & Emery, G. (1979) Cognitive therapy of depression. New York: Guilford Press. [ATB, KMN] Beck, A. T., Kovacs, M., & Weissman, A. (1975) Hopelessness and suicidal behavior: An overview. Journal of the American Medical Association 234:1146-49. [DdeC] Beck, J. C., 6t Worthen, K. (1972) Precipitating stress, crisis theory, and hospitalization in schizophrenia and depression. Archives of General Psychiatry 26:123-29. [taHA, DL] Beckman, H. & Goodwin, F. K. (1975) Antidepressant response to tricyclics and urinary MHPG in unipolar patients. Archives of General Psychiatry 32:1721. [taHA] Benner, P., Rosldes, E., & Lazarus, R. (1980) Stress and coping under extreme conditions. In: Survivors, victims, and perpetrators: Essays on the Nazi holocaust, ed. J. Dimsdale, pp. 219-58. New York: Hemisphere Publishers. Booth, D. (1968) Localization of the adrenergic feeding system in the rat diencephalon. Science 158:515-17. [KMN] Boume, H. R., Bunney, W. E., Colburn, R. W., Davis, J. M., Davis, N. J., Shaw, D. M., & Coppen, A. J. (1968) Noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in hindbrain of suicidal patients. Lancet 2:805-08. [taHA] Bower, G. H. (1981) Mood and memory. American Psychologist 36:12948. [VH] Bowers, M. B., Jr. (1969) Deficient transport mechanism for the removal of acid monoamine metabolites from cerebrospinal fluid. Brain Research 15:52224. [taHA] Bowers, M. B., Jr., Heninger, G. R., & Gerbode, F. (1969) Cerebral spinal fluid, 5-hydroxyindoleacetic acid and homovanillic acid in psychiatric patients. International Journal of Neuropharmacology 8:255-62. [taHA] Bowlby, J. (1980) Attachment and loss: Vol. 3, Loss, sadness and depression. London: Hogarth. [VH] Breznitz, S. (1971) A study of worrying. British Journal of Social and Clinical Psychology 10:271-79. [SRBJ Briscoe, C. W., & Smith, J. B. (1975) Depression in bereavement and divorce. Archives of General Psychiatry 32:439-43. [taHA] Broadbent, D. E. (1958) Perception and communication. New York: Pergamon Press. [STM] Brodie, H. K. H., Sack, R., & Siever, L. (1973) Clinical studies of 5-hydroxytryptophan in depression. In: Serotonin and behavior, ed. J. Barchas & E. Usdin, pp. 549-60. New York: Academic Press. [taHA] Brown, E., Brown, G. M., Kofman, O., & Quarrington, B. (1978) Sexual function and affect in Parkinsonian men treated with L-dopa. American Journal of Psychiatry 135:1552-55. [KMN] Brown, F. (1961) Depression and childhood bereavement. Journal of Mental Sciences 107:754-77. [taHA] Brown, G. W. (1979) The social etiology of depression: London studies. In: The psychobiologtj of the depressive disorders, ed. R. A. Depue, pp. 263-90. New York: Academic Press. [taHA, WPS] Brown, G. W., & Birley, J. L. T. (1968) Crisis and life changes and the onset of schizophrenia. Journal of Health and Social Behavior 9:203-14. [RN] Brown, C. W., Sklair, F., Harris, T. O., & Birley, J. L. T. (1973) Life-events and psychiatric disorders: 1. Some methodological issues. Psychosomatic Medicine 3:74-87. [RN] Bunge, R., Johnson, M., & Ross, C. D. (1978) Nature and nurture in development of the autonomic neuron. Science 199:1409-16. [KMN] Bunney, W. E. Jr., & Davis, J. M. (1965) Norepinephrine in depressive reactions. Archives of General Psychiatry 13:483-94. [KMN] Bunney, W. E., Jr., Goodwin, F. K., & Murphy, D. L. (1972) The "switch process" in manic depressive illness: 1, 2, and 3. Archives of General Psychiatry 27:295-317. [taHA] Bunney, W. E., Murphy, D. L., & Goodwin, F. K. (1970) The switch process from depression to mania: Relationship to drugs which alter brain amines. Lancet 1:1022-27. [taHA] Bunney, W. E., van Kammen, D. P., Post, R. M., & Garland, B. L. (1979) A possible role for dopamine in schizophrenia and manic depressive illness (a review of evidence). In: Catecholamines: Basic and clinical frontiers II, ed. E. Usdin, I. J. Kopin, &J. Barchas, pp. 1807-19. New York: Pergamon Press. [taHA] Burchfield, S. R. (1979) The stress response: A new perspective. Psychosomatic Medicine 41:661-72. [SRB] Butcher, L. L., ed. (1978) C/io/inerfiic-monamfncrgic interactions in the brain. New York: Academic Press. [rHA] Cameron, N. (1938a) Reasoning, regression and communication in schizophrenia. Psychological Monographs 50:1-30. [STM] (1938b) Study in thinking in senile deterioration and schizophrenic disorganization. American Journal of Psychology 51:650-64. [STM] (1939a) Deterioration and regression in schizophrenic thinking. Journal of Abnormal and Social Psychology 34:265-70. [STM] (1939b) Schizophrenic thinking in problem-solving situations. Journal of Mental Science 85:1012-35. [STM] Cannon, W. B. (1915) Bodily changes in pain, hunger, fear and rage. New York: Appleton. [AIL] Cantril, H. & Hunt, W. H. (1932) Emotional effects produced by the injection of adrenalin. American Journal of Psychology 44:300-07. [AIL] Caplan, M. G. & Douglas, V. T. (1969) Incidence of parental loss in children with depressed mood. Journal of Child Psychology and Psychiatry 10:22532. [taHA] Carlton, P. L. (1963) Cholinergic mechanisms in the control of behavior by the brain. Psychological Review 70:19-39. [KMN] Carrol, B., Curtis, G. C , & Mendels, J. (1976) Neuroendocrine regulation in depression: 1. Limbic system - adrenocortical dysfunction. Archives of General Psychiatry 33:1039. [RM]

IJED]
Berger, A., Faull, K., Davis, K. L., & Barchas, J. D. (1979) Monoamine metabolites in CSF in psychiatric disorders. In: Catecholamines: Basic and clinical frontiers, vol. 2, ed. E. Usdin, I. J. Kopin, & J. Barchas. pp. 1827-29. New York: Pergamon Press. [taHA] Berger, D. F., Starzec, J. J., & Mason, E. B. (1981) The relationship between plasma corticosterone levels and leverpress avoidance vs. escape in rats. Physiological Psychology 9:81-86. [RM] Berl, S., Puszkin, S., & Nicklas, W. J. (1973) Actomyosin-like protein in brain. Science 179:441^15. [KMN] Beskow, J., Gottfries, C. G., Roos, B. E., & Winoblad, B. (1976) Determination of monoamine and monoamine metabolites in the human brain: Postmortem studies in a group of suicides and in a control group. Ada Psychiatrica Scandinavica 53:7-20. [taHA] Birch, N. J. (1973) The role of magnesium and calcium in the pharmacology of lithium. Biological Psychiatry 7:269-72. [KMN] Birkmayer, W. & Rederer, P. (1975) Biochemical post-mortem findings in depressed patients. Journal of Neural Transmission 37:95-109. [taHA] Blanc, G., Herve, D., Simon, H., Lisoprawski, A., Glowinski, J., &Tassin, J. P. (1980) Response to stress of mesocortical-frontal dopaminergic neurons in rats after long-term isolation. Nature 284:265-76. [taHA] Blomberg, P. A., Kopin, I. J., Gordon, E. K., Markey, S. P., & Ebert, M. H. (1980) Conversion of MHPG to vanillylmandelic acid: Implications for the importance of urinary MHPG. Archives of General Psychiatry 37:109598. [taHA] Bobrow, D. G. & Norman, D. A. (1975) Some principles of memory schemata. In: Representation and understanding: Studies in cognitive science, ed. D. C. Bobrow & D. A. Norman, pp. 131^9. New York: Academic Press. [VH] Bond, P. A., Jenner, F. A., & Sampson, G. A. (1972) Daily variations of the urine content of 3-methoxy-4-hydroxyphenylglyeol in two manic depressive patients. Psychological Medicine 2:81-85. [taHA]

130

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

References/Anisman & Zacharko: Depression and stress

Carroll, B. J., Feinberg, M., Greden, J. F., et al. (1981) A specific laboratory test for the diagnosis of melancholia. Archives of General Psychiatry 38:1522. [JED) Casey, R. L., Masuda, M., & Holmes, T. H. (1967) Quantitative study of recall of life events. Journal of Psychosomatic Research 11:239-47. [RN] Cassens, C , Roffman. M., Kuruc, A., Orsulak, P. J., & Schildkraut, J. J. (1980) Alterations in brain norepinephrine metabolism, induced by environmental stimuli previously paired with inescapable shock. Science 209:113840. [taHAJ Chapman, L. J. (1956) Distractability in the conceptual performance of schizophrenics. Journal of Abnormal and Social Psychology 53:286-91. [STM] Chamey, D., Menkes, D., & Heninger, G. (1981) Receptor sensitivity and the mechanism of action of antidepressant treatment: Implications for the etiology and therapy of depression. Archives of General Psychiatry (in press). [CRHj Checkley, S. A., Slade, A. P., & Shur, E. (1981) Growth hormone and other responses to clonidine in patients with endogenous depression. British Journal of Psychiatry 138:51-55. [GRHJ Cherek, D. R., Lane, J. D., Freeman, M. E., & Smith, J. E. (1980) Receptor changes following shock avoidance. Society Neurosdence Abstracts 6:543. |taHA] Chikamori, Y., Sasa, M., Fujimoto, S., Takaori, S., & Matsuoka, I. (1980) Locus coeruleus-induced inhibition of dorsal cochlear nucleus neurons in comparison with lateral vestibular nucleus neurons. Brain Research 199:5363. ISTM] Chiodo, L. A., & Antehnan, S. M. (1980) Electroconvulsive shock: Progressive dopamine autoreceptor subsensitivity independent of repeated treatment. Science 210:799-801. [JWK] (1980) Repeated tricyclics induce a progressive dopamine autoreceptor subsensitivity independent of daily drug treatment. Nature 287:45154. [rHA] Clayton, P., Halikas, J., & Maurice, W. (1972) The depression of widowhood. British Journal of Psychiatry 120:71-77. [taHA, WPS] Coover, G. D., Ursin, H., & Levine, S. (1973) Plasma corticosterone levels during active avoidance learning in rats. Journal of Comparative and Physiobgical Psychology 82:170-74. (RMJ Coppen, A., Prange, A. J., Whybrow, P. C , & Nogura, R. (1972) Abnormalities of indoleamines in affective disorders. Archives of General Psychiatry 26:474-78. [KMN) Coppen, A., Rama Rao, V. A., Ruthven, C. R. J., Goodwin, B. L., & Sandier, M. (1979) Urinary 4-hydroxy-3-methoxy-phenylglycol is not a predictor for clinical response to amitriptyline in depressive illness. Pstjchopharmacology 64:95-97. [taHA] Coppen, A., Shaw, D., Hersberg, B., & Maggs, R. (1967) Tryptophan in the treatment of depression. Lancet 2:1178-80. [taHA] Costa, E., Tagliamonte, A., Brunello, N., & Cheney, D. L. (1980) Effect of stress on the metabolism of acetylcholine in the cholinergic pathways of extrapyramidal and limbic systems. In: Catecholamines and stress: Recent advances, ed. E. Usdin, R. Kvetnansky, & I. J. Kopin, pp. 59-68. New York: Elsevier. [taHAJ Costello, C. G. (1978) A critical review of Seligman's laboratory experiments on learned helplessness and depression in humans. Journal of Abnormal Psychology 87:21-31. [taHA] Crews, F. T., Paul, S. M. & Goodwin, F. K. (1981) Acceleration of /3-receptor desensitization in combined administration of antidepressants and phenoxybenzamine. Nature 290:787-89. [rHA] Crews, F. T. & Smith, C B. (1978) Presynaptic alpha-receptor subsensitivity after long-term antidepressant treatment. Science 202:322-24. [taHA] Crook, T., & Eliot, J. (1980) Parental death during childhood and adult depression: A critical review of the literature. Psychological Bulletin 87:252-59. [taHA, WPS] Crow, T. J. (1971) The relationship between electrical self-stimulation sites and catecholamine-containing neurons in the rat mesencephalon. Experientia 27:662. [KMN] Curzon, G. & Green, A. R. (1971) Regional and subcellular changes on the concentration of 5-hydroxytryptamine and 5-hydroxy indoleacetic acid in rat brain caused by hydrocortisone, DL-a-methyltryptophan, L-kynurenine, and immtinobilization. British Journal of Pharmacology 43:39. [ADS] Daly, M. & Wilson, M. (1978) Sex, evolution, and behavior. North Scituate, Mass.: Duxbury Press. [DdeC] Damasio, A. The frontal lobes. (1979) In: Clinical neuropsychology, ed. K. M. Heilman & E. Valenstein, pp. 360-412. New York: Oxford University Press. |RMB] Davis, G. C , Buchsbaum, M. S., & Bunney, W. E., Jr. (in press) Alterations of evoked potentials link research on attention dysfunction to peptide response symptoms of schizophrenia. In: Scurology, peptides, and neuronal communication, ed. M. Trabucci & E. Costa. New York: Raven Press. [TLR] Davis, J. M., & Janowsky, O. (1975) Cholinergic and adrenergic balance in mania and schizophrenia. In: Neurotransmitter balances regulating behavior, ed. E. F. Domino & J. M. Davis, pp. 135-48. Ann Arbor, Mich.: Edwards Brothers. [taHA] Davis, K. L., Mohs, R. C , & Tinklenberg, J. R. (1979) Enhancement of memory by physostigmine. New England Journal of Medicine 301:946. [KMN] Davis, K. L., Mohs, R. C , Tinklenberg, J. R., Pfefferbaum, A., Hollister, L. E., & Kopell, B. S. (1978) Physostigmine: Improvement in long-term memory processes in normal humans. Science 201:272-74. [KMN] de Catanzaro, D. (1980) Human suicide: A biological perspective. Behavioral and Brain Sciences 3:265-90. [DdeC] (1981) Suicide and self-damaging behavior: A sodobiological perspective. New York: Academic Press. [DdeC] Delongis, A., Coyne, J. C , Dakoff, G., Folkman, S., & Lazarus, R. S. (in press) Daily hassles, uplifts and life events in relation to health status. Journal of Health Psychology. [WPS] De Montigny, C. & Aghajanian, G. K. (1978) Tricyclic antidepressants: Longterm treatment increases responsivity of rat forebrain neurons to serotonin. Science 202:1303-06. [rHA] Dennehy, C. (1966) Childhood bereavement and psychiatric illness. British Journal of Psychiatry 112:1049-69. [taHA) Depue, R. A., ed. (1979) The psychobiology of the depressive disorders. New York: Academic Press. [HSA, KMN] Depue, R. A., & Monroe, S. M. (1978) Learned helplessness in the perspective of the depressive disorders: Conceptual and definitional issues. Journal of Abnormal Psychology 87:3-21. [taHA] (1978) The unipolar-bipolar distinction in the depressive disorders: Implications for stress-onset interaction. Psychological Bulletin 85:100129. [KMN] (1979) The unipolar-bipolar distinction in the depressive disorders: Implications for stress-onset interactions. In: The psychobiology of depressive disorders, ed. R. A. Depue, pp. 23-54. New York: Academic Press. [taHA] Devenport, L. D., Devenport, J. A , & Holloway, F. A. (1981) Reward-induced stereotypy: Modulation by the hippocampus. Science 212:1288-89. [LDH] Diagnostic and statistical manual of mental disorders. (1980) 3rd ed. American Psychiatric Association. [HSA, WPS] Dohrenwend, B. P., & Dohrenwend, B. S. (1979) The conceptualization and measurement of stressful life events. In: The psychobiology of the depressive disorders, ed. R. A. Depue, pp. 105-21. New York: Academic Press. [taHA, WPS] Dohrenwend, B. S. & Dohrenwend, B. P. (1974) Stressful life events: Their nature and effects. New York: John Wiley. [JED) Dresse, A., & Scuvee-Moreau, J. (1980) Selective action of the tricyclic antidepressants on the spontaneous firing of noradrenergic or serotonergic cerebral neurons. In: New advances in the diagnosis and treatment of depressive illness, ed. J. Mendlewiez. Amsterdam: Excerpta medica. [JWK] Dunner, D. L., Gershon, G. S., & Goodwin, F. K. (1976) Heritable factors in the severity of affective illness. Biological Psychiatry 11:31-42. [KMN] Dunner, D. L. & Goodwin, F. K. (1972) Effect of 1-tryptophan on brain serotonin metabolism in depressed patients. Archives of General Psychiatry 26:364-66. [taHA] Edwards, J., Spiker, D. G., Kupfer, D. J., & Neil, J. F. (1979) Platelet MAO and urinary MHPG in affective disorders. In: Catecholamines: Basic and clinical frontiers, ed. E. Usdin, I. J. Kopin, & J. Barchas, pp. 1869-71. New York: Pergamon Press. [taHA] Eitinger, L. (1964) Concentration camp survivors in Norway and Israel. London: Allen and Unwin. [taHA] (1973) A follow-up of Norwegian concentration camp survivors' mortality and morbidity. Israel Annals of Psychiatry and Related Disciplines 11:199209. [taHA] Ellertsen, B., Johnsen, T. B., & Ursin, H. (1978) Relationship between the hormonal responses to activation and coping. In: Psychobiology of stress: A study of coping men, ed. H. Ursin, E. Baade, & S. Levine, pp. 105-22. New York: Academic Press. [RM] Engel, G. L. (1961) Is grief a disease? A challenge for medical research. Psychosomatic Medicine 23:18-22. [SRB] Evetts, K. D., Uretsky, N. J., Iversen, L. L., & Iversen, S. D. (1970) Effects of 6-hydroxydopamine on CNS catecholamines, spontaneous motor activity and amphetamine-induced hyperactivity in rats. Nature 225:96162. [STM] Ewer, R. F. (1968) Ethology of mammals. London: Elek Science. [DdeC] Falek, A. & Britton, S. (1974) Phases in coping: The hypothesis and its implications. Social Biology 21-.1-T. [SRB] Farber, M. L. (1968) Theory of Suicide. New York: Funk and Wagnalls. [DdeC]

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

131

References/Anisman & Zacharko: Depression and stress

Fawcett, J., Maas, J. W., & Dekirmenjian, H. (1972) Depression and MHPG excretion. Archives of General Psychiatry 26:246-51. [taHA] Ferster, C. B. (1973) A functional analysis of depression. American Psychologist 28:857-70. [KMN] Fleisher, L. N., Simon, J. R., & Aprison, M. H. (1979) A biochemical-behavioral model for studying serotonergic super-sensitivity in brain. Journal of Neurochemistry 32:1613-20. [JNH] Flor-Henry, P. (1976) Lateralized temporal-limbic dysfunction and psychopathology. Annals of the New York Academy of Sciences 280:77795. [LDH] Forrest, A. D., Fraser, R. H., & Priest, R. G. (1965) Environmental factors in depressive illness. British Journal of Psychiatry 111:243-53. [taHA] Fowles, D. C. & Gersh, F. S. (1979) Neurotic depression: The endogenousneurotic distinction. In: The psychobiology of the depressive disorders, ed. R. A. Depue, pp. 55-80. New York: Academic Press. [taHA] Fraser, A., Pandy, G. N., & Mendels, J. (1973) Metabolism of tryptophan in depressive disease. Archives of General Psychiatry 29:528-35. [taHA] Garber, J., Miller, W. R., & Seaman, S. F. (1979) Learned helplessness, stress, and the depressive disorders. In: The psychobiology of the depressive disorders, ed. R. A. Depue, pp. 335-363. New York: Academic Press. [taHA, WPS] Carattini, S. (1981) A propos du mode d' action de la minaprine, Le Concours Medical (supplement no. 28, pp. 28-30). [HL] Gershon, E. S. (1978) The search for genetic markers in affective disorders. In: Psychopharmacology: A generation of progress, ed. M. A. Lipton, A. DiMascio, & K. F. Killam. New York: Raven Press. [DdeC] Gershon, E., Dunner, D., & Goodwin, F. (1971) Toward a biology of affective disorders: Genetic contributions. Archives of General Psychiatry 25:115. [HSA] Chose, K., Gupta, R., Coppen, A., & Lund, J. (1977) Antidepressant evaluation and the pharmacological actions of FG-4963 in depressive patients. European Journal of Pharmacology 42:31 -37. [GRH] Gillin, J. C., Duncan, W., Pettigrew, K. D., etal. (1979) Successful separation of depressed normal and insomniac subjects by EEC sleep data. Archives of General Psychiatry 36:85-90. [JED] Glass, D. C. (1977) Behavior patterns, stress and coronary disease. New York: John Wiley. [taHA] Cold, B. I., Bowers, M. B., Roth, R. H., & Sweeney, D. W. (1980) GABA levels in CSF of patients with psychiatric disorders. American Journal of Psychiatry 137:362-64. [KMN] Goodlet, F., Mireylees, S. E., & Sugrue, M. F. (1977) Effects of mianserin, a new antidepressant, on the in vitro and in vivo uptake of monoamines. British Journal of Pharmacology 61:307-13. [GRH] Goodwin, F. & Bunney, W. E., Jr. (1973) A psychobiological approach to affective illness. Psychiatric Annals 3:19-53. [HSA] (1973) Psychobiological aspects of stress and affective illness. In: Separation and depression: Clinical and research aspects, ed. J. P. Scott &E. C. Senay, pp. 91-112. Washington, D.C.: AAAS. [taHA] Goodwin, F. K., Cowdry, R. W., & Webster, M. H. (1978) Predictors of drug response in the affective disorders: Toward an integrated approach. In: Psychopharmacology: A generation of progress, ed. M. A. Lipton, A. DiMascio, & K. F. Killam, pp. 1277-88. New York: Raven Press. [taHA] Goodwin, F. K., & Post, R. M. (1974) Brain serotonin affective illness and antidepressant drugs: Cerebrospinal fluid studies with probenecid. In: Serotonin -new vistas: Biochemistry, behavioral and clinical studies, ed. E. Costa, G. L. Gessa, & M. Sandier, pp. 341-56. New York: Raven Press. [taHA] (1975) Cerebrospinal fluid amine metabolites in affective illness and schizophrenia: Clinical and pharmacological studies. Psychopharmacology Communications 1:641-53. [taHA] Goodwin, F. K. & Potter, W. Z. (1979) Norepinephrine metabolite studies in affective illness. In: Catecholamines: Basic and clinical frontiers, Vol. 2, ed. E. Usdin, I. J. Kopin, & J. Barchas, pp. 1863-65. New York: Pergamon Press. [taHA] Gordon, E. K. & Oliver, J. (1971) 3-Methoxy-4-hydroxyphenylethylene glycol in human cerebrospinal fluid. Clinical Chemistry Ada 35:145-50. [taHA] Greenspan, K., Schildkraut, J. J., Gordon, E. K., Baer, L., Aranoff, M. S., & Durrell, J. (1970) Catecholamine metabolism in affective disorders: 3. MHPG and other cateeholamine metabolites in patients treated with lithium carbonate. Journal of Psychiatric Research 7:171-83. [taHA] Greenspan, J., Schildkraut, J. J., Cordon, E. K., Levy, B., & Durrell, J. (1969) Catecholamine metabolism in affective disorders: 2. Norepinephrine, normetanephrine, epinephrine, metanephrine and VMA excretion in hypomanic patients. Archives of General Psychiatry 21:710-16. [taHA] Greer, S. (1964) The relationship between parental loss and attempted suicide: A control study. British Journal of Psychiatry 110:698-705. [taHA] Griswold, M. J. (1970) Life events, divorce, and sequelae of divorce: A pilot study. Unpubl. manuscript. Seattle: University of Washington. [SRB] Hall, K. S., Dunner, D. L., Zeller, C , & Fieve, R. R. (1979) Bipolar illness: A prospective study of life events. Comprehensive Psychiatry 18:497502. [RNJ Hamilton, V. (1979a) Personality and stress. In: Human stress and cognition: An information-processing approach, ed. V. Hamilton & D. M. Warburton, pp. 67-114. Chichester: Wiley. [VH] (1979b) Information-processing aspects of neurotic anxiety and the schizophrenias. In: Human Stress and cognition: An information-processing approach, ed. V. Hamilton & D. M. Warburton, pp. 383-430. Chichester: Wiley. [VH] Hamilton, V. & Warburton, D. M. (1979) Human stress and cognition: An information-processing approach. Chichester: Wiley. IVH] Hammen, C. L. & Cochran, S. D. (1981) Cognitive correlates of life stress and depression in college students. Journal of Abnormal Psychology 90:2327. [WPS] Harlow, H. F. (1974) Induction and alleviation of depressive states in monkeys. In: Ethology and psychiatry, ed. N. F. White. Toronto: University of Toronto Press. [DdeC] Harlow, H. & Harlow, M. (1965) The affectional system. In: Behavior of nonhuman primates: Modern research trends, vol. 2., ed. A. Schrier, H. Harlow, & F. Stollnitz, pp. 287-334. New York: Academic Press. [JED] Heinicke, C. (1973) Parental deprivation in early childhood. In: Separation and depression: Clinical and research aspects, ed. J. Scott and E. Senay. Washington, D.C.: AAAS. [taHA] Hellhammer, D. H., Hingtgen, J. N., Wade, S. E., Shea, P. A., & Aprison, M. H. (1982, in press) Biogenic amine changes in specific areas of rat brain associated with gastric lesions produced by two types of behavioral stress. Proceedings of the First World Congress of International Brain Research Organization. Lausanne. [JNH] Hendrie, H. (1978) Organic brain disorders: Classification, the symptomatic psychoses, misdiagnosis. Psychiatric Clinics of North America 1:319. [HSA] Hendrie, H. C. (1981) Depression in the course of physical illness. In: Machine pacing and occupational stress, ed. G. Salvendy. In press. London: Taylor and Francis Ltd. [JNH] Henry, A. & Short, J. (1954) Suicide and homicide. Glencoe, III.: Free Press. [DL] Henry, J. P. & Stephens, P. M. (1977) Stress, health, and the social environment: A sociobiologic approach to medicine. New York: SpringerVerlag. [JED] Herman, B. H., & Panskepp, J. (1981) Ascending endorphin inhibition of distress vocalization. Science 211:1060-62. [LDH] Hill, O. (1969) The association of childhood bereavement with suicidal attempt in depressive illness. British Journal of Psychiatry 115:301-04. [taHA] Hill, O. W. & Price, J. S. (1967) Childhood bereavement and adult depression. British Journal of Psychiatry 113:743-51. [taHA] Hinkle, L. E. (1974) The effect of exposure to culture change, social change, and changes in interpersonal relationships on health. In: Stressful life events: Their nature and effects, ed. B. P. Dohrenwend & B. S. Dohrenwend, pp. 9-44. New York: John Wiley. [taHA] Hingtgen, J. N., Smith, J. E., Shea, P. A., Aprison, M. H., & Gaff, T. M. (1976) Cholinergic changes during conditioned suppression in rats. Science 193:332-34. [taHA, JNH] Hollister, A. S., Breese, G. R., Kuhn, C. M., Cooper, B. R., & Schanberg, S. M. (1976) An inhibitory role for brain serotonin-containing systems in the locomotor effects of d-amphetamine. Journal of Pharmacology and Experimental Therapeutics 198:12-22. [KMN] Hollister, L. E., Davis, K. L., & Berger, P. A. (1980) Subtypes of depression based on excretion of MHPG and response to nortripyline. Archives of General Psychiatry 37:1107-10. [taHA] Hollon, S. D., & Beck, A. T. (1979) Cognitive therapy of depression. In: Cognitive-behavioral interventions, ed. P. C. Kendall & S. D. Hollon. New York: Academic Press. [WPS] Holmes, T. H. & Rahe, R. H. (1967) The social readjustment scale. Journal of Psychosomatic Research 11:213-18. [taHA] Hopldnson, G. & Reed, G. F. (1966) Bereavement in childhood and depressive psychosis. British Journal of Psychiatry 112:459-63. [taHA] Horowitz, M. (1979) Psychological response to serious life events. In: Human Stress and cognition: An information-processing approach, ed. V. Hamilton & D. M. Warburton, pp. 237-264. Chichester: Wiley. [VH] Horowitz, M., Schaefer, C , Hiroto, D., et al. (1977) Psychosomatic Medicine 39:413-31. [RN] Huang, Y. (1979) Chronic desipramine treatment increases activity of noradrenergic postsynaptic cells. Life Sciences 25:709-16. [tarHA, STM] Huang, Y. H., & Maas, J. W. (1980) The time course of noradrenergic presynaptic and postsynaptic activity during chronic desipramine treatment. European Journal of Pharmacology 68:41-47. [STM] Hudgens, R., Morrison, J., & Barchha, R. (1967) Life events and onset of

132

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

References/Anisman & Zacharko: Depression and stress

primary affective disorders. Archives ofGeneral Psychiatry 16:13445. [taHA] Hudgcns, R. W., Robins, E., & Delong, W. B. (1970) The reporting of recent stress in the lives of psychiatric patients. British Journal of Psychiatry 117:635-43. |RN) Isen, A. M., Shalker, T. E., Clark, M., & Karp, L. (1978). Affect, accessibility of material in memory and behavior: A cognitive loop? Journal of Personality and Social Psychology 36:1 -12. [VH] Jacobs, S. & Douglas, L. (1979) Grief: A mediating process between a loss and illness. Comprehensive Psychiatry 20:165-76. [SRB] Jacobs, S. C , Prusoff, B. A., & Paykel, E. S. (1974) Recent life events in schizophrenia and depression. Psychological Medicine 4:444-53. [taHA, DL] Janowsky, D. S., & Davis, J. M. (1979) Psychological effects of cholinomimetie agents. In: Brain acetylcholine and newopsychiatric disease, ed. K. L. Davis & P. A. Berger, pp. 3-14. New York: Plenum Press. [KMN] Janowsky, D. S., el-Yousef, M. K., Davis, J. M., Hubbard, B., &Sekerke, H. J. (1972) Cholinergic reversal of manic symptoms. Lancet 1:12361237. [taHA] Janowsky, D. S., el-Yousef, M. K., Davis, J. M., & Sekerke, H. J. (1972) A cholinergie-adrenergic hypothesis of mania and depression. Lancet 2:63235. [taHA, KMN] (1973a) Parasympathetic suppression of manic symptoms by physostigmine. Archives of General Psychiatry 28:542-547. [taHA] (1973b) Provocation of schizophrenic symptoms by intravenous methylphenidate. Archives of General Psychiatry 28:185-191. [taHA] Jenkins, C. D., Hurst, M. W., & Rose, R. M. (1979) Life changes: Do people really remember? Archives of General Psychiatry 36:379-84. [taHA, RN] Kalisker, A., Rutledge, C. O., & Perkins, J. P. (1973) Effect of nerve degeneration by 6-hydroxydopamine on cateeholamine-stimulated adenosine 3', 5'-monophosphate formation in rat cerebral cortex. Molecular Pharmacology 9:619-29. [EAS] Karczmar, A. G. (1975) Cholinergic influences on behavior. In: Cholinergic mechanisms, ed. P. G. Waser, pp. 501-29. New York: Raven Press. [rHA] Karczmar, A. G., Scudder, C. L., & Richardson, D. L. (1973) Interdisciplinary approach to the study of behavior in related mice types. In: Chemical approaches to brain function, ed. S. Ehrenpreis & I. J. Kopin, pp. 159-244. New York: Academic Press. [taHA] Katz, H. I., Chase, T. N., & Kopin, I. J. (1969) Effect of ions on stimulus-induced release of amino acids from mammalian brain slices. Journal of Ni-urochemistry 16:961-67. [KMN] Katz, R. J., Roth. K. A., & Carroll, B. A. (1981) Acute and chronic stress effects on open field activity in the rat: Implications for a model of depression. Neurosciencc and Blohchavioral Reviews 5:247. [ADS] Kiely, VV. F. (1975) From the symbolic stimulus to the pathophysiological response: Immune mechanisms. International Journal of Psychiatric Medicine 5:517-29. [SRB] Klein, D. C , & Seligman, M. E. P. (1976) Reversal of performance deficits in learned helplessness and depression. Journal of Abnormal Psychology 85:11-26. (taHA] Klinger, E. (1975) Consequences of commitment to and disengagement from incentives. Psychological Review 82:1-25. [SRB] Kobayashi, R. M., Palkovits, M., Kizer, J. S., Jacobowitz, D. M., & Kopin, I. J. (1976) Selective alterations of catecholamines and tyrosine hydroxylase activity in the hypothalamus following acute and chronic stress. In: Catecholamines and stress, ed. E. Usdin, R. Kvetnansky, & I. J. Kopin, pp. 29-38. Oxford: Pergamon Press. [taHA] Koella, W. P. (1974) Serotonin: A hypnagogic transmitter and an anti-waking agent. Advances in Biochemical Psychopharmacology 11:181-86. [KMN] Kokkinidis, L. & Anisman, H. (1980) Amphetamine models of paranoid schizophrenia: An overview and elaboration of animal experimentation. Psychological Bulletin 88:551-79. [rHA] Korf, J., Sebens, J. B., & Postema, F. (1979) Cyclic AMP in the rat cerebral cortex after stimulation of the locus coeruleus: Decrease by antidepressant drugs. European Journal of Pharmacology 59:23-30. [rHA] Kraemer, G. W., Breese, G. R., Prange, A. J., Moran, E. C , Lewis, J. K., Kemnitz, J. W., Bushnell, P. J., Howard, J. L., & McKinney, W. T. (1981) Use of 6-hydroxydopamine to deplete brain catecholamines in the rhesus monkey: Effects on urinary catecholamine metabolites and behavior. Psychopharmacology 73:1-11. [GWK] Kraemer, G. VV. & McKinney, W. T. (1979) Interactions of pharmacological agents which alter bigenic amine metabolism and depression: An analysis of contributing factors within a primate model of depression. Journal of Affective Disorders 1:33-54. [HSA, GWK] Kraepelin, E. (1923) U-hrbuch der Psychiatric. New York: A. R. Diependorf, Macmillan. [STM] Kragh, U. (1960) The defence mechanism test: A new method for diagnosis and personnel selection. Journal of Applied Psychology 44:303-09. [RM] Kupfer, D. J., & Detre, T. P. (1978) Tricyclieand monoamine-oxidase-inhibitor antidepressants: Clinical use. In: Handbook of psychopharmacology, vol. 14, ed. L. L. Iversen, S. D. Iversen, & S. H. Snyder, pp. 199-232. New York: Plenum Press. [taHA] Kupfer, D. J. & Foster, F. G. (1972) Interval between onset of sleep and rapid eye movement sleep as an indicator of depression. Lancet 2:684-86. IJED] Kvetnansky, R. (1980) Recent progress in catecholamines under stress. In: Catecholamines and stress: Recent advances, ed. E. Usdin, R. Kvetnansky, & I. J. Kopin, pp. 7-20. New York: Elsevier. [taHA] Kvetnansky, R., Mitro, A., Palkovits, M., Brownstein, M., Torda, T., Vigas, M., & Mikulaj, L. (1976) Catecholamines in individual hypothalamic nuclei in stressed rats. In: Catecholamines and stress, ed. E. Usdin, R. Kvetnansky, & I. J. Kopin, pp. 39-50. Oxford: Pergamon Press. [taHA] Laborit, H. (1974) Proposition d u n modeleintegredescomportements normaux et anormaux a partir de donnees biochimiques, neurophysiologiques, ethologiques, chimiques et sociologiques. Annales Medico-Psychologiques. 1:47-60. [HL] (1976) On the mechanism of activation of the hypothalamus-pituitary-adrenal reaction to changes in the environment (the "alarm reaction"). Resuscitation 5(1): 19-30. [HL] (1979) L'Inhibition de l'action: Biologic, physiologic psychologie, sociologie, vol. 1. Paris: Masson et cie. [HL] (1981) Physiopathologie de l'inhibition et proposition d'une reponse therapeutique originale. Agressologie 22(2):45-53. [HL] Laborit, H., Baron, C , Ferran, C , Bonifacj, J.-F., Topall, G., & Henriet, I. (1980) Variations de la toxicite du cadmium en rapport avec les possibility de controle des situations environnementales par l'activite motrice chez le rat. Agressologie 21(6):269-90. [HL] Laborit, H., Brunaud, M., Savy, J.-M., Baron, C., Vallee, E., Lamothe, C , Thuret, F., Muyard, J.-P., & Calvino, B. (1972) Etude biochimique et pharmacologique du 3/2 morpholinoethylamino 4-methyl 6-phenyl pyridazine dechlorhydrate (Agr 1240), Agressologie 13(5):291-318. [HL] Lader, M. (1975) The psychophysiology of mental illness. London: Routledge & Kegan Paul. [VH] Lapin, I. P. & Oxenkrug, G. F. (1969) Intensification of the central serotonergic process as a possible determinant of the thymoleptic effect. Lancet 2:13236. [KMN] Lazarus, R. S. & Launier, R. (1978) Stress-related transactions between person and environment. In: Internal and External Determinants of Behavior, ed. L. A. Pervin & M. Lewis. New York: Plenum Press. [SRB, WPS] Leconte, P. & Hennevin, E. (1981) Post-learning paradoxical sleep, reticular activation and noradrenergic activity. Physiology and Behavior 26:58794. [STM] Leff, M. J., Roatch, J. F., & Bunney, W. E. (1970) Environmental factors preceding the onset of severe depressions. Psychiatry 33:298-311. [taHA] Leshner, A. I. (1977) Hormones and emotion: In: Emotion, ed. D. K. Candland, J. P. Fell, E. Keen, A. I. Leshner, R. Plutchik, & R. M. Tarpy, pp. 85-148. Monterey: Brooks/Cole Publishing Company. [AIL] (1978) An introduction to behavioral endocrinology. New York: Oxford University Press. [AIL] (1979) Kinds of hormonal effects on behavior: A new view. Neuroscicnce and Biobehavioral Reviews 3:69-73. [AIL] Levi, L. D., Fales, C. H., Stein, M., & Sharp, V. H. (1966) Separation and attempted suicide. Archives of General Psychiatry 15:158-65. [taHA] Levine, S., Madden, J., Conner, R. L., Moskal, J. R , & Anderson, D. C. (1973) Physiological and behavioral effects of prior aversive stimulation (preshock) in the rat. Physiology and Behavior 10:467-71. [RM] Lewinsohn, P. M. & Amenson, C. S. (1978) Some relations between pleasant and unpleasant mood-related events and depression. Journal of Abnormal Psychology 87:644-54. [taHA] Lewinsohn, P. M., Youngren, M. A., & Grosscup, S. J. (1979) Reinforcement and depression. In: The psychobiology of the depressive disorders, ed. R. A. Depue, pp. 291-316. New York: Academic Press. [KMN] Lindemann, E. (1944) Symptomatology and management of acute grief. American Journal of Psychiatry 101:141-48. [SRB] Lints, C. E., & Harvey, J. A. (1969) Drug induced reversal of brain damage in the rat. Physiology and Behavior 4:29-31. [KMN] Lloyd, C. (1980a) Life events and depressive disorder reviewed: 1. Events as predisposing factors. Archives of General Psychiatry 37:529-35. [taHA, WPS] (1980b) Life events and depressive disorder reviewed: 2. Events as precipitating factors. Archives of General Psychiatry 37:541 -48. [taHA, ATB, WPS] Lloyd, K. G., Farley, J. J., Deck, G. H. N., & Hornykiewicz, O. (1974) Serotonin and 5-hydroxyindoleacetic acid in discrete areas of the brainstem of suicide victims and control patients. Advances in Biochemistry and Psychopharmacology 11:387-97. [taHA] Luria, A. (1973) The working brain. New York: Basic Books. [RMB] Lytle, L. D., Messing, R. B., Fisher, L., & Phebus, L. (1975) Effects of

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

133

Re/erences/Anisman & Zacharko: Depression and stress

long-term corn consumption on brain serotonin and the response to electric shock. Science 190:692-94. [KMN] Maas, J. W. (1975) Catecholamines and depression: A further specification of the catecholamine hypothesis of the affective disorders. In: Catecholamines and behavior, vol. 2, ed. A. J. Friedhoff, pp. 119-34. New York: Plenum Press. |taHA] Maas, J. W., Fawcett, J. A., & Dekirmenjian, H. (1972) Catecholamine metabolism, depressive illness and drug response. Archives of General Psychiatry 26:252-61. [taHA] Maas, J. W., Dekirmenjian, H., Carver, D., Redman, D. E., & Landis, D. H. (1973) Excretion of catecholamine metabolites following intraventricular injection of 6-hydroxydopamine in the macaca speciosa. European Journal of Pharmacology 23:121-30. [taHA] Maas, J. W., Dekirmenjian, H., & Jones, F. (1973) The identification of depressed patients who have a disorder of norepinephrine metabolism and/or disposition. In: Frontiers of catecholamine research, ed. E. Usdin & S. Snyder, pp. 1091-96. New York: Pergamon Press. [taHA] Maas, J. W., Creene, N. M., Hattox, S. E., & Landis, D. H. (1979) Neurotransmitter metabolite production by human brain. In: Catecholamines: Basic and clinical frontiers, ed. E. Usdin, I. J. Kopin, & J. Barchas, pp. 1878-80. New York: Pergamon Press. [taHA] Maas, J. W. & Huang, Y. (1980) Noradrenergic function and depression: Too much or too little? Canadian Journal of Neurological Sciences 7:26768. [tarHA, STM, DKR] Mackintosh, N. J. (1965) Selective attention in animal discrimination learning. Psychological Bulletin 64:124-50. [STM] Maranon, C. (1924) Contribution a l'etude de l'action emotive de l'adrenaline. Revue Franqaise dEndocrinologie 2:301-25. [AIL] Mason, S. T. (1979a) Noradrenaline and behavior. Trends in Neurosdence 2:82-84. [STM] (1979b) Noradrenaline: Reward or extinction? Neurosdence and Biobehaoioural Reviews 3:1-10. [STM] (1980) Noradrenaline and selective attention: A review of the model and the evidence. Ufe Sciences 27:617-31. [STM] (1981) Noradrenaline in the brain: Progress in theories of behavioural function. Progress in Neurobiology (in press). [STM] Mason, S. T. & Fibiger, H. C. (1978a) Evidence for a role of brain noradrenaline in attention and stimulus sampling. Brain Research 159:421-26. [STM] (1978b) 6-OHDA lesions of the dorsal noradrenergic bundle alters extinction of passive avoidance. Brain Research 152:209-14. [STM] (1979) Noradrenaline and extinction of conditioned taste aversion. Behavioral and Neural Biology 25:206-16. [STM] Mason, S. T. & Iversen, S. D. (1975) Learning in the absence of forebrain noradrenaline. Nature 258:422-24. [STM] (1977) Effects of selective forebrain noradrenaline loss on behavioral inhibition in the rat. Journal of Comparative and Physiological Psychology 91:16573. [STM] (1979) Theories of the dorsal bundle extinction effect. Brain Research Reviews 1:107-37. [STM] May, J. R. & Johnson, H. J. (1973) Physiological activity to internally elicited arousal and inhibitory thoughts. Journal of Abnormal Psychology 82:23945. [ATB] McDonald, B. S., Pugh, W. M., Gunderson, E. K. E., & Rahe, R. H. (1972) Reliability of life change cluster scores. British Journal of Social and Clinical Psychology 11:407-09. IRNj McLure, D. J. (1973) The role of dopamine depression. Canadian Psychiatric Association Journal 18:309-12. [taHA] Mendels, J., Fraser, A., Fitzgerald, R. C , Ramsay, T. A., & Stokes, J. W. (1972) Biogenic amine metabolites in cerebrospinal fluid in depressed and manic patients. Science 175:1380-82. [taHA] Miller, W. R. & Seligman, M. E. P. (1976) Learned helplessness, depression and the perception of reinforcement. Behavior Research and Therapy 14:717. [taHA] Modigh, K. (1976) Influence of social stress on brain catecholamine mechanisms. In: Catecholamines and stress, ed. E. Usdin, R. Kvetnansky, &I. J. Kopin, pp. 17-28. Oxford: Pergamon Press. [taHA] Morris, J. & Beck, A. (1974) The efficacy of antidepressant drugs: A review of research (1958-1972). Archives of General Psychiatry 30:667-74. [DLC] Morrison, J., Hudgens, R., & Barchha, R. (1968) Life events and psychiatric illness. British Journal of Psychiatry 114:423-32. [taHA] Moruzzi, G. & Magoun, H. W. (1949) Brain stem reticular formation and activation of the EEC. Electroencephalography and Clinical Neurophysiology 1:455-73. [RM] Munro, A. (1966) Parental deprivation in depressive patients. British Journal of Psychiatry 112:443-457. [taHA] Munro, A. & Griffiths, A. B. (1969) Some psychiatric nonsequelae of childhood bereavement. British Journal of Psychiatry 115:305-11. [taHA] Murison, R. & Isaksen, E. (1980) The effects of preshock on adrenocortical and somatic responses to later restraint stress. IRCS Medical Science 8:88889. [RM] Murphy, D. L., Campbell, I., & Costa, J. L. (1978) Current status of the indoleamine hypothesis of the affective disorders. In: Psychopharmacology: A generation of progress, ed. M. A. Lipton, A. DiMascio, & K. F. Killam, pp. 1235-48. New York: Raven Press. [taHA] Nagayama, H., Hingtgen, J. N., &Aprison, M. H. (1980) Pre- and post-synaptic serotonergic manipulations in an animal model of depression. Pharmacology, Biochemistry and Behavior 13:575-79. [JNH] (1981) Postsynaptic action by four antidepressive drugs in an animal model of depression. Pharmacology, Biochemistry and Behavior 15:125-30. [JNH] Nakai, Y. & Takaori, S. (1974) Influence of norepinephrine-containing neurone derived from locus coeruleus on lateral geniculate neuronal activities in cats. Brain Research 71:47-60. [STM] Nordin, G., Ottosson, J. O., & Roos, B. E. (1971) Influence of convulsive therapy of 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid in endogenous depression. Psychopharmacologia 20:315-20. [taHA] Olds, M. E., & Olds, J. (1962) Approach-escape interactions in rat brain. American Journal of Physiology 203:803-10. [KMN] Olpe, H.-R. & Schellenberg, A. (1980) Reduced sensitivity of neurons to noradrenaline after chronic treatment with antidepressant drugs. European Journal of Pharmacology 63:7-13. [rHA] Oswald, I., Brezinova, V., & Dunleavy, D. L. F. (1972) On the slowness of action of tricyclic antidepressant drugs. British Journal of Psychiatry 120:673-77. [GRH] Overall, J. E., Hollister, L. E., Pokorny, A. D., Casey, J. F., & Katz, G. (1962) Drug therapy in depressions: Controlled evaluation of imipramine, isocarboxazid, dextroamphetamine, amobarbitol, and placebo. Clinical Pharmacology Therapeutics 3:16. [GRH] Owen, S., Boarder, M. R., & Gray, J. A. (1977) The effects of depletion of forebrain noradrenaline on runway behavior in rats. Experimental Brain Research 28:R22-R23. [STM] Palkovits, M., Brownstein, M., Kizer, J. S., Saavedra, J. M., & Kopin, I. J. (1976) Effect of stress on serotonin and tryptophan hydroxylase activity of brain nuclei. In: Catecholamines and stress, ed. E. Usdin, R. Kvetnansky, & I. J. Kopin, pp. 51-59. Oxford: Pergamon Press. [taHA] Papeschi, R. & McLure, D. J. (1971) Homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid in depressed patients. Archives of General Psychiatry 25:355-58. [taHA] Pare, C. M. B., Yeung, D. P. H., Price, K., & Stacey, R. S. (1969) 5-hydroxytryptamine in brainstem, hypothalamus and caudate nucleus of controls and of patient committing suicide by coal-gas poisoning. Lancet 2:133-35. [taHA] Parkes. C. M. (1964) Recent bereavement as a cause of mental iflness. British Journal of Psychiatry 110:198-204. [taHA] Paykel, E. S. (1974) Life stress and psychiatric disorder. In: Stressful life events: Their nature and effects, ed. B. S. Dohrenwend & B. P. Dohrenwend. New York: John Wiley. [taHA] (1976) Life stress, depression, and attempted suicide. Journal of Human Stress 2:3-12. [HSA] (1979) Recent life events in the development of the depressive disorders. In: The psychobiology of the depressive disorders, ed. R. A. Depue, pp. 245-62. New York: Academic Press. [taHA, WPS] Paykel, E. S., DiMascio, A., Haskell, D., & Prusoff, B. A. (1975) Effects of maintenance amitriptyline and psychotherapy on symptoms of depression. Psychological Medicine 5:67-77. [taHA] Paykel, E., Myers, J. K., Dienelt, M. N., Klerman, G. L., Lindenthal, J. J., & Pepper, M. P. (1969) Life events and depression. Archives of General Psychiatry 21:753-60. [taHA] Paykel, E. S., Prusoff, B. A., & Uhlenhuth, E. H. (1971) Scaling of life events. Archives of General Psychiatry 25:340-47. [taHA, WPS] Paykel, E. S. & Tanner, J. (1976) Life events, depressive relapse and maintenance treatment. Psychological Medicine 6:481-85. [taHA] Payne, R. W., Ancevich, S. S., & Laverty, S. G. (1963) Overinclusive thinking in symptom-free schizophrenics. Canadian Psychiatric Association Journal 8:225-34. [STM] Payne, R. W. & Friedlander, D. (1962) A battery of simple tests for measuring overinclusive thinking. Journal of Mental Science 108:362-67. [STM] Peters, D. A. V., Anisman, H. & Pappas, B. A. (1978) Monoamines and aversively motivated behaviors. In: Psychopharmacology of aversivcly motivated behaviors, ed. H. Anisman & G. Bignami, pp. 257-343. New York: Plenum Press. [rHA] Petty, F. & Sherman, A. D. (1980a) Reversal of learned helplessness by imipramine. Communications in Psychopharmacology 3:371. [ADS] (1980b) A neurochemical differentiation between exposure to stress and development of learned helplessness. Drug Development Research (in press). [ADS] Pisa, M. & Fibiger, H. C. (1980) Noradrenaline and discrimination learning:

134

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

ReferencesVAnisman & Zacharko: Depression and stress

Failure to support the attentional hypothesis. Society for Neurosdence Abstracts 6:724. [rHA] Flaznik, A. 6c Kostowsld, W. (1980) Locus coeruleus lesions and avoidance behaviour in rats. Ada Seurobiology Experentia 40:217-25. [STM] Poschel, B. P. H. & Ninteman, F. W. (1971) Intracranial reward and the forebrain's serotonergic mechanism: Studies employing parachlorophenylalanine and para-chloroamphetamine. Physiology and Behavior 7:39-46. [KMN] Post, R. M. (1978) Frontiers in affective disorder research: New pharmacological agents and new methodologies. In: Psychopharmacology: A generation of progress, ed. M. A. Lipton, A. DiMascio, & K. F. Killma, pp. 1323-36. New York: Raven Press. [taHA] Post, R. M., & Goodwin, F. K. (1978) Approaches to brain amines in psychiatric patients: A reevaluation of cerebrospinal fluid studies. In: Handbook of Psychopharmacology, vol. 13, ed. L. L. Iversen, S. D. Iversen, 6c S. H. Snyder. New York: Plenum Press. [taHA] Post, R. M., Gordon, E. K., Goodwin, F. K., & Bunney, W. E., Jr. (1973) Central norepinephrine metabolism in affective illness: MHPG in the cerebrospinal fluid. Science 179:1002-03. [taHA] Post, R. M., Jimerson, D. C., Reus, V. I., Goodwin, F. K., Silberman, E., & Bunney, W. E. (1979) Dopaminergic agents in affective illness: Studies with pirebidil, amphetamine, and pimozide. In: Catecholamines: Basic and clinical frontiers, vol. 2, ed. E. Usdin, I. J. Kopin, & J. Barchas, pp. 1899-1901. New York: Pergamon Press. [taHA] Post, R. M., Kopin, J., & Goodwin, F. K. (1974) The effects of cocaine on depressed patients. American Journal of Psychiatry 131:511-17. [GRH] Post, R. M., Kotin, J. K., Goodwin, F. K., & Gordon, E. K. (1973) Psychomotor activity and cerebrospinal fluid amine metabolites in affective illness. American Journal of Psychiatry 130:67-72. [taHA] Prange, A., Wilson, I., Lynn, C. W., et al. (1974) L-tryptophan in mania: Contribution to a permissive hypothesis of affective disorders. Archives of General Psychiatry 30:56-62. [KMN, WTM] Rabkin, J. G. & Streuning, E. L. (1976) Life events, stress, and illness. Science 194:1013-20. [taHA] Rahe, R. H., Romo, M., Bennett, L., 6c Siltanen, P. (1974) Recent life changes, myocardial infarction, and abrupt coronary death. Internal Medicine 133:221-28. [RN] Ray, O. S. ot Barrett, R. J. (1975) Behavioral, pharmacological and biochemical analysis of genetic differences in rats. Behavioral Biology 15:391418. (taHA] Redmond, D. E. Jr. & Huang, Y. H. (1979) New evidence for a locus coeruleus-norepincphrine connection with anxiety. LAfe Sciences 25:214962. [rHA] Rennie, T. C. (1942) Prognosis in manic-depressive psychoses. American Journal of Psychiatry 98:801-14. [DL] Reynolds, S. H., ed. (1892) The table talk of John Selden. London: Oxford University Press. [RN] Ridley, R. M., Haystead, T. A. J., Baker, H. F., 6c Crow, T. J. (1981) A new approach to the role of noradrenaline in learning: Problem-solving in the marmoset after alpha-noradrenergic receptor blockade. Pharmacology, Biochemistry 6 Behavior 14:849-55. [STM] Rimin, D. C. 6c Litvak, S. B. (1969) Self-verbalization and emotional arousal. Journal of Abnormal Psychology 74:181-87. [ATB] Ritter, S. 6c Pelzer, N. L. Magnitude of stress-induced brain norepinephrine depletion varies with age. Brain Research 152:170-75. [taHA] Ritter, S., Pelzer, N. L., 6c Ritter, R. C. (1978) Absence of glucoprivic feeding after stress suggests impairment of noradrenergic neuron function. Brain Research 149:399-411, [STM] Roberts, D. C. S., Price, M. T. C , & Fibiger, H. C. (1976) The dorsal tegmental noradrenergic projection: Analysis of its role in maze learning. Journal of Comparative and Physiological Psychology 90:363-72. [STM] Rogers, T. 6c Craighead, W. E. (1977) Physiological responses to selfstatements: The effects of statement valence and discrepancy. Cognitive Therapy and Research 1:99-120. [ATB] Roos, B. E., & Sjostrom, R. (1969) 5-hydroxyindoleacetic acid (and homovanillic acid) levels in the CSF after probenecid application in patients with manic depressive psychosis. Clinical Pharmacology 1:153-55. [taHA] Rosenthal, T. L. (1980) Social cueing processes. In: Progress in behavior modification, ed. M. Hersen, R. Eisler, fit P. M. Miller, vol. 10, pp. 111-46. New York: Academic Press. [TLR] (in press) On the significance of differences between social learning and cognitive-behavioral conceptions: Type I and type II errors. In: Handbook of behavior therapy, ed. C. M. Franks 6c G. T. Wilson. New York: Guilford Press. [TLR] Rosenthal, T. L., Akiskal, H. S., Scott-Strauss, A., Rosenthal, R. H., & David, M. (1981) Familial and developmental factors in characterological depressions. Journal of Affective Disorders 3:183-92. [TLR] Rosenthal, T. L. 6c Bandura,. A. (1978) Psychological modeling: Theory and practice. In: Handbook of psychotherapy and behavior change, ed. S. L. Garfield 6c A. E. Bergin, 2nd ed., pp. 621-58. New York: Wiley. [TLR] Rosloff, B. N. & Davis, J. M. (1974) Effects of iprindole on norepinephrine turnover and transport. Psychopharmacologia (Berl.) 40:53-64. [GRH] Roy, A. (1978) Vulnerability factors and depression in women. Psychiatry 133:106-10. [taHA] Russell, P. L. 6c Brandsma, J. M. (1974) A theoretical and empirical investigation of the rational-emotive and classical conditioning theories. Journal of Consulting and Clinical Psychology 42:389-97. [ATB] Sachar, E. J. 6c Coppen, A. J. (1975) Biological aspects of affective psychoses. In: Biology of brain dysfunction, ed. G. E. Gaull, pp. 215-45. New York: Plenum Press. [taHA] Sachar, E. J., Hellman, L., Roffwarg, H., et al. (1973) Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Archives of General Psychiatry 28:19-24. [JED] Salzinger, K., Portnoy, S., 6c Feldman, R. S. (1966) In: Psychopathology of schizophrenia, ed. P. H. Hoch & J. Zubin. New York: Grune 6c Stratton. [STM] Sasa, M., 6cTakaori, S. (1973) Influence of the locus coeruleus on transmission in the spinal trigeminal nucleus neurons. Brain Research 55:203-08. [STM] Schildkraut, J. J. (1965) The catecholamine hypothesis of affective disorders: A review of supporting evidence. American Journal of Psychiatry 122:50922. [KMN] (1970) Neuropsychopharmacology and the affective disorders. Boston: Little Brown. [taHA] (1973) Norepinephrine metabolites as biochemical criteria for classifying depressive disorders and predicting responses to treatment: Preliminary findings. American Journal of Psychiatry 130:695-99. [taHA] (1974) Biogenic amines and affective disorders. Annual Review of Medicine 25:333-48. [taHA] (1978) Current status of the catecholamine hypothesis of affective disorders. In: Psychopharmacology: A generation of progress, ed. M. A. Lipton, A. DiMascio, 6c K. F. Killam, pp. 1223-34. New York: Raven Press. [taHA, GWK] (1978) Current status of the eatecholamine hypothesis of affective disorders. In: Progress in neuropsychopharmacology, vol. 2, pp. 5-31. Oxford: Pergamon Press. [JED] Schildkraut, J. J., Keeler, B. A., Grob, E. L., Kantrowich, J., & Hartmann, E. (1973) MHPG excretion as clinical classification in depression. Lancet 1:1251-52. [taHA] Schildkraut, J. J., Orsulak, P. J., Schatzberg, A. F., Gudeman, J. E., Cole, J. O., LaBrie, R. A., & Rohde, W. A. (1979) Biochemical discrimination of subtypes of depressive disorders. In: Catecholamines: Basic and clinical frontiers, vol. 2, ed. E. Usdin, I. J. Kopin, & J. Barchas, pp. 1860-62. New York: Pergamon Press. [taHA] Schildkraut, J. J., Winokur, A., 6c Applegate, C. W. (1970) Norepinephrine turnover and metabolism in rat brain after long-term administration of imipramine. Science 1168:867-69. [taHA] Schless, A. P. 6c Mendels, J. (1978) The value of interviewing family and friends in assessing life stressors. Archives of General Psychiatry 35:565-67. [RN] Schmale, A. H. (1958) Relationship of separation and depression to disease. Psychosomatic Medicine 20:259. [SRB] Schuster, D. H. 6c Schuster, L. (1969) Study of stress and sex ratio in humans. Proceedings, 77th Annual Convention, APA, pp. 335-336. [SRB] Segal, D. S., Kuczenski, R., 6c Mandell, A. J. (1974) Theoretical implications of a drug-induced adaptive regulation for a biogenic amine hypothesis of affective disorder. Biological Psychiatry 9:147-59. [taHA] Segal, M. & Sandberg, D. (1977) Analgesia produced by electrical stimulation of catecholamine nuclei in the rat brain. Brain Research 123:369-72. [STM] Seiden, L. S. (1976) The role of catecholamines in the action of drugs affecting behavior. Pharmacological Therapy 2:155-65. [KMN] Seligman, M. E. P. (1975) Helplessness: On depression, development and death. San Francisco: W. H. Freeman. [taHA, JED] Seligman, M. E. P. & Groves, D. (1970) Non-transient learned helplessness. Psychonomic Science 19:191-92. [DKR] Seligman, M. E. P., Klein, D. C , 6c Miller, W. R. (1976) Depression. In: Handbook of behavior modification and behavior therapy, ed. H. Leitenberg. Englewood Cliffs, N.J.: Prentice-Hall. [taHA] Seligman, M. E. P. & Maier, S. F. (1967) Failure to escape traumatic shock. Journal of Experimental Psijchology 74:1. [ADS] Seligman, M. E. P., Weiss, J. M., Weinraub, M., 6c Schulman, A. (1980) Coping behavior: Learned helplessness, physiological change and learned inactivity. Behavior Research 6 Therapy 18:459-512. [DKR] Selye, H. (1936) A syndrome produced by diverse nocuous agents. Nature 138:32. [RM] (1973) The evolution of the stress concept. American Scientist 61:69299. [taHA, DdeC] Serra, G., Argiolas, A., Fadda, F. 6c Gessa, G. L. (1980) Hyposensitivity of THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

135

References/Anisman & Zacharko: Depression and stress

dopamine "autoreceptors" induced by chronic administration of tricyclic antidepressants. Pharmacological Research Communications 12:61924. [rHA] Sethi, B. B. (1964) Relationship of separation to depression. Archives of Psychiatry 10:486-96. [taHA] Shaw, D. M., Kemps, F. E., & Ecclestone, E. J. (1967) 5-hydroxytryptamine in hindbrain of depressive suicides. British Journal of Psychiatry 113:140711. [taHA] Sherman, A. D. & Petty, F. (1980) Neurochemical basis of the action of antidepressants on learned helplessness. Behavioral and Neural Biology 30:119-34. [tarHA] Shopsin, B., Janowsky, D., Davis, J., & Cershon, S. (1975) Rebound phenomena in manic patients following physostigmine: Towards an understanding of the aininergic mechanisms underlying affective disorders. In: Neurotransmitter balances regulating behavior, ed. E. F. Domino & J. M. Davis, pp. 149-58. Ann Arbor: University of Michigan Press. [taHA] Shopsin, B., Wilk, S., Gershon, S., Davis, K., &Suhl, M. (1973) An assessment of norepinephrine metabolism in affective disorders. Archives of General Psychiatry 28:230-33. [taHA] Sitaram, N., Nurnberger, ]. I., Jr., Gershon, E. S , & Gillin, J. C. (1980) Faster cholinergic REM sleep induction in euthymic patients with primary affective illness. Science 208:200-02. [KMN] Sitaram, N., Weingartner, H., & Gillin, J. C. (1978) Human serial learning: Enhancement with arecholine and choline and impairment with scopolamine. Science 201:274-76. [KMN] Sldrboll, L. R., Grace, A. A., & Bunney, B. S. (1979) Dopamine auto and postsynaptic receptors: Electrophysiological evidence for differential sensitivity to dopamine agonists. Science 206:80-82. [JWK] Sklar, L. S. & Anisman, H. (1980) Social stress influences tumor growth. Psychosomatic Medicine 42:347-65. [taHA] (1981) Stress and cancer. Psychological Bulletin 89:369-406. [tarHA] Slater, S. & Roth, M. (1969) Mayer Gross clinical psychiatry. Baltimore: Williams and Wilkins. [taHA] Smith, R. D., Cooper, B. R , & Breese, G. R. (1973) Growth and behavioral changes in developing rats treated intracisternally with 6-hydroxydopamine: evidence for involvement of brain dopamine. Journal of Pharmacology and Experimental Therapeutics 185:609-19. [STM] Snyder, S. (1974) Madness and the brain. New York: McGraw-Hill. [DL] Sobrian, S. K. & Cornwell-Jones, C. (1977) Neonatal 6-hydroxydopamine alters olfactory development. Behavioral Biology 21:329-40. [STM] Spitzer, R. & Endicott, J. (1978) Schedule for affective disorders and schizophrenia, 3rd ed. New York: New York State Psychiatric Institute. [JED] Star, S. A. (1949) Psychoneurotic symptoms in the army. In: Studies in social psychology in World War II. The American soldier: Combat and its aftermath, ed. S. A. Stouffer, L. Guttman, E. A. Suchman, S. A. Star, & J. A. Clausen, pp. 411-55. Princeton, N.J.: Princeton University Press. [taHA] Steele, C. P., Henderson, S., & Duncan-Jones, P. (1980) The reliability of reporting adverse experiences. Psychological Medicine 10:301-06. [RN] Stein, L. (1962) Effects and interactions of imipramine, chlorpromazine, reserpine and amphetamine on self-stimulation: Possible neurophysiological basis of depression. In: Recent advances in biological psychiatry, vol. 4. New York: Plenum Press. [JWK] (1974) Norepinephrine reward pathways: Role in self-stimulation, memory consolidation, and schizophrenia. Nebraska Symposium on Motivation 22:113-59. [KMN] Stolk, J. M., Conner, R. L., Levine, S., & Barehas, J. D. (1974) Brain norepinephrine metabolism and shock-induced fighting behavior in rats: Differential effects of shock and fighting on the neurochemical response to a common footshock stimulus. Journal of Pharmacology and Experimental Therapeutics 190:193-209. [taHA] Stone, E. A. (1971) Hypothalamic norepinephrine after acute stress. Brain Research 35:260-63. [EAS] (1973) Adrenergic activity in the rat hypothalamus following extreme muscular exertion. American Journal of Physiology 224:165-69. [EAS] (1975) Stress and catecholamines. In: Catecholamines and behavior, vol. 2, ed. A. J. Friedhoff. New York: Plenum Press. [taHA] (1978) Effect of stress on norepinephrine-stimulated accumulation of cyclic AMP in rat brain slices. Pharmacology Biochemistry and Behavior 8:58391. [EAS] (1979a) Reduction by stress of norepinephrine-stimulated accumulation of cyclic AMP in rat cerebral cortex. Journal of Neurochemistry 32:133537. [taHA, EAS] (1979b) Subsensitivity to norepinephrine as a link between adaptation to stress and antidepressant therapy: An hypothesis. Research Communications in Psychology, Psychiatry and Behavior 4:241-55. [taHA, EAS] Stoner, H. B. & Elson, P. M. (1971) The effect of injury on monoamine concentrations in the rat hypothalamus. Journal of Neurochemistry 18:1837-46. [EAS] Stoner, H. B. & Hunt, A. (1976) The effect of trauma on the activity of central noradrenergic neurones. Brain Research 112:337-46. [EAS] Sugrue, M. F. (1981) Chronic antidepressant administration and adaptive changes in central monoaminergic systems. In: Antidepressants: Neurochemical, behavioral, and clinical perspectives, ed. S. J. Enna. New York: Raven Press. [GRH] Sulser, F. (1978) Functional aspects of the norepinephrine receptor coupled adenylate cyclase system in the limbic forebrain and its modification by drugs which precipitate or alleviate depression: Molecular approaches to an understanding of affective disorders. Pharmakopsychiatric Neuropsychopharmako 11:43-52. [tarHA] Sulser, F., Vetulani, J., & Mobley, P. L. (1978) Commentary: Mode of action of [tarHA, DKR] antidepressant drugs. BiochemicalPharmacology27:257-6l. Sutherland, N. S. (1964) The learning of discriminations by animals. Endeavour 23:148-52. [STM] Svensson, T. H. & Usdin, T. (1978) Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants: Alpha-receptor mediation. Science 202:1089-91. [taHA] Swank, R. L. (1949) Combat exhaustion. Journal of Nervous and Mental Disease 109:475-508. [taHA] Symons, D. (1980) Precis of The evolution of human sexuality. Behavioral and Brain Sciences 3:171-214. [DdeC] Takahashi, R., Condo, H., & Keto, N. (1975) Effect of 1-5-hydroxytryptophan on brain monoamine metabolism and evaluation of its clinical effect in depressed patients. Journal of Psychiatric Research 12:177-87. [taHA] Takahashi, R-, Utina, H., Mashiyama, Y., Kurihama, M., Otsuka, T,, Nakamura, T., & Konamura, H. (1968) Tyrosine metabolism in manic depressive illness. Life Sciences 7:1219-31. [taHA] Tang, S. W., Seeman, P., & Kwan, S. (1981) Differential effect of chronic desipramine and amitripryline treatment on rat brain adrenergic and serotonergic receptors. Psychiatry Research 4:129-38. [rHA] Teasdale, J. D. & Bancroft, J. (1977) Manipulation of thought content as a determinant of mood and corrugator eleetromyographic activity in depressed patients. Journal of Abnormal Psychology 86:235-41. [ATB] Telegdy, G., & Vermes, I. (1979) Changes induced by stress in the activity of the serotonergic system in limbic brain structures. In: Catecholamines and Stress, ed. E. Usdin, R. Kvetnansky, & I. J. Kopin, pp. 145-56. Oxford: Pergamon Press. [taHA] Thierry, A. M. (1973) Effects of stress on the metabolism of serotonin and norepinephrine in the central nervous system of the rat. In: Hormones, metabolism and stress: Recent progress and perspectives, ed. S. Nemeth. Bratislava: Publishing House of the Slovak Academy of Sciences. [taHA] Thierry, A. M., Fekete, M., & Clowinski, J. (1968) Effects of stress on the metabolism of noradrenaline, dopamine and serotonin (5-HT) in the central nervous system of the rat: 2. Modification of serotonin metabolism. European Journal of Pharmacology 4:384-89. [taHA] Thierry, A. M., Javoy, F., Glowinski, J., & Kety, S. S. (1968) Effects of stress on the metabolism of norepinephrine, dopamine and serotonin in the central nervous system of the rat. Journal of Pharmacological and Experimental Therapeutics 163:163-71. [taHA] Thierry, A. M., Tassin, J. P., Blanc, G., & Glowinski, J. (1976) Selective activation of the mesocortical DA system by stress. Nature 263:24244. [taHA] Thomson, K. & Hendrie, H. (1972) Environmental stress in primary depressive illness. Archives of General Psychiatry 26:130-32. [taHA] Thornton, E. W., Goudie, A. J., & Bithell, V. (1975) The effects of neonatal 6-hydroxydopamine-induced sympathectomy on response inhibition in extinction, life Sciences 17:363-8. [STM] Thurlow, H. J. (1971) Illness in relation to life situation and sick role tendency. Journal of Psychosomatic Research 15:73-88. [RN] Torda, T., Yamaguchi, I., Hirata, F., Kopin, I. J., & Axelrod, J. (1981) Mepacrine treatment prevents immobilization-induced desensitization of beta-adrenergic receptors in rat hypothalamus and brain stem. Brain Research 205:441-44. [EAS] Tremmel, F., Morris, M. D., & Gebhart, G. F. (1977) The effect of forebrain norepinephrine depletion on two measures of response suppression. Brain Research 126:185-88. [STM] Ungerstedt, U. (1971) Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Ada Physiologica Scandinavica Suppl. 367:95-122. [KMN] U'Prichard, D. C. & Kvetnansky, R. (1980) Central and peripheral adrenergic receptors in acute and repeated immobilization stress. In: Second international symposium on catecholamines and stress, ed. E. Usdin, R. Kvetnansky, & I. Kopin, pp. 299-308. New York: Elsevier/North Holland. [EAS]

136

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

References!'Anisman & Zacharko: Depression and stress

Ursin, H. (1978) Activation, coping and psychosomatics. In: Psycholnology of stress: A study of coping men, ed. H. Ursin, E. Baade, & S. Levine, pp. 202-28. New York: Academic Press. [RM] (1980) Personality, activation and somatic health: A new psychosomatic theory. In: Coping and health, ed. S. Levine & H. Ursin, pp. 259-79. New York: Plenum Press. [RM] Ursin, H., Baade, E., & Levine, S., eds. (1978) Psychobiology of stress: A study of coping men. New York: Academic Press. [RM] Usdin, E., Kvetnansky, R., & Kopin, I. J. (1980) Catecholamines and stress: Recent advances. New York: Elsevier. [tarHA] Vternes, R. (1981) Perceptual defence reactions predict inadequate performance under stress. Scandinavian Journal of Psychology, in press. [RM] Valenstein, E. & Heilman, K. M. (1979) Emotional disorders resulting from lesions in the central nervous system. In: Clinical Neuropsychology, ed. K. M. Heilman & E. Valenstein, pp. 413-38. New York: Oxford University Press. [RMB] van Praag, H. M. (1977) Significance of biochemical parameters in the diagnosis, treatment, and prevention of depressive disorders. Biological Psychiatry 12:101-31. [KMN] (1978a) Amine hypotheses of affective disorders. In: Handbook of psychophannacology, vol. 13, ed. L. L. Iversen, S. D. Iversen, & S. H. Snyder. New York: Plenum Press. [taHA] (1978b) Neuroendocrine disorders in depression and their significance for the monoamine hypothesis of depression. Acta Psychiatrica Scandinavica 57:389-404. [taHA] (1979) Central serotonin. Its relation to depression vulnerability and depression prophylaxis. In: Biological psychiatry today, ed. E. Objols, C. Ballus, E. Gonzales Monclus, & J. Pujol, pp. 485-98. Amsterdam: Elsevier/North Holland. [JNH] (1980) Central monoamine metabolism in depressions: I. Serotonin and related compounds. Comprehensive Psychiatry 21(l):30-43. (1981) Management of depression with serotonin precursors. Biological Psychiatry 16:291-310. [JNH) van Praag, H. M. & deHaan, S. (1980) Depression vulnerability and 5-hydroxytryptophan prophylaxis. Psychiatry Research 3:75-83. [taHA] van Praag, H. M. & Korf, J. (1971) Endogenous depressions with and without disturbances in the 5-hydroxytryptamine metabolism: A biochemical classification? Psychophannacologia 19:148-52. [taHA] (1975) The dopamine hypothesis of schizophrenia in some direct observations. In: On the origin of schizophrenic psychoses, ed. H. M. van Praag, pp. 81-98. Amsterdam: De Erven Bohn BV. [taHA] van Pragg, H. M., Korf, J., Dols, L. C. W., & Schut, T. (1972) A pilot study of the predictive value of the probenicid test in application of 5-hydroxytryptophan as an antidepressant. Psychophannacologia 25:1421. [taHA] van Praag, H. M., Korf, J., & Puite, J. (1970) 5-hydroxyindoleacetic acid levels in the cerebrospinal fluid of depressive patients treated with probenecid. Nature (London) 225:1259-60. [taHA] van Scheijen, J. D., van Praag, H. M., & Korf, J. (1977) A controlled study comparing nomifensine and clomipramine in unipolar depression using probenecid techniques. British Journal of Clinical Pharmacology 4:17951845. [taHA] Vellucci, S. V. (1977) The effects of ether stress and betamethasone treatment on the concentration of noradrenaline and dopamine in various regions of the rat brain. British Journal of Pharmacology 60:601. [ADS] Vinokur, A., or Selzer, M. L. (1975) Desirable and undesirable events: Their relationship to stress and mental distress. Journal of Personality and Social Psychology 32:329-37. [taHA] Wahlsten, D. (1979) A critique of the concepts of heritability and heredity in behavioral genetics. In: Theoretical Advances in Behavior Genetics, ed. T. R. Royce & L. P. Mos, pp. 425-81. Germantown, SijthoUfc Noordhoff. |rHA| Walinder, J., Scott, A., Nagy, A., Carlson, A., & Roos, B. E. (1975) Potentiation of antidepressant action of clomipramine by tryptophan. Lancet 1:984. [taHA) Wang, R. Y. & Aghajanian, G. K. (1980) Enhanced sensitivity of amygdaloid neurons to serotonin and norepinephrine after chronic antidepressant treatment. Communications in Psychopharmacology 4:83-90. [rHA] Warheit, G. J. (1979) Life events, coping, stress, and depressive symptomology. American Journal of Psychiatry 136(4B):502-07. [HSA, WPS] Weiss, J. M. (1971a) Effects of coping behavior in different warning signal conditions on stress pathology in rats. Journal of Comparative and Physiological Psychology. 77:1-13. [taHA) (1971b) Effects of punishing the coping response (conflict) on stress pathology in rats. Journal of Comparative and Physiological Psychology 77:1421. [taHA] (1971c) Effects of coping behavior with and without a feedback signal on stress pathology in rats. Journal of Comparative and Physiological Psychology 77:22-30. [taHA) Weiss, J. M. & Glazer, H. 1. (1975) Effects of acute exposure to stressors on subsequent avoidance-escape behavior. Psychosomatic Medicine 37:499. [ADS] Weiss, ]. M., Glazer, H. I., & Pohorecky, L. A. (1976) Coping behavior and neurochemical changes: An alternative explanation for the original "learned helplessness" experiments. In: Animal Models in Human Psychobiology, ed. G. Serban & A. Kling, pp. 141-73. New York: Plenum Press. [tarHA, DKR] Weiss, J. M., Glazer, H. I., Pohorecky, L. A., Bailey, W. H., & Schneider, L. H. (1979) Coping behavior and stress-induced behavioral depression: Studies of the role of brain catecholamines. In: The psychobiology of the depressive disorders, ed. R. A. Depue. New York: Academic Press. [taHA] Weiss, B. L., Kupfer, D. J., Foster, F. G., & Delgado, J. (1974) Psychomotor activity, sleep and biogenic amine metabolites in depression. Biological Psychiatry 9:45-54. [taHA] Weiss, J. M., Pohorecky, L. A., Salman, S., & Cruenthal, M. (1976) Attenuation of gastric lesions by psychological aggression in rats. Journal ofComparative and Physiological Psychology 90:252-59. [taHA] Welch, B. L., & Welch, A. S. (1970) Control of brain catecholamines and serotonin during acute stress and after d-amphetamine by natural inhibition of monoamine oxidase: An hypothesis. In: Amphetamines and related compounds, ed. E. Costa & S. Garattini. New York: Raven Press. [taHA] Whybrow, P., & Parlatore, A. (1973) Melancholia, a model in madness: A discussion of recent psychobiologic research into depressive illness. International Journal of Psychiatry in Medicine 4:351-78. [HSA) Williams, C. C , Williams, R. A., Griswold, M. )., & Holmes, T. H. (1975) Pregnancy and life change. Journal of Psychosomatic Research 19:12329. [SRB] Wilner, P. & Montgomery, T. (1980) Neurotransmitters and depression: Too much, too little, too unstable - or not unstable enough? Trends in Neurosdcnce 3:201. [STM] Wimer, R. E., Norman, R., & Eleftheriou, B. E. (1974) Serotonin levels in hippocampus: Striking variations associated with mouse strain and treatment. Brain Research 63:397-401. [taHA] Wise, R. A. (1978) Catecholamine, theories of reward: A critical review. Brain Research 152:215-48. [tarHA) (1981) Neuroleptics and operant behavior: The anhedonia hypothesis. Behavioral and Brain Sciences 5:39-87. [rHA] Wortman, C. B. & Dintzer, L. (1978) Is an attributional analysis of the learned helplessness phenomenon viable? A critique of the Abramson-SeligmanTeasdale reformulation. Journal of Abnormal Psychology 87:75-90. [taHA] Yager, J., Grant, I., Sweetwood, H. L., & Gerst, M. (1981): Life event reports by psychiatric patients, nonpatients, and their partners. Archives of General Psychiatry 38:343-47. [RN] Zajaczkowska, M. N. (1975) Acetylcholine content in the central and peripheral nervous system and its synthesis in the rat brain during stress and post-stress exhaustion. Acta Physiologica Polska 26:493-97. [taHA]

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5

137

Call for Papers

Investigators in Psychology, Neuroscience, Behavioral Biology, and Cognitive Science

Do you want to: draw wide attention to a particularly important or controversial piece of work? solicit reactions, criticism, and feedback from a large sample of your peers? place your ideas in an interdisciplinary, international context?

".. .superbly presented...the result is practically a vade mecum or Who's Who in each subject. [Articles are] followed by pithy and often (believe it or not) witty comments questioning, illuminating, endorsing or just plain arguing . . . I urge anyone with an interest in psychology, neuroscience, and behavioural biology to get access to this journal."New Scientist "... a high standard of contributions and discussion. It should serve as one of the major stimulants of growth in the cognitive sciences over the next decade."Howard Gardner (Education) Harvard ".. .keep on I ike this and you wil I be not merely good, but essential..."D.O. Hebb (Psychology) Dalhousie " . . . a unique format from which to gain some appreciation for current topics in the brain sciences . . . [and ] by which original hypotheses may be argued openly and constructively." Allen R. Wyler (Neurological Surgery) Washington ".. .one of the most distinguished and useful of scientific journals. It is, indeed, that rarity among scientific periodicals: a creative forum..."Ashley Montagu (Anthropology) Princeton "I think the idea is excellent."Noam Chomsky (Linguistics) M.I.T. ".. .should prove to be an invaluable tool for research and teaching." Quarterly Review of Biology "Care is taken to ensure that the commentaries represent a sampling of opinion from scientists throughout the world. Through open peer commentary, the knowledge imparted by the target article becomes more fully integrated into the entire field of the behavioral and brain sciences. This contrasts with the provincialism of specialized journals ..."Eugene Garfield Current Contents "... open peer commentary . . . allows the reader to assess the 'state of the art' quickly in a particular field. The commentaries provide a 'who's who' as well as the content of recent research." Journal of Social and Biological Structures "... presents an imaginative approach to learning w h i c h might be a d o p t e d by other journals."Library Journal "Neurobiologists are acutely aware that their subject Is in an explosive phase of development . . . we frequently wish for a forum for the exchange of Ideas and interpretations. . . . plenty of journals gladly carry the facts, very few are willing to even consider promoting ideas. Perhaps even more important is the need for opportunities publicly to criticize traditional and developing concepts and interpretations. [BBS ] Is helping to fill these needs."Graham Hoyle (Biology) Oregon " . . . like an international peripatetic seminar. Its open peer commentary on articles provides an exciting international forum for vigorous discussion of major issues in all areas of behavioral and neurological research."Stuart A. Altmann (Allee Laboratory of Animal Behavior) Chicago " . . . this exciting journal of open peer commentary emphasizes interdisciplinary communication between behavioral biology, cognitive science, neuroscience, and psychology." American Anthropologist

The Behavioral
an extraordinary journal now in its fourth year, provides a special service called Open Peer Commentary to researchers in any area of psychology, neuroscience, behavioral biology or cognitive science. Papers judged appropriate for Commentary are circulated to a large number of specialists who provide substantive criticism, interpretation, elaboration, and pertinent complementary and supplementary material from a full crossdisciplinary perspective. Article and commentaries then appear simultaneously with the author's formal response. This BBS "treatment" provides in print the exciting give and take of an international seminar. The editor of BBS is calling for papers that offer a clear rationale for Commentary, and also meet high standards of conceptual rigor, empirical grounding, and clarity of style. Contributions may be (1) reports and discussions of empirical research of broader scope and implications than might be reported in a specialty journal; (2) unusually significant theoretical articles that formally model or systematize a body of research; and (3) novel interpretations, syntheses or critiques of existing theoretical work. Although the BBS Commentary service is primarily devoted to original unpublished manuscripts, at times it will be extended to precis of recent books or previously published articles. Published quarterly by Cambridge University Press. Editorial correspondence to: Stevan Harnad, Editor, BBS, RO. Box 777, Princeton, NJ 08540