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Eur Arch Psychiatry Clin Neurosci (2001) 251: Suppl.

2, II/47II/52 Steinkopff Verlag 2001

Giovanni A. Fava Lara Mangelli

Assessment of subclinical symptoms and psychological well-being in


 Abstract A substantial body of research suggests that Psychometric assessment reected these orientations
subclinical symptoms characterize the longitudinal and often took a blanket approach. Several instruments
course of major depression and have important patho- are used, often highly redundant in nature, to differenti-
physiological and treatment implications. Specic treat- ate diagnostic groups, violating the psychometric princi-
ment of residual symptoms may in fact improve long- ple of incremental validity, whereby each distinct aspect
term outcome, by acting on those residual symptoms of psychological measurement should deliver a unique
that progress to become prodromes of relapse. The incremental increase in information (Fava 2001).
assessment of psychological well-being is also important, Per Bech has played a substantial role in shifting gears
since its absence may create conditions of vulnerability in clinical research in psychiatry. In a seminal paper on
to possible adversities. The route of recovery, thus, lies measurement of psychological distress and well-being
not exclusively in alleviating the negative, but in engen- (Bech 1990), he has anticipated several trends which have
dering the positive. become apparent only today. In particular he has out-
 Key words Subclinical symptoms Psychological well-
being Depressive disorder Prodromal symptoms  The importance of assessing subclinical symptoma-
Residual symptoms tology
 The role of psychological well-being in the balance
between health and disease
 The need of developing specic psychometric strate-
Introduction gies in assessment, with special reference to the issue
of recovery and to clinimetrics.
In the past two decades, mental health research has been
dramatically weighted on the side of psychiatric nosology We well outline the importance of this approach in the
and psychological dysfunction. Such emphasis has setting of unipolar depression. Similar considerations,
resulted in the development of diagnostic criteria (DSM- however, may be formulated in bipolar disorder (Fava
IV) aimed at identifying syndromes according to a cut- 1999; Benazzi 2001), panic disorder (Fava and Mangelli
off of severity and to disregard subclinical symptoms 1999) schizophrenia (Klosterkotter et al. 2001) and eat-
(Fava and Kellner 1991). Furthermore, mental health has ing disorders (Raf et al. 2000).
been equated with the absence of disease rather than the
presence of psychological wellness (Ryff and Singer
Psychopathology of unipolar major depression:
a longitundinal view
Prof. G. A. Fava () L. Mangelli
Department of Psychology Several studies have addressed the issue of symptom
University of Bologna development in unipolar depression. Most of the early
Viale Berti Pichat, 40127 Bologna, Italy
tel. 39-051-2091339
studies are just based on clinical observations.
fax. 39-051-243086 Hays (1964) examined prodromal symptoms in 81
E-mail: patients with endogenous depression. Four symptom

patterns emerged: a) sudden-onset depressions (associ- episode. Paykel et al. (1976) found some similarities in
ated with melancholic features and bipolar disorder); symptom patterns of 33 depressives between initial rat-
b) gradual-onset depressions, where mood disorder ings at height of a depressive illness and subsequent
takes months to develop and is related to common stress- relapse several months later, after intervening recovery.
ful life events; c) neurotic-onset depressions, commonly In a study associated with the NIMH Epidemiologic
preceded by anxiety disorders; and d) uctuating onset Catchment Area Program (Dryman & Eaton 1991),
depressions, in which symptoms displayed considerable women with sleep disturbances, diminished sexual drive,
uctuations in severity before reaching full force. Hop- feelings of worthlessness and trouble concentrating were
kinson (1965) interviewed 43 in patients suffering from over 5 times more likely to experience an onset of major
depressive psychosis. About 30% showed a prodromal depression than those without the specied symptoms.
phase characterized by tension and vague feelings of Using the same database, Judd et al. (1997) found that a
anxiety, and less often other symptoms such as indeci- subsyndromal depressive symptoms (dened by two or
sion and impaired concentration. Other studies dealt more depressive symptoms of at least 2 weeks in dura-
with the rapidity of onset of depressive symptoms. tion) were frequently prodromal to episodes of major
Winokur (1976) found, in a sample of 216 patients, that depressive disorder.
depression spectrum disease patients (i.e. patients who Early symptoms of subclinical depression and per-
had alcoholism in rst-degree relatives), were much less sistent helplessness were also found by Ernst et al. (1992)
likely to have an acute or abrupt onset that were other in a longitudinal prospective study on incidence in young
depressive patients. Cadoret et al. (1980) found that adults.
somatic complaints and anxiety preceded the onset of The results of these studies in unipolar depression
depression in 117 patients in primary care. Young and (whether naturalistic or based on rating scales) therefore
Grabler (1985) reported that in 11 depressed patients a suggest that a substantial prodromal symptomatology
rapid onset of symptoms was associated with the endoge- exists before the onset of depressed mood. Anxiety and
nous subtype, the absence of past or current non-affec- irritability appear to dominate the clinical picture.
tive disorders, older age and fewer stressful life events.
Fava et al. (1990) investigated prodromal symptoma-
tology occurring in the 6 months prior to the onset of  Residual symptoms
depressed mood in 15 outpatients at their rst episode of
primary major depressive disorder. A semistructured In 1973 Paykel and Weissman found social and interper-
interview based on Paykels (1985) Clinical Interview for sonal maladjustments in fully recovered depressed
Depression was performed 2 to 3 months after the initial patients compared to controls, despite considerable
evaluations, when the patients symptoms had improved. improvement in social adjustment upon treatment. Sub-
Family members who had observed the patient were missive dependency and family attachment improved
asked to provide additional information. Each of the 15 almost completely, whereas two other personal dysfunc-
patients reported having at least one prodromal symp- tions, interpersonal friction and inhibited communica-
tom before the onset of depressed mood. Generalized tion, showed little change and greatest residual impair-
anxiety was present in 13 cases and irritability in 9. Other ment. Residual social maladjustment was subsequently
common symptoms were impaired work and initiative, reported by other investigators (Goering et al. 1992;
fatigue, initial and delayed insomnia. These findings Coryell et al. 1993; Bauwens et al. 1991) and was found to
were independently replicated by Van Praag (1992) and correlate with long-term outcome (Goering et al. 1992).
by Mahnert et al. (1997). These latter authors also used Similarly, dysfunctional attitudes and attributions were
Paykels Clinical Interview for Depression. These results found to persist after recovery, despite clinical and cog-
support a description in the textbook by Mayer Gross- nitive improvement (Eaves & Rush 1984; Williams et al.
Slater-Roth (Mayer Gross et al. 1969, pp. 207208): The 1990; Brown et al., 1990). These cognitive patterns were
history of change in the patients behavior is characteris- positively correlated with vulnerability to persistent
tic and important; he retires from usual social activities, depression or relapse (Williams et al. 1990; Brown et al.
avoids his friends in the street, and, if forced into com- 1990; Power et al. 1995; Bothwell & Scott 1997). These
pany, seems bored and inattentive and takes little inter- ndings were consistent with the fact that vulnerable atti-
est in topics that usually elicit an active response (...). An tudes such as high neuroticism assessed when the
initial mood of indifference in depressive states may last depressed patients are symptomatic predict recovery
for a considerable time, but sooner or later is replaced by (Scott et al. 1992, 1995), but that for the prediction of
the one of sadness, . relapse, cognitive measures when patients are asympto-
During a 6 month follow-up, after antidepressant matic need to be used (Williams et al. 1990). Social mal-
drugs discontinuation, 4 of the 15 patients relapsed and adjustment and dysfunctional attitudes may overlap with
required further antidepressant drug treatment (Fava et characterological traits assessed after clinical recovery
al. 1990). In all cases, prodromal symptoms of relapse (Fava M et al. 1994, Peselow et al. 1994, Murray & Black-
closely resembled those of the rst episode. The consis- burn 1974; Perris et al. 1984, Chien & Dunner 1996, Sauer
tency of symptoms over time in each individual is not et al. 1997, Black & Sheline 1997, Enns & Cox 1997) or pre-
limited to prodromes but applies also to the affective morbid personality features (Clayton et al. 1994, Nystrom

& Lindegard 1975). In any case, there appears to be a ically reported when a reduction of 50% or more in the
residual attributional interpersonal component which is Hamilton Depression Rating Scale occurs. However,
refractory to otherwise successful treatment of depres- using a more conservative score for dening response,
sion. Such component may entail considerable predictive only 45 % of approximately 900 depressed patients
value. achieved a satisfactory response. Similarly, a major nd-
The notion that the majority of depressed patients ing of the NIMH Treatment of Depression Collaborative
experience mild but chronic residual symptoms or recur- Program was that 16 weeks of pharmacological or psy-
rence of symptoms after complete remission, that was chotherapeutic treatment were insufficient for most
well delineated in the 1970s (Weissman et al. 1976), did patients to achieve full recovery and lasting remission
not receive the attention it deserved in subsequent years. (Shea et al. 1992).
However, the presence of residual symptoms after com- Cornwall & Scott (1997) reviewed publications relat-
pletion of drug treatment (Mindham et al. 1973, Faravelli ing to a precise denition of partial remission (Frank et
et al. 1986, Prien & Kupfer 1986, Georgotas & McCue al. 1991). Partial remission was found to affect at least one
1989, Maj et al. 1992, Fava et al. 1994, Paykel et al. 1995, third of subjects treated for depression, to increase the
Judd et al. 1997, 2000) or cognitive behavioral therapy risk of further depressive relapse, and to adversely affect
(Simons et al. 1986, Thase et al. 1992) of depression has social and work performance.
been correlated with poor long-term outcome. This
would parallel the fact that patients with so-called dou-
ble depression (major depression overlapping on dys-  Rollback phenomena
thymia) have been shown to be less likely to make a full
recovery and more likely to relapse (Keller et al. 1983). In a study (Fava et al. 1994), the relationship of residual
Methodological problems in assessment of residual symptoms to prodromal symptomatology was speci-
symptoms, however, emerge. There is paucity of psycho- cally addressed. Almost 70% of the residual symptoms
metric studies addressing the phenomenology of that were found to occur in 40 remitted depressed
depressed patients after benefiting from treatment. patients were present also in the prodromal phase of ill-
Recovered depressed patients displayed significantly ness. This percentage increased to almost 90% of cases
more depression and anxiety than control subjects in one for residual generalized anxiety and irritability. The roll-
study (Fava et al. 1986), but not in another (Agosti et al. back phenomenon (Detre and Jarecki 1971) or, at least,
1993). Differences in the sensitivity of the rating scales a strong relationship between prodromal and residual
which were employed may account for such discrepant symptomatology was thus substantiated. These results
results. Using Paykels (1985) Clinical Interview for achieved independent replication (Mahnert et al. 1997)
Depression, only 6 (12.2 %) of 49 patients with major and are supported also by two other lines of evidence. In
depression successfully treated with antidepressant a prospective study (Shea et al. 1996), that examined the
drugs and judged to be fully remitted had no residual possibility that episodes of major depression result in
symptoms (Fava et al. 1994). The majority of residual lasting personality changes that persist beyond recovery
symptoms were present also in the prodromal phase of (the scar hypothesis), there was no evidence of negative
illness. The most frequently reported symptoms involved change from premorbid to postmorbid assessment. This
anxiety and irritability. This was consistent with previous would suggest continuity whether we rate it in charac-
studies on prodromal symptoms of depression (Fava et terological or symptomatological terms between the
al. 1990, Van Praag, 1992) and overlapped with ndings prodromal and residual phases. The second line of evi-
concerned with interpersonal friction (Paykel & Weiss- dence is based on recognition of specific temporal
man 1973), irritability (Nystrom & Lindegard 1975) and courses of change during treatment of depression
anxiety (Murray & Blackburn 1974). Using a similar (Haskell et al. 1975, Katz et al. 1987, Casper et al. 1994,
methodology, Paykel et al. (1995), found residual symp- Nierenberg et al. 1995). Different types of treatment may
toms to be present in 32% of 60 patients who remitted affect the temporal course of change in depression
from major depression. Previous diagnosis of dysthymia (Watkins et al. 1993), and the use of pattern analysis may
did not predict residual symptoms. Nierenberg et al. differentiate true drug and placebo responses early in
(1998) found that only 18% of 108 patients who fully treatment (Rotschild & Quitkin 1992). Patients do not
responded to uoxetine had no residual symptoms, and suddenly become well, but tend to gradually lose their
provided a full replication of the data by Fava et al. depressive symptoms over the months following treat-
(1994). ment (Keller et al. 1992). Stassen and associates (1993)
In conclusion, substantial residual symptomatology found that the time course of improvement among
appears to characterize depressed patients who success- responders to amitriptyline, oxaprotiline and placebo
fully responded to pharmacological or psychological was independent of the treatment modality, and thus
therapies. Anxiety, irritability and interpersonal friction identical in all three groups. Once triggered, the time
appear to be common residual symptoms. Angst, Kupfer course of recovery from illness became identical to the
& Rosenbaum (1996) observed that clinical trials overes- spontaneous remissions under placebo. Antidepressant
timate the likelihood of full recovery on a single antide- drugs, therefore, may not change the pattern of the nat-
pressant. The usual response rates of 60 to 70% are typ- ural course of recovery from illness, but simply speed the

recovery and change the boundary between respon- months. However, 40 % relapsed over the subsequent
ders and non-responders (Stassen et al. 1993). months, with all relapses occurring during the rst 10
months. This unfavorable outcome seems to parallel the
presence of substantial residual symptomatology in
 Demoralization patients judged to be remitted and no longer in need of
active treatment. Indeed, residual symptoms, as well as
Bech (1990) called attention to the clinical phenomenon persistence of altered biological markers such as the dex-
of demoralization. This led to the development of specic amethasone suppression test, are probably the most con-
criteria for demoralization (Fava et al. 1995), which iden- sistent predictors of relapse. In a large cohort study,
tify a feeling state characterized by the patients con- asymptomatic recoverers relapsed in 157 weeks, com-
sciousness of having failed to meet his or her own expec- pared to residual recoverers who relapsed in about 28
tations (or those of others) or being unable to cope with weeks (Judd et al. 1997).
some pressing problems. The patient experiences feel- However, the challenge of treatment of depression
ings of helplessness, hopelessness or giving-up. Some today appears the prevention of relapse more than
preliminary results obtained in the setting of medical attainment of recovery. And the question arises as to
disease (Porcelli et al. 2000, Fava et al. 2001, Grandi et al. whether reduction or disappearance of residual sympto-
2001) suggest that demoralization is frequently found matology may entail a more favorable long-term out-
and overlaps only to a certain degree with major depres- come of depression. A preliminary answer to this ques-
sion. Future studies may explore the presence of demor- tion was provided by a controlled therapeutic trial (Fava
alization in the residual phase of major depression. et al. 1994, 1996). Forty patients with major depressive
disorder who had been successfully treated with antide-
pressant were randomly assigned to either cognitive
behavioral treatment or clinical management of residual
Psychological well-being symptoms. In both groups, antidepressant drugs were
tapered and discontinued. The group that received cog-
Bech (1990) has emphasized the importance of psycho- nitive behavioral treatment had a signicantly lower level
logical well-being whether it is subsumed under Ryffs of residual symptoms after drug discontinuation in com-
(Ryff and Singer 2000) or Antonovskys (Schnyder et al. parison with the clinical management group. Cognitive
2000) conceptualizations as a component of quality of behavioral treatment also resulted in a lower rate of
life. He and Angst (1996) have reviewed the literature on relapse, which achievement of statistical signicance at a
quality of life in anxiety disorders. Several studies have 4 year follow-up (Fava et al. 1996). The rationale of this
shown impaired quality of life and well-being in patients approach was to spend cognitive behavioral treatment
with major depressive disorders, even in their remitted resources when they are most likely to make a unique and
status (Schoenfeld et al. 1997, Pyne et al. 1997, Stewart et separate contribution to patient well-being and to
al. 1993, Rafanelli et al. 2000). Thunedborg, Black and achieve a more pervasive recovery. It was fully validated
Bech (1995) found that quality of life measurements, and in a large controlled trial where cognitive therapy of
not symptomatic ratings, could predict the recurrence of residual symptoms was found to improve long-term out-
depression. In one study, the relationship of psycholog- come of major depression compared to clinical manage-
ical well-being to distress was investigated in remitted ment (Paykel et al. 1999). The sequential, stage oriented
patients with mood and anxiety disturbances (Rafanelli approach was applied to 40 patients with recurrent major
et al. 2000). The results suggested that well-being cannot depression, who had been successfully treated with anti-
be equated to lack of distress as implicitly endorsed by depressant drugs, using the same criteria that had been
current psychiatric paradigms and the need of a multidi- outlined by Frank et al. (1990), that is 3 or more episodes
mensional assessment in affective disorders. Further, the of unipolar depression (with the immediately preceding
hypothesis that the state-trait characteristic of a specic episode being no more than 2.5 years before the onset of
instrument may be population or stage dependent was the present episode). Patients were randomly assigned to
introduced (Rafanelli et al. 2000). either cognitive behavioral treatment of residual symp-
toms supplemented by lifestyle modication and well-
being therapy (Fava et al. 1998a) or clinical manage-
ment. In both groups, antidepressant drugs were tapered
Therapeutic implications and discontinued. At 2-year follow-up, cognitive behav-
ioral treatment resulted in a signicantly lower relapse
There has been increasing awareness of the bleak long- rate (25%) than did clinical management (80%) (Fava et
term outcome of depression as to relapse and recurrence al. 1998b). These results challenge the assumption that
(Piccinelli & Wilkinson 1994). Ramana et al. (1995) long-term drug treatment is the only tool to prevent
reported on the course of depression with respect to relapse in patients with recurrent depression. Although
remission and relapse in a two-year prospective follow- maintenance pharmacotherapy seems to be necessary in
up. Remission was rapid with 70% of subjects remitting some patients, a 2-stage, sequential, intensive approach
within 6 months and only 6 % failing to do so by 15 (pharmacotherapy for acute treatment of depression,

followed by cognitive behavioral treatment for its resid- Fava GA (2001) Clinical psychology: a psychosocial antidote to biolog-
ual phase) appears to be a viable alternative for other ical reductivism in psychiatry? Epidemiol Psychiat Soc 10: 150152
Fava GA, Freyberger HJ, Bech P, Christodoulou G, Sensky T, Theorell
patients (Fava et al. 1998b). Amelioration of residual T, Wise TN (1995) Diagnostic criteria for use in psychosomatic
symptomatology may reduce the risk of relapse in research. Psychother Psychosom 65: 18
depressed patients by affecting the progression of resid- Fava GA, Mangelli L (1999) Subclinical symptoms of panic disorder.
ual symptoms to prodromes of relapse. Psychother Psychosom 68: 281289
Fava GA, Mangelli L, Ruini C (2001) Assessment of psychological dis-
tress in the setting of medical disease. Psychother Psychosom 70:
Acknowledgment This paper was supported in part by a grant Outcome
evaluation in mental health from the Istituto Superiore di Sanit
Fava GA, Kellner R (1991) Prodromal symptoms in affective disorders.
(Rome), from a grant from the Ministero dellUniversit e della Ricerca
Am J Psychiatry 148: 823830
Scientica e Tecnologica (MURST, Rome), and from a grant from Con-
siglio Nazionale delle Ricerche (CNR, Rome) to Professor Fava. Fava GA, Grandi S, Canestrari R, Molnar G (1990) Prodromal symp-
toms in primary major depressive disorder. J Affect Disord 19:
Fava GA, Grandi S, Zielezny M, Canestrari, R, Morphy MA (1994)
Cognitive behavioral treatment of residual symptoms in primary
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