Beruflich Dokumente
Kultur Dokumente
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GENERAL PSYCHOPHARMACOLOGY
Key Words: affective instability, borderline personality disorder, dissociation, impulsivity, pain, self-injurious behavior, stress
Dr. Schmahl is research fellow in the Department of Psychiatry and Psychotherapy at the University of Freiburg Medical School in Germany. Dr. McGlashan is professor in the Department of Psychiatry at Yale University School of Medicine in New Haven, CT. Dr. Bremner is associate professor in the Department of Psychiatry and Behavioral Sciences and director of the Emory Center for Positron Emission Tomography at Emory University School of Medicine in Atlanta, GA, and director of mental health research at Atlanta VAMC in Decatur, GA. To whom correspondence should be addressed: Christian G. Schmahl, MD, Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany; Tel: (049) (761) 203-9316; Fax: (049) (761) 270-6619; E-mail: christian_schmahl@psyallg.ukl.uni-
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thinking re g a rding BPD, summarize the biological findings to date, and con c e p t u a l i ze BPD on a ph e n om e n o l o g i cal and biological level. Multiple factors, genetic and env i ronmental, p l ay a role in the deve lo pment of a neurobiological profile leading to the deve l o pment of BPD. Genetic factors, such as a genetic pre d i s p o s i t i on to impulsivity and avoidance of harm, m ay render an individual more vulnerable to the deve l o pment of the disord e r. E x p re s s i on of these genetic factors and the resulting interpersonal behavior of the growing child could i n c rease the risk of abuse, neglect, or failures of attachment betw e e n mother and child and lead to situations of abandon m e n t . For example, a growing child with strong impulsive features might be con s i d e re d by his or her parents to be a difficult ch i l d , thereby raising the pro b a b i lity for situations of abandonment or emotional neglect. Environmental factors, including interp e r s on al stress, such as sexual abuse or situat i ons of abandon m e n t , are proposed to lead to brain changes that then result in maladaptive behavior, s u ch as affe c t i ve instability or self-injurious or aggre s s i ve behavior. The com b i n a t i on of altera t i ons in diffe rent neurobiological systems ( e g, s e ro t on e r g i c , opioid, or cholinergic), w h i ch is determined by genetics, env i ronment, or more pro b a b ly some com b i n a t i on of these, dictates whether an individual will develop BPD rather than som e other disorder, s u ch as posttraumatic stress disorder (PTSD) or dissociative identity disorder (DID), foll owing stress. Seve ral inve s t i g a t o r s have argued that the neurobiology underlying person a l i ty disorders should be examined in terms of dimensional factors. Siever and Davis1 as well as Cocca ro and Kavoussi2 suggested that dimensions of affective instability, i m p u l s i ve aggre s s i on , and cognitive disturbances underlie the disord e r, and Soloff3 s t ressed the importance of a dimensional appro a ch for ph a rm a c o t h e rapy in BPD. We largely agree with this view but wish to shift the focus from perceptual disorganization to the clinically important domains of dissociation, pain regulation, and self-injurious behavior (SIB). In addition, we emphasize the importance of interpersonal stress as a factor in the development of the disorder. Consequently, we suggest that individuals who develop BPD have in common four core elements: interpersonal stress, affective instability, impulsivity, and dissociation and SIB. These core elements may be expressed to varying degrees in different patients with BPD. Variations in neurobiology may influence the expression of these core elements. This article briefly reviews the genetics of BPD and then reviews the neurobiological alterations that are hypothesized to underlie these four core elements.
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Genetics In a meta-analysis of epidemiologic investigations, Torgersen et al4 estimated the prevalence of BPD to be 1.35. Prospective studies have shown a range of 15.3% to 23.4% for morbid risk of BPD in firstdegree relatives of borderline probands.5-7 Dahl8 reviewed 13 family studies of BPD and stated that evidence for an increased family risk of BPD among first-degree relatives of BPD probands is limited. In a twin study of person a l i ty disorders that included 92 mon o zygotic and 129 dizygotic twin pairs, Torgersen et al9 found an ove ra ll heritability of 0.60 for person a l i ty disorders and a heritability of 0.69 for BPD. A genetic influence on the tra n s m i s s i on of BPD traits was found for affe c t i ve instability, impulsivity, and SIB.10 Using an instrument to assess seve ral dimensions of person a l i ty, Livesley et al11,12 found high levels of genetic influence on affective lability, self-harm, and, interestingly, identity pro b l e m s one of the bord e rline criteria in the Diagnostic and Statistical Manual of M e n tal Disorder s,13 Fourth Edition (D S M - I V)in the general population . These findings highlight the usefulness of examining BPD in dimensional terms.14 This is part i c ularly important in terms of neurobiological re s e a rch in person a l i ty disorders, in which biological altera t i ons pro b a b ly underlie dimensions of behavior, rather than specific person a l i ty disord e r s .15 Interpersonal Stress The most recent debate about whether BPD is a diagnostic entity of its own or part of another diagnostic spectrum deals with the high rate of childhood traumatic experiences in patients with BPD.16 Bremner17 has argued that BPD should be considered part of a group of trauma spectrum disorders, including PTSD and dissociative disorders, all related to common effects of stress on neurobiology. In five controlled studies of patients with BPD,18-22 the prevalence of childhood physical abuse ranged between 29% and 71%. Sexual abuse in childhood was experienced by 52%22 to 71% of patients with BPD, significantly more than control subjects.21 Clinically, the frequent stress-related symptoms in borderline patients, such as anxiety and dissociative phenomena, also highlight the overlap between BPD and other trauma spectrum disorders such as PTSD and DID. In a study investigating Axis II diagnoses in male PTSD patients,23 83% of inpatient and 69% of outpatient combat veterans with PTSD fulfilled Diagnostic and Statistical Manual of Mental Disorders,24 Third Edition-Revised, criteria for BPD. A recent study by Bollinger et al,25 however, found a prevalence of only 6% for BPD in inpatient male combat veterans with PTSD. Between 60% and 70% of patients with DID fulfill the criteria for BPD.26,27
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Although the rate of phys i cal and/or sexual abuse in BPD is high, not every BPD patient has a history of traumatization. According to Linehans28 biosocial theory of BPD, sexual abuse is a prototypical, although not necessary, invalidating experience in a growing child. The e x p e rience of emotional invalidation, neglect by caretakers, or situations of abandonment may play an important role in the development of BPD and could diffe rentiate this disorder from PTSD, which is more cl e a rly related to specific traumatic events. Consistent with a potentially important role for emotional abuse, Bremner et al29 re p o rted that emotion a l abuse (eg, t reating a child in a cold or unca ring manner, fre q u e n t ly shouting at a child, or a ca regivers failing to understand the childs needs) was associated with an equally poor outcome as phys i cal abuse. The question that arises is, Why do humans exposed to stre s s develop diffe rent disord e r s , s u ch as PTSD, BPD, or DID? A factor c on t ributing to the pre d i s p o s i t i on to a specific disorder may be the n a t u re of the stressor itself. Wh e reas single traumatic eve n t s , such as rape or an accident, m ay lead to the deve l o pment of PTSD, a lon g term exposure to stressors such as sexual abuse, in com b i n a t i on with e m o t i on al neglect or situations of abandonment, could cause the deve lo pment of BPD. St ressors early in deve l o pment are more likely to affect the deve l o pment of person a l i ty, thus increasing the risk for BPD or DID, while stressors later in life, such as com b a t , m ay be associated with more of a hyp e ra rousal pattern and a diagnosis of PTSD. The neurobiology of interp e r s onal stress is well characterized based on studies in animals. Several biological systems are sensitive to stress i n cluding the locus coeruleus/nora d renergic system and the hypothalam i c pituitary - a d renal (HPA) axis. The nora d renergic system plays an important role in the stress re s p on s e .30,31 St ress leads to a rapid and robust activation of the locus coeruleus/nora d renergic system. I n c reases in activity in the locus coeruleus during stress are associated with an increase in re g i onal turnover and the release of norepinephrine in brain re g i ons that are innervated by the locus coeruleus. A d m i n i s t ra t i on of ca t e cholamines results in re s p onses similar to those seen during stre s s , such as increases in blood pre s s u re, re s p i ratory ra t e, and subjective sensations of anxiety. A variety of evidence is con n e c t e d with increased nora d renergic function in PTSD, including peri ph e ra l m e a s u res of nore p i n e ph ri n e, pharmacologic ch a ll e n g e s , n e u ro i m a g i n g, and psych o physiology.30-33 Unlike in PT S D, the few studies of nora d renergic function in patients with BPD have not con s i s t e n t ly shown increased nora d re nergic function . Herpertz et al34 examined psych o physiological re a c-
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tions in 24 female patients with BPD and 27 normal con t rol subjects during exposure to a set of standard i zed ph o t o g ra phic slides with pleasant, neutral, or unpleasant emotional valence. T h e re was no difference in measures of startle amplitude, skin con d u c t a n c e, or heart rate re s p onses between patients and con t rol subjects during any of the conditions. Studies in patients with BPD did not show altera t i on s in c e re b rospinal fluid (CSF) levels of the noradrenergic metabolite MHPG (3-methox y - 4 - hyd rox y - ph e nyl g lyc o l ) .35-37 One study show e d that the number of platelet 2- a d renergic receptors was significa n t ly l ower in patients with BPD compared with con t rol subjects38 and also l ower in patients with both depre s s i on and BPD com p a red with d e p ressed patients without BPD.39 The nora d renergic system is hyp e r re s p on s i ve in individuals with high levels of engagement with the environ m e n t , e g, people with increased sensation-seeking behavior40 and ch i l d ren with attention-deficit hyp e ractivity disorder.41 In a study by Steinberg et al,42 a strong positive corre l a t i on betw e e n growth hormone (GH) responses to clonidine and irritability as measured by the Buss-Durkee Hostility Inventory was found. Male patients with BPD had increased peak GH responses to clonidine and increased basal CSF MHPG when compared with male patients without BPD measured by the Buss-Durkee Hostility Inventory.43 Tricyclic antidepressants (TCAs), which enhance synaptic noradrenergic transmission, have not been found to be efficacious in patients with BPD.44-46 In summary, t h e re is not sufficient evidence to conclude that altera t i ons in nora d renergic function are associated with BPD, w h i ch differentiates it from PTSD and depre s s i on . The hippocampus, a brain region that plays an important role in memory and in the emotions of fear and anxiety, is extremely sensitive to stress.47,48 Research in animals suggests that the high levels of glucocorticoids seen in stress are associated with damage to hippocampal neurons. The HPA axis plays a major role in the stress response. Exposure to stressful events is associated with a marked increase in the release of cortisol from the adrenal glands. Studies in humans with stress, PTSD, and depression49,50 showed a reduction in hippocampal volume and hippocampus-based memory deficits.51 A recent investigation also found a reduction in hippocampal as well as amygdala volumes in patients with BPD.52 The stress re a c t i on inv o lves the nora d renergic and HPA axis systems, but findings re g a rding the nora d renergic system in BPD are conflicting. Brain altera t i ons in patients with traumatic experiences could be show n . This is important for further re s e a rc h on BPD as a trauma spectrum disorder.
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Affective Instability Although affe c t i ve instability is a central trait of BPD, its neuro b i o logy is still quite uncl e a r. A f fe c t i ve instability has been defined as a pre d i s p o s i t i on to mark e d , rapidly reversible shifts in affe c t i ve state that are extre m e ly sensitive to meaningful env i ronmental eve n t s . 1 Linehan28 postulated high sensitivity to emotional stim u l i , emotional intensity, and slow re t u rn to baseline. The factor of irritability in re s p onse to external factors differentiates mood swings in patients with BPD from those seen in affe c t i ve disord e r s . Also in con t rast to affe ctive disord e r s , mood changes in patients with BPD last on ly a few minutes to a few days . The medial pre f rontal cortex (MPFC) regulates emotion and stre s s re s p on s e s , including impulse con t ro l , i n h i b i t i on of re s p onses to external stim u l i , and extinction of fear re s p onse. Altera t i on s in MPFC function have been associated with the development of violence and aggre s s i on . In addition, altera t i ons in MPFC function were found in patients with PTSD related to both combat and abuse53,54 and have been hypothesized to underlie many sym p t oms of PT S D. Altera t i on s in MPFC were also seen in depre s s i on, another disord e r that overlaps with BPD. 18-fluorodeoxyglucose positron emission t om o g ra phy (FDG-PET) studies in patients with BPD have demonstrated decreases in re g i onal glucose metabolism in areas of the left and right pre f rontal cortex. De la Fuente et al55 found re l a t i ve hyp ometabolism in premotor and pre f rontal cortex in 10 patients with BPD com p a red with 15 healthy con t rol subjects. G oyer et al56 found altera t i on s in frontal cortex metabolism in 6 patients with BPD com p a red with 43 con t rol subjects. Ne u roimaging studies employing emotional ch a llenge paradigms ca n be used to investigate neural correlates of emotion processing in h e a l t hy subjects and patients. Fu n c t i on al magnetic re s onance imaging inve s t i g a t i ons in healthy subjects using standard i zed emotional pict u res found activation patterns in the MPFC, amygdala, and anterior cingulate.57,58 In PET studies, manuscripts eliciting specific emotion s , such as grief, guilt, or anger, w e re used.59-61 Du ring imagination of anger situations in healthy subjects, altera t i ons in pre f rontal blood flow w e re found with an increase in activity in the anterior cingulate.60,62 In patients with BPD, re g i onal blood flow was investigated during imagi n a t i on of neutral situations as well as of person a l i zed scripts descri bing situations of abandonment (CG Schmahl, MD, et al, unpublished data, 2001). Significant increases in blood flow were found in the right dorsolateral pre f rontal cortex, and significant decreases in the anterior
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cingulate and the hippocampus/amygdala re g i on. Interestingly, a recent FDG - PET study found activation of right dorsolateral pref rontal cortex in rhesus mon k eys after separa t i on from their mothers c om p a red to after a period together with their mothers.63 In an analogy of affe c t i ve disord e r s , mood stabilizers were used in the ph a rm a c o l o g i cal treatment of BPD. Carbamazepine was effe c t i ve in i m p roving depre s s i ve symptoms in BPD64 and valproate was shown to be successful in the treatment of aggre s s i ve behavior in patients with BPD.65-67 La m o t rigine led to a general improvement in an open ca s e series of patients with BPD.68 Unfort u n a t e ly , most studies did not a d d ress the core symptom of affe c t i ve instability itself. In an older but s t i ll interesting study, Rifkin et al69 i nvestigated the effe c t i veness of lithium in patients with emotionally instable ch a racter disord e r, which is one of the historic precursors of BPD. In their cro s s ove r, d o uble-blind, placebo-con t ro lled trial, 21 patients were treated with lithium or placebo for 6 weeks each . I m p rovement was found in 14 of 21 patients during lithium treatment and in on ly 4 patients during placebo tre a t m e n t . In this study, mood swings from day to day and during the day were assessed. The mean daily range of mood swings was significantly lower for lithium com p a red to placebo. The inve s t igators con cluded that lithium is part i c u l a rly helpful in treating short t e rm mood swings, which are typ i cal for this patient population . A s e c ond placebo-con t rolled study did not find lithium to be very effe c t i ve in treating BPD sym p t oms but showed a trend for lithium to reduce anger and suicidal sym p t om s .46 Impulsivity According to the suggested model of BPD, the second core element contributing to the development of the disorder is impulsivity. We next review the neurobiology of impulsivity and its importance in BPD. Impulsivity can be related to the ability to avoid danger in com b ination with the ability to active ly explore a novel env i ron m e n t . An important aspect of the impulsive behavioral pattern is a deficit in the inhibition of re s p on d i n g. The sero t onin (5-HT) system plays a critical role in impulsivity and aggre s s i ve behavior. Le s i ons of the 5-HT c ontaining ra phe nuclei70 and treatment of the brain with the sero t onergic neuro t oxin 5,7-dihyd rox ytryptamine produce incre a s e s in shock-induced fighting.71 As mentioned previously, the MPFC also p l ays a major role in impulsivity. An inverse re l a t i onship between impulsive aggre s s i on and neurochemical indices of 5-HT system function has been re p o rted in several studies. An inverse re l a t i onship was also shown between a life
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history of aggre s s i ve behavior and basal CSF 5-hyd rox yindoleacetic acid (5-HIAA) in male patients with person a l i ty disord e r72 based on the criteria of the Diagnostic and Sta t i s t i cal Manual of M e n ta l Disord er s,73 Se c ond Edition . Linnoila et al74 demon s t rated that CSF 5-HIAA was reduced on ly if the aggre s s i on was impulsive, rather than pre m e d i t a t e d , in nature . Violent suicidal behavior was also linked to decreased levels of CSF 5-HI A A .75,76 Studies of brain tissue of suicide victims found reduced levels of brain 5-HT,77-79 as well as an i n c reased number of 5-HT2 receptors in the pre f rontal cortex and the hippocampus.80,81 CSF 5-HIAA was also lower in a group of patients with aggre s s i ve behavior not related to suicidal behavior.82 5-HT has a stimu l a t o ry influence on the secre t i on of prolactin and a d re n o c o rt i c o t ropic horm one (cortisol). T h e re f o re, ch a llenge studies of substances with sero t onergic activity have been used to delineate the f u n c t i onal status of the sero t onergic system in different psych i a t ri c c on d i t i on s . An increased cortisol response to oral 5-HT pre c u r s o r ch a llenge was found in patients with depre s s i on and mania com p a re d with normal con t rol subjects.83 When patients were ca t e go rized into those with a history of a suicidal act, suicidal thoughts, or no suicidal i d e a t i on at all, individuals who had attempted suicide had the most robust cortisol responses to ch a ll e n g e . This finding was interpreted as reflecting an upre g u l a t i on of 5-HT receptors as an adaptive re s p on s e to a ch ronic hyp o s e ro t onergic state. Using fenfluramine as a ch a ll e n g e for prolactin re s p onse in patients with major affe c t i vedisorders or personality disord e r s , Coccaro et al84 found a reduced re s p onse to fe n f l uramine ch a ll e n g e, both in patients with affe c t i ve disorders and in those with person a l i ty disorders as com p a red with healthy con t rol subjects. Patients with a history of suicide attempt also had a decreased re s p on s e to fe n f l u ramine ch a llenge com p a red with those without a history of suicide attempt. When the patients with person a l i ty disorders were divided into groups with BPD and other person a l i ty disord e r s , the patients with BPD had significa n t ly reduced values com p a red with the patients with other person a l i ty disorders and the con t rol subjects. Other challenge studies also demonstrated an inverse correlation between inwardly or outwardly directed impulsive aggressive behavior and prolactin responses to fenfluramine challenge in both humans and primates.85,86 These findings were interpreted as suggesting reduced overall or net serotonergic activity. Another study using the postsynaptic agonist m-chlorophenylpiperazine (m-CPP), however, could not demonstrate changes in prolactin response to m-CPP in patients with a history of aggression or suicidal behavior.87
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The 5-HT system has been widely investigated in BPD. Most studies did not find overall alterations in CSF levels of the serotonergic metabolite 5-HIAA.36,37,88 However, suicidal and aggressive behaviors were correlated with lower 5-HIAA levels in male patients with BPD.35 In a study by Gardner et al,36 female patients with BPD and a history of suicide attempts had significantly lower 5-HIAA concentrations than those without such a history. Several studies in patients with BPD found lower platelet monoamine oxidase activity,89-92 which has been associated with various forms of impulsive behavior.93 Furthermore, certain personality traits (eg, sensation seeking, impulsivity) were shown to correlate positively with the number of platelet serotonin-binding sites in patients with BPD.94,95 A fenfluramine challenge study comparing a small group of patients with BPD and healthy control subjects did not demonstrate differences in cortisol or prolactin response as a whole, but it did find an accelerated prolactin response and a faster return of cortisol levels to baseline in the group with BPD. Because the release of these two hormones is regulated by different 5-HT receptor subtypes, these findings were interpreted as reflecting increased 5-HT2 receptor activity and altered 5-HT1A activity.96 A PET study during fenfluramine challenge revealed the relative regional uptake of FDG in response to fenfluramine (as compared to placebo) to be diminished in the medial and orbital regions of the prefrontal cortex, left middle and superior temporal gyri, left parietal lobe, and left caudate body in five patients with BPD compared with eight control subjects.97 Consistent with findings of alterations in the serotonergic system in patients with BPD are the promising results of pharmacologic trials involving serotonergic agents. Three open trials demonstrated global improvement in patients treated with fluoxetine, a selective 5-HT reuptake inhibitor.98-100 An open trial of sertraline found a reduction in overt aggression in patients with BPD treated with 50200 mg of sertraline per day.101 Two placebo-controlled studies investigated changes in impulsive aggression in patients with BP D treated with fluoxetine: Salzman et al102 found a statistica lly significant reduction in anger using the Profile of Mood States, and Cocca ro and Kavoussi103 demon s t rated a significant reduction in scores on the irritability and aggre s s i on subscales of the Ove rt Aggre s s i on Scale with dosages between 20 and 60 mg of fluoxetine per day. In summary, the correlation between impulsivity and the serotonergic system as well as alterations in this system in BPD seems to be well established. Studies of serotonergic function in BPD suggest a stronger
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role for alterations in this system in patients with BPD relative to other neurobiological systems. Dissociation and Self-Injurious Behavior Few studies have examined the biology of dissociation and self-injury. One animal model is freezing, which involves the endogenous opioid system (EOS). If an animal is attacked, there are three possible reactions to this aversive stress. First, if a realistic chance of success exists, the animal can start fighting its attacker. Second, if there is a good chance of successful escape, the animal will take flight. Third, the animal may exhibit freezing, that is, behavioral immobility, a response pattern that is the dominant response in some species. Freezing increases chances of survival, probably because predators detect moving prey more easily, so the attention of predators may shift to other moving or noisy stimuli, and movement cues, which are critical releasing stimuli for predatory behavior, are eliminated.104 When an animal is about to be attack e d , f re ezing tends to be combined with analgesia, w h i ch is functional in that perc e p t i on of pain would dive rt the attention of the prey from defe n s i ve con c e rn s .105 This analgesia can also be ca lled stress-induced analgesia.106 The EOS, which consists of three classes of endogenous opioids (-endorph i n s , enkephalins, and dynorphins) that activate three types of opioid re c e ptors (- , - , and -opioid receptors),107 is thought to play a major ro l e in stress-induced analgesia by means of dampening nociception at diffe rent brain leve l s .108,109 Rats exposed to inescapable shock show a d e c rease in binding of the - receptor agonist [3H]DAGO, supporting the hypothesis that inescapable shock produces lon g - t e rm changes in the EOS.110 St ress in humans is accompanied by the release of -endorph i n s .111,112 Recently, an increase in the release of dynorphin A was found with hyp oxia stress, suggesting that not on ly -endorphin is inv o lved in the stress re s p on s e .113 Besides its role in pain regulation and the stress response, the EOS seems to play a role in other psychobehavioral processes, such as modulation of emotional/motivational states and, more specifically, in separation-attachment behaviors.114,115 This might suggest the inv o lve m e n t of the EOS in typical stress situations of patients with BPD, since attachment disru p t i ons are supposed to play a cri t i cal role in the deve l o pment of BPD.116 Dissociation is a frequently endorsed sym p t om in patients with PTSD and BPD19,117; b e cause of this, the DSM-IV included the addition of crit e ri on 9 for BPDtransient stress-related paranoid ideation or seve re d i s s o c i a t i ve symptomswhich explicitly connects dissociative sym p-
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toms to stress. D i s s o c i a t i veph e n omena include derealization, depersonalization, and analgesia. Studies using well-established instruments to measure dissociation, s u ch as the Dissociation Experience Scale (DES)118 and the Clinician-Ad m i n i s t e red Dissociative Sym p t om s Sca l e,119 h a ve established the re l a t i onship between trauma and cl i n i cal dissociation in patients with combat-related PTSD as well as in survivors of childhood sexual abuse.120-122 Subjects re p o rting analgesia related to childhood sexual abuse often suffer from accom p a nying sym p t oms such as emotional numbing, depersonalization, and dere a l i za t i on .123 In addition to the relationship between dissociation and traumatic experience, there seems to be a genetic component underlying the dissociative experience. A twin study of 177 monozygotic and 152 dizygotic volunteer twin pairs from the general population who were assessed using the DES found genetic influences to account for 48% and 55% of the variance in pathologic and nonpathologic dissociative experience, respectively.124 Furthermore, dissociation in patients with BPD seems to be associated with the disorder itself and not with childhood sexual abuse.125 Brodsky et al126 investigated correlations among dissociation, SIB, and childhood abuse and found the strongest correlation between dissociation and self-mutilation, followed by dissociation and childhood abuse. Seve ral classes of drugs can produce dissociative states in healthy individuals. Ph e nylcyclidine and ketamine, n on c om p e t i t i ve antagonists of the N- m e t hyl-D-aspartate (NMDA) subtype of glutamate receptor, p roduce a dere a l i zed and deperson a l i zed state characteri ze d by perceptual altera t i on s and psychosis at subanesthetic doses.127,128 Se ro t onergic hallucinogens, such as lysergic acid dye t hylamide and mesca l i n e, a re also capable of producing dissociative symptoms. Besides visual hallucinations and illusions, these substances pro d u c e seve re deperson a l i za t i on and dere a l i za t i on129,130 by stimulating 5-HT2 receptors.131,132 The -opioid receptor agonists ketocyclazocine and MR-2033 also lead to dissociative symptoms such as changes in perception, depersonaliza t i on , and dere a l i zation.133,134 From a neuroanatomic point of view, the thalamus seems to play a major role in the processes involved in the generation of dissociative states. The thalamus serves as a sensory gate or filter that directly and indirectly modulates the access of sensory information to the cortex, amygdala, and hippocampus.135-138 Interestingly, several relay stations of somatosensory pathways, such as the dorsal horn of the spinal cord, nucleus gracilis and cuneatus, sensory and spinal trigeminal nucleus, and somatosensory thalamic nuclei, have high concentrations of opioid receptors.139 This could be a hint of the involvement of the EOS in the
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m o d u l a t i on of sensory inform a t i on processes and, thus, in the generation of dissociative states. A second brain region hyp o t h e s i zed to play a role in the generation of dissociation is the hippocampus,140,141 and studies in PTSD have found a correlation between hippocampal atrophy and dissociation142 (also, JD Bremner, MD, unpublished data, 2001). T h e re are seve ral reports showing altera t i ons in endogenous opioid levels in patients with BPD. Plasma -endorphin imm u n o re a c t i v i ty was low in patients with nonmajor depre s s i on , m a ny of whom met criteria for BPD.143 Coid et al144 re p o rted raised plasma metenkeph a l i n leve l s , and Pickar et al145 reported low levels of opioid activity in CSF. In the Coid et al144 study, a ll subjects showed SIB, w h i ch , in most cases, was ca r ried out in the absence of pain and was foll owed by re l i e f of tension and dys ph o ria. A l t e red con c e n t ra t i ons of endogenous opioids were also re p o rted in subjects with SIB related to other disorders such as mental re t a rdation.146,147 Interestingly, plasma -endorphin was s h own to be elevated in a coh o rt of 69 adults with a history of permanent separa t i on from one parent during childhood or adolescence and significant adult psych o p a t h o l o gya con s t e llation frequently observed in the families of patients with BPDcom p a red with a control group of 21 subjects with a similar history of parental separa t i on but no adult psychopathology.148 SIB is a com m on fe a t u re of BPD.149 This behavior in patients with BPD is often associated with relief of dys ph o ria and analgesia. Regarding SIB, two hypotheses have been postulated: the pain hypothesis and the addiction hyp o t h e s i s .150 The pain hypothesis suggests that SIB does not induce pain because of exc e s s i ve activity of endogenous opioids. Ac c o rding to this hypothesis, SIB serves to terminate these ave r s i ve analgetic states.151 Ac c o rding to the addiction hypothesis, SIB stimulates the pro d u c t i on and release of endogenous opioids, thus providing a rew a rd , making further SIB more pro b a b l e . Special attention has been paid to pain perception in patients with BPD. Russ et al152 used the cold pressor test to evaluate pain perception under experimental conditions. They compared patients with BPD who reported feeling pain during SIB, patients with BPD who did not feel pain during SIB, and healthy control subjects. They found significantly attenuated pain perception and improvement in dysphoric mood in the group of patients with BPD who did not feel pain during SIB compared with the two other groups. Pain ratings in patients with BPD reporting pain during SIB were quite similar to those of control subjects. In a second study, Russ et al153 investigated the effect of the opioid antagonist naloxone on pain perception in self-injurious patients with BPD. Contrary to expectations, naloxone did not attenuate mood improve-
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ment connected with the cold pressor test, although there was a tendency to experience more pain in the group reporting no pain during SIB. Significantly reduced pain perception was found in patients with BPD even under nonstress conditions, and it was only slightly further reduced under stress.154 Only a few studies exist re g a rding pharm a c o l o g i cal treatment of diss o c i a t i ve symptoms and SIB in patients with BPD. Special attention has been paid to substances influencing the EOS. Na l oxone has been used successfully in reducing SIB in patients with mental re t a rd a t i on .155 Roth et al156 re p o rted a marked reduction in SIB after treatment with 50 mg/day of the opioid antagonist naltre xon e, and they also observe d a conve r s i on from analgesia and relief of dysphoria in com b i n a t i on with SIB to a loss of analgesia and lack of emotional relief under tre a tment with naltre xon e . A second study investigated the influence of n a l t re xo ne in flexible doses on sym p t oms of dissociation including t onic immobility and analgetic experience.157 Na l t re xo ne significa n t ly reduced dissociative symptoms assessed by a self-rating instrument for dissociation, analgesia, and tonic immobility. The simultaneous pre sence of dys ph o ria, d i s s o c i a t i ve sym p t om s , and analgesia was suggested to reflect an activation of -opioid receptors. N a l t re xon e, by blocking -opioid re c e p t o r s , would suppress this trigger for SIB, t h e reby re d u cing the need for this antidissociative behavior. Seve ral findings also suggest that the sero t onergic system is involved in the genera t i on of dissociative states and SIB. The sero t onin agonist m-CPP induced deperson a l i za t i on significa n t ly more than placebo.158 SIB in patients with personality disorder was correlated with sero t on e rgic dys f u n c t i on as assessed by platelet imipramine binding.88 Consequently , agents influencing the serotonin system have been used to treat these symptoms. Fl u oxetine reduced depersonalization,159,160 and SIB was reduced following treatment with fluoxetine161 as well as sert raline.162 Taken together, these findings suggest that mechanisms involving the EOS and the serotonergic system underlie, at least in part, the symptom complex of SIB and dissociation including depersonalization, derealization, altered sensory perceptions, tonic immobility, and analgesia. Conclusion Although BPD seems to have many features in common with other psychiatric disorders, such as affective disorders and PTSD, its neurobiology has not been studied as extensively as that of related disorders. The complexity of symptoms in patients with BPD is best understood in terms of combinations of alterations in different neurobiological systems. What we have proposed here is a model of BPD that includes
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genetic and environmental factors. Genetic factors include a genetic pre d i s p o s i t i on to impulsivity and avoidance of harm, and env i ronmental factors include interp e r s onal stre s s , including sexual abuse and situations of abandon m e n t . We have proposed four core elements of BPD: interp e r s onal stre s s , affe c t i ve instability, impulsivity, and dissoc i a t i on and SIB. Interp e r s on al stre s s , e s p e c i a lly when it occurs at a very early age, is thought to be inv o lved in the deve l o pment of the disorder and seems to involve the noradrenergic and the HPA axis systems. Affective instability may be related to alterations in MPFC. Impulsivity clearly correlates with alterations in the serotonergic system. Dissociation and SIB also involve the serotonergic system but seem to be correlated with dysregulations of the EOS. BPD is best understood in terms of these four dimensional factors and the biology underlying them. Further neurobiological research in BPD should concentrate on long-term sequelae of interpersonal stress on the brain and neurotransmitter systems. 82
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