Psychopharmacology of personality disorders - Springer Link

Psychopharmacology of Personality Disorders: Review and Emerging Issues Paul S. Links, MD, FRCP(C), Andrea Boggild, MS, and Nitin Sarin

Address University of Toronto, St. Michael’s Hospital, 30 Bond Street, Suite 2004 2DS, Toronto, Ontario, M5B 1W8, Canada. E-mail: [email protected] E-mail: [email protected] E-mail: [email protected] Current Psychiatry Reports 2001, 3:70–76 Current Science Inc. ISSN 1523-3812 Copyright © 2001 by Current Science Inc.

Progress with the development of models and general principles of psychopharmacologic management of personality disordered patients is reviewed. Recent research using mood stabilizers and novel antipsychotics are discussed. The effects of these medications on impulsive aggressiveness are supported and the effects are evident early and are independent of the effects on mood, including depression. Research is needed with other personality disorders beyond just borderline personality disorder. Future research must develop measurable outcomes and delineate the causal and temporal relationships between the psychopathologic features of personality disorders.

Introduction The psychopharmacologic management of personality disorders has progressed in several ways. First, models to approach the psychopharmacologic management of personality disorders have been developed. These models provide an important framework that clinicians can use in the pharmacologic management of these patients. Second, general principles for managing patients with personality disorders have been articulated and these are reviewed. Third, over the past few years, pharmacologic management has progressed with the beginning of trials using novel or next generation medication for the treatment of personality disorder. This review focuses on recent reports published since the appearance of two major review papers on the psychopharmacologic management of personality disorder. Soloff [1•] published comprehensive algorithms for pharmacologic treatment of personality disorders that took a symptomspecific approach to targeting pharmacologic management. Links et al. [2•] reviewed a number of models of pharmacologic management and proposed an outcome-focused model as the most practical approach to pharmacologic management of patients with personality disorder.

Models of Treatment Soloff [1•] suggested that pharmacologic management of personality disorders could be based on dimensions of personality that appeared to be mediated by variations in neurotransmitter physiology and that might be responsive to medication. He proposed that the targets of pharmacologic therapy could be based on three dimensions: cognitive-perceptual, affective, and impulsive behavioral dysregulation, which are regulated by the actions of specific neurotransmitter systems. Soloff’s [1•] model was derived from results of his previous research with borderline personality disordered patients, in which three broad response patterns were defined based on a factor analysis of symptom change. These broad patterns of symptom change included global depression, hostile depression, and schizotypal symptom change. He presented detailed algorithms for treating each of the dimensions and provided the supporting evidence, where available, for each of the steps in the algorithms. Unfortunately, the symptom-specific model must be criticized. First of all, it is unclear that the regulation of cognition, perception, affect, and impulses are each specific to single neurotransmitters that can be easily identified as targets for pharmacologic therapy. Previous reviewers have noted that medications typically have nonspecific effects when treating patients with personality disorders [3,4]. For example, in patients with borderline personality disorder, neuroleptic effectiveness is not restricted to improvement of psychotic-like symptoms, but also impacts on anxiety, obsessive-compulsive symptoms, affective symptoms, and suicidal behavior [5]. Study of specific serotonergic reuptake inhibitors in patients with borderline personality disorder have demonstrated improvements in depression, anxiety, paranoia, psychoticism, interpersonal sensitivity, obsessionality, hostility, and global functioning versus placebo comparisons [5,6•]. Second, the symptom-specific approach often chooses dimensions that are broadly characterized, and many of the psychopathologic features have not been well defined and adequately measured. Soloff [1•] himself noted that the definition and assessment of many of the target symptoms have not been sufficiently studied. In addition, there are few measures of change of these proposed target symptoms. For example, the target symptom of affective dysregulation is said to include such symptoms as lability, rejection sensitivity, inappropriate intense anger, depressed

Psychopharmacology of Personality Disorders: Review and Emerging Issues • Links et al.

"mood crashes," and temper outbursts. However, affective lability has been characterized as a personality trait, has been likened to emotional incompetence found in head injury patients, or has been considered within the spectrum of bipolar affective disorders [7•]. Finally, the symptom-specific approach in the algorithms as outlined by Soloff [1•] might increase patients’ exposure to untested interventions. During the past decade, use of medication specifically for borderline personality-disordered patients has changed from being an occasional intervention to an expected one. His algorithms might foster the use of medication without adequate scientific justification. Many of the second, third, and fourth steps in the algorithms are based only on evidence from case reports or case series. We presented an alternate model, which was described as the outcome-focused model [2•]. The rationale for this model was 1) to clearly delineate the purpose of a pharmacologic intervention for both the patient and the clinician, 2) to choose outcomes that are measurable and related to functional improvements, and 3) to foster our understanding of the underlying psychobiologic mechanisms. As these psychobiologic mechanisms become better understood, they may well provide meaningful targets for pharmacologic interventions.

General Principles of Psychopharmacologic Management of Personality Disorders Patients with personality disorders should be encouraged to be active participants in the decision to use psychopharmacologic agents. We have found the N of 1 trial, in which a particular medication regime is compared with a patient's prior treatment or placebo, is a useful way to engage a patient in therapy (for the discussion of the N of 1 trial, see Guyatt et al. [8]). This approach has merit for patients with personality disorders because it encourages their collaboration in assessing the medication, diminishes their fears of being controlled, prevents a long-term commitment to interventions that may do more harm than good, and makes the expectations for outcome of treatment clearer. When treating a patient with personality disorder, often the clinician is clear when aggressive treatment is needed and when to begin. The difficulty according to Soloff [6•] is when to settle for “modest gains” and maintain the current regime. Research clearly indicates that Axis I disorders comorbid with a personality disorder will have less dramatic responses to treatment, and a patient undergoing pharmacologic management should be aware of this and have appropriate expectations [2•]. Pharmacologic management will not realize a cure of the disorder but can lead to significant reduction in symptoms and improvement in functioning. Silk [9] suggested that the patient should be aware that medication changes are not to be initiated during acute interpersonal crises. It is unlikely that these events are related to specific biologic changes

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and are adequate targets for pharmacologic interventions. Finally, when symptoms are overlapping between Axis I and Axis II disorders, significant benefit can be realized by treating the comorbid Axis I disorder. Links et al. [2•] suggested that definitive treatment of a comorbid Axis I disorder should have priority, and can be successful and have impact on the underlying Axis II disorder. Gitlin [10] argued that this strategy was most important when the personality disorder is "reminiscent constitutionally of the Axis I disorder." An example would be treating comorbid social phobia that overlaps considerably with avoidant personality disorder. Social phobia with avoidant personality disorder, when treated pharmacologically, leads to improvement in both the Axis I and Axis II disorders [2•]. Another general principle of psychopharmacologic management is that special attention to monitor the effectiveness and to judge side effects are required. Because research has shown a lack of agreement between self-rated and observer-rated measures of outcome, particularly with borderline personality-disordered patients, it is useful to monitor both or to choose specific measurable behavioral outcomes to evaluate the patient's response [2•,11–13]. Prior to prescribing medication, the clinician should assess the patient for symptoms that are consistent with the sideeffect profile of the medications to be used. Such an evaluation provides a baseline for monitoring the appearance of new symptoms during the trial of medication. Completing self-report and observer ratings of symptoms targeted for treatment often assists with judging whether there has been a response to the medication. Pharmacologic interventions should facilitate the patient's availability for other therapeutic intervention. The patient’s adherence to other treatment modalities could well be used as a meaningful outcome of psychopharmacologic management. In addition, pharmacologic management should have an impact on the patient's overall functioning. An important outcome of pharmacologic trials should be an improvement in work, family, and other aspects of role performance. In the future, pharmacologic trials should include indicators of quality of life so they can be used as measures of effectiveness of pharmacologic interventions and provide a broader assessment of the impact of pharmacologic interventions beyond symptom reduction and side effects.

Nonestablished indications and new interventions In this section, we review the most recent psychopharmacologic trials of mood stabilizers and novel antipsychotics in patients with personality disorders that have been published since the major reviews by Soloff [1•] and Links et al. [2•]. The review is organized by medication type and a bulk of the recent research has been related to these two classes of medication. Focusing on medication type allows for more precision in discussing the recent research as there is still great variability in characterizing the samples

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Personality and Impulse Disorders

of personality-disordered patients and in selecting outcomes or measures of change. By discussing the types of pharmacologic interventions, it may clarify whether these new pharmacologic agents lead to more specific outcomes. Mood stabilizers The initial studies of mood stabilizers in borderline personality-disordered patients suggested that they may be effective in decreasing impulsivity and suicidality. Randomized controlled trials of lithium [12] and carbamazepine [14] showed effectiveness for impulsivity and behavioral dyscontrol but not so for mood stabilization. A later randomized control trial of carbamazepine [15] was not able to replicate the effectiveness of carbamazepine. More recently divalproex has been the focus of study both with case series and two recent randomized control trials. Stein et al. [16] carried out an open labeled case series study 8 weeks in duration looking at the effectiveness of valproate titrated to reach blood levels of 50 to 100 µg/ mL. The study demonstrated that only four of the eight completers were considered responders. Changes were noted primarily in mood and irritability. Wilcox [17] studied 30 inpatients with borderline personality disorder and monitored the amount of seclusion time required after patient’s exposure to divalproex sodium. The authors were able to demonstrate that divalproex significantly contributed to the variance in the decrease in seclusion scores after treatment with the medication. Kavoussi and Coccaro [18] carried out a study of divalproex sodium targeting its effects on impulsivity and aggressive behavior using as the outcome the Overt Aggression Scale Modified. The sample included a group of patients with Axis II disorders that had been drawn from an earlier study of fluoxetine. All the patients were characterized as having impulsive aggressive behavior. The study exposed the patients to an initial dose of 500 mg of divalproex and worked up to a dose of 2000 mg/d. The results indicated that 10 patients who were treated for at least 4 weeks showed significant declines in overt aggression. The change in overt aggression occurred very early by 2 weeks of study, and continued to be significant at the 8th week of study. Irritability was significantly reduced but not until the 4th week of the study. Out of the eight completers of the study, six were felt to be responders with a greater than 50% reduction in the Overt Aggression Scale Modified. Two randomized controlled trials have addressed the effectiveness of divalproex sodium. Donovan et al. [19] carried out a trial of divalproex in 20 children and adolescents 10 to 18 years of age. These subjects were selected because of a history of conduct disorder or oppositional defiant disorder. In addition, the subjects had to demonstrate an explosive temper, mood lability, impairment in school, family life, work, and duration of illness of at least 1 year. The study was a double-blind crossover trial, which included exposure to divalproex sodium at a dose of 10 mg/lb/d. The study had five dropouts so the authors

choose to examine both the phase one as a parallel design and the overall results from the crossover study. In the parallel design, there was evidence that divalproex produced a response in 80% of the subjects. The response was defined as a greater than or equal to 70% reduction in the Overt Aggression Scale Modified. There were no responders in the placebo group. In the overall cross over study, divalproex sodium lead to a 86% responder rate versus a 25% responder rate in the placebo group. This study showed a fairly dramatic response for aggression, impulsivity and for anger and hostility in children and young adolescents with antisocial or borderline features. Hollander [20] carried out a randomized control trial of divalproex sodium in well-defined patients with borderline personality disorders. The study was hampered by what appeared to be a large sample loss within the placebo arm even before patients were randomized to medication. This restricted the study to be pre-post design. In the patients exposed to divalproex, five of 12 were considered responders with a decrease in the Clinical Global Impression Scale and an increase in the Global Assessment Scale. Barratt et al. [21] studied the effects of phenytoin on impulsivity and premeditated aggression using a doubleblind randomized control cross over design. A total of 60 prison inmates were selected because of a specificity of aggression of either impulsive or premeditated type. These subjects were drawn from a larger sample of 126 subjects and those excluded had a mixed type of aggression. The subjects were exposed to phenytoin 300 mg/d. The results indicated that the inmates with impulsive aggression showed a significant reduction in the frequency of aggressive behaviors and in the intensity of the aggressive behaviors. There was no significant changed in those subjects with premeditated aggression. Hegarty [22] has completed a study of divalproex sodium in incarcerated men. These individuals were diagnosed as having borderline personality disorder and were characterized again by showing reduction of violence and irritability when treated with divalproex sodium. Pinto and Akiskal [23] studied lamotrigine in patients with borderline personality disorder and reported on a case series of eight patients. Patients were treated with lamotrigine beginning at 70 mg/d up to 300 mg/d. All patients were chosen because of the presence of borderline personality disorder and by frequent failed trials of antidepressants or mood stabilizers. The author reported that three of the eight (37.5%) showed a robust response to the lamotrigine. The response was illustrated by significant improvement in their global functioning, by reduction of impulsive behavior including suicidal behavior, and the patients no longer met the criteria for borderline personality disorder at 1-year follow-up. Summary The utility of mood stabilizers in patients with borderline personality disorders still requires further study. Previous


studies have been limited by small sample sizes, by selection of different diagnostic groups from a variety of clinical settings, and by little attention to the outcome of mood lability. Overall, mood stabilizers have not been utilized in any other personality disorders except borderline personality or related cluster B disorders. In these disorders, mood stabilizers seem to have a specific effect for impulsive aggressiveness rather than mood variability. When using this as the outcome, the response rates are modest varying from 37.5% to 80%, suggesting perhaps a subgroup of patients with cluster B personality disorders may be responders to mood stabilizers. There is little or no evidence that mood stabilizers actually led to the stabilization of mood in personalitydisordered patients. Although trials have been reported in bipolar disorder including bipolar II, they provide little insight into the usefulness of these medications in personality disorders. Most of the studies in bipolar patients have not specifically excluded Axis II comorbid patients, however, few of the studies specify the Axis II psychopathology. Studies are also limited because the new mood stabilizers are used as adjunctive agents with standard treatments. Only one study was found to specifically address the issue of stabilizing ultracircadian mood variation. A case report of the use of nimodipine in patients with refractory recurrent affective illness was found [24]. The clinical prescription of mood stabilizers, unfortunately, has out stripped the empiric evidence for their use. However, they do seem to have some utility in decreasing impulsive aggressiveness in cluster B and borderline personality disorder. Novel antipsychotics Low doses of traditional antipsychotics have been well studied in borderline personality disorder. Several randomized control trials have demonstrated the efficacy of low dose antipsychotics in reducing the overall symptom severity in the acute management of patients with borderline personality disorder [6]. However, traditional antipsychotics have low acceptability and significant longterm side effects including the possibility of tardive dyskinesia that limited their use in this chronic disorder. Novel antipsychotics have been studied beginning with clozapine. Frankenburg et al. [25] studied a series of 15 cases with borderline personality disorder and treatment resistant psychotic symptoms characterized as psychotic disorder not otherwise specified. These patients received clozapine with an average dose of 253 mg/d. The results showed that 12 of 18 symptoms on the Brief Psychiatric Rating Scale were significantly reduced with exposure to clozapine. The authors concluded that the medication was effective for reducing psychotic symptomatology and improving overall functioning. Side effects were common as all patients reported difficulty with them. Chengappa et al. [26] described the successful use of clozapine in a single case of borderline personality disorder. The patient

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was treated with 300 mg/d of clozapine. On this treatment the patient showed a reduction in the severity of selfmutilation. Benedetti et al. [27] carried out an open label trial of clozapine in a case series of 12 patients with borderline personality disorder evidencing psychotic-like features. Patients were exposed to low doses of clozapine with an average dose of 43.8 mg/d. The authors found that psychotic symptoms and general psychopathology were significantly reduced after exposure to clozapine. In addition, the number of physical fights and suicide attempts were significantly reduced during the period of time on clozapine. Again side effects were common with 10 of 12 patients reporting troubling side effects. Chengappa et al. [28] in a second publication reported on the use of clozapine in a case series of borderline personality-disordered patients. The target symptom was the patients’ self-mutilating behavior. The patients were exposed to clozapine with a mean dose of 421 mg/d. The authors demonstrated a reduced rate of seclusion and restraint upon exposure to clozapine, reduced injuries to peers and staff, and improvement in global functioning. Again, side effects were common, including one case of neutropenia. Risperidone has been studied in case reports and one recently reported randomized trial. Szigeth et al. [29] reported a case of a woman with dysthymia and borderline personality disorder who was treated with risperidone plus fluvoxamine. Risperidone at 2 mg/d plus fluvoxamine at 200 mg/d led to an improvement in the patients’ mood, obsessionality and paranoid-like symptoms. Khouzam et al. [30] reported on a case of a woman with severe selfmutilation. On 4 mg/d of risperidone, they were able to demonstrate a remission in the patient’s self-mutilative behaviors. Koenigsberg et al. [31] reported on the use of risperidone in patients with schizotypal personality disorder. Risperidone was hypothesized to be useful for both the positive and negative symptoms of the disorder. Twenty-one schizotypal patients were involved in the randomized control trial. They were treated with risperidone up to a maximum dose of 2 mg/d. Initial results of the study reported significant effects on both positive and negative psychotic symptoms. Using a 30% change in scores as a response rate, four of seven patients exposed to risperidone was considered responders versus none in the placebo arm. Olanzapine has been studied in an open-labeled 8week study by Schultz et al. [32•]. They studied subjects with borderline personality disorder and dysthymia recruited from community referrals and local advertisement. Patients were excluded from the trial if they suffered from a current diagnosis of schizophrenia, bipolar disorder, schizoaffective disorder, or met a criteria for a major depressive episode within the last 12 weeks prior to the study. Eleven patients began the study and nine completed the full 8 weeks of the protocol. The mean final dose of olanzapine was 7.73 mg/d. Significant reduction in all rating scales

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were found with the greatest percentages of change being in symptoms of anger, hostility, phobic anxiety, paranoia, obsessive-compulsive symptoms, interpersonal sensitivity, and psychoticism. No movement-related side effects were noted for any patients, however, four patients subsequently requested a change in medication because of weight gain while taking olanzapine. This preliminary study suggested that novel antipsychotics, such as olanzapine, were efficacious and produced few movement-related side effects. Zanarini et al. (Personal communication) have completed a randomized control trial of olanzapine in borderline personality disorder and the results are soon to be published. Summary The use of novel antipsychotics has been most studied in borderline personality disorder, although there is some studies beginning in schizotypal personality disorder. Overall, novel antipsychotics seem particularly helpful for aggressive and self-mutilative behaviors, although as with traditional antipsychotics, there is a board spectrum effect. Psychotic symptoms also seem to be alleviated with novel antipsychotics and the beginning evidence suggests they may have a role in the negative psychotic symptoms as typified in schizotypical personality disorder. Clozapine, although effective, must be restricted to treatment resistant patients as side effects are common and the risk of agranulocytosis exists.

Conclusions and Emerging Issues A review of the recent psychopharmacologic trials in patients with personality disorders leads to some important conclusions and to many unanswered questions. First, many different pharmacologic agents have been used in personality disordered patients. The research appears to reflect clinical practice as these patients are exposed to most emerging psychopharmacologic interventions. Unfortunately, pharmacologic research is falling rapidly behind clinical practice and little empiric evidence is available to direct clinical work. In general, pharmacologic agents have a role in the management of personality disorder patients and have a positive and broadly based effect, particularly in borderline personality disorder other cluster B personality disorders. Furthermore, pharmacologic agents repeatedly have pronounced affects on impulsive aggressiveness. This appears to be true of both mood stabilizers, novel antipsychotic agents and although not reviewed, specific serotonergic reuptake inhibitors (Soloff [6•] reviews antidepressant medications in borderline personality disorder). The effects on impulsive aggression are evident early and these effects are independent of effects on mood including depression. In general, it could be said that pharmacologic agents are an appropriate tool to lessen impulsive aggressive behavior and the clinician should make a choice based on the safety and side-effect profile of medications.

Emerging evidence suggest psychoticism found in borderline and schizotypal personality disorders can be a target symptom and that these symptoms are affected by novel antipsychotic agents. It is interesting to conjecture that the psychoticism that is responding to medication includes some dissociative symptoms. Future psychopharmacologic trials should target dissociative symptoms and this may help refine the underlying biologic mechanisms leading to psychotic and dissociative symptoms in Axis II disorders. The psychopharmacologic research has been hampered because of a focus on borderline personality disorder. Studies of other Axis II clusters are needed. However, the focus on borderline personality disorder probably reflects the severity and prevalence of this disorder. Studies of borderline personality disorder have been restricted by high dropout rates. As a result, studies have included either the most severe borderline personality disorder inpatients or volunteers with borderline personality disorder without comorbid disorder. Unfortunately, this greatly limits the generalizability of the results to the majority of outpatients with borderline personality disorder. The high drop out rate seems inherent to the disorder and will limit the field unless collaborative networks of researchers can come together. A collaborative network would allow the testing of pharmacologic agents in larger, representative samples. In addition, specific protocols could test an algorithm approach to the treatment of personality disorders based on systemized protocols. The study of Axis II disorders has been severely hampered by the limits of the measures of the psychopathology characteristic of these disorders. It may well be impulsive aggressiveness is the best-measured aspects of Axis II pathology and we have been able to demonstrate change in this because of its measurable behavioral component. There is a lack of definition of the affective and cognitive aspects of Axis II disorders. An example would be affective lability, that has been variously characterized along four dimensions; cyclicity, intensity, environmental reactivity and variability [7•]. Not only do we have to refine the definition of the various aspects of psychopathology but we also need to develop responsive measurements that can capture change through pharmacologic interventions. These measurement issues need to be address so that we may demonstrate beyond behavior that we are able to affect changes in affect and cognition. Although problems with sample selection and measurement need to be addressed, we have to change our current models of understanding of personality disorders. New models have been suggested to explain the relationship between impulsivity, affect lability, and depression as found in borderline personality disorder [7•,33•]. In the proposed model, impulsivity and affective lability are seen as the engines driving the development of self-generated negative life events. The self-generated life events are important in precipitating depression of significant intensity lead-


ing to self-destructive behavior. Using this causal chain of events interventions can be better targeted. Hypothetically, impulsivity could be reduced that would decrease the propensity for negative life events, decrease the occurrence of depression, and ultimately improved the course of borderline personality disorder. Further trials of sufficient duration to indicate the temporal relationship of change in psychopathology are needed to strengthen our understanding of these causal chains of events. In summary, clinicians should follow the general principles of management when treating personalitydisordered patients pharmacologically. Anticipated should be changes in behavior, particularly impulsive aggressiveness, and this improvement may well impact across a wide variety of symptoms. In the end, pharmacologic management should be seen as an adjunct in the overall care of patients with personality disorders.

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References and Recommended Reading

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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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1.• Soloff PH: Algorithms for pharmacological treatment of personality dimensions: symptom-specific treatments for cognitive-perceptual, affective, and impulsive-behavioral dysregulation. Bull Menninger Clin 1998, 62:195–214. Based on available research evidence, the author develops first detailed algorithms for the pharmacologic management of personality disordered patients using a symptom-target approach. 2.• Links PS, Heslegrave R, Villella J: Psychopharmacological management of personality disorders: an outcome-focused model. In Biology of Personality Disorders. Edited by Silk KR. Washington, DC: American Psychiatric Press; 1998:93–127. The authors reviewed existing models of the pharmacologic management of personality disorders and suggested an outcome-focused model based on using measurable outcomes. 3. Coccaro EF: Neurotransmitter function in personality disorders. In Biology of Personality Disorders. Edited by Silk KR. Washington, DC: American Psychiatric Press; 1998:1–25. 4. Links PS, Steiner M: Psychopharmacologic management of patients with borderline personality disorder. Can J Psychiatry 1988, 33:355–359. 5. Gunderson JG, Links PS: Borderline personality disorder. In Treatments of Psychiatric Disorders, edn 2. Edited by Gabbard GO. Washington, DC: American Psychiatric Press; 1995:2291–2309. 6.• Soloff PH: Psychopharmacology of borderline personality disorder. Psychiatr Clin North Am 2000, 23:169–192. This paper updates Dr. Soloff’s 1998 article [1•] specifically related to the psychopharmacologic management of borderline personality disorder. The appropriate use of antidepressant medication in this disorder is reviewed. 7.• Links PS, Boggild A, Sarin N: Modeling the relationship between affective lability, impulsivity, and suicidal behavior. J Psychiatr Pract 2000, 6:247–255. The article refines the concept of affective lability and develops a model explaining depression and suicidal behavior in borderline personality disorder. 8. Guyatt G, Sackett D, Adachi J, et al.: A clinician’s guide for conducting randomized trials in individual patients. Can Med Assoc J 1988, 139:497–503.

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Khouzam HR, Donnelly NJ: Remission of self-mutilation in a patient with borderline personality during risperidone therapy [letter]. J Nerv Ment Dis 1997, 195:348–349. 31. Koenigsberg HW, Goodman M, Mitropoulou V, et al.: Risperidone in the treatment of schizotypal personality. Presented at the American Psychiatric Association Annual Meeting 2000. Chicago: May 16, 2000. 32.• Schulz SC, Camlin KL, Berry SA, et al.: Olanzapine safety and efficacy in patients with borderline personality disorder and comorbid dysthymia. Biol Psychiatry 1999, 46:1429–1435. The first published trial of novel antipsychotics, other than clozapine, in borderline personality disorder. Specific attention is given to the occurrence of side effects during exposure to olanzepine.

33.• Koenigsberg HW, Anwunah I, New AS, et al.: Relationship between depression and borderline personality disorder. Depress Anxiety 1999, 10:158–167. An up-to-date review of the relationship between depression and borderline personality disorder.