Pharmacological treatment of borderline personality disorder: critical review of the literature and development of algorithms

Abstracts

INTRODUÇÃO: O transtorno de personalidade limítrofe (TPL) é uma síndrome psiquiátrica que causa significativa morbidade e mortalidade para pacientes internados e ambulatoriais tratados por profissionais de saúde mental. Dada a sua alta prevalência na população de pacientes psiquiátricos, esforços são necessários para tratar esse grupo apropriadamente. OBJETIVO: O objetivo do presente artigo é revisar evidências atuais acerca da efetividade das diversas abordagens farmacológicas empregadas como parte do plano de tratamento produzido para indivíduos que enfrentam essa doença. MÉTODOS: Para esse propósito, os autores revisaram o banco de dados MEDLINE em busca de ensaios clínicos publicados entre 1986 e 2003. Borderline personality disorder e clinical trials foram usados com descritores. RESULTADOS: Numerosos trabalhos foram encontrados, mas poucos estudos controlados estavam disponíveis. Notável é o fato de que virtualmente todas as classes de psicofármacos foram testadas nesse grupo de pacientes, comumente com desfechos modestos ou variáveis. Devido a limitações metodológicas na vasta maioria dos ensaios clínicos envolvendo drogas específicas nesse grupo de pacientes, foi difícil estimar o benefício real dos vários agentes testados. A evidência mais forte existe para os inibidores seletivos de serotonina, antipsicóticos e divalproato. DISCUSSÃO: Claramente, mais ensaios clínicos bem delineados são necessários, mas os dados revisados sugerem que psicofármacos são efetivos para tratar sintomas-alvo nesses pacientes. Conclui-se que psicotrópicos são adjuntos úteis às abordagens psicoterapêuticas usualmente empregadas para tratar pacientes limítrofes.

Transtorno de personalidade limítrofe; ensaios clínicos; revisão; psicofarmacologia; algoritmos; inibidores seletivos de recaptação da serotonina; divalproato; antipsicóticos

ORIGINAL ARTICLE

Pharmacological treatment of borderline personality disorder: critical review of the literature and development of algorithms

Tratamiento farmacológico del trastorno de personalidad limítrofe: revisión crítica de la literatura y desarrollo de algoritmos

André F. Carvalho^I; Cristiane B. Stracke^II; Fábio G. de Matos e Souza^III

^IPsychiatrist, Centro de Estudos da Memória (Biochemistry Department) and Ambulatório de Neurogeriatria, Neurology Service, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Brazil

^IIPsychiatrist, Fundação Universitária Mário Martins

^IIIProfessor of Psychiatry, Universidade Federal do Ceará (UFC), Fortaleza, Brazil

^{Correspondence}

ABSTRACT

INTRODUCTION: Borderline personality disorder (BPD) is a psychiatric syndrome that causes significant morbidity and mortality to both inpatients and outpatients treated by mental health care providers. Due to its relatively high prevalence in the psychiatric population, efforts are necessary to treat this problematic group of patients properly.

OBJECTIVE: The aim of this paper is to review current evidence of the effectiveness of the various pharmacological approaches employed as part of the treatment plan designed for individuals coping with this illness.

METHODS: For this purpose, the MEDLINE database was searched for clinical trials from 1986 to 2003. "Borderline personality disorder" and "clinical trials" were used as descriptors.

RESULTS: Numerous works were retrieved, but very few controlled trials were available. Noteworthy is the fact that virtually all classes of psychopharmacological agents were tested in this set of patients, often with modest and variable outcomes. Due to methodological limitations observed in the vast majority of trials involving specific drugs in this group of patients, it was difficult to estimate the real benefit of the several agents tested. The most robust evidence exists for selective serotonin reuptake inhibitors, antipsychotics and divalproex.

DISCUSSION: Clearly, more well-designed clinical trials are needed, but the data reviewed suggest that drugs are effective in the treatment of target symptoms in these patients. Psychotropics are useful when used in association with the psychotherapeutic approaches usually employed with borderline patients.

Keywords: Borderline personality disorder, clinical trials, review, psychopharmacology, algorithms, selective serotonin reuptake inhibitors, divalproex, antipsychotics.

RESUMEN

INTRODUCCÍON: El trastorno de personalidad limítrofe (TPL) es un síndrome psiquiátrico que causa significativa morbididad y mortalidad a pacientes internados y ambulatoriales tratados por profesionales de salud mental. Vista su alta prevalencia en la población de pacientes psiquiátricos, son necesarios esfuerzos para tratar apropiadamente a ese grupo.

OBJETIVO: El objetivo del presente artículo es revisar evidencias actuales sobre la efectividad de los diversos aportes farmacológicos empleados como parte del plan de tratamiento producido para individuos que enfrentan esa enfermedad.

MÉTODOS: Para ese propósito, los autores revisaron la base de datos MEDLINE buscando ensayos clínicos publicados entre 1986 y 2003. Se usaron como descriptores borderline personality disorder y clinical trials.

RESULTADOS: Se encontraron numerosos trabajos, pero pocos estudios controlados estaban disponibles. Es notable el hecho de que, en ese grupo de pacientes, virtualmente han sido probadas todas las clases de psicofármacos, comúnmente con resultados modestos o variables. Debido a limitaciones metodológicas en la vasta mayoría de los ensayos clínicos abarcando drogas específicas en ese grupo de pacientes, fue difícil estimar el beneficio real de los varios agentes probados. La evidencia más fuerte existe para los inhibidores selectivos de serotonina, antipsicóticos y divalproato.

DISCUSIÓN: Claramente, son necesarios más ensayos clínicos bien enmarcados, pero los datos revisados sugieren que psicofármacos son efectivos para tratar síntomas blanco en estos pacientes. Se concluye que los psicotrópicos son adjuntos útiles a los abordajes psicoterapéuticos usualmente empleados para tratar a pacientes limítrofes.

Palabras clave: Trastorno de personalidad limítrofe, ensayos clínicos, revisión, psicofarmacología, algoritmos, inhibidores selectivos de recaptación de la serotonina, divalproato, antipsicóticos.

INTRODUCTION

Borderline personality disorder (BPD) is a clinical diagnosis that encompasses a vast range of presentations. The clinical manifestations of the syndrome can be grossly grouped around three symptomatic nuclei: (1) affective symptoms, including: fluctuating mood states such as depression, anger and hostility; (2) perceptual and cognitive distortions, such as referential delusions, paranoid ideation, dissociative illusions and phenomena; and (3) aggressive and impulsive behaviors, such as: self-mutilation, physical and verbal aggression towards others, suicidal behavior, drug abuse and promiscuity.¹

The prevalence of BPD is relatively elevated (accounting for up to 25% of admissions to some psychiatric units)¹ and imposes serious morbidity and lethality to borderline patients. The interpersonal relationships of these patients are usually intense and chaotic.²

Since this disorder has such a wide range of clinical presentations, it is often difficult to find a specific group of psychopharmacological agents to treat BPD patients. This possibly explains why practically all classes of psychopharmacological agents have been tested in this group of patients. Clinicians often treat borderline patients empirically. Evidence-based guidelines are seldom encountered.

Objective

The objective of this study is to review the literature and relevant textbooks in search of evidence that guides the pharmacological treatment of borderline patients. The articles found will be analyzed by the authors in search of potential bias, external validity and study design errors. Thus, the ultimate goal of the present paper is to critically review the existing literature. Finally, algorithms are proposed for each symptomatic group.

METHODS

The authors ran a search of the MEDLINE database looking for articles published in English between 1986 and December 2003. "Borderline personality disorder" and "clinical trials" were used as primary descriptors. Well-regarded textbooks were also searched in the same manner. Authors renowned for their work in this area were also contacted by electronic mail in search of further studies that had not yet been published.

A file card was written out for each article by each author individually describing the type of study design, the method of sample selection, potential bias, internal and external validity and any possible conflicts of interest. Placebo controlled clinical trials (PCT) receive the greatest emphasis in this review. Relevant open-label studies (OS) will be briefly mentioned. For some drugs, the only evidence found comes from OS studies. These studies will be mentioned in detail in order to shed light on future perspectives of this active field of scientific inquiry.

RESULTS

The results are comprehensively grouped in the various pharmacological groups. A total of 30 clinical trials were found, of which sixteen were PCT while the remaining fourteen are OS (table 1).

Typical antipsychotics

Historically, BPD has been used to describe a continuum of clinical presentations that include both affective and schizotypal subtypes.² Borderline patients often present psychotic micro-episodes usually triggered by a number of different types of stressors. Furthermore, there is extensive co-morbidity between BPD and schizotypal personality disorder (SPD) according to the DSM-IV diagnostic criteria.³

Antipsychotic medications play a relevant role in the treatment of the psychotic-like symptoms found in a large proportion of BPD patients.⁴ In clinical practice, antipsychotics are typically prescribed to at low doses to treat these patients.

Goldberg et al studied the response to thiotixene in a small sample of patients matching DSM-III diagnostic criteria for BPD.⁵ This was a PCT-type study and outcomes included eight groups of symptoms derived from the Schedule for Interviewing Borderline (SIB) and the Hopkins Checklist 90 (HSCL-90). Thiotixene doses varied from 2 to 35 mg/day (with a mean of 8.67 mg/day). A significant response was observed in terms of reduction in psychotic, obsessive-compulsive and phobic-anxious symptoms. The study found that the response to thiotixene was directly proportional to the severity of symptoms immediately prior to being enrolled on the trial.

Cowdry & Gardner performed a complex, double-blind, placebo controlled crossover study, in which the therapeutic effects of four drugs (alprazolam, carbamazepine, trifluoperazine and tranylcypromine) were compared in BPD patients. Trifluoperazine produced significant improvement in anxiety symptoms after a minimum of three weeks of treatment. Depressive symptoms, suicidal behavior and sensitivity to rejection also improved within the experimental group, but there was disagreement between the scores provided directly by the patients and those obtained by the researchers.⁶

Soloff^7,8 conducted two studies in which haloperidol was tested as a therapeutic agent in BPD patients. In the first of these studies, both outpatients and inpatients patients meeting DSM-III criteria for BPD or SPD were enrolled in a PCT. A group treated with haloperidol was compared with another group treated with amitriptyline and a third placebo group. After three weeks of treatment, haloperidol (4-16 mg/day, mean of 7.24±3.19 mg/day) was superior to both placebo and amitriptyline in terms of global symptom severity reduction and also in terms of improved depressive symptoms, paranoid ideation, psychoticism and interpersonal sensitivity.⁷ In the second study, the authors tried to pharmacologically dissect borderline inpatients into schizotypal (who would respond to haloperidol according to the experimental hypothesis) and affective (who would respond to amitriptyline) subtypes. Haloperidol (average dose of 3.93±0.65 mg/day) was similar to placebo in terms of global symptomatic improvement.⁸ The two studies yielded contradictory outcomes. The sample enrolled in the second study presented less severe disturbances and a greater rate of concurrent major depressive disorder. Thus, the data suggest that haloperidol may have some benefit for the treatment of schizotypal and impulsive-aggressive symptoms, but the external validity of the results is inconsistent, probably reflecting significant variations in the characteristics of the two samples.

Cornelius et al.⁹ followed-up those of the sample of patients studied by Soloff⁸ who had responded to low doses of haloperidol and/or phenelzine. After five weeks of treatment, the patients who had responded to haloperidol were followed for additional sixteen weeks. The group that continued to receive haloperidol continuation therapy did not exhibit global improvement with the exception of irritability scores. Furthermore, 87.5% of the patients who received haloperidol did not complete the trial, resulting in confused conclusions. This possibly reflects the low efficacy of haloperidol for continuation therapy, its propensity to develop adverse effects, or simply the low level of compliance of this specific group of patients.

In summary, the results of these studies suggest that typical antipsychotics are effective for the treatment of psychotic-like symptoms and also improve symptoms of hostility and anger. The benefits of continuation and maintenance treatments with typical antipsychotics remain uncertain.

Atypical antipsychotics

This group of drugs offers clear advantages over the older typical antipsychotics. For example, atypical antipsychotics offer a relatively low risk of inducing extrapyramidal symptoms as treatment progresses. These drugs can also exhibit anti-manic and mood stabilization properties as recently reviewed by Ghaemi.¹⁰ This group of drugs, in particular clozapine, can enormously improve the aggression of severely psychotic patients.¹¹ Theoretically, therefore, atypical drugs have the potential to improve affective, cognitive-perceptual and impulsive-aggressive symptoms in borderline patients.

This possibility is being investigated by a number of recent clinical trials. An OS demonstrated that clozapine (75-550 mg/day) produced a global symptomatic improvement in patients meeting DSM-III-R criteria for BPD and axis I criteria for psychotic disorders with no other classification.¹² The results should be interpreted with caution since this is an OS and has a relatively small sample size (n=15).¹² Another OS using clozapine (25/100 mg/day) demonstrated that borderline patients presented a global improvement that was sustained through sixteen weeks of treatment.¹³ PCTs are needed to confirm these promising results.

Recently, women meeting DSM-IV criteria for BPD were treated with olanzapine in a PCT. Patients in the experimental group exhibited improvement in all symptoms on the SCL-90 scale with the exception of depressive symptoms.¹⁴ Nevertheless, this study has serious limitations since just nine patients completed the trial. It is not known if men with BPD would respond in a similar manner to the women that took place in the trial. Patients with co-morbidity of any type were excluded from the study. The external validity of the study could be questioned since the existence of co-morbidity is a major rule rather than an exception in the clinical practice with borderline patients.

An OS with risperidone was undertaken recently. With the exception of thought disorders, patients with BPD exhibited favorable outcomes for all symptoms graded after eight weeks of treatment. The authors speculate on the possibility that the low baseline scores exhibited by the sample for psychotic symptoms might have been responsible for the poor response in this symptomatic group.¹⁵

Mood stabilizers

Many authors, notably the Akiskal et al. group, have suggested that BPD as defined by the DSM-IV diagnostic criteria, could be added to the growing list of affective bipolar spectrum disorders.^16,17 There are several reasons for this theory: 1) the affective instability of a large number of these patients is often similar to a mixed bipolar episode; 2) many BPD patients exhibit epileptoid discharges on electroencephalograms, which may represent a type of kindling effect, which is historically associated with the pathophysiology of bipolar mood disorders;^18,19 and 3) some authors have demonstrated that behavioral dyscontrol occurs when borderline patients are treated with amitriptyline, which may indicate a phenomenon similar to the hypomaniac episodes often induced by tricyclic antidepressants in patients with bipolar mood disorders.²⁰ Thus, if the hypothesis that BPD patients belong to the bipolar spectrum disorder is actually correct then one would expect that these patients would respond favorably to mood stabilizing drugs, which are the core psychotropic drug group employed to manage bipolar mood disorders.²¹

One of the drugs tested in the study by Cowdry & Gardner mentioned earlier was carbamazepine.⁶ The average dose of carbamazepine used was 820 mg during a clinical trial lasting six weeks. Patients in the experimental group exhibited improvement in behavior dyscontrol and global symptom relief when compared with the placebo group. However, melancholy presented as a side effect in some of the patients who received carbamazepine.

A different PCT returned contrasting results. Patients with BPD, but without axis I co-morbidity and with no electroencephalographic evidence of epileptic disorder, received either carbamazepine or a placebo for 32 days.²² The group that received carbamazepine did not exhibit any improvement when compared to the placebo group. Two patients given carbamazepine dropped out of the trial early due to episodes of impulsiveness. The same problem did not occur within the control group.

Despite the widespread use of lithium to treat BPD patients being common, no evidence was found in the literature that could justify this practice. Just one PCT was identified. Links et al. compared the effects of lithium and desipramine in a six-week crossover study, involving a small sample of borderline patients (n=17).²³ Neither group exhibited improvements in depressive symptoms. The researchers recorded improvement in irritability, anger, and suicidal symptoms. The patients, however, did not confirm these improvements in a self-rated symptom scale.

Several studies were found in the literature involving the use of divalproex in the treatment of BPD.^24-27 Two of these studies were open and two were placebo-controlled. Briefly, the first OS investigated the use of concomitant divalproex and psychotherapy for eight weeks with a group of patients meeting the DSM-III-R criteria for BPD. Patients that completed the trial exhibited global symptom improvement and subjective improvement of irritability, without, however, presenting improvement in depression and anxiety scores.²⁴ Kavoussi & Coccaro,²⁵ carried out an OS in which patients with personality disorders (n=10; five presented with BPD) received divalproex for eight weeks. These patients had not responded to SSRIs treatments at maximum effective doses. Those patients who completed the study (n=8) exhibited improvements in the areas of aggression and impulsiveness. These data should be viewed with caution due to the small sample size. Patients with other personality disorders might respond to divalproex in a different fashion.

Hollander et al.²⁶ performed a PCT in which patients meeting the DSM-IV BPD criteria (n=21) were randomly allocated to groups receiving either divalproex (n=16, average maximum valproate serum level of 64.57±15.21µg/ml) or placebo for 10 weeks. At the end of the trial the BPD patients treated with divalproex exhibited a global improvement in symptoms when compared with the placebo group. Half of the patients did not complete the trial. There was no improvement in aggression and depression scores.

Another PCT studied the effects of divalproex on patients with BPD (DSM-IV). After six months of treatment, patients who had received divalproex presented improvements in anger, hostility and interpersonal sensitivity.²⁷ As with the study described above, there were no improvements in scores related to aggression or depression.

Lamotrigine, a new antiepileptic agent with antidepressant properties,^28,29 was used on patients with BPD (n=10; DSM-IV) who had not responded to other treatments with antidepressants or anticonvulsants. In this case series study, three patients responded to lamotrigine and their response was sustained for more than a year. The authors suggested that lamotrigine is a promising agent for BPD treatment, but these preliminary results need to be replicated in PCTs.

In conclusion, mood stabilizers (particularly divalproex) may be effective agents for the treatment borderline patients, especially for those who exhibit severe impulse dyscontrol and mood swings. Controlled trials with larger samples are needed to confirm these preliminary outcomes.

Selective serotonin reuptake inhibitors (SSRI)

Depressive moods and a subjective sensation of emptiness are predominant symptoms among BPD patients. Furthermore, according to the DSM-IV criteria, there is significant co-morbidity between BPD and affective disorders.³⁰ It is, therefore, a difficult task to define the exact point at which an axis I affective disorder begins and ends in patients with BPD.³¹ Even when the subjacent affective disorder is in remission, a borderline subject would usually continue to suffer from symptoms such as pessimism, sensitivity to rejection and suicide attempts.

The serotonergic neurotransmission system has been implicated in the etiology of patients with aggressive and impulsive behavior. For example, reduced levels of a metabolite of serotonin, 5-HIAA, have been observed in borderline patients following severe episodes of aggression and serious suicide attempts.^32,33 Reduced prolactin release, has been observed after acute treatment with fenfluramine, a serotonin agonist.³⁴ A reduced level of prefrontal cortex activity has been observed in areas that play an important role in mood regulation and impulse control in borderline patients.³⁵ There is, therefore a theoretical basis for predicting that SSRI would elicit a favorable treatment response in BPD patients.

Several studies involving SSRI in BPD treatment were indeed found. The methodological characteristics and primary outcomes of each study are summarized in table 2. Additional comments are made below.

One significant characteristic of the OS involving SSRS is the early appearance of a favorable therapeutic response in relation to impulsivity (after one week),³⁶ and irrespective of any improvement in affective symptoms.⁴⁰ The effect is irrespective of a concomitant diagnosis of major depression.⁴⁰ Also significant is that treatment withdrawal is associated with an almost immediate worsening of impulsive symptoms. The fact that one SSRI has been proven ineffective does not predict response to other SSRIs.⁴¹ For example, patients that did not respond to fluoxetine (up to 80 mg/day), subsequently responded to sertraline (up to 200 mg/day).⁴¹ A longer duration period of sertraline treatment (up to 24 weeks at a dosage of 200 mg/day), was therapeutically effective for patients for whom the drug had not produced an therapeutic effect.

Following these OS, four PCTs emerged in the literature. Markovitz et al.,⁴¹ studied for 14 weeks, 17 patients with BPD (nine receiving 80mg/day of fluoxetine and 8 receiving placebo) with significant co-morbidity with disorders of mood and anxiety. A global improvement (associated with improved depressive and anxiety symptoms) was observed in the experimental group. Salzman et al.⁴² studied 27 patients with mild BPD or even borderline traits for 12 weeks. Patients who received fluoxetine (20-60 mg/day), exhibited improvements in symptoms of anger, irrespective of concomitant affective improvement. The study may lack external validity, since severe cases and patients with concurrent axis I disorders were excluded. Furthermore, the improvement was discrete (approximately 20%) and response to placebo was high.

Coccaro & Kavoussi⁴³ studied aggressive and impulsive symptoms in 40 patients, a number of whom had axis II diagnoses (DSM-III-R). Aggression and impulsivity were defined as a single dimensional construct. The authors demonstrated that fluoxetine (up to 60 mg/day) resulted in an improvement in aggression toward objects and in irritability when compared to the control (placebo) group.

Rinne et al.⁴⁴ studied the effects of fluvoxamine on a sample of 38 female patients with BPD. The study consisted of a double-blind stage in which patients were randomly allocated to receive either placebo or fluvoxamine (fixed dose of 150 mg/day) for 6 weeks, followed by a six-week single-blind crossover period and an open period (12 weeks) in which all patients received fluvoxamine (up to 250 mg/day). Patients improved from symptoms related to mood fluctuations, but not in aggression and impulsivity scores. Low initial fluvoxamine doses and gender differences may explain the lack of effect of fluvoxamine over placebo in aggressive and impulsive symptoms.

Venlafaxine

Venlafaxine is an antidepressant that inhibits, in a dose-dependent manner, the pre-synaptic reuptake of norepinephrine and serotonin. Markovitz et al.,⁴⁵ performed an OS in which 45 patients with BPD (DSM-III-R) received venlafaxine (200-400 mg/day) for 12 weeks. The patients exhibited favorable outcomes in all of the symptoms studied. Some patients had previously failed to respond to trials with SSRIs. Data are promising, but need to be confirmed in PCTs.

Monoamine oxidase inhibitors (MAOI)

Studies involving MAOI in BPD patients demonstrate a wide range of efficacy, especially in terms of affective symptoms, but also in impulsive and aggressive symptoms. Cowdry & Gardner⁶ studied the effects of tranylcypromine in a study mentioned earlier. Patients that completed the trial receiving MAOI (n=7) had significant improvements in symptoms of depression, anxiety, sensitivity to rejection and suicidal behavior. There was no improvement in impulsivity or global function.

Some authors suggest that patients with atypical depression (a syndrome characterized by reactive mood, hyperphagia, weight gain, increased carbohydrate consumption, hypersomnia, and sensitivity to rejection) exhibit a favorable response to MAOIs when compared to other antidepressants.⁴⁶ Parsons et al. demonstrated the superiority of phenelzine over imipramine for patients with atypical affective disorders and concomitant BPD.⁴⁷ Phenelzine was tested on a sample of BPD patients with significant clinical features of atypical depression.⁸ The placebo group had an elevated response and phenelzine did not exhibit any additional effect in the majority of outcomes assessed, with the exception of self-assessed anger and hostility scales. This sample was followed-up through a continuation phase. After 16 weeks the patients sustained their responses, but many had discontinued the trial.⁹

The results suggest that MAOIs are effective for the treatment of atypical depressive symptoms in borderline patients and also for the treatment of anger and hostility. These favorable effects do not appear to depend on a concomitant diagnosis of an axis I mental disorder. The side effects of MAOIs should be considered. It is not clear whether patients with BPD would follow a restrictive, tyramine-limited diet.

Tricyclic antidepressants

A PCT of amitriptyline (average dose of 147.62±13.47 mg/day) for 5 weeks in borderline patients, compared with both placebo and haloperidol was undertaken by Soloff et al.⁷ The scores measuring depressive symptoms did not differ between the groups that received haloperidol and amitriptyline. Patients treated with amitriptyline had serious episodes of behavioral dyscontrol.²⁰ The response to amitriptyline was not related to a simultaneous affective disorder diagnosis.⁷ Tricyclic antidepressants therefore appear to have a limited role in the pharmacological management of BPD patients.

Anxiolytic agents

Anxiety symptoms are common in BPD patients and are usually exacerbated by stressors such as perceived rejection. Alprazolam (average dose of 4.7 mg/day) was tested in the controlled study performed by Cowdry and Gardner.⁶ This drug was associated with significant episodes of behavioral dyscontrol. For example, four patients had to prematurely discontinue the trial due to serious episodes of impulse dyscontrol, compared with none in the placebo group.

Clonazepam, a benzodiazepine with significant antimanic and anticonvulsant effects, which also increases serotoninergic neurotransmission in the brain, may show to be a better agent for treating anxiety symptoms in BPD patients.⁴⁸ No clinical trial involving this drug was retrieved.

Buspirone, a new anxiolytic agent that acts as a serotonin agonist, may offer advantages over other agents, but no clinical trials were found in the literature.

Naltrexone

The non-selective opioid antagonist, naltrexone, has proven efficacy for the treatment of many disorders in which self-mutilation is a core symptom, such as autism and mental retardation.⁴⁹ The rationale behind the use of this drug is that self-mutilation could be the result of a relative insensitivity to pain due to excessive endogenous opioid system activity within the brain.⁵⁰

Self mutilation is a common problem in borderline patients. Sonne et al.⁵¹ performed an OS in which five patients with BPD and severe self-harming behavior received naltrexone (50-100 mg/day). These patients had a significant reduction in self-mutilating acts and thoughts. Patients also improved on the Yale-Brown scale for obsessions and compulsions. Perhaps this is yet one more mechanism involved, since acts of self-mutilation are in part the result of obsessive thoughts.

Bohus et al.⁵² studied the effects of naltrexone on borderline patients. A significant reduction in dissociative symptoms was observed in this OS.

Omega-3 fatty acids

Omega-3 fatty acids have been shown effective in controlled trials as adjunctive agents in the treatment of depression and bipolar affective disorder.^53,54 Ethyl-eicosapentaenoate (E-EPA), omega-3 fatty acid, was tested recently in a PCT on 30 female borderline patients. After eight weeks of treatment the patients had improved in terms of symptoms related to aggression and depression.⁵⁵ Further studies are needed to confirm the effectiveness of these agents.

DISCUSSION

Following this literature review, algorithms for the three core symptom groups (affective, aggressive-impulsive and psychotic-like) found in borderline patients were developed (figures 1-3).Since SSRIs accumulate the strongest body of evidence in efficacy against affective and impulsive symptoms, these drugs were regarded as the first line of treatment for these symptoms. The agents of choice for cognitive and perceptual symptoms are the antipsychotics. Mood stabilizers, such as divalproate, are also effective for the treatment of affective and impulsive symptoms. Borderline patients often require the concomitant use of two or more drugs to achieve symptomatic relief.

The outcomes measured in the different experiments vary. It is difficult to estimate the effect size of each drug. Many studies present limitations in terms of design and sample selection. It is thus difficult to measure the real benefit of psychotropics for the treatment of borderline patients. However, psychopharmacological treatment is clearly useful for the management of patients with BPD, probably as an adjunct to psychotherapies that notably follow the psychodynamic or cognitive frameworks.⁵⁶ No studies were identified that compared medication with psychotherapy or with combined treatments. Indeed, an evaluation of psychotherapeutic approaches and their benefits in clinical management is beyond the scope of the current review.

The etiology of BPD remains obscure. As the neurobiological mechanisms involved in this disorder are further dissected, one would expect that better treatment options will soon be discovered.

Clearly, more well-designed trials with fewer methodological limitations and larger sample sizes are necessary in order to develop more precise algorithms. The authors recognize that algorithms should be ideally developed by a panel of experts. The algorithms presented in this paper are suggestions to shed light on the often difficult decision to select proper drugs to treat patients coping with this devastating disorder.

REFERENCES

Received on March 29, 2004.

Revised on April 20, 2004.

Approved on June 29, 2004.

• 1. Gunderson JG. Borderline Personality Disorder. Washington, D.C.: American Psychiatric Press; 1984.
• 2. Stone MH. Contemporary shift in the borderline concept of subschizophrenic to subaffective disorder. Psychiatr Clin North Am 1979;2:577-89.
• 3. Spitzer R, Endicott J, Gibbon M. Crossing the borderline into borderline personality and borderline schizophrenics. Arch Gen Psychiatry 1979;36:17-24.
• 4. Soloff PH. Psychopharmacology of borderline personality disorder. Psychiatr Clin North Am 2000;23:169-92.
• 5. Goldberg SC, Schulz SC, Schulz PM, Resnick RJ, Hamer RM, Friedel RO. Borderline and schizotypal personality disorders treated with low-dose thiotixene vs. placebo. Arch Gen Psychiatry 1986;43:680-6.
• 6. Cowdry RW, Gardner DL. Pharmacotherapy of borderline personality disorder: alprazolam, carbamazepine, trifluoperazine, and tranylcypromine. Arch Gen Psychiatry 1988;45:111-19.
• 7. Soloff PH, George A, Nathan S, Schulz PM, Ulrich RF, Perel JM. Progress in pharmacotherapy of borderline disorders: a double-blind study of amitryptiline, haloperidol and placebo. Arch Gen Psychiatr 1986;43:691-7.
• 8. Soloff PH, Cornelius J, George A, Nathan S, Perel JM, Ulrich RF. Efficacy of phenelzine and haloperidol in borderline personality pisorder. Arch Gen Psychiatry 1993;50:377-85.
• 9. Cornelius JR, Soloff PH, Perel JM, Ulrich RF. Continuation pharmacotherapy of borderline personality disorder with haloperidol and phenelzine. Am J Psychiatry 1993;150:1843-8.
• 10. Ghaemi SN. New treatments for bipolar disorder: the role of atypical neuroleptic agents. J Clin Psychiatry 2000;61 (Suppl 14):S33-42.
• 11. Chengappa KN, Vasile J, Lavine J, Ulrich R, Baker R, Gopalani A, Schooler N. Clozapine: its impact on aggressive behavior among patients with schizophrenia in a state psychiatry hospital. Schozophr Res 2002;53:1-6.
• 12. Frakenburg FR, Zanarini MC. Clozapine for the treatment of borderline patients: a preliminary study. Compr Psychiatry 1993;34:402-5.
• 13. Benedetti F, Sforzini L, Clombo C, Maffei C, Smeraldi E. Low-dose clozapine in acute and continuation treatment of severe borderline personality disorder. J Clin Psychiatry 1998;59:103-7.
• 14. Zanarini MC, Frakenburg FR. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo-controlled pilot study. J Clin Psychiatry 2001;62:849-54.
• 15. Rocca P, Marchiaro L, Cocuzza E, Bogetto F. Treatment of borderline personality disorder with risperidone. J Clin Psychiatry 2002;63:241-4.
• 16. Akiskal HS. Subaffective disorders: dysthymic, ciclothymic and bipolar II disorders in the "borderline" realm. Psychiatr Clin North Am 1981;4:25-46.
• 17. Deltito J, Martin L, Riefkohl J, Austria B, Kissilenko A, Corless C, Morse P. Do patients with borderline personality disorder belong to the bipolar spectrum? J Affect Disord 2001;67:221-8.
• 18. Snyder S, Pitts Jr JM. Electroencephalography of DSM-III borderline personality disorder. Acta Psychiatr Scand 1984;69:129-34.
• 19. Post RM, Weiss SR. Sensitization, kindling and anticonvulsivants in mania. J Clin Psychiatry 1989;50 Suppl:S23-30.
• 20. Soloff PH, George A, Nathan RS, Schulz PM, Perel JM. Paradoxical effects of amitriptyline on borderline patients. Am J Psychiatry 1986;143:1603-5.
• ²¹
  American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 2002;159 (Suppl 4):1-50.
• 22. De La Fuente JM, Lostra F. A trial of carbamazepine in borderline personality disorder. Eur Neuropsychopharmacol 1994;4:479-86.
• 23. Links P. Lithium therapy for borderline patients. J Personal Disord 1990;4:173-81.
• 24. Stein DJ, Simeon D, Frenkel M, Islam MN, Hollander E. An open trial of valproate in borderline personality disorder. J Clin Psychiatry 1995;56:506-10.
• 25. Kavoussi RJ, Coccaro EF. Divalproex sodium for impulsive aggressive behavior in patients with personality disorder. J Clin Psychiatry 1998;59:676-80.
• 26. Hollander E, Allen A, Lopez RP, Bienstock C, Grossman R, Siever L, Margolin L, Stein D. A preliminary double-blind placebo controlled trial of divalproex sodium in borderline personality disorder. J Clin Psychiatry 2001;62:199-203.
• 27. Frankenburg FR, Zanarini MC. Divalproex sodium treatment of women with borderline personality disorder and bipolar II disorder: a double-blind placebo-controlled pilot study. J Clin Psychiatry 2002;63:442-6.
• 28. Pinto OC, Akiskal HS. Lamotrigine as a promising approach to borderline personality disorder: an open case series without concurrent DSM-IV major mood disorder. J Affect Disord 1998;51:333-43.
• 29. Kusumakar V, Yatham LN. An open study of lamotrigine in refractory bipolar depression. Psychiatry Res 1997;72:145-8.
• ³⁰
  American Psychiatry Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC.: APA Press; 1994.
• 31. Soloff PH, Cornelius JH, George A. The depressed borderline: one disorder or two? Psychopharmacol Bull 1991;27:23-30.
• 32. Linnoila M, Virkkunen M, Scheinin M, Nuutila A, Rimon R, Goodwin FK. Low cerebrospinal fluid 5-hydroxyindolacetic acid concentration differentiates impulsive from nonimpulsive violent behavior. Life Sci 1983;33:2609-14.
• 33. Traskman-Benz L, Asberg M, Schalling D. Serotonergic function and suicidal behavior in personality disorders. Ann NY Acad Sci 1986;487:174-88.
• 34. O'Keane V, Moloney E, O'Neil H, O'Connor A, Smith C, Dinan TG. Blunted prolactin responses to D-fenfluramine in sociopathy: evidence for subsensitivity of central serotonergic function. Br J Psychiatry 1992;160:643-6.
• 35. De La Fuente JM, Goldman S, Stanus E, Vizuete C, Morlan I, Bobes J, Mendlewicz J. Brain glucose metabolism in borderline personality disorder. J Psychiatry Res 1997;31:531-41.
• 36. Norden MJ. Fluoxetine in borderline personality disorder. Prog Neuropsychopharmacol Biol Psychiatry 1989;13:885-93.
• 37. Cornelius JR, Soloff PH, Perel JM, Ulrich RF. Fluoxetine trial in borderline personality disorder. Psychopharmacol Bull 1990;26:151-4.
• 38. Cornelius JR, Soloff PH, Perel JM, Ulrich RF. A preliminary trial of fluoxetine in refractory borderline patients. J Clin Psychopharmacol 1991;11:116-20.
• 39. Markovitz PJ, Calabrese JR, Schulz SC, Meltzer HY. Fluoxetine in borderline and schizotypal personality disorders. Am J Psychiatry 2001;148:1064-7.
• 40. Kavoussi RJ, Liu J, Coccaro EF. An open trial of sertraline in personality disordered patients with impulsive aggression. J Clin Psychiatry 1994;55:137-41.
• 41. Markovitz PJ. Treatment of impulsivity, aggression and related disorders. In: Hollander E, Stein DJ, editors. Impulsivity and Aggression. Surrey, UK: John H. Wiley, Ltd.; 1995.
• 42. Salzman C, Wolfson NA, Schatzberg A, Looper J, Henke R, Albanese M, Schwartz J, Miyawaki E. Effect of fluoxetine on anger in symptomatic volunteers with borderline personality disorder. J Clin Psychopharmacol 1995;15:23-9.
• 43. Coccaro EF, Kavoussi RJ. Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Arch Gen Psychiatry 1997;54:1081-8.
• 44. Rinne T, van den Brink W, Wouters L, van Dyck R. SSRI treatment of borderline personality disorder: a randomized placebo-controlled trial for female patients with borderline personality disorder. Am J Psychiatry 2002;159:2048-54.
• 45. Markovitz PJ, Wagner SC. Venlafaxine in the treatment of borderline personality disorder. Psychopharmacol Bull 1995;31:773-7.
• 46. Liebowitz M, Quitkin F, Stewart J, McGrath PJ, Harrison W, Rabkin J, Tricamo E, Markovitz JS, Klein DF. Phenelzine versus imipramine in atypical depression: a preliminary report. Arch Gen Psychiatry 1984;41:669-77.
• 47. Parsons B, Quitkin FM, McGrath PJ, Stewart JW, Tricamo E, Ocepec-Welikson K, Harrison W, Rabkin JG, Wagner SC, Nunes E. Phenelzine, imipramine and placebo in borderline patients meeting criteria for atypical depression. Psychopharmacol Bull 1989;25:524-34.
• 48. Pollack MH. Innovative uses of benzodiazepines in psychiatry. Can J Psychiatry 1993;38 (Suppl 4):S122-6.
• 49. Harman BH, Hammock MK, Egan J, Arthur-Smith A, Chatoor I, Werner A, Zelnik N. Naltrexone decreases self-injurious behavior. Ann Neurol 1987;22:550-2.
• 50. Richardson JS, Zaleski WA. Naloxone and self-multilation. Biol Psychiatry 1983;18:99-101.
• 51. Sonne S, Rubey R, Brady K, Malcolm R, Morris T. Naltrexone treatment of self-injurious thoughts and behaviors. J Nerv Ment Dis 1996;184:192-5.
• 52. Bohus MJ, Landwehrmeyer BN, Stiglmayr CE, Limberger MF, Böhme R, Schmahl CG. Naltrexone in the treatment of dissociative symptoms in patients with borderline personality disorder: an open label trial. J Clin Psychiatry 1999;60:598-603.
• 53. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega-3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-12.
• 54. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477-9.
• 55. Zanarini MC, Frankenburg FR. Omega-3 fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry 2003;160:167-9.
• 56. Practice guideline for the treatment of patients with borderline personality disorder. Am J Psychiatry 2001;158 (Suppl 10):S1-52.

Publication Dates

• Publication in this collection
  13 Sept 2005
• Date of issue
  Aug 2004

History

• Accepted
  29 June 2004
• Reviewed
  20 Apr 2004
• Received
  29 Mar 2004