The final assignment for this class will be a 10-page critical review of the drug treatment for a psychiatric disorder (broadly defined to include psychological and neurological disorders as well). Th

PSYCHIATRIC ANNALS • Vol. 45, No. 8, 2015 431 The Efficacy of Pharmacotherapy for Borderline Personality Disorder: A Review of the Available Randomized Controlled Trials Dimitry Francois, MD; Steven D. Roth, MD, JD; and Daisy Klingman, MD ABSTRACT Although there are no medications ap - proved by the US Food and Drug Admin - istration for the treatment of borderline personality disorder (BPD), polypharmacy is commonly encountered in individu - als with BPD. This review summarizes the results of randomized controlled trials on the efficacy of pharmacologic agents in BPD. Pharmacotherapy in BPD is an ad - junctive treatment aimed at stabilizing symptoms and behavior in a crisis situa - tion, and it should be avoided whenever possible. Further studies are needed, in - cluding large, randomized controlled tri - als with long-term follow up, to examine the efficacy of psychiatric medications in patients with BPD. [Psychiatr Ann . 2015;45(8):431-437.] Dimitry Francois, MD, is an Assistant Professor of Psychiatry, Weill Cornell Medical Col - lege; an Associate Director, Psychiatry Clerkship, New York-Presbyterian Hospital; and the Site Director, Psychiatry Clerkship, New York-Presbyterian Hospital/Westchester. Steven D. Roth, MD, JD, is an Associate Professor of Clinical Psychiatry, Weill Cornell Medical College; the Acute Division Director and the Unit Chief, Personality Disorders Unit, New York- Presbyterian Hospital/Westchester Division. Daisy Klingman, MD, is an Assistant Professor of Psychiatry, Weill Cornell Medical College; and an Attending Psychiatrist, Personality Disorders Unit, New York-Presbyterian Hospital/Westchester Division.

Address correspondence to Dimitry Francois, MD, 21 Bloomingdale Road, White Plains, NY 10605; email: [email protected].

Disclosure: The authors have no relevant financial relationships to disclose.

doi: 10.3928/00485713-20150803-09 © Shutterstock 432 Copyright © SLACK Incorporated B orderline personality disorder (BPD) is present in about 6% of primary care patients 1 and in 15% to 20% of patients in psychi - atric hospitals and outpatient clinics. 2 BPD affects men and women equal - l y, 3 and is associated with increased medical and psychiatric use and health care expenses. 4 Although there are no medications approved by the US Food and Drug Administration (FDA) for the treatment of BPD, polypharmacy is a common occurrence in patients with BPD. Approximately 80% of pa - tients with the disorder take medica - tions regularly, and more than 40% take three or more medications daily. 5 This review summarizes results of ran - domized controlled trials (RCTs) on the efficacy of pharmacologic agents that have been studied in BPD. Results from open trials, case reports, case se - ries, and RCTs rejected from the 2010 Cochrane review 6 were not used. Stud - ies were identified from searches up to December 2014 in PubMed and Med - line.

ANTIDEPRESSANTS Selective Serotonin Reuptake Inhibitors Salzman et al. 7 described the results of a 13-week, double-blind, placebo- controlled study of the effects of fluox - etine on anger in patients with BPD or BPD traits. Thirteen patients received fluoxetine and nine received placebo.

All patients began with a single 20- mg capsule or identical placebo, and doses were titrated up to a maximum of 60 mg/day. The authors found a re - duction in anger among the fluoxetine recipients but no reduction in depres - sion. In 2004, the therapeutic effect of fluoxetine added to dialectical behav - ior therapy (DBT) for the treatment of BPD was examined by Simpson et al. 8 in a 12-week, randomized, double- blind, placebo-controlled study. Of the 20 patients that completed treatment, 9 were randomly assigned to receive up to 40 mg/day of fluoxetine and 11 were randomly assigned to placebo. The re - sult showed no significant group dif - ferences in scores from pretreatment to posttreatment on any measure. Rinne et al. 9 conducted a double- blind, placebo-controlled, random - ized trial of fluvoxamine (mean dose 150 mg/day) for 6 weeks followed by a blind half-crossover for 6 weeks and an open follow-up for another 12 weeks in 38 women with BPD. Fluvoxamine improved rapid mood shifts (standard - ized mean changes [SMD], -0.646) but not impulsivity and aggression. Jariani et al. 10 compared sertra - line (50-100 mg/day) to olanzapine (5-10 mg/day) for the treatment of BPD in 120 patients on methadone maintenance therapy for heroin de - pendence who were also diagnosed as having BPD. The results (evaluation of Symptom Checklist-90 [SCL-90] questionnaire before treatment and in the 4th, 8th, and 12th weeks of treat - ment) indicated that both drugs could generally ameliorate depression, anxi - ety, hypersensitivity in interpersonal relationships, aggression, obsession, and somatization symptoms in a 12- week treatment. Sertraline was more effective in decreasing symptoms of depression, hypersensitivity in in - terpersonal relationships, and obses - sion. Olanzapine was more useful for anxiety, aggression, and paranoia symptoms. There was no difference in decreasing somatization symptoms between both drugs. In regard to self- mutilation, there was a significant dif - ference in the olanzapine group.

Tricyclic Antidepressants Soloff et al. 11 described a 5-week, double-blind, placebo-controlled study of amitriptyline and haloperi - dol in 90 BPD inpatients. They found a significant effect for depression (SMD, -0.596) with amitriptyline, at a mean dose of 149 mg/day.

Monoamine Oxidase Inhibitors Soloff et al. 12 examined the data collected in a 5-week, double-blind, placebo-controlled trial of phenelzine (average dose, 60 mg/day), haloperi - dol, or placebo for atypical depression in 108 inpatients with BPD. Three- way comparisons between groups indicated superior efficacy for phen - elzine on measures of depression, bor - derline psychopathologic symptoms, and anxiety. Pair-wise comparisons between medication and placebo re - vealed significant efficacy for phenel - zine against anger and hostility but no efficacy against atypical depression.

Mianserin In 1983, Montgomery et al. 13 com - pared 30 mg/day of mianserin to pla - cebo in a 6-month, RCT of 38 indi - viduals with a personality disorder and a history of a suicidal act causing hospitalization. They found no signifi - cant difference in outcome between the groups. (Please note that mianserin is not approved by the FDA for use in the United States; its analogue is mir - tazapine.) Summary of Antidepressants Few antidepressants have been studied in BPD. There seems to be a benefit for tricyclic antidepressants (TCAs) in the reduction of depressive Sertraline was more effective in decreasing symptoms of depression, hypersensitivity in interpersonal relationships, and obsession. PSYCHIATRIC ANNALS • Vol. 45, No. 8, 2015 433 pathology. No statistically significant effects were observed for the selective serotonin reuptake inhibitors (SSRIs), phenelzine, and mianserin.

MOOD STABILIZERS Carbamazepine In a double-blind, parallel, placebo- controlled trial involving 20 hospital - ized BPD patients, De la Fuente and Lotstra 14 reported no significant posi - tive effects from carbamazepine.

Divalproex Sodium Divalproex sodium has been tested in three small RCTs. In the first, Hollander et al. 15 conducted a 10-week, parallel, double-blind study comparing divalpro - ex sodium to placebo in 16 outpatients with BPD. Only six patients completed the study. Five of the six completers were considered to be responders, as defined by a Clinical Global Impressions (CGI)-I score of 1 or 2 at endpoint. In the second investigation, Franken - burg and Zanarini 16 studied 30 women with BPD in a 6-month, placebo-con - trolled, double-blind trial comparing di - valproex sodium to placebo. Divalproex sodium proved to be superior to placebo in diminishing interpersonal sensitiv - ity (SMD, -1.046) and anger/hostility as measured by the SCL-90, as well as overall aggression as measured by the modified Overt Aggression Scale. In a study by Moen et al., 17 15 patients with BPD received 4 weeks of “con - densed DBT,” and then those patients with SCL-90 scores higher than 150 after this treatment were randomly and blindly assigned to placebo or divalproex extend - ed-release for 12 weeks. There were no significant differences between the par - ticipants assigned to divalproex extend - ed-release compared with placebo.

Lamotrigine Reich et al. 18 studied 28 patients with BPD in a 12-week, double-blind, placebo-controlled study of lamotrigine. Patients in the lamotrigine group had sig - nificantly greater reductions of affective instability and impulsivity. A study by Tritt et al. 19 compared the efficacy of lamotrigine versus placebo in the treatment of aggression in women with BPD. In comparison with the pla - cebo group, significant changes on anger (SMD, -1.696) were observed after 8 weeks in those patients treated with la - motrigine.

Topiramate Topiramate was evaluated in three RCTs by the same group of researchers.

First, Nickel et al. 20 examined the effect of topiramate on aggression in 29 women with BPD. Significant improvements on four subscales of the STAXI (state-anger, trait-anger, anger-out, anger-control) were observed in the topiramate-treated individuals after 8 weeks in comparison with the placebo group. A similar RCT by Nickel et al., 21 this one with 42 male outpatients, also found significant changes on anger. An RCT by Loew et al. 22 aimed to de - termine whether topiramate could influ - ence borderline psychopathology, health- related quality of life, and interpersonal problems in 58 women with BPD. Topi - ramate was found to reduce psychiatric symptoms (SMD, -1.196), anxiety (SMD, -1.406), anger (SMD, -3.006), and inter - personal difficulties (SMD, -0.916), and to improve health-related quality of life at 8 and 10 weeks.

Summary of Mood Stabilizers RCTs involving the mood stabilizers were limited by low statistical power. Divalproex sodium shows an effect for anger and interpersonal sensitivity. Topi - ramate and lamotrigine were found to have an effect on anger. No statistically significant effects were found for carba - mazepine.

ANTIPSYCHOTICS Loxapine versus Chlorpromazine Leone 23 studied 80 outpatients with BPD in a 6-week, double-blind study of loxapine (mean average dose 14.5 mg/day) and chlorpromazine (mean average dose 110 mg/day). The outcomes measured were BPD sever - ity, affective instability using the Pro - file of Mood State scale, psychotic symptoms using the Brief Psychiatric Rating Scale, and mental health sta - tus using the CGI and the Systematic Nurses’ Observation of Psychopathol - ogy. The author reported both groups improved significantly from baseline, and the individuals prescribed loxap - ine improved significantly more than the individuals prescribed chlorproma - zine in several symptom areas, partic - ularly depression and anger/hostility.

Flupenthixol Flupenthixol (which is not ap - proved by the FDA for use in the Unit - ed States) given as depot injections was found to significantly reduce the number of suicide attempts compared to placebo after 4 months and for the remainder of a 6-month RCT of pa - tients with personality disorders (23 of the 30 completers had BPD). 24 Thiothixene In a study by Goldberg et al., 25 50 outpatients with borderline and/or schizotypal personality disorder were randomly allocated to thiothixene or placebo treatment that was continued for 12 weeks (after 1 week of placebo washout). The mean daily dose of thio - thixene in the final week of the study was 8.7 mg. Significant drug-placebo Topiramate and lamotrigine were found to have an effect on anger. 434 Copyright © SLACK Incorporated differences were found for psychotic symptoms but not for depression.

Haloperidol Soloff et al. 26,27 published a study of haloperidol in two active drug versus active comparator drug trials. The first one was a 5-week (after 1-week wash - out) double-blind, placebo-controlled study of amitriptyline and haloperidol in 90 symptomatic BPD inpatients.

Haloperidol (average dose 5 mg/day) produced significant improvement over placebo in global functioning, de - pression, hostility, schizotypal symp - toms, and impulsive behavior. (For the amitriptyline findings from this study, please refer to the discussion of TCAs earlier in the article.) In the second 5-week (after 1-week washout), dou - ble-blind, placebo-controlled study, the authors compared the efficacy of haloperidol (average dose 4 mg/day) to phenelzine and placebo against the affective, cognitive, and impulsive-ag - gressive symptoms of 108 BPD inpa - tients. The results indicated a tendency for patients receiving haloperidol to suffer less from interpersonal prob - lems as compared to patients receiving phenelzine sulfate. (For the phenelzine findings from this study, please refer to the discussion of monoamine oxidase inhibitors earlier in the article.) Aripiprazole An RCT by Nickel et al. 28 of 52 subjects (43 women and 9 men) with BPD found a large effect of aripipra - zole, 15 mg/day for 8 weeks, for de - pression (SMD, -1.256), interpersonal problems (SMD, -0.77), impulsivity (SMD, -1.846), anger (SMD, 1.146), and paranoid thinking (SMD, -1.056), and a moderate effect for anxiety (SMD, -0.736). Ziprazidone Pascual et al. 29 examined 60 adult patients with BPD in a 12-week, single-center, double-blind, placebo- controlled study of ziprasidone (mean daily dose 84 mg). The CGI scale for use in BPD patients was the primary outcome measure, and other scales and self-reports related to affect, behavior, psychosis, general psychopathology domains, and clinical safety were also included. No statistically significant differences were found between zipra - sidone and placebo.

Quetiapine In a recent 8-week RCT compar - ing low (150 mg/day) and moderate (300 mg/day) dosages of extended- release quetiapine to placebo in 95 adults with BPD, Black et al. 30 found that participants treated with 150 mg/ day of quetiapine had a significant re - duction in the severity of the follow - ing BPD symptoms: interpersonal, affectivity, and anger and cognition problems. The effect size was -0.79 for the primary outcome measure (the Zanarini scale total score). No signifi - cant effects were found for impulsiv - ity, depression, and general psychopa - thology. The difference between the moderate-dosage quetiapine group and the placebo group was not statistically significant ( d = 20.41, P = .265). Olanzapine Olanzapine’s effect on BPD has been studied in nine RCTs. Six of these studies compared olanzapine to placebo. These studies are Bogen - schutz and Nurnberg 31 (n = 40); Line - han et al. 32 (olanzapine was added to psychotherapy, n = 24); Schulz et al. 33 (n = 314); Soler et al. 34 (all patients were in DBT, n = 60); Zanarini and Frankenberg 35 (n = 28); and Eli Lil - ly36 (n = 301). Of the remaining three studies, one compared olanzapine to haloperidol (Shafti and Shahveisi, 37 n = 28); one compared olanzapine to sertraline (Jariani et al, 10 n = 120 [all pa - tients were on methadone maintenance therapy]); and one with three different arms of treatment 38 compared olan - zapine to fluoxetine ( n = 30), then olan - zapine to olanzapine plus fluoxetine (n = 31), and finally fluoxetine to fluoxetine and olanzapine ( n = 29). The intervention times ranged from 12 weeks to 6 months. The trials by Zanarini and colleagues 33,35,38 were supported in part by a grant from Eli Lilly (Indianapolis, IN), the maker of olanzapine. Regarding the trials of olanzapine versus placebo, significant decreases in affective instability, anger, psychot - ic paranoid symptoms, and anxiety were found. Of note, two studies 31,33 of olanzapine-treated groups had a sig - nificantly lower degree of amelioration of recurrent suicidal ideation as com - pared to the placebo groups. No sig - nificant differences were found in the comparison of olanzapine with fluox - etine and olanzapine with haloperidol for any pathology-related outcome. In the study by Jariani et al., 10 olanzapine was more useful for anxiety, aggres - sion, paranoia symptoms, and self-mu - tilation. There were no significant dif - ferences indicating any benefits from combined treatment versus treatment with olanzapine or fluoxetine alone.

Summary of Antipsychotics Olanzapine has the most supporting data of the antipsychotics; studies have shown its use can lead to reductions in anger, paranoia, anxiety, and interper - sonal sensitivity. Effects were found for aripiprazole on impulsivity, anger, anxiety, psychosis, and interpersonal The difference between the moderate-dosage quetiapine group and the placebo group was not statistically significant. PSYCHIATRIC ANNALS • Vol. 45, No. 8, 2015 435 problems. No significant effect was found for ziprazidone. Regarding the typical antipsychotics, statistically significant effects were found for halo - peridol on anger and for flupenthixol on suicidal behavior.

MISCELLANOUS Omega-3 Fatty Acids Zanarini and Frankenburg 40 con - ducted an 8-week, placebo-controlled, double-blind study to compare the ef - ficacy of ethyl-eicosapentaenoic acid (EPA) at a dose of 1 g/day versus place - bo in 30 women with BPD. The results showed there was a significant effect of ethyl-EPA in reducing aggressive behaviors and depressive symptoms (SMD, -0.346). A 12-week RCT by Hal - lahan et al. 41 included 35 patients with BPD and found there was a significant improvement of depressive symptoms, suicidality, and reaction to daily stress - es in the group using EPA (1.2 g/day) and docosahexaenoic acid (DHA, 0.9 g/ day) in addition to standard psychiatric care. A small RCT of EPA, DHA, and vitamin E in 15 adolescents with BPD who also met ultra–high-risk criteria for psychosis found that 1.2 g/day of EPA significantly improved function - ing and reduced psychiatric symptoms (SMD, -1.516) compared with place - bo. 42 Bellino et al. 43 conducted a 12- week controlled trial aimed to assess the efficacy of the association of EPA and DHA with valproic acid compared to valproic acid alone in 43 consecu - tive BPD outpatients. The combination therapy of valproate and omega-3 fatty acids produced significant effects in reducing the severity of characteristic BPD symptoms such as impulsive be - havioral dyscontrol (SMD, -1.6343), outbursts of anger (SMD, -1.7843), and self-mutilating conduct.

Naltrexone (Opioid Antagonist) Two small, double-blind, placebo- controlled randomized trials (total N = 25) compared naltrexone (50 or 200 mg/day) to placebo in reducing dissociative symptoms in patients with BPD. 44 In both trials, the intensity and duration of dissociative symptoms were numerically lower with naltrexone than with placebo. However, the effects were too small to reach statistical sig - nificance.

Clonidine (Alpha-2 Adrenergic Agonist) Ziegenhorn et al. 45 used a double- blind, randomized, placebo-controlled crossover study to determine whether clonidine (450 mcg/day orally) was ef - fective in reducing hyperarousal in a sample of 18 patients with BPD, with or without comorbid posttraumatic stress disorder (PTSD), and with a prominent hyperarousal syndrome.

Hyperarousal, as measured by the clinician-administered PTSD scale, improved significantly (18% decrease) compared with placebo ( P = .003), ir - respective of PTSD comorbidity.

Oxytocin In a small RCT, 14 patients with BPD and 13 healthy control adults received 40 IU of intranasal oxytocin or placebo in a double-blind, random - ized order followed by the Trier So - cial Stress Test. 46 The authors noted a greater attenuation of stress-induced dysphoria in the BPD group after oxy - tocin administration.

DISCUSSION Results from the RCTs should be examined with caution, as the data were limited by (1) the small size of the trials; (2) short duration (often last - ing between 6 and 12 weeks); (3) high dropout rates; (4) inconsistent outcome measures; (5) enrollment bias (subjects were mostly women, and the hetero - geneity of clinical features, treatment settings, and assessment instruments); and (6) lack of replication (most effect estimates were based on single study effects). In addition, individuals with suicidal ideation or recent suicide at - tempt were excluded from most inves - tigations, which is uncharacteristic of severely ill or hospitalized BPD pa - tients. The American Psychiatric Associa - tion’s practice guidelines’ 47 endorse - ment of SSRIs as first-line therapies for BPD is not supported by the cur - rent literature. The World Federation of Societies of Biological Psychiatry guidelines for biological treatment of personality disorders 48 conclude that there is no evidence at either level of evidence that any drug improves BPD psychopathology in general. The Na - tional Institute for Health and Care Excellence guideline on treatment and management of BPD 49 recommends that “drug treatment should not be used specifically for BPD.” The authors of this review support a symptom-oriented pharmacologic ther - apy, as first recommended by Soloff in 1998. 50 A symptom-specific approach to drug trials for BPD will involve out - come measurements defined for the symptom, not the BPD syndrome as a whole. The three main areas that medi - cations should target are (1) affect, (2) impulse, and (3) cognition. For the af - fective dysregulation symptoms, data indicate beneficial effects for topira - mate, lamotrigine, divalproex sodium, haloperidol, aripiprazole, olanzapine, quetiapine extended-release, omega-3 fatty acids, and amitriptyline. The im - pulsive behavioral dyscontrol symp - toms might be decreased by topiramate, lamotrigine, aripiprazole, and omega-3 fatty acids. In regard to the psychotic symptoms, findings show significant beneficial effects for aripiprazole, olanzapine, and quetiapine extended- release. There is some evidence to sup - port the use of aripiprazole, divalproex sodium, and topiramate in managing interpersonal problems. Omega-3 fatty 436 Copyright © SLACK Incorporated acids show promise in terms of reduc - ing elevated suicidality.

CONCLUSION The mainstay of treatment for BPD is still psychotherapy; pharmacothera - py is an adjunctive treatment aimed at stabilizing symptoms and behavior in a crisis situation. A symptoms-specific approach has response overlap. Poly - pharmacy should be avoided whenever possible. Further studies are needed, including large RCTs with long-term follow up, to examine the efficacy of psychiatric medications in patients with BPD.

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