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

CNS Drugs 2008; 22 (8): 671-692 REVIEW A RTICLE 1172-7047/08/0008-0671/$48.00/0 © 2008 Adis Data Information BV. All rights reserved. Efficacy and Tolerability of Pharmacotherapies for Borderline Personality Disorder Silvio Bellino, Erika Paradiso and Filippo Bogetto Unit of Psychiatry, Department of Neurosciences, Service for Personality Disorders, University of Turin, Turin, Italy Contents Abstract....................................................................................671 1. Efficacy and Tolerability of Antidepressant Agents...........................................673 1.1 MAOIs..............................................................................673 1.2 Tricyclic and Heterocyclic Antidepressants.............................................674 1.3 SSRIs................................................................................675 2. Efficacy and Tolerability of Mood Stabilizers.................................................677 2.1 Lithium..............................................................................677 2.2 Carbamazepine.....................................................................678 2.3 Oxcarbazepine......................................................................679 2.4 Valproate Semisodium...............................................................679 2.5 Lamotrigine.........................................................................680 3. Efficacy and Tolerability of Antipsychotics..................................................681 3.1 First-Generation Antipsychotics........................................................ 681 3.2 Atypical Antipsychotics...............................................................683 4. Meta-Analyses...........................................................................687 5. Conclusions............................................................................. 687 Borderline personality disorder is a pervasive pattern of instability of inter- Abstract personal relationships, affects and self-image, as well as marked impulsivity.

Although psychotherapy is needed to attain lasting improvements in a patient’s personality and overall functioning, practice guidelines state that pharmacother- apy is indicated to manage state symptoms and trait vulnerabilities. Three psycho- pathological dimensions are the main targets for pharmacotherapy of borderline personality disorder: affective dysregulation, impulsive-behavioural dyscontrol and cognitive-perceptual symptoms. Guidelines recommend the use of antidepres- sant agents and mood stabilizers for affective dysregulation and impulsive- behavioural dyscontrol, and antipsychotics for cognitive-perceptual symptoms. 672Bellino et al. This review aims to report and discuss data from clinical trials, reviews and meta-analyses concerning drug efficacy and tolerability in the treatment of borderline personality disorder. Investigations that considered antidepressant agents mainly focused on SSRIs, which are recommended as first-line treatments for affective instability and impulse dyscontrol. Both open-label and randomized controlled studies have been performed, predominantly concerning the efficacy of fluoxetine and fluvoxamine. Other classes of antidepressants, such as TCAs and MAOIs, were investigated as alternative treatments for borderline personality disorder, but the risk of adverse effects and toxicity is a limitation to their use in clinical practice. Increasing amounts of data have recently been collected on the use of mood stabilizers to control mood instability and impulsivity in patients with borderline personality disorder. More substantial data were derived from control- led trials of valproate semisodium, although other drugs such as lithium, carbama- zepine, oxcarbazepine and lamotrigine were tested with promising results. Several first-generation antipsychotics were studied in open-label and controlled trials, with good effects on behavioural dyscontrol and psychotic-like symptoms. Selec- tion biases and heterogeneity of drugs and methods somewhat limited the value of these results. More recent investigations have examined atypical antipsychotics, with most of these studies being open-label trials with small sample sizes; however, a few controlled studies have been performed using olanzapine, show- ing improvements in impulsivity, anger and hostility.

In conclusion, a large number of different drugs have been evaluated in the treatment of patients with borderline personality disorder. Initial findings are encouraging for many of these drugs. However, data need to be replicated in further controlled studies with head-to-head comparisons and long-term follow- ups. Many questions remain to be answered. The essential feature of borderline personality evidence that some personality dimensions of pa- disorder is a pervasive pattern of instability of inter- tients appear to be mediated by dysregulation of personal relationships, affects and self-image, as neurotransmitter physiology and are responsive to well as marked impulsivity that begins by early medication. [5,6] Symptoms exhibited by patients adulthood and appears in a variety of contexts. [1] with borderline personality disorder often fall within Although psychotherapy is needed to attain and three psychopathological dimensions that are a tar- maintain lasting improvements in a patient’s person- get for pharmacotherapy: affective dysregulation, ality, interpersonal problems and overall function- impulsive-behavioural dyscontrol and cognitive- ing, [2,3] American Psychiatric Association (APA) perceptual symptoms. APA guidelines [4] recom- guidelines state that pharmacotherapy is indicated to mend choosing antidepressant agents, in particular manage state symptoms during periods of acute SSRIs and MAOIs, and mood stabilizers for affec- decompensation, as well as trait vulnerabilities. [4] tive dysregulation; SSRIs and mood stabilizers for The pharmacological approach to the treatment impulsive-behavioural dyscontrol; and antipsychot- of borderline personality disorder is based on the ics for cognitive-perceptual symptoms. Although © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 673 medications are widely used to treat patients with1. Efficacy and Tolerability of Antidepressant Agents borderline personality disorder, the US FDA has not approved any medications specifically for the treat- ment of this disorder. 1.1 MAOIs This article reviews available data concerning efficacy and tolerability of agents that have been studied in the treatment of borderline personality Three placebo-controlled studies have tested the disorder. A systematic search of published open- efficacy of MAOIs in the short-term treatment of label and randomized, placebo-controlled trials con- borderline personality disorder. [7-9] cerning pharmacotherapy of borderline personality In the trial by Cowdry and Gardner [7] tranyl- disorder was performed on the online database cypromine, trifluoperazine, alprazolam and carba- PubMed using the key words ‘borderline personality mazepine were compared with placebo in a group of disorder’, ‘pharmacotherapy’, ‘antidepressants’, patients with borderline personality disorder and ‘mood stabilisers’, ‘anticonvulsants’ and ‘antipsy- concomitant hysteroid dysphoria. Tranylcypromine chotics’. Data from open-label studies and from (40 mg/day) had significant effects on a variety of randomized controlled studies were distinguished mood symptoms, such as depression, anger and sen- for each class of drugs, in order to make clear the sitivity to rejection (table I). This drug also reduced different level of evidence.

the severity of impulsivity and suicide intentions, Table I. Double-blind controlled trials of antidepressants in the treatment of borderline personality disorder Drug and study Study design No. of Treatment Results with antidepressant drug (comparator drugs) patients duration (wk) MAOIs Tranylcypromine Cowdry and Gardner [7] db, pc (alprazolam, 16 6↓ Anger/hostility, ↓ depression, trifluoperazine,↓ impulsivity/suicidality vs placebo carbamazepine) Phenelzine Soloff et al. [9] co, pc (haloperidol) 108 5↓ Anger/hostility vs placebo TCAs Amitriptyline Soloff et al. [10] db, pc (haloperidol) 90 5↓ Depression, hostility, ↑ self-control vs placebo Desipramine Links et al. [11] co, pc (lithium) 10 6 No significant differences between desipramine and placebo SSRIs Fluoxetine Coccaro and Kavoussi [12] db, pc 40 12↓ Irritability, ↓ aggressiveness vs placebo Markovitz [13] db, pc 17 14↓ Anxiety/depression, ↓ global symptoms vs placebo Salzman et al. [14] db, pc 27 12↓ Anger/hostility, ↓ depression, ↑ global functioning vs placebo Fluvoxamine Rinne et al. [15] co, pc 38 12↓ Affective instability vs placebo co = crossover; db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased.

while the effect on behavioural dyscontrol was close sonality disorder present high levels of impulsivity to a significant level. and poor compliance; therefore, psychiatrists should carefully explain the serious consequences of violat- Parsons et al. [8] compared phenelzine (60 mg/ ing dietary restrictions, describe the picture of day) and imipramine (200 mg/day) in outpatients MAOI intoxication and give emergency instructions with atypical depression and secondary co-morbidi- in case a hypertensive crisis occurs. [4] Moreover, ty with borderline personality disorder. Global im- patients must be carefully informed that they must provement was reported by 92% of patients admin- discontinue an SSRI a long time (up to 5 weeks for istered phenelzine compared with 35% of patients fluoxetine) before beginning MAOI therapy, to administered imipramine.

avoid the risk of serotonin syndrome.

Phenelzine was administered by Soloff and col- In summary, available controlled studies indicate leagues [9] in inpatients with borderline personality that MAOIs can be useful in treating borderline disorder and co-occurrence of major depression personality disorder, with main effects on symptoms (53%), hysteroid dysphoria (44%) or atypical de- of atypical depression, anger and impulsivity. These pression (46%). The results of this controlled study effects are considered to be independent of the an- indicated that phenelzine significantly decreased tidepressive action of these drugs, [9] although a self-rated anger and hostility, but was not effective study found that patients with a history of major in reducing hysteroid dysphoria or atypical depres- depression or bipolar II disorder showed a non- sion compared with haloperidol or placebo.

significant trend to a better response.

[7] The three reported studies of MAOIs in border- line personality disorder had a short duration (5–6 1.2 Tricyclic and weeks). [7-9] When a 5-week treatment with phen- Heterocyclic Antidepressants lezine 90 mg/day was continued for a further 16 weeks in a continuation study, only a modest The TCAs amitriptyline, imipramine and desi- reduction of depression and irritability was obtained pramine have been tested in randomized controlled in comparison with placebo. [16] trials of inpatients and outpatients with borderline personality disorder.

Concerning tolerability, phenelzine can provoke weight gain, [9] but the most serious adverse event Soloff et al. [10] examined a group of inpatients related to MAOI administration is hypertensive cri- with borderline personality disorder, comparing the sis. Although hypertensive crises may be fatal, the effects of amitriptyline (mean dosage 149 mg/day) risk of these events in patients with psychiatric with haloperidol and placebo. Amitriptyline was disorders is estimated to be <1%, [17] and no cases of found to be superior to placebo in treating depres- hypertensive episodes have been reported in patients sive symptoms and indirect hostility, and signifi- with borderline personality disorder who failed to cantly improved self-control. It is notable that the comply with tyramine dietary restrictions. MAOI core symptoms of the Hamilton Depression Rating toxicity is characterized by delirium, agitation, Scale did not improve with amitriptyline, while the hyper-reflexia, hallucinations, tachycardia, tachy- antidepressant was effective on the associated pnoea, dilated pupils, diaphoresis and convulsions. symptoms of diurnal variation, depersonalization, Hyperpyrexia is a very serious symptom associated paranoid symptoms, obsessive-compulsive symp- with MAOI toxicity. [18] Adherence to dietary restric- toms, helplessness, hopelessness and worthlessness.

tions is of primary importance and must be the focus No significant differences were found between pa- of patient education. Patients with borderline per- tients with and without co-morbid major depression. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 675 On the contrary, schizotypal and paranoid symp- In conclusion, available data suggest that the response to TCAs in patients with borderline per- toms were associated with a poorer treatment res- sonality disorder appears modest. The risk of behav- ponse.

ioural toxicity and the potential lethality of TCAs in A few studies of TCAs in patients with borderline overdose support the preferential use of SSRIs or personality disorder showed less favourable re- related antidepressants for treating these patients.

sults. [8,11] Desipramine was not found to be better than 1.3 SSRIs placebo in treating depression, anger and suicide behaviours, when it was examined in a crossover A considerable number of studies have focused comparison of this drug (mean dosage 162.5 mg/ on the central serotonergic system as a possible day) with lithium carbonate (mean dosage target for psychopharmacological intervention for 985.7 mg/day) and placebo in outpatients with bor- impulsive-aggressive and suicidal patients. [12,20-25] derline personality disorder and a low level of co- On the basis of these pharmacological hypo- morbidity with mood disorders. Moreover, no dif- theses, open-label and randomized controlled trials ferences were found between desipramine and pla- have been performed to test the efficacy of SSRIs in cebo in the psychiatrist and patient perceptions of the treatment of symptoms of affective lability, im- global improvement at 3 and 6 weeks. [11] pulsivity and aggressiveness of patients with border- line personality disorder. [12-15,26-37] Findings of these In a group of outpatients with atypical depression trials showed that fluoxetine, sertraline and venla- and concomitant borderline personality disorder, the faxine (a reuptake inhibitor of serotonin and norad- TCA imipramine was less efficacious than the renaline [SNRI]) induced a significant decrease in MAOI phenelzine. [8] Imipramine 200 mg/day had a symptoms of affective instability, dyscontrol of im- 35% response rate, versus 92% for phenelzine. [8] pulsivity, cognitive-perceptual abnormalities and Symptoms of borderline personality disorder pre- global functioning in patients with borderline per- dicted a poor response to imipramine, but a good sonality disorder. [12-15,28,30,32,34,35,37] Fluoxetine (up response to phenelzine.

to 80 mg/day), sertraline (up to 200 mg/day) and TCAs induce frequent adverse effects, such as venlafaxine (up to 400 mg/day) produced effects on sedation, dry mouth, constipation and weight gain. [1] aggressiveness, depression, dysphoria and self-inju- These drugs present a considerable risk of toxicity rious tendencies after treatments of 8–12 weeks. [13] and particular caution is needed when they are ad- Some of these trials reported that improvement of ministered in patients with suicidal intentions. [4] Fa- impulsivity occurred in a short time, usually in the tal arrhythmias are possible in patients with first week of treatment, and was not related to ef- heart conduction disturbances. Blood concentra- fects on depression or anxiety. [12] Furthermore, tions should be measured to minimize the risk of some authors found that the lack of response to one toxicity.

SSRI was not a negative predictor of response for all Some authors have reported that the use of ami- SSRIs. They suggested switching patients who did triptyline in patients with borderline personality dis- not respond to a first trial with a serotonergic antide- order may be associated with behavioural toxici- pressant to another drug of the same class. [26] In fact, ty. [19] This term referred to the increase of such some patients who did not respond to fluoxetine symptoms as impulsivity, aggressive behaviours, 80 mg/day had good results with sertraline paranoia and suicidal intentions.

respond to SSRIs improved significantly after re- der were excluded, but dysthymic disorder, depres- ceiving the SNRI venlafaxine. Higher doses of the sive disorder not otherwise specified, anxiety disor- same SSRI and a longer duration of treatment (24 ders, and alcohol and substance abuse were weeks instead of the usual 12 weeks) can also con- common. Fluoxetine had significant effects on ver- vert a substantial proportion of patients from poor to bal aggression and aggression against objects after good response, as was the case in a group of patients 10 weeks of treatment. However, global improve- receiving sertraline. [13] ment was already significant at week 4 and irritabili- ty decreased at week 6. [12] To date, four double-blind, placebo-controlled studies are available on the efficacy and tolerability In a later study, Rinne et al. [15] tested the efficacy of SSRIs in the treatment of borderline personality of fluvoxamine (mean dosage 166 mg/day) versus disorder. [12-15] placebo in a sample of 38 women with borderline personality disorder. Results of the study showed Markovitz [13] conducted the first of these trials in that fluvoxamine, but not placebo, produced a robust a group of 17 patients with borderline personality and long-lasting reduction in the subscale scores for disorder and high co-occurrence of mood/anxiety rapid mood shifts. In contrast, no difference between disorders and somatic symptoms. The trial lasted 14 the fluvoxamine and placebo groups was observed weeks. Patients who received fluoxetine 80 mg/day with regard to the effect on impulsivity and aggres- had significantly better results in global symptoms, sion scores. Rinne et al. [15] suggested that this latter depression and anxiety in comparison with patients finding may be because of gender-specific differ- receiving placebo. Impulsivity and aggression were ences in impulsivity and aggression.

not assessed. Some patients taking fluoxetine show- ed an improvement in somatic symptoms, such as In summary, SSRIs (particularly fluoxetine and premenstrual symptoms and headache. fluvoxamine) were found to be efficacious in treat- ing borderline personality disorder in available con- In the same period, a 12-week, double-blind trial trolled studies. The effects of these drugs concerned of fluoxetine (20–60 mg/day) was performed by symptoms of affective instability (depression, [13-15] Salzman and colleagues [14] in 27 patients with bor- anxiety [12-14] and anger [14] ), impulsive dyscontrol derline personality disorder or traits. Patients had a (verbal aggression and aggression against ob- good level of functioning (a mean score of 74 on the jects, [12] and global severity of the disorder [12-14] ).

Global Assessment Scale) and did not present co- morbidity with Axis I or II disorders. Fluoxetine Concerning tolerability, SSRIs present a lower induced a significant improvement in symptoms of incidence and milder severity of adverse effects than anger and depression, and increased the level of tricyclic and heterocyclic antidepressants and global functioning in the 22 patients completing the MAOIs. Risk of toxicity is also lower. The highly trial. Reductions in anger and depression were inde- specific actions of SSRIs in enhancing serotonergic pendent of each other. neurotransmission appear to explain their benefit, while the lack of direct actions on other neurotrans- In a 12-week, double-blind trial of fluoxetine mitter systems is responsible for their superior toler- (20–60 mg/day), Coccaro and Kavoussi [12] studied a ability profile compared with older antidepres- group of 40 patients with severe symptoms of im- sants. [39,40] pulsivity and aggression in the context of a personal- ity disorder (approximately one-third had a DSM- Double-blind controlled trials of antidepressants III-R [38] diagnosis of borderline personality disor- in the treatment of borderline personality disorder der). Co-morbid major depression or bipolar disor- are summarized in table I. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 677 2. Efficacy and Tolerability ofality disorder affective instability and bipolar disor- Mood Stabilizersder rapid mood cycling could be a rationale for the use of mood stabilizers in patients with borderline The concept of mood stabilizers is widely applied personality disorder. [48] by clinicians and researchers to indicate a range of To date, several open-label and controlled trials compounds used in the treatment of bipolar disor- have been performed to test the efficacy and tolera- der, although international regulatory authorities do bility of these agents in borderline personality disor- not recognize mood stabilizing as a specific mecha- der, and to specify their effects on different dimen- nism of action. [41-46] A consensus definition of the sions of borderline psychopathology (table II).

term has not yet been established. [47] Nevertheless, mood stabilizers have been operationally described 2.1 Lithium as agents that are efficacious in at least one of the three phases of bipolar disorder (mania, bipolar de- In three reviews since the late 1980s, [54-56] lithium pression or long-term maintenance), while not in- was reported to be an effective treatment for patients creasing the frequency or severity of any of the other with borderline personality disorder. Its activity in- phases of the illness. [41] No drugs used as mood volves three interacting systems: (i) modulation of stabilizers have been approved by the FDA for the neurotransmitters, which may contribute to neuro- treatment of borderline personality disorder; how- protection by readjusting excitatory and inhibitory ever, these drugs are often prescribed off-label in activity balance; (ii) modulation of signals im- clinical practice and are suggested by the APA pacting on the cytoskeleton, including glycogen guidelines for the treatment of borderline personali- synthase kinase-3β, cyclic adenosine monophos- ty disorder. [4] phate-dependent kinase and protein kinase C, which Some investigators have suggested that a com- may be critical for the neural plasticity involved in mon mechanism underlying both borderline person- mood stabilization; and (iii) regulation of second Table II. Double-blind controlled trials of mood stabilizers in the treatment of borderline personality disorder Drug and study Study design No. of Treatment Results with mood stabilizers (comparator drugs) patients duration Lithium Links et al. [11] co (desipramine) 10 6 wk↓ Irritability/anger, ↓ self-mutilation vs desipramine Carbamazepine Gardner and Cowdry [49] co, pc 14 6 wk↓ Behavioural dyscontrol vs placebo Cowdry and Gardner [7] db, pc (alprazolam, 16 6 wk↓ Behavioural dyscontrol vs placebo trifluoperazine, tranylcypromine) Valproate semisodium Hollander et al. [50] db, pc 16 10 wk↓ Global symptomatology, ↓ irritability/ aggressivity, ↑ social functioning vs placebo Hollander et al. [51] db, pc 52 12 wk↓ Impulsive aggression vs placebo Frankenburg and Zanarini [52] db, pc 30 6 mo↓ Interpersonal sensitivity, ↓ anger/ hostility, ↓ aggressiveness vs placebo Lamotrigine Tritt et al. [53] db, pc 24 8 wk↓ Anger vs placebo co = crossover; db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased.

messengers, transcription factors and gene expres- thyroid function, ECG, blood counts and biochemis- try, should be undertaken before treatment.

sion. [57] Periodic monitoring of plasma lithium concentra- A review by Stein, [58] regarding lithium and the tions, as well as thyroid and kidney function, is antiepileptic drug carbamazepine in the treatment of indicated with prolonged lithium use.

patients with borderline or antisocial personality disorder, suggested the effectiveness of both agents 2.2 Carbamazepine on behavioural dysregulation and aggressiveness.

The only controlled trial of lithium in borderline Carbamazepine acts by blocking voltage-gated personality disorder was a crossover comparison sodium channels and is indicated by the FDA for use with desipramine performed in a group of ten pa- as an anticonvulsant drug. [63] Although this agent is commonly used by clinicians in the treatment of tients for 6 weeks. [11] Results showed the efficacy of borderline personality disorder, its use for this indi- lithium on core features of borderline personality cation has not been officially approved.

disorder psychopathology, such as irritability, anger A clinical practice survey performed by Denicoff and self-mutilation.

[11] and colleagues [64] compared carbamazepine with Lithium can be toxic to many organs, particularly many other agents (lithium, valproate sodium, anti- after long-term use; however, most adverse effects psychotics, clonazepam, phenytoin, calcium chan- are not severe and can be reduced or eliminated by nel antagonists) and electroconvulsive therapy in lowering the dose or changing the dosage sched- 1257 patients with different neurological and psy- ule. [59] Metabolic adverse effects are particularly chiatric disorders. These investigators reported that dangerous and include hypothyroidism (up to 36% carbamazepine led to significant global improve- of patients in the study of bipolar I disorder patients ment in the subgroup of patients with borderline by Fagiolini et al. [60] ), hyperparathyroidism and cal- personality disorder.

cium level changes, weight gain and nephrogenic In a crossover trial of carbamazepine in 14 fe- diabetes insipidus (almost 20% of patients accord- male outpatients with borderline personality disor- ing to Van Gerven and Boer [61] ). In addition, pa- der, Gardner and Cowdry [49] demonstrated its effi- tients may report other adverse effects related to the cacy in decreasing the frequency and severity of cardiovascular system (syncope, ECG abnormali- behavioural dyscontrol. These preliminary findings ties, circulatory failure), nervous system (blurred were confirmed by further investigations: a 6-week vision, tremors, vertigo, ataxia, nystagmus), kidney placebo-controlled study comparing carbamazepine (renal impairment) and gastrointestinal disturbance (mean dosage 820 mg/day), alprazolam (4.7 mg/ (nausea, vomiting, diarrhoea). [62] Concomitant ad- day), trifluoperazine (7.8 mg/day) and tranyl- ministration of NSAIDs, diuretics, renin-angioten- cypromine (40 mg/day) in the treatment of patients sin inhibitors, theophylline and antibacterials has with borderline personality disorder and co-morbid been reported to cause elevations in serum lithium hysteroid dysphoria; [7] and a review of double-blind concentrations. Furthermore, lithium is potentially trials of drug therapy for personality disorders that fatal in overdose, and current guidelines suggest that reported a marked improvement in impulsive ag- it should be used with caution in patients at risk of gression following treatment with carbamaze- suicide. [4] pine. [65] A full medical history, as well as laboratory Further controlled trials suggested the effective- investigations, including renal and liver function, ness of carbamazepine on a wider range of symp- © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 679 toms, including not only impulsive-aggressive be- Two patients withdrew from the study in the first 4 haviours [66] but also affective dysregulation, [67,68] weeks of treatment as a result of noncompliance. A which is often the main goal of the use of mood statistically significant improvement was observed stabilizers when treating patients with borderline in global psychopathology, anxiety, interpersonal personality disorder. relationships and borderline personality disorder core features, including impulsivity, affective insta- Carbamazepine can induce several adverse ef- bility and outbursts of anger. These initial findings fects, including CNS disturbances (diplopia, blurred appear promising and provide preliminary evidence vision, ataxia), fatigue and nausea. [69] Less common of a broad spectrum of action of this drug in patients are skin rash, mild leukopenia or thrombocytopenia, with borderline personality disorder; however, con- and hyponatraemia. [70] Idiosyncratic, potentially fa- trolled trials of larger patient groups are needed to tal events have rarely been reported: agranulocyto- replicate these data.

sis, aplastic anaemia, exfoliative dermatitis, and se- rious hepatic and pancreatic toxicity. Overdose of Concerning tolerability, the most frequent ad- carbamazepine may have fatal effects. Periodic verse events during treatment with oxcarbazepine measurement of the white blood cell count is recom- are dizziness, nausea, headache, somnolence and mended. [4] fatigue. [86] Hyponatraemia may occur (albeit often asymptomatically), particularly in the elderly. How- Data from a single study of patients with border- ever, serum sodium level monitoring is not neces- line personality disorder related the use of carbama- sary, unless relevant risk factors exist. [87] Severe zepine to the onset of melancholic depression. [49] haematological dyscrasias have not been report- 2.3 Oxcarbazepine ed. [86] The enzyme-inducing interaction of ox- carbazepine with ethinylestradiol and levonorgestrel Oxcarbazepine is an antiepileptic agent structur- requires additional precautions for women using ally related to carbamazepine, and shares the same hormonal contraception. [87] mechanism of action of blocking voltage-gated so- dium channels, but is less likely to induce cyto- 2.4 Valproate Semisodium chrome P450 enzymes and to cause drug interac- tions. [63] Valproate semisodium is an antiepileptic drug Several trials have shown the efficacy of ox- facilitating the transmission of GABA. [88] This drug carbazepine in the treatment of psychiatric disor- has been extensively studied in patients with border- ders, such as bipolar disorder, substance abuse dis- line personality disorder.

order, resistant psychosis and schizoaffective disor- Initial findings regarding possible efficacy of this der; [71-84] however, as in the case of carbamazepine, agent in treating patients with borderline personality oxcarbazepine has been approved by the FDA for disorder came from open-label studies. Firstly, Wil- treating seizure disorders only.

cox [89] tested valproate semisodium in a group of No randomized controlled trials are available that patients with psychomotor agitation due to different investigate the use of oxcarbazepine in the treatment underlying psychiatric disorders and observed a of borderline personality disorder. Initial data can be particularly marked reduction of agitation after drawn from an open-label trial that was performed treatment in patients with bipolar disorder or border- by our group, which investigated the 12-week treat- line personality disorder. Wilcox [90] then replicated ment of 13 borderline personality disorder outpa- these data in a further trial that focused on borderline tients with oxcarbazepine 1200–1500 mg/day. [85] personality disorder treatment. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 680Bellino et al. Another 8-week, open-label trial of valproate tors found significant effects on interpersonal sensi- tivity, anger, hostility and aggressiveness.

semisodium (daily dose titrated to reach blood con- centrations of 50–100 µg/mL) in 11 patients with Valproate semisodium causes dose-related ad- verse effects, such as gastrointestinal dysfunction borderline personality disorder by Stein and col- (nausea), mild transaminase elevations, tremor, se- leagues [91] suggested the effect of the molecule on dation and weight gain. [93] Less common adverse clinician-rated measures of overall psychopath- events are asymptomatic leukopenia and thrombo- ology, mood, anxiety, anger, impulsivity and rejec- cytopenia. Idiopathic and potentially fatal events are tion sensitivity in four of the eight patients who represented by rare agranulocytosis, and hepatic and completed the study.

pancreatic toxicity. [94] Periodic monitoring of blood Kavoussi and Coccaro [92] studied the efficacy of cell count and hepatic function should be pro- 8-week valproate semisodium therapy (up to 2000 vided. [4] After long-term treatment of women, poly- mg/day) in ten patients with several axis II diagno- cystic ovaries and hyperandrogenism can occur.

ses who had not responded to a previous trial with an SSRI (two patients met the criteria for borderline 2.5 Lamotrigine personality disorder). They reported a reduction in irritability and impulsive aggressiveness after treat- The antiepileptic lamotrigine has recently been ment.

employed in the treatment of depressive episodes of bipolar disorder and in the prevention of recurrences More reliable data derive from three placebo- of this disorder. This agent inhibits neuronal excita- controlled trials. [50-52] bility and modifies synaptic plasticity by inhibiting In a 10-week, double-blind trial of valproate voltage-activated sodium channels. Indirectly, these semisodium (medium plasma concentration 80 µg/ effects would be expected to regulate aberrant intra- mL) in 16 patients with borderline personality disor- cellular and intercellular signalling in critical re- der, Hollander and colleagues [50] found a marked gions of the limbic forebrain. [95] improvement in global symptomatology, social The use of lamotrigine in patients with borderline functioning and borderline personality disorder fea- personality disorder was firstly reported by Pinto tures, such as depressive symptoms, aggressiveness, and Akiskal [96] in a 1-year open-label trial of the irritability and suicidal ideation or behaviour. How- drug (daily dose up to 300 mg), suggesting an im- ever, a high dropout rate (ten patients) precluded provement in global functioning, sexual impulsive- finding any significant differences between val- ness, substance abuse and suicidal behaviour.

proate semisodium and placebo treatment groups.

A review by Green [97] of patients with mood More recently, in a 12-week, double-blind trial, disorders also suggested the efficacy of this agent in the same authors confirmed the efficacy of valproate treating mood instability of borderline personality semisodium (mean daily dose 1325 mg) on impul- disorder.

sive aggression in 52 outpatients with borderline More recently, Preston and colleagues [98] investi- personality disorder. [51] gated the frequency of co-morbid borderline person- Frankenburg and Zanarini [52] performed a ality disorder in 35 patients with bipolar disorder 6-month, placebo-controlled study of valproate who had previously undergone two open-label trials semisodium (plasma concentration 50–100 µg/mL) with lamotrigine, in order to evaluate the effects of in 30 women with borderline personality disorder this drug on borderline personality disorder symp- and co-morbid bipolar II disorder. These investiga- tom dimensions. Borderline personality disorder © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 681 was retrospectively diagnosed in 40% of the pa- symptoms (mood instability, anxiety, anger) and tients. Lamotrigine was reported to be efficacious in somatic complaints. [4] all borderline personality disorder-related symp- 3.1 First-Generation Antipsychotics toms, with a marked improvement of impulsivity and mood instability.

Early studies of antipsychotics targeted the Only one double-blind trial of lamotrigine in psychotic-like symptoms of patients with borderline borderline personality disorder is currently avail- personality disorder.

able. In 2005, Tritt and colleagues [53] compared the Thioridazine was tested at a mean dosage of efficacy of lamotrigine versus placebo in the treat- 92 mg/day in 13 patients with borderline personality ment of aggression in 24 women with borderline disorder. The open-label study lasted 12 weeks personality disorder. A highly significant improve- (with three patients withdrawing) and showed fa- ment in anger was observed after 8 weeks of the vourable effects on the global severity of symptoms, trial.

overall borderline psychopathology and impulsive The most common adverse events associated behaviours. [102] Flupentixol produced similar results with lamotrigine are dizziness, diplopia and head- at the mean dosage of 3 mg/day in a group of ache, [99] while the only serious adverse event is a adolescents with borderline personality disorder. [103] rare hypersensitivity reaction primarily presenting In particular, there was a decrease in depressive and as a rash (the Stevens-Johnson syndrome), which is impulsive symptoms and an improvement of global potentially fatal (0.1% incidence in the study by functioning.

Bowden et al. [100] ). Hirsch et al. [101] pointed out a More reliable indications were provided by initial correlation between lamotrigine serum concentra- comparison trials of antipsychotics, which were tion and tolerability: adverse effects requiring a dose found to be effective on a wide range of symptoms.

change are uncommon with the most frequently Loxapine (mean dosage 14.5 mg/day) and chlor- encountered lamotrigine concentrations (<10 µg/ promazine (mean dosage 110 mg/day) were both mL) and occur in only 7.4% of patients at concentra- found to be effective in reducing depression, anxie- tions obtained during the majority of clinical trials ty, anger and suspiciousness. [104] (<5 µg/mL). Lamotrigine did not appear to destabi- A double-blind comparison of tiotixene (mean lize mood and was not associated with sexual ad- dosage 9.4 mg/day) and haloperidol (mean dosage verse effects, weight gain or withdrawal symp- 3 mg/day) indicated that both drugs decreased the toms. [101] severity of a series of symptoms, including depres- sion, anxiety, derealization, ideas of reference and 3. Efficacy and Tolerability overall borderline psychopathology (table III). [105] of Antipsychotics More recent trials with a placebo control mostly confirmed these data. Nevertheless, it should be noticed that many studies of antipsychotics in pa- Antipsychotics are widely used in clinical prac- tients with borderline personality disorder present tice for treating borderline personality disorder-re- biases in sample selection that can affect both clin- lated symptoms. Although this use has not been ical picture and treatment outcome.

approved by the FDA, APA treatment guidelines recommend the use of antipsychotics, primarily for In a 12-week, double-blind study of patients with their effects on cognitive perceptual disturbances, borderline or schizotypal personality disorder and but also for their efficacy in reducing affective concomitant psychotic-like symptoms, tiotixene © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 682Bellino et al.

Table III. Double-blind controlled trials of first-generation antipsychotics in the treatment of borderline personality disorder Drug and study Study design No. of Treatment Results with antipsychotics (comparator drugs) patients duration Tiotixene Serban and Siegel [105] db (haloperidol) 52 3 mo Tiotixene = haloperidol: ↓ global symptomatology, ↓ depression/anxiety, ↓ paranoid ideation vs baseline Goldberg et al. [106] db, pc 50 12 wk↓ Psychotic symptoms, ↓ obsessive- compulsive symptoms, ↓ phobic anxiety vs placebo Trifluoperazine Cowdry and Gardner [7] db, pc (alprazolam, 16 6 wk↓Depression/anxiety, ↓ rejection sensitivity, tranylcypromine,↓ suicidal attempts vs placebo carbamazepine) Haloperidol Soloff et al. [10] db, pc (amitriptyline) 90 5 wk↓Depression, ↓ hostility, ↓ schizotypal symptoms, ↓ impulsiveness, ↑ global functioning vs placebo Soloff et al. [9] db, pc (phenelzine) 108 5 wk No significant differences vs placebo db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased; = indicates equivalent efficacy.

(mean dosage 8.7 mg/day) was significantly effec- age 4.8 mg/day) was significantly superior to place- tive in treating illusions, ideas of reference, and self- bo on all symptom clusters, [19] including global se- rated obsessive-compulsive and phobic symptoms, verity of symptoms, self- and clinician-rated depres- but not depression and global functioning. [106] The sion, anger, impulsivity, schizotypal symptoms and choice of patients with psychotic-like symptoms psychoticism. [10] In this group of patients, haloperi- biased the effects of treatment towards cognitive- dol induced the same improvement of depression as perceptual distortions. amitriptyline.

A placebo-controlled, crossover comparison was These results indicating the efficacy of haloperi- performed by Cowdry and Gardner [7] in a group of dol on a wide range of symptoms of borderline outpatients with borderline personality disorder. personality disorder were not replicated in another Four drugs were administered in a 6-week trial: trial by the same authors. [9] In the second study, the trifluoperazine, mean dosage 7.8 mg/day; alprazo- same design was used to compare haloperidol (mean lam, mean dosage 4.7 mg/day; carbamazepine, dosage 3.9 mg/day) with phenelzine and placebo.

mean dosage 820 mg/day; and tranylcypromine, The antipsychotic had only modest and nonsignifi- mean dosage 40 mg/day. Trifluoperazine signifi- cant effects on hostility and impulsive aggression.

cantly decreased depression, anxiety, rejection sen- A subgroup of patients in the above-cited trial of sitivity and suicide attempts. As these patients had a haloperidol, phenelzine or placebo [9] who had re- co-diagnosis of hysteroid dysphoria and a history of sponded to treatment received a 16-week continua- impulsive dyscontrol, results could be biased to- tion of treatment. [16] Haloperidol treatment produced wards affective symptoms and impulsivity.

further significant improvement in irritability, but A double-blind comparison of haloperidol and not hostility. Depression significantly increased in amitryptyline was conducted by Soloff and col- severity during prolonged haloperidol treatment, in leagues [10,19] in the 5-week acute treatment of a part as a consequence of akinesia. Global clinical group of inpatients. Haloperidol (mean dos- improvement was of modest importance. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 683 A 6-month continuation treatment was provided nin-2 (5-HT 2) receptors, has been associated not to patients with borderline or histrionic personality only with antipsychotic properties, but also with disorder and a history of recurrent parasuicidal be- antimanic and antidepressant effects. [100] These ef- haviours. [107] In this study, depot flupentixol 20 mg fects have been supported by the results of a number was administered once monthly to control for of studies. [47,110-114] Early studies regarding treat- nonadherence. A significant reduction in suicidal ment of borderline personality disorder with atypi- behaviours was obtained compared with placebo cal antipsychotics suggested the efficacy of cloza- Data on withdrawal rates in samples of outpa- pine. An initial report by Frankenburg and tients with borderline personality disorder who re- Zanarini [115] concerned the beneficial effects of this ceived treatment with antipsychotics depended on drug (mean dosage 253.3 mg/day) on positive and the duration of the trial: 13.7% in a 6-week trial, [104] negative psychotic symptoms and overall function- 48.3% in a 12-week trial [106] and 87.5% in a 22-week ing in 15 patients with a co-diagnosis of borderline continuation study. [16] In short-term treatments, lack personality disorder and psychotic disorder not oth- of compliance can be a consequence of adverse erwise specified. Patients had been resistant or intol- effects induced by typical antipsychotics, partic- erant to previous antipsychotic therapies. The relia- ularly extrapyramidal symptoms (EPS), sedation bility of these results is limited as it is difficult to and hypotension. [100,106,108,109] Some patients who ascertain whether psychotic symptoms were an ex- have obtained a clinical improvement with low pression of borderline personality disorder or were doses of antipsychotics in the acute treatment may due to co-morbidity with psychotic disorders.

withdraw when experiencing adverse effects in Benedetti and colleagues [116] tried to address this longer continuation therapy. [4] Clinicians must take issue. They selected a sample of patients with bor- into account the risk of tardive dyskinesia before derline personality disorder who were resistant to deciding to administer first-generation antipsychot- treatment (they had not responded to at least 4 ics for a long period. [4] months of prior treatment with medication and psy- Administration of thioridazine is not recommen- chotherapy) but did not meet the criteria for ded as this drug increases the duration of the QT psychotic disorders. The open-label study focused interval and can induce arrhythmias. [108,109] on psychotic-like symptoms, which were considered A reassuring doctor-patient relationship that more typical of personality disorder. A combination carefully considers problems related to adverse ef- of clozapine (mean dosage 43.8 mg/day) and psy- fects and compliance can be useful to prevent with- chotherapy was administered for 4 months to 12 drawal during antipsychotic treatment. [4] patients, and induced an improvement in all symp- Double-blind controlled trials concerning first- tom clusters – affective symptoms, impulsivity and generation antipsychotics in the treatment of border- cognitive-perceptual distortions.

line personality disorder symptoms are summarized Chengappa et al. [117] performed a similar investi- in table III.

gation, administering clozapine to seven female in- patients with borderline personality disorder and 3.2 Atypical Antipsychotics concomitant refractory psychosis, who had not re- sponded to previous treatment with other antipsy- Atypical antipsychotics represent a new treat- chotics. Patients were treated for up to 1 year and ment tool for borderline personality disorder. In fact, reported a reduction in self-destructive and aggres- their double mechanism of action, characterized by the antagonism of both dopamine-2 (D 2) and seroto- sive behaviours, isolation, drug intake and abuse. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 684Bellino et al. When considering the efficacy of risperidone in More extensive data have been reported for olan- zapine and quetiapine.

the treatment of borderline personality disorder, data are sparse and derive from some case reports and Olanzapine is a thienobenzodiazepine with a high two initial investigations. [118-122] affinity for D 2 through D 4 and 5-HT 2A receptors, and a lower affinity for histamine (H 1), muscarinic In their 8-week, open-label trial of risperidone (M 1 through M 5) and α 1-adrenergic receptors. Ant- (3.3 mg/day) in 15 outpatients with borderline per- agonism at D 2 through D 4 and 5-HT 2A receptors is sonality disorder, Rocca and colleagues [122] outlined thought to be the basis for its therapeutic efficacy, the efficacy of this agent on aggressive behaviour, while antagonism at H 1, M 1–M 5 and α 1-receptors is affective instability and global psychopathology.

probably responsible for its adverse effects. [127] Two patients discontinued treatment before the end The first open-label study of olanzapine in bor- of the trial because of lack of compliance.

derline personality disorder was conducted by Szighethy and Schulz [119] published the initial Schulz and colleagues [120] in a sample of 11 outpa- data of a double-blind comparison of risperidone tients with a co-diagnosis of dysthymic disorder.

(mean dosage 2.5 mg/day) and placebo. Twenty- The nine patients who completed the 8 weeks of seven patients with borderline personality disorder treatment presented a decrease in impulsivity, hos- were included and treated for 8 weeks (see table IV). tility, overall psychopathology and global function- ing.

Risperidone was not more effective than placebo in increasing global functioning, but produced an im- Since the completion of this study, several con- provement in psychoticism, paranoid ideas, phobias trolled trials have been published on this and interpersonal sensitivity.

drug. [37,123-125] Table IV. Double-blind controlled trials of atypical antipsychotics in the treatment of borderline personality disorder Drug and study Study design No. of Treatment Results with antipsychotics (comparator drugs) patients duration Risperidone Szighethy and Schulz [119] db, pc 27 8 wk No significant differences vs placebo Olanzapine Zanarini et al. [37] db (fluoxetine, olanzapine 45 8 wk↓ Impulsive aggression, ↓ chronic + fluoxetine) dysphoria vs baseline (olanzapine = olanzapine + fluoxetine > fluoxetine) Zanarini and Frankenburg [123] db, pc 28 6 mo↓ Anxiety/paranoid ideation, ↓ interpersonal sensitivity vs placebo Bogenschutz and Nurnberg [124] db, pc 40 12 wk↓ Global symptomatology, ↓ anger vs placebo Soler et al. [125] db, pc (dialectical behaviour 60 12 wk↓ Impulsive aggression, therapy, olanzapine +↓ depression/anxiety vs placebo dialectical behaviour therapy) Aripiprazole Nickel et al. [126] db, pc 52 8 wk↓ Global psychopathology, ↓ depression/anxiety, ↓ anger vs placebo db = double-blind; pc = placebo-controlled; ↓ indicates decreased; = indicates equivalent efficacy; > indicates better efficacy.

© 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 685 Two studies investigated the effects of olanza- of adverse events such as EPS, prolactin elevation and weight gain. [128-130] pine compared with placebo. [123,124] A 6-month double-blind, placebo-controlled trial of olanzapine Hilger and colleagues [131] described the effects of (mean dosage 5.33 mg/day) in 28 women with bor- this agent (400–800 mg/day) on two women with derline personality disorder was performed by borderline personality disorder with severe episodes Zanarini and Frankenburg, [123] who pointed out the of self-mutilation, and found it to be efficacious in efficacy of this agent on anxiety, paranoid ideation improving impulsive behaviour and overall func- and interpersonal sensitivity. Bogenschutz and tioning.

Nurnberg [124] reported findings of a 12-week, doub- A few pilot studies on quetiapine in the treatment le-blind, placebo-controlled trial of olanzapine of borderline personality disorder have recently (5–10 mg/day) in 40 outpatients with borderline been performed, with mostly concordant and prom- personality disorder. From the fourth week of treat- ising conclusions being reached. Adityanjee and ment, these investigators observed a significant im- Schulz [132] tested the efficacy of quetiapine (25–300 provement in borderline psychopathology and an- mg/day) in ten patients who completed an 8-week ger.

open-label trial. Results showed an improvement in overall symptomatology, hostility, impulsivity and Other studies considered combinations of olanza- functioning.

pine with another drug or psychotherapy. Zanarini and colleagues [37] compared the efficacy of fluoxe- Villeneuve and Lemelin [133] replicated these find- tine, olanzapine and the olanzapine-fluoxetine com- ings. They investigated the effects of quetiapine bination in the treatment of 45 women meeting the (175–400 mg/day for 12 weeks) in a group of 23 criteria for borderline personality disorder. In their outpatients with borderline personality disorder and 8-week, randomized, double-blind study, the inves- found a significant improvement in impulsivity, tigators found that all three treatment options signif- hostility, depression, anxiety and social functioning.

icantly improved chronic dysphoria and impulsive Perrella et al. [134] recently tested open-label que- aggression. However, olanzapine monotherapy and tiapine (400–800 mg/day) in 29 patients with bor- the olanzapine-fluoxetine combination were found derline personality disorder for 12-weeks. Six pa- to be superior to fluoxetine monotherapy in treating tients withdrew from the study because of adverse both features of borderline psychopathology. Soler effects. In the final sample of 23 patients, these et al. [125] recently compared the efficacy of olanza- investigators found a significant improvement in pine and placebo in a combined treatment with global symptoms, depressive symptoms, hostility/ dialectical behavioural therapy. In their 12-week suspiciousness, aggressiveness and functioning.

double-blind study of a group of 60 outpatients with Our group [135] performed a 12-week pilot study borderline personality disorder, they found that on the efficacy of quetiapine (mean dosage 309 mg/ olanzapine (mean dosage 8.83 mg/day) led to a day) for the treatment of 14 patients with borderline significant reduction of impulsive-aggressive beha- personality disorder. Three patients withdrew from viour, depression and anxiety compared with place- the study because of noncompliance. Results were bo.

mostly concordant with previous findings and con- Quetiapine is a dibenzothiazepine characterized firmed the improvement of global symptomatology, by low affinity for and rapid dissociation from post- impulsivity, outbursts of anger, anxiety and social synaptic D 2 receptors, which reduces the incidence functioning. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 686Bellino et al. Aripiprazole, an atypical antipsychotic with par- use of growth factors can reduce the risk of infec- tial agonist activity at D 2 and 5-HT 1A receptors, has tions. Transient leukocytosis and eosinophilia can recently been introduced for the treatment of schizo- also be observed, but these do not usually have any phrenia, schizoaffective disorder and bipolar disor- serious clinical effects. [145] der. [136-140] Aripiprazole augmentation of various The incidence of EPS differs among the atypical SSRIs has been reported to have good effects in antipsychotics, with risperidone being associated refractory unipolar depression. [141,142] with the highest incidence, and clozapine and que- tiapine with the lowest incidence. [146] The likelihood Data concerning the use of aripiprazole in the of developing EPS depends not only on the specific treatment of borderline personality disorder are very agent chosen, but also on the rapidity of dose escala- preliminary.

tion, the target dose and the vulnerability of the Three patients with borderline personality disor- patient to this adverse effect. [146] der and psychotic symptoms were treated with When taking into account metabolic effects, ris- aripiprazole, with heterogeneous results shown in peridone has a relatively low risk of causing obesity clinical response and tolerability. [143] and diabetes mellitus. [147] Nickel et al. [126] performed a double-blind, place- Data on the tolerability of atypical antipsychotics bo-controlled trial of aripiprazole (15 mg/day) in 52 specifically collected in samples of patients with patients with borderline personality disorder, find- borderline personality disorder are limited. In the ing the molecule to be efficacious after 8 weeks in study by Soler and colleagues, [125] patients with reducing global psychopathology, depression, anxi- borderline personality disorder treated with olanza- ety and anger. Drug therapy was well tolerated. In pine experienced significant weight gain, but there order to assess the long-term effects of the molecule was no dose-dependent relationship.

on borderline personality disorder, these investiga- tors performed an 18-month follow-up trial [144] of Some data concerning the tolerability of que- the sample of patients included in the previous in- tiapine in borderline personality disorder can be vestigation. [126] According to the intent-to-treat ana- drawn from the study performed by our group, [135] lysis, all scales of global psychopathology, depres- showing that the most common adverse effects were sion and anxiety showed a significant improvement, somnolence, dry mouth and dizziness. Adverse ef- suggesting that aripiprazole can be considered an fects were mild to moderate in most cases, but two effective agent in the long-term treatment of patients patients discontinued treatment because of excess- with borderline personality disorder.

ive somnolence. The pattern of adverse effects ap- peared to be in accordance with other investigations Concerning adverse effects, the newer antipsy- of quetiapine in patients with schizophrenia or bi- chotics present a more favourable tolerability profile polar disorder. [148,149] compared with first-generation antipsychotics.

More common adverse effects of aripiprazole are Clozapine presents a serious risk of blood dyscra- headache, insomnia and anxiety. This pattern of sia. Neutropenia and agranulocytosis can occur in a adverse effects can be found in patients affected by small percentage of patients (0.9% and 0.7%, re- other psychiatric disorders, [137,149,150] as well as in spectively, according to Lambertenghi De- patients with borderline personality disorder. [143] liliers [145] ), mainly during the first 18 weeks of clo- zapine treatment, and can lead to serious complica- Double-blind controlled trials of atypical anti- tions. Drug discontinuation usually results in the psychotics in borderline personality disorder are normalization of haematological parameters, and the summarized in table IV. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) Pharmacotherapy of Borderline Personality Disorder 687 4. Meta-Analysesity and psychotic symptoms. The only difference seen between MAOIs and placebo was that patients In recent years, a few reviews and meta-analytic receiving MAOIs were less hostile. The compari- studies have evaluated the available pharmacologi- sons of MAOIs with antipsychotics did not show cal interventions for borderline personality disorder, convincing differences, although some results were with the aim of defining which evidence supports significant. Antipsychotics may have some benefits the efficacy of pharmacotherapy on measures of for people with paranoid and psychotic symptoms, symptoms and functional level.

but there was little evidence for the advantage of one To date, we found two meta-analyses of random- antipsychotic over another. Mood stabilizers, such ized controlled trials of pharmacotherapy for pa- as valproate semisodium, may induce some change tients with borderline personality disorder. Both in clinical global scores, but data are not conclusive.

studies pointed out that the evidence for efficacy is These authors concluded that well designed, clini- very limited and a series of methodological limita- cally meaningful trials are needed and that the posi- tions affect the reliability of results.

tive effects of antidepressants could be considerable The meta-analysis by Nos` e et al. [151] included 20 and should be addressed first.

articles, reporting 22 placebo-controlled investiga- tions: eight studies involved antipsychotics, seven 5. Conclusions involved antidepressants and seven involved mood stabilizers. Antidepressants and mood stabilizers Investigations on psychotropic agents in the were found to be efficacious in reducing affective treatment of borderline personality disorder have instability and anger, but did not produce significant recently tested several new drugs belonging to the effects on impulsivity and aggression, unstable rela- classes of antidepressants, mood stabilizers and anti- tionships, suicidality or functioning. Antipsychotics psychotics. Results are promising and suggest that significantly improved impulsive aggression, inter- these medications can be useful in clinical practice, personal relationships and global functioning. No particularly to control impulsive aggression and af- difference was found between pharmacotherapy and fective instability.

placebo in terms of dropout rates. The authors con- However, available studies show a series of cluded that pharmacotherapy has shown modest methodological limitations, such as small sample beneficial effects on core traits of borderline person- sizes, the short duration of most trials, the lack of ality disorder.

long-term follow-up evaluations, the heterogeneity Binks et al. [152] presented evidence from the of selection criteria and outcome measures, and the Cochrane Database of Systematic Reviews, and in- high rates of dropouts. Sometimes, authors do not cluded all randomized trials comparing psycho- describe the reasons for patients withdrawing from active drugs with any other treatment for people trials, although a large proportion of withdrawals with borderline personality disorder. They found ten appear to be related to insufficient compliance small studies (n = 554) involving eight comparisons. among these patients. Furthermore, sponsorship Data on antidepressants indicated that fluoxetine concerns might have led to a bias in the objective may offer some improvement in ratings of anger. A evaluation of the effects of drugs. Considering these study investigating the effects of mianserin on at- limitations, meta-analyses have concluded that tempted suicide found no difference between drug pharmacological treatment of borderline personality and placebo. Data indicated that haloperidol may disorder may be of use but is not currently based on provide better results than antidepressants on hostil- good evidence from trials. © 2008 Adis Data Information BV. All rights reserved.CNS Drugs 2008; 22 (8) 688Bellino et al. 7. Cowdry RW, Gardner DL. Pharmacotherapy of borderline per- Forthcoming investigations should therefore fo- sonality disorder: alprazolam, carbamazepine, trifluoperazine, cus on a series of relevant topics such as: pilot and tranylcipromine. Arch Gen Psychiatry 1988; 45: 111-9 8. Parsons B, Quitkin FM, McGrath PJ, et al. Phenelzine, imipram- studies of new agents; controlled trials of drugs ine, and placebo in borderline patients meeting criteria for already tested in open-label case series; compari- atypical depression. Psychopharmacol Bull 1989; 25: 524-34 sons of new antiepileptic agents with better known 9. Soloff PH, Cornelius J, George A, et al. Efficacy of phenelzine and haloperidol in borderline personality disorder. Arch Gen mood stabilizers, such as lithium or valproate semi- Psychiatry 1993; 50 (5): 377-85 sodium; head-to-head comparisons of atypical and 10. Soloff PH, George A, Nathan S, et al. Amitriptyline versus haloperidol in borderlines: final outcomes and predictors of traditional antipsychotics to verify which differ- response. J Clin Psychopharmacol 1989; 9: 238-46 ences in clinical effects and adverse events specifi- 11. Links P, Steiner M, Boiago I, et al. Lithium therapy for border- cally occur in borderline personality disorder; defi- line patients: preliminary findings. J Personal Disord 1990; 4:

173-81 nition of appropriate doses to treat borderline per- 12. Coccaro EF, Kavoussi RJ. Fluoxetine and impulsive aggressive sonality disorder symptoms; maintenance studies to behaviour in personality disordered subjects. Arch Gen Psy- chiatry 1997; 54: 1081-8 assess persistence of therapeutic effects in a long- 13. Markovitz P. Pharmacotherapy of impulsivity, aggression, and lasting disorder such as borderline personality disor- related disorders. In: Hollander E, Stein DJ, editors. Impulsivi- der; add-on trials of mood stabilizers and atypical ty and aggression. New York: John Wiley & Sons, 1995:

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