Part #2
Oxcarbazepine
Oxcarbazepine is another anticonvulsant structurally related to carbamazepine, with the same mechanism of action of blocking voltage-gated sodium channels, but it is less likely to induce cytochrome P-450 and drug interactions.19 A series of studies indicated the efficacy of oxcarbazepine in the treatment of several psychiatric disorders, such as bipolar disorder, substance abuse, resistant psychosis, and schizoaffective disorder. 27-40 However, as in the case of carbamazepine, oxcarbazepine has been approved by the FDA for treating only seizure disorder.
Our research group recently performed a 12-week pilot study of oxcarbazepine in 13 outpatients with BPD.41 A statistically significant improvement was observed in global psychopathology; anxiety; interpersonal relationships; and BPD core features, including impulsivity, affective instability, and outbursts of anger.
Divalproex sodium and valproate
Among mood stabilizers, divalproex sodium has been extensively studied in patients with BPD. Its mechanism of action consists of facilitating transmission of y-aminobutyric acid.42 Wilcox43,44 was the first to suggest the role of divalproex in reducing agitation in patients with BPD. In 1994, Wilcox43 tested the efficacy of valproate in a group of patients with psychomotor agitation caused by various underlying psychiatric conditions. The decrease in agitation after treatment was particularly evident in patients with bipolar disorder or BPD. These data were replicated in a subsequent study by Wilcox44 concerning the treatment of BPD with divalproex sodium.
An 8-week open-label trial of valproate (daily dose titrated to reach blood levels of 50 to 100 μg/mL) in 11 patients with BPD by Stein and colleagues45 provided further data on this agent. Of the 8 who completed the study, half were responders on clinician-rated measures of overall psychopathology, mood, anxiety, anger, impulsivity, and rejection sensitivity.
Kavoussi and Coccaro46 administered valproate (up to 2000 mg/d) to 10 patients with several Axis II diagnoses who had failed to respond to an SSRI (2 patients met criteria for BPD). After 8 weeks of treatment, irritability and impulsive aggressiveness were significantly reduced.
Subsequently, 3 placebo-controlled trials were published. Hollander and colleagues47 performed a 10-week double-blind study of valproate (plasma level of 80 μg/mL) in 16 patients with BPD and found a marked improvement in global symptomatology; social functioning; and BPD features, such as depressive symptoms, aggressiveness, irritability, and suicidal ideation or behavior. However, a high dropout rate precluded finding significant differences between treatment groups.
More recently, the same study group confirmed the efficacy of valproate (mean daily dose, 1325 mg) on impulsive aggression of 52 outpatients with BPD in a 12-week double-blind trial.48 Frankenburg and Zanarini49 included 30 women with BPD and comorbid bipolar II disorder in a 6-month controlled study and showed that valproate (plasma level of 50-100 μg/mL) had significant effects on interpersonal sensitivity, anger, hostility, and aggressiveness.
Lamotrigine
The anticonvulsant lamotrigine has been considered in recent years for treating depressive episodes of bipolar disorder and preventing recurrences. This drug inhibits neuronal excitability and modifies synaptic plasticity by inhibiting voltage-activated sodium channels. Indirectly, these effects would be expected to regulate aberrant intracellular and intercellular signalling in critical regions of the limbic forebrain.50
The use of lamotrigine for treating BPD was initially reported by Pinto and Akiskal51 in a 1-year open-label trial focused on 8 outpatients. Their results showed that 40% reported a significant improvement in global functioning, sexual impulsiveness, substance abuse, and suicidal behavior. A review by Green52 of patients with mood disorders suggests the efficacy of this agent in also treating mood instability of BPD.
More recently, Preston and colleagues53 investigated the frequency of comorbid BPD in 35 patients with bipolar disorder who had previously participated in 2 open-label trials with lamotrigine, in order to evaluate the effects of this drug on BPD dimensions. BPD was retrospectively diagnosed in 40% of the patients. Results of the study showed the efficacy of lamotrigine on all BPD traits, with a marked improvement in impulsivity and mood instability.
In 2005, Tritt and colleagues54 compared the efficacy of lamotrigine and placebo in the treatment of aggression in 24 women meeting the criteria for BPD. Highly significant improvements in anger were observed after 8 weeks in patients treated with lamotrigine.
Novel antipsychotics as mood stabilizers in BPD
Second-generation antipsychotics antagonize both dopamine and serotonin- 2 (5-HT2) receptors. Because dopamine receptor blockade has been associated with antimanic properties and 5-HT2 antagonism with antidepressant effects, it has been postulated that novel antipsychotics may be effective in the treatment and prevention of bipolar mania and depression.55 These hypotheses have been substantiated by a number of studies.5,56-60
The mood-stabilizing properties of second-generation antipsychotics have also been considered for treatment of BPD-related symptoms (Table 2). Although this indication has not yet been approved by the FDA, these agents are indicated by BPD treatment guidelines both for their antipsychotic effects on cognitive-perceptual disturbances and for their mood stabilizing action on affective instability, anger, and impulsive aggression.4
Clozapine was found to be efficacious on overall symptomatology, aggressiveness, and severe psychotic symptoms related to BPD.61-65 However, patients with BPD treated with clozapine frequently had Axis I comorbidities and had been refractory to previous treatments. These patients did not have pure BPD and they had already been treated unsuccessfully with other drugs.
To date, studies on risperidone in BPD are sparse and derive from some case reports and an open-label trial.66-69 In their 8-week open-label trial of risperidone (3.3 mg/d) in 15 outpatients with BPD, Rocca and colleagues69 outlined the efficacy of this agent on aggressive behavior, affective instability, and global psychopathology.
More extensive data suggesting mood stabilizing properties have been reported for olanzapine and quetiapine. Olanzapine is a thienobenzodiazepine with a high affinity for dopamine (D2 through D4) and serotonin receptors (5-HT2A), and a lower affinity for histamine (H1), muscarinic (M1 through M5), and α-adrenergic (α1) receptors. Antagonism at D2 through D4 and 5-HT2A receptors is supposed to be the basis for its therapeutic efficacy, while antagonism at H1, M1-M5, and α1 receptors is probably responsible for adverse effects.70
Schulz and colleagues71 performed the first open-label study of olanzapine in a sample of 9 outpatients with BPD who had comorbid dysthymia. After 8 weeks of treatment, patients reported a significant improvement in impulsivity, hostility, global psychopathology, and global functioning.
Since then, the findings from several controlled trials have been published. A 6-month double-blind, placebo-controlled trial of olanzapine (mean dose, 5.33 mg/d ± 3.43) in 28 women with BPD was undertaken by Zanarini and Frankenburg,72 who pointed out the efficacy of this agent on anxiety, paranoid ideation, and interpersonal sensitivity. Bogenschutz and Nurnberg73 recently reported similar findings in a 12-week double-blind, placebo-controlled trial of olanzapine (5 to 10 mg/d) in 40 outpatients with BPD. A significant improvement in borderline psychopathology and anger was found after the fourth week of treatment.
Zanarini and colleagues74 compared the efficacy of fluoxetine, olanzapine, and the olanzapine-fluoxetine combination (OFC) in the treatment of 45 women meeting criteria for BPD. In their 8-week randomized double-blind study, the investigators found that all 3 treatment options significantly ameliorated chronic dysphoria and impulsive aggression. However, olanzapine monotherapy and OFC were found to be superior to fluoxetine monotherapy in treating both features of borderline psychopathology.
Soler and colleagues75 recently compared the efficacy of olanzapine and placebo in a combined treatment with dialectical behavioral therapy. In their 12-week double-blind study of a group of 60 outpatients with BPD, they found that olanzapine (mean dose, 8.83 mg/d) led to a significant reduction of impulsive- aggressive behavior, depression, and anxiety.
Quetiapine is a dibenzothiazepine characterized by low affinity for and rapid dissociation from postsynaptic D2 receptors, which reduces the incidence of adverse events, such as extrapyramidal symptoms, prolactin elevation, and weight gain.76-79 Hilger and colleagues80 described the impact of this agent (400 to 800 mg/d) on 2 women with BPD with severe episodes of self-mutilation and found positive effects on impulsive behavior and overall functioning.
A few pilot studies on quetiapine in BPD treatment have appeared in recent years. Adityanjee and Schulz81 evaluated the efficacy of quetiapine (25 to 300 mg/d) in 10 patients who completed an 8-week open-label trial. Results suggested a significant improvement in overall symptomatology, hostility, impulsivity, and functioning. Villeneuve and Lemelin82 recently replicated these findings. They investigated the effects of quetiapine (175 to 400 mg/d for 12 weeks) in a group of 23 outpatients and found a significant improvement in impulsivity, hostility, depression, anxiety, and social functioning.
Our group83 performed a 12-week pilot study on the efficacy of quetiapine (mean dose, 309 mg/d 83) for the treatment of BPD in 14 patients. Our results were mostly concordant with previous findings and confirmed the improvement of global symptomatology, impulsivity, outbursts of anger, anxiety, and social functioning.
Table 2
Clinical trials of some novel antipsychotics in the
treatment of borderline personality disorder
Agent Study
Design Number of
Patients Treatment
Duration Results
Risperidone
Rocca69 Open-label 15 8 weeks Decreased global symptomatology, aggression/mood instability
Olanzapine
Schulz71 Open-label 9 8 weeks Decreased global symptoms, impulsive aggression
Zanarini72 Double-blind
vs placebo 28 6 months Decreased anxiety/paranoid ideation, interpersonal sensitivity
Bogenschutz73 Double-blind vs placebo 40 12 weeks Decreased global symptomatology, anger
Zanarini74 Double-blind vs F vs 0 + F 45 8 weeks Decreased impulsive aggression, chronic dysphoria (O = O + F > F)
Soler75 Double-blind DBT + O vs DBT + placebo 60 12 weeks Decreased impulsive aggression, depression/anxiety
Quetiapine
Hilger80 Case report 2 NA Decreased impulsivity, improved global functioning
Adityanjee81 Open-label 10 8 weeks Decreased overall symptomatology, hostility/impulsivity; improved global functioning
Villeneuve82 Open-label 23 12 weeks Decreased impulsivity/hostility, depression/anxiety; improved global functioning
Bellino83 Open-label 14 12 weeks Decreased impulsivity/anger/
anxiety; improved social functioning
O, olanzapine; F, fluoxetine; DBT, dialectical behavior therapy; NA, not available.
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