Mood Stabilizers and Novel Antipsychotics in the Treatment of Borderline Personality Disorder

July 2006, Vol. XXIII, No. 8

Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability of interpersonal relationships, self-image, and affect, in addition to marked impulsivity.¹ Although psychotherapy plays a significant role in the treatment of borderline patients by focusing on maladaptive personality traits and patterns of interpersonal relationships, ^2,3 pharmacotherapy is indicated by the American Psychiatric Association guidelines to manage vulnerability traits, symptoms, and crises.⁴

Treatment strategies for BPD target different domains of psychopathology, such as cognitive-perceptual, affective, and impulsive-behavioral symptoms. Guidelines specify the use of antidepressant agents—in particular, selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors—and mood stabilizers for affective dysregulation; SSRIs and mood stabilizers for impulsive-behavioral dyscontrol; and antipsychotics for cognitive-perceptual symptoms. This article focuses on data concerning the efficacy of mood stabilizers in the treatment of BPD.

The role of mood stabilizer

A consensus definition of mood stabilizer remains to be established, and international regulatory authorities do not officially recognize the term as a mode of drug activity.⁵ Clinicians and researchers apply the concept of mood stabilization to a range of compounds used in the treatment of bipolar disorder, although considerable variability can be found in the literature concerning the meaning and use of the term.^6-11 In its broadest form, a mood stabilizer has been operationally described as an agent that is useful in at least 1 of the 3 phases of bipolar disorder (mania, bipolar depression, or long-term maintenance) while not increasing the frequency or severity of any of the other phases of the illness.⁶

Although no drugs used as mood stabilizers have been approved by the FDA for the treatment of BPD, these drugs are often prescribed off-label in clinical practice and are suggested for treating BPD-related symptoms by the guidelines of the American Psychiatric Association.⁴ Some investigators have proposed that the same mechanism may drive both the affective instability of BPD and the rapid mood cycling of bipolar disorder and that this could be a rationale for the use of mood stabilizers in BPD.¹²

To date, several open-label and controlled trials have been undertaken to test the efficacy of these agents in BPD and to define their effects on different dimensions of borderline psychopathology (Table 1).

Lithium carbonate

The first mood stabilizer considered for the treatment of patients with BPD is lithium(Drug information on lithium) carbonate; its effectiveness has been reported in 3 reviews since the late 1980s.^13-15 Concerning the mechanism of action, 3 interacting systems appear critical for lithium activity: modulation of neurotransmitters, which may contribute to neuroprotection by readjusting excitatory and inhibitory activity balance; modulation of signals impacting on the cytoskeleton, including glycogen synthase kinase-3β, cyclic AMP-dependent kinase, and protein kinase C, which may be critical for the neural plasticity involved in mood stabilization; and regulation of second messengers, transcription factors, and gene expression.¹⁶

The results of a 6-week, doubleblind, placebo-controlled crossover study that compared lithium with desipramine in 10 patients with BPD showed the efficacy of lithium on core features of borderline psychopathology, such as irritability, anger, and selfmutilation.¹⁷ A review by Stein¹⁸ concerning lithium and the anticonvulsant agent carbamazepine(Drug information on carbamazepine) in the treatment of patients with BPD or antisocial personality disorder pointed out the effectiveness of both agents on behavioral dysregulation and aggressiveness.

Carbamazepine

At about the same time, further data concerning treatment of BPD with carbamazepine were published. This agent blocks voltage-gated sodium channels and is indicated by the FDA as an anticonvulsant.¹⁹ Although its use in the treatment of BPD is common in clinical practice, this has not been officially approved. In a crossover trial with a sample of 11 female outpatients with BPD, Gardner and Cowdry²⁰ demonstrated decreased frequency and severity of behavioral dyscontrol. Their results were confirmed by other studies: a 6-week controlled investigation comparing carbamazepine (mean dose, 820 mg/d), alprazolam (4.7 mg/d), trifluoperazine(Drug information on trifluoperazine) (7.8 mg/d), and tranylcypromine (40 mg/d) in the treatment of 16 patients with BPD and comorbid hysteroid dysphoria,²¹ and a review of double-blind clinical trials.²² Both showed that carbamazepine induced a marked improvement in impulsive aggression.

Controlled trials suggest the efficacy of carbamazepine not only in reducing impulsive-aggressive behaviors²³ but also on affective dysregulation,^24,25 which is often the main goal of mood stabilizer use in the treatment of BPD. A clinical practice survey by Denicoff and colleagues26 compared carbamazepine with many other agents (lithium, valproate(Drug information on valproate), neuroleptics, clonazepam(Drug information on clonazepam), phenytoin(Drug information on phenytoin), calcium antagonists) and electroconvulsive therapy in 1257 patients with different neurologic and psychiatric disorders, and found a significant global improvement in the subgroup of patients with BPD treated with carbamazepine.