Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders

Abstract

Background: The objective of the current study was to examine possible clinical predictors of positive response to lamotrigine or gabapentin monotherapy in treatment-refractory affectively ill patients.

Methods: Forty-five patients with treatment refractory bipolar (n = 35) or unipolar (n = 10) affective disorder participated in a clinical study evaluating six weeks of treatment with lamotrigine, gabapentin, or placebo monotherapy given in a double-blind, randomized fashion with two subsequent cross-overs to the other agents. Patients received daily mood ratings and weekly cross-sectional scales. Much or very much improved on the Clinical Global Impression scale modified for bipolar illness was considered a positive response. Degree of response was correlated with a number of baseline demographic and course of illness variables in a univariate analysis and then by linear regression.

Results: Response rates to lamotrigine (51%) exceeded those to gabapentin (28%) and placebo (21%). A positive response to lamotrigine monotherapy was associated with a bipolar diagnosis; fewer hospitalizations; fewer prior medication trials; and male gender (of which the latter two variables survived logistic regression). For gabapentin, degree of response correlated with shorter duration of illness; younger age; and lower baseline weight (with the latter two surviving linear regression).

Conclusions: In this highly treatment-refractory population, lamotrigine appeared most effective for male patients with fewer prior medication trials. Gabapentin monotherapy, although not better than placebo, appeared most effective in those with younger age and lower baseline weight. These preliminary data in a treatment refractory subgroup may help in the further definition of the range of clinical utility of these widely used anticonvulsants.

Introduction

The pharmacological armamentarium for treatment of bipolar illness has expanded to encompass a large array of potential therapeutic agents Gelenberg and Hopkins 1993, McElroy and Keck 2000, Post et al 1998, Post 2000, Sachs and Thase 2000, Thase and Sachs 2000, making efforts to identify responsive categories and subtypes of bipolar disorder, as well as delineating clinical and biological markers of response, particularly important. The mood stabilizers lithium, valproate, and carbamazepine have partially overlapping as well as different mechanisms of action (Post et al 2000). Each has preliminarily been associated with different spectra of clinical efficacy and adverse effects Bowden 1995, Calabrese et al 1996a, Denicoff et al 1997, Swann et al 1999.

Bipolar modifiers or subtypes that are poorly responsive to lithium include the following: dysphoric mania Himmelhoch and Garfinkel 1986, Swann et al 1997; rapid cycling (Dunner and Fieve 1974); the depression-mania-well interval sequence (Faedda et al 1991); substance abuse comorbidity (O’Connell et al 1991); lack of family history of bipolar illness and noncompliance or discontinuation (Denicoff et al 1997). Valproate has shown efficacy in the treatment of some lithium refractory patients, such as those with rapid cycling (Calabrese and Woyshville 1995) and mixed states Bowden et al 1994, McElroy et al 1992, Swann et al 1997 . Correlates of better response to valproate include those with electroencephalogram abnormalities (McElroy et al 1987, but not subsequently replicated by the same group) and less cycle acceleration Calabrese et al 1993a, Calabrese et al 1993b. Subgroups of patients who show improvement during treatment with carbamazepine include those with greater initial depression severity and less chronicity (Post et al 1986); less rapid cycling Denicoff et al 1997, Okuma 1993; and atypical presentations with comorbidities and schizoaffective characteristics (Greil et al 1997). All three drugs appear to be more effective in acute mania than acute depression.

Several of the newer anticonvulsants are being investigated for their efficacy in acute affective episodes and as putative mood stabilizers. Like several other agents (tiagabine, vigabatrin, and valproate) gabapentin increases brain levels of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA) (Taylor et al 1998). Although open uncontrolled studies suggest that gabapentin may be a useful adjunct in the treatment of some residual bipolar symptoms Altshuler et al 1999, Erfurth et al 1998, Ghaemi et al 1998, Knoll et al 1998, McElroy et al 1997, Perugi et al 1999, Sokolski et al 1999, Young et al 1999, double-blind, controlled studies have not indicated efficacy in acute mania (Pande et al 2000) or as a mood stabilizer (Frye et al 2000).

Lamotrigine, like carbamazepine and phenytoin, blocks sodium channels (Xie and Hagan 1998). Preliminary data suggest that carbamazepine and lamotrigine also reduce the calcium influx through the N-methyl-D-aspartate receptor Hough et al 1996, Stefani et al 1996. In addition, lamotrigine is reported to block Ca2+ influx through the N-type channels Stefani et al 1996, Wang et al 1996, Wang et al 1998. Open (Calabrese et al 1996b) and blind studies Calabrese et al 1999, Frye et al 2000 suggested antidepressant efficacy and perhaps positive effects of lamotrigine as a mood stabilizer.

The current study, which is an extension of Frye et al (2000), attempts to delineate some of the possible clinical correlates of response to lamotrigine or gabapentin monotherapy. We examined the proposition that differences in the phenomenology and neurobiology of affective illness would be reflected in differences in the response to these two anticonvulsants with very different putative mechanisms of action—lamotrigine (as an antiglutamatergic agent) and gabapentin (as a GABA enhancing agent).