In two recent industry-sponsored controlled trials of long-term prophylaxis (following a recent manic or depressive episode), lamotrigine was significantly more effective than a placebo (Bowden et al and Calabrese et al, unpublished data). Lamotrigine was more effective than lithium in preventing depressive episodes, whereas lithium was more effective than lamotrigine for manic episodes, although lamotrigine was significantly better than the placebo.
These data suggest that lamotrigine may differ from valproate, carbamazepine, and lithium in being a more effective antidepressant than antimanic agent.
Topiramate Adjunctive use of topiramate in rapid-cycling and treatment-resistant patients has been examined in open studies, but controlled studies have not yet been published. In our open-label case series observations, 19 of 30 (63%) patients taking topiramate for mania or cycling were “much” or “very much” improved after 10 weeks, whereas only 3 of 11 (27%) patients taking topiramate for acute depression were so improved.19
Table 4
STUDIES IN PROGRESS BY SFBN INVESTIGATORS
| Study (authors) | Randomized | Design | Number enrolled* | Notes |
|---|---|---|---|---|
| Topiramate vs. sibutramine | Yes | Open | 42 | Relative weight loss and mood stabilization |
| Omega-3 fatty acids (6 grams EPA vs. placebo) (for depression cycling) (Keck et al) | Yes Yes | Double-blind Double-blind | 62 60 | Data from both studies being analyzed |
| Acamprosate (for alcohol craving) (Grunze et al) | No | Open | 23 | Goal: 60 patients |
| Levetiracetam (Post et al) | No | Open | 13 | Goal: 30 patients |
| Zonisamide (McElroy et al) | No | Open | 45 | Goal: 60 patients European sites only |
| Tranylcypromine vs. lamotrigine (for refractory depression) (Nolen et al) | Yes | Open | 17 | Single-site study |
| Quetiapine (McElroy et al) | No | Open | 48 | Apparent superior antidepressant effects compared with risperidone or clozapine |
| Risperidone (Grunze et al) | No | Open | 37 | No significant effect on IDS‡ depression ratings |
| Clozapine (Suppes et al) | No | Open | 19 | No significant effect on IDS depression ratings |
| Modafinil vs. placebo (Frye et al) | Yes | Double-blind | Started 4/02 | |
| * Enrollment as of April 2002 n = 696 total patients in tables 3 and 4 | ||||
| ‡ IDS = Inventory of Depressive Symptomatology | ||||
An industry-sponsored double-blind, randomized trial of topiramate in acute mania looked promising in the first 67 patients, but not as encouraging in subsequent subjects. A positive drug effect re-emerged if one eliminated patients whose manic episodes were precipitated by antidepressants.
The acute antidepressant effects of topiramate did not appear promising in our study. On the other hand, a single-blind, randomized study of topiramate versus bupropion as adjunctive therapy for breakthrough bipolar depression suggested excellent acute response (approximately 56%) to both agents.20 These data leave the potential antidepressant effects of topiramate undetermined.
In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).19 Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).
We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.21 This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.
We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.
Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.22 As monotherapy, however, gabapentin was not more effective than a placebo17 and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,23 although other double-blind, controlled studies have indicated positive effects in anxiety disorders24 and social phobias.25 Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.
Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.
Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.26 Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.27