The lamotrigine-treated group showed significantly lower relapse rates than placebo-treated patients in time-to-study dropout, time to intervention for a mood episode, and time to intervention for depressive relapse. Differences between the lamotrigine and placebo groups in time to intervention for manic relapse were insignificant. Lithium was superior to a placebo in time to relapse for any mood episode and time to intervention for a manic episode. Lithium also outperformed lamotrigine in that manic symptoms did not worsen as quickly from baseline to endpoint.
The results here are consistent with those of the rapid cycling study: Lamotrigine helps prevent recurrence of depressive symptoms and episodes. Evidence of prophylaxis against manic recurrences was not compelling, however.
The findings of these two maintenance trials are consistent with the results of a placebo-controlled, randomized, 6-week acute treatment trial of lamotrigine (50 mg/d and 200 mg/d) in patients with bipolar depression.17 Seventeen lamotrigine-treated patients in both dosage groups saw more-significantly reduced depressive symptoms than did placebo-treated patients on the MADRS (but not the HAMD) total score and on the CGI. The 200 mg/d group tended to have greater improvement than the 50 mg/d group. There was little difference among the three treatment groups in the incidence of switching into hypomania or mania.
These studies indicate that lamotrigine has acute and prophylactic efficacy against bipolar depression. In contrast, evidence of the agent’s acute or prophylactic efficacy in mania is lacking.
Other new antiepileptics: More testing needed
Use of the six other newer antiepileptics in patients with bipolar disorder is still being explored. (See “Comparing the known efficacy of antiepileptic agents in bipolar disorder,”) Let’s look at what we know about these agents to this point.
Gabapentin A number of case reports and case series published in recent years suggest that gabapentin may have mood-stabilizing properties. In two randomized, controlled trials, however, gabapentin did not display significantly greater efficacy than a placebo in treating acute mania.13,14 Gabapentin has not been studied in controlled trials as a maintenance treatment or for bipolar depression.
In contrast to these negative studies, gabapentin was superior to placebo in studies of patients with panic disorder, social anxiety disorder, and neuropathic pain. Overall, these studies suggest that gabapentin is not a bona fide mood stabilizer for most patients.
Topiramate More than 10 case reports and case series suggest that topiramate may have mood-stabilizing properties. A number of open trials also have found significant dose-related weight loss in patients with weight gain associated with other psychotropic agents.18 These observations have sparked interest in topiramate’s potential role as an obesity treatment.
Only one randomized, controlled trial of topiramate for bipolar disorder has appeared to date.19 An interim analysis of a placebo-controlled, randomized trial of two doses of topiramate (approximately 250 mg/d and 500 mg/d) in 97 hospitalized patients with acute bipolar I mania revealed strong trends toward reduced manic symptoms for both topiramate groups over placebo. These differences were not significant by the time the study was concluded, however.
CHARACTERISTICS OF THE NEWER ANTIEPILEPTICS
Lamotrigine is a novel drug that blocks voltage-sensitive sodium channels, thereby indirectly inhibiting the release of excitatory neurotransmitters, particularly glutamate and aspartate.
Gabapentin was developed to mimic the synaptic effects of gamma-aminobutyric acid (GABA); it does not appear to appreciably interact with GABA receptors, however, and its mechanism of action in epilepsy remains unknown. It has several attractive pharmacokinetic properties, including lack of protein binding, renal clearance rather than hepatic metabolism, and few known drug-drug interactions.
Topiramate is a sulfamate-substituted monosaccharide with a number of possible mechanisms of action, including blockade of voltage-gated sodium channels, antagonism of the kainate/AMPA glutamate receptor subtype, enhancement of GABA activity at the GABA A receptor via interaction with a nonbenzodiazepine receptor site, and carbonic anhydrase inhibition.
Oxcarbazepine is the 10-keto analogue of carbamazepine, a chemical difference that translates into a number of safety advantages over carbamazepine. Oxcarbazepine is converted to an active 10-hydroxy metabolite rather than to the 10,11-epoxide metabolite of carbamazepine. The 10,11-epoxide metabolite of carbamazepine is associated with neurological side effects. Oxcarbazepine is a weak inducer of the CYP450 system, appears to have fewer drug-drug interactions, and offers better overall tolerability.
Zonisamide, a sulfonamide derivative, blocks voltage-sensitive sodium channels and T-type calcium currents, modulates GABAergic and dopaminergic neurotransmission, and is a free-radical scavenger.
Tiagabine is a selective GABA reuptake inhibitor.
Levetiracetam is the S-enantiomer of the ethyl analogue of the nootropic agent piracetam. Its mechanism of action in treating epilepsy is unknown. It does not appear to interact significantly with voltage-sensitive sodium channels or T-type calcium channels, nor does it significantly alter levels of GABA, glutamate, or glutamine in the central nervous system.