Antidepressant and Antimanic Medications: Newer Anticonvulsants
Because many patients with bipolar disorder have a less than satisfactory response to available medication treatments, clinicians will often begin to experiment with new medications before they have been carefully studied in controlled trials. This is the case for several new anticonvulsants, most notably lamotrigine and gabapentin. Despite extremely limited short- or long-term efficacy data on these agents, their use for the treatment of bipolar disorder and refractory depression is widespread.
Lamotrigine is the best studied of the newer anticonvulsants. Along with many open-label studies, there is one large multisite placebo-controlled trial of lamotrigine monotherapy for treatment of depression in outpatients with bipolar disorder. In this study, 200 mg/day of lamotrigine demonstrated significant antidepressant effects in over 50% of these patients without inducing mania or rash. Lamotrigine inhibits voltage-gated sodium channels and reduces glutamate. It is absorbed within 1-3 hours and has a half-life of 25 hours. Rash can occur in up to 8% of adults, and serious rash requiring hospitalization can be seen in up to 0.5% of patients. Because of the possibility of Stevens-Johnson syndrome, toxic epidermal necrolysis, or angioedema, all rashes should be regarded as potentially serious and monitored closely. Starting with low dosages (25 mg/day) and titrating dosages slowly may help reduce the occurrence of rash. Lamotrigine may be more effective in treating depression in bipolar disorder than in treating mania. Studies are under way to investigate the efficacy of lamotrigine for the treatment of depression in unipolar mood disorders.
Gabapentin has been studied as both a monotherapy and an adjunctive treatment for mania and bipolar depression, and the results have generally been favorable, although no large-scale or double-blind trials have been published. The mechanisms of its anticonvulsant or antimanic action are not known. It is well absorbed and demonstrates a dose-dependent absorption, most likely due to its transport across the intestinal wall through a large neutral amino acid transporter. This transporter can be saturated by high concentrations of drug, possibly becoming an advantage during overdose. The relatively short half-life (6-7 hours) usually means that multiple daily doses should be used, but the availability of gabapentin in the CNS is sustained beyond what the serum half-life would suggest. Thus, gabapentin is usually dosed twice per day. Gabapentin is excreted unchanged by the kidney. Caution should be observed in those with renal disease. Gabapentin is generally well tolerated. The most common side effects are somnolence, ataxia, dizziness, and fatigue.
Topiramate is the least studied of this group of drugs. It inhibits rapid firing at voltage-dependent sodium channels, antagonizes kainate binding to the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and potentiates the effects of GABA at the GABA-A receptor. In a small number of cases, the addition of topiramate to ongoing treatment with other drugs has been reported to be effective in reducing acute mania or refractory depression. Topiramate has a half-life of 20 hours and is usually dosed twice daily. Eighty percent of the drug is excreted unchanged in the urine. In the presence of metabolism-enhancing drugs, topiramate is more extensively metabolized by the liver, causing the plasma levels and half-life to decrease by up to 50%. Topiramate can interfere with the efficacy of oral contraceptives; therefore, women of childbearing potential should be counseled and alternative methods of birth control should be considered. The most common side effects of topiramate include somnolence, dizziness, ataxia, speech and cognitive disorders, fatigue, and weight loss. Up to 20% of patients experience weight loss, a side effect that has led to the adjunctive use of topiramate in psychiatric patients solely for this effect.
Antidepressant and Antimanic Medications
Combined Medication and Psychotherapy
Treatment-Resistant Mood Disorders
Treatment of Mood Disorders in the Medically Ill Patient
Strategies and Tactics in the Treatment of Depression
Revision date: July 8, 2011
Last revised: by Andrew G. Epstein, M.D.