Antiepileptic drugs in psychiatry.

A ntiepileptic drugs (AEDs) have been widely used by psychiatrists to treat disorders other than epilepsy for two decades. Here I survey those uses and selectively review the side effects of AEDs in the psychiatric context. AEDs are now so widely used for nonepileptic indications that the appellation ‘‘anti-epileptic drug’’ may verge on mislabelling (to paraphrase David Healy’s comment about serotonin-reuptake inhibitors and ‘‘antidepressants’’). Nonetheless, no better designation is available, and I refer to these drugs as AEDs. Oddly, the newer AEDs may prove be more useful in psychiatric illness than in epilepsy, where their greater efficacy than the older agents has not yet been conclusively demonstrated. An assumption that the mechanisms of action of AEDs are the same in epilepsy and in psychiatric disorders would go beyond the evidence. Activity against kindling has been proposed to explain the psychotropic effect, but this seems to account for neither the spectrum of psychiatric benefits nor the range of beneficial drugs. A division of psychotropic effects into ‘‘sedating’’ (mediated by GABAergic action) and ‘‘activating’’ (mediated by antiglutamatergic action) likewise may fail to capture the diversity of psychotropic ‘‘principles’’ by which the diverse category of AEDs exerts psychotropic effects. Although I review scientific data regarding the use of AEDs in psychiatry, a non-scientific factor, of uncertain power, may partly account for the rise in prescription of AEDs. The interest of pharmaceutical firms in expanding the use of their products and their willingness, at least in some instances, to use improper means have recently been highlighted by the guilty plea of a major company in a case involving marketing an AED for off-label indications. Since the scientific evidence in the realm reviewed is far from complete, the clinician needs to be alert for nonscientific influences on practice. AEDS IN MOOD AND ANXIETY DISORDERS Lithium remains the agent for bipolar mood disorder with the best documentation of efficacy across the phases of the disorder, depressed and manic, acute and maintenance. However, AEDs are now commonly used in the treatment of bipolar mood disorder. Limited data suggest that over the course of the 1990s the use of AEDs approximately doubled, while the use of lithium fell below that of AEDs. At least three findings account for this development. First, certain syndromes of bipolar mood disorder respond poorly to lithium. Patients responding poorly to lithium include those with mixed bipolar states (states that include a mixture of manic and depressive features, often presenting in atypical fashion, for example as characterological irritability) and patients with rapid cycling (defined as having more than four episodes of mood disorder in a year). Second, bipolar mood disorder may be much more common than assumed: though conventional epidemiology has it that unipolar major depression is several times more common than bipolar mood disorder, recent studies suggest that half of patients presenting with major depression may have bipolarity. Third, patients with bipolar disorder often suffer from subsyndromal depressive symptoms during much of their lives, but the use of antidepressants in these patients risks evoking mania or exacerbating cycling. Thus agents with efficacy for bipolar depressive or mixed states or for lithium refractory patients are particularly welcome, and considerable high quality evidence—and much more anecdotal or uncontrolled evidence—supports the use of AEDs for these indications. Reports of psychotropic effects of valpromide (an amide derivative of valproic acid available in Europe but not in the United States) and carbamazepine emerged soon after their introduction. Divalproex (an enteric-coated formulation of valproic acid and sodium valproate, the most widely used preparation of valproic acid in the United States because it has fewer gastrointestinal side effects than valproic acid) and carbamazepine have now been shown to be effective in the treatment of acute mania, with a spectrum of action that includes the ‘‘non-classical’’ manic states of dysphoric mania and rapid cycling. 10 Efficacy for prophylaxis is less securely supported by clinical trial evidence, although many clinicians employ these agents as well as the newer AEDs in this fashion. Evidence for antidepressant efficacy is modest. Oxcarbazepine appears, on limited evidence, to have similar efficacy to carbamazepine but better tolerability. 12 Of the newer AEDs, lamotrigine has occasioned particular interest. Its efficacy for bipolar depression was foreshadowed by reports of efficacy against depressive symptoms in epileptic patients. Evidence of its acute and prophylactic effects against bipolar depression is now available, with efficacy against manic relapse in maintenance treatment also finding support. Whether it is effective as acute treatment for mania is a less pressing clinical matter, because the required slow titration precludes reliance on its use in many such circumstances. Topiramate is less well studied, but open trials indicate good tolerability as well as efficacy for non-classical mania. Levetiracetam is of considerable interest for bipolar disorder, with reports of benefit for mania, depression, and rapid cycling, but adequate data are not available. 17 Limited uncontrolled data suggest utility of zonisamide and tiagabine for bipolar disorder. 19 On present evidence, gabapentin does not appear effective for bipolar disorder. 21 However, gabapentin—an attractive compound because of a favourable side effect profile and a lack of drug interactions—appears on limited evidence to be of considerable use in anxiety states, including social phobia, post-traumatic stress disorder, panic disorder, and opiate withdrawal. The role of other AEDs in the treatment of anxiety is less well studied. Fortunately, electroconvulsive therapy can safely be undertaken in patients treated with AEDs (and indeed in patients with epilepsy). 26 Often it will be necessary to reduce the dose or hold a dose prior to the treatment so as not to elevate the seizure threshold, especially later in a course of ECT when the seizure threshold has risen.