Antiepileptic drugs are important psychotropic agents, meaning that some have been used to treat patients with mood, behavior and thought disorders. The dramatic rise in AED use in psychopharmacology outpaces efficacy (effectiveness) data. Large randomized, controlled trials on the behavioral effects of AEDs are few. Randomized, controlled trials have established the antimanic and mood-stabilizing properties of carbamazepine, valproate, and lamotrigine in bipolar disorder (1). One controlled study found that gabapentin was an effective treatment for social phobia (2). However, AEDs are used to treat a wide spectrum of other behavioral disorders including unipolar depression, aggression, borderline personality disorder, and binge eating. Anecdotal reports, small uncontrolled series, and clinical trials with limited power can be misleading. For example, despite multiple reports that gabapentin improved both bipolar and unipolar depression, two randomized, controlled trials showed that gabapentin is not effective for these disorders (3,4). The use of AEDs to treat psychiatric disorders can be hazardous. The cognitive side effects of topiramate were demonstrated in several randomized, controlled trials (5,6) and supported by systematic reviews of clinical experience in epilepsy centers (7,8). Depression can result from the use of this as well as other AEDs in patients without a past history of affective disorder. Although controlled data regarding topiramate’s efficacy for psychiatric disorders are restricted to bipolar disorder, its use in a wide spectrum of psychiatric disorders is growing steadily. Often, its appetite suppressant/weight loss effects are used to counterbalance the weight gain associated with many other psychotropic agents. Although obesity carries substantial morbidity and mortality, the potential cognitive and behavioral risks of this agent must also be considered.

Mechanisms underlying how AEDs' affect behavior

The mechanisms by which AEDs affect behavior are not well understood. They may affect behavior through actions that suppress seizures, such as increased GABA activity, (activity of the neurotransmitter GABA, the main inhibitory neurotransmitter in the brain)inhibition of fast-conducting sodium channels, or both. Sedative AEDs often possess anxiolytic, antimanic, and hypnotic efficacy but can impair energy level and attention and depress mood (9). Agents that enhance GABA activity include barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. Activating AEDs (e.g., felbamate and lamotrigine) paradoxically reduce excitatory neurotransmission. These drugs may possess antidepressant and attention-enhancing efficacy (10) but can cause anxiety, insomnia, and agitation. Some AEDs have both inhibitory and excitatory properties (e.g., topiramate, levetiracetam, and zonisamide) and tend to be more sedating than activating, but can also cause anxiety, irritability, and depression.

Side effects

For all AEDs, side-effect profiles vary considerably between patients. For example, barbiturates, valproate, vigabatrin, and levetiracetam cause sedation and, in some patients, irritability and anxiety. Children often show very different behavioral reactions than adults. All AEDs can have positive or negative psychotropic properties in different patients. Atypical behavioral responses to AEDs and other medications are more frequent in children and the developmentally disabled. An individual’s behavioral response to a specific AED is influenced by the neuropsychiatric disorder and drug interactions (Table 1), as well as genetic and environmental factors. While treatment concerns individual patients, studies identify group averages. We are limited in our ability to predict the behavioral changes associated with a specific AED in a specific patient.

Table 1. Interactions of psychotropic drugs and AEDs

References

1. DeLeon OA. Antiepileptic drugs for the acute and maintenance treatment of bipolar disorder. Harv Rev Psychiatry 2001;9:209–22.
2. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Psychopharmacol 1999;19:341–8.
3. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000;20:607–14.
4. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord 2000;2:249–55.
5. Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999;52:321–7.
6. Besag FM. Behavioural effects of the new anticonvulsants. Drug Saf 2001;24:513–36.
7. Crawford P. An audit of topiramate use in a general neurology clinic. Seizure 1998;7:207–11.
8. Stephen LJ, Sills GJ, Brodie MJ. Topiramate in refractory epilepsy: a prospective observational study. Epilepsia 2000;41:977–80.
9. Ketter TA, Post RM, Theodore WH. Positive and negative psychotropic effects of antiepileptic drugs in patients with seizure disorders. Neurology. 1999;53(suppl 1):S52–S66.
10. Uvebrant P, Bauziene R. Intractable epilepsy in children. The efficacy of lamotrigine treatment, including non-seizure-related benefits. Neuropediatrics 1994;25:284–9.

Reproduced and adapted with permission from Orrin Devinsky, M.D. and Epilepsia.

Topic Editor: Steven C. Schachter, M.D.
Last Reviewed:12/15/06