Antiepileptics for psychiatric illness: Find the right match

Discuss this article at http://currentpsychiatry.blogspot.com/2010/12/antiepileptics-for-psychiatric-illness.html#comments

Although antiepileptic drugs (AEDs) are used to treat a spectrum of psychiatric disorders, in some instances they are prescribed without clear evidence of clinical benefit or safety. When considering prescribing an AED, ask yourself:

• Does the evidence show the drug is efficacious for my patient’s disorder or symptoms?
• Which adverse effects are associated with this medication?
• What are the advantages of monitoring the patient’s serum drug concentration?

This review provides an evidence-based framework regarding the safe and effective use of AEDs in psychiatric patients.

For which disorders are AEDs effective?

Bipolar disorder. Multiple studies have found that AEDs are efficacious for treating bipolar disorder. Carbamazepine, valproate (divalproex), and lamotrigine have the most evidence supporting their use (Table 1). For an extensive bibliography of studies supporting AEDs for bipolar disorder and other psychiatric illnesses, see this article at CurrentPsychiatry.com. Carbamazepine and valproate are FDA-approved for treating acute manic or mixed episodes associated with bipolar I disorder in adults, and may be beneficial for maintenance treatment. Lamotrigine is FDA- approved for maintenance treatment of bipolar I disorder in adults; however, it lacks efficacy for mania and acute bipolar depression.¹ The use of newer AEDs—including gabapentin, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide—for bipolar disorder is not recommended because evidence is limited or inconclusive.

Major depressive disorder (MDD). Most studies of AEDs in MDD feature open-label designs with small samples. AEDs might have a role as an augmentation strategy, perhaps for patients with agitation or irritability or who partially respond to antidepressants.²

Schizophrenia. Although limited data support the practice, AEDs commonly are combined with antipsychotics to treat patients with schizophrenia.^3,4 Clinicians who prescribe carbamazepine should recognize the potential for drug-drug interactions with antipsychotics (ie, increased metabolism of antipsychotics caused by cytochrome P450 [CYP450] 3A4 induction).

Anxiety disorders. AEDs have a limited role in treating anxiety disorders. These agents may be used as augmentation for patients who exhibit partial response or treatment resistance to recommended agents for anxiety disorders, such as selective serotonin reuptake inhibitors (SSRIs) or benzodiazepines. For patients who cannot tolerate SSRIs or benzodiazepines, AEDs may be alternatives.⁵

Other disorders. AEDs could be used to treat other psychiatric conditions and disorders, including alcohol withdrawal and relapse prevention, benzodiazepine withdrawal, drug dependence and abstinence, obesity, and eating disorders.^4,6,7 A list of suggested AEDs for some of these disorders appears in Table 2. However, these recommendations are based on findings from small randomized controlled trials, open-label trials, or case reports.

Table 1

Evidence supporting antiepileptics for mood disorders and schizophrenia

Medication	Bipolar disorder			Major depressive disorder	Schizophrenia
	Mania	Depression	Maintenance
Carbamazepine					(aggression, impulsivity)
Lamotrigine					(adjunct to clozapine)
Valproate					(aggression, impulsivity)
Gabapentin
Levetiracetam
Oxcarbazepine
Tiagabine
Topiramate
Zonisamide
	: strong evidence supporting efficacy;
	: moderate evidence supporting efficacy;
	: weak evidence supporting efficacy
Source: For an extensive bibliography of studies that support these recommendations, see this article at CurrentPsychiatry.com

Table 2

Off-label use of antiepileptics for various psychiatric disorders

What about adverse effects?

A thorough understanding of each AED’s adverse effect profile is critical to determine which agent is most suitable for your patient. Factors that may affect the risk of adverse effects include:

• rate of dose escalation
• length of early tolerance development
• rate of increase in and magnitude of peak serum concentrations
• dosing frequency
• pharmacodynamic/pharmacokinetic interactions
• pharmacogenomics.

Cardiovascular effects. Although many AED clinical trials reported “edema” as an adverse effect, peripheral edema specifically has been reported with gabapentin, lamotrigine, tiagabine, and valproate.⁸ Peripheral edema with these agents generally has not been linked to cardiovascular complications in healthy adults. Carbamazepine and pregabalin may cause conduction abnormalities and should be used with caution in patients with underlying electrocardiogram abnormalities.⁸

Chronic carbamazepine use results in elevated plasma homocysteine and serum lipoprotein concentrations, which are biomarkers of cardiovascular disease.⁹ If clinically appropriate, switching from carbamazepine to a non-inducing AED (ie, lamotrigine) may ameliorate such effects. Chronic valproate use has been associated with increased plasma homocysteine levels; increases in serum lipoproteins may parallel valproate-induced weight gain.⁹

CNS effects. Common acute neurologic effects of AEDs include somnolence, dizziness, and ataxia. The incidence of these effects vary by agent; gabapentin and zonisamide appear to be the most sedating.⁸ However, in general these effects occur at the start of treatment and abate within a few days with continued treatment or dosage reduction. Starting at a low dose and slowly titrating may help prevent neurologic adverse effects.⁸ Peripheral neurologic effects—specifically paresthesias—are primarily associated with topiramate and zonisamide and may be attributed to carbonic anhydrase inhibition.⁸