Antiepileptics for psychiatric illness: Find the right match

AEDs’ primary cognitive effects include impaired attention/vigilance, psychomotor speed, and secondary involvement of other cognitive functions (eg, memory). Whereas carbamazepine and valproate have similar cognitive effects (ie, negative effects on attention, learning, memory, and psychomotor speed), newer AEDs except topiramate may produce fewer cognitive adverse effects (Table 3).¹⁰ Topiramate is associated with the highest rate of cognitive dysfunction, with frequent complaints of decreased concentration and attention, word-finding problems, and/or impaired memory.^8,10

The FDA recently announced a warning of a risk of aseptic meningitis with lamotrigine.¹¹ In 40 reported cases, symptoms—headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia, and myalgias—occurred between 1 and 42 days of treatment and typically resolved after lamotrigine was withdrawn. In 15 patients in whom lamotrigine was re-initiated, meningitis symptoms returned quickly and with greater severity.¹¹

Dermatologic effects. Skin rashes have been reported with all AEDs; the highest risk is associated with carbamazepine and lamotrigine.¹² Predictors of cutaneous reactions to lamotrigine include:

• high initial dose and rapid escalation
• concomitant valproate use without lamotrigine dosage adjustment
• young age.¹²

A history of AED-induced rash also increases risk. For example, patients with a history of rash with carbamazepine are at risk for rash with oxcarbazepine because of cross-reactivity.

Any AED-induced skin rash may progress to a fatal reaction, such as toxic epidermal necrolysis or Stevens-Johnson syndrome. Carbamazepine and lamotrigine are most strongly associated with these severe reactions.¹² Patients who exhibit painful rash, fever, enlarged lymph nodes, malaise, and mucosal involvement may be at risk for a more severe disease course.¹² If a patient taking an AED develops a rash, immediately stop the drug and perform a thorough risk-benefit analysis before considering re-initiation.

Hematologic effects. Thrombocytopenia has been reported with carbamazepine, lamotrigine, pregabalin, and valproate. The highest risk is for valproate at doses >50 mg/kg/d or serum concentrations >110 μg/mL in women or >135 μg/mL in men.^13,14 Decreased platelet count is common with valproate, but coagulation dysfunction may not be present until counts fall below 50,000/mL. Carbamazepine is associated with leukopenia, which usually occurs in early treatment and resolves without dosage adjustments; however, this agent carries a black-box warning for risks of agranulocytosis and aplastic anemia. Similar postmarketing findings have been reported with lamotrigine.⁸ Baseline hematologic testing and monitoring is recommended.

Hepatic effects. Transient abnormalities in liver function test (LFT) results often have been reported with carbamazepine, valproate, and zonisamide. Valproate has the highest risk of hepatotoxicity, which generally begins within the first 6 months of therapy and does not correlate with serum concentrations.⁸ Valproate-induced hepatotoxicity may have acute onset, and hepatic dysfunction may progress despite discontinuing the drug. LFTs are recommended at baseline and regular intervals.⁸

Metabolic effects. AEDs may increase appetite and body weight. Weight gain is common with valproate and pregabalin, but may occur with carbamazepine and gabapentin as well.⁸ Weight gain does not appear to be dose-related and may be minimized by diet and exercise. Lamotrigine and levetiracetam do not appear to affect weight, whereas weight loss and anorexia have been reported with topiramate and zonisamide.⁸

Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion have been reported with both carbamaze-pine and oxcarbazepine; the incidence is higher for oxcarbazepine. For both agents, hyponatremia risk is highest in elderly patients.¹² Valproate—alone and concomitant with topiramate—may elevate ammonia levels, but monitoring generally is necessary only in symptomatic patients. Topira-mate and zonisamide increase the risks of hyperchloremic, nonanion gap metabolic acidosis and hypohidrosis; serum bicarbonate should be monitored at baseline and as clinically indicated.^12,15

Psychiatric effects. Levetiracetam is associated with aggressive behavior, irritability, and increased anxiety and depression, which usually occur soon after drug initiation.⁸ Similarly, topiramate use is associated with affective and psychotic symptoms. Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and valproate have been associated with a decreased risk of psychiatric adverse effects compared with the overall incidence among AEDs.⁸

An FDA analysis suggested patients receiving AEDs have an elevated risk of suicidal ideation or behaviors, regardless of the indication.¹⁶ However, the data for increased suicidality are better supported for epilepsy patients than for those with a psychiatric diagnosis. The increased risk was noted as early as 1 week after initiating an AED and extended up to 6 months. The findings generally were consistent across demographic subgroups and AEDs.¹⁶ However, a recent study suggests the risk of suicidal acts or violent death is lowest with topiramate compared with gabapentin, lamotrigine, oxcarbazepine, and tiagabine.¹⁷ In patients with bipolar disorder, AEDs might not be associated with increased risk of suicidality and may be protective.¹⁸ All patients treated with AEDs should be closely monitored for emergence of or worsening depression, suicidality, and other behavior changes.¹⁶