AEDs and Mood: Not all the same?

April 17, 2009

As I have noted previously, the FDA pronouncements on suicide and AEDs are controversial.

As I have noted previously, the FDA pronouncements on suicide and AEDs (antiepileptic drugs) are controversial. Many epileptologists do not think that AEDs are a homogeneous group with regard to mood adverse effects. The "tarring" of this drug class with a warning about suicide may dissuade prescribers or patients from appropriate use. That is a problem.

A recent article adds to the data available on the effects different AEDs may have on mood. An illustrious group (Labiner et al.) looked at the differences between lamotrigine (Lamictal) and levetiracetam (Keppra). This study was a rigorous, randomized controlled blinded trial of persons (n=268) with complex partial epilepsy. Persons taking antidepressants or antipsychotic agents were excluded. After titration, patients were maintained on stable doses for 12 weeks. At each clinic visit, a variety of mood-related scales were administered, including measures of depression and irritability. Adverse effects were also objectively rated. Roughly 2/3 of the patients completed the study. The most common reason for study withdrawal was adverse effects: 11% due to lamotrigine and 18% levetiracetam.

At a majority of the visits, improvement with lamotrigine was statistically significantly superior to levetiracetam for the primary (anger/hostility subscale) outcome measure. Lamotrigine was also superior to levetiracetam on a number of other mood-related scales. On a few of the measures, however, no difference was noted. Seizure efficacy measures also did not show a difference (but the study was not powered to find such differences).

Adverse effects were also largely similar. Of note, "nonserious rash" was noted in 6% of the lamotrigine patients and 7% of the levetiracetam patients and no serious rashes were reported. Also quite interesting were the adverse events that most frequently led to discontinuation: Lamotrigine (2 patients each): Increased seizure activity, irritability, nervousness, and insomnia; Levetiracetam (3 patients each): Depression, suicidal ideation, and rash. So, depression and suicidal ideation was seen with levetiracetam therapy but not lamotrigine therapy in this study.

The authors comment that they encountered less of a problem with behavioral changes with levetiracetam than expected. They attribute this to very slow titration, which is rather different than is often the case in clinical practice. Also, excluding patients taking psychopharmacologic agents may have acted as a proxy for largely excluding those patients with active psychiatric disorders.

I must note that the drugs were tested as adjunctive therapy, so the effects of these drugs as monotherapy are not clear from this trial. Also, GlaxoSmithKline Research and Development funded the study, and the last author is an employee of GSK, the company which held the patent on lamotrigine until recently. Further, it is not clear whether the differences noted in the study were of clinical significance, although the authors note that lamotrigine was superior across several measures and the time frame of the study.

So, in this rigorously controlled and well analyzed study, lamotrigine was statistically superior to levetiracetam on the primary measure of anger and hostility, as well as a variety of other mood measures. This study strongly supports the idea that not all AEDs have the same effect on mood.