The rationale for controlled study of carbamazepine (CBZ) grew out of the need for finding treatment for lithium-refractory patients and several empirical and theoretical observations. CBZ improved mood in seizure patients and in open studies in Japan. It also was the most potent anticonvulsant in suppressing kindled seizures of the amygdala, dysregulation of which had been implicated in affective disorders.

Patients studied on our research unit at the NIMH in the 1980s using double blind off-on-off-on designs provided unequivocal evidence of responsiveness to CBZ in acute mania, depression, and prophylaxis. We subsequently found that different individuals were differentially responsive to different anti-convulsants such as CBZ and Valproate (VPA), and this led to a search for clinical and biological predictors of response to these drugs compared with lithium. We found that the dihydropyridine L-type calcium channel blocker (which also has anticonvulsant properties) was also effective in some lithium non-responders. The hypothalamic peptide TRH also has anticonvulsant properties and it too had positive effects on mood when administered parenterally.

Lamotrigine (LTG) and gabapentin (GPN) were next studied on our unit in a novel triple cross-over design with placebo (PBO), and were found not to be antimanic, although LTG exceeded both GPN and PBO for antidepressant effects. The lack of antimanic effects of GPN and other compounds that increased brain GABA levels (tiagabine, topiramate) indicated that the antimanic efficacy of valproate was not likely attributable to its ability to increase GABA. CBZ and VPA, like lithium, increased brain BDNF levels, and this among a multitude of other mechanisms could contribute to their psychotropic effects.

Valproate, but not valpromide, is a histone de-acetylase inhibitor also suggesting possible unique epigenetic mechanisms. Selected members of the anticonvulsant class have opened new treatment options for patients with bipolar disorder and its comorbidities and examination of their mechanisms of action have yielded insights into the pathophysiological alterations in bipolar illness.