This clinical study compares the effectiveness of two anticonvulsants Lamotrigine (Lamictal)
Monotherapy and Gabapentin (Neurontin) in patients with treatment resistant affective
disorders. We initially have found that the response rate to lamotrigine (51%) exceeded
that of gabapentin (28%) or placebo (21%). In this study the placebo phase has been dropped
so that we examine possible clinical and biological factors predictors of response. The
drugs will be given in a randomized order for six weeks each and you will not know when you
are on a given one. There will be a 2-4 week "washout" period between treatments. If you
respond well to one of these treatments, a longer open continuation period will be offered
at the end of this study. This would involve one or both drugs in combination. A variety
of rating scales and brain imaging procedures will also be offered before and during each
drug evaluation. Both lamotrigine and gabapentin are generally well tolerated. A serious
potentially life threatening rash occurs in about 1/500 patients treated with lamotrigine,
however. Common side effects are rash, dizziness, unsteadiness, double vision, blurred
vision, nausea, vomiting, insomnia, sedation, and headache. These side effects are usually
mild, and resolve with continued time on the drug or a decrease in dosage.
The anticonvulsants carbamazepine (CBZ) and valproate (VPA) have efficacy in the treatment
of mood disorders, suggesting that other anticonvulsants with related mechanisms of action
may have similar utility. Additional treatments are sorely needed because many patients
with recurrent affective disorder have symptoms refractory to treatment with conventional
agents, including lithium, carbamazepine, and valproate. This refractory group is the major
focus of our investigative efforts on 3-west in the Section of Psychobiology, NIMH.
Moreover, establishing differential clinical and biological predictors of response has
become increasingly important both to rapid allocation of appropriate treatment and as they
may supply insight into the pathophysiology of the mood disorders and their subtypes.
Lamotrigine, a phenyltriazine use-dependent sodium channel blocker that inhibits release of
excitatory amino acids, is a new anticonvulsant with fewer side effects than older agents
and was recently approved by the FDA as adjunctive therapy in the treatment of partial
seizures. Heretofore, only preliminary open clinical evidence suggested that lamotrigine
may have mood stabilizing properties.
Gabapentin is a neutral amino acid and gamma-aminobutyric acid (GABA) analog which increases
brain GABA levels and has fewer side effects than older agents and does not require
hematological or hepatic monitoring. Preliminary evidence only from open "add-on" series
had suggested that gabapentin therapy might have antidepressant and antianxiety effects, if
not mood stabilizing properties.
We wish to evaluate the efficacy of lamotrigine and gabapentin in the refractory mood
disorders. We also wish to examine the neurobiology and phenomenology of lamotrigine and
gabapentin responders and nonresponders to ascertain potential predictors and concomitants
of response to these medications. This study may lead to improvement in the treatment and
understanding of mood disorders by providing controlled data on efficacy of these potential
new treatments, potential predictors of response, and further insights into the
pathophysiology of mood disorders.
Patients between the ages of 18 and 75 who satisfy DSM-III-R criteria for mood disorders,
are refractory to at least two conventional treatments, and are inpatients or outpatients
at the NIMH are invited to participate provided that the following criteria are fulfilled:
Subjects having serious medical illness (or meeting current psychoactive substance
dependence will be excluded from entry.)