Riluzole Therapy Effective in Treatment-Resistant Depression

January 16, 2004

Jan. 16, 2004 — Riluzole is associated with antidepressant effects in patients with treatment-resistant depression, according to results of an open-label study reported in the January issue of the American Journal of Psychiatry. Riluzole is a glutamate-modulating agent currently approved by the U.S. Food and Drug Administration for the treatment of amyotrophic lateral sclerosis.

"Several lines of research implicate the glutamatergic system in the pathophysiology and treatment of depression, including the delayed, indirect effects of many antidepressants on the glutamatergic system as well as the antidepressant effects of N-methyl-D-aspartate receptor antagonists in animal models and in humans," write Carlos A. Zarate, Jr., MD, and colleagues, from the Mood and Anxiety Disorders Program at the National Institutes of Health in Bethesda, Maryland.

"There is increasing evidence that mood disorders are associated with regional reductions in CNS volume, possibly resulting from impairments of structural plasticity and cellular resistance," the authors point out. "The glutamatergic system has been implicated in regulating neuronal plasticity and cellular resistance in a variety of neuropsychiatric disorders."

The investigators enrolled 19 patients diagnosed with recurrent major depressive disorder who had a baseline Montgomery-Åsberg Depression Rating Scale score of 20 or higher at screening and start of treatment. All patients had been previously unresponsive to an adequate antidepressant trial. After a one-week drug-free period, patients received open-label riluzole monotherapy (100-200 mg/day; mean, 168.8 mg/day ± 27.2 mg) for six weeks.

Thirteen patients (68%) completed the trial. Reasons for discontinuation included adverse events (n = 3), nonresponse (n = 2), and withdrawn consent (n = 1). At weeks 3 through 6, data analyzed on an intent-to-treat basis showed significant improvement in Montgomery-Åsberg Depression Rating Scale scores compared with baseline for all patients (F = 5.44; df = 2, 39; P = .007), and weeks 2 through 6 for trial completers (F = 6.70; df=2, 25; P = .004).

Clinical Global Impression (CGI) severity scale and Hamilton anxiety scale scores also improved significantly during weeks 3 though 6 for all patients (R = 6.75; df = 1.9, 34; P = .04) and for trial completers on the CGI severity scale and Hamilton Anxiety scale, respectively (F = 7.62; df = 2.0, 24; P = .003; and F = 5.77; df = 1.2, 26; P = .0007). The Hamilton anxiety score decreased from a baseline mean of 19.3 ± 7.7 to 13.8 ± 9.4.

Response was defined as a 50% decrease in score on the Montgomery-Åsberg Depression Rating Scale at week 6. Overall, 32% of patients responded, and 46% of trial completers responded. Remission (score < 10) rates were 21% and 31%, respectively.

Common adverse effects included headache (58%), decreased salivation (47%), nausea and vomiting (43%), constipation (32%), and tension or inner unrest (26%).

"The response and remission rates in this study are comparable to those of antidepressants in studies of treatment-resistant depression," the authors write, adding that larger controlled studies are needed to confirm these preliminary findings. "Direct modulation of the glutamatergic system may have considerable use for the treatment of mood disorders."

Am J Psychiatry. 2004;160:171-174

Reviewed by Gary D. Vogin, MD