A new way of approaching bipolar depression and major depressive disorder, riluzole (Rilutek) takes aim at a novel target in mood regulation: glutamate. Commonly used medications like Prozac work based on the assumption that defects in the re-uptake of serotonin are at the root of depressive episodes. Recent research suggests this may not be true for all those experiencing depression and that another cause could be an excess of glutamate, the most abundant excitatory neurotransmitter in the body. Riluzole, a prescription drug approved for the treatment of Lou Gehrig’s disease (ALS), turns down the release of glutamate and increases its uptake.

One 8-week study showed possible response based on significant improvement in Montgomery-Asberg Depression Rating Scale scores in patients treated for acute bipolar depression when riluzole was added to other antidepressants.1 However, the small, non-randomized, non-blinded nature of the trial limits the conclusions that can be drawn. Of note, there were no instances of mania or hypomania in this trial, indicating that riluzole may not have the mood destabilizing effects of many other antidepressants. Trials with larger sample sizes would be necessary to confirm this result.

A recent study of 14 patients with bipolar disorder given 100-200 mg of riluzole per day showed a relative decrease in glutamate in the brain, as demonstrated by imaging studies.2 This suggests that imaging may play a role in determining response to therapy if further trials support the existing evidence.

Riluzole is being looked at with equal interest in the treatment of major depressive disorder. Another trial with a similar design that looked at response in treatment-resistant patients with major depression taking other antidepressants found a response in some.3 A third trial with high doses of 150-200 mg/day (ALS dose: 50 mg/day) found that riluzole could be effective—even when given without other antidepressants—over a 6-week period.4 However, as in the other two trials, this study was open-label and included fewer than 20 patients. Two randomized trials to be completed over the course of the next 2 years should provide additional evidence regarding the relative efficacy of riluzole in treating mood disorders.

From a safety perspective, the most pressing concern is that the medication may cause liver damage, especially in those already at risk or those who drink excessive amounts of alcohol. Coffee and other caffeinated drinks may increase the effect of riluzole, and smoking may speed its elimination from the body, making higher doses necessary. Riluzole also has to be taken 1 hour before or 2 hours after food, which may be inconvenient for many patients.

Recommendation: Based on preliminary study data, riluzole is a promising therapy that may provide an alternate treatment for bipolar depression and/or major depressive disorder, pending positive results in larger randomized, double-blind trails.

1. Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005 Feb 15;57(4):430-432.

2. Brennan BP, Hudson JI, Jensen JE, et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010 Feb;35(3):834-846.

3. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007 Mar 15;61(6):822-825.

4. Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004 Jan;161(1):171-174.

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