ALS Drug Appears to Ease Resistant Depression

By Goldman, Erik L. | Clinical Psychiatry News, February 2007 | Go to article overview

ALS Drug Appears to Ease Resistant Depression


Goldman, Erik L., Clinical Psychiatry News


NEW YORK -- Riluzole, a drug for amyotrophic lateral sclerosis that targets glutamate cycling in the brain, can markedly improve depression in some patients who remain highly symptomatic despite treatment with other antidepressants, Dr. Steven F. Kendell reported at a symposium sponsored by NARSAD, the Mental Health Research Association.

Though the findings are still preliminary, they are in accord with a growing body of data indicating that the glutaminergic and GABAergic neuron systems may be as important in the etiology of depression as are the more commonly targeted serotonergic and dopaminergic systems, he said.

"Of the currently available antidepressants, almost all of them target the monoamine neurotransmitters: epinephrine, serotonin, and dopamine. But despite treatment with these medications, almost half of all patients are stuck with residual symptoms, and some get very little benefit at all. There's a tremendous need to develop novel medications with novel mechanisms of action," said Dr. Kendell of the department of psychiatry at Yale University in New Haven, Conn.

The glutamate system is a very promising target. Dr. Gerard Sanacora, who heads Yale University's depression research programs, has identified clear abnormalities in both glutamate and cortical [gamma]-aminobutyric acid (GABA) in depressed versus non-depressed individuals.

Roughly half of all severely depressed patients will show markedly lower levels of GABA but markedly increased levels of glutamate (Arch. Gen. Psychiatry 2004;61:705-13).

Glutamate is normally taken up either by glutaminergic neurons and turned into glutamine, or by GABAergic neurons and turned into GABA.

This process is regulated in large measure by the glial cells.

Other research teams have shown that many patients with severe depression have reduced numbers of glial cells in many parts of their brains, including the anterior cingulate cortex and the prefrontal cortex (Arch. Gen. Psychiatry 2001;58:545-53).

The result is that in some depressed patients, there is a lot of glutamate, which can be toxic at high concentrations, hanging around in the synaptic spaces. This inhibits normal presynaptic glutamate release, reduces glutamate cycling, and inhibits GABA synthesis.

"The excess glutamate feeds back presynaptically and inhibits normal release of glutamate, leading to memory problems and impairment in the ability to think clearly," Dr. Kendell said.

Riluzole is a fairly unknown medication approved by the Food and Drug Administration for treatment of amyotrophic lateral sclerosis (Lou Gehrig's disease). …

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