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 γ-aminobutyric acid (GABA) in depressed versus nondepressed 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). It is one of the few available drugs that affect glutamate cycling.
It actually increases uptake of glutamate by the glial cells, thus reducing the buildup of synaptic glutamate and normalizing GABA synthesis.
Dr. Kendell and his colleagues tested riluzole as an add-on to other antidepressant medications in a cohort of 10 severely depressed individuals.
These patients were already on an average of three antidepressants and still had Hamilton depression (HAM-D) scores of more than 25 at the start of the study, he said.
Addition of riluzole produced a significant decrease in HAM-D scores in the cohort as a whole, knocking the mean score down from a baseline of 27 to 21 at the end of 12 weeks.
Four of the 10 patients showed a particularly strong response to riluzole, with HAM-D scores dropping from a mean of 26 at baseline to 7 by the close of the 3-month study. In these cases, the response was very rapid; the HAM-D scores took a fast nosedive within the first 2 weeks of treatment.
“We know that about 50% of individuals with depression have abnormal GABA and glutamine levels compared with controls. Are the individuals who had rapid responses to riluzole the same as those who have low GABA and high glutamate? We really need to study this,” Dr. Kendell said.
The next step in this line of research is to use neuroimaging techniques to compare GABA and glutamate levels before and after treatment with riluzole. Then, of course, comes the placebo-controlled clinical trial.
Dr. Kendell said that the Yale team became interested in glutamate cycling in the context of depression in response to reports that ketamine could have profound and long-lasting positive effects in some patients with severe depression.
Ketamine, which is known as “Special K” on the streets, affects GABAergic and glutaminergic neurons.
Some do not think this drug is a good candidate for routine treatment of depression, because it can also induce psychosis, he said.
This line of research also raises the question of whether over-the-counter GABA supplements can improve depression. Dr. Sanacora, who was present at the NARSAD symposium, said that so far there is no evidence to suggest that GABA, when taken orally, “can get into the brain compartments that we're interested in.”