From The Quarterly, Spring 2012

In the most recent series of experiments with the potential to revolutionize the treatment of mood disorders, a team led by NARSAD Independent Investigator Grantee Carlos A. Zarate, Jr., M.D., successfully replicated a previous trial in which patients with intractable bipolar depression treated with the drug ketamine experienced a rapid and robust antidepressant response, including the lifting of suicidal thoughts.

While there are a number of treatments currently prescribed for bi-polar depression, none improves depressive symptoms—including suicidal ideation—within a matter of hours or days. Standard antidepressants generally take six to eight weeks to take effect, and often fail to work at all. “And the delay in treating suicidal behavior,” Dr. Zarate explains, “is an issue of particular concern in this already vulnerable population.”

Dr. Zarate is Chief of Experimental Therapeutics and Pathophysiology Branch in the Intramural Program of the National Institute of Mental Health (NIMH), where he and his colleagues have been working to identify targets for the development of better, faster-acting drugs. Ketamine, widely used as an analgesic—and illicitly as a hallucinogen—targets the glutamatergic system, the neural system in the brain involving the neurotransmitter glutamate. Most current antidepressants target other neurotransmitters. The most widely prescribed, the selective serotonin reuptake inhibitor (SSRI) antidepressants, target the serotonin system.

Numerous studies have implicated the glutamatergic system in the pathophysiology of mood disorders.  In earlier studies, Brain & Behavior Research Foundation Scientific Council Member and NARSAD Independent and Distinguished Investigator Grantee John H. Krystal, M.D., of Yale University, developed the use of ketamine as a probe for glutamate receptor function. (Glutamate works through a molecule called the NMDA receptor.)

He tested ketamine on a small group of patients with severe major depressive disorder, or unipolar depression, with immediate positive results. Dr. Zarate led a successful follow-up study on patients with unipolar depression who had consistently failed to respond to many different medications. Building on that work, he and his team conducted the initial trial showing that ketamine had antidepressant effects in patients with treatment-resistant bipolar depression.

In the current study, reported in the Jan. 30, 2012 journal Biological Psychiatry, 15 subjects with bipolar depression received a single intravenous infusion of either ketamine or placebo on two test days, two weeks apart. Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine, compared with no improvement in the patients on placebo.

“These findings,” Dr. Zarate states, “support the hypothesis that targeting the NMDA receptor complex brings about rapid antidepressant and antisuicidal effects in patients with bipolar depression.” But he adds that “because the antidepressant effects of ketamine were not long-lasting for most patients, it will be important to develop alternate strategies to sustain ketamine’s rapid effects.”