From The Quarterly, Winter 2015

In its November 13, 2014 issue, a section of which was devoted to depression, the prestigious journal Nature invited three researchers to suggest “the best way forward” in discovering new antidepressants. All three are past recipients of NARSAD Grant awards, and two are members of the Foundation’s Scientific Council. The suggestions they presented contrast markedly, and represent two powerful schools of opinion within the research community.

One approach was advocated by Lisa Monteggia, Ph.D., of the University of Texas Southwestern Medical Center. She has twice received NARSAD Young Investigator Grants and in 2010 was an Independent Investigator Grantee. Dr. Monteggia, like the other scientists involved in the forum, acknowledged the problem: the absence of new antidepressants, including ones that might act more rapidly for urgent cases, as well as ones to help the large portion of depressed people whose depression does not respond to SSRIs––selective serotonin reuptake inhibitors* such as fluoxetine (Prozac).

Noting that many scientists are trying to study depression in rodents that “model” various depression symptoms such as loss of interest, the inability to experience pleasure, and susceptibility to anxiety, Dr. Monteggia instead recommends that we focus on better understanding drugs known to work in people. This approach has already been tried for SSRIs, but the answers have not been very helpful in figuring out how to make them work more rapidly. It often takes two to three months for SSRIs to show benefit.

Dr. Monteggia urges efforts to figure out how the fast-acting medication ketamine* exerts its often remarkable effects. Some people with recurring depression report the lifting of symptoms in as little as one hour. Scientists know ketamine blocks NMDA receptors* in the brain for the neurotransmitter glutamate. From this starting point, Dr. Monteggia argues, we should study how that blockade affects signaling in key brain networks. Such study might reveal powerful ways to make other drugs that act like ketamine, only better and with fewer side effects.

A second school of thought was represented in the Nature forum by Robert Malenka, M.D., Ph.D., and Karl Deisseroth, M.D., Ph.D., colleagues at Stanford University. Drs. Malenka and Deisseroth, both of whom are NARSAD Grant recipients and current Scientific Council members, think it makes more sense to stress research aimed at “a sophisticated understanding of the causes of illness [including, but not restricted to depression] at the level of neuronal circuits.”

Like lithium for bipolar disorder, ketamine for treatment-resistant depression can indeed be effective, Drs. Malenka and Deisseroth acknowledge, but these medications “affect neurons indiscriminately throughout the brain.” This makes it hard to figure out exactly how they benefit patients. Rather, the researchers argue, we should try to identify targets in malfunctioning brain circuits that, when manipulated using various advanced technologies, can actually repair the dysfunction.

Dr. Deisseroth and his colleagues are renowned for their invention, during the last decade, of a technology called optogenetics* that makes possible the manipulation of individual brain cells with colored laser light. Though experimental at this point, application of such methods to repair damaged circuits is a kind of “frontier approach” that contrasts with the “pharmaceutical approach” dominant until now. Both kinds of research––pharmaceutical- based and circuit-based––are certain to continue.