Developing Antidepressants That Go Beyond the “Serotonin Theory”

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Carlos A. Zarate, M.D. - Brain and behavior research expert on depression
Carlos A. Zarate, M.D.

From The Quarterly, Winter 2014

“It’s very likely that there are many different ways of getting an antidepressant response,” Dr. Zarate hypothesizes. For decades, most depressed people have been prescribed medications of the SSRI (selective serotonin reuptake inhibitor) class, such as fluoxetine (Prozac®) and others. One-half to two-thirds of patients don’t have a full response; those who do can wait weeks or months to see an effect. SSRIs affect levels of the neurotransmitter serotonin, which helps conduct messages between brain cells. Dr. Zarate says that some people might be biologically resistant to this form of therapy.

Research has shown that ketamine works through an entirely different mechanism than serotonin—in the glutamate neurotransmitter system. Ketamine blocks one of the key receptors for glutamate in brain cells, called NMDA receptors. “Ketamine causes a massive presynaptic release of glutamate,” Dr Zarate explains, in part by activating other glutamate receptors, called AMPA receptors. Scopolamine also appears to have similar effects on glutamate release. Both medications appear to target the same protein within the brain cell called mTOR. So far, research has shown that this protein is crucial to the mechanism of both ketamine and scopolamine. Dr. Zarate believes the key to the rapid antidepressant response in ketamine and scopolamine is their ability to quickly increase plasticity, including the formation of connections between brain cells.

The big question is long-term safety. Even though ketamine is now being used in clinics around the country by experienced doctors, Dr. Zarate believes that long-term efficacy and safety studies are needed. Another problem is duration of the effect: relief from ketamine may last only a few weeks, and there is still not enough data on whether repeated doses are safe. This is why Dr. Zarate and others are working on substitutes for ketamine––similar molecules that modulate glutamate targets in other ways than ketamine, for instance. These other molecules appear to have milder effects, but may be longer lasting and safer. Meantime, the pharmaceutical industry has taken notice and is investing in rapid-acting ketamine-like compounds. Johnson & Johnson and AstraZeneca, among others, have ketamine variants in active clinical trials.

“These medications are not yet ready for prime time,” Dr. Zarate says, “but hopefully in several years, pending FDA approval, there could be a medication available for our patients.”

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