Fast-Acting Antidepressant Restores Ability to Experience Pleasure in People with Bipolar Depression

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

Taking a bite of your favorite dessert. Hearing the first notes of your favorite song. Planning a vacation to a faraway beach. Many psychiatric patients lose interest in simple activities that once they may have enjoyed. It’s a condition known medically as anhedonia, and now there’s hope for relief, thanks to the work of two Foundation-funded researchers––Carlos Zarate, Jr., M.D., of the National Institute of Mental Health, and Jonathan Paul Roiser, Ph.D., of the University College London, both former recipients of NARSAD Independent Investigator Awards.

For the first time, their work reveals that, in patients with bipolar depression, the experimental drug ketamine can help quickly reduce feelings of disinterest when other treatments have failed.

Approved by the FDA decades ago as an anesthetic and known to have hallucinogenic side effects––particularly when abused as a recreational drug––ketamine has been the subject of intensive clinical research. Dr. Zarate and other investigators (including Foundation Scientific Council members Dennis Charney, M.D., and John Krystal, M.D.) have previously shown that controlled administration of ketamine can quickly relieve general symptoms in people with treatment-resistant major depression. Widely prescribed antidepressant medications (such as Prozac, Paxil, and Zoloft, all SSRIs) usually need several weeks to take effect. Thus, much hope has been placed on ketamine’s extraordinary short-term effectiveness, particularly in cases of acute depression. Only recently has ketamine’s effects on anhedonia specifically been explored. Standard depression treatments do little to alleviate this symptom, which can be present during long periods of intense depression, and may be a predictor of suicidal behavior.

As Drs. Zarate, Roiser, and colleagues reported on October 14th in Translational Psychiatry, 36 people with treatment-resistant bipolar depression received a dose of ketamine or a placebo on two test dates, two weeks apart. Patients who were given a single dose of ketamine reported a reduction in their levels of anhedonia in as little as 40 minutes. This improvement lasted for as long as two weeks in some patients and occurred independently of reductions in other depression symptoms. This suggests that ketamine helps relieve anhedonia specifically, in addition to its often remarkable antidepressant effect.

“No approved treatments for anhedonia currently exist, despite its prevalence across multiple psychiatric disorders,” said Dr. Zarate. “Ketamine’s rapid effects on anhedonia levels are a crucial clinical finding.”

The researchers also investigated the mechanisms that may help explain how ketamine works to provide rapid relief. Before and after injections, a subset of patients underwent PET scans, which measure brain activity. The researchers found that relative to a placebo, ketamine was associated with an increase in activity in two parts of the brain––the dorsal anterior cingulate cortex and putamen. According to researchers, this “may reflect increased motivation toward or ability to anticipate pleasurable experiences.”

While more research is needed, this study—in addition to being the first to show a possible treatment for anhedonia––provides further evidence that developing drugs with fewer side effects that act in a similar way to ketamine is worth pursuing.

Read more about this study.