From The Quarterly, Winter 2015

Rapid relief for people reporting suicidal thoughts or who are in a suicidal crisis may be on its way. The most talked-about drug to hit depression research in years is ketamine. This medication has been making waves for its ability to rapidly reduce depressive symptoms in some people, most importantly in those whose depression has not responded to other treatments. Now, a research team has found that ketamine can reduce suicidal thoughts (also called suicidal ideation), independent of its ability to reduce anxious and depressive symptoms.

Led by Carlos Zarate, M.D., recipient of a 1996 NARSAD Young Investigator (YI) Grant and 2005 NARSAD Independent Investigator (II) Grant, the new findings on ketamine were published in the Journal of Psychiatric Research in November 2014 and discussed in the journal Nature January 8th in an article about expectations surrounding ketamine’s clinical potential. The Nature story also mentioned research by 2010 YI Grantee Kyle A.B. Lapidus, M.D., Ph.D., 2009 YI Grantee James W. Murrough, M.D., 2001 Distinguished Investigator Grantee and Director of the National Institute of Mental Health Thomas Insel, M.D., and 1998 II Grantee and member of the Foundation’s Scientific Council, Husseini K. Manji, M.D.

Previous research has shown that ketamine can sharply reduce symptoms of depression within hours of being administered––quite an advantage over the most commonly used antidepressant drugs, selective serotonin reuptake inhibitors, which usually take one to three months to show full effects. The recent study led by Dr. Zarate is the first to show that, in addition to diminishing depression and anxiety, ketamine can separately and just as quickly reduce suicidal thoughts.

As discussed in the Nature article, the enthusiasm over ketamine’s quick effects has somewhat obscured the uncertainty over how well the drug works in the long term, which will be important for determining its role in depression treatment. Though ketamine is only clinically approved as an anesthetic, many doctors are already prescribing it off-label for treatment-resistant depression, and drug companies are rushing to develop alternative versions of the drug that could avoid ketamine’s serious side-effects, including hallucinations and “dissociation”* or detachment from reality.

Some argue that even if ketamine is not ultimately approved for long-term use, it could still be very beneficial as an emergency treatment for people in a suicidal state.

Ketamine works by reducing activity at NMDA (N-methyl-D-aspartate) receptors in the brain, which are implicated in the pathology of depression and act as a gate for the neurotransmitter glutamate. Other medications have been identified that regulate glutamate levels and have quick antidepressant effects, without causing hallucinations. But it is not yet known whether other glutamate regulators can reduce suicidal thoughts.

As noted in the Nature article, Dr. Zarate says that ketamine’s fast action is particularly promising for suicide prevention. His research suggests that ketamine seems specifically to affect the desire to attempt suicide, whether a person is clinically depressed or not. In a trial now under way, Dr. Zarate and colleagues are using ketamine to treat around 50 people with depression, some of whom have suicidal thoughts, to study this in more detail.