Magazine article Clinical Psychiatry News

Ketamine Continues to Show Potential in Treating Depression

Magazine article Clinical Psychiatry News

Ketamine Continues to Show Potential in Treating Depression

Article excerpt

In the near future, the anesthetic agent ketamine could play an important role in the treatment of patients who are depressed - and even suicidal.

Several recent studies support the drug's almost immediate and long-lasting effects. Animal trials suggest that ketamine might work by stimulating brain-derived neurotrophic factors (BDNFs), which spur neuronal growth. They also hint that variations in the genes that code for BDNF might confer resistance to ketamine; humans with this allele might be less likely to respond to ketamine's effects.

"These clues help focus the search for the molecular targets of a future generation of medications that will lift depression within hours instead of weeks," said Dr. Carlos A. Zarate, a primary investigator in some of the studies. "The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable side effects."

The National Institutes of Health funded all of the ketamine studies, which were published in several journals between December 2011 and June 2012.

A study of 30 patients with treatmentresistant major depressive disorder concluded that ketamine infusions were associated with significant increases in serum BDNF, accompanied by changes in slowwave activity on electroencephalograms. Dr. Wallace C. Duncan Jr., of the National Institute of Mental Health, found that the changes were directly related to response: Patients who experienced significant improvements in depression had the highest level of change (Int.J. Neuropsychopharmacol. 2012 June 7 [doi: 10.1017/S1461145712000545]).

"The induction of neurotrophic factors may therefore partially underlie the antidepressant effects of ketamine, given that major depressive disorder is associated with low levels of BDNF and that chronic treatment with antidepressants elevates BDNF levels," he said.

BDNF also is important in facilitating synaptic potentiation, he added.

A mouse study, published in the June issue of Biological Psychiatry, shed some additional light on how the drug might work, and in whom. Dr. George Aghajanian of Yale University Boston, and his colleagues examined mice specifically bred to express two copies of a gene that impairs BDNF signaling - an allele configuration expressed in about 30% of humans (Biol. Psychiatry 2012;71:996-1005).

The researchers compared the brains of these mice to those of mice with a single copy of the gene, and to those that lacked the risk allele completely. The homozygous mice displayed significantly less dendritic complexity in their brain neural networks. The density of individual dendritic spines also was much reduced.

Some of the mice received injections of ketamine. When their brains were examined 24 hours later, the heterozygous and wild-type mice showed significantly more dendritic complexity. The mice that were homozygous for the risk gene, however, had fewer improvements in neural health, showing that the gene blunts ketamine's neural benefits.

A study in humans supports that idea. Dr. Gonzalo Laje of the National Institute of Mental Health has reported on a series of 62 patients with major depressive disorder who were genotyped for the risk allele and treated with ketamine. The presence of a double copy of the gene accounted for 28% of the difference in patients' response to the drug (Biol. …

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