Ketamine Alternative Holds Hope for New Depression Treatment

Severe depression is life-threatening but most medications take up to several weeks to be effective. Ketamine according to clinical trials by Zarate can lift depression in hours, or even minutes.

But ketamine also has dissociative and euphoric effects which would make it a prime candidate for abuse.

Now a new study shows that the active part of ketamine is actually a metabolite which doesn’t have the same addictive properties.

NIMH grantee Todd Gould, M.D.(link is external), of the University of Maryland School of Medicine reported the findings in the current issue of Nature.

The research team looked for the exact mechanism which relieves depression in the class of drugs (including ketamine) which block cellular receptors for glutamate, the chemical which carries excitatory messages in the brain.

Previously it was thought ketamine worked by blocking N-methyl-D-aspartic acid (NMDA) glutamate receptors.

The NIH scientists and grantees traced ketamine’s rapid antidepressant effects to triggering AMPA receptors by (2R,6R)-HNK (above) – a completely different mechanism.

This proved ineffective so the researchers looked at the the metabolites - chemicals made in the body as the body utilizes ketamine and found that the key metabolite (2S,6S;2R,6R)-HNK (hydroxynorketamine) was pharmacologically active in mice.

Tests showed the metabolite (2R,6R)-HNK  worked like to ketamine in relieving depression and it lasted several days although it does not inhibit NMDA receptors.

These results are preliminary but hold much hope for producing a new class of fast-acting antidepressant medications which do not have the drawbacks of ketamine.