Research yields fresh insights into ketamine for depression

The year 2016 has brought answers to two key questions regarding the off -label use of intravenous ketamine in patients with treatment resistant depression: What’s the optimal dosing schedule! And what’s the likely mechanism of benefit?

Ketamine has generated enormous interest among psychiatrists and patients because the response is so dramatic, with marked improvement seen within hours in a much higher proportion of patients than respond to conventional antidepressants, which target the serotonergic system. But the benefits are not long lasting, and psychiatrists have wondered how often the treatment should be repeated. That question has been answered in a multicenter, double-blind US randomized trial, said the annual congress of the European College of Neuropsychopharmacology.

Investigators randomized 67 patients with treatmentresistant depression to ketamine at 0.5 mg/kg of body weight either two or three times per week, or to placebo.

The mean reduction on the Montgomery - Asberg Depression Rating Scale at day 15 was 18.4 points with twice-weekly therapy and similar at 17.7 with thrice-weekly therapy, both significantly better than with placebo.

“It turns out that two and three times per week were equally effective, so obviously twice per week is enough,” said by the professor of psychiatry and head of the bipolar disorder program at the University of Barcelona.

Ketamine’s approved indication is as an anesthetic agent. Its long-term safety as an antidepressant remains an open question. The drug has undesirable psychotropic side effects, including dissociation, but related compounds without those issues are speeding through the developmental pipeline.

The Food and Drug Administration has granted Pharmaceuticals “fast-track” and “breakthrough therapy status for intranasal esketamine, the S(+) enantiomer of ketamine, which is now in phase III clinical trials for treatment-resistant depression as well as for depression with suicidal thoughts.

The FDA reserves these designations for potential therapies addressing a major unmet need. Allergan has received the same designations from the FDA for its drug rapastinel, which also is now in phase III clinical trials.

Ketamine is clearly not something to use as first-line therapy. There is a problem in certain places: The US there are now plenty of ketamine clinics administering the drug to first comers. That doesn’t make sense. But ketamine does open an important new avenue.

The future of new drug development for mood disorders lies in the glutamatergic system. However, a recent study by investigators at the National Institute of Mental Health – who pioneered the use of ketamine as an antidepressant – and at the University of Maryland, Baltimore casts doubt upon the conventional wisdom that ketamine’s mechanism of benefit as an antidepressant involves N -methyl -D -aspartate receptor (NMDA) antagonism.

Instead, they reported, the antidepressant effect is actually exerted by a ketamine metabolite known as HNK. And HNK's antidepressant effect is not related to NMDA receptors, but is instead tied to activation of AMPA (alpha -amino -3- hydroxy -5- methyl -4isoxazole propionic acid) receptors. And in mice, at last, HNK lacks the unwelcome psychotomimetic side effects of ketamine.

This opens up a new avenue in drug development.