VIENNA – 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 U.S. randomized trial, Eduard Vieta, MD, PhD, noted at the annual congress of the European College of Neuropsychopharmacology.
Investigators randomized 67 patients with treatment-resistant depression to ketamine at 0.5 mg/kg of body weight at either two or three times per week, or to placebo. The mean reduction on the Montgomery-Åsberg 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 (Am J Psychiatry. 2016 Aug 1;173[8]:816-26).
“It turns out that two and three times per week were equally effective, so obviously twice per week is enough,” said Dr. Vieta, professor of psychiatry and head of the bipolar disorders 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 Janssen 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. I think there is a problem in certain places: I know in the U.S. there are now plenty of ketamine clinics administering the drug to first comers. That doesn’t make sense to me. But ketamine does open an important new avenue,” he said.
Dr. Vieta asserted that 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 colleagues 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, or (2S,6S;2R,6R)-hydroxynorketamine. And HNK’s antidepressant effect is not related to NMDA receptors, but is instead tied to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. And in mice, at least, HNK lacks the unwelcome psychotomimetic side effects of ketamine (Nature. 2016 May 4;533[7604]:481-6).
“This is a very nice paper and very important. This opens up a new avenue in drug development, looking at agents that act on AMPA receptors to provide rapid relief of depressive symptoms in unipolar depression but probably also in bipolar depression,” said Dr. Vieta.
He reported receiving research grants from numerous pharmaceutical companies having an interest in treatments for mood disorders.