Post by Former NIMH Director Thomas Insel: Ketamine
By now, everyone knows that medication development for mental disorders has hit a wall, pharmaceutical companies have abandoned the search for new medications, and there are no promising new medications on the horizon.1 So it is important to take a moment to consider ketamine, an anesthetic that has been around for decades. Intravenous ketamine was the anesthetic of choice for outpatient procedures in children when I was in medical training nearly 40 years ago. Twenty years ago ketamine achieved notoriety as a recreational drug under the moniker “Special K.” But in the past decade, ketamine has emerged as a potential antidepressant.
Recent data suggest that ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades. Three findings are worth noting. First and most important, several studies demonstrate that ketamine reduces depression within six hours, with effects that are equal to or greater than the effects of six weeks of treatment with other antidepressant medications.2 The shift from six weeks to six hours has already transformed what we could and should expect of antidepressant treatments.
Second, ketamine’s effects have been noted in people with treatment-resistant depression.3 Most of the studies to date have tested ketamine in people for whom other treatments were not effective, including both medications and psychotherapy. This promises a new option for people with some of the most disabling and chronic forms of depression, whether classified as major depressive disorder or bipolar depression.
Third, it appears that one of the earliest effects of the drug is a profound reduction in suicidal thoughts.4 Although lithium and clozapine have been reported to reduce suicide risk, we have not had medications that were specifically anti-suicidal. It is too early to label ketamine as an anti-suicide medication, but the reduction in suicidal thoughts even prior to the antidepressant effect is promising, especially given the risk of suicide in people with severe, treatment-resistant depression.
There are still a number of questions to resolve about the best dose, the mechanism, and the long-term efficacy and safety of ketamine. Dose-response studies are underway to determine if sub-anesthetic doses may be anti-depressant. While the antidepressant mechanism was assumed to be blockade of the brain’s NMDA receptor, other medications that block NMDA receptors are not antidepressants. And how ketamine would be used clinically is not yet clear. In most people, the antidepressant effects wear off within a week. We don’t know yet if repeated injections will be safe and effective.
But there is enough potential here that several universities and companies have launched research and development efforts. Reports of efficacy for both obsessive-compulsive disorder and post-traumatic stress disorder have surfaced in the past year 5, 6 Recently the Food and Drug Administration awarded breakthrough therapy designation for the development of intranasal ketamine for treating depression. This is the first time this special designation, usually reserved for drugs targeting an epidemic or a deadly form of cancer, has been awarded for the development of a medication for a mental disorder. This speaks not only to the scientific opportunity but the public health need for having a rapid antidepressant.
That need is leading to ketamine clinics using this drug “off-label” to treat depression. While the science is promising, ketamine is not ready for broad use in the clinic. We just don’t know enough about either efficacy or safety. But with the excitement generated by early results, we will have more information soon. The doom and gloom surrounding medication development, at least for depression, seems to be rapidly resolving.
1 Insel T. Treatment Development: The Past 50 Years.
2 Aan Het Rot M et al. Ketamine for depression: where do we go from here? Biol. Psychiatry. 2012 Oct 1;72(7):537-47.
4 DiazGranados N et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J. Clin. Psychiatry. 2010 Dec;71(12):1605-11.
5 Rodriguez CI et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013 Nov;38(12):2475-83.
6 Feder A et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014 Jun;71(6):681-8.