Ketamine for Unipolar Depression?

John McManamy Health Guide
  • Two years ago, I posted a piece, Ketamine for Bipolar Depression? It is time to revisit the topic, this time focusing on unipolar depression.


    In his Director’s Blog of Oct 1, Thomas Insel, head of the NIMH reports:


    Recent data suggest that ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades.


    Ketamine, which has been around for decades, is commonly used in veterinary practice to anesthetize animals. It also attained notoriety as a recreational drug under the alias “Special K.”


    Dr Insel goes on to say that the effect is almost immediate - within six hours as opposed to six weeks for standard antidepressants - and has shown positive results for people with treatment-resistant depression. On top of that, the drug appears to reduce suicidal thinking.

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    Sound too good to be true? Here are the major catches, according to Dr Insel: The antidepressant effects wear off in a week, we don’t know if repeated injections are the way to go, and we don’t yet know enough about the drug’s safety or efficacy.


    To that, we can add that the evidence base is slim. According to an Oct, 2012 article appearing in Biological Psychiatry (referenced in Dr Insel’s blog), only 163 patients in total have participated in open investigations, case studies, and controlled trials.


    By contrast, the labeling of the SSRI Prozac states that 671 patients took part in the two clinical trials that led to FDA approval.  


    Also, as I pointed out in my earlier piece, the optimistic findings of smaller studies are almost never replicated in larger (and presumably more rigorous) trials.


    On top of everything else, we’re not exactly sure how ketamine works. The current thinking is that ketamine, via the NMDA and AMPA receptors, stimulates the release of glutamate (an excitatory neurotransmitter). This in turn activates two proteins inside the neuron. These proteins (BDNF and mTor) are involved in signaling cascades that regulate cell growth and survival.


    But wouldn’t you know it? In healthy volunteers, ketamine does not raise glutamate levels, and in mice the drug appears to have no effect on mTor signaling. Let’s just say that something as infinitely complex as the human brain resists our best efforts in assigning causes to effects.


    Dr Insel in his blog notes the emergence of “ketamine clinics” that will administer the drug intravenously “off-label to depressed patients. Says Dr Insel: 


    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. 


    Further research, which is underway, may yield more answers. In the meantime, the authors of the Biological Psychiatry article (three of four who have direct financial interests in the drug), point out the potential of ketamine as an alternative to ECT in an emergency setting.


    Moreover, if ketamine itself doesn't pan out as an antidepressant, perhaps a similar compound will. Time will tell ...


Published On: October 24, 2014