Dr. Grossi's Blog


Dr. Philip Grossi
Monday, 15 October 2012

In the last couple of years, Zarate et. al. have done depression research with an old drug that has been used as an anesthetic. This research may be the most important development in depression therapeutics in the past fifty years. Antidepressants currently available are derived from developments in the 1950s.  At that time drugs used to treat tuberculosis were found to be monoamine oxidase inhibitors and this led to the monoamine theory of depression which was formally enunciated in the 1965 paper by Joseph Schilkraut. This led to research which eventuated in the SSRI drugs and other modern antidepressants. These drugs take weeks to produce a therapeutic response and are only moderately effective in about two thirds of patients.  In contrast, ketamine, an N-methyl-o-aspartate antagonist, produces an antidepressant effect within hour and works in individuals who are resistant to typical antidepressants.

There are accumulating studies that show that depression is associated with reduced brain size in the prefrontal cortex and hippocampus and decreased neuronal synapses in those regions.  Typical antidepressants can reverse these changes albeit slowly.  Ketamine rapidly produces synaptogenesis and reverses synaptic deficits produced by stress and depression. This in turn suggests a new theory of depression, i.e., one of synaptogenic impairment and impoverishment. It also suggests that treatment of depression should be directed to correct these connections.

Typical antidepressants increase neuroplasticity as demonstrated by Rath et.al. with their electrophysiological studies showing enhanced synaptic transmission and long term potentiation.  Other studies demonstrate antidepressant effects on BDNF, spine density, and blocking of spine atrophy by chronic stress. Yet these are slow-acting and work on modulatory neurotransmitters. A single dose of ketamine alleviates depressive symptoms within hours and the effects last about ten days. This drug increases the number and function of synaptic connections which has focused depression research on synaptogenesis as a central actor in mood control and regulation.

From a clinical standpoint, ketamine research has been done with infusions, i.e., I.V. drip done in a surgicenter.  More recently four psychiatrists at the Harvard medical school have treated bipolar II patients with IM injections. They have reported positive results in a letter to the editor in the August 2012 American Journal of Psychiatry.  It is likely that this treatment will be offered in my office in the next few months.