Important Research into the Relationship of Ketamine and Mood Disorders

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Ketamine’s Mechanism Of Action

Ketamine’s precise mechanism is not fully understood, but operates by blocking the N-methyl D aspartate glutamate receptor Ca2+ Channel to reduce the pre-synaptic release of glutamate.  The neurobiological mechanisms underlying the antidepressant actions of ketamine are more complex than the simple blockade of NMDA receptors. Some researchers speculate that increasing free glutamate in turn stimulates postsynaptic alpha-amino-3-hydroxy-5-mental-4-isoxazoleproprionic acid (AMPA) receptors, resulting in the release of brain-derived neurotrophic factor (BDNF), the activation of tropomyosin receptor kinase B (TrkB) and Akt, and subsequent increases in mammalian target of rapamycin complex 1 (mTORC1) signaling. Conversely, blockade of BDNF release or function or mTORC1 signaling eliminates the antidepressant effects of ketamine. There is growing research to suggest that the rapid antidepressant effects of ketamine are believed to be associated with synthesis of dendritic proteins required for synapse formation and maturation and the reversal of atrophy caused by chronic stress.  Simply put, ketamine seems to actually rebuild synapses.

Early Research into the relationship of Ketamine and Mood Disorders

As early as 2000, Berman et al demonstrated the first placebo-controlled double blinded trial to assess treatment effects of a single dose of ketamine in patients with depression.  A single sub-anesthetic dose of 0.5 mg/kilogram of ketamine was administered through a 40 minute infusion which produced significant antidepressant effects within hours 72 hours after ketamine, but not a placebo infusion.  In 2006, Zarate et al administered single intravenous ketamine dose to 18 patients compared to placebo.  Results indicated that the subjects ( who had been resistant to two or more typical antidepressants) receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 2 hours after the injection and the effect remained significant throughout the following week.  Of the 98% of subjects who received ketamine, 71% met treatment response, 30% met remission criteria the day following ketamine infusion and 35% of the subjects maintained the response for at least one week.  The importance of this research demonstrated the rapid antidepressant effect resulting from a single intravenous dose of ketamine. Ketamine is rapidly metabolized and has a half-life of approximately 180 minutes in humans. These results suggest that ketamine initiates a sequence of events that result in a rapid therapeutic response that is sustained even after the drug has been metabolized.

Additional controlled crossover studies examining ketamine’s treatment effects of major depressive episodes associated with both unipolar and bipolar disorder, similarly produced rapid and robust antidepressant effects lasting several days to weeks.  More recently, scientific research has supported the approach of a series of infusions producing more pronounced and more durable lasting benefits.  To date, research into the efficacy of intravenous ketamine has demonstrated at least a 70% success rate.