Although many medications are currently available for the treatment of major depression, 10-20% of patients treated with the common antidepressants do not achieve complete recovery and meet the criteria for what is referred to as “treatment-resistance.”  Treatment-resistant depression (TRD) affects more than 1% of people in the United States, and about 30% of all depressed patients are treatment refractory.  In most clinical studies, TRD is defined as a failure to respond to at least two different types of antidepressants for a period longer than 4 weeks at the maximum recommended dose.



According to the monoamine hypothesis, depressive symptoms are mainly related to a deficit in the availability of monoamine neurotransmitters, and most antidepressant drugs are believed to modulate these neurotransmitter systems (e.g., norepinephrine, dopamine, or serotonin) [1]. The therapeutic effect with the common antidepressant medications emerges only after 4-12 weeks of treatment [2], so pharmacological agents like ketamine, that exert rapid antidepressant effects, are desperately needed in clinical practice [3].



When used to treat depression and anxiety, ketamine has a different mechanism of action from standard antidepressants. Ketamine is thought to act by blocking N-methyl-d-aspartate (NMDA) receptors in the brain, which interact with the amino acid neurotransmitter glutamate. The resulting chemical changes in the brain are not yet fully understood, but could involve ketamine-induced gene expression and signaling cascades that act long after the drug has been eliminated from the body.  But since most studies have demonstrated that ketamine has rapid antidepressant effects, sometimes within hours of the first administration, it seems likely that glutamate does play an active role in the pathophysiology of depression



Based on three open-label studies [4], ketamine was found to be effective in reducing suicidality in TRD patients. Suicidal ideation in TRD patients improved in numerous cases after only a few minutes of ketamine infusion and remained stable for up to 4 hours post-infusion. These findings have been replicated in patients with treatment-resistant bipolar depression by Zarate et al. [5]. In this randomized double-blind placebo-controlled crossover study, 79% of subjects were reported to respond to ketamine at some point during the 2-week trial, although the effects of ketamine waned from days 7-10 and there was no significant difference compared to placebo at that point.



Interestingly, a family history of alcohol dependence seems to predict a rapid initial antidepressant response to an NMDA receptor antagonist, and this may serve as a useful marker for response to NMDA antagonists [6]. It has been suggested that NMDA receptors are one of the targets linked to the action of ethanol, and genetic alterations of NMDA receptor subunits have been associated with the emergence of alcohol dependence [7].


There is further evidence that ketamine may act as a neuroplastic modulator able to induce enhanced dendritic branching and changes in synaptic receptor number and density [8]. As suggested by Hayley and Litteljohn [9], ketamine could modify the connectivity of diverse cortical circuitry playing a critical role in determining consciousness, sense of self, and key depressive symptoms such as rumination. In particular, Scheidegger et al. [10] reported that ketamine reduced default mode network metabolic activity by reducing the connectivity within the cingulate and prefrontal cortices in a sample of healthy non-depressed subjects. Ketamine has also been reported to strengthen appropriate emotional neural connections, enhancing synaptogenesis in those brain areas affected by stress-related processes and associated with negative thinking in depressed individuals.


The rapid antidepressant activity reported by convergent evidence is consistent with existing preclinical observations indicating that ketamine rapidly (within hours) increases not only the number but even the functioning of synaptic connections involving cortical or hippocampal neurons [11]. The additional potential to rapidly reverse both behavioral and neuronal changes associated with chronic stress is presumably due to the stimulation of brain-derived neurotrophic factor (BDNF).

The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review

Curr Neuropharmacol. 2014 Sep; 12(5): 444–461. 

Published online 2014 Sep. doi:  10.2174/1570159X12666140619204251

Some information on this page is derived from the following:

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4. Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int. J. Neuropsychopharmacol. 2011;14:1127–1131

5. Zarate CA, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA. Replication of ketamine's antidepressant efficacy in bipolar depression a randomized controlled add-on trial. Biol. Psychiatry. 2012;71:939–946.

6. Luckenbaugh DA, Ibrahim L, Brutsche N, Franco-Chaves J, Mathews D, Marquardt CA, Cassarly C, Zarate CA. Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression. Bipol. Disord. 2012;14:880–887.

7. Schumann G, Johann M, Frank J, Preuss U, Dahmen N, Laucht M, Rietschel M, Rujescu D, Lourdusamy A, Clarke TK, Krause K, Dyer A, Depner M, Wellek S, Treutlein J, Szegedi A, Giegling I, Cichon S, Blomeyer D, Heinz A, Heath S, Lathrop M, Wodarz N, Soyka M, Spanagel R, Mann K. Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior. Arch. Gen. Psychiatry. 2008;65:826–838.

8. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–964.

9. Hayley S, Litteljohn D. Neuroplasticity and the next wave of antidepressant strategies. Front. Cell. Neurosci. 2013;7:218.

10. Scheidegger M, Walter M, Lehmann M, Metzger C, Grimm S, Boeker H, Boesiger P, Henning A, and Seifritz E. Ketamine decreases resting state functional network connectivity in healthy subjects implications for antidepressant drug action. PLoSOne. 2012;7:e44799.

11. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–964.