Evidence emerges that the neurotransmitter glutamate and N-methyl-D-aspartate (NMDA) glutamate receptors play a key role in higher cortical functions.
Yale investigators at the VA Connecticut Healthcare System and Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center utilize ketamine as a probe to explore the underlying mechanisms of common psychiatric disorders including schizophrenia and alcoholism. A test of ketamine's effects on patients with major depression is initiated. Almost immediately, the scientists begin hearing evidence of the rapid-acting antidepressant effects of ketamine. These effects appeared within hours and lasted for several days.1, 2
The results of the first placebo-controlled, double-blinded trial to assess the treatment effects of ketamine in patients with depression are published in Biological Psychiatry. The findings, by Yale researchers working at the VA Connecticut Healthcare System and the Connecticut Mental Health Center, outline the rapid antidepressant effects of the compound. The compelling results suggest a potential role for NMDA receptor modulating drugs in the treatment of depression.3
The 2000 Yale findings are replicated by a team at the National Institute of Mental Health.4 The NIMH team includes a Yale Department of Psychiatry alumnus and co-author of the original Biological Psychiatry article.
Yale research suggests an explanation for the rapid antidepressant effects of ketamine. Results published in Science demonstrate that a single dose of ketamine leads to an increased number and function of new synapses in the rodent prefrontal cortex. This restoration of connections between brain cells, a process called “synaptogenesis," is a much quicker process than forming entirely new neurons while accomplishing the same result of enhanced brain connectivity and circuit activity.5
Yale-led study published in Biological Psychiatry demonstrates that the atrophy of dendrites caused by chronic stress in rodents may be reversed by administration of ketamine.6
1 Krystal, J.H., Karper, L.P., Seibyl, J.P., Freeman, G.K., Delaney, R. Bremner, J.D., Heninger, G.R., Bowers, M.B. Jr, Charney, D.S. 1994 Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Arch Gen Psychiatry 51, 199-214. http://www.ncbi.nlm.nih.gov/pubmed/8122957
2 Krystal, J.H., Petrakis, I.L., Webb, E., Cooney, N.L., Karper, L.P., Namanworth, S., Stetson, P., Trevisan, L.A, Charney, D.S. 1998 Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics. Arch Gen Psychiatry 55, 354-360 http://www.ncbi.nlm.nih.gov/pubmed/9554431
3 Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S., Krystal, J.H. 2000 Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47, 351–354. http://www.ncbi.nlm.nih.gov/pubmed/10686270
4 Zarate, C.A. Jr., Singh, J.B., Carlson, P.J., Brutsche, N.E., Ameli, R., Luckenbaugh, D.A., Charney, D.S., Manji, H.K. 2006 A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63, 856–864. http://www.ncbi.nlm.nih.gov/pubmed/16894061
5 Li, N., Lee, B., Liu, R.J., Banasr, M., Dwyer, J.M., Iwata, M., Li, X.Y., Aghajanian, G., Duman, R.S. 2010 mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–64. http://www.ncbi.nlm.nih.gov/pubmed/20724638
6 Li, N., Liu, R.J., Dwyer, J.M., Banasr, M., Lee, B., Son, H., Li, X.Y., Aghajanian, G., Duman, R.S. 2011 Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69, 754–761. http://www.ncbi.nlm.nih.gov/pubmed/21292242