30 August 2010. A mechanism by which ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, produces a fast-acting antidepressive effect is proposed by Ron Duman and colleagues from Yale University School of Medicine in the August 20 issue of Science. In a tour de force of molecular, cellular, and behavioral experiments, the researchers identified cellular signaling pathways in the rat prefrontal cortex (PFC) that are rapidly activated by ketamine and have direct influence on behavior. The study may lead to development of rapid-action antidepressants that function through activation of these pathways.
Specifically, first author Nanxin Li and colleagues report that a single dose of ketamine activates the mammalian target of the rapamycin (mTOR) signaling pathway, resulting in increased synaptic protein expression within two hours and increased dendritic spine density and synaptic activity within 24 hours in the rat PFC. Inhibition of mTOR through infusion of rapamycin completely blocked ketamine’s influence on synaptic protein synthesis. Likewise, rapamycin blockade prevented increases in synaptogenesis, and the notable antidepressant effects following ketamine administration. Increased serotonin (5-HT) neurotransmission, a primary target of traditional antidepressants, was also observed by the researchers. It is noteworthy that traditional antidepressant treatments (ECT, imipramine, fluoxetine) did not influence mTOR signaling.
These findings have far-reaching implications for improved treatment of major depression, where standard treatment takes weeks or months to alleviate symptoms, and only 30 percent of patients respond to the first medication prescribed. Clinical researchers were thus pleasantly surprised, though a bit tentative, a decade ago when Berman and colleagues reported that ketamine produced antidepressant effects within a few hours for some depression patients (Berman et al., 2000). The tentativeness stems, understandably, from the psychotomimetic effects of this and other NMDAR antagonists, the very same reason they have drawn the attention of many schizophrenia researchers. However, Berman reported some evidence that the antidepressant effects may be mediated by mechanisms from the pro-psychotic effects.
Most recently, Carlos Zarate of the NIMH and colleagues extended the ketamine story to bipolar disorder. In the August issue of the Archives of General Psychiatry, they report that 71 percent of patients responded to ketamine, and that "…robust and rapid antidepressant effects resulted from a single intravenous dose" (Zarate et al., 2010). However, since ketamine has abuse potential and can also cause cognitive impairment in addition to psychosis, its clinical use is limited. Thus, identifying the mechanism underlying ketamine’s rapid antidepressant effect would open the door to drug discovery and development.
Following the hypothesis that remodeling of synapses might be involved, Li and colleagues assayed tissue from rat prefrontal cortex following ketamine exposure, looking particularly for molecules known to underlie synaptic plasticity. They noted an upregulation of molecules in the mTOR pathway, as well as two pathways that have been reported to activate mTOR—extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt). Another upstream suspect was also implicated, in that an AMPA receptor inhibitor interfered with the activation of these molecular cascades.
Moving to the morphology level, where mTOR is involved in local protein synthesis to support the building of dendritic spines at excitatory synapses, the researchers found first that ketamine induces the production of a number of synaptic proteins required for the building of spines, including the AMPA-R subunit GluR1. They found a corresponding morphological effect in slice preparations—increased spine density of prefrontal cortical pyramidal neurons. Electrophysiological recordings of these same cells revealed altered responses following ketamine that supported the functional modifications supported by the dendritic modifications. Carrying this chain of experiments through to the phenotype, Li and colleagues used a variety of behavioral experiments to show that perturbing either mTOR or its upstream pathways prevents ketamine from rescuing normal rat behavior in models of depression.
“The mechanisms underlying the induction of mTOR signaling are unclear," the authors write, "but the requirement for glutamate-AMPA receptor activation is consistent with the hypothesis that there is a subset of NMDA receptors, possibly on γ-aminobutyric acid (GABA)—releasing interneurons that, when antagonized, block GABA release and lead to disinhibition of glutamate signaling." Indeed, there are a number of gaps that can be filled in pursuit of an effective drug that preserves the antidepressant effects while discarding the psychotomimetic effects. As a step in this direction, the authors report that a compound that selectively blocks a subgroup of NMDA receptors—those containing the NR2B subunit—had similar effects on mTOR signaling, demonstrating the potential for the discovery of other, safer, swift-acting antidepressants.
One note of caution is raised in an otherwise laudatory Perspective article by John Cryan and Olivia O’Leary of University College Cork, Ireland. They write that treatments which unfetter mTOR signaling may have detrimental effects in humans since the enzyme is implicated in cancer and other human diseases. Cryan and O'Leary also note that whether or not ketamine and other NMDA antagonists promote mTOR activity in other brain regions implicated in major depression remains an unanswered question.
These findings may be of interest to those familiar with the glutamate hypothesis of schizophrenia (see complementary descriptions by Bita Moghaddam and Daniel Javitt), a working theory of schizophrenia dating back to the late 1980s. We invite our readers to comment on any insights to be gained in this regard.—Meggin Hollister and Hakon Heimer.
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 Aug 20 ; 329(5994):959-64. Abstract
Cryan JF, O'leary OF. Neuroscience. A glutamate pathway to faster-acting antidepressants? Science . 2010 Aug 20 ; 329(5994):913-4. Abstract