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Hunting for the Secret of Ketamine's Antidepressant Action

28 July 2011. A single dose of ketamine, an N-methyl-D-aspartate (NMDA) receptor blocker, can relieve depression in as little as two hours, but figuring out how it works is turning out to be less than straightforward, with recent studies pointing to diverse mechanisms. Schizophrenia researchers are also following the unfolding story, since NMDA blockers cause a psychosis that mimics schizophrenia, giving rise to the glutamate hypothesis of schizophrenia (see SRF hypothesis papers by Moghaddam and Javitt).

A study appearing in Nature on July 7, 2011, from Lisa Monteggia and colleagues at University of Texas Southwestern in Dallas, proposes a pathway involving rapid synthesis of brain-derived neurotrophic factor (BDNF) in mice as the basis of the antidepressant effect. Meanwhile, a study in April in Biological Psychiatry connects ketamine's effect with the mammalian target of the rapamycin (mTOR) pathway in chronically stressed rats, another study in April in Molecular Psychiatry implicates glycogen synthase kinase-3 (GSK3) in mice, and a review of human studies published in July in the International Journal of Neuropsychopharmacology proposes that ketamine works through alterations of circadian rhythms.

Ever since studies demonstrated that a sub-anesthetic dose of ketamine can relieve depression in people with major depressive disorder (Berman et al., 2000) or bipolar disorder (Zarate et al., 2006)—an effect that lasts for up to two weeks—researchers have been trying to identify the relevant pathways. A rapid-acting antidepressant would be enormously beneficial because it could hold people over until other antidepressants, like selective serotonin reuptake inhibitors (SSRIs) take effect, or offer relief to those who do not respond to SSRIs. But ketamine itself may be limited in its clinical usefulness because it can also spawn psychosis; thus, finding the pathways through which ketamine exerts its antidepressant effect could sidestep the psychomimetic problem, and open the door to new targets for drug development.

More mTOR
Last year researchers reported that, in rats, ketamine activates the mTOR signaling pathway, which increased local protein synthesis at synapses, upped the number of dendritic spines, and boosted synaptic activity within 24 hours in the prefrontal cortex (PFC) (see SRF related news story). Consistent with this scenario, suppressing activity in this pathway with rapamycin blocked ketamine's antidepressant effect. The study in Biological Psychiatry comes from the same group, led by Ron Duman at Yale University in New Haven, Connecticut, and it reports a similar story in chronically stressed animals: ketamine also induced mTOR-related changes in synapse protein composition and dendritic spine number—a testament to how quickly the brain can change—and rapamycin reverses these and the behavioral effects.

Looking downstream of mTOR, Richard Jope and colleagues at University of Alabama in Birmingham reported in Molecular Psychiatry that ketamine inhibits GSK3 proteins in mouse hippocampus and PFC. Specifically, ketamine induced phosphorylation at specific sites of GSK3-α and GSK3-β subunits, which suppress its activity. Mice carrying mutated forms of these proteins that cannot be phosphorylated at these sites—rendering GSK3 constitutively active—did not exhibit an antidepressant-like response to ketamine. Activation of mTOR also results in GSK3 inhibition, as does the antidepressant lithium, and this ketamine study suggests that finding ways to rapidly suppress GSK3 may be a viable strategy.

Found in translation?
The study in Nature has a different take on ketamine's antidepressant action, one involving the rapid manufacture of BDNF. First author Anita Autry and colleagues relied on the forced swim test (FST) to give a readout of the antidepressant effect of ketamine in mice. The amount of time a mouse spends immobile instead of swimming inside a water chamber was used as an index of helplessness, something akin to depression. Both normal mice and chronically stressed mice given a dose of ketamine spent less time immobile than mice treated with vehicle. This decrease was apparent only 30 minutes after the ketamine dose, and lasted until at least one week afterward—far beyond the drug's half-life of two to three hours.

This effect seemed to involve BDNF, because ketamine did not have this effect in BDNF knockout mice or in mice lacking BDNF's receptor, Ntrk2. Ketamine treatment also induced wild-type mice to translate more BDNF in the cortex, as early as 30 minutes after the dose, but it did not increase BDNF transcripts. Similarly, ketamine's effect was blocked when protein synthesis was inhibited, but not when transcription was blocked.

Further experiments linked BDNF translation to eukaryotic elongation factor 2 (eEF2) kinase, which phosphorylates eEF2. eEF2 normally helps guide a budding protein through the ribosome, but when phosphorylated, it puts the brakes on translation. The researchers found that ketamine quickly suppressed eEF2 kinase's activity, leaving eEF2 less phosphorylated and freeing BDNF to be translated into protein. Notably, eEF2 kinase inhibitors, called rottlerin or NH125, could also increase BDNF protein levels and induce a decrease in FST immobility within 30 minutes. This suggests that ketamine's action could involve rapid translation of transcripts already loaded and ready to go in the ribosome.

Like a previous study (Maeng et al., 2008), the researchers found that activation of another type of glutamate receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor, was essential for ketamine's antidepressant effect. However, they did not find evidence for mTOR's involvement in their paradigm, and they suggest it might be involved more in maintenance of the antidepressant effect than its induction.

Don't sleep on it
Rodents aside, a new review from Blynn Bunney and William Bunney at University of California Irvine focuses on circadian rhythms for an explanation of the rapid antidepressant effects of ketamine and sleep deprivation therapy alike. Circadian abnormalities have been noted in depression, and sleep deprivation therapy can alleviate depression symptoms within 24-48 hours. The authors note that ketamine, too, can alter the diurnal rhythm of NMDA and AMPA receptor expression, and clock gene expression, in the suprachiasmatic nucleus in animal studies. These changes could conceivably trickle down to affect sleep, hormones, and mood.

These diverse threads—mTOR, BDNF, and circadian rhythms—are rich with potential, and they might all have rapid protein production in common. Whatever the mechanism, hunting down the secret behind ketamine's rapid antidepressant action is revealing a brain that is more quickly malleable than previously appreciated. Understanding the distinct ways in which ketamine works will help disentangle ketamine's antidepressant and psychomimetic effects, and could provide insight for mood disorders and schizophrenia alike.—Michele Solis.

Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011 Jun 15;475(7354):91-5. Abstract

Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011 Apr 15;69(8):754-61. Abstract

Beurel E, Song L, Jope RS. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry. 2011 Apr 19. Abstract

Bunney BG, Bunney WE. Rapid-acting antidepressant strategies: mechanisms of action. Int J Neuropsychopharmacol. 2011 Jul 7:1-19. Abstract

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