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“Special K” could offer new hope for treatment-resistant depression

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Over the past several decades, the pharmaceutical industry has been abandoning the research and development of treatments for psychiatric disorders, despite the ever-growing need for novel, more efficacious, and better targeted therapeutics. Depression is the most prevalent psychiatric disorder and ranked among the top causes of disability and disease burden in the world.1 While common treatments for depression are effective for most patients, there is subset who fail to respond to at least two trials of antidepressant treatments (~10-30%). Additionally, recent estimates indicate up to ~30% of those do not respond to any treatment at all.2,3 For these patients with treatment-resistant depression, novel therapeutics are a necessity. With the advent of newer technologies and findings, psychiatry is vehemently trying to discover new treatments and better understand their therapeutic actions.

The field was reinvigorated by the discovery about 15 years ago that the anesthetic and recreational drug, ketamine, alleviated the depressive symptoms associated with major depressive disorder.4  Since this first report, there has been a boom of animal and human studies investigating ketamine’s mechanism of action and potential clinical application. Ketamine has fast pharmacological kinetics, with a rapid onset and elimination half-life of 2-3 hrs.5 In treatment-resistant depressed patients, subanesthetic doses of ketamine has been shown to rapidly improve symptoms in those with treatment-resistant depression.6 Although the precise mechanisms are unknown, converging evidence from human and animal studies suggest the therapeutic effects of ketamine are via increased glutamatergic (excitatory) transmission and neuronal activity of the prefrontal cortex (PFC). In a recent study published in the Proceedings of the National Academy of Sciences, the Duman laboratory at Yale University used rat models to investigate the potential role of the PFC to mediate the antidepressant and anxiolytic effects of ketamine by directly manipulating the activity of two subregions that have been implicated in cognitive and emotional processes—the infralimbic and prelimbic areas.6

The first set of experiments were designed to determine whether silencing neuronal activity in either one of these areas prevented the behavioral effects of ketamine. Prior to tests for anxiety and depression related behaviors, rats were infused with ketamine with or without muscimol (GABA receptor agonist promotes neuronal inhibition) directly into either the infralimbic or prelimbic areas. Only the infusion of muscimol into the infralimbic, but not the prelimbic area, following ketamine blocked the antidepressant and anxiolytic effects of ketamine, suggesting the therapeutic response may be through ketamine-induced excitatory transmission and neuronal activity in the infralimbic area of the PFC.

To assess whether enhanced neuronal activity is the key mechanism, the authors employed optogenetics to selectively drive the firing of pyramidal neurons, which form the major excitatory-inhibitory cortical networks. While in vivo optogenetic stimulation of prelimbic pyramidal neurons failed to have any behavioral effects, stimulation of infralimbic pyramidal neurons almost completely recapitulated the rapid antidepressant and anxiolytic effects of ketamine. Interestingly, the behavioral effects following acute optogenetic stimulation lasted for more than two weeks, which is similar to the persistent effects of an acute dose of ketamine in treatment-resistant depressed patients.5 It is possible that some of these therapeutic effects are due to an increased in the number of dendritic spines and their functionality in the PFC. Thus, ketamine seems to rapidly induce plasticity at glutamatergic-excitatory synapses, quickly alleviating anxiety and depressive symptoms.

Together, these preliminary animal studies indicate the therapeutic response to ketamine may be increased glutamatergic signaling in certain subregions of the PFC. In humans, these mechanisms may be similar, as ketamine may reverse reduced activity in the PFC of treatment-resistant depressed patients.7 Future investigations will need to more precisely determine which types of pyramidal neurons of the PFC are contributing to the therapeutic effects, and why these might be particularly poised to rapidly respond to an acute dose of ketamine. It will also be important to better understand the mechanisms underlying the persisting therapeutic effects even after a single dose of ketamine. Efforts are underway to develop analogs of ketamine, in addition to other glutamatergic agents, that produce longer antidepressant effects with fewer side-effects.


  1. Fuchikami M et al. (2015) Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions. Proceedings of the National Academy of Sciences 112(26):8106-8111. doi: 10.1073/pnas.1414728112
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