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New, Rapidly-Acting Treatments for Treatment-Resistant Depression (RAPID)

NAMHC Concept Clearance


Bruce Cuthbert, Ph.D.
Director, Division of Adult Translational Research and Treatment Development (DATR)


This initiative will promote the development of rapid treatments (within less than 48 hours of administration) for severe, treatment-resistant depression.


Over the last decade, a series of studies has shown the potential of multiple approaches—notably including ketamine hydrochloride and sleep deprivation therapy—to provide significant amelioration in symptoms of treatment-resistant depression (and a concomitant decrease in suicidal ideation) in the course of a few hours. However, symptoms typically return within a period of days after discontinuation of the acute intervention.  The promise of such initial effects suggests that a more ambitious program of research might accelerate development of these promising avenues of treatment.

The exact mechanism(s) of action of these modalities in relieving symptoms is not clear. The pharmacologic effect of ketamine appears to involve blockade of glutamatergic NMDA receptors and facilitation of AMPA receptors. One research question concerns whether variations in dose levels might produce longer-lasting effects without a significant increase in adverse events (which, to date, have been minimal). Finally, although a recent study has shown that repeated administration of ketamine over several days is well-tolerated, symptoms nevertheless returned within several days of drug discontinuation for almost all patients. While recent research has increased the understanding of the mechanism of circadian rhythms and the sleep-wake cycle, the rationale for an association between sleep deprivation and symptom relief remains unclear.

This initiative aims to test new compounds (e.g., ketamine, other NMDA antagonists, allosteric modulators of AMPA receptors, 5HT4 receptor drugs, thyrotropin-releasing hormone (TRH)) or non-pharmacologic interventions (e.g., sleep deprivation, TMS, ECT, MST) for the treatment of treatment-resistant depression. The outcome of this initiative could be expected to lead to the further understanding of underlying mechanisms and development of innovative, rapid treatment approaches for treatment-resistant depression.

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