The Promise of Rapidly Acting Antidepressants: Challenges and Opportunities

Despite availability of a variety of new monoaminergic re­ uptake blockers in the 50 years since imipramine, a meta­analysis of 28 trials found that full clinical response typically requires 6 weeks on average (1 ). This length of suffering is not only unacceptable but is also linked to an increased risk of suicide. De­spite suicide prevention programs, better recognition of depres­sion, and the availability of antidepressants and hospitalization, the overall rate of suicide has not improved over the last several de­cades. All this causes untold suffering to the victims, friends, and family.

But there is hope for more effective and faster-acting antide­pressants. Much of the excitement stems from the serendipitous finding that the N-methyl-D-aspartate (NMDA) antagonist ket­amine rapidly and robustly elevated mood in depressed patients (2). In addition to the discovery that a nonmonoaminergic mecha­nism had antidepressant effects, the study was most remarkable for the fact that mood elevation occurred within hours after the infu­sion and persisted for about a week in some individuals. Subse­quently Zarate et al. (3) replicated this finding in double-blind, pla­cebo-controlled, crossover studies in unipolar and bipolar depression. A body of evidence is now accumulating to indicate that the antidepressant effects of ketamine occur rapidly (within hours) and persist for days to weeks, depending on the individual patient (4). Of particular interest, there seems to be a rapid effect on suicidal ideation (5).

The ketamine findings add to the well-known effects of sleep deprivation to prove that the state of depression is indeed rapidly reversible. (Here we will define rapid response as a clinically mean­ingful and statistically significant treatment effect vs. placebo that is apparent within 24-72 hours after initiation of the therapy.) The sceptics are quick to note that ketamine infusions cause transient psychotomimetic side effects that effectively unblind the treat­ment to both patients and investigators. Clearly there is a need for a study directly comparing ketamine with another drug that has
obvious behavioral side effects but is known to be devoid of anti­depressant effects. Such a trial using midazolam is underway
(ClinicalTrials.gov identifier: NCT00768430).

Regardless of whether one is testing a glutamatergic agent, sleep deprivation, a device such as transcranial magnetic stimula­tion, or other potential drugs such as scopolamine, several caveats should be kept in mind when trying to document rapid antidepres­sant effects .