Major depressive disorder is one of the world’s great public health problems for several reasons: not only is it a common condition that typically begins relatively early in life and usually runs an episodic or chronic course, but it is also an illness for which there are no curative treatments. For example, both older (ie, tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors [MAOIs]) and newer (eg, selective serotonin reuptake inhibitors [SSRIs] and serotonin norepinephrine reuptake inhibitors [SNRIs]) generations of antidepressants have somewhat limited efficacy and are more likely to suppress the underlying pathophysiologic perturbations than actually reverse them. Moreover, for those fortunate enough to respond to antidepressant therapy, the benefits often dissipate within 6 to 9 months of stopping therapy [1]. Intent-to-treat response rates in randomized controlled trials (RCTs) typically hover around 50% for a first course of therapy [2], and a significant minority of depressed people do not remit even when they receive carefully monitored sequential trials of new and old antidepressants [3]. To try to relieve the suffering of patients who are not benefiting from first- and second-line antidepressants, most clinicians now use combinations of antidepressants and add various adjunctive medications, although the efficacy and safety of many of these strategies have not been well studied [4]. Development of novel treatment strategies that have more durable benefits and/or treat patients who have not responded to conventional therapies has thus been a high priority for research for decades, and the two articles in this issue provide concise summaries of the current status of the field of treatment development.
In the first article, Krishnan reviews recent research on the topic of treatmentresistant depression. Although this term can be used descriptively when a patient has not obtained an acceptable response to a course of antidepressant therapy that is both of adequate dose and sufficient duration (eg, a patient’s depression was resistant to an 8-week trial of citalopram titrated to 40 mg/day), in recent years it is more commonly used to describe the subset of treated patients who have not benefited from 2 successive adequate courses of antidepressant therapy in the current episode. Although clinicians and researchers alike often talk about treatment-resistant depression as if it is a subtype of depression, it is more accurately thought of as a description of a patient’s treatment history. Indeed, patients with any of the currently codified depressive subtypes (eg, single or recurrent, atypical, melancholic, psychotic, or chronic) can develop treatment-resistant depressive episodes. Indeed, it is likely that a number of personal pathways and illness trajectories can lead to a period of treatment resistance and treatment-resistant depression that is nearly as heterogeneous as major depressive disorder itself. Among the therapies reviewed by Krishnan, it is noteworthy that interventions as mechanistically diverse as aerobic exercise and deep brain stimulation show promise.
In the second article, Colasanti and Young review some of the more promising targets for novel drug development. Although the authors do not explicitly say so, it is clear from their coverage that we are nearing the “end of the line” for drug discovery targeted simply at monoamine systems, with perhaps “triple” reuptake inhibitors and drugs with complex activities across multiple serotoninergic and noradrenergic receptors being the final compounds to come out of what has been a fruitful 50+ years of research. Some believe that the progressively diminishing remission rates observed across trials in Sequenced Treatment Alternatives to Relieve Depression (STAR*D) [3] is likely to be the result of the similar actions of most of the antidepressants that are currently available. Of course, given the heterogeneity of depression, it is at least possible that the next big discovery will be an antidepressant that makes a large difference for a select subset of patients, with—in an idealized world—an objective method to identify those most likely to respond.
The antidepressant properties of ketamine, which are novel both in terms of speed of onset and likely mechanism of action (ie, NMDA [N-methyl-Daspartatic acid] receptor antagonism), are an important common thread in these two reviews. Although the drug ketamine has too many issues to be used on a wide scale for people with treatment-resistant depression, the fairly consistent and dramatic results observed in the studies completed to date, coupled with the intricate, multisubunit structure of the NMDA receptor, certainly justify the effort to carefully look for other safer compounds that can help those patients who do not obtain adequate relief from our current therapeutic standards.

REFERENCES

1. Thase ME. Preventing relapse and recurrence of depression: a brief review of therapeutic options. CNS Spectr 2006;11(12 Suppl 15):12-21.

2. Thase ME. Do antidepressants really work? A clinicians’ guide to evaluating the evidence. Curr Psychiatry Rep 2008;10(6):487-494.

3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163(11):1905-1917.

4. Thase ME. Antidepressant combinations: widely used, but far from empirically validated. Can J Psychiatry 2011;56(6):317-323.