Pharmacologic approaches to treatment resistant depression: a re-examination for the modern era

Treatment-resistant depression (TRD) is common and debilitating. Initial treatment is often insufficient to achieve full remission in a given depressive episode, resulting in more frequent episodes, worsened severity, and major disability.

This review surveys literature on the diagnosis and pharmacological management of TRD in light of recent developments. Evidence regarding commonly used treatment options is critically examined and key recommendations are offered. The review ends by considering drugs acting on the melatonin, acetylcholine, and glutamate systems that hold promise as future options for TRD.

Recent trends and research findings have impacted how the evidence supporting different approaches to TRD should be evaluated. For example, many earlier TRD studies employed tricyclics as the primary antidepressant, but tricyclics have now been superseded by selective serotonin reuptake inhibitors (SSRIs) in routine clinical practice. This deficiency has been addressed by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the largest effectiveness study of TRD ever conducted. However, design characteristics of the STAR*D study preclude simple comparisons with earlier studies.

A shortcoming of most treatment recommendations for TRD is their reliance on older studies that do not reflect the current preeminence of SSRIs in clinical practice. This has distorted the prioritization of pharmacological strategies for TRD. Efforts to correct this distortion with effectiveness research, designed to better reflect current practice trends, require critical consideration of the strengths and limitations of this approach.