Management of Treatment-Resistant Depression: Challenges and Strategies

Treatment-resistant depression (TRD) is a form of major depressive disorder that does not respond to standard first-line treatments. Although no consensus definition exists, all models require an inadequate response to at least two trials of antidepressant medication. This review compiles meta-analyses, trials, and reviews on TRD challenges and management. It discusses confounds in definitions and staging, difficulties in assessment, and pharmacological augmentation strategies (lithium, triiodothyronine, second-generation antipsychotics, switching antidepressant class). Somatic therapies (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation), psychotherapeutic approaches, and novel treatments (ketamine, psilocybin, anti-inflammatories) are reviewed. The evidence indicates that further large-scale work is needed to understand appropriate treatment pathways and prescribe effective options.

Study at a glance

Abstract

Treatment-resistant depression (TRD) is a subset of Major Depressive Disorder which does not respond to traditional and first-line therapeutic options. There are several definitions and staging models of TRD and a consensus for each has not yet been established. However, in common for each model is the inadequate response to at least 2 trials of antidepressant pharmacotherapy. In this review, a comprehensive analysis of existing literature regarding the challenges and management of TRD has been compiled. A PubMed search was performed to assemble meta-analyses, trials and reviews on the topic of TRD. First, we address the confounds in the definitions and staging models of TRD, and subsequently the difficulties inherent in assessing the illness. Pharmacological augmentation strategies including lithium, triiodothyronine and second-generation antipsychotics are reviewed, as is switching of antidepressant class. Somatic therapies, including several modalities of brain stimulation (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation) are detailed, psychotherapeutic strategies and subsequently novel therapeutics including ketamine, psilocybin, anti-inflammatories and new directions are reviewed in this manuscript. Our review of the evidence suggests that further large-scale work is necessary to understand the appropriate treatment pathways for TRD and to prescribe effective therapeutic options for patients suffering from TRD.