eatment-resistant depression: therapeutic trends, challenges, and future directions Review (3662) Total Article Views Authors: Al-Harbi KS Published Date May 2012 Volume 2012:6 Pages 369 - 388 DOI: http://dx.doi.org/10.2147/PPA.S29716 Received: 05 January 2012 Accepted: 21 February 2012 Published: 01 May 2012 Khalid Saad Al-Harbi Medical College, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia Background: Patients with major depression respond to antidepressant treatment, but 10%–30% of them do not improve or show a partial response coupled with functional impairment, poor quality of life, suicide ideation and attempts, self-injurious behavior, and a high relapse rate. The aim of this paper is to review the therapeutic options for treating resistant major depressive disorder, as well as evaluating further therapeutic options. Methods: In addition to Google Scholar and Quertle searches, a PubMed search using key words was conducted, and relevant articles published in English peer-reviewed journals (1990–2011) were retrieved. Only those papers that directly addressed treatment options for treatment-resistant depression were retained for extensive review. Results: Treatment-resistant depression, a complex clinical problem caused by multiple risk factors, is targeted by integrated therapeutic strategies, which include optimization of medications, a combination of antidepressants, switching of antidepressants, and augmentation with non-antidepressants, psychosocial and cultural therapies, and somatic therapies including electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation, transcranial direct current stimulation, and vagus nerve stimulation. As a corollary, more than a third of patients with treatment-resistant depression tend to achieve remission and the rest continue to suffer from residual symptoms. The latter group of patients needs further study to identify the most effective therapeutic modalities. Newer biomarker-based antidepressants and other drugs, together with non-drug strategies, are on the horizon to address further the multiple complex issues of treatment-resistant depression. Conclusion: Treatment-resistant depression continues to challenge mental health care providers, and further relevant research involving newer drugs is warranted to improve the quality of life of patients with the disorder.