title: Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach.
abstract: BACKGROUND
  Most adults with major depressive disorder (MDD) fail to achieve remission with index pharmacological treatment. Moreover, at least half will not achieve and sustain remission following multiple pharmacological approaches. Herein, we succinctly review treatment modalities proven effective in treatment-resistant depression (TRD).
  
  
  METHODS
  We conducted a review of computerized databases (PubMed, Google Scholar) from 1980 to April 2013. Articles selected for review were based on author consensus, adequacy of sample size, the use of a standardized experimental procedure, validated assessment measures and overall manuscript quality.
  
  
  RESULTS
  The evidence base supporting augmentation of conventional antidepressants with atypical antipsychotics (i.e., aripiprazole, quetiapine, and olanzapine) is the most extensive and rigorous of all pharmacological approaches in TRD. Emerging evidence supports the use of some psychostimulants (i.e., lisdexamfetamine) as well as aerobic exercise. In addition, treatments informed by pathogenetic disease models provide preliminary evidence for the efficacy of immune-inflammatory based therapies and metabolic interventions. Manual based psychotherapies remain a treatment option, with the most compelling evidence for cognitive behavioral therapy. Disparate neurostimulation strategies are also available for individuals insufficiently responsive to pharmacotherapy and/or psychosocial interventions.
  
  
  CONCLUSIONS
  Compared to non-treatment-resistant depression, TRD has been less studied. Most clinical studies on TRD have focused on pharmacotherapy-resistant depression, with relatively fewer studies evaluating "next choice" treatments in individuals who do not initially respond to psychosocial and/or neurostimulatory treatments.
  
  
  CONCLUSIONS
  The pathoetiological heterogeneity of MDD/TRD invites the need for mechanistically dissimilar, and empirically validated, treatment approaches for TRD.
authors: Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada. Electronic address: roger.mcintyre@uhn.ca.
authors: Roger S
authors: RS
authors: McIntyre
authors: Department of Psychiatry, Laval University, Québec City, QC, Canada; Laval University Robert-Giffard Research Centre, Québec City, QC, Canada; Clinique Marie-Fitzbach, Québec City, QC, Canada.
authors: Marie-Josée
authors: MJ
authors: Filteau
authors: Department of Psychiatry, McMaster University, Hamilton, ON, Canada.
authors: Lawrence
authors: L
authors: Martin
authors: Department of Psychiatry, Laval University, Québec City, QC, Canada; Department of Psychiatry, University of Montreal, Montreal, QC, Canada.
authors: Simon
authors: S
authors: Patry
authors: Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8; Psychiatry Research Group, Federal University of Ceará, Faculty of Medicine, Fortaleza, Ceará, Brazil.
authors: Andre
authors: A
authors: Carvalho
authors: Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8.
authors: Danielle S
authors: DS
authors: Cha
authors: Bristol-Myers Squibb Canada, Montreal, QC, Canada.
authors: Maxime
authors: M
authors: Barakat
authors: Bristol-Myers Squibb Canada, Montreal, QC, Canada.
authors: Maia
authors: M
authors: Miguelez
mesh_terms: D000328:Adult; D000465:Algorithms; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000628:therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000175:diagnosis / Q000628:therapy*; D006801:Humans
keywords: Atypical antipsychotics; Augmentation; Combination; Lithium; Major depressive disorder; Treatment-resistant depression (TRD)