Review
Treatment-resistant depression: Definitions, review of the evidence, and algorithmic approach

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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.

Limitations

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.

Conclusion

The pathoetiological heterogeneity of MDD/TRD invites the need for mechanistically dissimilar, and empirically validated, treatment approaches for TRD.

Introduction

Major depressive disorder (MDD) is a multidimensional common, often severe mental disorder with an age of onset below the age of 30 in most affected individuals (Kessler et al., 2012). Major depressive disorder is associated with a high rate of non-recovery and recurrence, with chronicity rates estimated at approximately 20% (van Randenborgh et al., 2012). The estimated annual costs attributable to MDD are approximately $83 billion, with indirect costs due to decreased psychosocial function (notably workforce performance) being a major contributor (Greenberg et al., 2003). For example, it is estimated that MDD is associated with an annual loss of 27.2 workdays per ill worker (Kessler et al., 2006). The significant illness burden attributable to MDD in the general population is disproportionately accounted for by individuals who have not exhibited recovery from illness.

Consensus exists that symptomatic remission increases the probability for recovery in MDD. Available evidence indicates that the majority of individuals with MDD receiving guideline-concordant and measurement-based care do not achieve and sustain a fully remitted state with index antidepressant treatment. Results from the STAR-D study indicate that remission rates decrease, and subsequent relapse rates increase, as a function of the number of failed acute therapies. For example, the overall remission rates reported in STAR-D for the medication options were 28%, 25%, 18%, and 10% at steps 1, 2, 3, and 4, respectively. Taken together, the burden of illness attributable to MDD, the high rates of non-remission with most first-line treatment strategies, and the increasing availability of mechanistically dissimilar agents (e.g., psychosocial interventions, neurostimulatory approaches and an expanding array of complementary and alternative medicines [CAM]) provide the impetus for refining therapeutic objectives in MDD, defining treatment-resistant depression (TRD) and providing evidence-based sequential treatment strategies capable of achieving symptomatic remission (Kennedy et al., 2009a, Kennedy et al., 2009b). This narrative review broadly aims to define TRD and succinctly review the evidence supporting treatment strategies in TRD.

Section snippets

Method

We conducted a review of computerized databases (PubMed, Google Scholar) from 1980 to April 2013. “Major Depressive Disorder” was cross-referenced with treatment-resistant depression, combination, augmentation, cognition, cognitive dysfunction, cognitive deficits, dementia, memory, learning, and functional outcome. The search was augmented with a manual review of relevant article reference lists. Articles selected for review were based on author consensus, adequacy of sample size, the use of

Results

Available modalities for TRD are outlined in Table 1.

Atypical antipsychotics

Three atypical antipsychotic agents are Food & Drug Administration (FDA) approved as adjunct (i.e., aripiprazole and quetiapine) or in combination (olanzapine-fluoxetine combination [OFC]) with antidepressant therapy (Spielmans et al., 2013). Results from two meta-analyses (Spielmans et al., 2013, Nelson and Papakostas, 2009) concluded that adjunctive atypical antipsychotics are significantly more effective than placebo with an approximate two-fold higher odds of achieving remission. The

Conclusion and synthesis

Major depressive disorder is a common and often severe mental disorder associated with substantial illness related burden. Most individuals receiving conventional pharmacotherapy fail to achieve and sustain remission; a critical determinant of full functional recovery. As a consequence, the majority of individuals starting antidepressant treatment will require either an adjunctive treatment strategy or a switch to a different treatment avenue, which may include initiating and combining

Role of funding source

Publication costs associated with this paper were paid to Elsevier by Bristol-Myers Squibb Canada Co. Bristol-Myers Squibb Canada Co. did not place restrictions on the form or content of this paper.

Conflict of interest

Dr. Roger McIntyre declares that he has been on advisory boards and/or received honoraria for educational activities and/or research grants from Astra Zeneca, Bristol-Myers Squibb, Janssen-Ortho, Eli Lily, Forest, Lundbeck, Pfizer, Shire, Merck, Sepracor and Otsuka.

Dr Marie-Josée Filteau declares that she has been on advisory boards, and/or received speaker's honorarium from Bristol-Myers Squibb, CANMAT Andropause Québec, Lilly, Lundbeck, Pfizer and Valeant.

Dr. Lawrence Martin declares that he

Acknowledgements

Editorial support was provided by Elsevier, Canada.

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