Review Treatment-resistant depression: Definitions, review of the evidence, and algorithmic approach Roger S. McIntyre a,b,c,d,n , Marie-Josée Filteau e,f,g , Lawrence Martin h , Simon Patry e,i , Andre Carvalho b,j , Danielle S. Cha a,b , Maxime Barakat k , Maia Miguelez k a Institute of Medical Science, University of Toronto, Toronto, ON, Canada b Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8 c Department of Psychiatry, University of Toronto, Toronto, ON, Canada d Department of Pharmacology, University of Toronto, Toronto, ON, Canada e Department of Psychiatry, Laval University, Québec City, QC, Canada f Laval University Robert-Giffard Research Centre, Québec City, QC, Canada g Clinique Marie-Fitzbach, Québec City, QC, Canada h Department of Psychiatry, McMaster University, Hamilton, ON, Canada i Department of Psychiatry, University of Montreal, Montreal, QC, Canada j Psychiatry Research Group, Federal University of Ceará, Faculty of Medicine, Fortaleza, Ceará, Brazil k Bristol-Myers Squibb Canada, Montreal, QC, Canada article info Article history: Received 4 October 2013 Accepted 22 October 2013 Available online 15 November 2013 Keywords: Major depressive disorder Treatment-resistant depression (TRD) Atypical antipsychotics Augmentation Combination Lithium 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. & 2013 Elsevier B.V. All rights reserved. Contents 1. Introduction .......................................................................................................... 2 2. Method.............................................................................................................. 2 3. Results .............................................................................................................. 2 Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/jad Journal of Affective Disorders 0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.10.043 n Corresponding author at: Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8. Tel.: þ1 416 603 5279; fax: þ1 416 603 5368. E-mail address: [email protected] (R.S. McIntyre). Journal of Affective Disorders 156 (2014) 1–7
Transcript
Review
Treatment-resistant depression: Definitions, review of the evidence,and algorithmic approach
Roger S. McIntyre a,b,c,d,n, Marie-Josée Filteau e,f,g, Lawrence Martin h, Simon Patry e,i,Andre Carvalho b,j, Danielle S. Cha a,b, Maxime Barakat k, Maia Miguelez k
a Institute of Medical Science, University of Toronto, Toronto, ON, Canadab Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8c Department of Psychiatry, University of Toronto, Toronto, ON, Canadad Department of Pharmacology, University of Toronto, Toronto, ON, Canadae Department of Psychiatry, Laval University, Québec City, QC, Canadaf Laval University Robert-Giffard Research Centre, Québec City, QC, Canadag Clinique Marie-Fitzbach, Québec City, QC, Canadah Department of Psychiatry, McMaster University, Hamilton, ON, Canadai Department of Psychiatry, University of Montreal, Montreal, QC, Canadaj Psychiatry Research Group, Federal University of Ceará, Faculty of Medicine, Fortaleza, Ceará, Brazilk Bristol-Myers Squibb Canada, Montreal, QC, Canada
a r t i c l e i n f o
Article history:Received 4 October 2013Accepted 22 October 2013Available online 15 November 2013
Background: Most adults with major depressive disorder (MDD) fail to achieve remission with indexpharmacological treatment. Moreover, at least half will not achieve and sustain remission followingmultiple pharmacological approaches. Herein, we succinctly review treatment modalities proveneffective in treatment-resistant depression (TRD).Methods: We conducted a review of computerized databases (PubMed, Google Scholar) from 1980 toApril 2013. Articles selected for review were based on author consensus, adequacy of sample size, the useof a standardized experimental procedure, validated assessment measures and overall manuscriptquality.Results: The evidence base supporting augmentation of conventional antidepressants with atypicalantipsychotics (i.e., aripiprazole, quetiapine, and olanzapine) is the most extensive and rigorous of allpharmacological 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 diseasemodels provide preliminary evidence for the efficacy of immune-inflammatory based therapies andmetabolic interventions. Manual based psychotherapies remain a treatment option, with the mostcompelling evidence for cognitive behavioral therapy. Disparate neurostimulation strategies are alsoavailable for individuals insufficiently responsive to pharmacotherapy and/or psychosocial interventions.Limitations: Compared to non-treatment-resistant depression, TRD has been less studied. Most clinicalstudies on TRD have focused on pharmacotherapy-resistant depression, with relatively fewer studiesevaluating “next choice” treatments in individuals who do not initially respond to psychosocial and/orneurostimulatory treatments.Conclusion: The pathoetiological heterogeneity of MDD/TRD invites the need for mechanisticallydissimilar, and empirically validated, treatment approaches for TRD.
Major depressive disorder (MDD) is a multidimensional common,often severe mental disorder with an age of onset below the age of30 in most affected individuals (Kessler et al., 2012). Major depres-sive disorder is associated with a high rate of non-recovery andrecurrence, with chronicity rates estimated at approximately 20%(van Randenborgh et al., 2012). The estimated annual costs attribu-table to MDD are approximately $83 billion, with indirect costs dueto decreased psychosocial function (notably workforce performance)being a major contributor (Greenberg et al., 2003). For example, it isestimated that MDD is associated with an annual loss of 27.2workdays per ill worker (Kessler et al., 2006). The significant illnessburden attributable to MDD in the general population is dispropor-tionately accounted for by individuals who have not exhibitedrecovery from illness.
Consensus exists that symptomatic remission increases theprobability for recovery in MDD. Available evidence indicates thatthe majority of individuals with MDD receiving guideline-concordant and measurement-based care do not achieve andsustain a fully remitted state with index antidepressant treatment.Results from the STAR-D study indicate that remission ratesdecrease, and subsequent relapse rates increase, as a function ofthe number of failed acute therapies. For example, the overallremission rates reported in STAR-D for the medication optionswere 28%, 25%, 18%, and 10% at steps 1, 2, 3, and 4, respectively.Taken together, the burden of illness attributable to MDD, the highrates of non-remission with most first-line treatment strategies,and the increasing availability of mechanistically dissimilar agents(e.g., psychosocial interventions, neurostimulatory approaches andan expanding array of complementary and alternative medicines[CAM]) provide the impetus for refining therapeutic objectives inMDD, defining treatment-resistant depression (TRD) and provid-ing evidence-based sequential treatment strategies capable ofachieving symptomatic remission (Kennedy et al., 2009a, 2009b).This narrative review broadly aims to define TRD and succinctlyreview the evidence supporting treatment strategies in TRD.
2. Method
We conducted a review of computerized databases (PubMed,Google Scholar) from 1980 to April 2013. “Major DepressiveDisorder” was cross-referenced with treatment-resistant depres-sion, combination, augmentation, cognition, cognitive dysfunction,cognitive deficits, dementia, memory, learning, and functional
outcome. The search was augmented with a manual review ofrelevant article reference lists. Articles selected for review werebased on author consensus, adequacy of sample size, the use ofstandardized experimental procedures, validated assessment mea-sures and overall manuscript quality.
3. Results
Available modalities for TRD are outlined in Table 1.
3.1. Treatment-resistant depression: definition
Operationalizing TRD begins with defining the therapeuticobjectives in MDD. Broadly speaking, the overarching aim intreating MDD is to achieve a fully recovered state with the affectedindividual no longer experiencing clinically significant symptoma-tology and/or functional impairment (e.g., at work, personal andfamily life). Replicated evidence indicates that achieving a“remitted” state significantly increases the probability of recoveryin MDD when compared to the categorical outcome of “responsewith residual depressive symptomatology” (Kennedy et al., 2009a,2009b; McIntyre and Donovan, 2004).
A universally accepted definition for TRD does not currentlyexist. Notwithstanding, it has been proposed that failure to achieve
Table 1Available modalities for treatment-resistant depression.
DBS¼deep brain stimulation; ETC¼electroconvulsive therapy; NSAIDs¼non-ster-oidal anti-inflammatory; and rTMS¼repetitive transcranial magnetic stimulation.
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remission with two or more adequate antidepressant trials definesTRD (Malhi et al., 2005; Souery et al., 1999). A recently publishedsystematic review identified five staging models for TRD (seeTable 2). Each of the staging models defines minimum dosingand duration of therapy, increasing complexity of treatmentmodality as a function of treatment resistance, and inefficacy withelectroconvulsive therapy (ECT) as the most resistant subgroupin MDD.
4. Treatment options
4.1. Pharmacological
4.1.1. Atypical antipsychoticsThree atypical antipsychotic agents are Food & Drug Adminis-
tration (FDA) approved as adjunct (i.e., aripiprazole and quetia-pine) or in combination (olanzapine-fluoxetine combination[OFC]) with antidepressant therapy (Spielmans et al., 2013).Results from two meta-analyses (Spielmans et al., 2013; Nelsonand Papakostas, 2009) concluded that adjunctive atypical anti-psychotics are significantly more effective than placebo with anapproximate two-fold higher odds of achieving remission. Theremission rates for the FDA approved atypical antipsychotic agentswere recently reviewed and are presented in Fig. 1. Atypicalantipsychotics have higher odds for discontinuation compared toplacebo due to akathisia (i.e., aripiprazole), sedation (i.e., quetia-pine), abnormal metabolic laboratory results and weight gain (i.e.,quetiapine, OFC). The adverse event profile of atypical antipsycho-tics have been reviewed elsewhere (Cha and McIntyre, 2012).
The dosing for atypical antipsychotic agents in MDD is notidentical to the effective dose reported in acute mania or psychoticepisodes in schizophrenia. The target dosing for aripiprazole inMDD appears to be between 5 and 20 mg per day with 2 mgrepresenting a reasonable starting dose in most patients (Favaet al., 2012). Quetiapine is reported to be efficacious at 50–300 mgper day with a greater reduction in symptoms seen across moredepressive items at a quetiapine dosing of 150 and 300 mg daily.The dosing for OFC is recommended at 3 mg/25 mg to 12 mg/50 mg tailored to the individual patient.
Taken together, atypical antipsychotics are the most studiedadjunctive agents to selective serotonin reuptake inhibitors (SSRIs)and serotonin-norepinepherine reuptake inhibitors (SNRIs) in thetreatment of adults with MDD, although double-blind recurrenceprevention data is largely unavailable. Moreover, atypicalantipsychotic-related adverse events – notably weight gain, meta-bolic disruption and sedation remain significant limitations forsome of these agents (Cha and McIntyre, 2012).
Combining antidepressants is a treatment strategy that is oftenused when the initial antidepressant is unsuccessful. Notwithstand-ing, the popularity of this approach, no antidepressant is FDAapproved and/or established as reliably effective as an “add-on”/combination treatment strategy in TRD. Moreover, the evidencesupporting adjunctive lithium, thyroid hormone (e.g., triiodothyro-nine) and buspirone is reported with heterogeneous antidepressants– tricyclic antidepressants (TCAs), monoamine oxidase inhibitors(MAOIs) and SSRI/SNRI antidepressants. Most studies have involvedTCAs and MAOIs (i.e., lithium, thyroid hormone). Treatment guide-lines would position combination antidepressants and lithium as afirst-line treatment strategy with thyroid hormone and buspirone asnext-line treatment options (Lam et al., 2009).
Table 2Staging models for TRD.
A. Antidepressant Treatment History Form (ATHF)
0 No treatment or pharmacological agentswith known psychotropic actions
1 Any drug Z4 weeks or less thanminimum adequate daily doseFor ECT 1–3 ECT sessions
2 Any drug Z4 weeks at less thanminimum adequate daily doseFor ECT 4–6 ECT sessionsFor psychotic MDD: whenchlorpromazine equivalent o400 for o3weeks or when monotherapy withantipsychotic (chlorpromazine equivalentZ400 and Z3 weeks)
3 Any drug Z4 weeks at higher thanminimum adequate daily dose, or anydrug at level 3 augmented with lithiumZ2 weeksFor ECT 10–12 unilateral/7–9 bilateral ECTsessionsFor psychotic MDD plus chlorpromazineequivalent Z400 and Z3 weeks
4 Any drug Z4 weeks at higher thanminimum adequate daily dose or any drugat level 3 augmented with lithium Z2weeksFor ECT 10–12 unilateral/7–9 bilateral ECTsessionsFor psychotic MDD plus chlorpromazineequivalent Z400 and Z3 weeks
5 Any drug at level 4 augmented withlithium Z2 weeksFor ECT Z13 unilateral/ Z10 bilateralECT sessionsFor psychotic MDD plus chlorpromazineequivalent Z400 and Z3 weeks
B. Thase and Rush Staging Model (TRSM) (1997)
Stage I Failure of at least one adequate trial of onemajor class of antidepressants
Stage II Failure of at least two adequate trials of atleast two distinctly different classes ofantidepressants
Stage III Stage II resistance plus failure of anadequate trial of a TCAStage IV resistance plus a course ofbilateral ECT
Stage IV Stage III resistance plus failure of anadequate trial of an MAOI
Stage V Stage IV resistance plus a course ofbilateral ECT
C. European Staging Model (ESM)
Stage Definition Durationof trial
a. Non-responder Non-response to oneadequate trial of TCA, SSRI,MAOI, SNRI, ECT or otherantidepressants
6–8 weeks
b. TRD Resistance to two or moreadequate antidepressanttrials of different classes
c. CRD Resistant to severalantidepressant trials,including augmentationstrategy
At least 12months
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4.1.3. Combination with psychostimulantsSeveral negative studies indicate that methylphenidate is not
reliably efficacious as an adjunct to conventional antidepressanttherapy in adults with MDD (Ravindran et al., 2008; Patkar et al.,2006). This suggests that psychostimulants are not effective fortreating TRD per se, but would be more efficacious for residualsymptoms including, but not limited to, fatigue and somnolence.Moreover, negative studies for modafanil in MDD provide ratio-nale for not recommending it as a broad-based treatment for TRD(though efficacy against fatigue and somnolence is suggested)(DeBattista et al., 2003; Dunlop et al., 2007; Fava et al., 2005).
Notwithstanding negative studies for methylphenidate andmodafanil, the prodrug lisdexamfetamine may be capable ofoffering symptom improvement in TRD. The efficacy of lisdexam-fetamine as an adjunct to escitalopram treatment was evaluated inadults (18–55 years old) with MDD. Following 8-weeks of open-label escitalopram treatment (titrated to 20 mg/day), participantswith residual depressive symptoms (17 item Hamilton Rating Scalefor Depression [HAM-D17] score Z4) were re-randomized to6-weeks of double-blind adjunctive lisdexamfetamine (20, 30, or50 mg/day) or placebo. Adults were further stratified as non-remitters (Montgomery–Asberg Depression Rating Scale [MADRS]
410) or remitters at randomization to augmentation (week 8).Efficacy assessments were mean change from week 8 in MADRStotal score. Lisdexamfetamine improved MDD symptoms vs. pla-cebo as determined by HAM-D17 and MADRS. The effect-sizeestimate of lisdexamfetamine was reported at 0.3; comparable tothe effect size estimate for atypical antipsychotic augmentation inMDD (Trivedi et al., 2013).
4.1.4. Glutamatergic agentsThe glutamatergic hypothesis of depression would suggest that
interventions which directly (e.g., ketamine and riluzole) orindirectly (e.g., scopolamine) modulate glutamate function maymitigate depressive symptoms in individuals with MDD (Khajaviet al., 2012; Salvadore and Singh, 2013; Carlson et al., 2013;Kavalali and Monteggia, 2012). The antidepressant effects ofketamine are hypothesized to be mediated by increasedpresynaptic glutamate release with the net effect of enhancingglutamatergic throughput at the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor relative to the N-Methyl-D-aspartic acid receptor (NMDAR) (Ibrahim et al., 2012).Single dose infusions of ketamine (0.5 mg/kg) have been demon-strated to improve depressive symptoms within 1–4 hours inindividuals with TRD. Moreover, suicidal ideation in the contextof TRD has also been reported to be significantly reduced withketamine infusion (Diazgranados et al., 2010).
4.1.5. Complementary alternative medicine (CAM)/nutraceuticalsSeveral CAM/nutraceutical agents have been evaluated and
reviewed comprehensively elsewhere (Kennedy et al., 2009a,2009b). Two recently published studies support the efficacy ofS-adenosyl-methionine (SAMe) as well as L-methylfolate (Papakostaset al., 2010, 2012). Papakostas et al. (2010) evaluated and com-pared SAMe (800 mg/twice a day) to placebo in outpatientsmeeting DSM-IV criteria for MDD aged 18–80. All subjects exhib-ited insufficient response to initial SSRI or SNRI at a stable dose ofadequate duration (which could be defined historically). The HAM-D response and remission rates were higher for subjects receivingadjunctive SAMe (36.1% and 25.8%, respectively) than adjunctiveplacebo (17.6% and 11.7% respectively). The number needed to treat(NNT) for remission was seven; there were no significant differ-ences between groups in the proportion of individuals whodiscontinued medications for any reason and/or to adverse event.
Papakostas et al. (2012) also evaluated the efficacy ofL-methylfolate as an adjunct to SSRIs in two separate clinical trials.The first trial was a 60-day multicentre, randomized, double-blind,sequential, parallel comparison trial of adjunctive L-methylfolatein adults ages 18–65 meeting DSM-IV criteria for MDD. Subjectsreceiving SSRI treatment (i.e., for at least 8 weeks and a stable dosefor at least 4 weeks) were eligible. The study was divided into two30-day phases with a sequential parallel comparison design. In thefirst step, L-methylfolate (7.5 mg) did not offer significant improve-ment in treatment outcome compared to placebo. In those sub-jects whose dose was increased to 15 mg, in phase 2, theyexhibited a significantly greater response rate when compared toindividuals receiving placebo (24% vs. 9%).
4.1.6. Anti-inflammatory-immune based treatmentsThe cytokine hypothesis of depression provides the rationale
for targeting the immune inflammatory system in MDD(Soczynska et al., 2011). A host of agents that are primarilyindicated for immune and/or inflammatory conditions have beenrepurposed for potential benefit in MDD. For example, small openand controlled studies suggest that celecoxib and some non-steroidal anti-inflammatory agents (NSAIDs) are capable of miti-gating depressive symptoms when adjunctively administered in
Table 2 (continued )
D. Massachusetts General Hospital Staging model (MGH-s)
Definition Points
1. Non-response to each adequate(at least 6 weeks of an adequatedosage of an antidepressant) trialof a marketed antidepressantgenerates an overall score ofresistance
1 Point per trial
2. Optimization of dose,optimization of duration, andaugmentation or combination ofeach trial (based on theMassachusetts General Hospitalor Antidepressant TreatmentResponse Questionnaire)increase the overall score
0.5 Point per trial peroptimization oraugmentation strategy
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adults with MDD receiving conventional pharmacotherapy (Abbasiet al., 2012; Gallagher et al., 2012). A recently published proof-of-concept study indicated that the tumor necrosis factor (TNF)antagonist, infliximab, was effective at mitigating depressivesymptoms in MDD (Raison et al., 2013).
Raison et al. (2013) administered the monoclonal antibody,infliximab, intravenously to outpatients with MDD (n¼60) whowere moderately resistant to antidepressant treatment as definedby the MGH staging method. Subjects received three infusions ofinfliximab (15 mg/kg) (n¼30) or placebo (n¼30) at baseline andweeks 2 and 6 of a 12 week trial. The Hamilton Depression RatingScale scores decreased significantly from baseline to endpoint inboth groups with no significant differences between groups. Asignificant interaction between treatments was noted favoringinfliximab-treated patients when the baseline high sensitivity C-reactive protein (hs-CRP) concentration was greater than 5 mg/L (i.e., greater than or equal to a 50% reduction in HAM-D scores at anypoint during treatment; 62% infliximab-treated vs. 33% of placebo-treated subjects).
4.2. Psychotherapy
Several modalities of psychotherapy have been evaluated inadults with MDD (Kennedy et al., 2009a, 2009b). Availableevidence indicates that failure to respond to pharmacotherapy inMDD is not a predictor of non-response to psychotherapy(Schatzberg et al., 2005). A recently published study evaluatedthe effectiveness of cognitive behavioral therapy (CBT) as anadjunct to conventional treatment in primary care patients insuf-ficiently responsive to pharmacotherapy (Wiles et al., 2013). Thestudy was conducted at 73 general practice settings in three UKcenters. Subjects (n¼469, age 18–75 years) were insufficientlyresponsive to antidepressant treatment (minimum 6 weeks dura-tion) with Beck Depression Inventory - Second Edition (BDI-II)
scores of 14 or greater. The intervention group received 12 sessionsof individual group CBT with up to 6 additional sessions if deemedclinically appropriate. Subjects receiving CBT exhibited a signifi-cantly higher response rate at 6 months (when compared to thosein the usual care group (i.e., 46% vs. 22%) (Wiles et al., 2013).
4.3. Neurostimulation
Disparate neurostimulation approaches (e.g., ECT, repetitivetranscranial magnetic stimulation [rTMS], and deep brain stimula-tion [DBS]) have documented efficacy in TRD (see Rizvi et al.,2011). Electroconvulsive therapy has been used in clinical psychia-try for severe depression and TRD for over a century. Efficacy andclinical guidance supporting the appropriate application of ECT iswell documented (Kellner et al., 2012; Kennedy et al., 2009a,2009b). Promising results are also reported for rTMS in TRD withthe advantage of reduced cognitive impairment and improvedpatient acceptability. The evidence for DBS is compelling as anacute treatment strategy in highly resistant populations (Lozanoet al., 2012). Follow-up evaluation after 3–6 years indicates thatresponse rates average 64% with progressive improvement infunction in areas of physical health and social functioning(Kennedy et al., 2011).
4.4. Aerobic exercise
Several lines of evidence indicate that exercise may be a viableaugmentation strategy for individuals with mood disorders insuf-ficiently responding to conventional pharmacotherapy (Kucyiet al., 2010). Trivedi et al. (2011) evaluated the role of aerobicexercise as an augmentation to antidepressant therapy in indivi-duals insufficiently responsive to adequate dose/duration SSRItherapy (i.e., HAM-D score 4 14). To be eligible, subjects couldnot exceed a daily energy expenditure of 35 kcal/kg/day (KKW) or
Fig. 1. Remission rates with atypical antipsychotics in major depressive disorder (adapted from Spielmans et al., 2013).
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exercise 3 or more days per week for 20 min or more per sessionover the past month. Eligible subjects were randomized to anacute (i.e., 12 week) trial of a higher end public health dose ofexercise (i.e., 16 KKW). The dosing of 16 KKW was based on publichealth physical activity recommendations and required walking atapproximately 4.0 mph for 210 min per week. The 4 KKW dosewas equivalent to walking 3.0 mph for 75 min per week andreflected minimal activity by public health standards. There weresignificant improvements in depressive symptoms in both groupsat study endpoint; adjusted remission rates at week 12 were 28.3%vs. 15.5% for the 16 KKW and 4 KWW groups, respectively, leadingto an NNT of 7.8 for the 16 KKW vs. 4 KKW group. Although theremission rates were higher in the 16 KKW group, they did notreach statistical significance. Nonetheless, the difference betweenthe two intervention groups was clinically significant as evidencedby the NNT.
5. Conclusion and synthesis
Major depressive disorder is a common and often severemental disorder associated with substantial illness related burden.Most individuals receiving conventional pharmacotherapy fail toachieve and sustain remission; a critical determinant of fullfunctional recovery. As a consequence, the majority of individualsstarting antidepressant treatment will require either an adjunctivetreatment strategy or a switch to a different treatment avenue,which may include initiating and combining different pharmaco-logical agents and/or psychosocial interventions.
Several definitions and staging models have been proposed forTRD. Although a universal definition does not exist, a generalconsensus is that failure to respond to two or more mechanisti-cally dissimilar antidepressants would identify a treatment-resistant population.
Accumulating evidence indicates that a principle determinantof whether a chosen treatment strategy will result in remission issymptomatic improvement within the first couple of weeks (i.e.,positive predictive value) (Kudlow et al., 2012). Conversely, thelack of symptomatic improvement in the first couple of weeks (i.e.,negative predictive value) may be a more robust predictor of non-remission after 6–8 weeks (Kudlow et al., 2012).
Combination antidepressants remain a popular treatmentstrategy with practitioners despite the absence of replicatedcontrolled trials demonstrating the superiority of this approachover placebo. The most robust evidence as augmentation ofconventional antidepressant therapy is with several atypical anti-psychotics (i.e., aripiprazole, quetiapine, and OFC). The evidencebase does not provide sufficient guidance as to whether indivi-duals should receive augmentation of index treatment or discon-tinuation of index treatment and switch to alternative treatmentstrategies. Patient preference and clinical experience supports thepractice of augmenting index agents when partial symptomaticimprovements are observed.
A variety of pharmacologically distinct agents have beenevaluated in heterogeneous TRD samples. The evidence for lithiumand thyroid hormone is disproportionally represented by combi-nation with TCAs and MAOIs. Emerging evidence for treatmentstargeting glutamate, inflammatory, and metabolic/oxidative path-ways is available. Evidence supporting psychostimulants and/oragents with stimulant-like properties is mixed, with the mostcompelling evidence available for lisdexamfetamine. The con-trolled trial evidence supports the use of CBT and aerobic exerciseas a behavioral treatment strategy in TRD; moreover, there isrobust evidence to support currently available neurostimulatorymodalities.
Research vistas in TRD include identifying baseline determi-nants of treatment response and tolerability (e.g., biomarkers) toreduce the proportion of individuals who have insufficient out-comes. There remains a paucity of long-term recurrence preven-tion data in TRD; a significant gap given the high recurrencevulnerability in this population. Combining pharmacological treat-ments with psychosocial/behavioral approaches at the indexepisode of depression in treatment naïve individuals have beeninsufficiently studied. Available evidence, albeit with mixedresults, indicates that complementary pharmacology may providea higher probability of remission when compared to singlemodality treatment (Rush et al., 2011; Blier et al., 2010). Theobservation that the majority of mental disorders begin prior toage 25, and that MDD exhibits a progressive course in manyaffected individuals underscores the importance of early detection,prodromal characterization, and eventual prevention of mentalillness.
Role of funding sourcePublication costs associated with this paper were paid to Elsevier by Bristol-
Myers Squibb Canada Co. Bristol-Myers Squibb Canada Co. did not place restrictionson the form or content of this paper.
Conflict of interestDr. Roger McIntyre declares that he has been on advisory boards and/or
received honoraria for educational activities and/or research grants from AstraZeneca, 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/orreceived speaker's honorarium from Bristol-Myers Squibb, CANMAT AndropauseQuébec, Lilly, Lundbeck, Pfizer and Valeant.
Dr. Lawrence Martin declares that he has been a speaker and a member ofadvisory committees for Bristol-Myers Squibb Canada, Ortho-Janssen, Lundbeck,Pfizer and Sunovion.
Dr. Simon Patry declares that he has been a speaker and a member of advisorycommittees, and has received travel and research grants from Astra Zeneca, BristolMyers Squibb, Forest, Janssen, Lilly, Lundbeck, Pfizer and Shire.
At time of writing Dr. Maxime Barakat was Executive Director, of Medical andRegulatory Affairs, Bristol-Myers Squibb, Canada.
At time of writing, Dr. Maia Miguelez was Senior Scientific Advisor, ofNeurosciences Medical Affairs, Bristol-Myers Squibb, Canada.
Dr. Andre Carvalho and Danielle S. Cha did not declare any conflicts of interest.
AcknowledgementsEditorial support was provided by Elsevier, Canada.
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