A Systematic Approach to Pharmacotherapy for Geriatric Major Depression

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  • A Systematic Approach toPharmacotherapy forGeriatric Major Depression

    Benoit H. Mulsant, MD, MSa,b,*, Daniel M. Blumberger, MD, MScb,c,Zahinoor Ismail, MDa,d, Kiran Rabheru, MDe,Mark J. Rapoport, MDb,f

    Funding: This work was supported in part by grant MH083643 from the US National Institute ofMental Health.Conflicts of Interest: See last page of the article.a Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, Ontario M6J 1H4,

    b onto, 250 Collegerain Intervention,nto, Ontario M6Jalgary, 1403 29th& ECT Program,

    Department of Psychiatry, The Ottawa Hospital, University of Ottawa, 75 Bruyere Street,


    Major depressive disorder Geriatrics Old age Antidepressant agents

    The effectiveness of antidepressants depends in large part on the way they are used. Un-der usual care conditions, the outcomes of antidepressant pharmacotherapy for geriatricdepression have been shown to be mediocre at best.

    Trying to individualize treatment by matching each patient with a specific antidepressantbased on the patients symptoms and an antidepressant putative side-effect profile isineffective. Instead, the outcomes of antidepressant pharmacotherapy for geriatricdepression can be improved markedly when antidepressants are prescribed followingan algorithmic (stepped-care).

    Published guidelines and algorithms for the antidepressant pharmacotherapy for geriatricdepression are informed by published evidence but they do not necessarily conform tothis evidence. This article presents an updated algorithm for the antidepressant pharma-cotherapy for geriatric depression that is based on the authors interpretation of the avail-able evidence.Clin Geriatr Med 30 (2014) 517534* Corresponding author. Centre for Addiction and Mental Health, 1001 QuToronto, Ontario M6J 1H4, Canada.E-mail address: benoit.mulsant@camh.caSuite 137 Y, Ottawa, Ontario K1N 5C7, Canada; f Sunnybrook Health Sciences Centre,FG37-2075 Bayview Avenue, Toronto, Ontario M4C 5N6, Canada

    een Street West,Canada; Department of Psychiatry, Faculty of Medicine, University of TorStreet, Toronto, ON, M5T 1R8, Canada; c Temerty Centre for Therapeutic BCentre for Addiction and Mental Health, 1001 Queen Street West, Toro1H4, Canada; d Hotchkiss Brain Institute, Foothills Hospital, University of CStreet Northwest, Calgary, Alberta T2N 2T9, Canada; e Geriatric PsychiatryKEY POINTS Drug therapy Guidelines Algorithm Stepped carehttp://dx.doi.org/10.1016/j.cger.2014.05.002 geriatric.theclinics.com0749-0690/14/$ see front matter 2014 Elsevier Inc. All rights reserved.

  • Mulsant et al518INTRODUCTION

    Approximately 14% of older Americans are now taking an antidepressant.13 How-ever, this broad use has not been associated with a notable decrease in the burdenof geriatric depression.4,5 This article, based on a selective review of the literature, ex-plores several explanations for this paradox. First, the possible explanations that an-tidepressants are not effective in the treatment of depression or that the results ofrandomized, controlled clinical trials (RCTs) are not applicable to the treatment ofdepression in real-world clinical settings, are discussed and rejected. Instead, the au-thors propose that the efficacy of antidepressants depends in large part on the waythey are used. Evidence is presented to support the proposition that the use of anti-depressant pharmacotherapy is associated with better outcomes when guided by atreatment algorithm (a stepped-care approach) as opposed to an attempt to individ-ualize treatment. Published guidelines and pharmacotherapy algorithms developedfor the treatment of geriatric depression are reviewed. Finally an updated algorithmis proposed, based on the authors interpretation of the available evidence.


    Some investigators have proposed that antidepressants are either not effective or onlyminimally effective except in patients with the most severe depression, pointing outthe small effect sizes in meta-analyses including both published and unpublishedplacebo-controlled RCTs of antidepressants (eg, Refs.68). Several analyses havebeen published specifically to refute these results (eg, Refs.912) or show that psychotro-picmedications (includingantidepressants) are asefficacious asdrugsused to treat gen-eral medical conditions.13 The debate about the true efficacy of antidepressants (ie,whether there is a meaningful difference in the remission or response rates experiencedbypatients randomized to an antidepressant or a placebo) continues.1416Regardless ofthe degree towhich antidepressants aremore efficacious than placebo, patients treatedwith active antidepressants should experience at least the improvement associatedwiththe use of a placebo. However, some published data suggest that patients whosedepression is treated under usual care (nonstudy) conditions are actually less likely torespond to antidepressant treatment or to experience remission of their depressivesymptoms than depressed patients who receive a placebo in an RCT. Poor outcomesfor depressed patients treated under usual care conditions have been reported in boththose treated by primary care providers (PCPs) and those treated by psychiatrists. Forinstance, Meyers and colleagues17 reported that only 30% of adult patients with a majordepressive disorder (MDD) who were treated by a psychiatrist experienced remission oftheir major depressive episode after 3 months, a rate lower than the 30% to 40% rate ofremission typically associated with placebo in RCTs of adults with MDD.12,13


    Some investigators have proposed that antidepressants are not as effective in clinicalpractice as in RCTs because patients who participate in RCTs are not representativeof patients treated in real-world clinical practice. This argument is supported by somepublished data showing that, because of the required eligibility criteria they have tomeet to participate, depressed subjects included in RCTs differ from the populationfrom which they are drawn.18,19 However, the gap between the efficacy of antidepres-

    sants when used in an RCT and their lower effectiveness when used under usual care

  • conditions persists in studies that randomize depressed participants who meet thesame eligibility criteria to either an experimental intervention or usual care. Forinstance, in 2 large geriatric studies, IMPACT20,21 and PROSPECT,2225 olderdepressed participants who met the same eligibility criteria were randomized to eitheran experimental intervention or treatment as usual. In these 2 studies, the responserates associated with usual care (IMPACT: 16% after 12 months; PROSPECT: 19%after 4 months) (Table 1) were less than half the response rates associated with pla-cebo (mean standard deviation: 40% 10%; median: 38%; range: 19%54%)(Fig. 1A) in the 9 published placebo-controlled RCTs that have assessed the efficacyof second-generation antidepressants in older patients with MDD.2634

    Table 1Treatment algorithm and outcomes in 2 randomized studies comparing a stepped-careapproach with treatment as usual for the treatment of late-life depression

    Study (Authors,Ref.

    Year)No. ofPatients Treatment Algorithm Outcomes

    IMPACT (Unutzeret al,20,21

    2001, 2002)

    1801 Step 1: AD (typically an SSRI) orPST (812 wk)

    Step 2:Nonresponse: switch toother AD or PST

    Partial response: combinewith other AD or PST

    Step 3:Combine AD and PSTConsider ECT or otherspecialty services

    Rate of response (50%reduction in depressionscore) after 12 mo:Intervention: 45%Usual care: 19%

    PROSPECT (Mulsantet al,22 2001;Bruce et al,23 2004;Alexopouloset al,24,25

    2005, 2009)

    599 Step 1: Optimize current AD(if applicable)

    Nonresponse: Switch to:Step 2: citalopram 30 mgonce daily

    Step 3: bupropion SR100200 mg twice daily

    Step 4: venlafaxine XR150300 mg once in AM

    Step 5: nortriptyline (target80120 ng/mL)

    Step 6: mirtazapine3045 mg in the evening

    Partial response: Add:Step 2: bupropion SR

    Rate of response (HDRSscore of 10)

    After 4 mo:Intervention: 33%Usual care: 16%

    After 12 mo:Intervention: 54%Usual care: 45%

    Pharmacotherapy for Geriatric Major Depression 519100200 mg twice dailyStep 3: nortriptyline (target80120 ng/mL)

    Step 4: lithium (target0.600.80 mEq/L)

    Then steps 2, 4, 6 fornonresponders

    Also, IPT can be used as analternative to AD or as anaugmentation to AD

    Abbreviations: AD, antidepressant; ECT, electroconvulsive therapy; HDRS, Hamilton Depression

    Rating Scale; IPT, interpersonal therapy; PST, problem-solving therapy; SSRI, selective serotonin re-uptake inhibitor; SR, sustained release; XR, extended release.

  • Fig. 1. (A) Response rates in 9 published randomized placebo-controlled trials of newer an-tidepressants. (B) Remission rates in 9 published randomized placebo-controlled trials ofnewer antidepressants. (C) Discontinuation rates attributed to adverse effects in 9 publishedrandomized placebo-controlled trials of newer antidepressants. (D) Overall discontinuationrates published in 9 published randomized placebo-controlled trials of newer antidepres-sants. Asterisk indicates significant difference between antidepressant and placebo.CR, controlled release; IR, immediate release. (Data from Refs.2634)

    Mulsant et al520

  • Fig. 1. (continued)

    Pharmacotherapy for Geriatric Major Depression 521

  • The process of care in the experimental intervention group in IMPACT and PROS-PECT, or other RCTs, is very different from the process of usual care in primarycare or psychiatric practice (Table 2). Several lines of evidence suggest