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Sertraline for the Treatment of Depression in Alzheimer Disease: Week-24 Outcomes

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Background

Depression and antidepressant use are common in Alzheimer disease (AD), but the effect of antidepressant treatment for depression on longer term outcomes is unknown. The authors report the Week-24 outcomes of patients who participated in a 12-week efficacy study of sertraline for depression of AD.

Methods

One hundred thirty-one participants (sertraline = 67, placebo = 64) with mild-moderate AD and depression participated in the study. Patients who showed improvement on the modified Alzheimer's Disease Cooperative Study Clinical Global Impression-Change (mADCS-CGIC) after 12 weeks of randomized treatment with sertraline or placebo continued double-blinded treatment for an additional 12 weeks. Depression response and remission at 24 weeks were based on mADCS-CGIC score and change in Cornell Scale for Depression in Dementia (CSDD) score. Secondary outcome measures included time to remission, nonmood neuropsychiatric symptoms, global cognition, function, and quality of life.

Results

One hundred seventeen (89.3%) participants completed all study assessments and 74 (56.5%; sertraline = 38, placebo = 36) completed all 24 weeks on randomized treatment. By 24 weeks, there were no between-group differences in depression response (sertraline = 44.8%, placebo = 35.9%; odds ratio [95% CI] = 1.23 [0.64–2.35]), change in CSDD score (median difference = 0.6 [95% CI: −2.26 to 3.46], χ2 [df = 2] = 1.03), remission rates (sertraline = 32.8%, placebo = 21.8%; odds ratio [95% CI] = 1.61 [0.70–3.68]), or secondary outcomes. Common selective serotonin reuptake inhibitor-associated adverse events, specifically diarrhea, dizziness, and dry mouth, and pulmonary serious adverse events were more frequent in sertraline-randomized patients than in placebo subjects.

Conclusions

Sertraline treatment is not associated with delayed improvement between 12 and 24 weeks of treatment and may not be indicated for the treatment of depression of AD.

Section snippets

Subjects

Details of the study design have been published.13 Briefly, participants 1) were recruited from five memory disorder clinics in the United States; 2) met criteria for dementia due to AD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,15 criteria; 3) had Mini-Mental State Examination (MMSE)16 scores of 10–26, inclusive; and 4) met criteria for dAD.17, 18 dAD criteria differ from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-TR15

Demographics and Clinical Variables

One hundred thirty-one patients met eligibility criteria and underwent randomization (sertraline = 67, placebo = 64).14 At study entry participants had a median age of 79 years. Fifty-four percent were women; 67% were non-Hispanic white, 21% African American, and 11% Hispanic/Latino. Participants randomized to sertraline had more years of formal education than those in the placebo group. Baseline MMSE and CSDD scores reflected mild-moderate dementia severity and a moderately depressed group,

DISCUSSION

Sertraline treatment is not associated with long-term improvements in mood outcomes and did not lead to any long-term benefit in nonmood NPSs, function, QoL, or global cognition when dAD criteria were used to specify the presence of depression. Although there was no antidepressant treatment effect, there was significant improvement for the entire study sample in mood, NPSs, and QoL. For instance, 41% of all patients met response criteria and CSDD scores decreased on average by approximately 50%

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    This work was supported by the National Institute of Mental Health, 1U01MH066136, 1U01MH068014, 1U01MH066174, 1U01MH066175, 1U01MH066176, and 1U01MH066177.

    The disclosures given below refer to the period between July 1, 2002, and October 31, 2008, and include any anticipated conflicts through December 31, 2009, according to the Depression of Alzheimer's Disease-2 Conflict of Interest Policy (available on request from the study PI).

    Barbara K. Martin is involved in another trial for which Pfizer donated a different drug; Paul B. Rosenberg has received research funds from Pfizer, Elan, Lilly and Merck in amounts greater than $10,000; Jacobo Mintzer has received research support from Abbott to study donepezil and divalproex sodium, from AstraZeneca to study quetiapine, from BMS to study aripiprazole, from Eli Lilly to study olanzapine, from Forest to study both citalopram and memantine, from Janssen to study galantamine and risperidone, and from Pfizer to study donepezil and memantine; Dr. Mintzer also has been a consultant, paid directly or indirectly, for AstraZeneca, BMS, Eli Lilly, Janssen, Pfizer, Forest, and Aventis. He also has been an unpaid consultant for Targacept and has participated in Speaker's Bureaus for Janssen, Forest, and Pfizer; Daniel Weintraub has received research support from Boehringer Ingelheim; Dr. Weintraub also has been a paid consultant for Acadia Pharmaceuticals, Novartis Pharmaceuticals, Boehringer Ingelheim, Osmotica Pharmaceutical, BrainCells Inc., Merck Serono, and Sanofi Aventis, and has participated on a Speaker's Bureau for Pfizer; Anton P. Porsteinsson is involved in research sponsored by Pfizer to study donepezil and PF04494700, Eli Lilly to study atomoxetine, a gamma-secretase inhibitor and a beta amyloid antibody, Wyeth to study a beta amyloid antibody, GSK to study a PPAR-gamma agonist inhibitor and Forest to study memantine and neramexane; Dr. Porsteinsson has been a paid consultant and participated on a Speaker's Bureau for Pfizer and Forest; Lon S. Schneider is involved in research sponsored by Pfizer; Dr. Schneider has been a paid consultant for Forest, GlaxoSmithKline, Lilly, Merck, and Wyeth; Constantine Frangakis has no conflict of interests; Lea T. Drye has no conflict of interests; Peter V. Rabins has participated on Speaker's Bureaus for Wyeth, Eli Lilly, and Pfizer and has received reimbursement for legal testimony from Janssen Pharmaceutica. Cynthia A. Munro has no conflict of interests; Curtis L. Meinert is involved in another trial for which Pfizer donated a different drug; Dr. Meinert owns shares of GSK stock; Constantine G. Lyketsos was involved in another trial for which Pfizer donated a different drug; he also was involved in research sponsored by Forest to study escitalopram and citalopram and Pfizer to study sertraline and donepezil; and Dr. Lyketsos served as a consultant for Organon, Eisai, GSK, Lilly, Wyeth, and Pfizer.

    Role of the funding source: NIMH scientific collaborators participated on the trial's Steering Committee. Sertraline and matching placebo were provided by Pfizer, Inc., which did not otherwise participate in the design or conduct of the trial. After database lock and study unblinding, the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. All coinvestigators had access to the raw data.

    Roles of Authors and Contributors: All authors participated in data collection and revision of the paper. Initial drafting of the paper was done by DW. Data analyses were performed by LTD, CF, BKM, and CLM.

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