Regular Research Articles
Sertraline for the Treatment of Depression in Alzheimer Disease

https://doi.org/10.1097/JGP.0b013e3181c796ebGet rights and content

Objective

Depression is common in Alzheimer disease (AD), and antidepressants are commonly used for its treatment, however, evidence for antidepressant efficacy in this population is lacking. The authors conducted a multicenter, randomized, placebo-controlled trial titled “Depression in Alzheimer's Disease-2” to assess the efficacy and tolerability of sertraline for depression in AD.

Methods

One hundred thirty-one participants from five U.S. medical centers with mild-to-moderate AD (Mini-Mental State Examination scores 10-26) and depression of AD were randomized to double-blinded treatment with sertraline (N = 67) or placebo (N = 64), with a target dosage of 100 mg daily. Efficacy was assessed using logistic regressions and mixed effects models in an intention-to-treat analysis with imputation of missing data. Principal outcome measures were modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC), change in Cornell Scale for Depression in Dementia (CSDD) scores, and remission defined by both mADCS-CGIC score ≤2 and CSDD score ≤6.

Results

mADCS-CGIC ratings (odd ratio [OR = 1.01], 95% confidence interval [CI]: 0.52-1.97, p = 0.98), CSDD scores (median difference at 12 weeks 1.2, 95% CI: 1.65-4.05, p = 0.41), and remission at 12 weeks of follow-up (OR = 2.06, 95% CI: 0.84-5.04, p = 0.11) did not differ between sertraline (N = 67) and placebo (N = 64). Sertraline-treated patients experienced more adverse events, most notably gastrointestinal and respiratory, than placebo-treated patients.

Conclusion

Sertraline did not demonstrate efficacy for the treatment depression symptoms in patients with AD. In addition, its use was associated with an increased incidence of adverse events. Thus, selective serotonin reuptake inhibitors may be of limited value for treating depression in patients with AD.

Section snippets

Patients

Participants were recruited from memory clinics at five academic centers in the United States. Participants met criteria for dementia of AD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and had Mini-Mental State Examination scores22 from 10 to 26, inclusive. They also met criteria for depression of AD,4, 5 which compared with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDE requires the presence of three or

Demographics and Clinical Variables

A CONSORT flow chart of study recruitment and retention is in Fig. 1. One hundred thirty-one patients met eligibility criteria and were randomized: 67 to sertraline and 64 to placebo. Participants had a median age of 79 years, and 54% women, 67% were white, 21% African American, and 11% Hispanic/Latino (Table 1). A majority were married, living in their own home, and had at least a high school education. Participants randomized to sertraline had more years of formal education than those in the

DISCUSSION

During the course of 12 weeks, nearly 40% of the study population was judged to be either “better” or “much better” in terms of mood compared with baseline, and nearly 70% were judged at least “a bit better.” Moreover, depression severity, as measured by CSDD score, improved by nearly 50%. However, there were no significant differences between treatment groups on any of the three primary or secondary mood outcomes. In addition, sertraline treatment was associated with an increased rate of

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      Although overall there was evidence of validity of the diagnostic criteria, results indicated that MinD in AD may be an heterogeneous condition, and that patients with MinD may experience higher levels of apathy. The Depression in Alzheimer's Disease Study-2 (DIADS-2) (Rosenberg et al., 2010; Drye et al., 2011) was a 24-week randomised, parallel, placebo controlled clinical trial evaluating efficacy of sertraline in people with mild to moderate AD that also met criteria for MinD (DSM-IV). Sertraline was not superior to placebo on the modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (mADCS-CGIC) at 12 weeks (odds ratio (OR) sertraline = 1.1, 95% CI: 0.4–3.1); or on CSDD scores at 12 (difference = −3, 95% CI: −6.5–0.8) and 24 weeks (difference = −0.2, 95% CI: −4–3.5) or on proportion of patients in remission at 12 (OR sertraline = 1.7, 95%CI: 0.5–6.5) or 24 weeks (OR sertraline = 0.8, 95% CI: 0.3–2.9).

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

    All authors participated in data collection and revision of the paper. Drafting of the paper was done by P.B.R. Data analyses were performed by LTD, CF, BKM, and CLM.

    These disclosures refer to the period between 7/1/02 and 10/31/08, and include any anticipated conflicts through 12/31/09, according to the DIADS-2 Conflict of Interest Policy (available upon 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 Abbot 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., EMD 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 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; Dr. Lyketsos served as a consultant for Organon, Eisai, GSK, Lilly, Wyeth, and Pfizer.

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