Antidepressants and Dementia: More Risk than Benefit?

Evidence shows increased side effect risk, but no improvement in symptoms with antidepressants

By Christie Fleetwood, ND, RPh

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Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomized, multicentre, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):403-411.


A parallel-group, double-blind, placebo-controlled, Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial in participants from old-age psychiatry services in 9 centers in England.


Old-age psychiatry services in 9 centers in England provided the participants. Participants were eligible if they had probable or possible Alzheimer's disease, depression (lasting ≥4 weeks), and a Cornell scale for depression in dementia (CSDD) score of 8 or more. Participants were ineligible if they were clinically critical (eg, suicide risk), contraindicated to study drugs, on antidepressants, in another trial, or had no caregiver.

Study Medication and Dosage

Sertraline (target dose 150 mg per day), mirtazapine (45 mg), or placebo

Outcome Measures

The primary outcome was reduction in depression (CSDD score) at 13 weeks (outcomes to 39 weeks were also assessed), assessed with a mixed linear-regression model adjusted for baseline CSDD, time, and treatment center.

Key Findings

Decreases in depression scores at 13 weeks did not differ between 111 controls and 107 participants allocated to receive sertraline (mean difference 1.17; 95% CI: -0.23–2·58; P=0.10) or mirtazapine (0.01; 95% CI: -1.37–1.38; P=0.99), or between participants in the mirtazapine and sertraline groups (1.16; 95% CI: -0.25–2.57; P=0.11); these findings persisted to 39 weeks. Fewer controls had adverse reactions (29 of 111 [26%]) than did participants in the sertraline group (46 of 107 [43%]; P=0.010) or mirtazapine group (44 of 108 [41%]; P=0.031), and fewer serious adverse events rated as severe (control group) (P=0.003). Five patients in every group died by week 39.

Practice Implications

Antidepressants did not improve results over placebo; however they did increase risk of adverse events. Therefore, the current practice of using antidepressants with usual care as first-line treatment of depression in Alzheimer's disease should be reconsidered. “Usual care” in this study included referral to old age psychiatric care.


The study noted that, “Despite these findings, present practice is to use antidepressants, often sertraline, as first-line treatment for depression in dementia.” What were the findings? In searching the literature, which they found to be “sparse and equivocal,” the authors of the article found 6 relevant studies (systematic reviews from PubMed and Cochrane Library databases) on the treatment of depression in people with dementia, and only 3 of those could be meta-analyzed. One study had balanced findings (using the tricyclic antidepressant clomipramine in 24 individuals)1, the 2nd was negative (using the tricyclic antidepressant imipramine in 61 individuals)2, and the 3rd positive (using selective serotonin reuptake inhibitor sertraline in 44 individuals).3 The review concluded that there was only weak evidence of the effectiveness of antidepressants in dementia. The tricyclics are drugs not commonly used in the population (depression in dementia) secondary to anticholinergic side effects. One other relevant randomized trial looked at 67 people given sertraline compared with 64 given placebo.4,5 No benefit of sertraline was reported at 12 or 24 weeks.

Despite these studies’ findings, present practice is to use antidepressants, often sertraline, as first-line treatment for depression in dementia. Knowing how severe and challenging a public-health issue dementia is and that depression is common in dementia, the authors of the current study set out to determine whether this subset of depressed patients were better served on antidepressants or not. And after 13 weeks of the trial, they found that the greatest absolute improvement occurred with placebo.

“Because of the absence of benefit compared with placebo and increased risk of adverse events, the present practice of use of these antidepressants, with usual care, for first-line treatment of depression in Alzheimer’s disease should be reconsidered,” the authors concluded.

The caregivers of these depressed dementia patients scored higher on the quality of life scores and higher on mental health scores if their relatives were given placebo.

Antidepressants, as a drug category, have established side effects such as increased suicidal ideation and potentially severe changes in mood. Mood changes are prominent in dementia patients as well, so the use of such an agent to an individual dealing with dementia is problematic from the outset. In addition, many of our elders are taking multiple prescription drugs, and antidepressants have a long list of drug-drug interactions. Unfortunately, dementia patients may not be able to adequately communicate new or changing symptoms from these interactions.

Interestingly, the caregivers of these depressed dementia patients scored higher on the quality of life scores and higher on mental health scores if their relatives were given placebo, rather than sertraline. The caregivers of participants in the mirtazapine group also had higher quality of life scores than did the sertraline group, at least at the 13-week mark.

And who fared the best, overall? Remember that “usual care” in this study included referral to old-age psychiatric services. Those depressed dementia patients who were referred to old-age psychiatric services showed a strong, consistent pattern of improvement in the depression at 13- and 30-week follow-ups. Maybe our elders just need someone to spend time with them, rather than yet another pill to pop. Maybe our reliance on technology has overrun our reason and common sense. Maybe if we spent time engaged in conversation and actually lived life with our elders, they wouldn’t develop dementia to begin with. Maybe if we focused on true prevention—eating real foods, drinking clean water, exercising daily exercise in a way we enjoy, engaging in healthy relationships, keeping minds active, maintaining supportive social structures—we would all have a better chance at growing old without a disease to mar our elder years of wisdom.

About the Author

Christie Fleetwood, ND, RPh, is a naturopathic doctor and registered pharmacist in private practice in central Virginia. She’s a new contributor to the Natural Medicine Journal.


1. Petracca G, Tesón A, Chemerinski E, Leiguarda R, Starkstein SE. A double-blind placebo-controlled study of clomipramine in depressed patients with Alzheimer's disease. J Neuropsychiatry Clin Neurosci. 1996;8(3):270-275.

2. Reifler BV, Teri L, Raskind M, et al. Double-blind trial of imipramine in Alzheimer's disease patients with and without depression. Am J Psychiatry. 1989;146(1):45-49.

3. Lyketsos CG, Sheppard JM, Steele CD, et al. Randomized, placebo-controlled, double-blind clinical trial of sertraline in the treatment of depression complicating Alzheimer's disease: initial results from the Depression in Alzheimer's Disease study. Am J Psychiatry. 2000;157(10):1686-1689.

4. Rosenberg PB, Drye LT, Martin BK, et al. Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry. 2010;18(2):136-145.

5. Weintraub D, Rosenberg PB, Drye LT, et al. Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes. Am J Geriatr Psychiatry. 2010;18(4):332-340.