12/08/11

LONDON – Sertraline and mirtazapine, two commonly prescribed antidepressants shown to carry risks of adverse events in dementia patients, had no more clinical benefit than placebo in people with possible or probable Alzheimer’s disease, a multicenter trial in the United Kingdom found.

Image ©Yvonne Chamberlain/iStockphoto.com Placebo reduced depression more than antidepressants did in dementia.

An estimated 20% of patients with dementia experience depression, and physicians often prescribe antidepressants even though studies of their effectiveness are mixed.

Given the uncertainty, the U.K. National Institute of Health commissioned the Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial, a multi-center, double-blind, randomized trial, to of sertraline and mirtazapine. Researchers led by Dr. Sube Banerjee of the Institute of Psychiatry, Kings College, London, reported their results online first July 18, 2011 in The Lancet (Lancet, 2011;d.o.i.:10.1016/S0140-6736(11)60830-1).

The team recruited more than 300 patients from geriatric psychiatry services in nine centers in England between January 2007 and December 2009. Eligibility criteria were probable or possible Alzheimer’s disease, depression lasting 4 weeks or longer, and a dementia-related depression score of 8 or higher on the Cornell scale for depression in dementia (CSDD). Patients were ineligible if they were clinically critical (e.g., suicide risk), if the study drugs were contraindicated for them, if they already used antidepressants, were in another trial, or had no caregiver.

The researchers assigned 107 patients to receive sertraline, a selective serotonin reuptake inhibitor; 107 to receive mirtazapine, a noradrenergic and specific serotonergic antidepressant; and 111 to receive a placebo. The primary outcome was reduction in depression, as measured by CSDD score, at 13 weeks. One of the secondary outcomes was clinical effectiveness at 39 weeks.

At 13 weeks, the severity of depression decreased in all three groups, but the greatest reduction in CSDD scores occurred with placebo (-5.6, to 7.7) vs. sertraline (-3.9, to 8.6) and mirtazapine (-4.0, to 7.6). At 39 weeks, the change was -4.8 for placebo (to 8.6), -4.0 for sertraline (to 8.5), and -5.0 (to 7.7) for mirtazapine.

By week 13, 3 severe adverse events had occurred in the control group, 8 in the sertraline group, and 10 in the mirtazapine group. Total adverse reactions by week 39 occurred in 29 participants (26%) in the placebo group, 46 (43%) in the sertraline group, and 44 (41%) in the mirtazapine group.

"Our trial has negative findings but important clinical implications," the researchers said. "Analysis of the data suggests clearly that antidepressants, given with normal care, are not clinically effective when compared with placebo for the treatment of clinically significant depression in dementia. This finding implies a need to change the present clinical practice of prescription of antidepressants as the first-line treatment of depression in dementia caused by Alzheimer’s disease."

Instead, the researchers suggested a stepped approach of watchful waiting followed by psychosocial interventions (starting at low-intensity and, if necessary, moving on to complex interventions).

Limitations to the study include the possibility of study bias because the 95 dropouts might have had different responses to the interventions or placebo than did patients who completed the trial, the researchers acknowledged. Other potential limitations include the need to revise the target sample size during the trial, measurement error caused by cognitive impairment, and failure to consider nondrug elements that may have played a role in recovery. However, the researchers said they attempted to replicate clinical practice. Strengths of the study include its size and the broad ranges of depression and dementia severity among the study group.

Many of the 25 study authors had received consultancy fees, speakers’ fees, research funding, or educational support to attend conferences from pharmaceutical companies involved in the manufacture of antidepressants and anti-dementia drugs.

Jeffrey S. Eisenberg is a freelance writer based in Philadelphia.