Antidepressants and Dementia in the Elderly

Elderly patients with Alzheimer’s disease and other types of dementia commonly develop depression. First-line therapy for these patients routinely includes antidepressant drugs. However, studies evaluating the effectiveness of these drugs for depression in dementia patients — including a large, well-designed study published in the British medical journal The Lancet — suggest that antidepressants offer little benefit and increase the risk of adverse events.

Overview of dementia and depression in the elderly

Dementia is caused by progressive deterioration of the brain, which results in impaired cognition and memory loss. Dementia patients cannot perform many normal daily activities. Alzheimer’s disease, the most common cause of dementia among the elderly, accounts for more than half of all cases. Other causes include multiple small strokes (which produce vascular dementia), Parkinson’s disease, Huntington’s disease and multiple sclerosis.

Detecting depression in dementia patients can be difficult. Symptoms of depression may be mistaken for progression of the underlying dementia. The following may be symptoms of depression in dementia patients:
 

• increased confusion or forgetfulness
• agitation, restlessness or irritability
• loss of appetite
• decreased weight
• fatigue and lack of energy
• withdrawal from others
• decreased talkativeness
• loss of interest or pleasure in once-enjoyed activities
• thoughts of death or suicide
• sleeping difficulty or excessive sleeping

Treatment options for depression in the elderly include drugs (see the table below) and psychosocial and behavioral interventions, including exercise and occupational therapy programs.

Antidepressants Available in the U.S.

* Do Not Use
** Limited Use (offers limited benefit or benefits certain people or conditions)
*** Do Not Use Until Seven Years After Approval

The Lancet study

In a study published on July 30, 2011, researchers in the U.K. conducted a randomized, placebo-controlled trial — the gold standard for clinical trial design — to evaluate two antidepressant drugs for the treatment of depression in patients with dementia. The study involved the drugs sertraline (ZOLOFT, a selective serotonin reuptake inhibitor) and mirtazapine (REMERON, REMERON SOLTAB; a noradrenergic and specific serotonergic antidepressant).

From nine geriatric psychiatric clinics, the researchers enrolled 326 subjects who had probable or possible Alzheimer’s disease and depression, making the study the largest randomized trial ever conducted to evaluate antidepressant drugs for such patients. In an editorial published along with the Lancet study, Dr. Henry Brodaty, an expert on dementia, noted that “this landmark study [is] the largest trial of antidepressant drugs in dementia ever … almost equaling the combined total [number of subjects] from previously published work.”

To be eligible to participate, the patients had to have had depression for at least four weeks. Patients considered to be at high risk of suicide were excluded from the study.

Of the 326 subjects, 107 were randomly assigned to receive sertraline, 108 to receive mirtazapine and 111 to receive placebos (pills that looked like sertraline or mirtazapine tablets but did not contain any active drug). The trial was double-blinded, meaning no one — including the researchers, health care providers of the subjects, pharmacists dispensing the study drugs and subjects themselves — knew to which study group the subjects were assigned. Such blinding is very important for studies evaluating the effect of different treatments on psychological and behavioral symptoms because it helps to minimize the potential for study bias.

All patients also received the usual nondrug treatments provided by the geriatric psychiatric clinics, including a broad range of supportive and problem-solving interventions.

Subjects’ depression was assessed at the beginning of the study and after 13 and 39 weeks of study treatment using a standardized survey instrument called the Cornell Scale for Depression in Dementia (CSDD), which has been shown to be a valid tool for measuring the severity of depression in elderly patients with dementia. The CSDD is completed based upon information obtained from the patient and a caregiver, as well as observations made by the researcher completing the survey instrument. The primary outcome of interest in the study was the change in CSDD scores. A decrease in the CSDD score from baseline indicated an improvement in depression, whereas an increase in the score indicated a worsening of depression.

The researchers found that after 13 weeks of study treatment, subjects in all three groups had significant improvements in their CSDD scores, and this improvement persisted at 39 weeks. Moreover, there was no statistically significant difference in the degree of improvement in depression scores between the three groups after 13 or 39 weeks of treatment, demonstrating that the antidepressant drugs sertraline and mirtazapine were no more effective than placebo for treating depression in patients with dementia.

In addition to getting no benefit from treatment with sertraline or mirtazapine, subjects receiving these drugs experienced significantly more adverse events than subjects receiving placebos. By 39 weeks, 29 of the 111 subjects (26 percent) in the placebo group had experienced one or more adverse events, compared to 46 of the 107 subjects (43 percent) in the sertraline group and 44 of the 108 subjects (41 percent) in the mirtazapine group. The investigators reported that gastrointestinal reactions (usually nausea) were most common with sertraline use, and psychological reactions (usually drowsiness and sedation) were most common with mirtazapine use.

A major strength of this study is that it was designed to closely match real-world clinical practice, increasing the probability that the results are applicable to typical dementia patients with depression.

Prior studies

Seven prior randomized, placebo-controlled studies evaluating the use of antidepressant drugs for treatment of depression in elderly dementia patients were published between 1989 and 2010. These earlier studies provided mixed results, with two studies suggesting that antidepressants offered some benefit and five finding no evidence of benefit.

Six of the seven studies — including the two providing evidence that antidepressants offered some benefit in treating depression in elderly dementia patients — had significant limitations. These limitations included small numbers of enrolled subjects (ranging from 24 to 44 per study), short duration (only six to 12 weeks of study intervention) and, in three cases, inadequate assessment tools (using a survey instrument that has not been validated in elderly dementia patients).

The best prior study, published in The American Journal of Psychiatry in 2010, was a randomized, placebo-controlled, double-blind study evaluating the antidepressant sertraline in Alzheimer’s disease patients with depression. One hundred thirty-one subjects at five medical centers in the U.S. were enrolled, with 67 subjects assigned to receive sertraline and 64 assigned to receive a placebo. The researchers assessed the subjects’ depression symptoms using the CSDD at baseline and at 12 and 24 weeks after starting treatment.

Consistent with the Lancet study results, the researchers for the 2010 study found that depression scores improved for both groups, with no statistically significant difference between the two groups. However, adverse events (particularly diarrhea, dizziness and dry mouth) occurred more frequently in subjects receiving sertraline.

Implications of the Lancet study

In discussing the implications of their study results, the researchers for the Lancet study noted the following:
 

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.

They go on to recommend that the treatment of depression in the setting of dementia should follow a stepped approach, starting with watchful waiting and followed by low-intensity psychosocial interventions. More complex psychosocial interventions can be used later, if needed.

Public Citizen’s Health Research Group strongly agrees with the researchers’ assessment. The evidence from the best studies done to date indicates that for depressed Alzheimer’s disease patients who are not suicidal, antidepressant drugs provide no significant benefit but do increase the risk of adverse events. Thus, the risks of antidepressant drugs as an initial treatment in such patients outweigh their benefits. Treatment with antidepressant drugs generally should be reserved for those patients who do not respond to nondrug interventions.