Long-Term SSRI Use May Slow Progression to Alzheimer’s Dementia

Long-term selective serotonin reuptake inhibitor (SSRI) maintenance treatment might be beneficial for elderly patients, even after depressive symptoms have resolved, suggested a study published in November 28, 2017, in the American Journal of Psychiatry.

Patients with mild cognitive impairment (MCI) and previous depression who used SSRIs long term (more than four years) experienced a delay in the onset of Alzheimer’s dementia by about three years, compared with those who used SSRIs only short term or who had no treatment. In fact, using other, non-SSRI antidepressants was associated with a higher risk of progression from MCI to Alzheimer’s dementia.

Katharina Wislsperger

The researchers were not surprised that the data showed long-term SSRIs were beneficial in this way, given the spate of animal and human studies suggesting similar findings. “However, we had not expected to find that use of non-SSRI antidepressants was associated with a higher risk of progression from mild cognitive impairment to Alzheimer’s disease,” explained study co-author Anja Schneider, M.D., chair of the Department of Neurodegenerative Diseases and Geriatric Psychiatry at the University Hospital in Bonn, Germany.

As has been previously reported, the study also found that MCI and Alzheimer’s dementia are associated with a history of depression. Those with MCI were 2.6 times more likely to have a history of depression, compared with those without cognitive impairments. Participants with Alzheimer’s were 3.77 times more likely to have had depression.

Even a modest delay in the progression from MCI to Alzheimer’s could have a huge impact on public health costs, lead author Claudia Bartels, Ph.D., of the University Medical Center GɆttingen in Germany, and colleagues wrote. According to a report by the Alzheimer’s Association, delaying the onset of Alzheimer’s by five years would save more than $220 billion within the first five years.

SSRIs Delay, Don’t Stop Progression to Alzheimer’s

Previous studies on the effects of SSRIs on dementia progression have been inconclusive, with some finding favorable effects; others, no effects; and some suggesting that SSRIs hasten disease pathology. Most, however, covered only short time spans, ranging from 8 weeks to 24 weeks of treatment, and typically involved patients who already had Alzheimer’s. For this analysis, Bartels and colleagues included patients with MCI who had taken SSRIs for more than four years (1,610 days), on average.

In total, 755 patients aged 55 to 90 were culled from the multicenter Alzheimer’s Disease Neuroimaging Initiative (ADNI). The participants, who did not currently have major depression, underwent MRI scans, genetic and cerebrospinal fluid (CSF)/blood biomarker testing, and participated in regular follow-up assessments of their cognitive state by clinicians. Participants were categorized at baseline as cognitively normal control subjects, patients with MCI, and patients with Alzheimer’s dementia; they were comprehensively reassessed every six months or annually for progression from cognitively normal to MCI or Alzheimer’s dementia, or from MCI to Alzheimer’s dementia.

The researchers found a delay of approximately three years in MCI progression to Alzheimer’s dementia in patients with previous depression who received long-term SSRI treatment. However, three years from the start of observation, the advantage of long-term SSRI treatment “dissolved,” researchers noted, and all had similar rates of progression from MCI to Alzheimer’s dementia, regardless of treatment. “The data indicate that SSRIs can delay the progression of Alzheimer’s disease pathology, but cannot stop it,” Schneider said.

CSF Beta-Amyloid Levels Similar Across Treatment Groups

The researchers also examined whether long-term use of SSRIs can lower CSF beta-amyloid plaque loads—an important precursor of Alzheimer’s. Previous studies on animals have also shown that SSRI treatment reduces amyloid plaque burden and cognitive impairment.

The AJP study, however, found no differences in the CSF beta-amyloid levels among those in the different antidepressant treatment groups in the study. Schneider explained that the SSRIs might still have worked by inhibiting beta-amyloid production, because it is not proven that effects of amyloid-lowering drugs are reflected in cerebrospinal fluid beta-amyloid concentrations. Alternatively, she said, it is possible that SSRIs act in a different way, such as by modulating neuroinflammation or nerve growth factors.

Research by Donald R. Royall, M.D., chief of Aging and Geriatric Psychiatry at the University of Texas Health Science Center in San Antonio, concurred that depression, even subclinical depressive symptoms, causes cognitive decline. While he has found that presence of depressive symptoms boosts dementia conversion risk, it is not necessarily by an Alzheimer’s disease-specific process.

“That would explain why the beta-amyloid biomarkers were negative in their study,” said Royall, who has done numerous research studies on Alzheimer’s dementia, cognitive issues, and depression.

It is not clear whether SSRIs work in reducing conversion risk by reducing depressive symptom burden or by some other mechanism, he said. “I’ve shown (the SSRI) sertraline to improve cognition, but by an unknown mechanism. Ultimately, I don’t think it protects people from dementia because its effect seems limited to frontal functions.”

Since there are currently no treatments indicated for MCI, Royall suggested clinicians could consider prescribing SSRIs off label for patients with MCI and a history of depression or even subclinical depression.

Ultimately, the data may have important clinical practice implications, pending validation in an intervention trial, Bartels and colleagues wrote. “A prospective study to confirm SSRI effects on MCI progression is now warranted, as an SSRI-mediated delay may contribute to an overall lower prevalence of Alzheimer’s dementia, with a major impact on affected individuals, caregivers, public health, and health costs.”

Patients live between four to eight years on average after being diagnosed with Alzheimer’s. According to the Alzheimer’s Association, care for people living with the disease cost a total of $226 billion in the United States in 2015—and that figure is expected to nearly double over the next 13 years. ■