Antidepressants for Dementia Prevention?

Treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram lowers amyloid-beta-42 (Aβ42) levels in the cerebrospinal fluid (CSF) of cognitively normal older adults, suggesting a potential role for these drugs in the prevention of Alzheimer’s disease (AD), researchers say.

However, it remains to be seen whether the “relatively modest” reduction in CSF Aβ42 will translate into clinical benefit, they acknowledge.

Dr Yvette Sheline

“We see two potential ways to advance this area,” Yvette Sheline, MD, University of Pennsylvania, Philadelphia, Pennsylvania, told Medscape Medical News. “One is to increase the drug effect by finding a molecule that more specifically binds to the receptors that induce the amyloid-beta reduction,” she said.

“The other avenue would be to combine it with another effective drug and thereby gain additive reductions in amyloid. For example, it is possible that combining it with an antiamyloid drug such as an antibody might increase the potency,” she added.

The study was published online September 10 in Neurology.

In retrospective studies, in individuals who had a history of treatment with SSRIs, there was a significant reduction in amyloid plaque binding, as evidenced on positron-emission tomography.

In addition, studies in mice have shown that SSRIs increase alpha-secretase, which causes the cleavage of the amyloid precursor protein, resulting in less amyloid.

In the current study, Sheline and colleagues examined the effects of escitalopram in 114 cognitively normal adults aged 50 years and older.

They used lumbar puncture to determine CSF Aβ42 levels before and after the patients received escitalopram 20 mg/day for 2 or 8 weeks or 30 mg/day for 8 weeks. Control participants were given placebo.

When the two dose regimens were evaluated together, there was a significant overall 9.4% percentage point greater reduction in CSF Aβ42 in escitalopram-treated patients compared with placebo-treated patients (P < .001; 95% CI, 4.9% to 14.2%; Cohen’s d = 0.81).

Positive baseline amyloid-beta status (CSF Aβ42 levels <250 pg/mL) correlated with smaller Aβ42 reduction (P = .006; 95% CI, -16.7% to -0.5%; d = -0.52) compared with negative baseline amyloid status (CSF Aβ42 levels >250 pg/mL).

“Development of safe and effective therapeutic approaches that can reduce Aβ levels even modestly may prevent pathological amyloid accumulation and the subsequent cascade of neuronal damage which could prevent or slow progression to symptomatic AD,” the investigators conclude.

Clinical Impact Still Unclear

Reached for comment, Vijay K. Ramanan, MD, PhD, Department of Neurology, Mayo Clinic, Rochester, Minnesota, noted that some literature from model system and human studies, including the current study, indicate that SSRIs may affect amyloid pathophysiology and have the potential to influence underlying disease mechanisms.

However, he added, “It is still unclear what any modest lowering of amyloid in the CSF in this setting may mean for longer-term amyloid levels in the brain parenchyma or, for that matter, for other AD biomarkers and relevant clinical outcomes.”

Ramanan pointed out that few medications designed to lower brain parenchymal amyloid have been very effective at doing so, and whether such lowering can result in substantial, clinically meaningful benefit to patients “is still a tricky issue.”

Also commenting for Medscape Medical News, Constantine G. Lyketsos, MD, professor of psychiatry and behavioral sciences, Johns Hopkins Medicine, Baltimore, Maryland, described the study as “important.”

“In the broader context, we and many others have shown pretty conclusively that many people who go on to get dementia develop atypical moodlike symptoms, such as irritability and personality changes, years before they develop memory symptoms,” he said.

“The view is that these moodlike symptoms are a reflection of the underlying Alzheimer’s that starts with mood symptoms then progresses to memory symptoms. And there is more and more evidence that escitalopram and other medicines from this class alleviate these mood symptoms, which are not typical for depression,” Lyketsos added.

This new research “strengthens the view that not only might we be able to get the mood symptoms better, but that these medicines might alleviate the underlying amyloid biology, therefore being a true way of preventing memory loss and dementia. That’s not been shown until this paper, which is so important.”

The study received no funding. Sheline, Ramanan and Lyketsos have no disclosed no relevant financial relationships.

Neurology. Published online September 10, 2020. Abstract

https://www.medscape.com/viewarticle/937684