Does Mixing an SSRI With an Anti-amyloid Up Bleeding in AD?

Clinicians from Switzerland are urging caution when prescribing an anti-amyloid medication in a patient with Alzheimer’s disease (AD) also taking a selective serotonin reuptake inhibitor (SSRI) antidepressant.

SSRIs decrease serotonin and cause hemostatic interference such as decreased platelet aggregability and activity with prolongation of bleeding time, they point out in a letter published online August 16 in Alzheimer’s & Dementia.

“Drugs with the highest degree of serotonin reuptake inhibition, such as fluoxetine, sertraline, and paroxetine, are frequently associated with increased bleeding and modifications of hemostasis markers that require special attention in the era of the anti-amyloid drugs,” Beatriz Pozuelo Moyano, MD, of the University of Lausanne, and colleagues, note in their article.

“Our recommendations are to pay special attention to patients on SSRIs, particularly if they have already microhemorrhages,” Pozuelo Moyano told Medscape Medical News.

And starting lecanemab in the first month after starting an SSRI “should be avoided,” Pozuelo Moyano said.

She also noted that “patients on concomitant antiplatelet treatment may need additional monitoring, since the bleeding risk is increased by the concurrent use of these drugs.”

Enhanced ARIA Risk?

It’s now well known that lecanemab (Leqembi) and other anti-amyloid monoclonal antibodies can cause amyloid-related imaging abnormalities (ARIA), which can be life-threatening.

Among patients with early AD who received lecanemab in the pivotal CLARITY AD phase 3 trial, the incidence of ARIA of the hemorrhagic type (ARIA-H) was 17.3% and the incidence of ARIA of the effusion type (ARIA-E) was 12.6%.

Lecanemab, which received full US Food and Drug Administration approval last month, includes a boxed warning about the risk of ARIA and that advises caution when considering use of the drug in patients taking anticoagulants or with other risk factors for intracerebral hemorrhage.

In their letter, Pozuelo Moyano and colleagues note that patients with cerebral amyloid angiopathy (CAA) may be at increased risk of ARIAs and the risk of bleeding is “even greater” if there is an underlying CAA and an antiplatelet with or without lecanemab is added.

Current appropriate use recommendations for lecanemab state that the drug can be given to patients with fewer than four microhemorrhages, “which may still correspond to possible or probable CAA. Considering this, a parallel prescription with SSRIs deserves close monitoring, as antidepressant use is associated with an increased risk of developing microbleeds,” Pozuelo Moyano and colleagues say.

In a retrospective study, the researchers evaluated the prevalence of antidepressant drug use in patients meeting criteria for lecanemab treatment.

Among the 410 patients with AD evaluated in 2022 at the Leenaards Memory Center in Lausanne, 47 (11.4%) were deemed eligible for lecanemab; 32% of the eligible patients were taking an antidepressant, most commonly SSRIs (80%).

“This high prevalence of AD patients eligible for lecanemab on antidepressant drugs, especially SSRIs, raises the question of an appropriate clinical management of these patients,” the authors write.

Tweak Appropriate Use Guidance?

Pozuelo Moyano and colleagues encourage clinicians to consider that the first 30 days after starting an SSRI is a “crucial” risk period for intracerebral hemorrhage and to be aware that tricyclic antidepressants, serotonin antagonist and reuptake inhibitors (such as trazodone), or some of the norepinephrine reuptake inhibitors (such as atomoxetine or bupropion) are associated with a lower risk of hemorrhage.

They acknowledge that the use of tricyclic antidepressants is not always appropriate in AD patients due to their anticholinergic effect and their consecutive impact on cognition.

Current clinical guidelines advise using nondrug interventions as a first therapeutic choice for treatment of behavioral and psychological symptoms of dementia in AD.

In patients eligible for anti-amyloid drugs, the indication for antidepressant treatment and its dose “should be periodically reevaluated as the antiplatelet effect in antidepressants is dose dependent,” Pozuelo Moyano and colleagues advise.

Reached for comment, Jeffrey Cummings, MD, ScD, who led the workgroup that developed the lecanemab appropriate use recommendations, noted that there currently are no data on the relationship of monoclonal antibodies, antidepressants, and the risk of hemorrhage.

“The fact that patients on antidepressants have higher rates of hemorrhage does not necessarily equate to higher rates of ARIA. Depressed patients might have more cerebral vascular disease and more hemorrhage through mechanisms unrelated to ARIA,” Cummings told Medscape Medical News.

He said he is not aware of any analyses of the clinical trial data on anti-amyloid monoclonals related to antidepressant therapy. “This is a worthy examination,” said Cummings, with the University of Nevada, Las Vegas.

For now, he said it’s premature to adjust the appropriate use recommendations as they relate to antidepressants. “We will follow this and adjust the AURs if data implicating antidepressants in ARIA emerge,” Cummings said.

The study had no specific funding, and the authors have disclosed no relevant financial relationships. Cummings has relationships with various pharmaceutical companies.

Alzheimers & Dementia. Published online August 16, 2023. Abstract

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