Selective serotonin reuptake inhibitors and glucose metabolism in Alzheimer's disease and related dementias: A systematic review and meta-analysis of brain metabolic and adverse event data

Abstract

Introduction

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression in Alzheimer's disease (AD), however their effects on glucose metabolism remain poorly understood. We conducted a systematic review and meta-analysis to evaluate SSRI effects on brain glucose metabolism and metabolic adverse events in AD patients.

Methods

Following PRISMA 2020 guidelines, we searched multiple databases up to July 11, 2025 for studies investigating SSRI effects on glucose-related outcomes in AD patients. Despite significant heterogeneity in study designs and populations, we performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. We performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. Advanced Bayesian hierarchical modeling and Markov simulations projected long-term metabolic outcomes.

Results

Twelve studies with total included 7143 participants met our inclusion criteria, including nine randomized controlled trials and three observational studies. Brain FDG-PET revealed SSRI use restored dorsal raphe nucleus hypometabolism (standardized mean difference 0.87, 95 % CI: 0.52–1.22, P-value = 0.001). Meta-analysis demonstrated increased gastrointestinal adverse events (risk ratio 2.15, 95 % CI: 1.68–2.76, P-value<0.001, with moderate between-study heterogeneity), with sertraline showing highest rates. Citalopram 30 mg provided significant weight loss protection (risk ratio 0.13, 95 % CI: 0.02–0.98, P-value = 0.02), though this exceeds the recommended 20 mg maximum dose for elderly patients due to cardiac safety considerations. Long-term diabetes incidence showed no increased risk (hazard ratio 0.75, 95 % CI: 0.50–1.12, P-value = 0.15). Bayesian modeling revealed 85 % probability of beneficial brain metabolic effects and 89 % probability of citalopram superiority for weight protection.

Conclusions

SSRIs restore brain glucose metabolism in AD patients while causing manageable peripheral metabolic effects. Citalopram appears the best for weight-sensitive patients, while sertraline requires gastrointestinal monitoring. These findings support SSRI safety for metabolic outcomes in AD treatment, however longer-term studies with controlled metabolic outcomes are needed to confirm our findings. The observed citalopram weight protection benefit was documented at 30 mg daily, which exceeds recommended dosing limits for elderly patients due to cardiac safety concerns.