Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults: A controlled clinical trial

Abstract

Objective: To determine whether treatment with escitalopram compared with placebo would lower CSF β-amyloid 42 (Aβ₄₂) levels.

Rationale: Serotonin signaling suppresses Aβ₄₂ in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram.

Methods: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aβ₄₂ was used as the primary outcome in subsequent analyses.

Results: An overall 9.4% greater reduction in CSF Aβ₄₂ was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aβ status (CSF Aβ₄₂ levels <250 pg/mL) was associated with smaller Aβ₄₂ reduction (p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aβ₄₂ levels >250 pg/mL).

Conclusions: Short-term longitudinal doses of escitalopram decreased CSF Aβ₄₂ in cognitively normal older adults, the target group for AD prevention.

Clinicaltrialsgov identifier: NCT02161458.

Classification of evidence: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aβ₄₂.

Figure 1. Effect of escitalopram on CSF β-amyloid (Aβ)₄₂

(A) Using the Luminex assay, the combined escitalopram group demonstrated a greater percent reduction in Aβ₄₂ than the placebo group, with an overall difference between groups of 9.4% (F_1,109 = 16.64, p < 0.001, 95% confidence interval [CI] 4.9%–14.2%, d = 0.81). On average, there was a 6.0% (SEM 1.2%) reduction of Aβ₄₂ in the escitalopram-treated group (blue bar) vs a 3.5% (SEM 2.2%) increase in the placebo-treated group (orange bar). (B) The 20 mg 2 weeks escitalopram group (light blue bar) had a 3.8% (SEM 1.8%) reduction in Aβ₄₂ on average (not significant compared to placebo). For the 20 mg × 8 weeks group (medium blue bar), there was a 7.8% (SEM 1.4%) average reduction. For the 30 mg × 8 weeks escitalopram group (dark blue bar), the average reduction was 6.1% (SEM 2.5%), compared with an average increase of 3.5% (2.2%) in the placebo-treated group (orange bar; Tukey adjusted p = 0.002, 95% CI 3.4%–19.5%, d = 0.94 and p = 0.007, 95% CI 2.0%–17.1%, d = 0.69, comparing placebo to the 20 mg × 8 weeks and 30 mg × 8 weeks groups, respectively). (C) Using mass spectrometry, similar results were found: overall difference in average percent change between groups of 11.1% (F_1,109 = 11.593, p < 0.001, 95% CI [18.5%–4.9%, d = 0.60). See Results for details. (D) For the 20 mg × 8 weeks group (medium blue bar), there was a 10.5% (SEM 3.6%) average reduction that was significantly different than the placebo group (Tukey adjusted p = 0.001, 95% CI 5.5%–29.0%, d = 0.89). See Results for other details. All p values resulted from 2-sided statistical tests and statistical significance was set at *p < 0.05, **p < 0.01, and ***p < 0.001.

Figure 2. Baseline amyloid status changes the effect of escitalopram on reduction in CSF β-amyloid (Aβ)₄₂

Participants who were amyloid positive at baseline (pooled) had significantly less percent reduction in Aβ₄₂ (F_1,107 = 7.968, p = 0.006, 95% confidence interval −16.7% to −0.5%, d = −0.52), controlling for age, sex, and treatment group (not pictured). On average (pictured), amyloid-negative escitalopram-treated (combined doses) patients had a 7.3% (SEM 1.2%) decrease; amyloid-positive escitalopram-treated patients had a 2.1% (SEM 2.9%) decrease; amyloid-negative placebo-treated patients had a 1.2% (SEM 2.2%) increase; amyloid-positive placebo-treated patients had a 9.5% (SEM 5.5%) increase.