Cognitive Effects of Antidepressant Pharmacotherapy in Late-Life Depression

Lior Hilsenrath, MD;Kari Wolatz, MD;Haley Schuster, MD;Mullen,Mark;Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP;

A monthly column dedicated to reviewing the literature and sharing clinical implications.

Late-life depression (LLD) affects a significant portion of older adults, with more than 10% of individuals over the age of 60 reporting symptoms consistent with major depressive disorder (MDD). Cognitive impairment is prevalent among individuals with LLD, and this condition is a major modifiable risk factor for dementia. Nearly all patients with LLD experience some degree of cognitive decline, and up to 40% of these individuals meet the criteria for mild cognitive impairment. As cognitive impairment often accompanies LLD, understanding whether pharmacological treatments for LLD can improve cognitive functioning is crucial.

This systematic review and meta-analysis explored the value of antidepressant pharmacotherapy in improving cognition in individuals with LLD, focusing on global cognition and specific cognitive domains such as attention, processing speed, learning and memory, and executive function. The review also addressed whether certain antidepressants offer greater cognitive benefits than others and examined whether improvements in cognition were associated with a reduction in depressive symptoms.

University of British Columbia Clinician Investigator Program and the Canadian Institutes of Health Research (CIHR)

To evaluate whether antidepressant treatment of LLD leads to changes in cognitive function.

Study Strengths

1. This was the first published meta-analysis evaluating cognitive outcomes of antidepressant pharmacotherapy for LLD.

2. The study addresses an important clinical question relevant to public health.

3. The study limited confounding variables by excluding participants with a primary psychiatric diagnosis other than MDD or significant neurological comorbidities.

4. The authors used SMCRH and random-effects models to account for methodological heterogeneity in included studies.

Study Weaknesses

1. The authors did not have access to patient-level data, including education level, race/ethnicity, or baseline cognitive function.

2. Most included studies had no placebo or healthy-control comparators.

3. Substantial methodological heterogeneity in included studies led to lower statistical power and prevented meta-analysis of secondary outcomes.

This study was a systematic review and meta-analysis that was registered with PROSPERO. The primary outcome was whether antidepressant treatment of LLD led to improved cognition, either globally or in specific cognitive domains. The secondary outcomes were: (1) whether specific antidepressants improve cognitive outcomes more than others, and (2) the association between improvement in depressive symptoms and improvement in cognition after antidepressant treatment.

The investigators conducted a comprehensive literature search across 3 electronic databases—MEDLINE, Embase, and PsycInfo—through December 31, 2022, to identify eligible prospective studies. Studies were included if they enrolled adults aged 50 years or older (or with a mean age of 65 years or older) and included individuals with a diagnosis of nonpsychotic MDD receiving 1 specific antidepressant or placebo. Studies were required to report cognitive test scores at baseline and at least 1 follow-up time point within a maximum of 26 weeks. Studies were excluded if they included participants with a diagnosis of dementia, a Mini-Mental State Examination score less than 23, a primary psychiatric diagnosis other than MDD (eg, bipolar disorder), or significant neurological comorbidities (eg, Parkinson disease, stroke, multiple sclerosis).

For the qualitative synthesis, cognitive tests were categorized into several domains. To examine whether there was an improvement in cognition after antidepressant treatment and whether certain antidepressants improved cognition more than others, the authors synthesized results from studies that administered at least 1 test relevant to a particular cognitive domain. The authors classified studies as reporting cognitive improvement if there was statistically significant superiority of an antidepressant over placebo and/or another antidepressant or a statistically significant increase in cognitive test scores from baseline to post treatment. To address whether cognitive improvements were associated with reductions in depressive symptoms, the authors synthesized results from studies that reported either patient-level or group-level data.

For the meta-analysis, studies were screened for sufficient quantitative data. The authors derived mean changes between pre- and posttreatment cognitive test scores. The cognitive test scores taken closest to 12 weeks after treatment initiation were used as posttreatment scores. Because cognitive outcomes were measured with different scales in each study, standardized mean changes were calculated using raw score standardization with heteroscedastic population variances (SMCRH). Separate random-effects meta-analytic models were conducted for each cognitive domain.

A total of 19 of 22 studies were included in the qualitative synthesis. Improvement in 1 or more cognitive domains after treatment with an antidepressant was reported in 13 of 19 studies. The most consistent evidence of cognitive improvement was observed in processing speed (7 of 10 studies), followed by memory and learning (9 of 16 studies). Evidence for improvement in immediate memory was frequent but more limited (4 of 6 studies). Evidence for improvement was limited for global cognition (3 of 12 studies), verbal fluency (1 of 3), and attention and working memory (1 of 3). No studies found improvements in executive function (0 of 7 studies).

Sertraline had the most consistent evidence of cognitive benefit, with data from all 5 relevant studies showing improvement in at least 1 cognitive domain. The strongest evidence for sertraline was found in processing speed (3 of 4 studies) and memory and learning (4 of 5 studies).

Eight studies examined the association between changes in depressive symptoms and cognitive performance. Data from 7 of these studies demonstrated some level of association. Four studies reported a group-level effect where participants who responded or remitted after pharmacotherapy showed greater cognitive improvement than those who did not. Findings from 2 studies showed patient-level associations between improvements in depressive symptoms and cognitive performance. Data from 1 study revealed worsening of cognitive performance (specifically memory and learning) in a nonresponder subgroup.

Eight studies had sufficient quantitative data for meta-analysis of standardized mean changes of pre- and posttreatment cognitive test scores. Memory and learning scores showed statistically significant improvement (SMCRH = 0.254; 95% CI, 0.103-0.404; P = .001). Processing speed scores showed improvement that was not statistically significant (SMCRH = 0.198; 95% CI, −0.090 to 0.486; P = .178). Executive function and global cognition scores showed no statistically significant change. There were insufficient quantitative data to examine attention and working memory. There were also insufficient data to conduct a meta-analysis of secondary outcomes.

The authors conducted a post hoc analysis of pooled change in memory and learning scores stratified into selective serotonin reuptake inhibitor (SSRI) and non-SSRI subgroups. In this stratified analysis, significant improvement remained in the SSRI subgroup, but no significant improvement remained in the non-SSRI subgroup.

Antidepressant treatment for LLD may improve cognitive domains such as memory, learning, and processing speed, with improvements potentially linked to reductions in depressive symptoms. Although sertraline shows the strongest evidence for cognitive benefit, this may reflect the larger body of literature studying sertraline compared with other antidepressants. Further controlled research, particularly involving non-SSRIs and SSRIs other than sertraline, is needed to clarify causality and broaden the understanding of cognitive outcomes.

The findings from this study reinforce the link between LLD and cognitive impairment. Antidepressant treatment not only alleviates depressive symptoms but may also enhance certain cognitive functions. For domains such as executive function, where response to antidepressant therapy is limited, consideration of adjunctive or alternative therapies may be warranted.

Antidepressant treatment of LLD may lead to improvement in certain cognitive domains, such as learning and memory and processing speed, but may not lead to improvement in other domains, such as executive function. Cognitive improvement shows an association with reduction in depressive symptoms, reinforcing the important interaction between LLD and cognitive dysfunction.

Dr Hilsenrath is a second-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Wolatz is a second-year psychiatry resident at Creighton University. Dr Schuster is a fourth-year psychiatry resident at Creighton University. Dr Mullen is an assistant professor of psychiatry at Saint Louis University School of Medicine in Missouri. Dr Tampi is a professor and the chair of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and a member of the Psychiatric Times editorial board.

Cognitive Effects of Antidepressant Pharmacotherapy in Late-Life Depression

Key Takeaways

Study Strengths

Study Weaknesses

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