The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis

Jones, Helen; Joshi, Alka; Shenkin, Susan D.; Mead, Gillian

doi:10.1093/ageing/afw053

Cited by 27 publications

(20 citation statements)

References 22 publications

(14 reference statements)

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“…All the reviews suggested promising effects of SSRIs. [88][89][90] However, before embarking on large trials in these other conditions, the relevance of the neutral results of the FOCUS trial needs to be considered carefully.…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine to improve functional outcomes in patients after acute stroke: the FOCUS RCT

Dennis

Forbes

Graham

et al. 2020

Health Technol Assess

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Background Our Cochrane review of selective serotonin inhibitors for stroke recovery indicated that fluoxetine may improve functional recovery, but the trials were small and most were at high risk of bias. Objectives The Fluoxetine Or Control Under Supervision (FOCUS) trial tested the hypothesis that fluoxetine improves recovery after stroke. Design The FOCUS trial was a pragmatic, multicentre, parallel-group, individually randomised, placebo-controlled trial. Setting This trial took place in 103 UK hospitals. Participants Patients were eligible if they were aged ≥ 18 years, had a clinical stroke diagnosis, with focal neurological deficits, between 2 and 15 days after onset. Interventions Patients were randomly allocated 20 mg of fluoxetine once per day or the matching placebo for 6 months via a web-based system using a minimisation algorithm. Main outcome measures The primary outcome was the modified Rankin Scale at 6 months. Patients, carers, health-care staff and the trial team were masked to treatment allocation. Outcome was assessed at 6 and 12 months after randomisation. Patients were analysed by their treatment allocation as specified in a published statistical analysis plan. Results Between 10 September 2012 and 31 March 2017, we recruited 3127 patients, 1564 of whom were allocated fluoxetine and 1563 of whom were allocated placebo. The modified Rankin Scale score at 6 months was available for 1553 out of 1564 (99.3%) of those allocated fluoxetine and 1553 out of 1563 (99.4%) of those allocated placebo. The distribution across modified Rankin Scale categories at 6 months was similar in the two groups (common odds ratio adjusted for minimisation variables 0.951, 95% confidence interval 0.839 to 1.079; p = 0.439). Compared with placebo, patients who were allocated fluoxetine were less likely to develop a new episode of depression by 6 months [210 (13.0%) vs. 269 (16.9%), difference –3.78%, 95% confidence interval –1.26% to –6.30%; p = 0.003], but had more bone fractures [45 (2.9%) vs. 23 (1.5%), difference 1.41%, 95% confidence interval 0.38% to 2.43%; p = 0.007]. There were no statistically significant differences in any other recorded events at 6 or 12 months. Health economic analyses showed no differences between groups in health-related quality of life, hospital bed usage or health-care costs. Limitations Some non-adherence to trial medication, lack of face-to-face assessment of neurological status at follow-up and lack of formal psychiatric diagnosis during follow-up. Conclusions 20 mg of fluoxetine daily for 6 months after acute stroke did not improve patients’ functional outcome but decreased the occurrence of depression and increased the risk of fractures. These data inform decisions about using fluoxetine after stroke to improve functional outcome or to prevent or treat mood disorders. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) (Australasia/Vietnam) and Efficacy oF Fluoxetine – a randomisEd Controlled Trial in Stroke (EFFECTS) (Sweden) trials recruited an additional 2780 patients and will report their results in 2020. These three trials have an almost identical protocol, which was collaboratively developed. Our planned individual patient data meta-analysis will provide more precise estimates of the effects of fluoxetine after stroke and indicate whether or not effects vary depending on patients’ characteristics and health-care setting. Trial registration Current Controlled Trials ISRCTN83290762. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 22. See the NIHR Journals Library website for further project information. The Stroke Association (reference TSA 2011101) funded the start-up phase.

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Section: Discussionmentioning

confidence: 99%

Fluoxetine to improve functional outcomes in patients after acute stroke: the FOCUS RCT

Dennis

Forbes

Graham

et al. 2020

Health Technol Assess

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“…Though some studies have claimed an association between SSRI use and lower dementia risk (Brodrick & Mathys, 2016), others have pointed out the difficulty of disentangling improved cognition as a result of ameliorated depressive symptoms, and improved cognition as a result of pharmacological intervention (Doraiswamy et al, 2003). Still others have failed to observe a relationship between antidepressant use and cognition (Carri–re et al, 2017; Jones, Joshi, Shenkin, & Mead, 2016) or have implicated SSRI use as an independent risk factor in the development of dementia (Lee, Lin, Sung, Liang, & Kao, 2016).…”

Section: Introductionmentioning

confidence: 99%

Latent Classes of Cognitive Functioning Among Depressed Older Adults Without Dementia

Morin

Insel

Nelson

et al. 2019

J Int Neuropsychol Soc

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OBJECTIVE: Use latent class analysis to identify patterns of cognitive functioning in a sample of older adults with clinical depression and without dementia, and assess demographic, psychiatric and neurobiological predictors of class membership. METHOD: Neuropsychological assessment data from 121 participants in the Alzheimer’s Disease Neuroimaging Initiative – Depression Project (ADNI-D) were analyzed, including measures of executive functioning, verbal and visual memory, visuospatial and language functioning, and processing speed. These data were analyzed using latent class analysis, with predictors of class membership such as depression severity, depression and treatment history, amyloid burden, and APOE e4 allele also assessed. RESULTS: A two-class model of cognitive functioning best fit the data, with the Lower Cognitive Class (46.1% of the sample) performing approximately one standard deviation below the Higher Cognitive Class (53.9%) on most tests. When predictors of class membership were assessed, carrying an APOE e4 allele was significantly associated with membership in the Lower Cognitive Class. Demographic characteristics, age of depression onset, depression severity, history of psychopharmacological treatment for depression, and amyloid positivity did not predict class membership. CONCLUSION: Latent class analysis allows for identification of subgroups of cognitive functioning in a mostly cognitively intact late life depression (LLD) population. One subgroup, the Lower Cognitive Class, more likely to carry an APOE e4 allele, may be at greater risk for subsequent cognitive decline, even though current performance on neuropsychological testing is within normal limits. These findings have implications for early identification of those at greatest risk, risk factors, and avenues for preventive intervention.

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“…This pathological change has been suggested to contribute to the depressive symptoms that frequently precede the cognitive decline in patients with AD [6–8]. It is still being disputed whether antidepressive treatment of patients with AD with selective serotonin reuptake inhibitors (SSRIs) impacts on the decline of cognition in AD [9–12] or the conversion from mild cognitive impairment to AD [13]. In AD, the density of specific cortical 5‐HT receptors correlates positively to amyloid β (Aβ) pathology and negatively to cognitive performance [14], with a reduced density of the 5‐HT 4 R and 5‐HT 6 R being observed in mild cognitive impairment [15–17].…”

Section: Introductionmentioning

confidence: 99%

Established amyloid‐β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine

Severino

Sivasaravanaparan

Olesen

et al. 2018

A&D Transl Res & Clin Interv

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IntroductionTreatment with selective serotonin reuptake inhibitors has been suggested to mitigate amyloid-β (Aβ) pathology in Alzheimer's disease, in addition to an antidepressant mechanism of action.MethodsWe investigated whether chronic treatment with paroxetine, a selective serotonin reuptake inhibitor, mitigates Aβ pathology in plaque-bearing double-transgenic amyloid precursor protein (APP)swe/presenilin 1 (PS1)ΔE9 mutants. In addition, we addressed whether serotonin depletion affects Aβ pathology. Treatments were assessed by measurement of serotonin transporter occupancy and high-performance liquid chromatography. The effect of paroxetine on Aβ pathology was evaluated by stereological plaque load estimation and Aβ42/Aβ40 ratio by enzyme-linked immunosorbent assay.ResultsContrary to our hypothesis, paroxetine therapy did not mitigate Aβ pathology, and depletion of brain serotonin did not exacerbate Aβ pathology. However, chronic paroxetine therapy increased mortality in APPswe/PS1ΔE9 transgenic mice.DiscussionOur results question the ability of selective serotonin reuptake inhibitor therapy to ameliorate established Aβ pathology. The severe adverse effect of paroxetine may discourage its use for disease-modifying purposes in Alzheimer's disease.

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The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis

Abstract: a small number of relatively low-powered studies showed no benefit or harm from SSRIs in terms of cognition, mood, agitation or ADLs. Large, methodologically robust studies are needed.

Cited by 27 publications

References 22 publications

Fluoxetine to improve functional outcomes in patients after acute stroke: the FOCUS RCT

Fluoxetine to improve functional outcomes in patients after acute stroke: the FOCUS RCT

Latent Classes of Cognitive Functioning Among Depressed Older Adults Without Dementia

Established amyloid‐β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine

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