Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery

Lynn A Legg, Ann-Sofie Rudberg, Xing Hua, Simiao Wu, Maree L Hackett, Russel Tilney, Linnea Lindgren, Mansur A Kutlubaev, Cheng-Fang Hsieh, Amanda J Barugh, Graeme J Hankey, Erik Lundström, Martin Dennis, Gillian E Mead, Lynn A Legg, Ann-Sofie Rudberg, Xing Hua, Simiao Wu, Maree L Hackett, Russel Tilney, Linnea Lindgren, Mansur A Kutlubaev, Cheng-Fang Hsieh, Amanda J Barugh, Graeme J Hankey, Erik Lundström, Martin Dennis, Gillian E Mead

Abstract

Background: Selective serotonin reuptake inhibitors (SSRIs) might theoretically reduce post-stroke disability by direct effects on the brain. This Cochrane Review was first published in 2012 and last updated in 2019.

Objectives: To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post-stroke, and to determine whether treatment with SSRIs is associated with adverse effects.

Search methods: We searched the Cochrane Stroke Group Trials Register (last searched 7 January 2021), Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, 7 January 2021), MEDLINE (1946 to 7 January 2021), Embase (1974 to 7 January 2021), CINAHL (1982 to 7 January 2021), PsycINFO (1985 to 7 January 2021), and AMED (1985 to 7 January 2021). PsycBITE had previously been searched (16 July 2018). We searched clinical trials registers.

Selection criteria: We included randomised controlled trials (RCTs) recruiting stroke survivors within the first year. The intervention was any SSRI, at any dose, for any period, and for any indication. The comparator was usual care or placebo. Studies reporting at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, cognition, healthcare cost, death, adverse events and leaving the study early) were included in the meta-analysis. The primary analysis included studies at low risk of bias.

Data collection and analysis: We extracted data on demographics, stroke type and, our pre-specified outcomes, and bias sources. Two review authors independently extracted data. We used mean difference (MD) or standardised mean differences (SMDs) for continuous variables, and risk ratios (RRs) for dichotomous variables, with 95% confidence intervals (CIs). We assessed bias risks and applied GRADE criteria.

Main results: We identified 76 eligible studies (13,029 participants); 75 provided data at end of treatment, and of these two provided data at follow-up. Thirty-eight required participants to have depression to enter. The duration, drug, and dose varied. Six studies were at low risk of bias across all domains; all six studies did not need participants to have depression to enter, and all used fluoxetine. Of these six studies, there was little to no difference in disability between groups SMD -0.0; 95% CI -0.05 to 0.05; 5 studies, 5436 participants, high-quality evidence) or in independence (RR 0.98; 95% CI 0.93 to 1.03; 5 studies, 5926 participants; high-quality evidence) at the end of treatment. In the studies at low risk of bias across all domains, SSRIs slightly reduced the average depression score (SMD 0.14 lower, 95% CI 0.19 lower to 0.08 lower; 4 studies; 5356 participants, high-quality evidence) and there was a slight reduction in the proportion with depression (RR 0.75, 95% CI 0.65 to 0.86; 3 studies, 5907 participants, high-quality evidence). Cognition was slightly better in the control group (MD -1.22, 95% CI -2.37 to -0.07; 4 studies, 5373 participants, moderate-quality evidence). Only one study (n = 30) reported neurological deficit score (SMD -0.39, 95% CI -1.12 to 0.33; low-quality evidence). SSRIs resulted in little to no difference in motor deficit (SMD 0.03, -0.02 to 0.08; 6 studies, 5518 participants, moderate-quality evidence). SSRIs slightly increased the proportion leaving the study early (RR 1.57, 95% CI 1.03 to 2.40; 6 studies, 6090 participants, high-quality evidence). SSRIs slightly increased the outcome of a seizure (RR 1.40, 95% CI 1.00 to 1.98; 6 studies, 6080 participants, moderate-quality evidence) and a bone fracture (RR 2.35, 95% CI 1.62 to 3.41; 6 studies, 6080 participants, high-quality evidence). One study at low risk of bias across all domains reported gastrointestinal side effects (RR 1.71, 95% CI 0.33, to 8.83; 1 study, 30 participants). There was no difference in the total number of deaths between SSRI and placebo (RR 1.01, 95% CI 0.82 to 1.24; 6 studies, 6090 participants, moderate quality evidence). SSRIs probably result in little to no difference in fatigue (MD -0.06; 95% CI -1.24 to 1.11; 4 studies, 5524 participants, moderate-quality of evidence), nor in quality of life (MD 0.00; 95% CI -0.02 to 0.02, 3 studies, 5482 participants, high-quality evidence). When all studies, irrespective of risk of bias, were included, SSRIs reduced disability scores but not the proportion independent. There was insufficient data to perform a meta-analysis of outcomes at end of follow-up. Several small ongoing studies are unlikely to alter conclusions.

Authors' conclusions: There is high-quality evidence that SSRIs do not make a difference to disability or independence after stroke compared to placebo or usual care, reduced the risk of future depression, increased bone fractures and probably increased seizure risk.

Trial registration: ClinicalTrials.gov NCT02683213.

Conflict of interest statement

Lynn A Legg: none known.

Ann‐Sofie Rudberg: none known.

Xing Hua: none known.

Simiao Wu: none known.

Maree L Hackett: Grants and contracts: Project grant (NHMRC funding for AFFINITY trial), HTA Program (National Institute for Health Research funding for FOCUS), Framework grant (Swedish Research Council funding for EFFECTS); all funding received by the author's institution. Payment for a fellowship: National Health and Medical Research Council (NHMRC), received by the author's institution.

Russel Tilney: none known.

Linnea Lindgren: none known.

Mansur A Kutlubaev: none known.

Cheng‐Fang Hsieh: none known.

Amanda Barugh: none known.

Graeme J Hankey: Grants and contracts: Chief Investigator for the AFFINITY trial, National Health and Medical Research Council of Australia, received by the author's institution. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: Discussion about antithrombotic therapy to prevent stroke, Medscape, received by the author. Consulting fees: Consulting on design of a possible phase III trial of a new anticoagulant in atrial fibrillation, Janssen Research and Development, received by the author. Payment for participation on a Data Safety Monitoring Board, Advisory Board, or Guideline Panel: Chair or Member of Data Safety Monitoring Committees, of ACI trials of an immune therapies for Alzheimer's disease, AC Immune, Lausanne, Switzerland, received by the author; Member of Stroke Prevention Initiative, Bayer, received by the author; Other: Associate Editor of Circulation, American Heart Association, received by the author. Published opinions in medical journals, the public press, broadcast and social media relevant to the interventions in the work: Publication, Lancet Neurology, AFFINITY Trial Collaboration. Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double‐blind, placebo‐controlled trial. Lancet Neurology 2020; 19(8): 651‐660. doi: 10.1016/S1474‐4422(20)30207‐6. PMID: 32702334; Publication, Stroke. Declaring involvement in eligible studies: Yes, National Health and Medical Research Council of Australia (for AFFINITY trial).

Erik Lundström: Grants and contracts: Funding, STROKE‐Riksförbundet, received by author's institution. Leadership or other fiduciary role in other board, society, committee, or advocacy group: Chief Investigator of the EFFECTS trial, received by author. Declaring involvement in eligible studies: The Swedish Research Council, The Swedish Heart‐Lung Fund, The Swedish Brain Fund, STROKE‐Riksförbundet, The Swedish Medical Society, Konung Gustaf V:s och Drottning Victorias Frimurarstiftelse.

Martin Dennis: Grants and contracts: Grants received to carry out FOCUS trial ‐ and RCT which is included in the review, NIHR, Stroke Association, received by the author's institution

Gillian E Mead: Grants and contracts: Research grants, HTA NIHR, co‐applicant on grants led by Prof Graeme Hankey and Maree Hackett, and Erik Lundstrom; NIHR incentive award for updating this review, both received by the author's institution.

Gillian Mead, Martin Dennis, Maree Hackett, Erik Lundstrom and Graeme Hankey are investigators on the FOCUS trial (Fluoxetine or control under supervision) in the UK, the AFFINITY (Assessment of fluoxetine in stroke recovery) trial in Australia, and the EFFECTs trial in Sweden designed to assess the impact of fluoxetine on disability and dependency after stroke. None of these review authors extracted data from these three trials.