What literature is available on selective serotonin reuptake inhibitor use for post-stroke recovery?

Introduction

Affecting nearly one third of patients who have experienced a stroke, post-stroke depression (PSD) is a common occurrence, undermining recovery efforts after stroke, according to the American Heart Association (AHA) and American Stroke Association (ASA).¹ Selective serotonin reuptake inhibitors (SSRIs), indicated for the treatment of depression, have been associated with improvements after stroke independent from their effects on depression. There are multiple mechanisms by which SSRIs are thought to impact stroke recovery, since compensation for cerebral ischemia post-stroke involves reorganization of cerebral motor networks.² Some mechanisms include modulating motor cortical excitability, decreasing inflammation, and reopening the critical period in neurological development, thereby increasing neuroplasticity and stimulating neurogenesis.^3-5 Motor impairment is a frequent complication post-stroke, affecting patients’ quality of life and the ability to live independently; greater initial impairment often predicts worse functional recovery, therefore a multi-modal approach is recommended during post-stroke recovery.⁶ While SSRIs aid in the recovery after stroke, their use in patients for the treatment of depression has been associated with an increased risk of all-cause mortality, intracerebral hemorrhage (ICH) and stroke due to the effects of serotonin on platelet function and clotting, particularly in hemorrhagic stroke patients, as well as upper gastrointestinal bleeds, fractures, myocardial infarction, and seizure.^7-9 The known risks of SSRIs, potentially outweighed by the improvements in recovery after stroke, have led to ongoing efforts to assess their effects in patients after stroke with depression, and in those without mood disorders to aid motor recovery.

Current Guidelines

Clinical performance measures issued by a working group of the stroke rehabilitation experts from the AHA and ASA outlines several aspects of stroke rehabilitation in the acute, post-acute, outpatient, and home settings, based on the 2016 AHA/ASA stroke rehabilitation guidelines.¹⁰ Based on the guidelines, post-stroke treatment and rehabilitation should address a variety of measures, one of which is screening for depression and treatment if depression is diagnosed. The 13 performance measures outlined by the working group for the improvement of rehabilitative care of people with stroke are listed in Table 1. Based on these performance measures, the recommendation for potential treatment with SSRIs for stroke recovery is limited to patients with PSD, with the AHA/ASA 2016 guidelines citing the use of prophylactic SSRIs post-stroke for motor recovery as unclear (Level of Evidence: A [based on data derived from multiple randomized controlled, trials or meta-analyses], Class IIb [efficacy is less well-established based on evidence]).¹¹ The benefits of SSRI treatment in stroke recovery, however, continues to be explored in clinical trials. The following is a summary of the evidence of SSRI use in post-stroke recovery to date.

Literature Review

A recent Cochrane Review assessing the use of SSRIs in post-stroke recovery was published, which included a comprehensive literature search through January 7, 2021.¹² Individual studies before that date are therefore are not discussed. Since the Cochrane Review, one observational study on the use of sertraline¹³, as well as 12-month outcomes from the AFFINITY trial have been published.¹⁴ The 6-month results from the AFFINITY study were included in the Cochrane Review assessment, as the 12-month follow-up was not yet published. Since the 12-month data from AFFINITY was not included in the Cochrane Review, it will therefore be discussed in this literature summary.

The Cochrane Review published in 2021 explored the effects of SSRI use in stroke survivors within the first year after stroke.¹² Seventy-six randomized controlled trials (RCTs) were eligible that reported on at least one disability or independence score for primary outcome analysis, or on secondary outcomes of impairment, depression, anxiety, quality of life (QOL), fatigue, cognition, healthcare cost, death, leaving the study early, or adverse events. Studies were included with patients who had experienced ischemic stroke or primary intracerebral hemorrhage. Of the included studies, 38 required a diagnosis of depression for study entry. Thirty-eight studies used fluoxetine in their investigation, while other studies used paroxetine, citalopram, sertraline, and escitalopram. Dose and length of treatment with each agent varied across studies. A subgroup analysis was to be performed for patients with subarachnoid hemorrhage, however no studies were identified that included this patient population. The primary analysis included 6 studies that were considered high-quality with a low risk of bias across all domains based on author opinion. These studies included AFFINITY 2020, Asadollahi et al 2018, Bembenek et al 2020, EFFECTS 2020, FOCUS 2019, and Marquez Romero et al 2013.^15-20 All 6 studies used fluoxetine, recruited patients within 90 days of stroke onset, and did not require depression for entry into studies. For the 2 co-primary outcomes assessed using high-quality studies, treatment with fluoxetine was not associated with an improvement in disability, as assessed using the Barthel index (BI) or Functional Independence Measure (FIM) or a similar scoring system (standard mean difference [SMD] versus control, -0.0; 95% CI, -0.05 to 0.05; 5 studies, high quality evidence) or in independence as measured by the modified Rankin Scale (mRS) (risk ratio [RR] versus control, 0.98; 95% CI, 0.93 to 1.03; 5 studies, high quality evidence) by the end of treatment. Fluoxetine use was associated with a slight decrease in depression versus control (SMD, -0.14; 95% CI, -1.19 to -0.08; 6 studies) with neurological deficit scores also found to improve with fluoxetine use (SMD, -0.39; 95% CI, -1.12 to 0.33). The improvement in neurological deficit, however, is limited to findings from one small study, and was therefore categorized as low-quality evidence. The proportion of patients with depression was also reduced in SSRI users (RR, 0.75; 95% CI, 0.65 to 0.86; 3 studies, high quality evidence). Based on safety outcomes, the use of SSRIs was found to be associated with an increased risk of seizure (RR versus control, 1.4; 95% CI, 1 to 1.98; 6 studies, moderate quality evidence) and bone fractures (RR versus control, 2.35; 95% CI, 1.62 to 3.41, 6 studies, high quality evidence). Rates of death were similar between fluoxetine users and control by the end of treatment, (RR, 1.01; 95% CI, 0.82 to 1.24; 6 studies, moderate quality evidence).

Twelve-month follow-up outcomes after SSRI use was assessed in the AFFINITY study. In AFFINITY, patients (n=1280) with persistent neurological deficits were randomized to fluoxetine 20 mg daily or placebo after their acute stroke diagnosis for a period of 6 months.¹⁴ After completion of treatment, patients were reassessed at 12 months post-randomization to determine if there were any delayed effects of fluoxetine treatment on stroke recovery. Functional status at 12 months, as assessed by mRS, was similar between groups (common odds ratio [OR], 0.93; 95% CI, 0.76 to 1.14). There was also determined to be no significant differences between treatment groups across secondary outcomes at 12 months. The secondary outcomes of falls (4.21% for fluoxetine versus 2.35% for placebo, p=0.08), fractures (3.58% for fluoxetine versus 1.72% versus placebo; p=0.054), and seizures (1.71% versus 1.25%; p=0.64) no longer showed significant differences between treatment and placebo groups at 12 months. Patients on fluoxetine at 12 months were found to have fewer recurrent ischemic strokes (2.18% for fluoxetine versus 4.55% for placebo; p=0.02), however the authors postulate that the lower rate in the fluoxetine group is likely is a chance finding.

Conclusion

Complications after stroke remain a persistent issue, with a multi-modal approach necessary for optimal recovery. The treatment of underlying depression, a common occurrence post-stroke, is recommended by the AHA/ASA’s stroke rehabilitation measures, with appropriate evidence-based treatment. Selective serotonin reuptake inhibitors are potential treatment options for PSD, but their role in the improvement of motor recovery in patients without mood disorders remains unclear. Fluoxetine, of the available SSRIs, has the most literature to date, however this agent, along with rest of the SSRI class of medications, is associated with an increased risk of falls, seizure, gastrointestinal bleeding, and fracture. Based on high quality evidence, SSRI use did not impact measures of independence or disability after stroke, and had minimal effects on depression scores, but did reduce the proportion of patients with depression. Follow-up from the AFFINITY trial at 12 months reiterates these findings, that were assessed at 6 months and included in the Cochrane Review analyses. Neurological deficit scores were improved with SSRI use; however, this improvement is based on data from only one study and is therefore considered low-quality evidence. Based on the aforementioned high-quality evidence, as well as the recommendations from the AHA and ASA performance measures, SSRI use should not be recommended as empiric treatment for post-stroke mobility and cognitive recovery in patients without underlying mood disorders.

References

1. Towfighi, Amytis, MD, Chair, Ovbiagele, Bruce, et al. Poststroke Depression: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2017;48(2):e30-e43. doi:10.1161/STR.0000000000000113.
2. Krisak A. Abstract W P301: Post stroke use of fluoxetine to improve functional recovery unrelated to its beneficial effect on depression. Stroke. 2014;45(suppl_1):AWP301-AWP301. doi:10.1161/str.45.suppl_1.wp301.
3. Schneider CL, Majewska AK, Busza A, Williams ZR, Mahon BZ, Sahin B. Selective serotonin reuptake inhibitors for functional recovery after stroke: similarities with the critical period and the role of experience-dependent plasticity. J Neurol. 2021;268(4):1203-1209. doi:10.1007/s00415-019-09480-0.
4. Abe H, Jitsuki S, Takahashi T. Pharmacological enhancement of stroke rehabilitation. Stroke. 2019;50(11):3323-3329. doi:10.1161/STROKEAHA.119.023720
5. Lim CM, Kim SW, Park JY, Kim C, Yoon SH, Lee JK. Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect. J Neurosci Res. 2009;87(4):1037-1045. doi:10.1002/jnr.21899.
6. Stinear C. Prediction of recovery of motor function after stroke. Lancet Neurol. 2010;9(12):1228-1232. doi:10.1016/S1474-4422(10)70247-7.
7. Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ. 2011;343:d4551. Published 2011 Aug 2. doi:10.1136/bmj.d4551.
8. Coupland C, Hill T, Morriss R, Moore M, Arthur A, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in people aged 20-64 years: cohort study using a primary care database. BMC Med. 2018;16(1):36. Published 2018 Mar 8. doi:10.1186/s12916-018-1022-x.
9. Hankey, Graeme, MBBS, MD, FRACP, FRCP. Selective serotonin reuptake inhibitors and risk of cerebral bleeding. Stroke. 2014;45(7):1917-1918. doi:10.1161/STROKEAHA.114.005844.
10. Stein J, Katz DI, Black Schaffer RM, et al. Clinical Performance Measures for Stroke Rehabilitation: Performance Measures From the American Heart Association/American Stroke Association. Stroke. 2021;52(10):e675-e700. doi:10.1161/str.0000000000000388
11. Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2016;47(6):e98-e169. doi:10.1161/str.0000000000000098
12. Legg LA, Rudberg AS, Hua X, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev. 2021;11(11):CD009286 doi:10.1002/14651858.CD009286.pub4
13. Stuckart I, Siepmann T, Hartmann C, et al. Sertraline for functional recovery after acute ischemic stroke: a prospective observational study. Front Neurol. 2021;12:734170. doi:10.3389/fneur.2021.734170
14. Hankey GJ, Hackett ML, Almeida OP, et al. Twelve-month outcomes of the AFFINITY trial of fluoxetine for functional recovery after acute stroke: AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration. Stroke. 2021;52(8):2502-2509. doi:10.1161/strokeaha.120.033070
15. AFFINITY Trial Collaboration. Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020;19(8):651-660. doi:10.1016/S1474-4422(20)30207-6.
16. Asadollahi M, Ramezani M, Khanmoradi Z, Karimialavijeh E. The efficacy comparison of citalopram, fluoxetine, and placebo on motor recovery after ischemic stroke: a double-blind placebo-controlled randomized controlled trial. Clin Rehabil. 2018;32(8):1069-1075. doi:10.1177/0269215518777791.
17. Bembenek JP, Niewada M, Kłysz B, et al. Fluoxetine for stroke recovery improvement – the doubleblind, randomised placebo-controlled FOCUS-Poland trial. Neurol Neurochir Pol. 2020;54(6):544-551. doi:10.5603/PJNNS.a2020.0099.
18. EFFECTS Trial Collaboration. Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020;19(8):661-669. doi:10.1016/S1474-4422(20)30219-2.
19. FOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. Lancet. 2019;393(10168):265-274. doi:10.1016/S0140-6736(18)32823-X.
20. Marquez-Romero JM, Reyes-Martínez M, Huerta-Franco MR, Ruiz-Franco A, Silos H, Arauz A. Fluoxetine for motor recovery after acute intracerebral hemorrhage, the FMRICH trial. Clin Neurol Neurosurg. 2020;190:105656. doi:10.1016/j.clineuro.2019.105656.

Prepared by:

Christie Denton, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

December 2021

The information presented is current as November 16, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.