PDF: EFFECTS
(2021)Objective
To determine whether any functional or secondary benefits of fluoxetine seen at 6 months after acute stroke persist, delay, or emerge at 12 months.
Study Summary
• Fluoxetine 20 mg daily for 6 months did not improve functional outcome at 12 months after acute stroke (adjusted common OR 0.92, 95% CI 0.76–1.10).
• Fluoxetine arm scored significantly worse on memory (median 89 vs 93, P=0.0021) and communication (median 93 vs 96, P=0.024) domains of the Stroke Impact Scale — authors attribute this to chance.
• Antidepressant use at 12 months was similar in both groups (9.0% fluoxetine vs 8.8% placebo); the ~4% depression benefit seen at 6 months was not sustained.
• Fluoxetine arm scored significantly worse on memory (median 89 vs 93, P=0.0021) and communication (median 93 vs 96, P=0.024) domains of the Stroke Impact Scale — authors attribute this to chance.
• Antidepressant use at 12 months was similar in both groups (9.0% fluoxetine vs 8.8% placebo); the ~4% depression benefit seen at 6 months was not sustained.
Intervention
Fluoxetine 20 mg orally once daily for 6 months vs. matching placebo, with follow-up continued to 12 months. Randomization 2–15 days after acute stroke.
Inclusion Criteria
Adults ≥18 years with clinical diagnosis of acute ischemic or hemorrhagic stroke within 2–15 days, brain imaging consistent with stroke, persisting neurological deficit at randomization, no pre-existing depression or antidepressant use, no contraindication to fluoxetine, expected survival ≥12 months.
Study Design
Arms: Fluoxetine 20 mg/day vs. Placebo (matched capsules)
Patients per Arm: Fluoxetine: 750; Placebo: 750
Outcome
• Primary (mRS at 12 months): no significant difference (adjusted common OR 0.92, 95% CI 0.76–1.10).
• Memory (SIS): fluoxetine median 89 (IQR 75–100) vs placebo 93 (IQR 82–100), P=0.0021.
• Communication (SIS): fluoxetine median 93 (IQR 82–100) vs placebo 96 (IQR 86–100), P=0.024.
• Antidepressant use at 12 months: 9.0% vs 8.8% (diff 0.2%, 95% CI −3.1 to 3.8%).
• Mortality at 12 months: 34/750 (4.5%) each group.
• All other SIS domains, EQ-5D-5L, fatigue, MHI-5 — no significant differences.
• Memory (SIS): fluoxetine median 89 (IQR 75–100) vs placebo 93 (IQR 82–100), P=0.0021.
• Communication (SIS): fluoxetine median 93 (IQR 82–100) vs placebo 96 (IQR 86–100), P=0.024.
• Antidepressant use at 12 months: 9.0% vs 8.8% (diff 0.2%, 95% CI −3.1 to 3.8%).
• Mortality at 12 months: 34/750 (4.5%) each group.
• All other SIS domains, EQ-5D-5L, fatigue, MHI-5 — no significant differences.
Bottom Line
Fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome at 12 months (adjusted common OR 0.92, 95% CI 0.76–1.10). Patients on fluoxetine scored significantly worse on the memory and communication domains of the Stroke Impact Scale, though this is likely a chance finding given multiple comparisons. The depression benefit seen at 6 months was not sustained at 12 months (antidepressant use 9.0% vs 8.8%).
Major Points
- EFFECTS was an investigator-led, randomized, double-blind, placebo-controlled parallel-group trial in 35 Swedish hospital stroke units enrolling 1500 patients from October 2014 to June 2019; last 12-month follow-up was July 8, 2020.
- Patients were randomized 1:1 to fluoxetine 20 mg orally once daily or matching placebo for 6 months, then followed for an additional 6 months without treatment — this paper reports the predefined 12-month secondary analysis.
- Stroke types: 87.4% ischemic stroke, 12.3% intracerebral hemorrhage, 0.2% non-stroke; mean age 71 years (SD 11); 38.3% women; 96.3% previously independent; median NIHSS 3.
- Primary outcome (mRS distribution at 12 months): adjusted common OR 0.92 (95% CI 0.76–1.10) — no significant difference. Unadjusted common OR 0.96 (95% CI 0.80–1.15). Both favor placebo numerically but are not significant.
- mRS 0–1 at 12 months: fluoxetine 53% (160+224/715) vs placebo 53% (178+201/712); mRS 6 (dead at 12 months): 34 (5%) each group.
- Fluoxetine was significantly worse on memory domain of Stroke Impact Scale v3 at 12 months: median 89 (IQR 75–100) vs 93 (IQR 82–100), P=0.0021; and communication domain: median 93 (IQR 82–100) vs 96 (IQR 86–100), P=0.024 — authors attribute these to chance due to multiple comparisons. No significant differences in these domains were replicated in FOCUS or AFFINITY.
- At 6 months, fluoxetine reduced new depression (antidepressant use: 4.8% fluoxetine vs 6.8% placebo); by 12 months this benefit had disappeared: 9.0% (65/725) fluoxetine vs 8.8% (64/728) placebo (diff 0.2%, 95% CI −3.1 to 3.8%). Of those on antidepressants at 6 months, 41% fluoxetine vs 59% placebo continued at 12 months.
- All other secondary outcomes at 12 months were non-significant: SIS strength (P=0.88), hand ability (P=0.75), mobility (P=0.84), motor composite (P=0.88), daily activities (P=0.97), physical function composite (P=0.98), mood/emotional control (P=0.63), participation (P=0.79), recovery VAS (P=0.58), fatigue/vitality (P=0.22), MHI-5 (P=0.57), EQ-5D-5L (P=0.86).
- Compliance was high: 89% (1338/1500) took trial medication for ≥150 days; median treatment duration 180 days (IQR 180–180) in both groups. 12-month mRS data available in 715 (95%) fluoxetine and 712 (95%) placebo patients. Lost to follow-up: 4.1% (62/1500).
- EFFECTS (n=1500, Sweden), FOCUS (n=3124, UK), and AFFINITY (n=1260, Australia/NZ/Vietnam) all showed identical null results for fluoxetine on functional outcome. A prospective individual patient data meta-analysis of all three trials is planned.
- Adverse events and safety data (fractures, hyponatremia) were only collected through 6 months; not re-assessed at 12 months except for mortality. Long-term follow-up via Swedish central registries is planned to ≥3 years.
Study Design
- Study Type
- Investigator-led, randomized, placebo-controlled, double-blind, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind (participant, care provider, investigator, and outcomes assessor all masked until 12-month assessment)
- Sample Size
- 1500
- Follow-up
- 12 months total (6 months on treatment + 6 months post-treatment observation)
- Centers
- 35
- Countries
- Sweden
Primary Outcome
Definition: Distribution of modified Rankin Scale (mRS) scores at 12 months (ordinal shift analysis)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - (0.76–1.10) | Not significant |
Limitations & Criticisms
- Adverse event data (fractures, hyponatremia) not collected between 6 and 12 months — the 6-month safety signals cannot be assessed for continuation or resolution after drug cessation.
- Depression at 12 months defined only as antidepressant use (ATC code N06A), which is a crude proxy — likely underestimates true prevalence; no face-to-face psychiatric assessment performed at 12 months as was done at 6 months.
- The statistically significant worse memory and communication scores in the fluoxetine group are not supported by FOCUS or AFFINITY and are interpreted as chance findings from multiple comparisons — no correction for multiplicity was applied to secondary outcomes.
- Excluded patients with pre-existing depression or antidepressant use — limits generalizability to a population with lower baseline depression risk; pooled observational data suggest post-stroke depression rates of 31–33% at 6–12 months vs only ~7–11% in EFFECTS.
- Rehabilitation intensity between 6 and 12 months was not monitored or controlled — any differential rehabilitation could confound functional outcome comparisons.
- Only 12.3% hemorrhagic stroke — primarily an ischemic stroke population; results may not generalize to hemorrhagic stroke.
- Single country (Sweden) with high-income healthcare structure — limits generalizability to lower-income settings where stroke burden is highest.
- This paper reports secondary predefined analyses of the EFFECTS trial; the primary 6-month outcomes were published separately in Lancet Neurology 2020.
Citation
Lundström E, et al. Stroke. 2021;52:3082–3087. DOI: 10.1161/STROKEAHA.121.034705