New analysis of AFFINITY finds no change between treatment and placebo

Fluoxetine (20 mg daily) was not effective for post-stroke depression in patients with a recent stroke, a secondary analysis of AFFINITY trial data found.

Daily use of 20 mg of fluoxetine for 26 weeks did not reduce the proportion of people with a recent stroke who developed clinically significant symptoms of depression compared with placebo (cumulative prevalence of 20.2% versus 21.1%), reported Osvaldo Almeida, PhD, of the University of Western Australia in Perth, and co-authors in JAMA Neurology.

AFFINITY was one of three recent randomized double-blind placebo-controlled trials that found fluoxetine was not effective for improving motor functional recovery after stroke. In the other two, FOCUS and EFFECTS, fluoxetine was associated with a decreased prevalence of depression.

“Routine daily treatment with 20 mg of fluoxetine did not decrease the proportion of people affected by clinically significant symptoms of depression after a stroke, nor did it affect the proportion of people prescribed an antidepressant or receiving nonpharmacologic treatments compared with placebo,” Almeida and colleagues wrote.

“Our findings also show that treatment with fluoxetine did not prevent the emergence of depressive symptoms in this population nor was it more effective than placebo in treating depression among those with clinically significant symptoms of depression at baseline,” they added. “Patients with recent stroke should not be treated routinely with 20 mg daily of fluoxetine to prevent or treat clinically significant symptoms of depression during the first 6 months after the stroke.”

Researchers included 1,221 AFFINITY participants from Vietnam, Australia, and New Zealand with ischemic or hemorrhagic stroke with mild to moderate deficits recruited between January 2013 and June 2019. Participants had been randomized to placebo (n=607, mean age 64, 62% men) or 20 mg fluoxetine daily (n=614, mean age 63, 65% men), and were assessed at baseline, 4, 12, and 26 weeks.

Depressive symptoms were measured with the 9-item Patient Health Questionnaire (PHQ-9

Additional findings included:

  • A clinician diagnosis of depression was reported by 7.0% and 4.3% of the placebo and fluoxetine groups, respectively (P=0.05).
  • Agreement between a PHQ-9 score of 9 or more and a clinician diagnosis of depression was poor (κ=0.19).
  • A similar proportion of people in the fluoxetine and placebo groups with baseline PHQ-9 scores less than 9 developed PHQ-9 scores of 9 or higher during the trial (fluoxetine 13.0% versus placebo 14.8%, P=0.43).
  • At 26 weeks, 8.2% of participants in the placebo group (47 of 575) and 7.0% of participants in the fluoxetine group (39 of 555) had a PHQ-9 score of 9 or higher.

“Current approaches to the prevention and management of clinically significant symptoms of depression after stroke require systematic assessment and attenuation of modifiable risk factors for depression, standardized diagnostic measures, and personalized interventions that are effective and safe rather than the routine prescription of antidepressants for all patients,” Almeida and co-authors concluded.

“The main result is that fluoxetine had no effect on PHQ-9 scores,” wrote Michael Hill, MD, MSc, and Sean Dukelow, MD, PhD, both of the University of Calgary in Canada, in an accompanying editorial.

“Interestingly, the agreement between a PHQ-9 score of 9 or higher and a clinical diagnosis of depression (reported by 218 trial participants) was poor (κ=0.19),” the editorialists added. “This finding may reflect common practice, in which the PHQ-9 is used as a screening tool rather than a diagnostic tool.”

“The diagnosis of depression is made by clinical assessment rather than by self-assessment,” they continued. “This point is critical because we must interpret the study as assessing change in the self-reported PHQ-9 symptom and sign rating scale but not necessarily in the clinical diagnosis of depression.”

Use of fluoxetine in the stroke population increased risk for bone fracture, the researchers noted. “Given the long half-life of fluoxetine and its metabolites, its use in a predominantly older population with concurrent morbid conditions should be judicious,” they wrote.

The conclusions of the present study differ from those supporting a depression benefit from fluoxetine in FOCUS and EFFECTS, noted Almeida and colleagues.

“Although the results of these trials suggest that fluoxetine reduces the proportion of patients who had a stroke and received a clinical diagnosis of depression, our data using repeated assessments with a valid depression instrument failed to replicate these results and showed that agreement between the PHQ-9 definition of depression and participant-reported diagnosis of depression is poor,” they said.

“This finding could indicate poor sensitivity of clinicians involved in the care of patients with stroke to recognize cases of depression, reluctance of participants to disclose a diagnosis of depression, or the differing time frames used for the assessments (since last assessment vs during the last 2 weeks for the PHQ-9), or it could be due to the poor specificity of the PHQ-9 in identifying true cases of depression among patients who had a stroke,” they added.

The study included stroke patients with mild or moderate deficits; whether results apply to people with more severe deficits is unclear. By week 26, the percentage of participants still alive with good adherence to study protocol was only 63.3%, “which may have decreased the power of the study to exclude a modest but potentially important reduction in the risk of depression,” the researchers acknowledged.

  1. Fluoxetine 20 mg daily was not effective for post-stroke depression, a secondary analysis of AFFINITY trial data found.

  2. Daily use of 20 mg of fluoxetine for 26 weeks did not reduce the proportion of people with a recent stroke who developed clinically significant symptoms of depression compared with placebo (cumulative prevalence of 20.2% versus 21.1%).

Paul Smyth, MD, Contributing Writer, BreakingMED™

The AFFINITY trial was funded by the Australian National Health and Medical Research Council.

Almeida reported receiving grants from National Health and Medical Research Council of Australia outside the submitted work.

Hill reported receiving grants from NoNO Inc, Boehringer-Ingelheim, and Medtronic outside the submitted work; having a patent licensed to Circle NVI; owning stock in PureWeb Inc; being a director of the Canadian Federation of Neurological Sciences; the Canadian Stroke Consortium; and Circle NeuroVascular Inc; and receiving grant support from Alberta Innovates Health Solutions, Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, and National Institutes of Neurological Disorders and Stroke. Dukelow reported receiving grants from Brain Canada; personal fees from Prometheus Medical, Sinntaxis, Ipsen, and Allergan outside the submitted work.

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