Fluoxetine (PROZAC) Not Effective for Preventing Depression Following a Stroke

A stroke is a medical emergency that can result in significant temporary or permanent disability and decreased quality of life. Unsurprisingly, during the first year following a stroke, approximately one-third of patients develop depression or clinically significant symptoms of depression.[1]

A series of randomized clinical trials conducted from 1986 to 2011 suggested that antidepressants may reduce the occurrence of depression following a stroke.[2] However, these trials had significant limitations — including enrolling small numbers of subjects — and, therefore, the evidence that they provided was of very low certainty and thus inconclusive.

Results of a large, well-designed, randomized clinical trial published in the September 2021 issue of the Journal of the American Medical Association (JAMA) Neurology provided strong evidence that the commonly prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine (PROZAC) was not effective for preventing depression in the first six months after a stroke.[3]

The JAMA Neurology trial[4]

The trial was led by a team of researchers based in Australia and funded by the Australian National Health and Medical Research Council. From January 2013 to June 2019, the researchers enrolled a total of 1,221 adult subjects living in Australia, New Zealand or Vietnam who had experienced a stroke within two to 15 days of enrollment and subsequently had persistent minimal-to-moderate neurologic deficits. Patients who previously had epilepsy, bipolar disorder, liver or kidney impairment, or who had already been taking an antipsychotic medication or SSRI or another medication that had potentially dangerous interactions with fluoxetine (see the article for a discussion of important drug interactions for fluoxetine) were excluded from the trial. Pregnant women or women trying to get pregnant were also excluded.

The subjects were randomly assigned to receive a 20-milligram fluoxetine capsule (607 subjects) or a look-alike placebo (614 subjects) daily for 26 weeks. The subjects were screened for depression symptoms at the time of enrollment and at four, 12 and 26 weeks after randomization using a standardized questionnaire to ascertain symptoms of depression known as the 9-item Patient Health Questionnaire (PHQ-9). PHQ-9 scores range from 0 to 27, and scores of 9 or higher were considered to be indicative of clinically significant symptoms of depression in patients who had a stroke.

Consistent with successful randomization, the resulting fluoxetine and placebo groups were well-balanced on the following parameters: age; gender; nationality; living alone status; stroke severity, type and classification; and depression history.

At baseline prior to randomization, 116 fluoxetine-group subjects (19%) and 112 placebo-group subjects (19%) had PHQ-9 scores of 9 or higher. During the entire 26-week treatment period, 121 of the fluoxetine-group subjects (20%) and 126 of the placebo-group subjects (21%) had a PHQ-9 score of 9 or higher at least once, a difference that was not statistically significant. Notably, the percentage of subjects who had a PHQ-9 score of 9 or higher gradually decreased in both groups over time, from 13% in the fluoxetine group and 15% in the placebo group at week 4 to 7% in the fluoxetine group and 8% in the placebo group at week 26.

Twenty-six subjects (4%) in the fluoxetine group reported being diagnosed with depression during the 26-week treatment period compared with 42 placebo-group subjects (7%), a difference that did reach statistical significance. Notably, the proportion of subjects who were prescribed another antidepressant during the trial was similar in both groups: 7% in the fluoxetine group and 8% in the placebo group. Likewise, the proportion of subjects who received nondrug treatment for depression during the trial was the same in both groups (3% in each group).

Based on these results, the researchers concluded that routine daily treatment with fluoxetine following a stroke did not decrease the proportion of people who experienced clinically significant symptoms of depression, nor did it affect the proportion of people prescribed an antidepressant or provided nondrug therapy for depression.

Finally, the researchers cautioned that fluoxetine use does not come without risks. In particular, they noted that results of their trial and two other trials found that daily treatment with fluoxetine following a stroke increases the risk of bone fractures.

What You Can Do

If you suffer a stroke, you should avoid treatment with antidepressants unless you develop symptoms consistent with major depression. If you experience limited depression symptoms or mild depression (sometimes referred to as dysthymia) following a stroke, the first-line therapy should be talk therapies and even physical or occupational therapy, both of which are safer than any medications and may be equally or more effective. Post-stroke depression, as well as depression in other circumstances, should only be treated with an antidepressant if the formal diagnosis of major depression has been made by a qualified health care professional.
 

References

[1] Hackett ML, Pickles K. Part I: frequency of depression after stroke: an updated systematic review and meta-analysis of observational studies. Int J Stroke. 2014;9(8):1017-1025.

[2] Allida S, Cox KL, Hsieh CF, et al. Pharmacological, psychological, and non-invasive brain stimulation interventions for treating depression after stroke. Cochrane Database Syst Rev. 2020;Issue 5. Art. No: :CD003689.

[3] Almeida OP, Hankey GJ, Ford A, et al. Depression outcomes among patients treated with fluoxetine for stroke recovery: The AFFINITY randomized clinical trial. JAMA Neurol. 2021;78(9):1072-1079.

[4] Almeida OP, Hankey GJ, Ford A, et al. Depression outcomes among patients treated with fluoxetine for stroke recovery: The AFFINITY randomized clinical trial. JAMA Neurol. 2021;78(9):1072-1079.