Final Word on SSRI for Post-Stroke Depression?

Pauline Anderson

August 12, 2021

The antidepressant fluoxetine does not prevent or alleviate post-stroke depression, new findings from a randomized, placebo-controlled trial confirm.

Dr Osvaldo Almeida

The results suggest the routine use of the selective serotonin reuptake inhibitor (SSRI) "can't be recommended for the prevention or treatment of post-stroke depression," lead author Osvaldo P. Almeida, PhD, professor of geriatric psychiatry, Medical School, University of Western Australia, Perth, Australia, told Medscape Medical News.

"Depressive symptoms are common after stroke, but for a large proportion of patients these symptoms are short-lived, resolving within a few weeks. General supportive measures and early rehabilitation may override any potential benefits associated with the use of fluoxetine," said Almeida.

The new analysis from the AFFINITY trial were published online August 2 in JAMA Neurology.

Multiple Trials

It's estimated that depression affects 1 in 3 people during the first year after a stroke. There's some evidence that antidepressants reduce depression after a stroke, but the number, size, and quality of studies is limited and difficult to generalize, the investigators note.

Fluoxetine hydrochloride, a widely used SSRI, has been shown to be better than placebo in treating depression in adults. It has also been studied, with some success, in patients who have suffered stroke.

The randomized FLAME trial, which included 118 adults with a recent stroke, showed treatment with the drug enhanced motor recovery and decreased the proportion of those with depression compared with placebo (7% vs 29%) after three months.

Two other studies — FOCUS and EFFECTS — also provided supportive evidence for fluoxetine use in stroke patients.

However, these trials had drawbacks. "The trouble with these studies is that their approach to assess depression relied on clinical reports," said Almeida.

He added the EFFECTS study collected data on depressive symptoms, but not from all participants, and although the FLAME study used the Montgomery-Åsberg Depression Rating Scale to assess depression, it was limited to 12 weeks and the definition of what constituted 'depression' was unclear.

The double-blind AFFINITY trial randomly assigned adult stroke patients in Australia, New Zealand, and Vietnam to receive daily treatment with 20 mg of fluoxetine hydroxide or matching placebo for 6 months. Subjects had a median baseline National Institute of Health Stroke Scale of 6, indicating moderate stroke severity.

Vietnamese patients were included in part to ensure the results could be generalized to ethnic and cultural groups outside the West, said Almeida.

Study participants had a modified Rankin Scale score of 1 or higher (range, 0-6, where 0 indicates no signs or symptoms and 6 indicates death). The authors note study participants had mild to moderate neurologic deficits.

No Impact on Mood

The primary outcome of the trial was functional recovery after 6 months of treatment. As reported in Lancet Neurology last year, these results were negative.

A planned secondary endpoint of this trial was clinically significant depression. At baseline and at 4, 12, and 26 weeks, researchers measured depressive symptoms with the 9-item Patient Health Questionnaire (PHQ-9), a self-administered scale with each item scored on a 4-point scale ranging from 0 (not at all) to 3 (nearly every day).

The PHQ-9 total score can range from 0 (no symptoms) to 27 (most symptoms). Scores of 9 or higher indicate clinically significant symptoms of depression among stroke patients.

The new analysis included 1221 participants, with 607 in the placebo group (62.3% men, mean age 64.3 years) and 614 in the fluoxetine group (64.7% men, mean age 63.4 years).

The two groups were balanced in terms of all baseline measures. About 18.5% in the placebo group and 18.9% in the fluoxetine group had a PHQ-9 score ≥9 (P = .84). The mean PHQ-9 score was 4.9 in the placebo group and 4.8 in the fluoxetine group (P = .80).

The investigators note PHQ-9 scores were lower in subjects from Vietnam. Evidence from other studies suggests depression is more prevalent among Australian adults than Vietnamese people living in Vietnam or Australia, they said.

After 4 weeks, 14.6% of participants in the placebo group and 12.8% in the fluoxetine group had a PHQ-9 score of 9 or higher.

The corresponding percentages were 9.7% and 10.8% at 12 weeks, and 8.2% and 7% at 26 weeks.

There was no evidence of a differential rate of change between the groups The proportion of participants with a PHQ-9 score of 9 or higher decreased over time (odds ratio [OR], 0.96; 95% CI, 0.80 - 1.27; P < .001). The main effect of treatment group was not significant (OR, 1.01; 95% CI, 0.80 - 1.27; P = .94), and the interaction between treatment group and time was also not significant.

The cumulative prevalence of clinically significant depression over the course of follow-up was 21.1% of those treated with placebo and 20.2% treated with fluoxetine (for a mean difference of 0.9%; 95% CI –3.7% to 5.5%).

The findings were not confounded by sex, country, or stroke type. They were also not affected by history of depression, although Almeida noted only about 5% of study participants reported past history of treatment for depression.

The proportion of patients with clinically significant symptoms of depression at each assessment was "lower than anticipated" and "surprising," said Almeida. "I was expecting to see an effect of fluoxetine on mood."

A Depression Subtype?

The results suggest post-stroke depression is not necessarily the same as a major depressive disorder, said Almeida. "The signs and symptoms may overlap but have a different physiological basis."

It's unclear whether results would be similar with other SSRIs. While studies of sertraline and other antidepressants have shown some evidence of efficacy, results have been inconsistent.

"The problem is that those studies were small and relatively brief," said Almeida. "If our interpretation about acute post-stroke depression is correct, we would not expect these antidepressants to be helpful either."

The same uncertainly would apply to other classes of antidepressants such as tricyclics, selective serotonin and norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors (MAOIs), said Almeida.

"The side-effect profile of some of these medications would raise concerns about using them in the management of acute post-stroke patients."

The study showed there was a poor agreement between the PHQ-9 definition of depression and clinical diagnosis of depression, which may impair clinicians' ability to recognized depression in stroke patients. It could also be that stroke patients are reluctant to disclose depressive symptoms.

It might also be a result of differing time frames used for depression assessment ("since last assessment" vs "during the last 2 weeks" for the PHQ-9), or to the poor specificity of the PHQ-9 in identifying true cases of depression in stroke patients, the investigators add.

The FOCUS, EFFECTS, and AFFINITY trials all showed daily treatment with fluoxetine for 6 months increased the risk of bone fractures, although Almeida explained the number of people needed to be treated for one extra fracture to occur was "high."

This suggests use of fluoxetine to prevent post-stroke depression "should be considered only if the evidence of benefit outweighs the potential risk of harm," the investigators note.

Almeida said he's "confident" the new results represent "the best evidence we have available to guide practice," and added that general supportive measures and rehabilitation may be the best approach for post-stroke depression.

"Given that study participants were recruited from specialized stroke services, it's possible that the potential benefits of fluoxetine were 'overridden' by the benefits of these more generic measures."

The authors acknowledge that by the end of the study, only 63.3% of the participants were alive and showed good adherence to the study protocol. This, they said, may have decreased the power of the study to exclude a modest, but potentially important, reduction in depression risk.

Screening vs Diagnostic Tool

In an accompanying editorial, Michael D. Hill, MD, and Sean P. Dukelow, MD, PhD, both from the Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Canada, noted the large sample size of study subjects who had evidence of disability and were enrolled within 15 days of stroke onset.

They also point out the study investigators were able to assess both absolute scores and change in scores over time.

They highlight the poor agreement between a PHQ-9 score of 9 or higher and a clinical diagnosis of depression, which, they note, may reflect common practice where the PHQ-9 is used as a screening tool rather than a diagnostic tool.

"The PHQ-9 scale and the actual diagnosis of depression may be different beasts," Hill told Medscape Medical News. "The trial shows that treating with fluoxetine didn't change the PHQ-9, but that doesn't necessarily mean that it did not affect the clinical entity of depression."

Hill emphasized that SSRIs are useful for chronic anxiety and "certainly have a role in treating depression." He added these drugs "also seem to be helpful in post-stroke emotional lability."

The fact that PHQ-9 scores were lower in Vietnamese participants might reflect "ethnic differences in reporting and true depression," the editorialists note.

Exploring New Options for Stroke Rehab

Dukelow said there are "multiple possibilities" for post-stroke rehabilitation in the pipeline, adding that there has been an "explosion" in research examining noninvasive brain stimulation, including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These modalities are under investigation to treat a variety of stroke-related deficits including aphasia, motor recovery, hemispatial neglect, and post-stroke pain, he said.

Researchers are also looking at a C-C chemokine receptor 5 (CCR5) antagonist, maraviroc (Selzentry), in combination with exercise to improve both upper and lower extremity recovery after a stroke. Maraviroc may augment skills learning during rehabilitation training by acting on unique molecular components for novel learning.

"If the results are as good as were seen in the preclinical studies, which is certainly not guaranteed, then the medication may be a game-changer for stroke rehabilitation," said Dukelow.

Research teams are also examining the impact of modafinil (Provigil), a drug that modulates the level of chemical messengers in the brain and exerts a stimulant effect, for post-stroke fatigue.

Technologies that allow for home rehabilitation, such as virtual reality and wearable sensors for tracking patient activity, are fast gaining interest, pushed somewhat by the COVID pandemic, said Dukelow

His team is starting a trial that monitors brain activity through near infrared spectroscopy while a patient does their rehabilitation in his or her home.

Perfecting robotic devices to help stroke patients walk or assist with their upper extremity therapy is another avenue of investigation. Such devices may supplement the therapy provided by a therapist, which "has the potential to lead to larger gains," said Dukelow.

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, and from National Health and Medical Research Council of Australia.

Hill reported grants to the University of Calgary, including those from NoNO Inc, Boehringer Ingelheim, and Medtronic; having a patent (for an automated decision-making system for stroke treatment); owning stock in Pure Web Inc, a company that makes medical imaging software; 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, and personal fees from Prometheus Medical, Sinntaxis, Ipsen, and Allergan.

JAMA Neurology. Published online August 2, 2021. Abstract

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