As many as a third of individuals may be affected by depression after a stroke. Changes in mental health post-stroke may result from damage from the stroke, itself, or they may also develop in concert with reduced independence and quality of life as a person realizes there are certain tasks they are no longer able to perform. A Cochrane review published earlier this year provided the first update in over a decade analyzing pharmacological, psychological, and non‐invasive brain stimulation interventions for treating depression after stroke. It comes on the heels of the US Department of Veterans Affairs (VA) and the Department of Defense (DoD) issuing an update to their clinical practice guidelines regarding stroke rehabilitation in late 2019. Let’s take a closer look.

The primary objective of the Cochrane review was “to determine whether pharmacological therapy, non‐invasive brain stimulation, psychological therapy, or combinations of these interventions reduce the prevalence of diagnosable depression after stroke.” The findings may be especially reliable because the review was limited exclusively to randomized controlled trials (RCTs) that compared various interventions (pharmaceuticals, psychological therapy, non-invasive brain stimulation, or combinations of these) to placebo, “sham” brain stimulation, and/or usual care. These were trials with human subjects, so their conclusions may be more robust than research that relies on animal studies, in vitro research, or speculation based on mechanisms. 

The Cochrane selection criteria resulted in 49 trials encompassing 3342 subjects. The main findings were that pharmacological or psychological therapies can reduce the prevalence of depression, but this was based on “very low-certainty evidence.” Very low-certainty evidence also indicated that pharmacological therapy, psychological therapy, non-invasive brain stimulation, and combinations of these can reduce depressive symptoms. (The evidence was graded as very low because “estimates of treatment effects were imprecise due to small numbers in most studies and recruitment of people with very different baseline characteristics,” along with other limitations in study design.)

What is especially troubling is that adverse events related to the central nervous system with “significant harm” were reported for subjects across five trials using pharmacological treatment, and “significant gastrointestinal adverse events” were noted for subjects in four such trials. (No significant adverse events were found in association with psychological therapy.) The Cochrane authors noted, “Any use of pharmacological agents in people with persistent depressive disorder after stroke would require caution, as little is known about the risks, especially of seizures, falls, delirium, and interaction with other medications.” (Emphasis added.)

Weak evidence also underpins the VA/DoD guidelines. Regarding mental health after stroke, there was (weak) evidence in favor of exercise (including “mind-body” exercise such as yoga and tai chi) as adjunctive treatment for post-stroke depression or anxiety. Supportive evidence was found neither in favor of nor against combinations of psychotherapy and pharmaceuticals (SSRIs, SNRIs) for treating post-stroke depression (PSD). Weak evidence was identified in favor of SSRIs or SNRIs for treatment of PSD, and weak evidence also supported use of cognitive behavioral therapy. 

According to Sabine Allida, PhD, lead author of the Cochrane review:

“We found a small benefit of antidepressants and talking therapies (like cognitive behavioural therapy) in treating depression. Studies of repetitive Transcranial Magnetic Stimulation (rTMS - a mild form of brain stimulation applied through the scalp and skull) and combined antidepressant and talking therapy, or antidepressant and rTMS interventions reduced the number and severity of depressive symptoms people experienced. Our results suggested an increase in side effects for antidepressant medications such as confusion, sedation and gastrointestinal problems. Also, the individual trials often included only a small number of people – we are generally more confident of results when trials include a lot of people and are well conducted. So more research is need before recommendations can be made about the routine use of such treatments.” (Emphasis added.)

Finding effective treatments for patients who experience depression post-stroke is important because the depression itself may hinder the efficacy of other therapies and rehabilitation. For example, it may lead someone to stop taking medications that may be aiding in recovery, or it may reduce their drive to participate in physical rehab or occupational therapy. With this in mind, there might be nutritional compounds that may be of benefit as adjunctive interventions in addressing PSD.

Saffron, which is most commonly known for lending the characteristic yellow-orange color to the Spanish dish paella, has some surprising potential properties with regard to helping ameliorate depressive symptoms. A meta-analysis of RCTs found that saffron supplementation significantly reduced depression symptoms compared to placebo and was similarly effective to antidepressant medications in subjects with major depressive disorder (MDD). Research is needed specifically in post-stroke patients, but considering the excellent safety profile of saffron, it may be worth a trial period.

Omega-3 fats may also be worth exploring to support those with depression after a stroke. A study published last year in the European Journal of Nutrition determined that increases in red blood cell concentrations of EPA and DHA—achieved via supplementation—were associated with a decrease in depressive symptoms in patients with MDD. EPA concentration was more strongly correlated than DHA concentration, and higher baseline levels of omega-6 fatty acids also correlated with depression reduction, suggesting that omega-3 repletion may be particularly beneficial in those with a higher n-6:n-3 ratio at baseline. (See here for a brief synopsis of this research.) Again, research remains to be done specifically in the post-stroke population.

Other nutrients that may be helpful include vitamins D, B12, B6 and folate. Low serum vitamin D levels (25[OH]D) have been associated with depression six months post-stroke, and elevated homocysteine and hs-CRP are associated with increased risk for depression 1 year after a stroke. Compared to stroke patients with both hs-CRP and homocysteine levels below the median, those whose levels of both were above the median had an odds ratio of 6.05 (95% CI 3.13-10.15; P < 0.001) for developing PSD. Adequate levels of B12, B6 and folate are critical for maintaining effective function of the homocysteine pathway and may also play a direct role in alleviating depressive symptoms and supporting healthy cognitive function. (See here for a review of the role of nutritional status in recovery from stroke.)