Understanding the Mechanisms in Poststroke Depression

older woman laying in hospital bed
older woman laying in hospital bed
The connection between PSD and mortality appears to result from increased cardiovascular mortality.

Each year in the United States, there are an estimated 700,000 strokes and 163,000 stroke-related deaths.1 Among the many complications that can result from stroke, depression is one of the most commonly reported. Various studies and meta-analyses indicate that depression occurs in roughly one-third of those who survive a stroke, compared with 5% to 13% of adults without a history of stroke.2 In the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, mood disorders that occur following stroke include depressive features, major depressive-like episode, and mixed-mood features.

Evidence suggests that poststroke depression (PSD) is a form of vascular depression. “Although vascular depression is related to small-vessel ischemia and PSD usually is related to large-vessel infarction (except lacunar infarcts), most studies have found similarities between these conditions, such as lower frequency of family and personal history of depression” and greater cognitive dysfunction and disability vs nonmicrovascular forms of geriatric depression, a review published in 2016 in the American Journal of Psychiatry reported.3 “Thus, a single cerebral infarct may trigger the same pathophysiological changes of depression as slowly evolving vascular ischemia.”

Worse outcomes linked with PSD

Previous findings identified PSD as the factor that most strongly predicts quality of life in those who survive a stroke, and numerous studies have linked PSD with greater disability, cognitive impairment, increased risk for falls, worse rehabilitative progress, and increased mortality.4 A study revealed significantly higher mortality rates among those who survived a stroke and in whom PSD developed during the acute poststroke period compared with those in whom PSD did not develop (odds ratio [OR], 3.4; 95% CI, 1.4-8.4, P =.007).5

In other research, patients with a score of ≥7 on the Hospital Anxiety and Depression Scale at 3 months post-stroke had increased mortality vs patients whose scores were lower (hazard ratio 1.41; 95% CI, 1.13-1.77; P =.02).6 The connection between PSD and mortality appears to result from increased cardiovascular mortality, to which autonomic dysfunction may be a contributing factor.

Risk factors and etiology

The limited number of prospective studies that investigated risk factors for the development of PSD point to the following3:

  • Genetic factors, such as 5-HTTLPR and STin2 VNTR polymorphisms of the serotonin transporter gene, and epigenetic modifications of 5-HTTLPR
  • Medical and psychiatric history, including a personal history of diabetes mellitus, depression, or anxiety, and a family history of depression
  • Stroke characteristics and lesion location, including links between stroke severity and PSD and between PSD and left frontal or left basal ganglia lesions within the first 2 months following stroke
  • Functional and cognitive impairment, such as poststroke impairment in activities of daily living and executive dysfunction in particular
  • Social support, including findings of an inverse correlation between PSD severity and number of social ties, and an association between lack of social support and PSD onset at 3-months follow-up

The etiologic mechanisms of PSD have yet to be elucidated and are likely to include a combination of psychological, social, and biological factors, as with many psychiatric disorders. Associated biological factors supported by empiric data include “alterations in ascending monoamine systems, hypothalamic-pituitary-adrenal axis abnormalities, disruption of prefrontal-subcortical circuits, alterations in neuroplasticity and in glutamate neurotransmission, and an excess of proinflammatory cytokines,” the review authors stated.

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Treatment, prevention, and next steps

“PSD has a major impact on both recovery and survival. There is also good evidence that PSD can be prevented,” Robert G. Robinson, MD, FANPA, a researcher and psychiatry professor at the University of Iowa Carver College of Medicine, and co-author of the 2016 review, told Psychiatry Advisor.

The American Heart Association recommends the use of antidepressants for PSD, which is supported by pooled results of 12 trials (eg, involving nortriptyline and citalopram), although more research is needed to clarify optimal timing, duration, and medications.2 In addition, pooled analyses of 8 randomized controlled trials demonstrated that the odds for PSD developing were lower among patients who received active pharmacologic treatment (OR, 0.34; 95% CI, 0.22-0.53).

Findings also show substantially lower poststroke mortality rates among patients taking antidepressants. In a trial published in 2003, for instance, those who survived a stroke and did or did not have PSD who received nortriptyline (100 mg/day) or fluoxetine (40 mg/day) for 12 weeks were found to have a higher probability of survival at 9-year follow-up vs patients who received placebo (59.2% for active treatment vs 36.4% for placebo [adjusted OR, 3.7; 95% CI, 1.1-12.2, P =.03]).7

A pathophysiologic hypothesis for PSD that integrates the various potential underlying mechanisms “into a coherent explanatory model has yet to be formulated…. We believe future studies should attempt to identify the mechanism of specific symptoms or clinical characteristics of PSD rather than the whole syndrome,” the authors wrote. Further research should also investigate “mechanisms of mortality as well as the treatment of PSD using novel approaches like anti-inflammatory drugs or other psychological treatments,” Dr Robinson added.


  1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-322.
  2. Towfighi A, Ovbiagele B, El Husseini N, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Poststroke depression: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48:e30-e43.
  3. Robinson RG, Jorge RE. Post-stroke depression: a review. Am J Psychiatry. 2016;173:221-231.
  4. Paolucci S. Epidemiology and treatment of post-stroke depression. Neuropsychiatr Dis Treat. 2008;4:145-154.
  5. Morris PL, Robinson RG, Andrzejewski P, Samuels J, Price TR. Association of depression with 10-year poststroke mortality. Am J Psychiatry. 1993;150(1):124-129.
  6. Ayerbe L, Ayis S, Crichton SL, Rudd, AG, Wolfe CD. Explanatory factors for the increased mortality of stroke patients with depression. Neurology. 2014;83:2007-2012.
  7. Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160(10):1823-1829.