Predicting Poststroke Depression: Biomarkers and Beyond

Poststroke depression (PSD), which affects up to one-third of all stroke patients, is the most common psychiatric disorder to emerge after an acute stroke.1 Because PSD can presage poor outcomes, including longer hospitalizations and functional impairment, clinicians are seeking methods to identify PSD with more specificity than current measures and at an earlier stage of the disorder.1

The Quest to Objectively Identify PSD

Levada and Troyan investigated several categories in a 90-study narrative review to better characterize the landscape of biomarkers most predictive of PSD.1 Biomarkers from the neuroimaging, molecular, and neurophysiologic domains may help clinicians predict who will get PSD and better understand the underpinnings of the disease.1


In the 42 imaging studies culled for PSD, researchers found that only ischemic stroke lesions and their volume predicted PSD occurrence.1 The region most affected 1 year after a stroke was the frontal-subcortical affective network in the left hemisphere. The studies also found that pontine and lobar cerebral microbleeds and those with disease in the brain’s small blood vessels also had a higher incidence of PSD.1

“We can conclude that ischemic stroke lesion localization, its size, and additional

burdening anatomical factors are pathogenically related to PSD,” said Oleg A. Levada, MD, ScD, PhD, and Alexandra S. Troyan, MD, from the Zaporizhzhia Medical Academy of Post-Graduate Education Ministry of Health of Ukraine in Zaporizhzhia, Ukraine. “Lesions affecting the frontal-subcortical circles of mood regulation (prefrontal cortex, basal nuclei, and thalamus) predominantly in the left hemisphere can be considered as imaging markers for PSD and also as predictors of PSD development for at least 1 year after the stroke onset.”1

Molecular Markers

In the field of molecular biomarkers, most of the evidence stems from the neuroinflammation and genetic markers, which each had 10 studies. Collectively, the studies examined early markers of inflammation, including high sensitivity C reactive protein (hs CRP), ferritin, neopterin, and glutamate, and the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β, IL-6, IL-18, and interferon-γ. Lower vitamin D levels were also found in patients with PSD.1

The genetic markers S/S 5-HTTLPR, STin2 9/12, and 12/12 genotypes of the serotonin transporter genes SLC6A4, 5-HTR2a 1438 A/A, and BDNF met/met genotypes may predispose acute stroke patients to PSD. The genes SLC6A4 and BDNF may be implicated in epigenetic factors for PSD.1

The 6 studies covering the hypothalamic-pituitary-adrenal axis domain found that the most prominent markers for PSD were hypercortisolemia and diminished cortisol awakening response.1 In the 2 meta-analyses of growth factors, the common association to PSD was lower serum expression of brain-derived

neurotrophic factor levels. The insulin-like growth factor 1 needs further investigation.1

The 8 metabolite studies that evaluated the effects of serum glucose, uric acid, bilirubin, ApoE, serum leptin, and others were not predictive for PSD.1 In some cases, the biomarkers could not differentiate among PSD and other psychiatric disorders.  Likewise, the oxidative stress biomarker serum malondialdehyde lacked specificity to distinguish patients with PSD from patients without PSD, although higher levels were associated with greater PSD severity.1

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Neurophysiologic Markers

The 4 studies that reviewed abnormalities in the electroencephalograms of patients with PSD were all case-control studies of less than 100 patients with PSD.1 One of the studies found that patients with PSD had less neural complexity than healthy controls and nondepressed poststroke patients. Another study pointed to theta power in predicting PSD, particularly in the right hemispheric lesion and the prefrontal and temporal areas of the left hemisphere. Two studies that tracked the amplitude of the event-related potentials found that patients with PSD had impaired responses to stimuli, which indicated weaker perceptual abilities and cognitive processing.1

Associations Among Biomarkers

Wang and colleagues were among the first researchers to study the relationship among vitamin D levels and inflammatory biomarkers such as Hs-CRP, leukocyte count, neutrophil-to-lymphocyte ratio, IL-6, and TNF-α in 152 poststroke patients.2 The researchers discovered an inverse relationship between vitamin D levels and the inflammatory marker IL-6. PSD was associated with low vitamin D and high serum IL-6 levels.2

Apathy Also Predicts Poor Outcomes

PSD is not the sole determinant of a poor prognosis for stroke patients. Douven and colleagues investigated the effects that vascular cognitive impairment (VCI) had on PSD and poststroke apathy (PSA), as measured by the Montgomery-Åsberg Depression Rating Scale and the Apathy Evaluation Scale, respectively.3 In the 250-patient study, the team assessed patients at baseline (3 months poststroke), 6 months, and 12 months. Although VCI did not predict PSD, higher apathy levels were recorded in patients with any VCI, with a significant increase in apathy scores noted at 12-month follow-up. The more VCI patients had in cognitive domains, the greater the chance of developing PSA, which presages low quality of life and poor outcomes.3

Beyond Biomarkers for Detecting PSD

Before clinicians can rely on biomarkers to identify PSD, several screening questionnaires can identify PSD in poststroke patients. For those with intact language skills, the self-administered questionnaires can be completed in less than 10 minutes.4 Several screens that can be administered to aphasic patients include:

  • Stroke Aphasic Depression Questionnaire 10
  • Stroke Aphasic Depression Questionnaire 10–Hospital version
  • Signs of Depression Scale

“Biomarkers are useful insofar as they may enable clinicians and researchers to better understand the complex physiologic underpinnings of depression in patients after stroke,” said Gwendolyn M. Hamid, MSN, RN, adjunct clinical instructor at Villanova University in Pennsylvania. “I hope that clinicians are aware of how common post-stroke depression is as well as factors that place patients at increased risk, such as greater cognitive and physical disability. Patients need to know that post-stroke depression is not a given after stroke, but rather, is a common side effect that can be prevented or mitigated with increased awareness that should begin as soon as possible and be incorporated into stroke rehabilitation programs.”


  1. Levada OA, Troyan AS. Poststroke depression biomarkers: a narrative review. Front Neurol. 2018;9:577.
  2. Wang Q, Zhu Z, Liu Y, Tu X, He J. Relationship between serum vitamin D levels and inflammatory markers in acute stroke patients. Brain Behav. 2018;8(2):e00885.
  3. Douven E, Köhler S, Schievink SHJ, et al. Baseline vascular cognitive impairment predicts the course of apathetic symptoms after stroke: the CASPER study. Am J Geriatr Psychiatry. 2018;26(3):291-300.
  4. Hamid GM, MacKenzie MA. CE: Early intervention in patients with poststroke depression. Am J Nurs. 2017;117(7):32-40.