[5][1] The exact mechanisms behind PSD are not completely understood, as the condition results from a complex interplay of neurochemical, structural, and inflammatory disruptions of brain function.

Key mechanisms implicated in PSD include glutamate toxicity, HPA axis dysfunction, abnormal neurotrophic response, decreased monoamine levels.

Some evidence also suggests that strokes of the left side of the brain are more commonly associated with PSD, and with greater severity, than the right; this is the classically accepted view.

[8] This influx can lead to neuronal death,[8] contributing to brain damage of the emotional regulation and reward pathways in the prefrontal cortex, amygdala, and especially the hippocampus.

[3] This disruption particularly affects the hippocampus and prefrontal cortex, leading to diminished neurogenesis and neuroplasticity, which are critical for emotional regulation and cognitive function.

[3][11] Screening for PSD should be a standard, routine, and repeated part of post-stroke care,[13] with tools like the Hamilton Depression Rating Scale (HDRS) and the Patient Health Questionnaire-9 (PHQ-9) recommended for this purpose; there is no consensus on a single screening tool to use, and some experts recommend using two different scales before establishing a diagnosis, to reduce the risk of a false positive result.

While PSA involves diminished goal-directed behavior and a lack of spontaneous movement or speech, it does not encompass low mood, thoughts of death or suicide, or feelings of guilt and worthlessness, which are associated with depression.

[3] Some, but not all, sources recommend the prophylactic use of antidepressant medications (primarily SSRIs and SNRIs) in patients with strokes considered to be high risk for PSD.