As a leading provider of stroke research services, Ace Therapeutics assists clients in investigating the pathology of post-stroke depression and in developing potential treatment strategies.

Post-stroke depression is considered a common stroke complication and a major cause of poor recovery, poor quality of life, poor rehabilitation outcomes, and reduced functional capacity. Post-stroke depression is an important research topic because it may affect an increasing number of stroke survivors and may provide a unique window into the pathophysiology of depression.

Fig. 1 Major risk factors contributing to post-stroke depression. (Sarkar, et al., 2021)

Pathophysiology of PSD

The pathophysiological mechanisms of PSD are not well understood. The etiology of PSD is complex, with biological, behavioral, and social factors involved. Further understanding of the pathophysiology of PSD can help to develop targeted preventive and therapeutic interventions.

Below we focus on the biological factors that influence stroke pathology.

PSD and Location of the Stroke Lesion

The evidence is inconsistent regarding the correlation between lesion laterality and PSD risk, likely due to methodological biases. However, specific brain regions, such as the frontal cortex, basal ganglia, and amygdala, may play roles in PSD development.

PSD and Types of Stroke

Different stroke types contribute to PSD development through mechanisms such as vascular damage, white matter lesions, chronic lacunar strokes, and cerebral microhemorrhages. Small vessel disease, cerebral perfusion, and cumulative damage in specific brain regions are significant factors.

PSD and Neurobiological Pathways

There is a link between PSD and lesions in different brain pathways.

• Subcortical lesions in the frontal lobe of monoaminergic pathways reduce biogenic amine release and lead to an increased likelihood of depression.
• Changes in glutamate transmission after stroke.
• Dysregulation of the hypothalamic-pituitary-adrenal axis after stroke, with the resulting persistent hypercortisolism, is associated with the development of depression, poorer prognosis, and increased mortality.

PSD and Inflammation

Cerebral ischemia increases levels of cytokines like IL-1β, TNF-α, and IL-18, which may reduce serotonin production and promote depression. Antidepressants may offer therapeutic benefits by targeting inflammatory pathways.

PSD and Genetic Factors

Genetic variability, particularly in serotonin transporter-related genes, significantly influences the risk of developing PSD, highlighting genetic susceptibility as a key factor. For example, homozygosity for the s/s variant of the serotonin transporter gene SLC6A4 may also contribute to PSD development.

Fig. 2 Pathophysiological mechanisms of PSD. (Fang, et al., 2022)

Diagnosis of PSD

Diagnosing PSD is challenging, both in the acute phase and during long-term recovery, often leading to it being overlooked or inadequately treated.

The DSM-IV criteria for diagnosing post-stroke depression (PSD) follow a non-etiological approach, defining it as "depression due to stroke with a major depressive-like episode or depressive features." One significant challenge with these criteria is that they require the presence of somatic symptoms—such as fatigue, energy loss, weight loss, appetite reduction, insomnia, concentration issues, and psychomotor changes—that can also be a direct result of the stroke itself. This overlap may lead to an overestimation of depression in stroke patients, as some symptoms may be attributed to the physical effects of the stroke rather than depression.

Depression rating scales are essential for quantifying and monitoring depressive symptoms, but they should be used carefully. These scales often emphasize somatic symptoms and may have low specificity when compared to established diagnostic standards.

Biomarkers of PSD

Early detection of PSD is critical, prompting the need for reliable biomarkers. Current findings include:

Current Drug Research in PSD

The complexity of PSD mechanisms has made it challenging for healthcare providers and researchers to develop effective prevention and treatment strategies. However, extensive scientific research has led to the creation of various drug categories that have been clinically proven to prevent and treat PSD. Most drugs are manufactured and developed to counter the effects of damages caused by factors involved in the pathogenesis of post-stroke depression. Pharmacological treatment is considered to be the first choice for PSD.

Nonpharmacological Therapies for PSD

There are several nonpharmacological interventions that can be prescribed for PSD. The mechanisms underlying the beneficial effects of these strategies are unknown but likely involve reductions in inflammatory signaling, improved immunity, enhanced neurotransmitter release, reduced HPA axis activation, or elevations in endogenous growth factors.

• Electroconvulsive therapy (ECT) is used for major depression resistant to medication but can worsen cognitive dysfunction and requires anesthesia and close monitoring.
• Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that uses magnetic stimulation to target specific brain regions, showing promise as a safe and effective treatment for PSD, though more research is needed.
• Cognitive behavioral therapy (CBT), which modifies dysfunctional emotions and behaviors, has been proven effective for depression and may aid physical recovery in stroke patients.
• Transcranial direct current stimulation (tDCS) is an emerging non-pharmacological treatment for depression. This technique involves applying a low electrical current to brain regions responsible for regulating mood and emotions, with the goal of modulating neural activity to improve mood balance.
• Vagus nerve stimulation (VNS) is a therapeutic treatment for severe, treatment-resistant depression, involving the implantation of a device that delivers intermittent electrical stimulation to the left cervical vagus nerve. Approved in the United States and Europe, it is used for long-term treatment in patients who have not responded to at least four antidepressant medications.
• Other therapies like music therapy, exercise, and light therapy also show potential benefits for PSD and quality of life but require further study.

Fig. 3 Nonpharmacological treatment options for PSD. (Lai, et al., 2019)

1. Sarkar, A., et al. (2021). Post-stroke depression: chaos to exposition. Brain research bulletin, 168, 74-88.
2. Fang, C., et al. (2022). Natural products for the treatment of post-stroke depression. Frontiers in Pharmacology, 13, 918531.
3. Lai, Y. J., & McCullough, L. D. (2019). Poststroke depression: Pathophysiology and treatment strategies. Neurobiology of Depression, 197-205.