Managing Mood Disorders, Behavioral Changes, and Psychosis in People Living with Vascular Dementia

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer disease (AD), accounting for ~15% to 20% of cases of dementia worldwide.¹ VaD results from ischemic or hemorrhagic brain damage that leads to cognitive and neuropsychiatric dysfunction.² Unlike AD, which primarily affects memory, VaD affects multiple cognitive domains, leading to heterogeneous cognitive deficits that are frequently accompanied by prominent neuropsychiatric symptoms (NPS).³ These symptoms, including depression, apathy, agitation, and psychosis, not only affect the individual’s quality of life but also pose considerable management challenges for caregivers and health care providers. The burden of these symptoms is often underestimated in clinical practice, despite the strong correlation of NPS with more rapid disease progression and increased institutionalization rates.

Understanding the pathophysiology and management of NPS in VaD is crucial for optimizing outcomes. This article provides an in-depth exploration of the neuropsychiatric manifestations associated with VaD, their underlying mechanisms, and management strategies, integrating recent research and clinical perspectives.

NPS in VaD
NPS in VaD are common and often more severe than those observed in people living with AD.⁴ They may present as mood disorders, behavioral changes, or psychotic symptoms, and greatly affect disease prognosis and caregiver burden.

Mood Disorders
Depression is one of the most prevalent NPS in VaD, affecting up to 40% of individuals.⁵ The association between cerebrovascular disease and depression is well-established, with poststroke depression providing a model for understanding this phenomenon.⁶ Dysfunction in frontostriatal circuits and subcortical vascular lesions disrupts mood regulation, manifesting as persistent sadness, loss of interest, fatigue, and psychomotor retardation. Depression in VaD is not simply a psychologic reaction to cognitive decline but a direct consequence of vascular pathology.

Apathy, often mistaken for depression, is a distinct syndrome characterized by a lack of motivation, reduced emotional responsiveness, and diminished goal-directed behavior.⁷ It is consistently reported as the most common NPS associated with VaD, affecting up to 65% of individuals.⁴ Apathy correlates strongly with executive dysfunction and poor rehabilitation outcomes.⁸ Apathy is particularly debilitating because it contributes to reduced engagement in therapy and progressive functional decline.

Emotional lability and anosognosia are more pronounced in ischemic VaD compared with AD. Therefore, when executive functions are tested, impairments in planning ability, sequencing, and verbal fluency are more frequently found in ischemic VaD than in AD.⁹

Agitation and Behavioral Disturbances
Agitation and delirium are major challenges in individuals living with VaD and encompass a spectrum of behaviors, including verbal and physical aggression, restlessness, and disinhibition.¹⁰ These symptoms often stem from frontal lobe dysfunction, impairing impulse control and social behavior. In addition, behavioral disturbances may be exacerbated by environmental factors, medication side effects, and underlying medical conditions, such as infections or metabolic abnormalities.¹¹ High sleep disturbance scores have also been identified as among the most consistent differences in people with cortical VaD.¹² Delirium has also been independently associated with a greater burden of white matter small vessel disease, which is a common cause of VaD.¹³ Caregiver stress is exacerbated by these behaviors, often leading to earlier institutionalization of people with VaD.

Psychotic Symptoms: Hallucinations and Delusions
Although less commonly seen than in people with AD, psychotic symptoms such as hallucinations and delusions can occur in those living with VaD.^14,15 Hallucinations, primarily visual, and paranoid delusions may develop due to disrupted thalamocortical connections.¹⁶ The restlessness and agitation caused by these symptoms not only affect individuals and their quality of life, but also place a burden on caregivers and can lead to hospitalization and institutionalization.¹⁷

The American Heart Association noted that in inherited small vessel diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), adjustment disorders, dysthymia, apathy, and pseudobulbar affect were particularly notable.¹⁸ VaD is an important phenotypic characteristic of CADASIL, illustrating that small vessel disease and lacunar infarcts are associated with these mood disorders. 

Pathophysiology of NPS in VaD
The underlying neurobiologic causes of NPS in VaD involve multiple mechanisms, including the following:

1. Vascular damage and neuroinflammation: Chronic cerebral hypoperfusion leads to neuronal injury, white matter degeneration, and neuroinflammatory responses, exacerbating neuropsychiatric manifestations.¹⁹
2. Neurotransmitter dysregulation: Dopaminergic, serotonergic, and cholinergic pathways are frequently disrupted in VaD, contributing to mood disturbances and cognitive impairment.⁴
3. Frontal-subcortical circuit dysfunction: Damage to white matter tracts connecting the frontal cortex with the basal ganglia and limbic system results in behavioral and emotional dysregulation.²⁰

The heterogeneity of vascular pathology in VaD contributes to the variability in neuropsychiatric presentations. Whereas small-vessel disease is more commonly associated with mood disturbances, apathy, aberrant motor behavior, and hallucinations, large-vessel disease may result in more severe acute behavioral changes, such as agitation, aggression, or euphoria.⁴ Recognizing these pathophysiologic patterns can aid in tailoring treatment strategies.

Clinical Implications and Management Strategies
Some NPS in VaD have been found to have prognostic value in the memory clinic population. For example, in a study of participants found to have vascular brain injury on MRI, 89% of them had NPS, with hyperactive and apathetic behaviors being most prevalent. In that group, apathetic behavior was associated with higher mortality and cognitive deterioration risks. In contrast, hyperactive behavior was associated with lower mortality risk. Furthermore, in people with mild cognitive impairment, psychotic behavior was associated with increased institutionalization.²¹ Addressing NPS in VaD requires a multidisciplinary approach encompassing pharmacologic and nonpharmacologic interventions (Table).

Future Directions and Research Considerations
There remains a need for further research to develop targeted treatments for NPS in VaD. Potential future studies could explore:

• The role of neuroinflammation and immune dysregulation in the development of NPS
• The efficacy of novel pharmacologic agents, such as neuroprotective and anti-inflammatory drugs, in mitigating NPS in VaD
• Longitudinal studies to assess the impact of early intervention on NPS progression

Conclusion
NPS in VaD greatly affect disease progression and patient care. A comprehensive understanding of their underlying mechanisms and targeted interventions can improve clinical outcomes and quality of life for both patients and caregivers. Given the high burden of NPS in VaD, a proactive approach integrating pharmacologic and nonpharmacologic strategies is essential. Future research should focus on refining treatment strategies and developing novel therapeutic approaches to address these complex symptoms.²⁴