New treatments in sight for challenging neuropsychiatric symptoms in neurodegenerative diseases

By Dr. Chinta SidharthanReviewed by Susha Cheriyedath, M.Sc.Apr 3 2024

In a recent study published in the journal JAMA Neurology, researchers reviewed the progress thus far in pharmacologically managing the various neuropsychiatric syndromes that manifest in neurodegenerative disorders and discussed the recent advances in understanding the pathobiology of neurodegenerative disorders that help improve clinical care and therapy.

Study: Progress in Pharmacologic Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders. Image Credit: PopTika / Shutterstock

Neurodegenerative disorders and neuropsychiatric syndromes

Neurodegenerative disorders encompass a wide range of conditions, many of which are a factor of progressing age and manifest symptoms only in late middle age or old age. However, with the growing aging population in the world, the frequency of neurodegenerative disorders and associated conditions continues to increase. While Lewy body dementia, Parkinson's disease, Huntington's disease, and Alzheimer's disease are some of the more commonly heard neurodegenerative disorders, others include frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, amyotrophic lateral sclerosis, chronic traumatic encephalopathy, traumatic encephalopathy syndrome, and multiple system atrophy.

All neurodegenerative disorders are associated with neuropsychiatric syndromes, with neuropsychiatric syndromes being part of the diagnostic criteria for some of the neurodegenerative disorders. These neuropsychiatric syndromes can occur sequentially or simultaneously and play a major role in functional impairment and overall decline in quality of life, not to mention adding to caregiver distress.

Non-pharmacological interventions such as psychosocial treatments have been extensively explored to ameliorate neuropsychiatric syndromes in cases of neurodegenerative disorders and to prevent relapse. These include exercise programs, environmental modifications, music, acupressure and massage therapy, activities such as art in combination with music, and animal-assisted interventions.

However, in cases where psychosocial interventions are not successful in reducing the symptoms of neuropsychiatric syndromes or in cases where the patient might be a threat to themselves or others, pharmacological interventions are preferred. Although the development of pharmacological therapies to treat neuropsychiatric syndromes has been challenging, several medications have been approved for use by the United States (U.S.) Food and Drug Administration (FDA), specifically for patients with neurodegenerative disorders.

In the present review, the researchers discussed in detail five of the major neuropsychiatric syndromes, their occurrence, symptoms, and options for pharmacological management of these syndromes.

Depression

Depression is one of the common symptoms of neurodegenerative disorders, with a high prevalence of major depressive disorders among patients with dementia. In patients with Alzheimer's disease dementia, depression that is not diagnosed or treated in time often accelerates cognitive decline, suicide risk, and mortality risk. The incidence of depression in other neurodegenerative disorders such as Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies can often be close to 80%.

Although the diagnosis of depression in patients with neurodegenerative disorders is challenging, selective serotonin reuptake inhibitors and selective serotonergic and noradrenergic reuptake inhibitors have been prescribed. For depression that is life-threatening or psychotic, electroconvulsive therapy has often been effective. However, studies have found that Alzheimer's disease pathology involving a high brain amyloid burden can result in resistance to pharmacotherapy.

Disinhibition

Disinhibition has often been observed in patients with progressive supranuclear palsy, Huntington's disease, and Alzheimer's disease. It involves behavior that is considered inappropriate according to social norms, such as touching strangers, making sexually explicit jokes or remarks, improper sexual acts, speaking loudly, and oversharing personal details. It is most common in patients with the behavioral variant of frontotemporal dementia.

Atypical antipsychotics, selective serotonin reuptake inhibitors, and antiepileptic or mood-stabilizing agents have often been used to treat disinhibition. However, none of these are specifically for treating disinhibition in patients with neurodegenerative disorders.

Apathy

Apathy in dementia patients is often linked to a two-fold increase in the risk of cognitive decline. It is believed to increase caregiver distress, decrease treatment responses, and elevate the risk of frailty. While no approved treatments exist for apathy in patients with neurodegenerative disorders, psychosocial interventions, noninvasive brain stimulation, and non-psychostimulant pharmacologic interventions have been explored.

Psychosis

Psychosis, which involves a wide range of delusions and hallucinations, has varied associations with different neurodegenerative disorders. Patients with dementia with Lewy bodies often experience misidentification, misrepresentation, visual hallucinations, and feelings of presence, while frontotemporal dementia patients often also experience paranoia. The antipsychotics that have been approved for patients with neurodegenerative disorders based on results from placebo-controlled, double-blind trials include Pimavanserin, Risperidone, and Aripiprazole.

Agitation

One of the most prevalent and disruptive neuropsychiatric syndromes in most neurodegenerative disorders is agitation, which involves kicking, shoving, shouting, hitting, and resisting care. It is associated with rapid progression of dementia and earlier mortality. Agitation also results in a higher probability of hospitalization and substantially negatively impacts the quality of life of the patients and their families.

Agitation is often treated with antipsychotics such as Risperidone, Aripiprazole, Quetiapine, and Brexpiprazole. Antidepressants such as Citalopram and the anticonvulsant Carbamazepine have also been used as pharmacological treatment options for agitation.

Conclusions

To summarize, the review examined the latest advances in the pharmacological management of neuropsychiatric syndromes associated with neurodegenerative disorders. The researchers provided a comprehensive summary of the symptoms of five major neuropsychiatric syndromes and the pharmacological options for their management.