Presentation and Management of Psychosis, Depression, Agitation, Apathy, and RBD in People Living with Lewy Body Dementia

Lewy body dementia (LBD) is the second most common neurodegenerative disease causing dementia after Alzheimer disease (AD).¹ The pathology of LBD is rooted in the buildup of α-synuclein within neuronal cells, which manifests in clinical presentations of cognitive decline, soft motor features of parkinsonism, and various neuropsychiatric symptoms that profoundly affect quality of life (Figure; Table). Psychiatric manifestations of LBD are particularly relevant as they are not only exceedingly common but often precede notable cognitive changes. The most common of these include psychosis, depression, agitation, apathy, and rapid eye movement (REM) sleep behavior disorder (RBD). 

Treatment options, particularly those that seek to mitigate neuropsychiatric symptoms, demonstrate varied efficacy and may produce considerable side effects.¹ Insight into the psychiatric components of LBD is essential for their management as well as for limiting disease burden for both patients and caregivers. Management has proven to be challenging because the symptoms and pathology of LBD tend to overlap with those of other dementia subtypes, ultimately leading to trends of underdiagnosis and misdiagnosis. We provide insight into the neuropsychiatric components of LBD and provide an overview of tactics to improve patient care and outcomes. 

Neuropsychiatric Symptoms 

Psychosis

Psychosis is a prevalent and early occurring neuropsychiatric symptom in LBD, affecting up to 80% of individuals with LBD over the disease course.² Individuals can have minor symptoms of psychosis, including delusions, presence hallucinations (ie, the feeling that someone is close by or just left the room), and passage hallucinations (ie, the vision of a shadow or someone passing by in the periphery), which often precede the onset of well-formed visual hallucinations.³ Complex hallucinations are one of the clinical hallmarks of LBD. These consist of inanimate objects, animated figures (eg, children playing), normal-sized figures, miniature people or animals, images from daily life experiences, and images from television programs.⁴ Delusions—particularly paranoid themes or misidentification, such as Capgras syndrome (believing that a loved one is an imposter)—are common in LBD, occurring in up to 70% of individuals.⁵

The etiology of psychosis in LBD is multifactorial. Misfolded α-synuclein aggregates in limbic, cortical, and subcortical regions cause disruption of neurotransmitter systems, particularly cholinergic and dopaminergic pathways involved in perception and cognition.³ In addition, neuroimaging studies have demonstrated frontal and subcortical gray matter loss as well as visual attention deficits in people with LBD with visual hallucinations compared with those without, indicating that such findings may underlie the vivid nature of this symptom.⁶ These mechanisms are compounded by the cognitive fluctuations and poor insight often associated with LBD, making management of symptoms of psychosis particularly challenging.

First-line management strategies include nonpharmacologic options, such as environmental modifications (eg, improving lighting, minimizing visual perceptions), structured routines, and caregiver education for reducing triggers. In addition, validating the individual’s perception and using redirection rather than confrontation are recommended to reduce distress.⁷

There are no Food and Drug Administration (FDA)–approved treatments for psychosis in LBD. However, when medications are necessary, cholinesterase inhibitors such as rivastigmine and donepezil have shown efficacy in reducing hallucinations while preserving cognition and motor function.⁸ Due to severe neuroleptic sensitivity in LBD, typical and many atypical antipsychotics can precipitate worsening parkinsonism, sedation, or death. Therefore, low-dose quetiapine is sometimes used cautiously.⁹ Pimavanserin (Nuplazid; Acadia Pharmaceuticals Inc., San Diego, CA), a selective serotonin 5-HT2A inverse agonist that is FDA-approved for the treatment of people with Parkinson disease psychosis, has shown promise in LBD and may offer a safer pharmacologic alternative.¹⁰ Low-dose clozapine can also be used to treat hallucinations and psychosis in LBD because it is less likely than other medications to worsen motor symptoms due to its weak dopamine D₂ receptor blockade and dominant 5‑HT2A antagonism.¹¹ However, clozapine carries a low but serious 0.38% risk of agranulocytosis. Individuals were previously required to undergo regular blood monitoring when on this drug, but recently the FDA has removed the rigorous monitoring of absolute neutrophil count blood tests to ensure the benefits of this medication outweigh the risks.¹² Ultimately, managing psychosis in LBD requires a delicate balance of minimizing distressing symptoms while avoiding harm, underscoring the importance of individualized care and multidisciplinary oversight.

Depression

Depression, which emerges at varying times in the typical LBD disease course and often may precede cognitive decline, is a prevailing neuropsychiatric symptom seen in those with LBD with prevalence estimates ranging from 30% to 50%.¹³ Proposed mechanisms for the etiology of depression in LBD are complex and include neurobiologic and structural brain changes. α-Synuclein pathology in LBD affects brain regions integral to mood regulation including the limbic system, prefrontal cortex, and brainstem nuclei such as the locus coeruleus and dorsal raphe, which disrupt serotonergic and noradrenergic transmission.¹⁴ In addition, coexisting cognitive fluctuations and parkinsonian symptoms may exacerbate feelings of helplessness, loss of autonomy, and social withdrawal, further contributing to depressive symptoms. Clinical features of depression in individuals with LBD may manifest as persistent low mood, anhedonia, apathy, irritability, sleep disturbances, and psychomotor slowing, which can overlap with both dementia and parkinsonism, making diagnosis challenging. Individuals may also exhibit less overt sadness and more somatic complaints or social withdrawal, which can be misinterpreted as cognitive decline or apathy alone.³

Management of these symptoms in people with LBD requires a multifaceted approach. Nonpharmacologic strategies such as cognitive stimulation therapy, a structured group intervention that engages individuals in mentally stimulating activities, has shown promise in improving cognition and mood in people with dementia including those with LBD.¹⁵ Additional interventions such as caregiver support, physical activity, light therapy, and mindfulness-based interventions may also help improve mood without the risks associated with pharmacotherapy.¹⁶

When medications are needed, selective serotonin reuptake inhibitors such as sertraline or fluoxetine are prescribed frequently for depression in LBD.¹² Tricyclic antidepressants such as amitriptyline have the most consistent evidence for efficacy but have considerable anticholinergic properties. Therefore, selective serotonin reuptake inhibitors are preferred for their minimal anticholinergic activity and to avoid exacerbation of cognitive or autonomic symptoms. Individuals with treatment-refractory depression may benefit from transcranial magnetic stimulation or electroconvulsive therapy, although the latter may cause confusion and exacerbate dyskinesia.¹² Antidepressant therapy should be monitored carefully in individuals with LBD as response may be slower, and treatment should be integrated with comprehensive dementia care.¹²

Agitation 

Agitation is a common presenting feature of LBD characterized by increased and often undirected motor activity, restlessness, aggressiveness, and emotional distress with an estimated prevalence of at least 30%.¹⁷ Proposed mechanisms for its development in various dementia subtypes include dysfunction of the frontal lobe as well as dysregulated activity levels and hypoperfusion within the parietal lobule, precuneus, and angularis gyrus, and hyperperfusion in the fusiform, lingual gyrus, and thalamus.¹⁸ In addition, a compensatory increase in noradrenergic sensitivity is believed to result from the destruction of norepinephrine-producing regions such as the locus coeruleus, ultimately leading to increased reactivity and decreased regulation of decision-making behaviors.¹⁹ However, the majority of evidence supporting these mechanisms is based on AD and its related pathology, thus revealing a need for studies that specifically examine LBD.

Nonpharmacologic management of agitation should always precede pharmacotherapy and prioritize the identification of triggers other than LBD that may cause agitation. Examples of potential triggers include painful conditions, all causes of delirium including infections, and drugs that can cause irritability. Strategies such as music therapy and caregiver education have shown some efficacy in reducing symptom severity, although supporting data are relatively limited, and there is a need for further research in this area.²⁰

There are no FDA-approved treatments for agitation in LBD. Pharmacologic management often involves the off-label use of atypical antipsychotics including low-potency agents such as quetiapine, which has demonstrated moderate efficacy in reducing agitation in people with LBD and has favorable tolerability and motor side effect profile.²¹ The use of anticonvulsants may be considered when symptoms are refractory to nonpharmacologic and first-line pharmacologic options, however data supporting their use in LBD is sparse, and further research is needed to confirm their clinical benefit and safety profile.²² Brexpiprazole has shown promise in reducing agitation in dementia-related disorders, particularly AD, although comparable data in LBD remain limited.²³

In severe or treatment-resistant cases, electroconvulsive therapy has been used as a management strategy. Supporting data are limited, but small studies suggest that this method may reduce agitation across various dementia subtypes without worsening cognitive or motor symptoms in most individuals, making it a potentially valuable option.²⁴

Overall, whereas nonpharmacologic approaches are the first line of treatment, management of agitation is highly dependent on individualized responses and requires a cautious, individual-centered approach. 

Apathy

Apathy is a common presenting feature of LBD, with recent studies demonstrating prevalence rates ranging from 35% to 100%.²⁵ Classically described as an unmotivated and directionless state, apathy substantially increases difficulty in completing daily tasks as well as maintaining personal relationships. As such, it has been strongly linked to extent of functional impairment as well as caregiver burden throughout the progression of LBD. Distinguishing apathy from depression can be challenging due to potential symptom overlap and co-occurrence. A recent review that included an analysis of a sample of patients with AD emphasized the frequency of fatigue, psychomotor agitation or retardation, and decreased pleasure in depression, whereas apathy typically manifested as loss of or diminished goal-directed cognitive activity. This review noted that apathy often does not include the anxiety, vegetative symptoms, suicidal ideation, and rumination seen in depression.²⁶ Further studies are needed to examine the complex interplay of these symptoms in LBD.

Apathy has been shown to be associated with the degeneration of frontal and subcortical regions across various dementia subtypes, although mechanisms specific to LBD remain largely undefined. Nonetheless, a recent study revealed an association between MRI-visualized orbitofrontal sulci atrophy and apathy in individuals with various forms of dementia including LBD.^27,28

Nonpharmacologic treatment lacks clear evidence that demonstrates the efficacy of one approach over another. However, management strategies that have shown some symptom improvement include the use of individual-based therapeutic activities such as those that emphasize creativity and hands-on learning as well as music therapy.²⁹ However, efficacy data supporting their use are variable and lack disease-specific studies, making apathy a particularly challenging area of management in LBD that also lacks FDA-approved treatments.

Pharmacologic treatment may include cholinesterase inhibitors such as rivastigmine and donepezil due to their global effects on cognitive functioning and demonstration of efficacy in some studies, however further research is warranted to confirm their ability to reduce apathy in LBD.³⁰ In addition, the use of psychostimulants such as methylphenidate may be considered a first-line approach, as recent data demonstrated positive effects in people with AD.³¹

Overall, apathy has a profound impact on patient and care partner emotional wellbeing as well as functional impairment, making its presentation and management of exceeding relevance.

Rapid Eye Movement Sleep Behavior Disorder

RBD is a hallmark feature of LBD, with prevalence estimates varying; a recent study reported prevalence rates ranging between 30% and 76% of individuals with LBD.³² RBD is characterized by recurrent dream enactment behavior and an absence of normal REM sleep atonia, often resulting in self-imposed injuries that are of primary concern for clinicians. Its etiology is complex but has been strongly linked to synucleinopathy pathology and associated dysfunction in regions of the brain that regulate REM sleep, such as the pontine and medullary structures. RBD carries a strong association with LBD compared with other dementia subtypes, and evidence suggests it often precedes and may predict eventual disease development.³³

The primary goals of RBD treatment focus on reducing the unpleasantness of dreams, improving overall sleep quality, and reducing injury risk. Low-dose benzodiazepines such as clonazepam have demonstrated successful reductions in both dream unpleasantness and associated reenactment behavior during sleep when taken close to bedtime.³³ In addition, melatonin has shown comparable efficacy and may be used as a monotherapy, in conjunction with clonazepam, or as an alternative treatment.³³ Melatonin has demonstrated favorable tolerability and may be considered as a first-line therapy.³⁴ Nonpharmacologic management also prioritizes reducing risk for self-injury during sleep by emphasizing a safe sleeping environment (eg, sleeping in a separate bedroom from others and removing objects from sleeping areas that have the potential to cause injury).^33,34 Light-based therapy may also be considered due to its well-established role in the regulation of circadian rhythm cycling, although supporting data are limited and this treatment requires further exploration.^32,35

Conclusion 

Neuropsychiatric symptoms of LBD including psychosis, depression, agitation, apathy, and RBD are highly prevalent and often precede or parallel the hallmark cognitive and motor features of the disease, making them crucial targets for timely diagnosis and treatment. Symptoms have various etiologies and clinical presentations, with overlapping manifestations that complicate both recognition and subsequent intervention, leading to unique challenges in management. Nonpharmacologic treatment approaches should be considered first including evaluating for physical ailments that may be provoking behavioral disturbances. Avoidance of or reduction in doses of medications that can worsen neuropsychiatric or motor manifestations should also be prioritized. When medications are necessary to modify behaviors, they should be used at the lowest dose for the shortest duration possible, with an overview of potential options provided in the Table.¹¹ Despite these strategies, the current evidence base for managing neuropsychiatric symptoms in LBD is limited by a lack of large, disease-specific clinical trials. Further research is needed to develop and validate targeted therapies that address the unique neurobiology and associated clinical manifestations of LBD. Until then, clinicians must rely on a cautious, evidence-informed approach that emphasizes safety, support, and the preservation of quality of life for both patients and caregivers.