Managing Symptoms of Depression, Apathy, Psychosis, and Agitation in People Living with Alzheimer Disease

Alzheimer disease (AD) is a neurodegenerative disorder characterized by a progressive decline in meAmory and cognitive function. This decline eventually leads to functional impairments as well as degradation of neurologic integrity and destabilization of thought processes and mood. Several neuropsychiatric symptoms (NPS) are seen commonly in individuals living with AD, with the most prevalent being depression, apathy, psychosis, and agitation. Given the rapidly increasing aging population within the United States and globally, the burden of AD is immense.¹ This review provides an overview of the prevalence, diagnosis, and interventions for each of these core NPS in individuals with AD. 

Depression 

Depression is a mood disorder in which an individual feels persistently sad and despondent for at least 2 weeks along with experiencing symptoms such as fatigue, appetite changes, etc that impair daily functioning. As illustrated in Figure 1, depression is often found in earlier, milder stages of AD in an estimated 40% of people diagnosed with AD.² If untreated, depression can worsen AD symptoms and progression by compounding cognitive decline.² Diagnosis of depression in AD requires the presence of ≥3 of the following symptoms over a 2-week period: depressed mood; changes in sleep, appetite, or both; decreased positive affect or pleasure response; fatigue; feelings of worthlessness, hopelessness, or excessive or inappropriate guilt; impaired cognitive function with focus or thought; suicidal ideation or recurrent thoughts of death; social isolation; irritability; and changes to psychomotor function, such as retardation or agitation.³

Figure 1. Alzheimer disease stages: prevalence of neuropsychiatric symptoms (NPS). Created in BioRender (https://biorender.com/ij304mr).

It is important to distinguish between depression and apathy in AD because their management and interventions differ. Part of the challenge in differentiating depression and apathy is the overlap of symptoms.⁴ A key component of depression that does not overlap with apathy is the presence of anhedonia, which is defined as a marked decrease in pleasure or interest in all or nearly all daily or near-daily activities.⁵ Vegetative symptoms, such as poor appetite, poor sleep, and easy fatigability, are more common in clinically significant depression vs apathy. Two aids for diagnosing depression are the 9-item Patient Health Questionnaire⁶ and a clinical interview with insights from care partners and family members.⁷ A specific screening tool to diagnose depression in people with AD is the Cornell Depression in Dementia Scale.⁴

Various pharmacologic and nonpharmacologic interventions are available for the management of depression in people with AD. For mild depression and cognitive decline, nonpharmacologic treatments include psychotherapy, specifically cognitive behavioral therapy,⁹ and exercise therapy, a specific type of physical therapy that consists of structured and repetitive movements.¹⁰ Electroconvulsive therapy (ECT) has been shown to be beneficial for alleviating severe depression and other behavioral symptoms associated with AD,¹¹ but it may also be associated with adverse effects, such as worsened cognitive function and learning ability.¹² ECT is not typically recommended for treating depression in people with AD unless the depression is resistant to pharmacotherapy, is severe or life-threatening, or includes elements of psychosis.¹³ Given the limited research in the field, there is great opportunity for further research on nonpharmacologic interventions for AD-related depression.

The Food and Drug Administration (FDA) has not approved any medications specifically for the treatment of depression in people with AD¹⁴; however, several medications have demonstrated varying levels of favorable response. Effective off-label pharmacologic medications to treat AD-related depression include selective serotonin reuptake inhibitors (SSRIs) (citalopram¹⁵ and sertraline¹⁶), serotonin–norepinephrine reuptake inhibitors (SNRIs; venlafaxine¹⁶), and other antidepressants (vortioxetine,¹⁴ mirtazapine,¹⁶ and trazodone¹⁵). The tricyclic antidepressant clomipramine lacked positive benefit in improving depression symptoms according to one study.¹⁶ When choosing an antidepressant for an older adult with dementia (such as AD), the choice of antidepressant is generally based on desired or undesired side effects. Medications associated with a risk of orthostatic hypotension (eg, trazodone, tricyclic antidepressants) can worsen the risk of falls. The tricylic agents and the SSRI paroxetine, in particular, carry the risk of anticholinergic side effects, which tend to worsen cognition especially in this vulnerable group. Some agents are associated with sedation (eg, mirtazepine), which could lead to better sleep and less evening agitation. Nearly all antidepressants (with few exceptions, eg, bupropion) can reduce libido and may have a benefit to decreasing sexually themed agitation. Once an appropriate antidepressant has been selected, it should be initiated at a low dose. It’s important to note that older adults, including those with AD, take longer to respond to therapeutic doses of antidepressants vs younger adults (commonly 6 to 8 weeks, up to 12 weeks). 

Apathy

Apathy, also known as amotivational syndrome, is defined as a chronic state of emotional indifference. Its prevalence is anywhere from 24% to 85% among people with AD, in whom apathy generally increases as dementia worsens.⁴ A key diagnostic feature of apathy in people with AD is diminished initiative (decreased spontaneity or activity in one’s usual temperament) or diminished interest and expression for ≥1 month.¹⁷

Despite containing some diagnostic overlap, as displayed in Figure 2, apathy is a separate NPS from depression. Apathy is characterized by a decrease or loss of goal-directed cognitive activity.¹⁸ In contrast to depression, apathy appears with decreased interest but passive or compliant engagement, and on its own does not contribute to suicidal ideation. Apathy alone is typically not comorbid with rumination or anxiety, unlike depression.¹⁴ Apathy is associated with decreased hippocampal volume¹⁹ and reduced cortical thickness in the temporoparietal and right frontal regions of the brain on positron emission tomography scans.²⁰

Figure 2. Depression vs apathy: differential and overlapping symptoms. Created in BioRender (https://biorender.com/r2g79m4).

Nonpharmacologic treatments, in particular music therapy and physical activity, have produced some positive results in management of apathy.¹⁴ An often helpful nonpharmacologic approach to treatment of apathy in people with AD is to counsel care partners to direct, rather than ask about, engaging in an activity (ie, “We are going for a walk.”). In this manner, the individual is less able to defer and will often participate and enjoy the activity.

There are no FDA-approved treatments for apathy in AD.¹⁴ Stimulant medications, particularly methylphenidate,²¹ have shown the best results for AD-related apathy; however, hypertension, tachycardia,²² and increased anxiety are potential side effects of psychostimulants, especially at higher doses (>20 mg/day of methylphenidate), making them unsuitable for many older individuals.²³ The wake-promoting agent modafinil has yet to produce consistent, positive results in individuals living with AD.¹⁴ Donepezil, a cholinesterase inhibitor, has recently shown promise in reducing apathy,²⁴ but adverse events have been reported, including gastrointestinal symptoms as well as, less commonly, bradycardia.²⁵

Psychosis

Psychosis is defined by the presence of delusions or visual or auditory hallucinations for ≥1 month, even if intermittent.²⁶ Delusions are present in ~35% of people with AD,²⁷ whereas hallucinations are, on average, experienced by 23% of individuals with AD.²⁸ Psychosis tends to occur in the moderate to severe stages of AD¹⁴ and is associated with an increase in cognitive decline.²⁷ The Jeste and Finkel diagnostic criteria preclude symptoms of psychosis that appeared before AD onset and any other symptoms of psychosis that are secondary to delirium or functional psychosis.²⁷ Psychosis in individuals with severe AD dementia must be differentiated from confabulations, which may appear similar to psychosis-induced errors in memory.¹⁴ Delusions typically decrease as AD progresses.²⁹ Psychosis can be difficult to differentiate from cognitive deficits, such as mirrored-self misidentification (ie, failure to recognize oneself in the mirror). Diagnosis of AD psychosis needs to be differentiated from psychosis in Lewy body dementia (LBD), primary psychosis, and delirium with psychosis. Hallucinations in AD and LBD are most commonly visual; hallucinations in primary psychotic disorders (such as schizophrenia) are predominantly auditory.²⁹

To diagnose AD-related psychosis, there must be a change from baseline that cannot be attributed to a coexisting psychiatric disorder such as delirium or substance intoxication. Diagnosis requires a detailed clinical assessment, care partner corroboration, and exclusion of alternative medical or psychiatric causes.^30,31 When diagnosing AD-related psychosis, it is crucial to rule out delirium and LBD. Delirium is noted for its acute onset and fluctuating attention,³¹ which differs from psychosis. LBD is characterized by early visual hallucinations and soft motor features of parkinsonisms.³⁰ Medication-induced psychosis secondary to anticholinergics, narcotic analgesics, or corticosteroids must also be considered.³² Primary psychiatric disorders, such as late-onset schizophrenia, are distinguished by symptoms of psychosis preceding cognitive decline.³³

First-line management of psychosis in AD prioritizes nonpharmacologic approaches, which include modifying the environment (eg, reducing clutter and noise), establishing consistent routines, educating care partners, and using reassurance tactics. Distress associated with psychosis can also be modulated with structured activities and meaningful engagement.³¹ Pharmacologic treatment is reserved for situations where psychosis causes considerable distress, poses a danger to the individual or others, or when nonpharmacologic strategies have been unsuccessful.³⁴ There are no FDA-approved treatments for psychosis in AD. Choice of an antipsychotic agent, as with antidepressants, is often based on side effect profile. Most commonly, the use of atypical antipsychotics is preferred. Careful monitoring and prescribing the lowest effective dose are crucial in mitigating side effects and toxicity, with periodic dose reduction and discontinuation attempts required. Risperidone is approved in other countries, but not the United States, for the short-term treatment of aggression and psychosis in AD.³⁵

Agitation

Agitation affects ~50% of people with AD. Most commonly, agitation appears in moderate to severe stages of AD, often correlating with greater cognitive and functional deterioration.³⁸

Agitation is characterized by excessive motor activity, such as pacing or restlessness; verbal aggression, including shouting and cursing; or physical aggression, such as hitting or grabbing.³⁶ These behaviors often trigger considerable distress or functional impairment. These behaviors must represent a change from the individual’s baseline and cannot be attributed solely to delirium, other psychiatric disorders, or environmental factors.³⁶

Figure 3³⁶ delineates how accurate diagnosis of agitation in AD requires careful differentiation from other potential causes. Pain is a common and often underrecognized contributor to agitation, particularly in individuals with impaired communication.⁴⁰ Delirium must also be considered, particularly when there is acute onset of symptoms, fluctuating attention, or altered consciousness, which distinguish it from the more gradual behavioral changes seen with dementia progression.³⁷ Agitation may also be secondary to features of psychosis, such as hallucinations or delusions, as well as to environmental or psychosocial stressors. Psychosocial stressors include changes in routine, sensory overstimulation, or unmet basic needs, and may precipitate or exacerbate agitation episodes.³⁸

Figure 3. Fecision tree.³⁶ Created in BioRender (https://BioRender.com/u7xrluv). Abbreviation: IPA, International Psychogeriatric Association. 

The management of agitation in AD prioritizes nonpharmacologic interventions as first-line therapy. Effective strategies include structured routines, personalized activities, music therapy, environmental modifications to minimize overstimulation, and caregiver education.⁴¹ Addressing underlying medical issues and unmet needs, such as hunger, pain, or toileting, is critical to mitigating agitation.⁴⁰ Pharmacologic treatment is reserved for cases where agitation causes substantial distress or safety risks and nonpharmacologic measures have been insufficient.³⁶

Brexpiprazole is the only agent approved by the FDA for the treatment of agitation associated with dementia due to AD. Although clinical trials demonstrated reductions in agitation severity, brexpiprazole, as with all atypical antipsychotic agents in its class, carries a boxed warning for increased mortality risk among older individuals with dementia-related psychosis, necessitating careful risk–benefit analysis.⁴² Off-label pharmacologic options include atypical antipsychotics (which also carry a boxed warning for increased mortality risk among older individuals with dementia-related psychosis), such as quetiapine and olanzapine, used primarily for their sedating properties, although their adverse effects—including sedation, extrapyramidal symptoms, cognitive decline, and fall risk—demand cautious, short-term use at the lowest effective dose.³⁹

Benzodiazepines are generally contraindicated due to their negative impact on cognition, balance, and fall risk, as well as their potential for dependence and paradoxical agitation.39 SSRIs have been explored as alternative therapies; citalopram has shown modest efficacy, but the effective dose studied (30 mg/day) exceeds the FDA-recommended maximum for older adults and is associated with QTc prolongation and cognitive worsening.³⁹ Escitalopram is under investigation as a potentially safer option, with preliminary evidence suggesting modest benefit.³⁸ A study conducted on escitalopram (S-CitAD) showed escitalopram to be ineffective for AD agitation as well as linked to cardiac conduction delays (with similar associations for citalopram).³⁹

Emerging modalities, such as repetitive transcranial magnetic stimulation, show promise for refractory cases, although further research is needed to establish their efficacy and safety.⁴³ Electroconvulsive therapy has been shown to be a safe, effective, and well-tolerated option in severe, treatment-resistant cases of agitation or aggression in AD.⁴³ There is a rich pipeline of emerging drugs nearing approval, including combination dextromethorphan/bupropion, which looks particularly promising.³²

Conclusion

Depression, apathy, psychosis, and agitation are the most prevalent NPS in AD. Given the growing number of individuals in the United States who are diagnosed with AD, it is crucial to identify NPS properly and respond with appropriate and effective management strategies, both nonpharmacologic and pharmacologic. Optimal treatment necessitates early identification, rigorous clinical differentiation, and the development of individualized therapeutic approaches, while addressing the complexities of overlapping features of the various NPS as well as other health issues. Nonpharmacologic interventions remain the cornerstone of care; pharmacologic therapies must be used judiciously, given the heightened susceptibility of the geriatric population to adverse events, such as falls and worsened cognition. Emerging advancements in neuroimaging, biomarker discovery, and precision pharmacotherapy offer promising avenues for transforming the future of NPS management. Until such transformative therapies emerge, a nuanced, multidisciplinary, and individual-centered approach remains imperative to optimize clinical outcomes, sustain quality of life, and mitigate caregiver burden throughout the trajectory of AD.