Rajesh R. Tampi, MD, MS, DFAPA

(This is the second article in a series discussing psychotic disorders in late life. The 

appeared in the August issue, pages 16-17. —Ed)

Psychosis in late life may result from any of an array of different illnesses with varied etiologies. Indeed, available evidence indicates that secondary causes for psychosis are more common among older adults (65 years and older) when compared with 

 It is also necessary to distinguish between late-onset schizophrenia (LOS), very late–onset schizophrenia-like psychosis (VLOS), and early-onset schizophrenia (EOS). Having an appreciation of these possible etiologies is important, as this information will help with early identification and treatment of these disorders.

Cognitive decline, poor health status, visual impairment, and negative life events have been identified as 

 for the development of psychotic disorders among older adults.

 Older age of onset for schizophrenia is known to be associated with female gender, a lower family history of schizophrenia, lower rates of substance use, better early psychosocial functioning, higher educational attainment, and a greater number of comorbid physical health problems.

 For LOS and VLOS, female gender appears to be a prominent risk factor.

 Additional risk factors for VLOS are more abnormalities in brain structures, family history of schizophrenia or avoidant personality, paranoid or schizoid personality disorder, hearing loss, being from an immigrant population, or having a lower socioeconomic status.

A detailed cognitive assessment and thorough physical examinations can help differentiate among the various etiologies for psychotic symptoms in late life. Secondary causes for psychotic disorders in late life can be identified by a complete blood count and complete metabolic panel; further blood work that measures thyroid-stimulating hormone, vitamin B12, folate level, rapid plasma reagin, and erythrocyte sedimentation rate; urine toxicology; and autoimmune panels and HIV 

 Additionally, neuroimaging studies like magnetic resonance imaging or computerized tomography can rule out structural brain abnormalities causing psychotic symptoms. In complicated cases, neuropsychological testing can help differentiate among the possible etiologies for psychotic symptoms in late life.

. The prevalence of schizophrenia among individuals 65 years or older is approximately 0.1% to 0.5%.

 Between 20% and 25% of schizophrenia cases are either LOS or VLOS, and the incidence of schizophrenia among individuals 65 years or older is 7.5 per 100,000.

 The incidence rate of VLOS is 37.66 per 100,000 person-years at risk (an estimation based on observation time per participant), and 60% of individuals with VLOS are women.

 Often debilitating in its own right, schizophrenia is also a risk factor for developing dementia (relative risk = 2.2).

. Among older adults, the prevalence of schizoaffective disorder is approximately 0.14%.

 Older adults have higher severity of illness, more treatment resistance, and higher risk for suicide when compared with younger adults.

 Not all schizoaffective disorders in older adults carry the same risk. Older adults with the depressive type of schizoaffective disorder have a higher history of suicide attempts and are more likely to take antidepressant medications when compared with those with the bipolar-type illness.

 The prevalence of delusional disorder is approximately 0.03% in this population.

 Individuals with this condition can have normal cognitive, personal, and occupational functioning, but significant social dysfunction.

Depressive and bipolar disorders (affective psychosis)

. Among older adults, the incidence of affective psychosis is approximately 30.9 per 100,000 person years.

 Older patients with bipolar disorder have more paranoia when compared to younger adults, and delusions are present in 45% of older adults admitted to hospitals for depression.

 Older adults with psychotic depression also have a higher prevalence of comorbid anxiety and somatic symptoms.

. Psychotic symptoms occur in approximately 40% of individuals with major neurocognitive disorders. Psychotic symptoms are seen in approximately 41.1% of individuals with Alzheimer disease.

 Psychosis occurs in 15% of the individuals with vascular neurocognitive disorders.

 Visual and auditory hallucinations and delusions occur in 78% and 25% of individuals with neurocognitive disorders with Lewy bodies.

. The prevalence of psychotic symptoms among individuals with delirium is approximately 42.7%.

 Visual hallucinations occur in 27%, delusions in 25.6%, auditory hallucinations in 12.4%, and tactile hallucination in 2.7%.

The risk for developing secondary psychosis due to drug use, environmental toxins like lead or mercury and medical illness is greater among older adults due to comorbidities, polypharmacy, and sensitivity to drugs.

When it comes to patient background and risk factors, there are significant differences between LOS, VLOS, and EOS (

It has been noted that LOS is associated with a genetic variant indopamine D2 receptor (DRD2), rs2734839.

 Additionally, individuals with LOS appear to have larger thalamic volumes and abnormalities in white matter integrity when compared with individuals with EOS.

 Individuals with LOS also present with reduced cerebral blood flow in both postcentral gyri when compared with individuals with EOS who present with reduced blood flow to the precentral gyrus and inferior frontal gyrus.

 Older adults with delusional disorders appear to have larger lateral ventricular volumes than older adults with schizophrenia and almost twice those of age-matched controls.

Psychosis in late life is not uncommon, with secondary causes of psychosis being more prevalent than primary psychotic disorders. Among older adults who present with psychotic symptoms, a thorough history, the evaluation of risk factors, and conducting an appropriate work-up that includes neuroimaging studies and neuropsychological testing for complicated cases will result in early identification of the etiologies and prompt treatment of these symptoms.

 is chairman of the Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, Ohio; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Ohio; and professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

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Articles

Secondary causes for psychosis are more common in older adults (65 years or older) than in younger patients. Here are 6 possible culprits. 

Exploring Possible Etiologies for Psychotic Disorders in Late Life

Although psychosis often emerges relatively early in life, it can also appear for the first time in older patients. These cases raise special challenges. The morbidity and mortality rates for psychosis in late life are 

 when compared with those for psychosis among younger individuals.

 Furthermore, greater incidence of adverse effects is noted when antipsychotic medications are prescribed to older adults.

 But once clinicians determine the root of the problem, they have an array of potentially effective treatment options.

In identifying psychotic disorders in late life, a 

must be made between primary psychotic disorders and secondary psychotic disorders.

 The term primary psychotic disorders describes conditions in which the psychotic symptoms are the main clinical presentation of the illness. Primary psychotic disorders include illnesses along the schizophrenia spectrum, major depressive disorder (MDD), and bipolar disorder with psychotic features.

The term secondary psychotic disorders refers to illnesses in which psychosis is the secondary or associated symptom, not the core clinical feature of the disorder. Examples of secondary psychotic disorders including delirium, neurocognitive disorders, psychosis due to drugs of abuse or prescribed medications, or psychosis due to medical or 

 Available evidence indicates that among older adults, approximately 60% of the cases are secondary disorders.

A thorough history, including information from collateral sources, can help 

 Acute or subacute onset of symptoms might suggest the occurrence of delirium or of substance- or medication-induced psychosis. Insidious onset of symptoms may suggest a primary psychotic disorder, such as a schizophrenia spectrum disorder.

Workup for Psychotic Disorders in Late Life

Features suggestive of a secondary psychotic disorder include an atypical age of onset of symptoms, visual hallucinations presenting independently of auditory hallucinations, the occurrence of psychotic symptoms in an individual with no previous psychiatric history or no family history, the presence of abnormal findings on physical examinations, or evidence of the use of prescribed medications or abuse of illicit substances.

describes a workup for psychotic disorders in late life.

involves addressing possible causes, including the discontinuation of offending medications or drugs of abuse or the treatment of underlying medical or neurological causes.

 For psychotic symptoms that are unresponsive to these strategies, pharmacological treatment becomes essential.

 Antipsychotic medications should be prescribed to older adults cautiously, as their long-term use may cause significant adverse effects.

 Available guidelines recommend the short-term use of antipsychotics to treat the psychotic symptoms.

 Before initiating treatment with antipsychotic medications, clinicians should always perform a risk-benefit analysis, keeping in mind the individual’s physical condition and comorbid medical disorders.

 Starting medication at a lower dose (one-fourth to half the starting dose for adults) and gradually titrating to the optimal dose may reduce the incidence of adverse effects.

 indicates that risperidone and olanzapine may be useful in the treatment of older adults with schizophrenia.

 One randomized controlled trial study that evaluated the use of amisulpride (not available in the United States) at 100 mg daily in patients who were diagnosed with very-late–onset schizophrenia found a significant improvement in the Brief Psychiatric Rating Scale compared with placebo.

 There is also some evidence for using paliperidone among older adults with schizophrenia.

 Expert consensus guidelines recommend using risperidone at 1.25 mg to 3.5 mg a day as the first-line agent for older adults with schizophrenia, followed by quetiapine at 100 mg to 300 mg a day, olanzapine at 7.5 mg to 15 mg a day, or aripiprazole at 15 mg to 30 mg a day.

 There is little support for using clozapine among older individuals with psychotic disorders, possibly due to its significant adverse effect profile.

Among older adults who have MDD with psychotic features, the combination of olanzapine and sertraline was associated with higher remission rates during the treatment period when compared with treatment with olanzapine or placebo, with 

 In a systematic review of meta-analyses that evaluated the use of antipsychotics among individuals with dementia, the investigators found that antipsychotics had modest efficacy in treating psychosis, aggression, and agitation.

 The use of these medications was often limited by their AE profile. The investigators noted that the use of antipsychotics should be reserved for severe symptoms that have failed to adequately respond to nonpharmacological management strategies.

A meta-analysis that evaluated the prevention and treatment of delirium among surgical and medical patients found that antipsychotics had 

 There is also significant controversy regarding the use of antipsychotics among older adults who present with severe psychosis due to dementia.

 The FDA has a boxed warning indicating an association between the use of antipsychotics among older adults with dementia and increased risk for mortality.

 Additionally, the use of antipsychotics in this patient population increases the risk for cerebrovascular adverse events, metabolic side effects, and pneumonia, when compared with age-matched controls who were not prescribed these drugs.

Antipsychotic medications should be discontinued as soon as clinically possible to avoid serious adverse effects among older adults.

 regarding discontinuation, especially among individuals with schizophrenia.

 It would be prudent to attempt discontinuation of antipsychotics among older adults only when 1 or more of the following 3 conditions have been met: (1) the patient has not adequately responded to these medications; (2) the medications have resulted in intolerable adverse effects; or (3) the individual has demonstrated long-standing clinical remission. Decreasing the dose of medications to the lowest effective dosage should be attempted when discontinuation of these medications is not feasible due to persistent psychotic symptoms.

Bilateral electroconvulsive therapy has been found to be a safe and effective treatment for older patients with schizophrenia, in conjunction with antipsychotic medications, especially among those individuals who present with catatonia, aggression, or acute suicidal states, or when there is an 

 for cognitive behavioral social skills training (CBSST), functional adaptation skills training (FAST), supported employment, social skills training, and preventative health care programs among older individuals with psychotic disorders.

 Additionally, better work outcomes and superior quality of life were noted for older individuals with schizophrenia who received supported employment when compared with conventional vocational rehabilitation programs.

Treatment for Psychotic Disorders in Late Life

describes further treatments for psychotic disorders arising in late life.

Most cases of psychotic disorders in late life likely occur due to underlying medical or neurological illnesses and/or due to the effects of medications or illicit drugs. The differentiation of primary and secondary causes can be accomplished via a thorough history, a comprehensive mental status examination, a focused physical examination, appropriate laboratory data or imaging studies, and a formal neuropsychological assessment for difficult-to-diagnose cases.

The use of antipsychotic medications among older adults is fraught with risks given these drugs’ significant adverse effect profile, including the increased risk of death among individuals with dementia. It is recommended that antipsychotic medications be used among older adults at the lowest effective doses and for the shortest time period.

The early identification and prompt removal or treatment of secondary causes of psychosis will reduce undue suffering among vulnerable older adults. Psychosocial treatments have been found to be effective in the treatment of primary psychotic disorders among older individuals. Future studies should focus on the risk factors, neurobiology, and treatment of psychotic disorders in late life, so that we better understand and treat these varied group of disorders.

is professor and chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, and Chief, Section for Geriatric Psychiatry, Department of Psychiatry and Psychology, Cleveland Clinic.

1. Talaslahti T, Alanen H-M, Hakko H, et al. Patients with very-late-onset schizophrenia-like psychosis have higher mortality rates than elderly patients with earlier onset schizophrenia.

2. Gareri P, Segura-García C, Manfredi VGL, et al. Use of atypical antipsychotics in the elderly: a clinical review. 

3. Colijn MA, Nitta BH, Grossberg GT. Psychosis in later life: a review and update. 

4. Holroyd S, Laurie S. Correlates of psychotic symptoms among elderly outpatients. 

5. Tampi RR, Young J, Hoq R, et al. Psychotic disorders in late life: a narrative review. 

6. Freudenreich O, Schulz SC, Goff DC. Initial medical work-up of first-episode psychosis: a conceptual review. 

7. Marsh L, Williams JR, Rocco M, et al. Psychiatric comorbidities in patients with Parkinson disease and psychosis. 

8. Targum SD. Treating psychotic symptoms in elderly patients. 

9. Nerius M, Johnell K, Garcia-Ptacek S, et al. The impact of antipsychotic drugs on long-term care, nursing home admission, and death in dementia patients. 

10. Chahine LM, Acar D, Chemali Z. The elderly safety imperative and antipsychotic usage.

11. Steinberg M, Lyketsos CG. Atypical antipsychotic use in patients with dementia: managing safety concerns. 

12. Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. 

13. Marriott RG, Neil W, Waddingham S. Antipsychotic medication for elderly people with schizophrenia. 

14. Howard R, Cort E, Bradley R, et al; ATLAS Trialists Group. Antipsychotic treatment of very late-onset schizophrenia-like psychosis (ATLAS): a randomised, controlled, double-blind trial. 

. 2018;5(7):553-563. Published correction appears in 

15. Tzimos A, Samokhvalov V, Kramer M, et al. Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension. 

16. Alexopoulos GS, Streim J, Carpenter D, Docherty JP; Expert Consensus Panel for Using Antipsychotic Drugs in Older Patients. Using antipsychotic agents in older patients. 

2004;65 Suppl 2:5-99; discussion 100-102; quiz 103-104.

17. Shanker Reddy Mukku S, Sivakumar PT, Varghese M. Clozapine use in geriatric patients – challenges. 

18. Meyers BS, Flint AJ, Rothschild AJ, et al; STOP-PD Group. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). 

. 2009;66(8):838-847. Published correction appears in 

19. Tampi RR, Tampi DJ, Balachandran S, Srinivasan S. Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses. 

20. Neufeld KJ, Yue J, Robinson TN, et al. Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis. 

21. Mittal V, Kurup L, Williamson D, et al. Risk of cerebrovascular adverse events and death in elderly patients with dementia when treated with antipsychotic medications: a literature review of evidence. 

22. Rochon PA, Normand S-L, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med. 2008;168(10):1090-1096.

23. Takeuchi H, Suzuki T, Remington G, et al. Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study. 

24. Meyer JP, Swetter SK, Kellner CH. Electroconvulsive therapy in geriatric psychiatry: a selective review. 

25. Granholm E, McQuaid JR, McClure FS, et al. A randomized, controlled trial of cognitive behavioral social skills training for middle-aged and older outpatients with chronic schizophrenia. 

26. Granholm E, McQuaid JR, McClure FS, et al. Randomized controlled trial of cognitive behavioral social skills training for older people with schizophrenia: 12-month follow-up. 

27. Patterson TL, Mausbach BT, McKibbin C, et al. Functional adaptation skills training (FAST): a randomized trial of a psychosocial intervention for middle-aged and older patients with chronic psychotic disorders. 

28. Bartels SJ, Pratt SI, Mueser KT, et al. Long-term outcomes of a randomized trial of integrated skills training and preventive healthcare for older adults with serious mental illness. 

29. Mueser KT, Pratt SI, Bartels SJ, et al. Randomized trial of social rehabilitation and integrated health care for older people with severe mental illness. 

30. Twamley EW, Narvaez JM, Becker DR, Bartels SJ, Jeste DV. Supported employment for middle-aged and older people with schizophrenia. 

31. Twamley EW, Padin DS, Bayne KS, et al. Work rehabilitation for middle-aged and older people with schizophrenia: a comparison of three approaches. 

Most psychotic disorders appear in adolescents or young adults, but some also occur during later life. Here's how to recognize and treat them. 

Diagnosing and Treating Psychotic Disorders in Late Life

The English word apathy originates from the Greek word apathes, which means “without pathos or feeling,”

 but scholars have shared various definitions. For example, Robert S. Martin, MD, defined apathy as a syndrome of primary motivational loss that is not attributable to emotional distress, intellectual impairment, or 

 According to Drs Richard Levy and Bruno Dubois apathy is the quantitative reduction of self-generated voluntary and purposeful behaviors, which are observable and can be quantified.

 In addition, the underlying mechanism(s) responsible for apathy may be seen as dysfunctions occurring at the level of elaboration, execution, and control of goal-directed behaviors. According to an international consensus criterion, apathy is defined as a disorder of motivation in which the symptoms are present for at least 4 weeks.

 In addition, 2 of the following 3 should be present: reduced goal-directed behavior, reduced goal-directed cognitive activity, and reduced emotions. Furthermore, these symptoms cause clinically significant impairments in personal, social, occupational, or other important areas of functioning, with such symptoms not exclusively explained by or due to other causes (ie, physical disabilities [such as blindness or loss of hearing], motor disabilities, diminished level of consciousness, or direct physiological effects of a substance [such as a drug of abuse or a medication]).

 of individuals who have no cognitive deficits.

 It is also seen among individuals with major depressive disorder, schizophrenia, strokes, multiple sclerosis, and traumatic brain injury. Apathy is more prevalent among individuals with neurodegenerative disorders than in those free of such disorders.

Apathy has been noted throughout the spectrum of neurocognitive disorders (

 The prevalence rates for apathy among individuals with mild cognitive impairment ranges from 

 Apathy is also the most frequently reported behavioral symptom among individuals with dementia. The results of one study showed that individuals with frontotemporal dementia (FTD) and vascular dementia (VaD) report more severe apathy than individuals with Alzheimer disease (AD).

Apathy Among Individuals With Neurocognitive Disorders

Apathy usually appears early in dementia and tends to persist throughout; it is associated with longer illness duration and it worsens with the 

 Risk factors for developing apathy include older age and greater severity of cognitive impairment. Akyol et al found that apathy was correlated with the degree of cognitive impairment among individuals with AD and VaD, but not with FTD; but apathy did not correlate with age or gender in individuals with AD, FTD, and VaD. Additionally, the degree of apathy correlated with the level of functional impairment and dementia severity across all 3 types of dementia.

Individuals with dementia who present with apathy often have more rapid cognitive decline and are more impaired in their activities of daily living.

 In addition, apathy increases the risk for earlier institutionalization among individuals with dementia.

 Distress is also significantly higher among caregivers of individuals with dementia who have apathy, when compared with individuals with dementia without it.

Emerging evidence indicates that apathy in individuals with dementia occurs due to a complex interaction among neuroanatomy, neuropathology, neurochemistry, and genetics.

 Among individuals with AD, apathy is associated with an increased neurofibrillary tangle burden in the parahippocampal, frontal, and parietal regions, in addition to the anterior cingulate gyrus. Emerging evidence indicates that the severity of apathy is also associated with amyloid plaque burden, especially in bilateral frontal cortices and the right anterior cingulate gyrus along with 

One study that evaluated the cerebrospinal fluid (CSF) biomarkers among individuals with AD showed that apathy was significantly correlated with tau and p-tau, but not with amyloid β١–٤٢.

 Another study examined regions of cortical thinning and CSF biomarkers (amyloid-β ١-٤٢, total tau, and phosphorylated tau) among 3 groups—clinically normal elderly individuals, individuals with mild cognitive impairment, and individuals with mild AD dementia with apathy—and found that reduced baseline inferior temporal cortical thickness was predictive of increasing apathy over time.

 The investigators of this study did not find any association between CSF biomarkers and the severity of apathy in cross-sectional or longitudinal analyses.

Another study found that individuals with AD and apathy had a loss of white matter integrity in the genu of the corpus callosum when compared with individuals with AD without apathy.

 In addition, the loss of white matter integrity in the genu, body, and splenium of the corpus callosum was negatively correlated with the severity of apathy among individuals with AD. Neuroradiological studies indicate that the dysfunction of the anterior cingulate cortex is the strongest anatomical correlate of apathy in AD, whereas lesions of the basal ganglia are the most common correlates of apathy in cerebrovascular disorders.

Neuroimaging studies indicate that the apathy among individuals with behavioral variant of FTD is associated with prominent atrophy in: the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, right caudate (including the ventral striatum), right temporoparietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum-anterior insula region.

A recent meta-analysis that analyzed data from 41 studies indicated that apathy is associated with hypometabolism and a decrease in gray matter volume in the left inferior frontal gyrus.

 The investigators also found altered brain perfusion and decreased gray matter volume in the anterior cingulate cortex among individuals with AD, and decreased gray matter volume in the inferior frontal gyrus and parietal cortex among individuals with FTD. These findings indicate that apathy occurs due to a cortical dysfunction of areas involved with executive cognitive processing (action planning) and emotional regulation (autoactivation and reward processing).

Individuals with AD and apathy have been found to have reduced dopaminergic activity in the putamen, reduced acetylcholine in the lateral frontal cortex, and lower levels of plasma gamma-aminobutyric acid.

 In evaluating the association between apolipoprotein E ɛ4 allele and apathy in probable AD, investigators found that the presence of this allele was indeed significantly associated with apathy in these individuals.

Among individuals with dementia, the assessment of apathy is often complicated. It is particularly difficult to distinguish between reduced motivation to do things due to apathy and the loss of ability or motivation secondary to cognitive dysfunction. Additionally, there may be overlap between symptoms of apathy and depression (

 Often, as well, psychotropic medications (ie, antipsychotics, antidepressants) are used to treat neuropsychiatric symptoms (NPS) of dementia, and the adverse effects of these medications include fatigue, lethargy, listlessness, and decreased initiative to respond to external stimuli. These AEs can mimic symptoms of apathy among individuals with dementia.

The scales that have been developed for the assessment of apathy include the Apathy Evaluation Scale (AES), the Structured Clinical Interview for Apathy, the Apathy Scale, the Apathy Inventory, the Dementia Apathy Interview and Rating (DAIR), and the Lille Apathy Rating Scale (LARS).

 Among these scales, only the DAIR was designed for use among individuals with dementia. The Apathy Scale for Dementia Patients in Nursing Homes was designed to measure apathy among individuals with dementia who live in institutional settings.

 The Neuropsychiatric Inventory (NPI) is considered the gold standard for the assessment of NPS among individuals with dementia. However, the use of a single domain from the NPS prevents a comprehensive assessment of all dimensions of apathy among individuals with dementia. A recent systematic review found that the DAIR, the AES–clinical version (AES-C) in AD, and the LARS in Parkinson disease (PD) had psychometrically favorable qualities and the highest quality among the scales used to assess apathy among individuals with neurodegenerative disorders.

Available evidence indicates that both nonpharmacological and pharmacological treatment modalities can benefit individuals with dementia who present with apathy (

Selected Pharmacotherapy and Nonpharmacological Treatments

A systematic review by Brodaty et al found that therapeutic activities—including stimulation, creative activities, cooking, Montessori methods, music, exercise, multisensory stimulation, and pet therapy—as well as placement in special care units may improve apathy among individuals with dementia.

 Another recent systematic review by Cai et al, evaluating the effectiveness of nonpharmacological interventions among individuals with dementia and apathy, also found that multisensory stimulation, music therapy, cognitive stimulation, and pet therapy are useful in improving symptoms of apathy.

 Cai et al found limited evidence as well for the efficacy of art, exercise, reminiscence, and occupational therapies; dementia special care units; comprehensive interventions; nursing staff education; and behavioral management techniques (ie, therapeutic conversations, progressive muscle relaxation). They found that the effects of psychomotor therapy and validation therapy were still unclear; evidence also indicates that receptive music therapy is better than interactive music therapy. Pet therapy that includes the introduction of domestic pets and companion robots tends to reduce loneliness and improve well-being. Tailoring the overall lifestyle of individuals with dementia to increase recreational activities, physical exercise, cognitive stimulation, and social activities also reduces apathy.

Various pharmacological agents have been trialed for the treatment of apathy,

 including acetylcholinesterase inhibitors (ChEIs), memantine, stimulants, calcium antagonists, and antipsychotics.

 In their systematic review and meta-analysis, Sepehry et al found a total of 15 randomized controlled trials that assessed the efficacy of pharmacotherapy.

 For cognitive enhancers (donepezil and galantamine), there was no was significant effect of treatment on apathy (Hedges’ g = –0.055; 

 = .687). The average donepezil dosage was 10 mg/day, while galantamine dosage ranged between 16 mg/day and 32 mg/day. All but 1 study used the NPI-apathy subscale as an outcome measure, and these trials included individuals with mild-to-severe AD.

For memantine, the investigators found a small and nonsignificant benefit for apathy (Hedges g = .092; P = .423). The average dose of memantine was 20 mg/day, and the trials included individuals with moderate-to-severe AD and used the NPI-apathy subscale. The effect of psychostimulants on apathy was small and nonsignificant when compared with placebo (Hedges’ g = –.063; 

 = .903). All stimulant trials included individuals with mild-to-moderate AD, used multiple scales including the NPI-apathy and Frontal Systems Behavior Scale (FrSBe) apathy subscale, and included mixed drugs with noncomparable dosages. The investigators did not find enough individual studies to do a meta-analysis for antipsychotics and drug classes with antidepressant properties, but the data from the individual atypical antipsychotic studies did not support their use for apathy in AD. The investigators indicated that the analysis for cognitive enhancers and memantine were appropriately powered, whereas the psychostimulant studies were underpowered due to limited patient enrollment in each arm of the trials.

In another quantitative meta-analysis, Ruthirakuhan et al included data from 21 studies.

 The investigators found that methylphenidate may improve apathy when compared with placebo; this held true when apathy was assessed using the AES (mean difference [MD] = – 4.99) but not when using the NPI-apathy subscale (MD = –.08).

The investigators further found that methylphenidate may also improve cognition (MD = –.08) and instrumental activities of daily living (MD = 2.30), when compared with placebo. There was no difference between methylphenidate and placebo in the risk of developing an adverse event (risk ratio = 1.28). The investigators indicated that there was insufficient evidence from a small study of modafinil to determine its effect on apathy assessed with the FrSBe-apathy subscale (MD = 0.27). They reported that in all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. The investigators considered the evidence on apathy from these studies to be indirect and associated with publication bias. They reported that there was low or very low quality of evidence on ChEIs, ChEI discontinuation, antipsychotics, antipsychotic discontinuation, antidepressants (2 studies), and valproate for the treatment of apathy in dementia.

A recent systematic review by Theleritis et al evaluated data from 90 unique studies and relevant reviews but noted that in many studies, apathy was not considered the primary outcome measure.

Apathy occurs throughout the spectrum of neurocognitive disorders, but it is easy to mistake for other conditions, like depression. How can clinicians identify apathy, and treat it?

Rajesh R. Tampi, MD, MS, DFAPA

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Exploring Possible Etiologies for Psychotic Disorders in Late Life

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