SPECIAL ARTICLE. Pharmacologic Treatment of Apathy in Dementia

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1 SPECIAL ARTICLE Pharmacologic Treatment of Apathy in Dementia Karen Berman, M.B. B.Ch., Henry Brodaty, D.Sc., Adrienne Withall, Ph.D., Katrin Seeher, Dipl.Psych. Apathy in patients with dementia is common, underrecognized, and undertreated. We sought to improve understanding of the pharmacologic treatment of apathy in dementia by performing a systematic literature review of studies that used apathy outcome scales to document results of pharmacologic treatments for apathy. There is limited evidence of efficiency of pharmacotherapy for treatment of apathy in dementia. The best results were found for acetylcholinesterase inhibitors. There was some evidence of efficacy for memantine, but less evidence of efficacy for stimulants, calcium antagonists, and antipsychotics. There was no evidence to support the use of antidepressants or anticonvulsants. The research quality of studies was modest. Recommendations for standardizing research and for holistic evaluation and treatment are provided. (Am J Geriatr Psychiatry 2012; 20: ) Key words: abulia, acetylcholinesterase inhibitors, amotivation, antipsychotic agents, apathy, cerebral stimulants, memantine, passivity I don t know, I don t care, and it doesn t make any difference! Jack Kerouac, , American novelist Apathy is a universal emotion variably experienced by all, depending on personality; chronologic age; context; time; and contemporaneous conditions such as health state and influences of medications and drugs. Apathy may be normal as evidenced by public reactions to political campaigns, or pathologic, as a symptom of a neurologic or psychiatric syndrome or as an adverse effect of medication or as a syndrome in itself. Other commonly used terms for apathy include amotivation, avolition, abulia, loss of initiative/drive, social disengagement, withdrawal, passivity, and loss of interest. Apathy has been defined as diminished motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress 1 (and see companion paper). Lack of goal-directed behavior and decreased emotional responsiveness form a large part of the picture of apathy, which should be viewed as significant if it represents change from the patient s previous personality and/or causes significant impairment in functioning. 2 These factors should be taken into account when treatment is Received June 25, 2010; revised November 29, 2010; accepted February 25, From the Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Randwick, New South Wales, Australia (KB, HB, AW, KS); and Dementia Collaborative Research Centre, School of Psychiatry, University of New South Wales, Sydney, Australia (HB, AW, KS). Send correspondence and reprint requests to Henry Brodaty, D.Sc., Dementia Collaborative Research Centre, University of New South Wales, Sydney, NSW 2052, Australia. h.brodaty@unsw.edu.au Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal s Web site ( C 2012 American Association for Geriatric Psychiatry DOI: /JGP.0b013e a6 104 Am J Geriatr Psychiatry 20:2, February 2012

2 Berman et al. considered. Apart from scales specifically designed to rate apathy such as the Apathy Evaluation Scale, 3 a number of neuropsychiatric or behavioral scales such as the Neuropsychiatric Inventory 4,5 include items that rate apathy. 6 Although specific scales differentiate components of apathy such as motivation, interest, and behavior, omnibus neurobehavioral scales do not. This may be important as different components of apathy appear to become more prominent over time in the older population generally 7 and at different stages in those with dementia. The aim of this article is to review the pharmacologic treatment of apathy in dementia. Currently, apathy treatment includes a variety of pharmacologic and nonpharmacologic therapies (such as environmental modification) but there are no clear guidelines. The high prevalence of apathy and its detrimental effect on patients and their families make such a review timely. Also, the search for and development of a suitable treatment regimen over the past four decades is of interest. This review focuses on the pharmacologic treatment of apathy occurring in dementia. DEFINITION AND PREVALENCE Despite an increasing literature indicating that apathy is an independent syndrome, 8 there is no structured definition for this construct. The International Classification of Diseases (ICD)-10 9 makes no mention of apathy and the Diagnostic and Statistical Manual of Mental Diseases (DSM)-IV 10 uses the term to refer to a subtype of personality change due to a general medical condition, but no specific definition is provided. However, apathy is widely recognized by workers in the dementia field as a syndrome of decreased motivation, initiation, and persistence, as well as social disengagement and emotional indifference or absence. Others think of apathy as an absence of will. 11 The prevalence of apathy varies from 1.4% in older, community-based individuals with normal cognition 12 to as high as 6%, increasing over a 5-year period. 7 The change over time is more pronounced in males and in persons older than 65 years. 7 Clinically significant apathy is also more common in mild cognitive impairment (see companion paper). Apathy affects a high proportion (but not all 8 ) of patients with all forms of dementia. In the Cache County study, 13 apathy was the most frequently reported behavioral symptom in persons with dementia, with rates of 20% at baseline increasing to 51% at 5.3-year follow-up. 14 Broadly speaking, increased risks for developing apathy include older age 7,15 and greater severity of cognitive impairment. 15 Apathy occurring in the course of dementia is frequently accompanied by one or more neuropsychiatric symptoms, 16 which may fluctuate during the course of the disease, unlike cognition, which worsens steadily. 17,18 Apathy appears early in dementia, increases with dementia severity, 4,25 tends to persist, 26 and is consistently reported globally ,19,27 29 Apathy is the neuropsychiatric symptom most consistently identified in mild clinical and community-dwelling samples of patients with Alzheimer s disease (AD), 19 affecting up to 70% of patients with mild to moderate AD and up to 90% of patients with late-stage AD. 28,32,33 Apathy is more common in certain types of dementia such as Parkinson s disease (PD), Lewy body dementia, Huntington disease, and frontotemporal dementia (see companion paper). IMPORTANCE AND EFFECTS OF APATHY IN AD Apathy is distinct from but overlaps with depression. 1,3,34 Although not accompanied by the emotional distress, agitation, vegetative symptoms, suicidal ideation, and hopelessness of depression, 35 apathy is significantly associated with the later development of depression. 36 Apathetic patients easily descend into a downward spiral of lack of activity, loss of confidence, and learned helplessness, 37 with those affected responding poorly to rehabilitation, due to absent motivation. 38 Overall, apathy is associated with worsening functional impairment and poorer quality of life for both patients and caregivers, with family life often disrupted. 41 A strong association has been reported in vascular dementia (VaD) between apathy and patients ability to complete both basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs), 45 and apathy contributes above and beyond dementia severity in adversely affecting basic ADLs. 45 It is also associated with more severe impairments in cognitive function, with older Am J Geriatr Psychiatry 20:2, February

3 Pharmacologic Treatment of Apathy in Dementia age, with poor awareness of behavioral and cognitive changes, and with more rapid cognitive decline. 36,46 Apathy is under-recognized 31 and difficult to treat, not least because patients have poor insight into their condition but also are often unable to give informed consent for treatment. It thus imposes high levels of economic, social, and physical burden and distress on partners and caregivers, compounding patients disability 16 and frequently leading to earlier institutionalization than for similarly impaired patients without apathy. 51 The responsiveness of apathy to treatment may therefore have important implications in delaying institutionalization, alleviating caregiver burden, and in turn improving quality of life for patients with dementia. modafinil, atomoxatine, cabergoline, pramipexole, ropinirole, apomorphine, rotigotine, or anticonvulsant. Search engines used were the Cochrane Database of Systemic Review, MEDLINE ( ), Embase ( ), and PreMEDLINE. This search yielded 1,462 articles whose abstracts were screened and full text accessed if deemed relevant. Reference lists of included articles were hand searched to find relevant articles. Where several articles reported the same trial, these were included in Table 1; Treating Apathy in Dementia, but grouped together. Post-hoc studies, case series, and studies of pooled data are marked as such. Over-the-counter products such as vitamins and herbal products were not included in this search. THE NEUROANATOMIC AND NEUROCHEMICAL BASIS FOR APATHY Apathy is associated with both neuropathologic and neurochemical alterations to frontosubcortical circuits, which include two motor and three behavioral circuits in the areas of the frontal lobe, striatum, globus pallidus, substantia nigra, and thalamus. 34,52 54 Neurochemical transmitters (e.g., acetylcholine, dopamine, and serotonin), receptor subtypes, and second messengers underpin disruptions to all these circuits, 52,55 thus forming the basis for possible therapeutic interventions; studies suggest, for example, that acetylcholinesterase inhibitor (AChI) medications reduce apathy and other behavioral alterations in patients with AD. 18,56 Our aim was to examine the clinical trial evidence for pharmacotherapy of apathy in patients with dementia. METHODS The following search terms were used: apathy, abulia, amotivation, or passivity, combined with treatment, management, pharmacological, drug, cholinesterase inhibitor, donepezil, galantamine, rivastigmine, memantine, typical antipsychotic, atypical antipsychotic, amisulpride, risperidone, antidepressant, bromocriptine, d-amphetamine, methylphenidate, amantadine hydrochloride, gabapentin, INCLUSION/EXCLUSION CRITERIA FOR STUDIES We included full-text versions available in English in any patient settings, be it community, residential care, or nursing home, for patients with dementia, and where there were pre- and posttreatment measures of apathy. Articles with data on five or fewer patients are included in this article as case reports. We excluded articles without specific information on change in apathy following treatment and reports not written in English. RATING OF METHODOLOGY The quality of the methodology used for individual studies was rated using two methods. (Table 1, column Research Quality ; see Tables I V, column Research Quality, Supplemental Digital Content 1, The first rating used our own rating scale (using Arabic numerals), developed according to criteria on the basis of published guidelines and listed in Table 2. Inter-rater reliability was established by two assessors rating 10 randomly chosen articles (κ = 0.76), indicating substantial agreement between raters. Characteristics of the design, subjects, outcomes, and statistics were considered when rating the quality of the studies. We arbitrarily selected 11 out of 15 as the cutoff score for studies to be judged as good quality, on the basis of the difficulties in satisfying the following four 106 Am J Geriatr Psychiatry 20:2, February 2012

4 Berman et al. TABLE 1. Treating Apathy in Dementia (Randomized Controlled Trials Included) Patient Apathy Research Author Trial Description Description Measures Quality Results Treating apathy in dementia using ACHI and/or memantine (17 studies) Ahlin et al. 72 THA (tacrine) 15 NOSIE 9 II No change in apathy scores mg/day All completed ( Interest on NOSIE scale) 9 weeks, double AD blind, crossover Pantev et al. 100 Memantine mg/day, 4 weeks including 7-day run-in, randomized, double blind, placebo 60 All completed Mild/moderate Primary degenerative dementia/vad Long-term care facilities SCAG NOSIE 11 II SCAG: Significant improvement in apathy (lack of drive) in treated group in second and fourth week of treatment NOSIE: Significant improvement in apathy score (social interest) after 4 weeks Kaufer 92 Metrifonate 408, 393 ITT Primary: NPI II Significant difference mg/day for 2 weeks, then mg/day, 36 weeks total 334 completed Mild-mod AD MMSE = Metrifonate > placebo: apathy, depression, hallucinations Morris et al weeks run in, 26 weeks treatment, 8-week follow-up, randomized, double blind, placebo Raskind et al. 94 Winblad and Poritis 101 Metrifonate 50 mg/day, 36 weeks including26weeksof treatment, prospective, double-blind completed Mild-mod AD MMSE Secondary: NPI II Hallucinations significantly improved Other scales, including apathy, showed non-significant trend to improvement 13 II Significant decrease in agitation, aggression & aberrant motor behavior. Non-significant trend to decreased delusions. Apathy: non-statistically significant improvement Memantine 10 mg/day 12-week, double blind, placebo 167 inpatients 151 completed Moderate-severe dementia 49% AD 51% VaD Primary: BGP 11 II Memantine treated patients showed significant improvement in BGP (sub-score hobbies/interest = apathy showed significant improvement) Dubois et al., 93 Metrifonate 605 randomized Secondary: NPI 13 II Significant improvement in (MALT study) 40/50 mg vs. 60/80 mg/day by patient weight McKeith et al weeks, randomized, double-blind, placebo- 594 ITT 518 completed Mild-moderate AD 60/80 mg dose group versus placebo at week 26 on NPI subitems of apathy and hallucinations Rivastigmine 6 12 mg/day 23 weeks, with 20 weeks treatment, randomized, double blind, placebo ITT 92 completed DLB MMSE >9 Primary: NPI-4 sub-score of NPI-12 Secondary: NPI II Symptoms significantly improved on rivastigmine: apathy, indifference, anxiety, delusions, hallucinations & aberrant motor behavior Apathy & indifference improved most McKeith et al. 84 Rivastigmine 11 NPI 8 III-3 Mean apathy scores over 3 12 mg/day, 35 weeks total, 20 weeks double-blind, 12 weeks open label, placebo All completed DLB MMSE weeks decreased by 63%. (delusions decreased 73%, hallucinations decreased 27%, agitation decreased 45%) (Continued) Am J Geriatr Psychiatry 20:2, February

5 Pharmacologic Treatment of Apathy in Dementia TABLE 1. (Continued) Patient Apathy Research Author Trial Description Description Measures Quality Results Tariot et al. 75 Donepezil 5 10 mg, 24 weeks, randomized, double blind, placebo completed N/H AD/mixed MMSE = Primary: NPI II No significant differences noted between donepezil & placebo groups in individual NPI scores (including apathy score) at any assessment Secondary: 11 II Donepezil > placebo for all NPI items 11 Significantly better for Feldman et al. 77 Gauthier et al. 105 Donepezil 5 10 mg versus placebo completed Gauthier et al weeks, randomized, Mod-severe AD double blind MMSE 5 17 apathy, depression, anxiety Erkinjuntti et al. 90 Galantamine 592 Secondary: NPI 14 II Apathy and anxiety improved 24 mg/day, 7 months, 456 completed significantly from baseline double blind, placebo VaD/Mixed in galantamine group MMSE No change from baseline in ADAS-Cog>11 placebo group Holmes et al. 79 Donepezil 134 Primary: NPI II Donepezil treated patients Secondary: NPI-D showed significant improvement in apathy after 24 weeks 5 10 mg, 12 week open-label, ff by 12 week withdrawal: double blind, randomized, placebo 80 completed AD > 6months NPI>11 in at least 3 domains MMSE = Cummings et al. 91 Galantamine 1178 screened Secondary: NPI-10 NPI-D Herrmann et al. 111 Pooled data, Original 3 trials notincludedin table as no apathy scores, Post-hoc analysis 8, 16, 24 mg, 25 weeks, randomized, double blind, placebo 978 randomized 782 completed Mild-mod AD MMSE = Galantamine 16, 24, 32 mg/day, randomized 2033 ITT Secondary: NPI-10 months, randomized, Mild-mod AD double blind, placebo Outpatients MMSE = ADAS Feldman et al. 112 Donepezil 145 Secondary: NPI-12 Post-hoc analysis of 5 10 mg/day Severe AD subgroup of 145 patients 77 Gauthier et al. 97 Post-hoc analysis of databases of two trials 102, weeks, randomized, double blind, placebo Community/ assisted living facility 128 completed MMSE II Galantamine associated with improved existing behavioral problems Less emergence of new behavioral problems, including apathy in the 16 mg/day group 13 II Mean changes in total NPI score, some individual domains and some clusters, including apathy were significantly improved in patients treated with galantamine vs placebo 12 II Differences favoring donepezil were seen for all outcome measures at 24 weeks, including 11/12 NPI measures Apathy was significantly improved Reisberg patients NPI 13 II Memantine showed Memantine 20 mg only, Mod-severe AD both randomized 28 weeks double blind, placebo MMSE 3 14 Tariot patients Donepezil5 10mgfor Mod-severe AD 3/12 plus Community Memantine 20 mg MMSE 5 14 Treating apathy in dementia using antipsychotic medication (10 studies) Barton and Hurst 123 Chlorpromazine mg/day, 7 weeks, double blind 53; 50 completed Female patients Senile psychosis Seven scale item designed by hospital staff Arteriosclerotic psychosis Post traumatic dementia statistically significant improvement in agitation/aggression in both studies. There was a trend to improvement in apathy, but this was not significant 2 III-1 No change in idleness (Continued) 108 Am J Geriatr Psychiatry 20:2, February 2012

6 Berman et al. TABLE 1. (Continued) Patient Apathy Research Author Trial Description Description Measures Quality Results Birkett and Chlorpromazine 56 in-patients NOSIE 7 II No greater tendency toward Boltuch mg 50 completed BPRS improvement in treated 30 treated patients Senile = 27 group than in control group 20 control patients Paraphrenia = 6 in any measure on the NOSIE 6 weeks, including 2 drug free weeks Schizophrenia = 5 Other = 18 Blinded rater Kirven and Thioridazine 40 mg 60 in-patients NOSIE 10 II The improvement in social Montero 122 Diazepam 10 mg 56 completed interest in the thioridazine 2 week washout, Behavioral problems group was not significant. ff 4 weeks associated with Social interest deteriorated senility in the diazepam group Cahn and Penfluridol 8 pilot N/H BOP 8 III-2 No change in inactivity in Diesfeldt mg twice weekly patients, then treated vs untreated patients 4 weeks 12 N/H patients Repeat observations 12 N/H placebo Gotestam et al. 118 at 10 weeks Haloperidol & cis (Z)-clopenthixol Haloperidol 0.5 mg vs Clopenthixol 5 mg 8 weeks, Double-dummy controls 12 N/H patients: no psychotropes 35 completed Organic psychosyndrome (Schizophrenics excluded) 47 demented patients 40 completed Gottfries/ Cronholm Geriatric Scale Crichton Geriatric Scale 8 III-2 Haloperidol: improved sleep, decreased motor activity & confusion. Clopenthixol: agitation & sleep improved No change in apathy scores Petrie et al. 115 Haloperidol 64 Inpatients BPRS 9 II Loxapine & haloperidol caused 2 10 mg 37 completed SCAG significant improvement in Loxapine > 60 years NOSIE unsociability on SCAG 1 50 mg PDD, MID, SDD scores vs placebo. 10 weeks, including 2 weeks washout Some behavior disorder Loxapine significantly improved social interest on NOSIE scale vs haloperidol and placebo Barnes et al. 121 Lovett et al. 117 Pollock et al. 127 Thioridazine 25 mg vs Loxapine 5mgvsPlacebo 10 weeks, including 2 weeks washout Randomized comparison completed N/H patients with dementia & behavioral problems BPRS SCAG NOSIE 8 II SCAG total scores improved significantly for all three groups but the improvement in individual items (including apathy) not significant Trifluorperazine 1 mg 54 started BPRS 8 II Apathy significantly improved bd vs Haloperidol 44 completed NOSIE at week 2 in favor of 0.5 mg bd Chronic Brain SCAG triflourperazine 6 weeks Syndrome Randomized Senile psychosis Citalopram a 85 Neurobehavioral mg/day 39 completed Rating Scale Perphenazine Non-depressed Udvalg for mg/kg daily Dementia Kliniske Placebo in-patients with NPI Undersogelser 17 days symptoms Randomized AD = 61 VaD = 6 Placebo- Mixed = 2 10 II Patients treated with citalopram/ perphenazine showed statistically significant improvement on NPI sub-scores (agitation, psychosis and lability) Citalopram groups also showed significant improvement in cognition & retardation factors. (Continued) Am J Geriatr Psychiatry 20:2, February

7 Pharmacologic Treatment of Apathy in Dementia TABLE 1. (Continued) Patient Apathy Research Author Trial Description Description Measures Quality Results Dementia, not specified = 16 Placebo group did not show significant change in any factor No significant improvement in apathy scores from baseline De Deyn et al. 131 Olanzapine 652 Primary: CGIC 12 II Apathy significantly improved 1.0mg,2.5mg,5mg, 465 completed NPI-12 vs baseline in patients treated 7.5 mg/placebo AD Secondary: Placebo lead-in of 2 Age >39 NPI-12 with olanzapine 5.0 mg only weeks, then Long-term N/H BPRS 10 weeks Moderate delusions/ hallucinations MMSE>4 Treating apathy in dementia using antidepressant medication (4 studies) Lawlor et al. 138 Chlorophenylpiperazine 12 patients with AD BPRS 10 II Psychomotor activation, Cross-over study 10 controls 19 completed restlessness and perceptual abnormalities improved significantly more in AD patients. No change in apathy Nyth et al. 133 Citalopram a 149 GBS 12 II A non-significant improvement mg/day 94 completed in motivation was seen in 6 weeks Major depression both the citalopram and 29 = mild-mod placebo-treated groups at the dementia end of treatment Freedman et al. 141 L-deprenyl 10 mg 101 screened Primary: BPRS 12 II No detectable benefit on 6months 60randomized general behavior, neuropsychiatric symptoms or cognitive function Randomized Placebo- 51 entered double-blind phase 41 completed Mild-mod AD Lebert et al. 135 Trazodone 31 at baseline Primary: NPI 10 II Trazodone associated with mg/day 26 completed 12 weeks FTD Randomized NPI> 8 Placebo- Crossover study statistically improved irritability, depression, agitation and eating disorders. No improvement in apathy. Treating apathy in dementia using psychostimulants (2 studies) Kaplitz 147 Methylphenidate 60 patients NOSIE 7 II All NOSIE scores (including 10 mg bd 40 completed apathy) improved 8 weeks, including 2 week pretreatment significantly compared to baseline in treated patients Chronically ill Senile institutional patients with apathy phase Randomized Placebo- Herrmann et al. 146 Methylphenidate 13 patients AES 11 II Greater improvement with mg 11 completed NPI 5 weeks AD Randomized Stable AChI for 3/12 MMSE>10 Placebo- Crossover study methylphenidate vs placebo according to AES (Continued) 110 Am J Geriatr Psychiatry 20:2, February 2012

8 Berman et al. TABLE 1. (Continued) Patient Apathy Research Author Trial Description Description Measures Quality Results Treating apathy in dementia using other medication (3 studies) Ban et al. 148 Nimodipine 178 SCAG 10 II Apathy scores in the 30 mg tds 175 completed nimodipine group improved 2 week washout Primary significantly from baseline 12 weeks treatment degenerative Randomized dementia compared to placebo group Mixed Placebo- MID Bayer et al. 150 Pentofylline 289 randomized Primary : GBS 12 II Total GBS score significantly 400 mg tds 269 ITT Secondary: improved 10 months, including 4/52 washout Placebo- 239 completed SCAG SCAG scores improved in MID MMSE = treated patients, with significant treatment effect in cognitive functions subtest Apathy scores not affected Sival et al. 151 Sodium valproate 43 Secondary: 10 II Restlessness, melancholy & 480 mg/day 39 completed Nurses anxiety improved 8 weeks In-patients observation significantly Randomized Placebo- Crossover aggressive (AD, VaD, PD, not specified, mixed) Trend for improved suspicion and dependent behavior No change in apathy scores Notes: Record quality: Arabic numerals refer to number of Table 1 criteria met; Roman numerals refer to NHMRC Level of Evidence, I-IV scale. AChI: acetylcholine esterase inhibitor; AD: Alzheimer disease; ADAS-Cog: Alzheimer s Disease Assessment Scale cognitive subscale AES: Apathy Evaluation Scale; BGP: Behaviour Rating Scale for Geriatric Patients; BOP: Rating Scale for Elderly Patients; BPRS: Brief Psychiatric Rating Scale; CGI-C: Clinician s Global Impression of Change; DLB: Dementia with Lewy bodies; ff: followed by; FTD: frontotemporal dementia; GBS: Gottfries Bråne Steen Scale; ITT: intention-to-treat; MID: multi-infarct dementia; mild-mod: mild to moderate; mixed: mixed dementia; MMSE: Mini Mental State Exam; mod-severe: moderate to severe; N/H: nursing home; NOSIE: Nurses Observation Scale for In-patient Evaluation; NPI-10 : 10 Item Neuropsychiatric Inventory Scale; NPI-12 : 12 Item Neuropsychiatric Inventory Scale; NPI- D: NPI caregiver distress scale; PD: Parkinson disease; PDD: Primary degenerative dementia; SCAG: Sandoz Clinical Assessment Geriatric; SDD: Secondary degenerative dementia; Senile: senile dementia; VaD: vascular dementia; vs: versus. a Study of citalopram has been included with antipsychotic medication as citalopram was compared with perphenazine and placebo. criteria: randomized according to Delphi specifications, 58 groups similar at baseline regarding most important prognostic indicators, follow-up assessment at 6 months or beyond, and intention-totreat analysis included. As the term follow-up was used differently by authors; we defined follow-up as an assessment after a specified period of time had elapsed after the completion of an intervention. We also rated the methodology of each study according to the Australian National Health and Medical Research Council evidence hierarchy where Level I evidence, the highest level, is a systematic review of Level II studies; Level II studies are randomized trials (RCTs); Level III-1 is a pseudo-randomized trial, III-2 a comparative study with concurrent controls, and III-3 a comparative study without concurrent controls; and level IV, the lowest level, is a case series with either posttest or pretest/posttest outcomes. 61 This rating is located in Table 1 in the column named Research Quality, using Roman numerals. (see Tables 1-V, Supplemental Digital Content 1, We present details of RCTs by class of medication in this article and a full list of all trials meeting our inclusion criteria online (see Tables 1-V, Supplemental Digital Content 1, RESULTS Acetylcholinesterase Inhibitors As a result of the cholinergic hypothesis of AD, several mechanisms for augmenting central cholinergic function have been developed. Presynaptically, cholinergic transmission can be enhanced by increasing levels of acetylcholine precursors: choline and lecithin; neither showed cognitive benefits in early Am J Geriatr Psychiatry 20:2, February

9 Pharmacologic Treatment of Apathy in Dementia TABLE 2. Criterion Criteria for Rating the Quality of Included Studies Score Design Randomized 1 Randomized according to Delphi specifications 1 Control or comparison group 1 Blind ratings 1 Subjects Groups similar at baseline regarding most 1 important prognostic indicators Eligibility criteria specified 1 Use of standardized diagnostic criteria 1 All subjects accounted for or withdrawals noted 1 Outcomes Well-validated, reliable measures 1 Follow-up assessment at 6 months or beyond 1 Statistics Point estimates and measures of variability presented for primary outcome measures Statistical significance considered 1 Adjustment for multiple comparisons 1 Evidence of sufficient power 1 Intention-to-treat analysis included 1 Rating Good quality 1 11 studies 62 and have not been further investigated as therapies for dementia or apathy. Despite the loss of cholinergic neurons, because postsynaptic cholinergic receptors remain relatively intact in AD, 63 levels of acetylcholine can be increased by inhibiting the action of acetylcholinesterase, hence the development of the AChIs (Table 1). Primarily used for treating cognitive symptoms in dementia, more recent findings indicate that AChIs have beneficial effects on noncognitive symptoms such as apathy, depression, anxiety, and purposeless motor behaviors. 18,33,56,64,65 Of all medications in this review, the AChIs have the largest number of patients treated for apathy 66,67 (Table 3). However, they have rarely been tested in patients with well-defined neuropsychiatric symptoms at baseline and with behavior measured as a primary trial outcome. 18 Deanol, an acetylcholine precursor, was used successfully to treat apathy in 14 patients in an openlabel study in Wilcock et al. 69 did not examine apathy as an outcome measure in their study of 79 patients with AD treated with tetrahydroaminoacridine without lecithin. However, carers reported an improvement in patient motivation and increased awareness of interest in their surroundings. Tacrine, the first cholinesterase inhibitor used in trials from the early 1980s, 70,71 was reported to be beneficial in treating AD either alone or in combination with lecithin. Only three tacrine trials fulfilled our criteria The earliest trial 72 failed to find an improvement in apathy levels, but there was an inadequate washout period of 7 days between treatment arms. 69 In the longest trial, of more than 24 weeks, 73 apathetic behaviors were the most consistently responsive Neuropsychiatric Inventory symptom. Tacrine has since fallen into disfavor due to liver and gastrointestinal adverse effects. With the exception of one study, which showed no improvement in apathy for nursing home residents with AD or mixed dementia, 75 all studies indicated significant improvement in apathy symptoms associated with the use of donepezil. 23,76 80 The studies ranged in duration from 8 weeks to 1 year and the majority were open label. Two studies showed that patients with the most marked apathy were more likely to respond to donepezil, with apathy symptoms worsening in nonresponders. 23,78 Donepezil may be useful for the treatment of apathy in Lewy body dementia, with one small case series reporting marked improvements in three of four patients who had initial apathy symptoms and followup scores. 81 The use of donepezil for other dementias has not been further explored. Rivastigmine also appears to have positive effects on behavioral symptoms, including apathy. Six of seven studies meeting our criteria for review found significant decreases in apathy. In one large naturalistic study, which involved 2,633 participants with mild to moderate AD, the degree of improvement was clinically significant. 82 One open-label trial showed a 39% reduction in apathy symptoms in nursing home residents with moderately severe AD 83 and another study in persons with Lewy body dementia reported a 63% reduction in apathy. 84 This last study indicated that most of the beneficial effects of the medication were lost when the drug was ceased. Positive effects on apathy were also reported in mixed dementia 85 but not in frontotemporal dementia (FTD). 86 The two studies that failed to reach significance (only a trend was found) were most likely underpowered with just 16 patients with VaD 87 and 40 patients with FTD. 86 All four galantamine studies and one post-hoc analysis that met our requirements reported improvement in apathy levels. Two studies were open-label trials, ranging from 3 to 6 months in 112 Am J Geriatr Psychiatry 20:2, February 2012

10 Berman et al. TABLE 3. Summary of Medications and Their Efficacy in the Treatment of Apathy in the 63 Drug Studies Included in this Review Apathy Improvement Studies Statistically Patients Case Series/ Medication(s) Used Reviewed Significant Trend No Change Completed Post-Hoc Analyses Dementia type Deanol 1 1/1 0/1 0/1 14 OBS Tacrine 3 2/3 1/3 0/3 83 AD = 3 Donepezil or donepezil and memantine 7 6/7 0/7 1/7 760 AD = 6, AD/mixed = 1 1 case series (donepezil) 7 1 post-hoc analysis 145 DLB = case series (donepezil) 1 post-hoc analysis (donepzil and memantine) 1/1 0/1 0/1 252 AD = Post-hoc Rivastigmine 8 6/8 1/8 1/ DLB = 2, VaD = 1, AD = 3, Mixed = 1, FTD = 1 Galantamine 4 4/4 0/4 0/ AD/mixed = 1, AD = 3 1 pooled data 1/1 0/1 0/1 Pooled = AD Metrifonate 3 2/3 2/3 0/3 AD = 3 1 pooled data 1/1 1 0/ Pooled = AD Subtotal AChI studies (excluding case series, post hoc analyses and 26 21/26 4/26 2/ AD = 20 VaD = 1 DLB = 2 FTD = 1 Mixed = 3 pooled data) Memantine 3 2/3 0/3 1/3 224 Dem = 2 FTD = 1 1 post-hoc analysis 0/1 1/1 0/1 656 Post-hoc = AD 1 case series Case series = FTD Typical antipsychotics 14 4/14 2/14 8/ Senile/mixed Atypical antipsychotics 4 3/4 0/4 1/ Mixed = 1AD= 3 Antidepressants 8 0/8 4/8 4/8 227 Mixed = 1AD= 4 FTD = 3 1 post-hoc analysis Post-hoc = AD 1 letter 0/1 0/1 1/1 44 FTD = Letter Psychostimulants 2 2/2 0/2 0/2 55 AD Anticonvulsants 2 0/2 1/2 1/2 59 Mixed = 1AD= 1 Calcium antagonists 2 2/2 0/2 0/2 306 Mixed = 1 VaD = 1 Pentofylline 1 0/1 0/1 1/1 239 MID Total non-achi/ nonmemantine studies (excluding post-hoc analyses and letter) 33 11/33 7/33 15/ AD = 12 FTD = 2 Notes: Two publications of a single metrifonate trial reported slightly different results, one reporting a significant improvement and the other a trend to improvement. AChI: acetylcholine esterase inhibitor; AD: Alzheimer disease; Dem: dementia; DLB: dementia with Lewy bodies; FTD: frontotemporal dementia; Mixed: mixed dementia; OBS: organic brain syndrome; Senile: senile dementia; stat.: statistically; VaD: vascular dementia. duration, 88,89 with one trial reporting a significant (27%) improvement in apathy levels. The remaining two studies were large double-blind placebo trials. The first included patients with VaD or AD plus VaD and showed a significant improvement in apathy from baseline in the galantaminetreated group only. 90 The other study also showed that galantamine use was associated with improved behaviors in AD and the emergence of fewer new behavioral symptoms, including apathy. 91 Until 1999, the AChI metrifonate seemed likely to become the fifth AChI to be licensed to treat AD. Positive effects on apathy were reported in two large 26- week randomized double-blind studies, 92,93 although one study only reported effects at a higher dose. 93 Another similarly designed study failed to show a significant improvement in apathy symptoms 94 but when its data were pooled with data of Morris et al., 95 improvement was evident at 12 weeks and maintained to 26 weeks. 96 This suggests that the two negative Am J Geriatr Psychiatry 20:2, February

11 Pharmacologic Treatment of Apathy in Dementia studies may have been underpowered. Reports of respiratory paralysis and problems with neuromuscular transmission with metrifonate caused further studies of this drug to be suspended. 66 Overall, there is Level II (15 studies supportive versus three showing no benefit) plus a preponderance of various Level III evidences (11 positive and 7 negative studies) that AChIs are beneficial in the treatment for apathy. There is no clear indication that any one AChI is superior. Memantine Memantine (Table 1) is a specific N-methyl-Daspartate receptor antagonist and is the only drug approved worldwide for treating severe AD. 97 It appears to work by regulating the activity of glutamate, allowing a amount of calcium to flow into nerve cells (enabling information processing, storage, and retrieval 98 ) protecting neurons against glutamatergic excitotoxicity and, potentially, having a neuroprotective effect by reducing toxic calcium influx. 99 Two studies of memantine alone 100,101 were randomized, double-blind, placebo- trials, which indicated significant improvements in apathy levels for those in the treatment group. Both studies were of short duration (4 and 12 weeks, respectively) and included persons in residential care settings with AD and VaD but differed in severity of dementia, with the study by Diehl-Schmid 99 randomizing 60 residents with mild to moderate dementia and the study by Pantev 100 randomizing 317 patients with severe dementia. 100 A post-hoc analysis, 97 which pooled data from 656 patients with moderate to severe dementia participating in an RCT of memantine versus placebo with no adjunctive treatment 102 and in an RCT of memantine versus placebo in patients on donepezil 103 over a 28-week period showed only a trend toward improvement. A small open-label study of memantine in patients with FTD showed no improvement in apathy; 99 however, a case series of three patients with FTD showed some improvement in apathy. 104 In summary, there is some evidence of benefit from memantine in AD and VaD but this has not been confirmed in other studies Antipsychotics Typical Many studies investigating the effects of typical antipsychotics in dementia and apathy occurred during the 1970s and 1980s. Few showed significant improvement in apathy ratings. A 1970 study of haloperidol in 18 patients with senile mental syndrome reported an appreciable improvement in withdrawal. 114 A comparison of loxapine versus haloperidol in a 10-week double-blind placebo trial in 64 hospitalized psychogeriatric patients indicated benefits of both medications, with loxapine being superior on social interest. 115 Birkett et al. 116 also reported an improvement in emotional withdrawal in 26 patients with senile psychosis or psychosis due to arteriosclerosis treated over 8 weeks with thiothixene. Another study showed benefits of trifluoperazine on apathy levels at week 2, but not week 6, in 54 patients with chronic brain syndrome and senile psychosis. 117 However, most studies have not found benefits with this class of drug. The 10 negative studies had similar sample sizes, diagnostic mix, and study durations as those reporting positive results. A range of typical antipsychotics has been investigated across the 10 studies: haloperidol, thioridazine, 121,122 loxapine, 121 chlorpromazine, 123,124 penfluridol, 125 mesoridazine, 126 and perphenazine (phenothiazine). 127 A randomized, double-blind, placebo- trial in 85 nondepressed inpatients with dementia and behavioral and psychological symptoms of dementia found no change in apathy levels over 17 days. 127 Antipsychotics Atypical Only four studies have investigated the effects of atypical antipsychotics on apathy and all reported significant improvements in symptoms (Table 1). Two studies used a retrospective chart review. The first followed 16 patients with severe dementia over a mean period of 15 months. 128 Low-dose clozapine was then withdrawn for a range of 2 35 days, before being reintroduced. Apathy, as measured with the Sandoz Clinical Assessment Geriatric scale showed no significant change, although social interest on the Nurses Observation Scale for Inpatient Evaluation showed significant deterioration and then improvement following recommencement of clozapine. The second retrospective chart review 129 indicated significant improvements on both apathy (28%) and social withdrawal (27%) over 12 weeks associated with risperidone treatment. This was the only 114 Am J Geriatr Psychiatry 20:2, February 2012

12 Berman et al. study to evaluate whether improvement in negative symptoms was independent of a positive treatment effect on positive symptoms. After post-hoc covariant analysis to account for positive symptoms, the avolition and emotional withdrawal subscales of the Scale for the Assessment of Negative Symptoms in Alzheimer Disease (SANS-AD) significantly improved but the total negative SANS-AD symptom score showed only a trend to improvement. A further 12-week open-label study 130 of risperidone in 135 patients with AD showed increasing and significant improvement in apathy. An RCT of 652 nursing home residents with severe AD reported improvement in apathy for residents treated with olanzapine 5 mg/day but not with 1, 2.5, or 7.5 mg/day, and there was no adjustment for multiple comparisons. 131 In summary, there is no good evidence of benefit of traditional antipsychotics in general (four negative and three positive level II studies with fairly even split between level III studies). There is level III evidence, but no RCTs, demonstrating that atypical antipsychotics may have some beneficial effect, although it is not possible to differentiate improvement in apathy directly from the medication versus as a secondary phenomenon to improvement in neuropsychiatric comorbidity. Antidepressants Trials of antidepressants (Table 1) to relieve apathy have largely been negative, providing further support for the theory that apathy is independent of depression. 132 Three studies used citalopram with no significant improvements in apathy. 127,133,134 Similarly, a small open-label study of trazodone in FTD 135 and another randomized double-blind crossover study of trazodone in AD 136 showed no change in apathy levels, although a single case study did report improvement. 137 One double-blind, randomized, study involving only 12 AD patients showed no effect of chlorophenylpiperazine on apathy. 138 An open-label study of 11 patients over 6 months noted increased motivation with deprenyl 139 but two other randomized, double-blind studies, including a 6-month study of deprenyl alone in 60 patients with mild to moderate AD, were negative. 140,141 Moclobemide and fluvoxamine have also been trialed over short periods in FTD with no changes in apathy scores. 142,143 In summary, there is good evidence at levels II (5 studies), III-3 (1 study) and IV (2 studies) that antidepressants do not significantly improve apathy in people with dementia. Psychostimulants Psychostimulants (Table 1) influence anatomic substrates that regulate wakefulness and executive function 144 and significantly improve wakefulness compared with placebo in patients with excess sleepiness. 145 Despite a perception that apathy is readily treated by psychostimulants, there were only two eligible trials of methylphenidate, both of which were small and showed significant improvements (level II evidence). 146,147 The first reported in 1975 was conducted in institutional, chronically ill, senile patients who had a diagnosis of senile apathy and who mostly had depression as a prominent feature, and did not use intention-to-treat analysis. 147 Depression was not rated but self-esteem improved more in methylphenidate treated patients. In the more rigorous 2008 crossover study of 13 patients with AD taking concurrent cholinesterase inhibitors, two patients developed psychosis and other symptoms leading to discontinuation. 146 Although both studies used doses of methylphenidate 10 mg twice a day, the earlier study did not report adverse effects. In summary, there is some evidence of modest efficacy with stimulants for treatment of apathy but tolerability may be a concern. Other Medication Several other drugs (Table 1) have been used to treat apathy. Calcium antagonists. Two studies involving nimodepine conducted in the 1990s 148,149 resulted in a significant improvement in apathy scores, although the sample size for one was small, including only 31 cognitively impaired patients. 149 Pentofylline. Pentofylline selectively dilates blood vessels of the limbs, brain and retina. These vasodilatative effects are a result of inhibition of the enzyme phosphodiesterase and the increasing of the concentration of cyclic adenosine monophosphate in the smooth muscle cells of the blood vessel wall. Pentofylline was not shown to affect apathy scores in one double-blind, placebo- study of 289 patients with multi-infarct dementia. 150 Am J Geriatr Psychiatry 20:2, February

13 Pharmacologic Treatment of Apathy in Dementia Anticonvulsants. The two small studies of anticonvulsants yielded negative results. The first study used sodium valproate over 8 weeks in a randomized, double-blind, placebo-, crossover study involving 42 inpatients with senile dementia (AD, VaD, PD, not specified, mixed). Apathy scores were unchanged. 151 The other trialed gabapentin, a novel anticonvulsant that acts on the γ -amino butyric acid (GABA) system, as an add-on to existing AChI therapy, in 20 nursing home patients with probable AD. 152 There was a nonsignificant trend for apathy to decrease at 15 months. Dopaminergic agents. Several positive reports were found using dopamine agonists to treat PD, alcoholic dementia, Wilson s disease, and depression. No study fulfilling our criteria was found. DISCUSSION Successful treatment of apathy can benefit patients, caregivers, other family members, nursing home staff, and healthcare professionals. Surprisingly few studies have examined apathy treatment considering its high prevalence and considerable burden on caregivers. Even fewer have used apathy as a primary outcome, and most studies are open label. Of all treatments reviewed, AChIs have the best evidence of improvement with most responders improving in cognition as well as in apathy levels. For many patients, stabilization of apathy levels may be a positive result as the natural history of apathy is progression with dementia severity. 153 There is some evidence for benefits of memantine and mixed evidence for benefits of atypical antipsychotics on apathy. It was not possible to disentangle primary effects of atypical antipsychotics on psychosis from effects on apathy. As antipsychotics can have serious adverse effects they are not recommended primarily for treatment of apathy. 154 There is modest evidence of benefit with stimulants but potential adverse effects limit its use. It is possible that stimulants exert their effects on apathy secondary to improvement in depression, but we note that antidepressants have not been successful in treating apathy. It is interesting to trace the pharmacologic treatment of apathy over 40 years. The overall quality of research was modest with only 17 of our 63 studies achieving an arbitrary cut off of greater than or equal to 11 out of 15 on our rating scale. Over time, there was little change in quality of research despite trial participant numbers increasing and journal articles becoming longer and more detailed. However, medical terminology, study methods, and pharmacologic treatment have changed markedly in this time. Despite an increased number of available medications, there is as yet no treatment that works well in treating patients with apathy. Summary of Treatment Guidelines for Apathy A holistic approach to treating apathy is advocated: Comprehensive assessment, tailored to each patient, including comorbidities and concomitant medication and differentiation from depression. Treat any underlying cause, for example urinary tract infection, use of marijuana or selective serotonin reuptake inhibitors, which have been reported to induce an amotivational or apathy syndrome and which is reversible when stopped or the dose decreased Attend to environmental contributors to apathy, that is, optimize level of stimulation and activities Monitor symptoms for up to 1 month before starting pharmacologic therapy, as some problems may resolve spontaneously Educate caregivers, involving them in the treatment plan. 5. Unless the patient is very distressed or at risk of harm to themselves or others, attempt nondrug methods first. (See companion paper on non-pharmacologic therapies for apathy.) 6. Pharmacologic therapy try AChIs first if not contraindicated. Other possible medications are memantine, atypical antipsychotics, and psychostimulants, though there is insufficient evidence to support them routinely. There is no support for antidepressants or antiepileptics. 7. Review and reassess patient and therapy regularly. When to Initiate and How Long to Maintain Therapy? The threshold of initiating pharmacotherapy is not defined and varies with the setting and with those 116 Am J Geriatr Psychiatry 20:2, February 2012

14 Berman et al. providing care. No data were found on this topic with regard to apathy treatment. However, it has been argued that earlier initiation of AChI treatment is better 161 and may prevent emergence of behavioral changes. 65,91 Indications for treatment of apathy are unclear and differ from other psychiatric conditions such as depression as patient distress rarely applies to apathetic patients and apathy in dementia usually worsens with time rather than remitting. The following indications may be useful in deciding on treatment of apathy in dementia: a) Excess disability of the patient. b) Potential for improvement in quality of life (or changed quality of life) of patient. c) Distress/burden to caregivers and/or family although this depends on the expectations of the caregiver, the premorbid personality of the patient and the setting in which the patient is living. For example, family members are more likely to be distressed in seeing a premorbidly active person become apathetic, while apathy in a nursing home setting is much easier for staff to tolerate, as apathetic patients make few demands. Deciding whether intervention has been successful may be obvious, even dramatic in some cases, but should be monitored using one of a variety of scales. 6 There are no data to guide clinicians on how long pharmacotherapy should be continued for treatment of apathy but as apathy increases with severity of dementia a positive response suggests long-term therapy is indicated. LIMITATIONS Best levels of evidence are from randomized, double-blind, placebo- studies, but few studies reviewed here were in this category. Many studies had small sample sizes and methodologic shortcomings. There was a wide range of definitions of apathy, measurement tools, and terminologies for both dementia and apathy. Also, samples constituted mixed types of dementias; primary outcome measures were not specified and intention-totreat analyses were not reported. There is no evidence to guide the clinician as to whether how the components of apathy emotional, cognitive, and behavioral 162 which may appear at different phases of the dementia, respond to interventions. We were unable to calculate effect sizes as apathy was not the primary outcome in most of the included studies and standard deviations or means were missing for most apathy scales. This heterogeneity hampered comparison of different medications and studies. Further research on pharmacotherapy of apathy in dementia would be advanced by using recognized apathy scales, defining dementia diagnosis, ensuring adequate power and sample sizes, and stating hypotheses a priori. CONCLUSION Apathy, as part of the spectrum of behavioral disturbances in dementia, remains underdiagnosed and difficult to treat. Initial therapy should aim to alleviate intercurrent/underlying illnesses, address unsuitable physical/environmental factors, and employ appropriate nonpharmacologic therapies. Only once all these measures have been attempted, should pharmacologic intervention be employed. The best evidence is for the use of AChIs. All four authors have worked on drug trials for patients with MCI and AD sponsored by major pharmaceutical companies including Eisai Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, H Lundbeck A/S, Janssen-Cilag Pty Limited, Medivation Inc., Novartis Pharmaceuticals, Pfizer Inc., Prana Biotechnology Limited, Sanofi-aventis, Voyager Pharmaceutical Corporation, and Wyeth Limited. Dr. Brodaty has been a consultant, advisory board member, and sponsored speaker for H Lundbeck A/S, Janssen-Cilag Pty Limited, Medivation Inc., Novartis Pharmaceuticals, Pfizer Inc., Prana Biotechnology Limited, Voyager Pharmaceutical Corporation, and Wyeth Limited. References 1. Marin RS: Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991; 3: Robert P, Mulin E, Malléa P, et al: Apathy diagnosis, assessment, and treatment in alzheimer s disease. CNS Neurosc Therapeutics 2010; 16: Marin RS, Biedrzycki RC, Firinciogullari S: Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res 1991; 38: Cummings JL: The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997; 48: S10 S16 Am J Geriatr Psychiatry 20:2, February

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