Special Article
Pharmacologic Treatment of Apathy in Dementia

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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.

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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)-109 makes no mention of apathy and the Diagnostic and Statistical Manual of Mental Diseases (DSM)-IV10 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

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,

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, 53, 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;

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, methyl-phenidate, amantadine hydrochloride, gabapentin, modafinil, atomoxatine, cabergoline, pramipexole, ropinirole, apomorphine, rotigotine, or anticonvulsant.

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, http://links.lww.com/AJGP/A20). The first rating used our own rating scale (using Arabic numerals), developed according to criteria on the basis of published guidelines57, 58, 59, 60 and listed in Table 2. Inter-rater reliability was established by two assessors rating 10 randomly chosen articles

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 studies62 and have not been further investigated as therapies for dementia or apathy. Despite the loss of cholinergic neurons, because postsynaptic cholinergic receptors remain relatively

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

LIMITATIONS

Best levels of evidence are from randomized, double-blind, placebo-controlled 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-to-treat analyses were not reported. There is no evidence to guide

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.

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    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 (www.AJGPonline.org).

    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.

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