Cochrane for Clinicians

Putting Evidence into Practice

Pharmacologic Interventions for Apathy in Patients with Alzheimer Disease


Am Fam Physician. 2019 Jan 1;99(1):14-15.

Author disclosure: No relevant financial affiliations.

Clinical Question

Is methylphenidate (Ritalin) safe and effective for reducing apathy in patients with Alzheimer disease (AD)?

Evidence-Based Answer

Methylphenidate may improve apathy in select patients with AD (mean difference [MD] = –4.99 on the apathy evaluation scale [AES]; 95% confidence interval [CI], –9.55 to –0.43), although the clinical significance associated with these findings remains unclear and the evidence is considered low quality. The risk of developing an adverse effect is no more likely with methylphenidate than with placebo (relative risk [RR] = 1.28; 95% CI, 0.67 to 2.42).1 (Strength of Recommendation: B, based on limited-quality patient-oriented evidence.)

Practice Pointers

AD is a debilitating, prevalent, and costly condition affecting 5.7 million Americans.2 Behavioral and psychological symptoms of dementia such as apathy are common and among the most troubling aspects of dementia care. Apathy is a state of reduced motivation affecting goal-directed cognitive activity, goal-directed behavior, and the accompanying emotional response.3 Apathy is a highly prevalent and persistent behavioral and psychological symptom of dementia and is associated with disability, poor health, caregiver burden, and mortality.4,5 The objective of this review was to assess the safety and effectiveness of pharmacotherapies for the treatment of apathy in patients with AD.

This Cochrane review included 21 randomized controlled trials (published between 1998 and 2017) involving 6,384 participants.1 The authors looked for any placebo-controlled trials investigating pharmacologic treatments in persons with AD or mixed AD (i.e., AD with vascular pathology) reporting an effect on apathy. Of the 21 trials, only four reported apathy as a primary outcome measure; three of these featured an examination of methylphenidate, whereas one featured modafinil (Provigil). Apathy outcomes were measured using the AES or the neuropsychiatric inventory apathy subscale (NPIa). The AES is scored from 0 to 42 and the NPIa from 0 to 12, with higher scores on each indicating greater apathy.

Methylphenidate (20 mg taken daily for two to 12 weeks) may have improved apathy compared with placebo in those with AD who had clinically significant apathy at baseline (MD = –4.99 on the AES; 95% CI, –9.55 to –0.43). This finding was present only with use of the AES. When apathy was measured using the NPIa, methylphenidate did not improve apathy (MD = –0.08; 95% CI, –3.85 to 3.69). Methylphenidate may have had slight benefits for cognition based on the Mini-Mental State Examination (MD = 1.98; 95% CI, 1.06 to 2.91). There appeared to be no difference between methylphenidate and placebo in the risk of developing an adverse effect (RR = 1.28; 95% CI, 0.67 to 2.42). Overall, the data regarding methylphenidate were considered low quality. The one small trial (n = 22) that evaluated whether modafinil was effective for treating apathy in patients with AD had insufficient evidence.

The remaining 17 trials included in this meta-analysis did not investigate apathy as a primary outcome measure. These studies provided low- or very-low-quality evidence on cholinesterase inhibitors, atypical antipsychotics, antidepressants, valproate (Depacon), and two pharmacotherapies from research trials that were discontinued, mibampator (not available in the United States) and semagacestat (not available in the United States). Given the small number of studies within each drug class, as well as the risk of bias and imprecision of these studies, no evidence exists to support the use of these medications for apathy in AD.

Currently, there are no guidelines with recommendations regarding the pharmacologic treatment of apathy in AD. Nonpharmacologic therapies remain the cornerstone strategy for behavioral and psychological symptoms of dementia. Based on this review, a trial of methylphenidate may be reasonable in a patient with AD who has clinically significant apathy. Physicians are encouraged to exercise caution given the risk of medication noncompliance and mishap in the cognitively impaired, as well as potential drug-drug and disease-drug interactions (e.g., agitation, open-angle glaucoma, hypertension, other cardiovascular conditions) in this aging population.

The practice recommendations in this activity are available at

This article reflects the opinions of the authors alone and does not reflect the opinion of the Department of the Army, Air Force, Defense Health Agency, Department of Defense, or the U.S. government.

Author disclosure: No relevant financial affiliations.


show all references

1. Ruthirakuhan MT, Herrmann N, Abraham EH, Chan S, Lanctôt KL. Pharmacological interventions for apathy in Alzheimer's disease. Cochrane Database Syst Rev. 2018;(5):CD012197....

2. Alzheimer's Association. 2018 Alzheimer's disease facts and figures. Alzheimers Dement. 2018;14(3):367–429.

3. Robert P, Onyike C, Leentjens AF, et al. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry. 2009;24(2):98–104.

4. van der Linde RM, Matthews FE, Dening T, Brayne C. Patterns and persistence of behavioural and psychological symptoms in those with cognitive impairment: the importance of apathy. Int J Geriatr Psychiatry. 2017;32(3):306–315.

5. Steinberg M, Shao H, Zandi P, et al.; Cache County Investigators. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry. 2008;23(2):170–177.

These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, Assistant Medical Editor.

A collection of Cochrane for Clinicians published in AFP is available at



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