Methylphenidate and Other Pharmacologic Treatments for Apathy in Alzheimer’s Disease

J Clin Psychiatry 2022;83(1):22f14398

To cite: Andrade C. Methylphenidate and other pharmacologic treatments for apathy in Alzheimer’s disease. J Clin Psychiatry. 2022;83(1):22f14398.
To share: https://doi.org/10.4088/JCP.22f14398

© Copyright 2022 Physicians Postgraduate Press, Inc.

Alzheimer’s disease (AD) is the commonest form of dementia. In addition to suffering from cognitive deterioration, patients with AD, especially later in the course of the illness, commonly exhibit neuropsychiatric symptoms. These are also referred to as behavioral and psychological symptoms of dementia, and they include anxiety, agitation, irritability, aggression, delusions, hallucinations, and other symptoms. Neuropsychiatric symptoms are best treated with nonpharmacologic interventions but, if severe, may necessitate the use of pharmacologic interventions such as antipsychotic drugs.^3,4Dementia is a neurocognitive disorder characterized by a clinically significant, sustained decline in a wide range of cognitive functions; there is an associated decrease in independence resulting from impairments in instrumental activities of daily living. The estimated global prevalence of dementia was 43.8 million in 2016¹ and 57.4 million in 2019.²

Apathy in Dementia

Apathy is an example of a common neuropsychiatric symptom in patients with dementia. In a systematic review and meta-analysis of mood symptoms reported in 20 studies that included 5,897 persons with dementia, Leung et al⁵ found that the pooled prevalence of apathy was 43%–59%, depending on the severity of the dementia; these prevalence rates for apathy were higher than those for depression (37%–41%) and anxiety (also 37%–41%).

Apathy is characterized by indifference, loss of spontaneity, lack of motivation, decreased interest in and emotional reactivity to the surroundings, and reduced participation in domestic and social activities; diagnostic criteria for apathy have recently been suggested.⁶ Apathy receives less clinical attention because it is not as disturbing a symptom as other neuropsychiatric symptoms (such as aggression and agitation) can be. Apathy is nevertheless problematic. In a population-based, longitudinal cohort study of aging (n = 3,626), apathy was found to be one of the most stable among behavioral and psychological symptoms in subjects with cognitive impairment. Apathy increased disability, increased caregiver burden, and compromised the management of other diseases. Apathy was also strongly associated with mortality.⁷

Apathy in dementia is a difficult symptom to treat. In a systematic review and meta-analysis of 4 randomized, placebo-controlled trials (RCTs) of cholinesterase inhibitors (pooled N for drug vs placebo = 1,669 vs 967), 4 RCTs of memantine (pooled N = 902 vs 833), and 3 RCTs of psychostimulants (pooled N = 53 vs 55), Sepehry et al⁸ found that no category of drugs attenuated ratings of apathy severity in patients with AD.

Treatment of Apathy in Alzheimer’s Disease: Meta-Analysis

Many authors have speculated about the neurobiology of apathy in AD.^8,9 One view is that apathy results from degeneration of the prefrontal cortex and that manifestations of apathy can be attenuated by increasing the levels of the catecholamines norepinephrine and dopamine in prefrontal-striatal-thalamocortical circuits.⁹ If this is true, then psychostimulant drugs such as modafinil and methylphenidate (MPH) may reduce apathy in AD. In this context, Kishi et al¹⁰ described a systematic review and meta-analysis of RCTs of psychostimulants in AD.

These authors searched online research publication databases, clinical trial registries, and reference lists and identified 3 parallel-group and 1 crossover RCT of psychostimulants for apathy in AD^11–14; only 1 of these, examining modafinil (200 mg/d), was industry-sponsored. The remaining 3 RCTs, examining MPH (20 mg/d), were industry-independent. These RCTs were conducted in the US and Canada. The duration of the crossover trial was 2 weeks; the remaining trials were 6–12 (median, 8) weeks long. Sample sizes were n = 13 in the crossover trial and n = 23 to 60 in the parallel group trials.

In random effects meta-analysis, the meta-analysis authors¹⁰ found psychostimulants superior to placebo for the attenuation of apathy ratings (standardized mean difference [SMD], −0.63; 95% CI, −1.22 to −0.04; 4 RCTs; N = 166) as well as for improvement in Mini-Mental State Examination (MMSE) scores (SMD, −0.58; 95% CI, −1.14 to −0.02; 3 RCTs; N = 144). Both analyses were characterized by moderate to high heterogeneity.

In sensitivity analyses, when the crossover RCT was excluded, psychostimulants were no longer superior to placebo against apathy (SMD, −0.63; 95% CI, −1.41 to 0.17); however, when the modafinil RCT was excluded, the advantage for MPH over placebo was statistically significant (SMD, −0.82; 95% CI, −1.43 to −0.20). Heterogeneity was moderate to high in both of these analyses, as well. In meta-analysis of 1 modafinil and 1 MPH RCT, psychostimulants were not superior to placebo for instrumental activities of daily living and for caregiver burden outcomes. Finally, all-cause discontinuation, discontinuation due to adverse events, and report of at least 1 adverse event did not differ between psychostimulant and placebo groups.

Comments on the Meta-Analysis

Although the results of this meta-analysis¹⁰ suggest that psychostimulants are safe and effective against apathy in AD, they must be viewed with much caution for many reasons. There were only 4 RCTs. Of these 4, 1 examined modafinil, and so there were only 3 MPH RCTs. Of the 3 MPH RCTs, 1 was a crossover trial, leaving only 2 parallel-group RCTs. Study sample sizes were small. Study durations were short; as short as 2 weeks in 1 RCT. Heterogeneity for all efficacy outcomes was moderate to high. Adverse effects specific to psychostimulants were not examined. These are not data based on which confident guidance can be offered.

Methylphenidate for Apathy in Alzheimer’s Disease: Randomized Controlled Trial

A large, well-designed, well-conducted, and well-analyzed RCT is the gold standard in research, and one such study investigating MPH for apathy in AD has now been published by Mintzer et al.¹⁵ This study was named Apathy in Dementia Methylphenidate Trial 2 (ADMET 2). In this RCT, 200 patients with clinically significant apathy (of at least 4 weeks duration) and possible or probable AD were recruited from 9 US and 1 Canadian dementia clinic. Patients with a current or past major depressive episode and those with clinically significant other neuropsychiatric symptoms were excluded. All patients were clinically stable for at least the past month. No patient had recent clinically significant weight loss or contraindications for MPH.

The median age of the sample was 76 years. The sample was 66% male and 90% white. Patients had been diagnosed with dementia for a mean of 3 years. The mean MMSE score was about 19, indicating mild to moderate dementia. The mean apathy score was nearly 8 on the apathy subscale of the Neuropsychiatric Inventory. Very surprisingly, the mean apathy score was only 1.9 on a 16-item informant-rated interview.

These patients were randomized to receive MPH (n = 99) or placebo (n = 101). The dose of MPH was uptitrated across 3 days to 10 mg twice daily; all concurrent medications, including psychotropic and antidementia medications, were continued unchanged. All patients and their caregivers also received a standardized psychosocial intervention at each study visit. Visits were scheduled monthly for 6 months. At the 6-month study endpoint, data for analysis were available for 89 MPH and 92 placebo patients. Important findings from the RCT are presented in Table 1 and Table 2.

In summary, 6 months of treatment with MPH (20 mg/d) was associated with a small but statistically significant advantage over placebo in the attenuation of apathy scores in patients with mild to moderate AD who were on treatment with antidementia drugs; the advantage became apparent by the end of the second month of treatment and persisted to the end of 6 months. However, importantly, MPH was not superior to placebo on a wide range of other outcomes, including informant-rated apathy, dependence, activities of daily living, quality of life, and neurocognitive performance. MPH appeared safe and well tolerated across 6 months of treatment.

Comments on the RCT by Mintzer et al¹⁵

Neuropsychiatric Inventory apathy subscale scores improved substantially: by about 56% vs 41% in the MPH vs placebo groups, respectively. However, in absolute terms, the estimated MPH vs placebo treatment effect was just 1.25 points, and the effect size (Cohen d = 0.37) was correspondingly small. There was little to no advantage associated with MPH treatment across a range of neuropsychological and real-life outcomes. These findings do not encourage the use of MPH to treat apathy in AD. But there is an elephant in the room. All patients and caregivers in the RCT received a psychosocial intervention that comprised a 20–30 minute counseling session at the monthly study visits. Caregivers were also provided with educational materials and 24-hour access to study staff for crisis management. Whereas this is excellent clinical practice, it is unlikely to be standard clinical care or treatment as usual in most parts of the world. What if the psychosocial intervention boosted the response in the placebo group; in other words, might the advantage for MPH have been greater had the placebo group received what passes as treatment as usual elsewhere? This is an important clinical question because MPH, as dosed in the study, was safe and well tolerated, and effective against apathy for as long as 6 months. Given that MPH is available as a generic drug in many parts of the world, it would have been useful to learn how effective it is against apathy in AD patients who are seen in routine, real world practice.

It is surprising that Mintzer et al¹⁵ did not study caregiver burden. However, if ratings of dependence, activities of daily living, and quality of life did not differ between MPH and placebo groups, it is unlikely that differences would have been observed for assessments of caregiver burden.

There were 2 other curiosities. One is that MPH was dosed “twice a day.” The first dose was presumably administered in the morning. It is not clear whether the second dose was administered later in the day or at night; if the latter, one wonders whether the second dose, with its actions spent during the hours of sleep, contributed to benefit. The other curiosity is that the mean 16-item, informant-rated interview apathy score was just 1.9 at baseline. The informants, presumably, were the caregivers. Why did the caregivers rate apathy so low, and could this explain why MPH did not separate from placebo on other outcomes for which caregivers would have contributed information?

Take-Home Message

Although both meta-analysis and a large, well-designed, well-conducted, and well-analyzed RCT suggest that psychostimulants in general and MPH in particular attenuate the severity of apathy in patients with AD, and that the benefit with MPH (20 mg/d) may extend for as long as 6 months, the absence of improvements in measures of dependence, activities of daily living, and quality of life suggest that this effect of MPH may not be clinically significant. An unanswered question is whether the benefits of MPH may be clinically significant in real world practice settings in which the delivery of behavioral interventions is not feasible.

Parting Note

Bupropion is a catecholaminergic antidepressant; it inhibits the reuptake of dopamine and norepinephrine.¹⁶ Maier et al¹⁷ described a 12-week multicenter German RCT that examined the efficacy of bupropion (300 mg/d) vs placebo in treating apathy in 108 patients (mean age, 75 years; 62% male) with mild to moderate AD. Bupropion was no better than placebo in improving apathy, and, unexpectedly, improvements in neuropsychiatric symptoms, depression, and quality of life were actually greater with placebo than with bupropion.

Published online: February 1, 2022.

Each month in his online column, Dr Andrade considers theoretical and practical ideas in clinical psychopharmacology with a view to update the knowledge and skills of medical practitioners who treat patients with psychiatric conditions.

Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India ([email protected]).

Financial disclosure and more about Dr Andrade.