Contributed by: Dr. Jed Shimizu - View bio
Case
Mr. AP is a 78-year-old retired high school teacher with a diagnosis of Alzheimer’s-type dementia. He resides with his wife who serves as his primary caregiver. Mr. AP is relatively healthy but requires reminders and cueing for tasks around the home, including sometimes for grooming and dressing. His wife has been coping with her caregiving role but is becoming increasingly frustrated by his lack of “get up and go.” She notes that he will sit around all day, not helping with chores or wanting to do any of the activities he used to enjoy, such as walking or reading. When assessed by his family physician, Mr. AP describes no depressed mood or feelings of hopelessness.
Background
Alzheimer’s disease primarily affects the cognitive abilities of an individual, but it is often the associated symptoms that most impact quality of life as well as increasing caregiver burden. These neuropsychiatric symptoms (also called behavioural and psychological symptoms of dementia [BPSD]) include changes to sleep and appetite; mood lability and irritability; behaviours such as calling out and hoarding,; psychotic symptoms such as delusions and hallucinations; and the most common, apathy.1 During the course of Alzheimer’s disease, apathy has the highest baseline prevalence, persistence and incidence relative to other neuropsychiatric symptoms.2 Apathy has various definitions, though is generally characterized as diminished motivation affecting goal-directed thought, behaviour and emotional activity. Patients with significant apathy are often described as indifferent, disengaged and passive, and this can cause frustration and distress to family and caregivers. Apathy is also associated with increased deficits in cognition and function,3 requiring increased levels of support and adding to caregiver burden and need for supportive services. Even mortality is increased in Alzheimer’s disease when apathy is present.4
Although apathy shares some features with depression, such as diminished interest and psychomotor retardation, it is recognizable as a distinct symptom of dementia. Studies have shown that apathy and depression do not correlate in Alzheimer’s disease,5 and functional neuroimaging in the same population has pointed to anatomically distinct areas of the brain affected in apathy versus depression.6 Apathy lacks some of the main characteristics of depression, including dysphoria, suicidal ideation and feelings of guilt or hopelessness.5
Pharmacologic management of apathy in Alzheimer’s disease
Unfortunately there is limited evidence for pharmacologic options in treating apathy in Alzheimer’s disease. Cholinesterase inhibitors have shown a possible slight improvement in apathy compared to placebo, however evidence is of low quality.7 Similar levels of evidence for other agents including atypical antipsychotics, valproate and antidepressants have demonstrated no benefit.7 Up to this point, methylphenidate is the only treatment option that has shown some positive effect in smaller randomized controlled trials.8, 9, 10 The most recent of these studies by Padala et al. compared methylphenidate to placebo in the treatment of apathy in early stage Alzheimer’s disease in a population of male veterans (N=60). Patients were initiated on methylphenidate 5mg BID increasing to 10mg BID at two weeks. They were followed for 12 weeks and results revealed statistically significant improvement in apathy scores as well as secondary outcome improvements in cognition, function and caregiver burden. Adverse effects, primarily dizziness and insomnia, were similar in both placebo and methylphenidate groups. One serious adverse effect, seizure, was described as possibly or probably related to the intervention. A median elevation of 7mmHg systolic blood pressure was found in the methylphenidate group.
This recent study is notable for relatively greater improvements in apathy and cognition compared to both previous studies, leading to a few points worth discussion. The study duration was longer than previous randomized controlled trials (RCTs) (12 weeks versus 2 and 6 weeks), and outcome measures trended toward greater improvement as time progressed. Study authors also note that the male population may have contributed to the more robust improvements in apathy as this symptom is recognized to be more significant in men. The relatively earlier stage of dementia could also be a factor in the improvements in secondary outcomes of cognition, function and caregiver burden. Although the overall evidence for methylphenidate in apathy remains limited and in need of further trials, this recent study adds to the body of work demonstrating it as a potentially useful tool in managing apathy.
Other interventions for apathy
As with most neuropsychiatric symptoms of dementia, non-pharmacologic interventions have a significant role to play. So far evidence regarding specific interventions is limited, though creative activities in music or art, reminiscence therapy and sport therapy may have some benefit, especially when activities are individualized.11, 12, 13 The role of neuromodulation is also an area of study given its benefits in treating depression.14
Bottom line
Apathy is a common neuropsychiatric symptom in Alzheimer’s disease and is associated with poor disease outcomes and caregiver stress. Although similar to depression, it is a distinct entity in dementia patients and does not respond to antidepressants. Evidence from three small RCTs in patients with Alzheimer’s disease have shown that methylphenidate may improve apathy as well as related outcomes of cognition, function and caregiver burden. This is noteworthy as few pharmacologic interventions have significant evidence to warrant use in neuropsychiatric symptoms of dementia. As always, considering non-pharmacologic interventions for these symptoms of dementia should be attempted first and foremost. That being said, for a patient such as Mr. AP a trial of methylphenidate would be reasonable if non- pharmacological interventions fail. This should include routine follow-up for potential adverse effect including blood pressure changes, and monitoring of outcomes from the caregiver to ensure positive benefit.
References
1. Lanctôt KL, Agüera-Ortiz L, Brodaty H, et al: Apathy associated with neurocognitive disorders: Recent progress and future directions. Alzheimers Dement 2017; 13:84–100.
2. van der Linde RM, Dening T, Stephan BC, et al: Longitudinal course of behavioural and psychological symptoms of dementia: systematic review. Br J Psychiatry 2016; 209:366–377.
3. Kales HC, Gitlin LN, Lyketsos CG: Assessment and management of behavioral and psychological symptoms of dementia. BMJ 2015; 350:h369.
4. van der Linde RM, Matthews FE, Dening T, et al: Patterns and persistence of behavioural and psychological symptoms in those with cognitive impairment: the importance of apathy. Int J Geriatr Psychiatry 2017; 32:306–315.
5. Ishii S, Weintraub N, Mervis JR: Apathy: a common psychiatric syndrome in the elderly. J Am Med Dir Assoc 2009; 10:381–93.
6. Starkstein SE, Mizrahi R, Capizzano AA, Acion L, Brockman S, Power BD: Neuroimaging correlates of apathy and depressionin Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 2009; 21(3):259–65.
7. Ruthirakuhan MT, Hermann N, Abraham EH, et al: Pharmacological interventions for apathy in Alzheimer’s disease. Cochrane Database of Syst Rev 2018; Issue 5.
8. Herrmann N, Rothenburg LS, Black SE, et al: Methylphenidate for the treatment of apathy in Alzheimer’s disease: prediction of response using dextroamphetamine challenge. J Clin Psychopharmacol 2008; 28:296–301.
9. Rosenberg PB, Lanctôt KL, Drye LT, et al: Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: a randomized, placebo-controlled trial. J Clin Psychiatry 2013; 74:810–816.
10. Padala PR, Padala KP, Lensing SY, et al: Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer’s Disease: a double blind, randomized, placebo-controlled trial. Am J of Psychiatry 2018; 175: 159-168.
11. Kolanowski A, Litaker M, Buettner L, Moeller J, Costa PT Jr: A randomized clinical trial of theory-based activities for the behavioral symptoms of dementia in nursing home residents. J Am Geriatr Soc 2011; 59:1032–41.
12. Ferrero-Arias J, Goni-Imizcoz M, Gonzalez-Bernal J, Lara-Ortega F, da Silva-Gonzalez A, Diez-Lopez M: The efficacy of nonpharmacological treatment for dementia-related apathy. Alzheimer Dis Assoc Disord 2011; 25:213–9.
13. Hsieh CJ, Chang C, SU SF, Hsiao YL, Shih YW, Han WH, et al: Reminiscence group therapy on depression and apathy in nursing home residents with mild-to-moderate dementia. J Exp Clin Med 2010; 2:72–8.
14. Padala PR, Padala KP, Lensing SY, Jackson AN, Hunter CR, et al: Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study. Psychiatry Res 2018; 261:312-318.