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#363 Making a difference in indifference? Medications for apathy in dementia

In patients with dementia, how safe and effective are stimulants, antidepressants, and antipsychotics for treating apathy?

Methylphenidate may improve apathy scores by a small but potentially clinically meaningful amount compared to placebo (example: 5 points more on a 72-point scale) at ~12 weeks. Methylphenidate does not impact cognition in randomized, controlled trials (RCTs). Antipsychotics and antidepressants do not improve apathy compared to placebo.

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  • Results statistically different unless indicated. Comparisons versus placebo.
  • Two systematic reviews (4-7 RCTs, 346-1341 patients) from the last 5 years of treating apathy in mild-moderate Alzheimer’s dementia over 2-24 weeks.1,2
  • Methylphenidate (immediate-release 10mg BID). Reporting most inclusive systematic review (4 RCTs, 346 patients):2
    • Apathy (mix of informant- and clinician-rated)
      • 72-point apathy scale (Baseline ~50; 3.3-point change clinically significant).3-6
        • 6 point improvement versus 1 point (placebo) at ≤12 weeks.2
      • 12-point apathy scale (Baseline ~7; 1-2 point change clinically significant).2,3,5,7
        • No difference versus placebo at <12 weeks.2
        • 4.5 point improvement versus 3.1 (placebo) at 24 weeks.2
    • Clinicians’ global impression:
      • Any improvement: 46% versus 34% (placebo).2
    • Mini-mental state exam:
      • No difference.2
    • Any adverse events or dropouts due to adverse events:
      • No difference.2
  • Antipsychotics (2 RCTs, 421-649 patients):1
    • Apathy: No difference.
  • Antidepressants:
    • SSRIs (2 RCTs, 43-83 patients, neither required apathy diagnosis):1
      • Apathy: Inconsistent results.8,9
    • Bupropion (One RCT not in systematic reviews, 108 patients) versus placebo:10
      • Apathy: No difference.
      • Quality of Life (52-point scale): 1.2 points worse versus 0.4 better (placebo).
  • Limitations: Small studies; one cross-over RCT (26 patients) negatively skewed meta-analyzed results;5 apathy a secondary outcome in antidepressant and antipsychotic RCTs; trial exclusion criteria (examples: cardiac abnormalities, uncontrolled hypertension, agitation) limit generalizability and safety data.

  • No improvement in apathy with cholinesterase inhibitors alone versus placebo,2 but 60-100% of RCT methylphenidate patients used cholinesterase inhibitors.1,2
  • Methylphenidate associated with weight loss, behavioural changes, insomnia, and cardiovascular harms.11
  • Depression and apathy often overlap and can be difficult to distinguish in practice.12
  • Non-pharmacologic options include sensory stimulation (example music therapy) and pet therapy based on low-quality evidence of benefit.13

Elionora sofronova April 19, 2024

thank you for the info, helpful

David Reesor April 24, 2024

Frustratingly poor results.

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  • Wyatt Baloun PharmD candidate
  • Bradley LeDrew PharmD candidate
  • Jen Potter MD CCFP
  • Jamie Falk PharmD

1. Dean RL, Ruthirakuhan M, Herrmann N, et al. Cochrane Database Syst Rev. 2018 May; 5(5):CD012197.

2. Lee C, Chen J, Ko C, et al. Psychopharmacology (Berl). 2022 Dec; 239(12):3743-3753. Epub 2022 Oct 15.

3. Rosenberg P, Lanctôt K, Drye L, et al. J Clin Psychiatry. 2013 Aug; 74(8):810-6.

4. Padala PR, Padala KP, Lensing SY, et al. Am J Psychiatry. 2018; 175:159–168.

5. Herrmann N, Rothenburg LS, Black SE, et al. J Clin Psychopharmacol. 2008; 28(3):296-301.

6. Lanctôt K, Chau S, Herrmann N, et al. Int Psychogeriatr. 2014 Feb; 26(2):239–246. Epub 2013 Oct 29.

7. Mintzer J, Lanctôt K,.Scherer RW, et al. JAMA Neurol. 2021; 78(11):1324-1332.

8. Lanctôt KL, Herrmann N, Van Reekum R, et al. Int J Geriatr Psychiatry. 2002; 17(6):531-41.

9. Leonpacher AK, Peters ME, Drye LT, et al. Am J Psychiatry. 2016; 173(5):473-80.

10. Maier F, Spottke A, Bach J, et al. JAMA Netw Open. 2020 May; 1;3(5):e206027.

11. Sassi KLM, Rocha NP, Colpo GD, et al. Curr Neuropharmacol. 2020; 18(2):126-135.

12. Brodaty H, Connors MH. Alzheimers Dement. 2020; 12:e12027.

13. Cai Y, Li L, Xu C, et al. Worldviews Evid Based Nurs. 2020 Aug; 17(4):311-318.

Authors do not have any conflicts of interest to declare.