Pharmacologic Treatment of Neuropsychiatric Symptoms of Dementia

First, consider removing potentially offending medication (anticholinergic, sedating, benzodiazepines, etc.) (Davies et al, 2018; Livingston et al, 2014)

Antipsychotic black box warning

• Absolute increased risk of death is 1-2%, even when considering increased comorbidities in population receiving antipsychotics (Wang et al, 2005)
• American Psychiatric Association recommends an attempt to taper off antipsychotics in dementia within four months, provided no history of adverse reaction to taper (Reus et al, 2016)

Psychotic symptoms (delusions / hallucinations)

• Citalopram 30mg was shown to reduce hallucinations and delusions in AD patients by 9 weeks (Leonpacher et al, 2016)
• Risperidone
• Acetylcholinesterase inhibitors for visual hallucinations

Anxiety

• Citalopram 30mg QD was shown to reduce irritability, anxiety, and delusions compared to placebo in AD patients by 9 weeks (Leonpacher et al, 2016)
• Memantine was shown to have benefit on behavioral symptoms in several meta-analyses of Alzheimers dementia patients (Rive et al, 2013)

Agitation / aggression

• Citalopram 30mg QD was shown to reduce irritability, anxiety, and delusions compared to placebo in AD patients by 9 weeks (Leonpacher et al, 2016)
• Risperidone most effective out of antipsychotic studies, followed by aripiprazole and olanzapine though antipsychotics confer increased cerebrovascular risks, mortality, and extrapyramidal symptoms. Quetiapine has been found to have negative studies
• Memantine not shown to be helpful with significant aggressive behaviors in a double-blind placebo controlled trial with moderate-severe Alzheimers patients (Herrmann et al, 2013)

Depression

• Unfortunately, A Cochrane review found no strong evidence for antidepressants as treatment of depression in dementia, including subgroup analyses of SSRIs, venlafaxine, mirtazapine, and TCAs (Dudas et al, 2018)
  • There is some evidence that antidepressants may increase remission rates (Dudas et al, 2018)
• Because depression and dementia share significant overlap in symptoms (apathy, amotivation, cognitive deficits, etc.), if studies isolate core symptoms of depression such as sadness, pessimism, and low self-esteem, some evidence may exist for mirtazapine (but not sertraline) (Zuidersma et al, 2019)

Apathy

• Apathy is associated with significantly worse functioning and more impairment than cognitive status alone would suggest, with strongest effects in mild dementia, leading to worse patient quality of life and increased distress of caregivers; prevalence is correlated with dementia severity (27.8% in patients w/ CDR 0.5; 58.8% in patients with CDR 2) (Zhu, Grossman, and Sano, 2019)
• Best pharmacologic results for apathy treatment in dementia were found in acetylcholinesterase inhibitors, with some evidence for memantine, less for stimulants and atypical antipsychotics, and no evidence for antidepressants and anticonvulsants (Berman et al, 2012)

Night-time behaviors (waking and getting up at night)

• a Cochrane review found insufficient evidence of any drug trials to treat sleep in patients with moderate-severe AD. Melatonin up to 10mg and ramelteon were ineffective; low-quality evidence for trazodone 50mg to improve nocturnal sleep time and sleep efficiency (McCleery, Cohen, and Sharpley, et al 2016).

References

Berman, K., Brodaty, H., Withall, A. & Seeher, K. Pharmacologic treatment of apathy in dementia. Am. J. Geriatr. Psychiatry Off. J. Am. Assoc. Geriatr. Psychiatry 20, 104–122 (2012). https://pubmed.ncbi.nlm.nih.gov/21841459/

Davies, S. J. et al. Sequential drug treatment algorithm for agitation and aggression in Alzheimer’s and mixed dementia. J. Psychopharmacol. Oxf. Engl. 32, 509–523 (2018). https://pubmed.ncbi.nlm.nih.gov/29338602/

Dudas, R., Malouf, R., McCleery, J. & Dening, T. Antidepressants for treating depression in dementia. Cochrane Database Syst. Rev. 8, CD003944 (2018) https://pubmed.ncbi.nlm.nih.gov/30168578/

Herrmann, N., Gauthier, S., Boneva, N. & Lemming, O. M. A randomized, double-blind, placebo-controlled trial of memantine in a behaviorally enriched sample of patients with moderate-to-severe Alzheimer’s disease. Int. Psychogeriatr. 25, 919–927 (2013). https://pubmed.ncbi.nlm.nih.gov/23472619/

Leonpacher, A. K. et al. Effects of Citalopram on Neuropsychiatric Symptoms in Alzheimer’s Dementia: Evidence From the CitAD Study. Am. J. Psychiatry 173, 473–480 (2016). https://pubmed.ncbi.nlm.nih.gov/27032628/

Livingston, G. et al. Non-pharmacological interventions for agitation in dementia: systematic review of randomised controlled trials. Br. J. Psychiatry 205, 436–442 (2014). https://pubmed.ncbi.nlm.nih.gov/25452601/

McCleery, J., Cohen, D. A. & Sharpley, A. L. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst. Rev. (2016) doi:10.1002/14651858.CD009178.pub3. https://pubmed.ncbi.nlm.nih.gov/27851868/

Reus, V. I. et al. The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients With Dementia. Am. J. Psychiatry 173, 543–546 (2016). https://pubmed.ncbi.nlm.nih.gov/27133416/

Rive, B., Gauthier, S., Costello, S., Marre, C. & François, C. Synthesis and Comparison of the Meta-Analyses Evaluating the Efficacy of Memantine in Moderate to Severe Stages of Alzheimer’s Disease. CNS Drugs 27, 573–582 (2013). https://pubmed.ncbi.nlm.nih.gov/23765561/

Wang, P. S. et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N. Engl. J. Med. 353, 2335–2341 (2005). https://pubmed.ncbi.nlm.nih.gov/16319382/

Zhu, C. W., Grossman, H. T. & Sano, M. Why Do They Just Sit? Apathy as a Core Symptom of Alzheimer Disease. Am. J. Geriatr. Psychiatry Off. J. Am. Assoc. Geriatr. Psychiatry 27, 395–405 (2019). https://pubmed.ncbi.nlm.nih.gov/30655032/

Zuidersma, M., Chua, K.-C., Hellier, J., Voshaar, R. O. & Banerjee, S. Sertraline and Mirtazapine Versus Placebo in Subgroups of Depression in Dementia: Findings From the HTA-SADD Randomized Controlled Trial. Am. J. Geriatr. Psychiatry 27, 920–931 (2019). https://pubmed.ncbi.nlm.nih.gov/31084994/