Atypical antipsychotic drugs and dementia

NICE guidance on dementia recommends that antipsychotics should be used only in exceptional circumstances in elderly patients with dementia (1):

• only offer antipsychotics for people living with dementia who are either:
  • at risk of harming themselves or others
  • or experiencing agitation, hallucinations or delusions that are causing them severe distress
    
    
• be aware that for people with dementia with Lewy bodies or Parkinson's disease dementia, antipsychotics can worsen the motor features of the condition, and in some cases cause severe antipsychotic sensitivity reactions
  
  
• before starting antipsychotics, discuss the benefits and harms with the person and their family members or carers (as appropriate)
  
  
• when using antipsychotics:
  • use the lowest effective dose and use them for the shortest possible time
  • reassess the person at least every 6 weeks, to check whether they still need medication
    
    
• stop treatment with antipsychotics:
  • if the person is not getting a clear ongoing benefit from taking them and
  • after discussion with the person taking them and their family members or carers (as appropriate)
    
    
• valproate should not be used to manage agitation or aggression in people living with dementia, unless it is indicated for another condition
  

Antipsychotics can be classified into two subgroups:

• typical (conventional, first-generation) and atypical (second-generation) agents
  • typical antipsychotics include haloperidol, chlorpromazine and thiothixene
  • atypical antipsychotics include risperidone, olanzapine, quetiapine, clozapine, and aripiprazole
  • the most commonly used atypical antipsychotic for agitation and psychosis in dementia
  • the US Food and Drug Administration (FDA) has not approved any antipsychotics for use in people with dementia; in the EU, only risperidone is licensed for short-term use for aggression in this patient population (2)

A systematic review concluded that (2)

• there is some evidence that typical antipsychotics might decrease agitation and psychosis slightly in patients with dementia
• atypical antipsychotics reduce agitation in dementia slightly, but their effect on psychosis in dementia is negligible
• both drug classes increase the risk of somnolence and other adverse events
• if antipsychotics are considered for sedation in patients with severe and dangerous symptoms, this should be discussed openly with the patient and legal representative
• guidance concerning the management of behavioural and psychiatric symptoms in dementia and the treatment of psychosis in people with a history of stroke/TIA is linked
• antipsychotic drugs should be avoided in patients suspected of having dementia with Lewy bodies - in these patients, antipsychotics may precipitate irreversible parkinsonism, further disturb consciousness levels and induce an autonomic disturbance similar to neuroleptic malignant syndrome, and increase mortality rates 2-3 fold (3)

Mortality and use of antipsychotics (2,3,4)

• regulatory agencies issued a warning about the use of atypical antipsychotics in people with dementia in the mid-2000s due to an increased risk of death and stoke in this population
• cohort studies have also shown an association between use of typical antipsychotics and an increased risk of mortality in older people
• Luijendijk et al have postulated that this the co-occurrence of the use of typical antipsychotics and deaths might result from "confounding by indication" because many cohort studies included people with terminal illness and delirium, but did not adjust for severity of disease
  • "..conclude that terminal illness has not been adjusted for in observational studies that reported an increased risk of mortality risk in elderly users of conventional antipsychotics. As the validity of the evidence is questionable, so is the warning based on it.."
  • may be an explanation why mortality is highest during the first month of use

Risperidone in the treatment of neuropsychiatric symptoms of dementia:

• Huang et al concluded (5):
  • risperidone is probably the best pharmacological option to consider for alleviating neuropsychiatric symptoms in people with dementia in short-term treatment when considering the risk-benefit profile of drugs

Reference:

• 1. NICE (June 2018). Dementia
• 2 Muhlbauer V et al. Antipsychotics for agitation and psychosis in people with Alzheimer's disease and vascular dementia. Cochrane Database of Systematic Reviews 2021, Issue 12. Art. No.: CD013304. DOI: 10.1002/14651858.CD013304.pub2.
• 3. Rochon PA et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med. 2008 May 26;168(10):1090-6
• 4. Luijendijk HJ, de Bruin NC, Hulshof TA, Koolman X. Terminal illness and the increased mortality risk of conventional antipsychotics in observational studies: a systematic review. Pharmacoepidemiology and Drug Safety 2016;25(2):113-22.
• 5. Huang Y and others, Pharmacological treatment of neuropsychiatric symptoms of dementia: a network meta-analysis, Age and Ageing, Volume 52, Issue 6, June 2023, afad091, https://doi.org/10.1093/ageing/afad091