Unmet Need for the Treatment of Dementia-Related Psychosis

Dr. Stahl: Hello, my name is Dr. Stephen M. Stahl and I am an adjunct professor of psychiatry at the University of California, San Diego, an honorary visiting senior fellow at the University of Cambridge, and director of psychopharmacology for the California Department of State Hospitals.

Dr. Brunton: And I’m Dr. Stephen Brunton, executive vice president for the Primary Care Education Consortium and associate adjunct clinical professor in the department of family medicine at Touro University in Vallejo, California. In this video, we will discuss proposed diagnostic criteria for dementia-related psychosis and certain considerations that may inform the management of dementia-related psychosis. 

Dr. Stahl: We will also explore the unmet need for FDA-approved treatments for dementia-related psychosis, and the evidence for efficacy and adverse events associated with the use of atypical antipsychotic medications in patients with dementia.

Dr. Stahl: There is a need for specific diagnostic criteria for psychosis in dementia. The following criteria, published by Jeste and Finkel, were intended to distinguish symptoms of delusions and hallucinations in Alzheimer’s disease from those seen in schizophrenia and related psychotic disorders after excluding other causes of psychotic symptoms.1

Dr. Stahl: A. Characteristic symptoms. To meet this criterion, a patient must exhibit visual or auditory hallucinations, delusions, or both.1 

Dr. Stahl: B. Primary diagnosis. All criteria for dementia of the Alzheimer’s type must be met. For other dementias, Criterion B will need to be modified appropriately.1

Dr. Stahl: C. Chronology of symptom onset. Evidence from patient history should indicate that the symptoms defined in Criterion A have not been present continuously since prior to the onset of dementia symptoms.1

Dr. Stahl: D. Duration and severity. To fulfill this criterion, the symptoms present in criterion A must be present, at least intermittently, for 1 month or longer. Additionally, the symptoms must be severe enough to cause disruption in the patient’s and/or others’ functioning.1

Dr. Brunton: Criterion E specifies that schizophrenia and related disorders should be excluded in order to reach a diagnosis of dementia-related psychosis. Criteria for schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features should never have been met.1 

Dr. Brunton: F. Relationship to delirium. The disturbance must not occur exclusively during the course of a delirium, although the two can coexist for a time.1

Dr. Brunton: G. Other causes of psychotic symptoms must be excluded. The disturbance should not be better accounted for by another general medical condition or direct physiological effect of a substance, for example, a drug of abuse or a medication.1

Dr. Brunton: The Jeste and Finkel criteria also suggest that certain associated features should be considered. Specifically, it should be noted when there is evidence, from history or examination, of prominent agitation with or without physical or verbal aggression in association with a patient’s psychosis. Additionally, it should be specified whether prominent negative symptoms, such as apathy, affective flattening, avolition, or motor retardation, are present. Lastly, it should be noted if there is evidence of depressive symptoms, such as depressed mood, insomnia or hypersomnia, feelings of worthlessness or excessive or inappropriate guilt, or recurrent thoughts of death.1

Dr. Stahl: Decision-making regarding the use of antipsychotic therapy in patients with dementia may involve several key considerations. The Alzheimer’s Association recommends nonpharmacologic interventions as first-line therapy for individuals experiencing behavioral and psychological symptoms of dementia, or BPSD, and provides several considerations relevant to decision-making regarding the use of antipsychotics for BPSD.2

Dr. Brunton: The Alzheimer’s Association recommends that triggers of behavioral disturbances be identified and removed, and that nonpharmacologic alternatives should be considered as first-line therapy. Additionally, the severity and consequences of BPSD should be evaluated with respect to the overall risk to the self or others. The risks and benefits with and without antipsychotic therapy should be considered. Lastly, it is important to accept that interventions for the treatment of BPSD are short-term and must be regularly re-evaluated.2

Dr. Stahl: Currently, no antipsychotic medications are approved to treat dementia-related psychosis and all antipsychotic medications carry a boxed warning indicating that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.3

Dr. Brunton: The FDA analyzed 17 placebo-controlled trials that demonstrated an approximately 1.6- to 1.7-fold increase in mortality with the use of atypical antipsychotics in older patients with dementia-related psychosis compared to placebo-treated patients.3 Most of the deaths appeared to be either cardiovascular, for example heart failure or sudden death, or infectious, for example pneumonia, in nature.3

Dr. Stahl: Following the FDA analysis, an independent, individual study-based meta-analysis of 15 placebo-controlled atypical antipsychotics clinical trials was conducted by Schneider and colleagues to assess the evidence for efficacy and adverse events associated with the use of atypical antipsychotic medications in patients with dementia.4 The included trials were parallel group, double-blind, placebo-controlled, and randomized.4 All of the included patients had Alzheimer’s disease, vascular dementia, mixed dementia, or a primary dementia.4 Overall, 3,353 patients were randomized to drug and 1,757 to placebo.4

Dr. Brunton: This analysis revealed inconsistent evidence of efficacy for the treatment of BPSD in patients with dementia, and that the use of atypical antipsychotics in patients with dementia may be associated with adverse events, as shown here.4 Schneider and colleagues also analyzed the odds ratio of death associated with the use of atypical antipsychotics in patients with dementia. This analysis reported an odds ratio of 1.54, with a 95% confidence interval of 1.06 to 2.23, which was consistent with the FDA analysis.3,5 It may be important to consider these findings when evaluating the risks and potential benefits of antipsychotic therapy in patients with dementia.

Dr. Stahl: The use of antipsychotic medications may be associated with clinical cognitive decline.4 Schneider and colleagues analyzed MMSE scores from 7 clinical trials to determine the overall effect of atypical antipsychotics on cognitive function in patients with dementia. The results of this analysis indicated that atypical antipsychotics are associated with greater worsening of cognitive function compared to placebo.4 Moreover, a nested case-control study of 1812 patients and 3400 matched controls conducted by Coupland and colleagues found an increased risk of dementia associated with the use of antipsychotic medications with anticholinergic activity.6

Dr. Brunton: Additionally, the use of antipsychotics for dementia-related psychosis may be associated with an increased risk of metabolic events in older adults.7 In a retrospective chart review of 81 patients, Trinkley and colleagues determined that 30% of adults with dementia treated with atypical antipsychotics for BPSD experienced metabolic events, including hypo- or hyperglycemia, elevated lipids or increased weight.7 It is important to note that due to the small sample size utilized in the Trinkley study, additional studies are warranted to further evaluate these findings.

Lastly, antipsychotics functioning as D2 antagonists can induce movement disorders in adults with Parkinson’s disease.8 As you can see, there are several factors to consider when evaluating the risks and benefits of antipsychotic therapy in patients with dementia, including the type of dementia that a patient may have. 

Dr. Stahl: Jeste and Finkel published diagnostic criteria for psychosis in dementia. These criteria were intended by the authors to distinguish delusions and hallucinations in Alzheimer’s disease from those seen in other disorders.1

Dr. Brunton: Currently, no antipsychotic medications are approved to treat dementia-related psychosis. The use of atypical antipsychotics in older patients with dementia-related psychosis is associated with increased mortality.3 Moreover, the use of atypical antipsychotics in patients with dementia is associated with inconsistent evidence of efficacy and an increased risk of certain adverse events, such as clinical cognitive decline.4,6

We hope that the information presented in this video may be relevant as you navigate the management of dementia-related psychosis. Please view the other videos in this series, and thank you for watching!

References

    1. Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related dementias. Am J Geriatr Psychiatry. 2000;8(1):29-34.
    2. Alzheimer’s Association. Position on Challenging Behaviors. https://www.alz.org/national/documents/statements_antipsychotics.pdf. Accessed October 2019.
    3. US Food and Drug Administration. FDA Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances. Silver Spring, MD: US Food and Drug Administration; April 11, 2005.
    4. Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14(3):191-210.
    5. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294(15):1934-1943.
    6. Coupland CAC, Hill T, Dening T, et al. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Intern Med. 2019.
    7. Trinkley KE, Sturm AM, Porter K, Nahata MC. Efficacy and safety of atypical antipsychotics for behavioral and psychological symptoms of dementia among community dwelling adults. J Pharm Pract. 2020;33(1):7-14.
    8. Goldman JG, Vaughan CL, Goetz CG. An update expert opinion on management and research strategies in Parkinson’s disease psychosis. Expert Opin Pharmacother. 2011;12(13):2009-2024.

Faculty

Touro University
Vallejo, CA
University of California, San Diego
La Jolla, CA