What Is the Unmet Medical Need for People With Dementia-Related Hallucinations and Delusions?

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Hello. I’m Dr. Gary Small. I’m a professor of psychiatry, the Parlow‐Solomon Professor on Aging, and Director of the Division of Geriatric Psychiatry at UCLA.

During this presentation, I’m going to share information on the unmet medical need of our patients who experience dementia-related hallucinations and delusions.

Before we start, I want to provide some context around these symptoms. We know that dementia is common in older adults in the United States, and as the US population ages, the number of people with dementia is expected to grow. It is important to also understand that dementia involves more than cognition: Hallucinations and delusions are prevalent across all types of dementia. In fact, approximately 2.4 million people with dementia in the US experience dementia-related hallucinations and delusions. These symptoms are a potentially burdensome healthcare challenge for patients, caregivers, and society, and can have considerable consequences. This calls attention to a vital need for accurate diagnosis and effective management of hallucinations and delusions in dementia.

Please note that this disease-awareness, non-CME program is intended only for healthcare professionals involved in the management of people with dementia-related hallucinations and delusions. It is sponsored by Acadia Pharmaceuticals, and I’m presenting on behalf of Acadia as a paid consultant. This presentation is not meant to discuss specific treatment options for dementia-related psychosis.

So, let’s begin. Although we know that the psychotic symptoms of hallucinations and delusions are prevalent among people with dementia, diagnostic criteria for psychosis in dementia do not currently exist.

To fill a need for specific diagnostic criteria for psychosis in Alzheimer’s disease, Jeste and Finkel proposed the following1:

A. The presence of visual or auditory hallucinations, delusions, or both.
B. A primary diagnosis of Alzheimer’s dementia. For all other dementias, such as vascular dementia, this criterion will need to be modified appropriately.
C. Regarding symptom chronology, symptoms of dementia must occur before symptoms of psychosis
D. The hallucinations and/or delusions must have been present, at least intermittently, for 1 month or more. The symptoms also must be severe enough to cause some disruption in patients’ or caregivers’ functioning.
E. Schizophrenia, related psychotic disorders, or other diagnoses that could explain the symptoms have been ruled out.
F. The disturbance does not occur exclusively during the course of a delirious episode.
And G. Other causes of psychosis, such as a general medical illness or drug abuse, have also been ruled out.

Finally, it is important to note whether the disturbance is associated with agitation, with or without physical or verbal aggression; negative symptoms; or depression.1

The authors introduced these criteria to distinguish symptoms of psychosis with Alzheimer’s disease from those seen with delirium, although they can coexist for a time; other medical conditions; and primary psychiatric conditions, such as schizophrenia, drug abuse, or treatment-induced psychosis.1 The authors believe that these criteria may also apply to psychosis with other dementia types, but more research is needed.1

For patients experiencing behavioral and psychotic symptoms of dementia, or BPSD, a position statement from the Alzheimer’s Association outlines considerations for making treatment decisions.2 In addition to initiating nonpharmacologic interventions as first-line therapy, the position statement suggests identifying and removing triggers, such as pain, disruption of routine, and infection.2 Similarly, it may be helpful to separate the patient from what seems to be upsetting him or her; avoiding finger-pointing, scolding, or threatening; or having the caregiver leave the room if he or she seems to be contributing to the problem.2

It’s also key to assess the severity and consequences of BPSD, including the overall risk to the patient or others.2 In terms of pharmacologic therapy, the Alzheimer’s Association advises healthcare professionals to assess the risks and benefits to the patient with and without antipsychotics, bearing in mind that the frequency and nature of some behaviors may result in harm to the caregiver or person with dementia, essentially limiting the length and quality of his or her life.2 Lastly, it is important to note that these treatments are a short-term intervention that must be regularly reevaluated.2

Currently, no antipsychotic medications are approved for the treatment of dementia-related psychosis, and all antipsychotic drugs carry a Boxed Warning indicating that elderly patients with dementia-related psychosis who are treated with antipsychotics have an increased risk of death.3

The Boxed Warning resulted from an FDA analysis of 17 placebo-controlled trials that demonstrated an approximate 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.3 Most of the deaths appeared to be due to cardiovascular events or infections.3

Following the FDA analysis, Schneider and colleagues conducted an independent meta-analysis of 15 placebo-controlled trials to assess the efficacy and adverse events associated with the use of atypical antipsychotics in patients with Alzheimer’s disease and other types of dementia.4

Trials were included in the study if they met 3 criteria4:

  • One, the study was parallel group, double-blinded, placebo-controlled with random assignment to an orally administered atypical antipsychotic or placebo
  • Two, the patients enrolled had Alzheimer’s disease, vascular dementia, mixed dementia, or a primary dementia
  • And three, the patients were randomized and at least 1 outcome measure or adverse event was obtainable

This meta-analysis included more than 3300 patients who were randomized to drug and more than 1700 who were randomized to placebo.4

The results of this analysis revealed inconsistent evidence of efficacy for the treatment of BPSD in patients with dementia.4 Reported outcomes varied from trial to trial and were limited in detail, affecting the researchers’ ability to abstract or estimate effect sizes.4

Further, the use of atypical antipsychotics in this patient population may be associated with adverse events. There was a statistically significant increase in odds ratio comparing drug to placebo for4:

  • Abnormal gait
  • Somnolence
  • Cerebrovascular adverse events
  • Edema
  • Extrapyramidal effects
  • And UTIs

Finally, this meta-analysis demonstrated an approximate 1.5-fold increase in death with the use of atypical antipsychotics in patients with dementia, which was consistent with the FDA analysis. 3,5

Another relevant, large, naturalistic study was CATIE-AD, which stands for the Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer’s Disease.6 This study was performed to determine the effectiveness of atypical antipsychotics versus placebo in outpatients with Alzheimer’s disease with associated hallucinations, delusions, aggression, or agitation severe enough to warrant the use of antipsychotics.6

The double-blind, placebo-controlled trial was conducted between 2001 and 2004 at 45 US sites and consisted of 2 phases.6 In Phase 1, 421 patients were randomized to atypical antipsychotics or placebo.6 Study physicians could adjust doses as clinically indicated, and treatment could be discontinued after the first 2 weeks if the response was inadequate. Patients with an adequate response could be treated up to 36 weeks.6 In Phase 2, 253 patients were randomized to receive one of the antipsychotic drugs to which they were not initially assigned in Phase 1 or to receive a selective serotonin reuptake inhibitor.6

The primary outcome measure was the time until discontinuation of treatment for any reason.6 The main secondary outcome was the attainment of minimal or greater improvement in the Clinical Global Impression of Change scale at week 12 while the patients continued to receive the Phase 1 drug.6

In Phase 1, there were no significant differences among the treatment groups on the primary outcome of time to discontinuation for any reason.6 In addition, there were no significant differences in response rate among the groups.6

The overall rate of discontinuation for any reason was 63%.6 Differences in time to discontinuation due to intolerance of study drug, adverse events, or death favored placebo.6 Furthermore, the discontinuation rate due to adverse events ranged from 16 to 24%, depending on the atypical antipsychotic, and it was 5% with placebo.6

There were no significant differences among the groups with regard to the proportion of patients who had at least 1 serious adverse event and the proportion who had any adverse event.6

In Phase 1, the rate of individual adverse events was also examined.6 The following adverse events were reported more commonly with atypical antipsychotics than with placebo, and the differences among the treatment groups were statistically significant6:

  • Sedation
  • Cognitive disturbance
  • Psychotic symptoms
  • Confusion or mental-status change
  • And extrapyramidal symptoms or parkinsonism

Let’s take a closer look at the incidence of EPS and parkinsonism in the CATIE-AD study on the next slide.

As I just noted, patients in Phase 1 of the CATIE-AD study experienced higher rates of EPS or parkinsonism.6 These rates ranged from 2 to 12%, depending on the atypical antipsychotic, relative to 1% of patients who received placebo.6

The researchers also assessed the neurologic effects of atypical antipsychotics on patients with dementia using 3 scales.6 Consistent with the higher adverse event rates of EPS or parkinsonism, a greater proportion of patients treated with atypical antipsychotics scored 1 or higher on the Simpson-Angus Scale, which indicates at least mild EPS, compared to those given placebo.6 No significant differences were seen among the atypical antipsychotics and placebo groups on the Abnormal Involuntary Movement Scale or the Barnes Akathisia Rating Scale.6

The CATIE-AD study also measured the patients’ weight and other metabolic parameters throughout the 36-week time frame.6 In a prospective analysis of the data, Zheng and colleagues found that the duration of antipsychotic use was significantly associated with weight gain among the 418 patients with weight data at randomization and at end of trial, after adjusting for age.7

Clinically significant weight gain was defined as a 7% or greater increase from baseline. The likelihood of this significant weight gain was higher among patients taking antipsychotics for at least 24 weeks than among those who did not take antipsychotics, after adjusting for age and gender.7

No changes in systolic and diastolic blood pressure, glucose, and triglycerides were noted in association with antipsychotic use in this study population.7

By design, the CATIE-AD study included measures at baseline and during follow-up to assess the effects of time and treatment on cognitive function.8 Vigen and colleagues analyzed these outcomes among 357 patients for whom baseline measures and at least 1 follow-up assessment during the 36-week observation period were available.8

These measures included the Mini-Mental State Examination, or MMSE; the cognitive factor on the Brief Psychiatric Rating Scale, or BPRS; and the subscales of cognition, concentration/distractibility, number cancellation, and executive function on the Alzheimer’s Disease Assessment Scale, or ADAS.8 They also included tests of category instances, finger-tapping, and working memory deficit, as well as the Trail Making Test, Part A.8

The researchers also calculated a cognitive summary score of the ADAS subscales; tests of category instances, finger-tapping, and working memory deficit; and the Trail Making Test, Part A, via a 2-step process: They averaged the normalized z scores for each of the component measures, and then they normalized these averaged scores.8

The researchers found that atypical antipsychotics significantly worsened patients’ cognitive function over 36 weeks on the MMSE, the BPRS cognitive factor, the tests of category instances, and the cognitive summary score.8

Let’s shift our focus a bit and take a look at the cognitive effects specifically associated with anticholinergic medication.

One study of 26 people with moderate to severe dementia analyzed clinical trial baseline data and showed that higher levels of serum anticholinergic activity were associated with poorer cognitive performance, as measured by the MMSE.9

Additionally, a separate analysis of data from the Alzheimer’s Disease Neuroimaging Initiative, or ADNI, and the Indiana Memory and Aging Study, or IMAS, longitudinal studies noted a significant association between anticholinergic medication use and clinical progression to mild cognitive impairment or Alzheimer’s disease or both among older adults who were cognitively normal at baseline.10 The figure shows the proportion of ADNI patients without or with a history of treatment with anticholinergic agents who remained free of mild cognitive impairment or dementia over a 96-month follow-up.10 The use of anticholinergic medication was associated with a higher likelihood of clinical cognitive decline.10

In an observational, nested case-control study, Coupland and colleagues examined whether exposure to anticholinergic drugs was associated with greater likelihood of dementia diagnosis.11

This study included more than 58,000 patients with a diagnosis of dementia and more than 225,000 matched controls.11 In the 36,666 cases in which the dementia type was recorded, about 60% had a diagnosis of Alzheimer’s disease, including mixed dementia; about 36% had vascular dementia; and about 4% had other types of dementia.11 On average, the study patients were 82 years of age.11

Exposure to drugs with strong anticholinergic properties was categorized according to cumulative use over time.11 For each individual, researchers noted an index date, which was the date of dementia diagnosis or equivalent date in matched controls.11 The highest adjusted increased odds of dementia for individuals with the greatest exposure 1 year to 11 years before the index date was 49% compared with nonuse of anticholinergics.11

In the same study from Coupland and colleagues, the adjusted odds ratio for dementia in the same time frame and exposure rate was even higher for anticholinergic antipsychotics, with an increased adjusted odds of 70% compared with nonuse of anticholinergic antipsychotics.11 For the highest exposure category, significant increases in dementia risk also were associated with anticholinergic antidepressants, antiparkinson drugs, bladder antimuscarinics, and antiepileptic drugs.11

The American Geriatrics Society Beers Criteria 2019 update addressed the potential risks associated with various medications in older adults with dementia or cognitive impairment.12 Let’s take a look at these criteria and other factors to consider when selecting treatment for this group of individuals.

The AGS Beers Criteria provide a list of potentially inappropriate drugs that are typically best avoided when treating older individuals, including the drug classes of anticholinergics, benzodiazepines, nonbenzodiazepine or benzodiazepine receptor agonist hypnotics, and antipsychotics.12

One large, population-based study showed that older patients with dementia often have specific vulnerabilities, including multiple comorbidities and polypharmacy, that healthcare professionals should consider when devising a treatment regimen.13

In conclusion, while some progress has been made in the diagnosis and management of dementia-related hallucinations and delusions, the complexity of these symptoms contributes to the ongoing unmet medical need of individuals who are experiencing them. Current antipsychotics are not FDA approved for the treatment of hallucinations and delusions associated with dementia-related psychosis and can lead to death and potentially other serious adverse effects. These adverse effects can be of particular concern for older people, who often have specific vulnerabilities, such as multiple comorbidities and polypharmacy, that factor into their treatment regimen.

This completes today’s presentation. I want to thank you for joining me.


    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. Challenging Behaviors. https://www.alz.org/national/documents/statements_antipsychotics.pdf. September 2011. Accessed June 19, 2020.
    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):191-201.
    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. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525-1538.
    7. Zheng L, Mack WJ, Dagerman KS, et al. Metabolic changes associated with second-generation antipsychotic use in Alzheimer’s disease patients: the CATIE-AD study. Am J Psychiatry. 2009;166(5):583-590.
    8. Vigen CL, Mack WJ, Keefe RS, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD. Am J Psychiatry. 2011;168(8):831-839.
    9. Chew ML, Mulsant BH, Pollock BG. Serum anticholinergic activity and cognition in patients with moderate-to-severe dementia. Am J Geriatr Psychiatry. 2005;13(6):535-538.
    10. Risacher SL, McDonald BC, Tallman EF, et al. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurol. 2016;73(6):721-732.
    11. Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Intern Med. 2019;179(8):1084-1093.
    12. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694.
    13. Clague F, Mercer SW, McLean G, Reynish E, Guthrie B. Comorbidity and polypharmacy in people with dementia: insights from a large, population-based cross-sectional analysis of primary care data. Age Ageing. 2017;46(1):33-39.

Faculty Insights

Being aware of psychiatric symptoms in dementia can shorten time to diagnosis and treatment.

–Davangere P. Devanand, MD