expert Q&A

Cholinesterase Inhibitors for Neuropsychiatric Symptoms in Alzheimer Disease, Parkinson Disease

Emile d’Angremont, MSc

Cholinesterase inhibitors are widely used to treat cognitive symptoms in some neurodegenerative disorders. To date, three cholinesterase inhibitors – donepezil, rivastigmine, and galantamine – have been approved by the US FDA to manage Alzheimer disease (AD) symptoms, whereas rivastigmine has been approved for Parkinson disease (PD)-related dementia.

Despite ample evidence on these medications for the management of cognitive symptoms, less is known about the use of cholinesterase inhibitors for psychotic symptoms in these patients. These psychotic symptoms, such as delusions and hallucinations, prove difficult to manage due to the risk of severe adverse effects and tolerability issues associated with other available medications.

Therefore, researchers conducted a meta-analysis of 17 randomized clinical trials to examine the impact of cholinesterase inhibitor treatment among individuals with AD and PD on neuropsychiatric symptoms.

To learn more about the study, Consultant360 reached out to the lead study author, Emile d’Angremont, MSc, with the Department of Biomedical Sciences of Cells and Systems at University Medical Center Groningen (Groningen, Netherlands).

Consultant360: What prompted this study?

Emile d’Angremont, MSc: We noticed that many clinicians prescribe cholinesterase inhibitors for patients with PD and with hallucinations or delusions off-label, but that the efficacy for these specific symptoms had never been established. We wanted to see if a meta-analysis could give us some clearance.

C360: The primary outcome of your study was hallucinations and delusions, while the secondary outcomes included other neuropsychiatric symptoms, such as agitation/aggression and anxiety, as well as the total neuropsychiatric score. Could you discuss what led your team to defining the outcome measures in this way?

Emile d’Angremont: We were specifically interested in psychotic symptoms, but we soon realized that in the context of clinical trials, these symptoms were only assessed within larger neuropsychiatric scales like the Neuropsychiatric Inventory. Individual items were rarely reported. Therefore, we had to collect the individual participant data to be able to investigate the effect of treatment on psychotic symptoms directly. But now that we also had all these other items available, such as apathy and depression, it was of course also interesting to include those in our analysis as secondary outcome.

C360:  Your study mentioned that other treatments for psychotic symptoms in this patient population was associated with severe adverse effects and increased mortality. What are some of the adverse effects associated with cholinesterase inhibitor therapy?

Emile d’Angremont: The most frequent adverse effects of cholinesterase inhibitor therapy are nausea and vomiting. Rivastigmine, one of the most common cholinesterase inhibitors, can also be administered in the form of a patch, which reduces the risk for these adverse effects. Additionally, treatment with cholinesterase inhibitors may increase tremor in patients with PD.

C360: What is the current standard of care for treating psychotic symptoms in individuals with Alzheimer disease or Parkinson disease?

Emile d’Angremont: If a psychotic symptom is distressing for the patient or caregiver, treatment is warranted. Generally, it is advised to start with non-pharmacological management of the symptoms. If this does not make the symptom manageable, a pharmacological intervention may be necessary.

In an individual with AD, the standard of care is to start an atypical antipsychotic, commonly aripiprazole or risperidone. In an individual with PD, practitioners can start with decreasing dopaminergic drugs, specifically dopamine agonists. If this does not improve symptoms, the standard of care is to initiate clozapine or quetiapine. However, clozapine requires regular monitoring of white blood cell and neutrophile count. Pimavanserin has less adverse effects compared with clozapine, but also has a lower efficacy. This drug currently does not have approval from the European Medicine Agency. However, pimavanserin has been approved for use by the US FDA.

C360: What does cholinesterase inhibitor therapy add to the treatment landscape for individuals with psychotic symptoms and neurodegenerative disorders?

Emile d’Angremont: Psychotic symptoms can be very burdensome for patients and/or caregivers and treatment options are limited. Cholinesterase inhibitors are not a new type of drug for treatment of AD or PD, making it relatively easy to initiate treatment or increase dose in a patient with psychotic symptoms. Thus, cognitive functioning may simultaneously be improved and treatment with atypical antipsychotics, a type of drug that commonly has high risk for adverse effects, may become redundant or postponed.

C360: What are the next steps for research in this area?

Emile d’Angremont: We are currently investigating how we can use imaging technologies to assess which patients may particularly benefit from cholinergic treatment, to prevent overtreatment of patients who will only suffer from adverse effects. We think that by doing this, we may be able to increase the effect size of treating psychotic symptoms with cholinesterase inhibitors.



d’Angremont E, Begemann MJH, van Laar T, Sommer IEC. Cholinesterase inhibitors for treatment of psychotic symptoms in ALzheimmer disease and Parkiinson disease: a meta-analysis. JAMA Neurol. 2023;80(8);813-823. doi:10.1001/jamaneurol.2023.1835

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