Anticholinergic Deprescription for Schizophrenia

Overseen By Shaun M. Eack, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Deepak K. Sarpal, M.D.

Must be taking: Anticholinergics

Must not be taking: Anticholinergics, others

Disqualifiers: Neurologic conditions, Substance use disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 6 months

105 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether stopping unnecessary anticholinergic medications, such as benztropine or trihexyphenidyl, can improve quality of life and mental function in people with schizophrenia. Participants will either continue their current medication or have it gradually reduced if deemed unnecessary, with progress tracked over six months. Individuals with schizophrenia or schizoaffective disorder, who have been prescribed these medications for at least six months and experience mild or no movement side effects, may be suitable candidates. As a Phase 4 trial, this research aims to understand how an already FDA-approved and effective treatment can benefit more patients, offering an opportunity to contribute to broader knowledge.

Will I have to stop taking my current medications?

The trial focuses on stopping unnecessary anticholinergic drugs like benztropine or trihexyphenidyl for some participants. If you are taking these medications and they are deemed unnecessary, you might be asked to stop them as part of the study.

What is the safety track record for anticholinergic deprescription?

Research shows that stopping unnecessary anticholinergic medications, like benztropine or trihexyphenidyl, is generally safe. Studies have found that even in a busy clinic, reducing these drugs by 30% can be achieved with few problems. This indicates that removing these medications, when unnecessary, usually doesn't harm patients.

Stopping these medications is a normal part of care when they aren't needed. Doctors often discontinue these drugs without expecting serious side effects. The goal is to improve patients' quality of life by reducing unneeded medication. Overall, evidence supports the safety of this approach. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about anticholinergic deprescription for schizophrenia because it focuses on reducing the unnecessary use of medications like benztropine and trihexyphenidyl, which are commonly prescribed to manage side effects of antipsychotics. Unlike the standard approach that often involves adding more medications to address side effects, this method aims to streamline treatment by removing unneeded drugs, potentially reducing overall medication burden and side effects. This could improve patients' quality of life by minimizing harmful cognitive effects linked to long-term anticholinergic use.

What evidence suggests that anticholinergic deprescription might be an effective treatment for schizophrenia?

Research has shown that stopping unnecessary anticholinergic drugs, such as benztropine or trihexyphenidyl, can improve the quality of life for people with schizophrenia. In this trial, one arm will focus on anticholinergic deprescription, where clinicians will deprescribe benztropine or trihexyphenidyl deemed unnecessary. Studies have found that discontinuing these medications, when not needed, may enhance thinking and daily activities. A recent study found that stopping these drugs succeeded 30% of the time in clinics with minimal intervention. Although some anticholinergic medications have been used to treat symptoms, strong evidence does not support their superiority or fewer side effects compared to other treatments. This suggests that removing them when unnecessary could be beneficial. ^{1 2 3 4 5}

Who Is on the Research Team?

Deepak K Sarpal, M.D.

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for individuals with schizophrenia, schizoaffective disorder, or psychosis who are currently prescribed anticholinergic drugs (benztropine or trihexyphenidyl) that may not be necessary. Participants will undergo evaluations and MRI scans.

Inclusion Criteria

ACBS score >= 3

I have been prescribed benztropine or trihexyphenidyl for 6 months or more.

I am able to understand and willing to sign the consent form.

Exclusion Criteria

I have severe side effects from anticholinergic drugs that require stopping them.

Significant risk of suicidal or homicidal behavior

Cognitive or language limitations, or any other factor that would preclude subjects providing informed consent

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Evaluation

Participants undergo baseline evaluation and MRI before randomization

1 week

1 visit (in-person)

Treatment

Participants are randomized to either continue or deprescribe anticholinergic drugs

6 months

Regular follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Anticholinergic Deprescription

Trial Overview The study aims to see if stopping unnecessary anticholinergic medications can improve life quality, functioning, and brain function in patients with schizophrenia. Participants will either continue their medication or stop it under medical supervision over six months.

How Is the Trial Designed?

Group I: Anticholinergic Deprescription Experimental Treatment 1 Intervention

In this arm, clinically determined unneeded benztropine or trihexyphenidyl will be deprescribed, per routine care by clinical providers.

Group II: Healthy Controls Active Control 1 Intervention

In this arm, a healthy control group with minimal anticholinergic burden will be examined longitudinally.

Group III: No Anticholinergic Deprescription Active Control 1 Intervention

In this arm, no deprescription of benztropine or trihexyphenidyl will occur.

Who Is Running the Clinical Trial?

Deepak K. Sarpal, M.D.

Lead Sponsor

Trials

2

Recruited

140+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

In a study of 70 patients with schizophrenia over approximately 3 years, higher anticholinergic burden negatively affected patients' ability to participate in and benefit from psychosocial treatment programs, with a decrease of -0.27 points in program completion scores for each unit increase on the Anticholinergic Cognitive Burden scale.

The negative impact of anticholinergic burden on psychosocial treatment outcomes was found to be mediated by cognitive function, as measured by the MATRICS consensus cognitive battery, highlighting the importance of monitoring cognitive side effects of antipsychotic medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic burden in schizophrenia and ability to benefit from psychosocial treatment programmes: a 3-year prospective cohort study. O'Reilly, K., O'Connell, P., Donohoe, G., et al.[2018]

A 27-year-old patient with schizophrenia experienced worsening symptoms after reducing anticholinergic medication and increasing neuroleptic dosage, highlighting the complexity of managing medication in psychiatric conditions.

Rapid improvement was achieved by recognizing and treating a cholinergic syndrome, demonstrating the importance of accurately distinguishing between cholinergic overdrive and exacerbation of schizophrenia for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic syndrome following anticholinergic withdrawal in a schizophrenic patient abusing marijuana. Tandon, R., Dutchak, D., Greden, JF.[2019]

In a study monitoring 86,439 patients treated with neuroleptics from 1993 to 2000, severe adverse drug reactions (ADRs) occurred in 1.1% of patients, with atypical neuroleptics causing more severe ADRs than typical ones, primarily due to clozapine-related issues.

When excluding clozapine, typical and atypical neuroleptics showed similar rates of severe ADRs, but their profiles differed, highlighting the importance of considering real-life ADR data for better treatment decisions in psychiatric care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics. Bender, S., Grohmann, R., Engel, RR., et al.[2007]

The use of anticholinergic medications among patients with schizophrenia significantly decreased from 11.7% in 1996 to 5.7% in 2012, indicating a shift in treatment practices over time.

In 2012, the prescription of anticholinergics varied by region in Denmark, with long-term use being associated with factors like older age, typical antipsychotic use, and greater illness severity, suggesting a need for careful monitoring of these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frequency and correlates of anticholinergic use among patients with schizophrenia in Denmark: A Nation-wide pharmacoepidemiological study. Pristed, SG., Correll, CU., Nielsen, J.[2018]

In a study of 274 schizophrenic outpatients, 10.4% (22 patients) were found to be taking anticholinergic drugs in higher amounts than prescribed, indicating a significant issue with medication compliance.

The research suggests that there may be various reasons for this excessive use, highlighting the need for further investigation into patient behavior and medication management in schizophrenia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Excessive use of anticholinergic drugs in a sub-sample of Italian schizophrenics. Schifano, F., di Costanzo, E.[2013]

Anticholinergic drugs, like biperiden, are commonly used to prevent and treat side effects from neuroleptic medications, but they can also be misused, leading to serious conditions such as hypoactive delirium.

Clinicians should be vigilant in identifying potential anticholinergic misuse in patients who present with delirium, especially if the cause is unclear, as this can significantly impact treatment and recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biperiden dependence: case report and literature review. Espi Martinez, F., Espi Forcen, F., Shapov, A., et al.[2021]

A quality improvement project involving 29 patients with severe mental illness showed that reducing the use of anticholinergic medications led to significant improvements in side effects, memory, and overall quality of life.

Patients who had their anticholinergic medications either discontinued or dosages reduced experienced these benefits, highlighting the potential for better management of antipsychotic treatment without increasing extrapyramidal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reducing Anticholinergic Medication Burden in Patients With Psychotic or Bipolar Disorders. Lupu, AM., Clinebell, K., Gannon, JM., et al.[2019]

In a quality improvement project at a community mental health center, 29.4% of patients receiving chronic anticholinergic medications (ACM) had their medications discontinued or dosages reduced after implementing prescriber education and support.

The study highlighted that while deprescription of ACM is feasible, higher rates of success were previously achieved with more direct involvement of clinical pharmacists, indicating their critical role in the deprescribing process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deprescribing anticholinergic medication in the community mental health setting: A quality improvement initiative. Gannon, JM., Lupu, A., Brar, J., et al.[2021]

In a quality improvement project, over 75% of patients with serious mental illness successfully tapered or discontinued long-term anticholinergic medications, leading to significant improvements in memory, quality of life, and reduction of adverse effects.

The deprescription process was well tolerated, with only about 10% of patients needing to restart anticholinergic medications due to re-emergent extrapyramidal symptoms, suggesting that gradual tapering is a safe and effective strategy for managing chronic ACM use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Less is more: Deprescribing anticholinergic medications in persons with severe mental illness. Lupu, AM., MacCamy, KL., Gannon, JM., et al.[2023]

In a study involving 15 medication-free schizophrenic patients, treatment with the anticholinergic drug biperiden for 2 days significantly increased positive symptoms of schizophrenia.

While positive symptoms worsened, there was a trend suggesting a decrease in negative symptoms, indicating that anticholinergic agents may have complex effects on schizophrenia symptomatology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of anticholinergic medication on positive and negative symptoms in medication-free schizophrenic patients. Tandon, R., Mann, NA., Eisner, WH., et al.[2019]

Anticholinergic antiparkinsonism agents can counteract the positive effects of neuroleptic treatment in patients with schizophrenia, potentially reversing therapeutic benefits when added to ongoing treatment.

In untreated patients, these anticholinergic drugs may worsen psychosis, suggesting that cholinergic mechanisms play a significant role in both the expression of schizophrenia and its response to neuroleptic medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic antagonism between anticholinergic antiparkinsonism agents and neuroleptics in schizophrenia. Implications for a neuropharmacological model. Singh, MM., Kay, SR.[2018]

Citations

1. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.20250124

A Call to Psychiatrists: Deprescription of Unnecessary ... A call to psychiatrists: Deprescription of unnecessary anticholinergic medications in schizophrenia must start now.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06562608?term=benztropine&viewType=Table&rank=8

Anticholinergic Deprescription in Schizophrenia | ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1551741120312353

Deprescribing anticholinergic medication in the community ... A 30% deprescription rate in a busy clinic was achieved with minimal intervention.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9152135/

Prescription of Anticholinergic Drugs in Patients With ... To our knowledge, there is no clear evidence showing that biperiden is more effective or has fewer side effects than other anticholinergics.

5. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/528458

Anticholinergic Deprescription in Schizophrenia In this study, the investigators will examine whether a deprescription of unnecessary anticholinergic drugs (benztropine or trihexyphenidyl) ...