- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00715377
Anticholinergic Burden in Schizophrenia
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Anticholinergic antiparkinsonian agents (AAAs) are frequently prescribed in patients with a primary psychotic disorder either to treat or prevent the emergence of antipsychotic induced extrapyramidal symptoms (EPS). Second generation antipsychotics (SGAs) are by definition associated with fewer neurological side effects. This would be expected to be associated with a lower use of AAAs. However, in a recent prescription survey, Park and colleagues found that while the rate of concomitant use of antiparkinsonian agents dropped by 9.2% in patients with schizophrenia after changing their antipsychotic from typical antipsychotics to SGAs, 30% of prescriptions for SGAs included a concomitant antiparkinsonian agent. This is consistent with the results of other cross-sectional surveys demonstrating anticholinergic co-prescription rates of 12 - 65% in patients treated with SGA. These high rates are remarkable especially when one considers that the incidence of EPS reported in past clinical trials using SGAs (3 - 20%) is much lower than this reported co-prescription rate. This apparent discrepancy is likely explained, in part, by the established tradition of prophylactic (or routine) use of AAAs for patients starting antipsychotic drugs.
The adverse effects of AAAs are well known, and are particularly significant clinically in the elderly, who are at high risk of cognitive impairment with AAAs. Anticholigergic effects have been reported to impair cognitive function both globally as well as in specific domains, including memory and executive functioning. The association between anticholinergic activity and cognitive performance are also strongly supported by recent studies measuring serum anticholinergic activity (SAA).
Furthermore, in addition to their well-known side effects such as dry mouth, blurred vision, and constipation, they have also been reported to increase the risk of tardive kinesia and have been claimed to have a negative impact on the clinical efficacy of antipsychotic drugs.
In view of these adverse effects, the World Health Organization has discouraged the prophylactic use of AAAs, and a careful risk-benefit analysis is necessary for each individual patient. Since most cases of antipsychotic-induced EPS present within 11 weeks of initiation of antipsychotic treatment or a dosage increase, a trial of AAA taper and discontinuation has been recommended following 3 months of regular AAA treatment. These recommendations emerged prior to the widespread use of SGAs, and one might expect that successful discontinuation of concomitant AAAs would be higher for SGAs than conventional antipsychotics. AAA discontinuation trials for conventional antipsychotics have been inconsistent, with some studies reporting favorable outcomes and others reporting re-emergence of EPS. More recently Mori et al reported a favorable outcome following AAA discontinuation for both cognition and EPS in patients maintained on chlorpromazine, risperidone, or haloperidol in mixed age population with schizophrenia.
The only study of AAA discontinuation in older patients with schizophrenia also reported improved cognitive function in a sample of 21 elderly inpatients with schizophrenia. However, this study did not include extrapyramidal symptoms, psychopathology, or other side effects from AAAs as outcome measures. Furthermore, improvement in cognitive function reported in this study could be attributed to practice effects: the Alzheimer's Disease Assessment Scale-Cognitive subscale was administered at intervals of 10 days - though the learning effects of this scale have not been studied in patients with schizophrenia.
Older patients with schizophrenia would be expected to be particularly sensitive to side effects to both antipsychotics and AAAs due to age-related changes in pharmacokinetics and pharmacodynamics. However, in view of the well known adverse effects of AAAs in the elderly, use of anticholinergic drugs is specifically included in the 2002 criteria for potentially inappropriate medication used in older adults. This may be especially relevant to older patients with schizophrenia since their cognitive function is already impaired as a function of the dual effects of age-related decline and the cognitive difficulties inherent to the psychotic illness itself. Concomitant use of AAAs would be expected to lead to a further decline in their cognitive and social functioning.
We therefore propose an open-label prospective trial to assess the feasibility of reducing the dose of a frequently prescribed AAA at our Centre, benztropine, in older subjects with a primary psychotic disorder on SGAs using validated assessment scales and methods. In order to quantify the anticholinergic burden in these patients before and after AAA dose reduction, serum anticholinergic activity will be also assessed.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Ontario
-
Toronto, Ontario, Canada, M5T 1R8
- Centre for Addiction and Mental Health
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age of 50 and older
- DSM-IV/SCID diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or psychotic disorder NOS
- Having been treated with benztopine at a steady daily dose of 3 mg or less for at least three months
- Having been treated with risperidone, quetiapine, olanzapine, or clozapine at a steady dose for at least two weeks.
- Willingness to provide consent for investigator to communicate with their physician of record regarding their participation in the study.
Exclusion Criteria:
- Unstable physical illness or clinically significant neurological disorder
- A history of severe or life-threatening dystonia
- Presence of EPS defined as a total score of 7 or more or a score of 3 or more on any individual item on the SAS at baseline
- Positive urine drug screen for illegal drugs
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 1
|
Patients aged ≥ 50 years suffering from a primary psychotic disorder treated with a SGA and benztropine concomittantly at any dose steadily for at least 3 months will be eligible to participate in this study.
The dose of benztropine will be reduced by 0.5mg per week.
During this 8-week study period, extrapyramidal symptoms will be assessed on a weekly basis.
The clinical assessments will be repeated 8 weeks after the initial assessments.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
percentage of participants who successfully withdraw from anticholinergic antiparkinsonian agents.
Time Frame: at the end of the study
|
at the end of the study
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
effect of reducing the dose of benztropine on EPS and anticholinergic side-effects including cognitive impairments.
Time Frame: intermittent
|
intermittent
|
Collaborators and Investigators
Investigators
- Principal Investigator: Ariel Graff, MD, Centre for Addiction and Mental Health
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Schizophrenia Spectrum and Other Psychotic Disorders
- Schizophrenia
- Disease
- Psychotic Disorders
- Mental Disorders
- Schizophrenia, Paranoid
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Parasympatholytics
- Autonomic Agents
- Peripheral Nervous System Agents
- Muscarinic Antagonists
- Cholinergic Antagonists
- Cholinergic Agents
- Neurotransmitter Uptake Inhibitors
- Membrane Transport Modulators
- Dopamine Agents
- Dopamine Uptake Inhibitors
- Antiparkinson Agents
- Anti-Dyskinesia Agents
- Benztropine
Other Study ID Numbers
- 118/2007
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Psychotic Disorders
-
Medical College of WisconsinCompletedSchizophrenia | Affective Disorders | Psychotic Disorder | Psychotic Mood Disorder
-
Søren Dinesen ØstergaardCompletedAffective Disorders, PsychoticDenmark
-
Instituto de Investigación Hospital Universitario...CompletedSchizophrenia and Disorders With Psychotic Feature | Psychotic EpisodeSpain
-
Instituto de Investigación Hospital Universitario...Carlos III Health Institute; European Regional Development FundCompletedSchizophrenia and Disorders With Psychotic Features | Psychotic EpisodeSpain
-
VA Office of Research and DevelopmentNot yet recruitingMI-CBTech: A Mobile Intervention for Community Integration in Homeless-Experienced Veterans With SMIHomelessness | Schizophrenia Spectrum Disorders | Psychotic Mood Disorders | Psychotic Affective Disorders | Ill-Housed PersonsUnited States
-
Centre hospitalier de Ville-Evrard, FranceRecruiting
-
University of MinnesotaUniversity of California, San FranciscoCompletedPsychotic Disorders | Schizophrenia | Schizoaffective Disorder | Cognitive Impairment | Psychosis | Treatment | Psychotic Depression | Psychotic Episode | Active Control | Psychotic Mood DisordersUnited States
-
University Hospital, CaenRecruiting
-
University of California, San DiegoActive, not recruitingSchizophrenia | Schizoaffective Disorder | Mood Disorder, PsychoticUnited States
-
Boston Medical CenterNational Institute of Mental Health (NIMH); Beth Israel Deaconess Medical CenterCompletedPsychotic Disorders | Psychosis | Psychotic EpisodeUnited States
Clinical Trials on Benztropine
-
Johns Hopkins UniversityNational Institute of Dental and Craniofacial Research (NIDCR)CompletedTemporomandibular Joint DisordersUnited States
-
Aarhus University HospitalUniversity of Aarhus; Central Denmark Region; Vejle Hospital; TrygFonden, Denmark; Aalborg University Hospital and other collaboratorsRecruiting
-
Cycle Pharmaceuticals Ltd.FARMOVS Clinical Research OrganisationCompletedBioequivalenceSouth Africa
-
Cycle Pharmaceuticals Ltd.FARMOVS Clinical Research OrganisationCompletedBioequivalenceSouth Africa
-
VA Office of Research and DevelopmentUniversity of California, San DiegoCompleted
-
National Institute of Allergy and Infectious Diseases...Boehringer IngelheimCompletedHIV Infections | Peripheral Nervous System DiseaseUnited States, Tanzania
-
National Institute on Drug Abuse (NIDA)Washington D.C. Veterans Affairs Medical CenterCompleted
-
US Department of Veterans AffairsCompleted
-
University of Southern CaliforniaAstraZenecaCompleted
-
National Institute of Mental Health (NIMH)CompletedSchizophreniaUnited States