Minimizing Doses of Antipsychotic Medication in Older Patients With Schizophrenia.
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|ClinicalTrials.gov Identifier: NCT00716755|
Recruitment Status : Completed
First Posted : July 16, 2008
Last Update Posted : February 26, 2016
|First Submitted Date ICMJE||July 14, 2008|
|First Posted Date ICMJE||July 16, 2008|
|Last Update Posted Date||February 26, 2016|
|Study Start Date ICMJE||October 2009|
|Actual Primary Completion Date||August 2015 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Occupancy of risperidone/olanzapine at the dopamine D2 receptor [ Time Frame: intermittently ]|
|Original Primary Outcome Measures ICMJE
||Occupancy of risperidone at the dopamine D2 receptor [ Time Frame: intermittently ]|
|Change History||Complete list of historical versions of study NCT00716755 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Minimizing Doses of Antipsychotic Medication in Older Patients With Schizophrenia.|
|Official Title ICMJE||The Minimal Effective Dose of Antipsychotic Medication in Older Patients With Schizophrenia: a PET Study.|
|Brief Summary||Since side effects of antipsychotics, dopamine D2 receptor blockers, frequently occur in older patients with schizophrenia and the risk is dose dependent, clinical guidelines universally advocate the use of lower doses. However, there is no report to test this dosing guideline with measurements of D2 receptor blockade caused by antipsychotics. In this study, dopamine D2 receptor occupancy will be measured, using Positron Emission Tomography (PET), in 40 patients aged 50 and older with schizophrenia-spectrum disorders before and after a gradual 40 % dose reduction of antipsychotics that was safely achieved in the past study while setting a target dose still above the lower limit of the dose range recommended in clinical guidelines for older patients. Our goal is to relate changes in clinical outcome, including subjective and objective clinical ratings, to dopamine D2 receptor occupancy, and compare these results with the data for younger patients in the literature.|
Antipsychotics play a central role in the treatment of schizophrenia irrespective of a patient's age. Aging is associated with an increased sensitivity to drug adverse effects, including adverse effects from antipsychotics. This concern is reflected in clinical guidelines recommending the use of lower doses of antipsychotics in elderly patients. For example, the Expert Consensus Guideline recommends dosing risperidone at 1.25 - 3.5 mg/d for older patients aged 65 and older with schizophrenia, compared with the recommended dose at 2.5 - 6.5 mg/d for younger patients. For olanzapine the recommended dose is 7.5 mg/day.
The risk for most adverse effects from antipsychotic drugs is dose-related and contributes to poor adherence and worse outcome. In addition to "objective" (in the sense of externally manifested) adverse effects including motor and autonomic side effects, it has been long been recognized that antipsychotics are also associated with a negative subjective sense of well-being that has been termed "neuroleptic dysphoria". This adverse effect has recently returned to the limelight in the literature since it has critical implications for adherence and recovery, and has also been associated with levels of striatal D2 receptor occupancy associated with motor side effects of both typical and atypical antipsychotics. Conceptually, therefore, it can be considered a subtle non-motor form of extrapyramidal symptoms (EPS) that may be manifested at doses lower than for motor EPS and may indeed represent the true "neuroleptic threshold" described by McEvoy two decades ago. Thus, optimal dosing of antipsychotic drugs (at clinical levels of D2 occupancy) would be expected to lead to better subjective experience, resulting in enhanced adherence to antipsychotic drugs.
Atypical antipsychotic drugs have been reported to show differential effects on weight gain and metabolic side effects, with an effect of dose established for olanzapine but not risperidone. The effect of dose on prolactin elevation has also been reported, which has raised concerns about the risk of osteoporosis and to a lesser extent breast carcinoma. Finally, motor side-effects are perhaps the best known dose-related consequence of antipsychotic drugs, and this is particularly true for risperidone. Lemmen et al. showed that higher doses of antipsychotics were reported to be associated with development to EPS in a combined analysis of 12 double-blind trials with risperidone, including 2,074 patients; moreover, the influence of this factor was more prominent in the elderly. Furthermore, higher cumulative amounts of prescribed antipsychotics have been reported to increase risks of developing tardive dyskinesia. These motor side-effects often not only impair the activities of daily living but also are expected to be associated with undesirable incidents such as falls and aspiration. In addition, EPS have been reported to be associated with cognitive dysfunction, although it is still uncertain of to what extent EPS affect this cognitive impairment directly and indirectly.
Risperidone and olanzapine are the most widely used antipsychotic drugs, and risperidone has been marketed for use of behavioral disturbance in dementia in the United States. Moreover, they are both available in generic form, making it more widely available. Our clinical experience, as well as preliminary data at CAMH, suggests that the dosing guidelines for elderly patients with schizophrenia may not be universally followed and patients' dosing may not necessarily be adjusted with age (personal communication, Dr Beth Sproule). Given the dose-related concerns, age-related sensitivity, and recent concerns about excess mortality in patients with dementia treated with atypical antipsychotics, it is both reasonable and standard practice to gradually reduce the dose of antipsychotics with increasing age in patients with schizophrenia. Gradual antipsychotic dose reduction was successfully completed in a naturalistic study, of carefully selected patients (n = 27) with schizophrenia and related psychotic disorders aged 45 years and older. A 40 % dose reduction (from mean dose 190 to 110 mg chlorpromazine equivalent) was tolerated by 70% of the sample who experienced no increase in psychotic symptoms after 6 months, suggesting that most older patients tolerate a lower dose of antipsychotic without adverse clinical outcome. Further, those subjects who demonstrated worsening of psychotic symptoms were stabilized within several days with a small increase in neuroleptic dosage over the last dosage on which the patient was stabilized and no patients required hospitalization. These results are consistent with the documented safety and clinical value of gradual antipsychotic dose reduction in younger patients with schizophrenia.
Previous PET studies in adult patients with schizophrenia have shown that clinical response is unlikely below striatal dopamine D2 receptor occupancy of 65 %, and conversely motor side effects very likely at occupancies in excess of 80 %. This therapeutic window for risperidone in terms of occupancy is consistent with the clinical therapeutic dose range of 2 - 6 mg, with the 2 mg dose barely reaching the occupancy threshold of 65 %. The lower dose range recommended by clinical guidelines for elderly patients with schizophrenia (1.25 - 3.5 mg for risperidone) suggests that the therapeutic window is lower for elderly patients. Thus dosing the antipsychotic at either the upper limits of this dose range, or above these limits would be expected to be associated with subjective or objective EPS, and warrants a trial of lower dosing as per guidelines. Indeed, Tort et al have simulated the relationship between plasma level and D2 occupancy for the atypical antipsychotic drugs based on their affinity for the D2 receptor and concluded that in the presence of EPS the antipsychotic dose could well be halved and the resultant D2 occupancy would be expected to stay well within the D2 occupancy therapeutic window of 65-80 %. If the elderly patients with schizophrenia do indeed respond and show maintenance of wellness at lower doses, this suggest one or more of the following mechanisms may be involved: (a) for a given dose they are reaching equivalent plasma levels as younger patients, (b) for a given plasma drug level they are achieving higher central occupancy, or (c) they show clinical response at a lower level of occupancy.
We propose a prospective study to assess dopamine D2 receptor occupancy before and after a gradual 40% dose reduction of risperidone and olanzapine that was safely achieve in patients over the age of 45 in a past study while setting a target dose above the lower limit of the dose range recommended in clinical guidelines, ie., 1.5 mg/day and 7.5 mg/day for risperidone and olanzapine respectively, for older patients. Our goal is to relate changes in clinical outcome, including subjective and objective clinical ratings, to striatal dopamine D2 receptor occupancy, and compare these results with the data for younger patients in the literature.
|Study Type ICMJE||Interventional|
|Study Phase||Not Applicable|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Drug: Risperidone/Olanzapine and PET scans
Current risperidone/olanzapine users who are 50 or older will be recruited. Dopamine D2 dopamine receptors using a selective D2 dopamine receptor ligand, [11C]-raclopride, and plasma levels of risperidone and 9-OH-risperidone, or of olanzapine, and prolactin will be measured on the 1st PET visit. Subsequently, there will be gradual dose reductions of risperidone or olanzapine by 0.5 and 2.5 mg per week, respectively (as long as the total reduction does not exceed 40%). At least 5 days after the termination of the dose taper, participants will have the second PET scan. Participants will be followed up for 24 weeks after the termination of the dose reduction.
|Study Arms||Experimental: Dose Reduction
Intervention: Drug: Risperidone/Olanzapine and PET scans
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date||August 2015|
|Actual Primary Completion Date||August 2015 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||50 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Canada|
|Removed Location Countries|
|NCT Number ICMJE||NCT00716755|
|Other Study ID Numbers ICMJE||156/2007|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||Ariel Graff, Centre for Addiction and Mental Health|
|Study Sponsor ICMJE||Centre for Addiction and Mental Health|
|Collaborators ICMJE||Not Provided|
|PRS Account||Centre for Addiction and Mental Health|
|Verification Date||February 2016|
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