Clinical Trial: Minimizing Doses of Antipsychotic Medication in Older Patients With Schizophrenia.

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: 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.

Detailed Summary:

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
Sponsor: Centre for Addiction and Mental Health

Current Primary Outcome: Occupancy of risperidone/olanzapine at the dopamine D2 receptor [ Time Frame: intermittently ]

Original Primary Outcome: Occupancy of risperidone at the dopamine D2 receptor [ Time Frame: intermittently ]

Current Secondary Outcome:

  • Tolerability of 40 % antipsychotic dose reduction and its relation to the % change in occupancy following dose reduction [ Time Frame: intermittent ]
  • Relationship between plasma concentration of risperidone and its active metabolite, 9-OH-risperidone(or olanzapine) and dopamine D2 receptor occupancy in older patients, in comparison to historic young controls. [ Time Frame: intermittent ]


Original Secondary Outcome:

  • Tolerability of 40 % risperidone dose reduction and its relation to the % change in occupancy following dose reduction [ Time Frame: intermittent ]
  • Relationship between plasma concentration of risperidone and its active metabolite, 9-OH-risperidone, and dopamine D2 receptor occupancy in older patients, in comparison to historic young controls. [ Time Frame: intermittent ]


Information By: Centre for Addiction and Mental Health

Dates:
Date Received: July 14, 2008
Date Started: October 2009
Date Completion:
Last Updated: February 25, 2016
Last Verified: February 2016