Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00716755 |
| Other study ID # |
156/2007 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 2009 |
| Est. completion date |
August 2015 |
Study information
| Verified date |
June 2022 |
| Source |
Centre for Addiction and Mental Health |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
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.
