• Occupancy of risperidone at the dopamine D2 receptor [ Time Frame: intermittently ] [ Designated as safety issue: No ]
  

• Tolerability of 40 % risperidone dose reduction and its relation to the % change in occupancy following dose reduction [ Time Frame: intermittent ] [ Designated as safety issue: No ]
  
• 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 ] [ Designated as safety issue: No ]
  

Antipsychotics play a central role in the treatment of schizophrenia irrespective of a patients' age. Aging is associated with an increased sensitivity to drug adverse effects, including adverse effects from antipsychotics.(1) This concern is reflected in clinical guidelines recommending the use of lower doses of antipsychotics in elderly patients.(2-4) 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,(2) compared with the recommended dose 2.5 - 6.5 mg/d for younger patients.(3)

The risk for most adverse effects from antipsychotic drugs is dose-related(5) 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".(6) 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.(7, 8) 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(9) and may indeed represent the true "neuroleptic threshold" described by McEvoy two decades ago.(10) 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.(11) The effect of dose on prolactin elevation has also been reported,(12, 13) which has raised concerns about the risk of osteoporosis (14-16) and to a lesser extent breast carcinoma.(17-19) 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.(5) Furthermore, higher cumulative amounts of prescribed antipsychotics have been reported to increase risks of developing tardive dyskinesia.(20) 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.(21-24) 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.(25)

Risperidone is one of the most widely used antipsychotic drugs, and has been marketed for use of behavioral disturbance in dementia in the United States. Moreover, it will soon be 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(26) 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.(27) 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.(28)

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 %. (29) The lower dose range recommended by clinical guidelines for elderly patients with schizophrenia (1.25 - 3.5 mg for risperidone)(2) 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 %.(30)

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(31), (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. As an initial attempt to address this question, we are currently performing a cross-sectional PET study in older schizophrenia patients (> 50 years old) treated with risperidone. Since one of the major goals of that study was to test the feasibility of completing the study procedures in older patients with schizophrenia, it is reassuring that 15 subjects (9 patients and 6 healthy controls) have successfully completed all study procedures to date - NONE had to discontinue the study due to imaging-related issues.

While cross-sectional data (using healthy controls to calculate occupancy) will be the first step in elucidating these mechanisms, using a within-subject prospective design has the potential to provide a more powerful methodology to test the current dosing guidelines in elderly patients with schizophrenia and related psychotic disorder. We therefore propose a prospective study to assess dopamine D2 receptor occupancy before and after a gradual 40 % dose reduction that was safely achieved in patients over the age of 45 in the past study(27) while setting a target dose above the lower limit of the dose range recommended in clinical guidelines, i.e. 1.25 mg/day, for older patients.(2) 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.