Regular Research Article
Sensitivity of Older Patients to Antipsychotic Motor Side Effects: A PET Study Examining Potential Mechanisms

https://doi.org/10.1097/JGP.0b013e318198776dGet rights and content

Objective

It is generally held that the elderly are more sensitive to motor side effects of antipsychotics, although the mechanisms for such an effect are not fully understood. The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect.

Design

Crosssectional.

Setting

Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Participants

Thirteen subjects aged 50 (mean ± standard deviation age: 62 ± 9 years) with schizophrenia or schizoaffective disorder who were receiving risperidone.

Measurements

Dopamine D2 binding potential in the striatum, using [11C]raclopride positron emission tomography scan. D2 receptor occupancy was calculated, using age-corrected measure from healthy individuals and region of interest analysis.

Results

The authors observed the expected nonlinear relationship between total risperidone and 9-hydroxyrisperidone plasma level and striatal D2 receptor occupancy. The estimated plasma level of risperidone plus 9-hydroxyrisperidone associated with 50% maximal receptor occupancy was 7.3 ng/mL, which is similar to what has been reported in younger patients. However, extrapyramidal side effects (EPS) were observed in seven subjects at D2 occupancy of 34%–79%, occupancy levels that are lower than previously reported for younger patients in whom EPS are rare at occupancies lower than 80%.

Conclusion

The observation of greater functional effect (EPS in this case) for a given drug occupancy than the younger patients supports a pharmacodynamic mechanism for age-related antipsychotic drug sensitivity. This finding has important implications for dosing of antipsychotics in older patients with schizophrenia.

Section snippets

Participants

In- and outpatients were included if they were ≥50 years, met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition/Structured Clinical Interview for DSM-III-R criteria for either schizophrenia or schizoaffective disorder,17 had received antipsychotic monotherapy with a steady dose of oral risperidone for at least 8 weeks and were capable of providing informed consent. Subjects were excluded if they received antiparkinsonian agents or had a history of treatment with a depot

Clinical Characteristics of Study Participants

Thirteen subjects with a mean ± SD age of 62 ± 9 (range: 50–77) completed the study. Table 1 summarizes their demographic and clinical characteristics. Mean ± SD duration of illness and duration of antipsychotic treatment were 36 ± 9 years (range: 20–55 years) and 26 ± 14 years (range: 1–42 years), respectively, indicating they were in the chronic stage of schizophrenia or schizoaffective disorder with onset in early adulthood. Mean ± SD PANSS total and Mini-Mental State Examination scores were

DISCUSSION

To our knowledge, this is the first published study to assess the central D2 binding of an antipsychotic in older patients with schizophrenia. It yields two main findings: 1) the relationship between striatal D2 occupancy and plasma risperidone level in older patients is similar to that reported in younger adult patients,25, 26 and 2) EPS were observed at relatively low D2 occupancy, which is in striking contrast to the published literature in younger patients in whom the presence of EPS is

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    The authors gratefully acknowledge Dr. Alan Wilson for supervising the radiochemical syntheses and Dr. Sylvain Houle, Dr. Armando Garcia, Gabriella Golea, Penny Barsoum, Regina Simon, Heidi Marcon, Dielle Miranda, Irina Vitcu, Alvina Ng, Jeannie Fong, and Dr. Isabelle Boileau for their assistance.

    This work was supported by the Sandra A. Rotman Chair in Neuropsychiatry (BGP), the Japanese Society of Clinical Neuropsychopharmacology (HU), and the Mochida Memorial Foundation (HU).

    Some of these data was presented at the annual meeting of the International College of Geriatric Psychoneuropharmacology, San Diego, USA, October 30–November 2, 2007 and the biannual meeting of the Collegium Internationales Neuro-psychopharmacologicum, Munich, Germany, July 14, 2008.

    HU's fellowship has been supported by the Japanese Society of Clinical Neuropsychopharmacology, Pfizer Health Research Foundation, and Mochida Memorial Foundation. He has received speaker's honoraria or manuscript fees from Dainippon Sumitomo Pharma.

    SK has received grant support from AstraZeneca, Bristol Meyers Squibb, Eli Lilly, EMD-Darmstadt, GlaxoSmithKline, Janssen, Neuromolecular Inc., Pfizer and has served as a consultant, scientific advisor, or speaker for AstraZeneca, Bristol Meyers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Otsuka, Organon, Pfizer, Sanofi-Synthelabo, Servier, and Solvay Wyeth.

    BHM holds stock (less than $10,000) in Akzo-Nobel, Alkermes, AstraZeneca, Biogen Idec, Celsion, Elan, Eli Lilly, Forest, General Electric, Orchestra Theraputics, and Pfizer. He has received grants, consultant fees or other financial support from the National Institute of Health, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, Fox Learning System, GlaxoSmithKline, Janssen, Lundbeck, and Pfizer. He has been a member of the speakers' bureaus of AstraZeneca, Eisai, Forest, GlaxoSmithKline, and Pfizer.

    AG-G has received professional services compensation from Abbott Laboratories.

    BGP has received grants or research support from the National Institute of Health. He has served on the advisory board of Forest Laboratories and is a faculty member of the Lundbeck Institute. He is also currently a consultant for Lundbeck and Wyeth. He served as a consultant for Takeda in July 2007.

    DCM has received grants, consultant fees, or other financial support from the Canadian Psychiatric Research Foundation, the Schizophrenia Society of Canada, the Stanley Medical Research Institute, and Bristol-Myers Squibb, and has received speaker's honoraria from AstraZeneca.

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