Sensitivity of older patients to antipsychotic motor side effects

A PET study examining potential mechanisms

Hiroyuki Uchida, Shitij Kapur, Benoit H. Mulsant, Ariel Graff-Guerrero, Bruce G. Pollock, David C. Mamo

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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 [C]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.

Original languageEnglish
Pages (from-to)255-263
Number of pages9
JournalAmerican Journal of Geriatric Psychiatry
Volume17
Issue number3
DOIs
Publication statusPublished - 2009 Mar
Externally publishedYes

Fingerprint

Antipsychotic Agents
Risperidone
Schizophrenia
Raclopride
Corpus Striatum
Ontario
Positron-Emission Tomography
Psychotic Disorders
Canada
Dopamine
Mental Health
Pharmacokinetics
Observation
Pharmaceutical Preparations
Paliperidone Palmitate

Keywords

  • Aging
  • Antipsychotic
  • Dopamine
  • Extrapyramidal side effects
  • Schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology

Cite this

Sensitivity of older patients to antipsychotic motor side effects : A PET study examining potential mechanisms. / Uchida, Hiroyuki; Kapur, Shitij; Mulsant, Benoit H.; Graff-Guerrero, Ariel; Pollock, Bruce G.; Mamo, David C.

In: American Journal of Geriatric Psychiatry, Vol. 17, No. 3, 03.2009, p. 255-263.

Research output: Contribution to journalArticle

Uchida, Hiroyuki ; Kapur, Shitij ; Mulsant, Benoit H. ; Graff-Guerrero, Ariel ; Pollock, Bruce G. ; Mamo, David C. / Sensitivity of older patients to antipsychotic motor side effects : A PET study examining potential mechanisms. In: American Journal of Geriatric Psychiatry. 2009 ; Vol. 17, No. 3. pp. 255-263.
@article{f07bcf9ea61646a3bb7bb8072f2a70b4,
title = "Sensitivity of older patients to antipsychotic motor side effects: A PET study examining potential mechanisms",
abstract = "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 [C]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.",
keywords = "Aging, Antipsychotic, Dopamine, Extrapyramidal side effects, Schizophrenia",
author = "Hiroyuki Uchida and Shitij Kapur and Mulsant, {Benoit H.} and Ariel Graff-Guerrero and Pollock, {Bruce G.} and Mamo, {David C.}",
year = "2009",
month = "3",
doi = "10.1097/JGP.0b013e318198776d",
language = "English",
volume = "17",
pages = "255--263",
journal = "American Journal of Geriatric Psychiatry",
issn = "1064-7481",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Sensitivity of older patients to antipsychotic motor side effects

T2 - A PET study examining potential mechanisms

AU - Uchida, Hiroyuki

AU - Kapur, Shitij

AU - Mulsant, Benoit H.

AU - Graff-Guerrero, Ariel

AU - Pollock, Bruce G.

AU - Mamo, David C.

PY - 2009/3

Y1 - 2009/3

N2 - 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 [C]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.

AB - 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 [C]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.

KW - Aging

KW - Antipsychotic

KW - Dopamine

KW - Extrapyramidal side effects

KW - Schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=67649283706&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649283706&partnerID=8YFLogxK

U2 - 10.1097/JGP.0b013e318198776d

DO - 10.1097/JGP.0b013e318198776d

M3 - Article

VL - 17

SP - 255

EP - 263

JO - American Journal of Geriatric Psychiatry

JF - American Journal of Geriatric Psychiatry

SN - 1064-7481

IS - 3

ER -