Abstract
Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.
| Original language | English |
|---|---|
| Pages (from-to) | 564-574 |
| Number of pages | 11 |
| Journal | Schizophrenia Bulletin |
| Volume | 39 |
| Issue number | 3 |
| DOIs | |
| State | Published - May 2013 |
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Keywords
- antipsychotic
- cognition
- dopamine
- olanzapine
- risperidone
- schizophrenia
- ziprasodine
ASJC Scopus subject areas
- Psychiatry and Mental health
Cite this
Dopamine D2 receptor occupancy and cognition in schizophrenia : Analysis of the CATIE data. / Sakurai, Hitoshi; Bies, Robert; Stroup, Scott T.; Keefe, Richard S E; Rajji, Tarek K.; Suzuki, Takefumi; Mamo, David C.; Pollock, Bruce G.; Watanabe, Koichiro; Mimura, Masaru; Uchida, Hiroyuki.
In: Schizophrenia Bulletin, Vol. 39, No. 3, 05.2013, p. 564-574.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dopamine D2 receptor occupancy and cognition in schizophrenia
T2 - Analysis of the CATIE data
AU - Sakurai, Hitoshi
AU - Bies, Robert
AU - Stroup, Scott T.
AU - Keefe, Richard S E
AU - Rajji, Tarek K.
AU - Suzuki, Takefumi
AU - Mamo, David C.
AU - Pollock, Bruce G.
AU - Watanabe, Koichiro
AU - Mimura, Masaru
AU - Uchida, Hiroyuki
PY - 2013/5
Y1 - 2013/5
N2 - Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.
AB - Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.
KW - antipsychotic
KW - cognition
KW - dopamine
KW - olanzapine
KW - risperidone
KW - schizophrenia
KW - ziprasodine
UR - http://www.scopus.com/inward/record.url?scp=84876592957&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876592957&partnerID=8YFLogxK
U2 - 10.1093/schbul/sbr189
DO - 10.1093/schbul/sbr189
M3 - Article
C2 - 22290266
AN - SCOPUS:84876592957
VL - 39
SP - 564
EP - 574
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
SN - 0586-7614
IS - 3
ER -