Brief reportDopamine D2/3 receptor availability in the striatum of antipsychotic-free older patients with schizophrenia—A [11C]-raclopride PET study
Introduction
Antipsychotics exert their effects mostly by blocking dopamine D2/3 receptors (D2/3R). Aging is associated with increased adverse effects of antipsychotics including extrapyramidal symptoms (EPS) (Caligiuri et al., 1999). Age-related decrease in striatal D2/3R availability, which may be also influenced by lifetime environmental or medical history (Nader and Czoty, 2005), would be expected to result in an increased sensitivity to antipsychotics in older patients (Uchida et al., 2009).
Several in vivo brain imaging studies suggest that striatal D2/3R availability decreases with age in healthy humans (Backman et al., 2006), a finding we recently replicated with [11C]-raclopride (Nakajima et al., In submission). Talvik et al. found that striatal D2/3R availability decreased by 7–8% per decade in antipsychotic-naive patients with schizophrenia (age = 28.8 ± 10.2 years) (Talvik et al., 2006). Wong et al. also observed similar age-related decreases in caudal D2/3R availability (8–9%) between antipsychotic-naive patients (age = 45 ± 24 years) and healthy controls (HC) (Wong et al., 1997a). Similarly, Nordström et al. found that age-dependent decreases in putamen-to-cerebellum ratios did not differ between antipsychotic-naive younger patients (age = 24.3 [18–29] years) and HC (Nordström et al., 1992). Collectively, these findings suggest that striatal D2/3R availability decreases with age in patients with schizophrenia in a similar magnitude to that seen in HC. However, the age range of subjects in these studies is not wide enough to examine this issue in older patients with schizophrenia.
Despite its clinical relevance, no study has investigated D2/3R availability exclusively in older patients with schizophrenia. Thus, using [11C]-raclopride, we addressed this issue among those who were 50 years and older and had not received antipsychotics for at least 3 months to compare striatal D2/3R availability between antipsychotic-free older patients with schizophrenia and age- and sex-matched HC. We also explored relationships between D2/3R availability and clinical symptoms, such as positive and negative symptoms, and adverse effects in the former population.
Section snippets
Materials and methods
All procedures of this cross-sectional [11C]-raclopride PET study were approved by the Centre for Addiction and Mental Health (CAMH) Research Ethics Board and complied with the 1975 Helsinki Declaration (5th revision, 2000). The study was conducted following completion of informed consent procedure at CAMH between 2008 and 2014.
Results
Demographic and clinical characteristics of the ten patients are summarized in Table 1.
BPND in each region is summarized in Fig. 1 and Table 2. No differences were found between patients and HC in BPND in any ROI irrespective of antipsychotic treatment history. We found no differences in BPND in any ROIs between antipsychotic-naive and antipsychotic-free patients (all p's > .05).
No correlation was found between [11C]-raclopride BPND and PANSS total or subscale scores or those of extrapyramidal
Discussion
To our knowledge, this study demonstrated for the first time that there were no differences in D2/3R availability in the basal ganglia between older patients with schizophrenia and HC, irrespective of antipsychotic treatment history. The most recent meta-analysis noted no difference in D2/3R availability in antipsychotic-naive younger patients with schizophrenia and controls (Howes et al., 2012). Our finding extends the age range (up to 83 years) of patients whose D2/3R availability in the basal
Role of funding source
This study was supported by the Canadian Institutes of Health Research (MOP-97946 and MOP-114989; Drs. Graff-Guerrero and Mamo) and the US National Institutes of Health (RO1MH084886) (Drs. Graff-Guerrero and Mamo).
Contributors
D. Mamo, A. Graff-Guerrero, B. Mulsant, and H. Uchida led the study design. D. Mamo, A. Graff-Guerrero, S. Nakajima, T. Suzuki, and H. Uchida conducted the literature review and the acquisition of data. A. Graff-Guerrero, S. Nakajima, and F. Caravaggio analyzed and interpreted the data, and prepared the manuscript. All authors contributed to and approved to submit its current version of the manuscript.
Conflict of interest
Dr. Nakajima has received fellowship grants from the Canadian Institutes of Health Research (CIHR), Japan Society for the Promotion of Science, and Nakatomi Foundation, and manuscript fees from Dainippon Sumitomo Pharma and Kyowa Hakko Kirin. Dr. Mamo has received investigator-initiated grant support from Pfizer. Dr. Gerretsen has received fellowship support from the CAMH Foundation, Ontario Mental Health Foundation (OMHF), and CIHR. Dr. Uchida has received grants from Astellas Pharmaceutical,
Acknowledgments
We thank the PET Centre staff at the Centre for Addiction and Mental Health, including Alvina Ng and Laura Nguyen, for technical assistance in data collection. We also thank Kathryn Kalahani-Bargis, Zhe Feng, Thushanthi Balakumar, Alex Naber, Ausmeema Hossain, and Danielle Uy for their assistance in participant recruitment and data administration.
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