Stefan P Brugger1, Ilinca Angelescu2, Anissa Abi-Dargham3, Romina Mizrahi4, Vahid Shahrezaei5, Oliver D Howes6. 1. Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London, United Kingdom; Division of Psychiatry, University College London, London, United Kingdom; Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, United Kingdom. Electronic address: bruggersp@cardiff.ac.uk. 2. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom. 3. Departments of Psychiatry and Radiology, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York. 4. Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 5. Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London, United Kingdom; Department of Mathematics, Imperial College London, London, United Kingdom. 6. Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Abstract
BACKGROUND: It has been hypothesized that dopamine function in schizophrenia exhibits heterogeneity in excess of that seen in the general population. However, no previous study has systematically tested this hypothesis. METHODS: We employed meta-analysis of variance to investigate interindividual variability of striatal dopaminergic function in patients with schizophrenia and in healthy control subjects. We included 65 studies that reported molecular imaging measures of dopamine synthesis or release capacities, dopamine D2/3 receptor (D2/3R) or dopamine transporter (DAT) availabilities, or synaptic dopamine levels in 983 patients and 968 control subjects. Variability differences were quantified using variability ratio (VR) and coefficient of variation ratio. RESULTS: Interindividual variability of striatal D2/3R (VR = 1.26, p < .0001) and DAT (VR = 1.31, p = .01) availabilities and synaptic dopamine levels (VR = 1.38, p = .045) but not dopamine synthesis (VR = 1.12, p = .13) or release (VR = 1.08, p = .70) capacities were significantly greater in patients than in control subjects. Findings were robust to variability measure. Mean dopamine synthesis (g = 0.65, p = .004) and release (g = 0.66, p = .03) capacities, as well as synaptic levels (g = 0.78, p = .0006), were greater in patients overall, but mean synthesis capacity did not differ from that of control subjects in treatment-resistant patients (p > .3). Mean D2/3R (g = 0.17, p = .14) and DAT (g = -0.20, p = .28) availabilities did not differ between groups. CONCLUSIONS: Our findings demonstrate significant heterogeneity of striatal dopamine function in schizophrenia. They suggest that while elevated dopamine synthesis and release capacities may be core features of the disorder, altered D2/3R and DAT availabilities and synaptic dopamine levels may occur only in a subgroup of patients. This heterogeneity may contribute to variation in treatment response and side effects.
BACKGROUND: It has been hypothesized that dopamine function in schizophrenia exhibits heterogeneity in excess of that seen in the general population. However, no previous study has systematically tested this hypothesis. METHODS: We employed meta-analysis of variance to investigate interindividual variability of striatal dopaminergic function in patients with schizophrenia and in healthy control subjects. We included 65 studies that reported molecular imaging measures of dopamine synthesis or release capacities, dopamine D2/3 receptor (D2/3R) or dopamine transporter (DAT) availabilities, or synaptic dopamine levels in 983 patients and 968 control subjects. Variability differences were quantified using variability ratio (VR) and coefficient of variation ratio. RESULTS: Interindividual variability of striatal D2/3R (VR = 1.26, p < .0001) and DAT (VR = 1.31, p = .01) availabilities and synaptic dopamine levels (VR = 1.38, p = .045) but not dopamine synthesis (VR = 1.12, p = .13) or release (VR = 1.08, p = .70) capacities were significantly greater in patients than in control subjects. Findings were robust to variability measure. Mean dopamine synthesis (g = 0.65, p = .004) and release (g = 0.66, p = .03) capacities, as well as synaptic levels (g = 0.78, p = .0006), were greater in patients overall, but mean synthesis capacity did not differ from that of control subjects in treatment-resistant patients (p > .3). Mean D2/3R (g = 0.17, p = .14) and DAT (g = -0.20, p = .28) availabilities did not differ between groups. CONCLUSIONS: Our findings demonstrate significant heterogeneity of striatal dopamine function in schizophrenia. They suggest that while elevated dopamine synthesis and release capacities may be core features of the disorder, altered D2/3R and DAT availabilities and synaptic dopamine levels may occur only in a subgroup of patients. This heterogeneity may contribute to variation in treatment response and side effects.
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