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Imaging synaptic dopamine availability in individuals at clinical high-risk for psychosis: a [11C]-(+)-PHNO PET with methylphenidate challenge study

Molecular Psychiatry volume 26, pages 2504–2513 (2021)Cite this article

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Abstract

Patients at clinical high-risk (CHR) for psychosis show elevations in [18F]DOPA uptake, an estimate of dopamine (DA) synthesis capacity, in the striatum predictive of conversion to schizophrenia. Intrasynaptic DA levels can be inferred from imaging the change in radiotracer binding at D2 receptors due to a pharmacological challenge. Here, we used methylphenidate, a DA reuptake inhibitor, and [11C]-(+)-PHNO, to measure synaptic DA availability in CHR both in striatal and extra-striatal brain regions. Fourteen unmedicated, nonsubstance using CHR individuals and 14 matched control subjects participated in the study. Subjects underwent two [11C]-(+)-PHNO scans, one at baseline and one following administration of a single oral dose (60 mg) of methylphenidate. [11C]-(+)-PHNO BPND, the binding potential relative to the nondisplaceable compartment, was derived using the simplified reference tissue model with cerebellum as reference tissue. The percent change in BPND between scans, ΔBPND, was computed as an index of synaptic DA availability, and group comparisons were performed with a linear mixed model. An overall trend was found for greater synaptic DA availability (∆BPND) in CHR than controls (p = 0.06). This was driven entirely by ∆BPND in ventral striatum (−34 ± 14% in CHR, −20 ± 12% in HC; p = 0.023). There were no significant group differences in any other brain region. There were no significant differences in DA transmission in any striatal region between converters and nonconverters, although this finding is limited by the small sample size (N = 2). There was a strong and negative correlation between ΔBPND in VST and severity of negative symptoms at baseline in the CHR group (r = −0.66, p < 0.01). We show abnormally increased DA availability in the VST in CHR and an inverse relationship with negative symptoms. Our results suggest a potential early role for mesolimbic dopamine overactivity in CHR. Longitudinal studies are needed to ascertain the significance of the differential topography observed here with the [18F]DOPA literature.

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Fig. 1: Binding potentials (BPND) before and after methylphenidate (MP).
Fig. 2: Percent displacement (−∆BPND) following methylphenidate.
Fig. 3: Regression of SIPS symptoms scores in CHR onto ∆BPND in the VST (R = 0.66, p < 0.01).

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Acknowledgements

We would like to acknowledge the patients who participated in this study. We thank Xiaoyan Xu, Rawad Ayoub and Jiayan Meng for excellent technical support. The project described was supported by the Doris Duke Charitable Foundation as well as the Brain and Behavior Research Foundation.

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Authors and Affiliations

  1. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA

    Ragy R. Girgis, Gary Brucato, Lawrence S. Kegeles, Tiziano Colibazzi & Jeffrey A. Lieberman

  2. New York State Psychiatric Institute, New York, NY, USA

    Ragy R. Girgis, Gary Brucato, Lawrence S. Kegeles, Tiziano Colibazzi & Jeffrey A. Lieberman

  3. Department of Psychiatry and Behavioral Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA

    Mark Slifstein & Anissa Abi-Dargham

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RRG has recently received research support from Otsuka, Allergan, BioAdvantex and Genentech and has received advances/royalties from books published by Wipf and Stock and Routledge/Taylor and Francis. MS has consulted for Curasen Therapeutics. GB discloses that he receives royalties and/or advances from Routledge/Taylor and Francis and Prometheus Books. LSK has received research support from Amgen. JAL has received support administered through his institution in the form of funding or medication supplies for investigator-initiated research from Lilly, Denovo, Biomarin, Novartis, Taisho, Teva, Alkermes, and Boehringer Ingelheim, and is a member of the advisory board of Intracellular Therapies and Pierre Fabre. He neither accepts nor receives any personal financial remuneration for consulting, advisory board or research activities. He holds a patent from Repligen and receives royalty payments from SHRINKS: The Untold Story of Psychiatry. AAD reports serving on an advisory board for Sunovion, receiving an honorarium from Otsuka, receiving stock options from Terran Biosciences and System1 Biosciences, and receiving research support from Neurocrine and LB Pharmaceuticals in the previous year. No other authors report relevant conflicts of interest.

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Girgis, R.R., Slifstein, M., Brucato, G. et al. Imaging synaptic dopamine availability in individuals at clinical high-risk for psychosis: a [11C]-(+)-PHNO PET with methylphenidate challenge study. Mol Psychiatry 26, 2504–2513 (2021). https://doi.org/10.1038/s41380-020-00934-w

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