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Kappa opioid receptor availability predicts severity of anhedonia in schizophrenia

Neuropsychopharmacology (2024)Cite this article

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Abstract

The kappa opioid receptor (KOR) and its endogenous agonist dynorphin have been implicated in multiple psychiatric conditions including psychotic disorders. We tested the hypotheses that kappa expression is elevated and associated with psychotic symptoms in schizophrenia. We measured kappa expression in unmedicated patients with schizophrenia (7 female, 6 male) and matched controls (7 female, 6 male) with positron emission tomography (PET). We also acquired a measurement of cumulative dopamine activity over the life span in the same subjects using neuromelanin sensitive MRI. We hypothesized that neuromelanin accumulation would be higher in patients than controls and that in patients there would be a positive association between KOR availability and neuromelanin accumulation. Fourteen patients and thirteen controls were enrolled. Whole brain dynamic PET imaging data using the KOR selective tracer [18F]LY245998 were acquired. Distribution volume (VT) was measured with region of interest analysis in 14 brain regions. Neuromelanin accumulation in midbrain dopaminergic nuclei was assessed in the same subjects. Positive and negative symptoms were measured by a clinical psychologist. We did not observe group level differences in KOR expression, neuromelanin accumulation or relationships of these to positive symptoms. Unexpectedly, we did observe strong positive associations between KOR expression and symptoms of anhedonia in the patients (Pearson r > 0.7, uncorrected p < 0.01 in 8 cortical brain regions). We also observed moderate associations between KOR expression and neuromelanin levels in patients. In conclusion, we did not observe a relationship between kappa and symptoms of psychosis but the observed relationship to the negative symptom of anhedonia is in line with recent work testing kappa antagonism as a therapy for anhedonia in depression.

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Fig. 1: Summed LY245 images averaged across 13 HC subjects in MNI space, showing high binding regions (Insula, Amygdala).
Fig. 2: Relationship between KOR availability and clinical measures of anhedonia in SCZ participants.

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Funding

This study was supported by an NIMH R21 grant (NIMH 5R21MH125454-02).

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Authors and Affiliations

  1. Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA

    Mark Slifstein, Wenchao Qu, Roberto Gil, Jodi J. Weinstein, Greg Perlman, Thomas Jaworski-Calara, Jiayan Meng, Bao Hu, Scott J. Moeller & Anissa Abi-Dargham

  2. Vagelos College of Physicians and Surgeons, Columbia University, Stony Brook, New York, USA

    Guillermo Horga

  3. New York State Psychiatric Institute, Stony Brook, New York, USA

    Guillermo Horga

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  1. Mark Slifstein
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Contributions

Mark Slifstein had oversight of all data acquisition, study design, analysis, statistical analysis and primary manuscript preparation. Wenchao Qu developed the radiochemistry methods and had oversight of radiopharmaceutical production. Roberto Gil performed all patient recruitment and screening, medical assessment, guidance of research participants through the imaging protocol and editing of the manuscript. Jodi Weinstein oversaw acquisition and performed analysis of neuromelanin MRI and participated in manuscript preparation. Greg Perlman performed all clinical assessments (PANSS, SAPS/SANS, SCID-5) and participated in manuscript preparation. Thomas Jaworski-Calara was the primary research coordinator on the study. He guided all participants through all aspects of the study and had primary responsibility for healthy control recruitment. Jiayan Ming performed all preprocessing of the PET data and manual delineation of regions of interest for PET analysis. Bao Hu was the chief production chemist who contributed to radiochemistry methods and had oversight of all radiopharmaceutical production. Scott Moeller provided guidance on interpretation of clinical measures and provided editorial oversight and participation in manuscript preparation. Guillermo Horga provided guidance on neuromelanin MRI methods and interpretations and contributed editorial oversight during manuscript preparation. Anissa Abi-Dargham was the principal investigator of NIMH 5R21MH125454-02. She developed the study design and had oversight of all aspects of the study performance and manuscript preparation.

Corresponding author

Correspondence to Mark Slifstein.

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Competing interests

MS is a consultant to Neurocrine Biosciences Inc. GH has an investigator-initiated research agreement with Terran Biosciences and has filed patents for neuromelanin sensitive MRI in central nervous system disorders. AA is on the Scientific Advisory Boards of Neurocrine Biosciences Inc, Boehringer Ingelheim International, and Abbvie, has received honoraria from Sunovion, holds stock in Herophilus, has stock options in Terran Life Sciences and is on the DSMB for Merck. WQ, RG, JJW, GP, TJ-C, JM, BH, and SJM have nothing to report.

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Slifstein, M., Qu, W., Gil, R. et al. Kappa opioid receptor availability predicts severity of anhedonia in schizophrenia. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01975-3

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