Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical correlation but no elevation of striatal dopamine synthesis capacity in two independent cohorts of medication-free individuals with schizophrenia

Molecular Psychiatry volume 27, pages 1241–1247 (2022)Cite this article

Subjects

Abstract

Dysregulation of dopamine systems has been considered a foundational driver of pathophysiological processes in schizophrenia, an illness characterized by diverse domains of symptomatology. Prior work observing elevated presynaptic dopamine synthesis capacity in some patient groups has not always identified consistent symptom correlates, and studies of affected individuals in medication-free states have been challenging to obtain. Here we report on two separate cohorts of individuals with schizophrenia spectrum illness who underwent blinded medication withdrawal and medication-free neuroimaging with [18F]-FDOPA PET to assess striatal dopamine synthesis capacity. Consistently in both cohorts, we found no significant differences between patient and matched, healthy comparison groups; however, we did identify and replicate robust inverse relationships between negative symptom severity and tracer-specific uptake widely throughout the striatum: [18F]-FDOPA specific uptake was lower in patients with a greater preponderance of negative symptoms. Complementary voxel-wise and region of interest analyses, both with and without partial volume correction, yielded consistent results. These data suggest that for some individuals, striatal hyperdopaminergia may not be a defining or enduring feature of primary psychotic illness. However, clinical differences across individuals may be significantly linked to variability in striatal dopaminergic tone. These findings call for further experimentation aimed at parsing the heterogeneity of dopaminergic systems function in schizophrenia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: [18F]-FDOPA specific uptake (Ki) and negative symptoms.

Similar content being viewed by others

References

  1. Snyder SH, Banerjee SP, Yamamura HI, Greenberg D. Drugs, neurotransmitters, and schizophrenia. Science 1974;184:1243.

    Article  CAS  PubMed  Google Scholar 

  2. Masri B, Salahpour A, Didriksen M, Ghisi V, Beaulieu J-M, Gainetdinov RR, et al. Antagonism of dopamine D2 receptor/β-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci USA. 2008;105:13656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lieberman JA, Kane JM, Alvir J. Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology 1987;91:415–33.

    Article  CAS  PubMed  Google Scholar 

  4. Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, et al. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology 2000;22:125–32.

    Article  CAS  PubMed  Google Scholar 

  5. Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M. Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol Psychiatry. 2009;65:1091–3.

    Article  CAS  PubMed  Google Scholar 

  6. Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: Relationship to illness phases. Biol Psychiatry. 1999;46:56–72.

    Article  CAS  PubMed  Google Scholar 

  7. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, et al. Increased striatal dopamine transmission in schizophrenia: Confirmation in a second cohort. Am J Psychiatry. 1998;155:761–7.

    CAS  PubMed  Google Scholar 

  8. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA. 1997;94:2569–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA. 1996;93:9235–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thompson JL, Urban N, Slifstein M, Xu X, Kegeles LS, Girgis RR, et al. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol Psychiatry. 2013;18:909–15.

    Article  CAS  PubMed  Google Scholar 

  11. Reith J, Benkelfat C, Sherwin A, Yasuhara Y, Kuwabara H, Andermann F, et al. Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci USA. 1994;91:11651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hietala J, Syvälahti E, Kuoppamäki M, Hietala J, Syvälahti E, Haaparanta M, et al. Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet. 1995;346:1130–1.

    Article  CAS  PubMed  Google Scholar 

  13. Lindström LH, Gefvert O, Hagberg G, Lundberg T, Bergström M, Hartvig P, et al. Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(β-11C) DOPA and PET. Biol Psychiatry. 1999;46:681–8.

    Article  PubMed  Google Scholar 

  14. Hietala J, Syvälahti E, Vilkman H, Vuorio K, Räkköläinen V, Bergman J, et al. Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia. Schizophrenia Res. 1999;35:41–50.

    Article  CAS  Google Scholar 

  15. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002;5:267–71.

    Article  CAS  PubMed  Google Scholar 

  16. Gefvert O, Lindström LH, Waters N, Waters S, Carlsson A, Tedroff J. Different corticostriatal patterns of L-DOPA utilization in patients with untreated schizophrenia and patients treated with classical antipsychotics or clozapine. Scand J Psychol. 2003;44:289–92.

    Article  PubMed  Google Scholar 

  17. McGowan S, Lawrence AD, Sales T, Quested D, Grasby P. Presynaptic dopaminergic dysfunction in schizophrenia: A positron emission tomographic [18F]Fluorodopa study. Arch Gen Psychiatry. 2004;61:134–42.

    Article  PubMed  Google Scholar 

  18. Howes OD, Montgomery AJ, Asselin M-C, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66:13–20.

    Article  PubMed  Google Scholar 

  19. Nozaki S, Kato M, Takano H, Ito H, Takahashi H, Arakawa R. et al. Regional dopamine synthesis in patients with schizophrenia using L-[β-11C]DOPA PET. Schizophrenia Res.2009;108:78–84.

    Article  Google Scholar 

  20. Dao-Castellana M-H, Paillère-Martinot M-L, Hantraye P, Attar-Lévy D, Rémy P, Crouzel C, et al. Presynaptic dopaminergic function in the striatum of schizophrenic patients. Schizophrenia Res. 1997;23:167–74.

    Article  CAS  Google Scholar 

  21. Elkashef AM, Doudet D, Bryant T, Cohen RM, Li S-H, Wyatt RJ. 6-18F-DOPA PET study in patients with schizophrenia. Psychiatry Res: Neuroimaging. 2000;100:1–11.

    Article  CAS  PubMed  Google Scholar 

  22. Shotbolt P, Stokes PR, Owens SF, Toulopoulou T, Picchioni MM, Bose SK, et al. Striatal dopamine synthesis capacity in twins discordant for schizophrenia. Psychological Med. 2011;41:2331–8.

    Article  CAS  Google Scholar 

  23. Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry. 2012;169:1203–10.

    Article  PubMed  Google Scholar 

  24. Kim E, Howes OD, Veronese M, Beck K, Seo S, Park JW, et al. Presynaptic dopamine capacity in patients with treatment-resistant schizophrenia taking clozapine: An [18F]DOPA PET study. Neuropsychopharmacology 2017;42:941–50.

    Article  CAS  PubMed  Google Scholar 

  25. Jauhar S, McCutcheon R, Borgan F, Veronese M, Nour M, Pepper F, et al. The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: A cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study. Lancet Psychiatry. 2018;5:816–23.

    Article  PubMed  PubMed Central  Google Scholar 

  26. McCutcheon RA, Jauhar S, Pepper F, Nour MM, Rogdaki M, Veronese M, et al. The topography of striatal dopamine and symptoms in psychosis: An integrative positron emission tomography and magnetic resonance imaging study. Biol Psychiatry: Cogn Neurosci Neuroimaging. 2020;5:1040–51.

    Google Scholar 

  27. Kay SR, Flszbein A, Opfer LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bull. 1987;13:261–76.

    Article  CAS  Google Scholar 

  28. Jauhar S, Nour MM, Veronese M, Rogdaki M, Bonoldi I, Azis M, et al. A test of the transdiagnostic dopamine hypothesis of psychosis using positron emission tomographic imaging in bipolar affective disorder and schizophrenia. JAMA Psychiatry. 2017;74:1206–13.

    Article  PubMed  PubMed Central  Google Scholar 

  29. First M, Gibbon M, Spitzer R, Williams J User’s Guide for the SCID-I for DSM-IV Axis I Disorders - Research Version. New York: Biometrics Research; 1996.

  30. Eisenberg DP, Yankowitz L, Ianni AM, Rubinstein DY, Kohn PD, Hegarty CE, et al. Presynaptic dopamine synthesis capacity in schizophrenia and striatal blood flow change during antipsychotic treatment and medication-free conditions. Neuropsychopharmacology 2017;42:2232–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wallwork RS, Fortgang R, Hashimoto R, Weinberger DR, Dickinson D. Searching for a consensus five-factor model of the positive and negative syndrome scale for schizophrenia. Schizophrenia Res. 2012;137:246–50.

    Article  CAS  Google Scholar 

  32. Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab. 1985;5:584–90.

    Article  CAS  PubMed  Google Scholar 

  33. Tohka J, Reilhac A. Deconvolution-based partial volume correction in Raclopride-PET and Monte Carlo comparison to MR-based method. NeuroImage. 2008;39:1570–84.

    Article  PubMed  Google Scholar 

  34. Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean? Schizophrenia Res. 2005;79:231–8.

    Article  Google Scholar 

  35. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: A meta-analysis. Lancet. 2009;373:31–41.

    Article  CAS  PubMed  Google Scholar 

  36. Carpenter WT Jr, Heinrichs DW, Alphs LD. Treatment of negative symptoms. Schizophrenia Bull. 1985;11:440–52.

    Article  Google Scholar 

  37. Swerdlow NR, Bhakta SG, Talledo J, Benster L, Kotz J, Lavadia M, et al. Lessons learned by giving amphetamine to antipsychotic-medicated schizophrenia patients. Neuropsychopharmacology 2019;44:2277–84.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sabe M, Kirschner M, Kaiser S. Prodopaminergic drugs for treating the negative symptoms of schizophrenia: Systematic review and meta-analysis of randomized controlled trials. J Clin Psychopharmacol. 2019;39:658–64.

    Article  CAS  PubMed  Google Scholar 

  39. Shukla DK, Chiappelli JJ, Sampath H, Kochunov P, Hare SM, Wisner K, et al. Aberrant frontostriatal connectivity in negative symptoms of schizophrenia. Schizophrenia Bull. 2019;45:1051–9.

    Article  Google Scholar 

  40. Radua J, Schmidt A, Borgwardt S, Heinz A, Schlagenhauf F, McGuire P, et al. Ventral striatal activation during reward processing in psychosis: A neurofunctional meta-analysis. JAMA Psychiatry. 2015;72:1243–51.

    Article  PubMed  Google Scholar 

  41. Jauhar S, Veronese M, Nour MM, Rogdaki M, Hathway P, Turkheimer FE, et al. Determinants of treatment response in first-episode psychosis: an [18F]-FDOPA PET study. Mol Psychiatry. 2019;24:1502–12.

    Article  PubMed  Google Scholar 

  42. Jauhar S, McCutcheon R, Borgan F, Veronese M, Nour M, Pepper F, et al. The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study. Lancet Psychiatry. 2018;5:816–23.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kumakura Y, Cumming P, Vernaleken I, Buchholz H-G, Siessmeier T, Heinz A, et al. Elevated [18F]Fluorodopamine turnover in brain of patients with schizophrenia: An [18F]Fluorodopa/Positron emission tomography study. J Neurosci. 2007;27:8080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Eisenberg DP, Kohn PD, Hegarty CE, Ianni AM, Kolachana B, Gregory MD, et al. Common variation in the DOPA Decarboxylase (DDC) gene and human striatal DDC activity in vivo. Neuropsychopharmacology 2016;41:2303–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Maharjan S, Serova L, Sabban EL. Transcriptional regulation of tyrosine hydroxylase by estrogen: Opposite effects with estrogen receptors α and β and interactions with cyclic AMP. J Neurochemistry. 2005;93:1502–14.

    Article  CAS  Google Scholar 

  46. Criswell SR, Perlmutter JS, Videen TO, Moerlein SM, Flores HP, Birke AM, et al. Reduced uptake of [18F]FDOPA PET in asymptomatic welders with occupational manganese exposure. Neurology 2011;76:1296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Allen GFG, Neergheen V, Oppenheim M, Fitzgerald JC, Footitt E, Hyland K, et al. Pyridoxal 5′-phosphate deficiency causes a loss of aromatic l-amino acid decarboxylase in patients and human neuroblastoma cells, implications for aromatic l-amino acid decarboxylase and vitamin B6 deficiency states. J Neurochemistry. 2010;114:87–96.

    CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank the research volunteers for their generous participation in this study, the staff of the NIH PET Center for their assistance in data acquisition, the nursing staff and multidisciplinary care team on the 7SE-S Inpatient Clinical Research Unit for their support of inpatient care, the CTNB Recruitment Team for their help with participant recruitment, and the CTNB administrative and research staff for their facilitation of this work. Some of this work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

Funding

This research was supported by the Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, MD, 20892. Project ZIAMH002652 (NCT00001247, NCT00024622). All authors report no financial conflict of interest with regard to this paper.

Author information

Authors and Affiliations

  1. The Clinical & Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, 20892, USA

    Daniel Paul Eisenberg, Philip D. Kohn, Catherine E. Hegarty, Nicole R. Smith, Shannon E. Grogans, Jasmin B. Czarapata, Michael D. Gregory, José A. Apud & Karen F. Berman

Authors
  1. Daniel Paul Eisenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip D. Kohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catherine E. Hegarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicole R. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shannon E. Grogans
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jasmin B. Czarapata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael D. Gregory
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. José A. Apud
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karen F. Berman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DPE and KFB were involved in the conception and design of the study. DPE drafted the paper, and all authors have substantially revised it critically for intellectual content. All authors have contributed to data acquisition, analysis, or interpretation of the data. All authors have reviewed and approved the final version of this article.

Corresponding authors

Correspondence to Daniel Paul Eisenberg or Karen F. Berman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eisenberg, D.P., Kohn, P.D., Hegarty, C.E. et al. Clinical correlation but no elevation of striatal dopamine synthesis capacity in two independent cohorts of medication-free individuals with schizophrenia. Mol Psychiatry 27, 1241–1247 (2022). https://doi.org/10.1038/s41380-021-01337-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01337-1

This article is cited by

Search

Advanced search

Quick links