A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia

JAMA Psychiatry. 2017 Dec 1;74(12):1206-1213. doi: 10.1001/jamapsychiatry.2017.2943.


Importance: The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis.

Objectives: To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class.

Design, setting, and participants: This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-l-alanine ([18F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016.

Main outcomes and measures: Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning).

Results: The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08] × 10-3 min-1; P = .002) and the schizophrenia group (mean [SD], 12.94 [0.79] × 10-3 min-1; P = .04) compared with controls (mean [SD], 12.16 [0.92] × 10-3 min-1). There was no significant difference in striatal Kicer between the bipolar and schizophrenia groups. Kicer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode, explaining 27% of the variance in symptom severity (n = 32, r = 0.52, P = .003). There was a significant positive association between Kicer and positive psychotic symptom severity in individuals with bipolar disorder experiencing a current psychotic episode (n = 16, r = 0.60, P = .01), which remained significant after adjusting for manic symptom severity.

Conclusions and relevance: These findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bipolar Disorder* / complications
  • Bipolar Disorder* / metabolism
  • Case-Control Studies
  • Cross-Sectional Studies
  • Dihydroxyphenylalanine / pharmacology*
  • Dopamine Agents / pharmacology
  • Dopamine* / analysis
  • Dopamine* / biosynthesis
  • Dopamine* / metabolism
  • England
  • Female
  • Fluorine Radioisotopes / pharmacology
  • Humans
  • Male
  • Positron-Emission Tomography / methods*
  • Psychiatric Status Rating Scales
  • Psychotic Disorders* / diagnosis
  • Psychotic Disorders* / etiology
  • Psychotic Disorders* / metabolism
  • Reproducibility of Results
  • Schizophrenia* / complications
  • Schizophrenia* / metabolism


  • Dopamine Agents
  • Fluorine Radioisotopes
  • Dihydroxyphenylalanine
  • Fluorine-18
  • Dopamine