Converging in vivo evidence from neuroimaging studies indicates that psychotic disorders are associated with dysregulated striatal dopaminergic function, but whether the latter leads to the de novo onset of psychosis remains unclear (see reviews1-6). We investigated this by using positron emission tomography (PET) to measure the longitudinal change in presynaptic striatal dopaminergic function within subjects as they progressed from a prodromal phase to the first episode of psychosis.
The onset of psychotic disorders is often preceded by a prodromal phase characterized by paranoid ideas and perceptual disturbances termed attenuated psychotic symptoms, and a marked functional decline7. Structured assessments and operationalized criteria have been developed for identifying individuals with these features, who are said to be at Ultra High Risk (UHR) for psychosis, as about one third will develop a psychotic disorder within two years.7, 8 Presynaptic striatal dopamine synthesis capacity is increased when subjects first present with UHR symptoms9, but it is not known how this changes with the later onset of psychosis. In the present study we tested the published hypothesis that the onset of frank psychosis in these subjects would be associated with a longitudinal increase in dopamine synthesis capacity.10 The study was approved by the hospital research ethics committee. All subjects gave written informed consent to participate. Subjects meeting UHR criteria (n=20, mean age=25.0 years [SD=4.1], 11 male) were studied using 6-[18F]fluoro-L-DOPA (18F-DOPA) PET on two occasions; at first clinical presentation with UHR symptoms (scan 1) and again after two years (scan 2), by which time 8 subjects (36%) had developed a DSM-IV psychotic disorder (UHR-P group, schizophrenia [n=6], schizophreniform disorder [n=1] and bipolar I affective disorder with psychotic manic episodes [n=1]). The remaining subjects had not developed a psychotic disorder at scan 2, nor after further follow-up for at least 12 months (UHR-NP group). Graphical analysis was used to calculate influx constants (kicer values/min, denoted as Ki in earlier publications) for the striatum and its functional sub-divisions using the cerebellum as a reference region. Paired t-tests were used to test the primary hypothesis that there was an increase in kicer value in the subjects that developed psychotic disorders, and to test if there was a change in the UHR-NP group. See supplementary information for further details on the methods.
The region-of-interest analysis revealed that the transition from the prodromal phase to the onset of psychosis was associated with a significant longitudinal increase in the kicer value for the sensorimotor subdivision of the striatum (figure 1; mean (SD)/min change=+0.00090 (0.0008), 95% confidence interval: +0.0016 to +0.00019; t=3.01, df=7, p=0.020), with an effect size (ES) of 1.125 (using the SD of the change). This increase remained significant after excluding subjects (n=2) who were antipsychotic treated before the second scan (mean (SD) change =+0.00077 (0.00058)/min; ES=1.3; t=3.2, df=5, p=0.023). There was no significant change in the striatum as a whole, or in the other striatal subdivisions (mean (SD) change in the whole striatum=+0.00031 (0.0008)/min; [t=1.1, df=7, p=0.327]; limbic striatum=−0.00070 (0.0011)/min; [t=1.8, df=7, p=0.109]; associative striatum=+0.00022 (0.0008)/min [t=0.74, df=7, p=0.486]). A separate voxel-based analysis of the data showed a longitudinal increase in kicer in the subjects who developed psychosis with a peak in the right putamen (within the sensorimotor striatum, figure 2). Both region-of-interest and voxel-based analyses indicated that there were no significant longitudinal changes in kicer between baseline and follow up in the subjects who had not developed psychosis.
To our knowledge these are the first longitudinal PET imaging data examining dopaminergic changes associated with clinical progression from the prodrome to a psychotic illness. The findings provide preliminary evidence to support the hypothesis that dopaminergic dysregulation progressively increases with the development of psychosis. There was no group by time interaction (F1,38=0.97, p=0.416), so we could not demonstrate that this increase was statistically different from any alteration in the UHR-NP group, but this may reflect a lack of power to detect an interaction in a small sample, and the possibility remains that some of these UHR-NP may yet develop psychotic disorders. Further investigation in larger samples, and additional follow-up, is thus warranted. Nevertheless, these findings are of particular interest in relation to early indications that administration of antipsychotic medication in UHR subjects, which acts on striatal dopamine receptors, may reduce the risk of progression to psychosis.11, 12