Hallucinations, a cardinal feature of psychotic disorders such as schizophrenia, are known to depend on excessive striatal dopamine. However, an underlying cognitive mechanism linking dopamine dysregulation and the experience of hallucinatory percepts remains elusive. Bayesian models explain perception as an optimal combination of prior expectations and new sensory evidence, where perceptual distortions such as illusions and hallucinations may occur if prior expectations are afforded excessive weight. Such excessive weight of prior expectations, in turn, could stem from a gain-control process controlled by neuromodulators such as dopamine. To test for such a dopamine-dependent gain-control mechanism of hallucinations, we studied unmedicated patients with schizophrenia with varying degrees of hallucination severity and healthy individuals using molecular imaging with a pharmacological manipulation of dopamine, structural imaging, and a novel task designed to measure illusory changes in the perceived duration of auditory stimuli under different levels of uncertainty. Hallucinations correlated with a perceptual bias, reflecting disproportional gain on expectations under uncertainty. This bias could be pharmacologically induced by amphetamine, strongly correlated with striatal dopamine release, and related to cortical volume of the dorsal anterior cingulate, a brain region involved in tracking environmental uncertainty. These findings outline a novel dopamine-dependent mechanism for perceptual modulation in physiological conditions and further suggest that this mechanism may confer vulnerability to hallucinations in hyper-dopaminergic states underlying psychosis.

The clinical high-risk state in psychosis is most often characterized by subthreshold psychotic symptoms (STPS) and represents a target for psychosis prevention. However, evidence suggests that between 30% and 50% of patients with a first episode of psychosis (FEP) report no prior history of STPS, indicating that not all patients with FEP experience a previous clinical high-risk phase. As with other early characteristics of illness onset, this diversity in the early course of symptoms may offer prognostic value for subsequent clinical trajectories. OBJECTIVE To determine whether a history of pre-onset STPS is associated with differential 1-year treatment outcomes in an early intervention service for FEP. DESIGN, SETTING, AND PARTICIPANTS Data on 195 patients 15 to 35 years of age who were recruited between January 17, 2003, and October 17, 2013, were collected from a catchment-based specialized early intervention service for FEP. Patients who reported experiencing at least 1 STPS prior to the onset of FEP were identified as STPS present (STPSp; n = 135); those who reported no such history were identified as STPS absent (STPSa; n = 60). Statistical analysis was conducted from December 15, 2016, to February 15, 2018. MAIN OUTCOMES AND MEASURES Summary scores on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia, Hamilton Anxiety Rating Scale, Global Assessment of Functioning scores, and Social and Occupational Functioning Assessment Scale scores at baseline and after 1 year of treatment were analyzed to evaluate 1-year outcomes. RESULTS Individuals in the STPSp group (39 female and 96 male participants; mean [SD] age, 23.4 [4.2] years) and the STPSa group (20 female and 40 male participants; mean [SD] age, 23.9 [5.1] years) did not differ in symptom severity or functioning at baseline. Although both groups improved by 1 year of treatment, mixed analyses of covariance (controlling for duration of untreated psychosis) revealed group-by-time interactions for scores on the Scale for the Assessment of Negative Symptoms (F 1,192 = 6.17; P = .01), the Global Assessment of Functioning (F 1,188 = 7.54; P = .006), and the Social and Occupational Functioning Assessment Scale (F 1,192 = 3.79; P = .05). Mixed analyses of covariance also revealed a group effect for scores on the Scale for the Assessment of Positive Symptoms (F 1,192 = 5.31; P = .02). After controlling for multiple comparisons, all significant results indicate poorer 1-year outcomes for patients with STPSp compared with patients with STPSa. CONCLUSIONS AND RELEVANCE A history of pre-onset STPS consistent with a prior clinical high-risk state is associated with poorer outcomes in psychotic symptoms and global functioning for patients after 1 year of treatment for FEP. The presence or absence of pre-onset STPS therefore has prognostic value for treatment outcomes, even during a later stage of psychotic illness.

Recent genetic, molecular and postmortem studies suggest impaired D2R trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using dopamine-D2 receptor (D2R) radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when post-challenge dopamine (DA) levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used “late”-phase imaging post-challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late phase displacement, or a faster return to baseline, in patients compared to healthy controls (HC). We imaged 10 patients with SZ and 9 HC with PET and [11C]raclopride at baseline and twice (3–5hr and 6–10hr) following 0.5 mg/kg dextro-amphetamine. We measured binding potential relative to non-displaceable compartment (BPND) and derived percent reduction from baseline (ΔBPND) for each post-amphetamine scan. To test the hypothesis that time course of return of striatal BPND to baseline differed between SZ and HC, we implemented a linear model with ΔBPND as dependent variable, time post-amphetamine as repeated measure, and time post-amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time post-amphetamine significantly affected striatal ΔBPND (F=1.38, p=0.26; F=0.51, p=0.61). These results show similar pattern of return of BPND to baseline as a function of time in patients with SZ and HC, suggesting striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

Hyper-responsivity of the dopaminergic system in family history-positive participants to expectation of alcohol may contribute to the expression of familial risk for AUD.