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The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential. To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia. Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions. The meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d = -0.32 (95% CI -0.68 to 0.03) for the thalamus, d = -0.23 (95% CI -0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI -0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus. There is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis.

Abi-Dargham and Horga discuss the challenges of developing and standardizing brain-imaging technologies to aid with the diagnosis and treatment of psychiatric disorders. The field of medicine is moving toward the use of biomarkers for the optimization of individualized care. This is a particular challenge for the field of psychiatry, in which diagnosis is based on a descriptive collection of behaviors without the availability of any objective test to stratify patients. Neuroimaging techniques such as molecular imaging with positron-emission tomography (PET) or structural and functional magnetic resonance imaging (MRI) provide an opportunity to bring psychiatry from an era of subjective descriptive classification into objective and tangible brain-based measures. Here we provide steps toward the development of robust, reliable and valid biomarkers. The success of such development is crucial because it will enable the field of psychiatry to move forward into the era of modern medicine.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Perceptual disturbances in psychosis, such as auditory verbal hallucinations, are associated with increased baseline activity in the associative auditory cortex and increased dopamine transmission in the associative striatum. Perceptual disturbances are also associated with perceptual biases that suggest increased reliance on prior expectations. We review theoretical models of perceptual inference and key supporting physiological evidence, as well as the anatomy of associative cortico–striatal loops that may be relevant to auditory perceptual inference. Integrating recent findings, we outline a working framework that bridges neurobiology and the phenomenology of perceptual disturbances via theoretical models of perceptual inference.Emerging data suggest a key role for dopamine in the perceptual disturbances that occur in psychotic disorders. In this Review, Horga and Abi-Dargham discuss a framework focused on perceptual inference, emphasizing the role of dopamine and the relevant associative cortico–striatal circuits.

Neuromelanin-sensitive MRI (NM-MRI) provides a noninvasive measure of the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). NM-MRI has been validated as a measure of both dopamine neuron loss, with applications in neurodegenerative disease, and dopamine function, with applications in psychiatric disease. Furthermore, a voxelwise-analysis approach has been validated to resolve substructures, such as the ventral tegmental area (VTA), within midbrain dopaminergic nuclei thought to have distinct anatomical targets and functional roles. NM-MRI is thus a promising tool that could have diverse research and clinical applications to noninvasively interrogate in vivo the dopamine system in neuropsychiatric illness. Although a test-retest reliability study by Langley et al. using the standard NM-MRI protocol recently reported high reliability, a systematic and comprehensive investigation of the performance of the method for various acquisition parameters and preprocessing methods has not been conducted. In particular, most previous studies used relatively thick MRI slices (~3 ​mm), compared to the typical in-plane resolution (~0.5 ​mm) and to the height of the SN (~15 ​mm), to overcome technical limitations such as specific absorption rate and signal-to-noise ratio, at the cost of partial-volume effects. Here, we evaluated the effect of various acquisition and preprocessing parameters on the strength and test-retest reliability of the NM-MRI signal to determine optimized protocols for both region-of-interest (including whole SN-VTA complex and atlas-defined dopaminergic nuclei) and voxelwise measures. Namely, we determined a combination of parameters that optimizes the strength and reliability of the NM-MRI signal, including acquisition time, slice-thickness, spatial-normalization software, and degree of spatial smoothing. Using a newly developed, detailed acquisition protocol, across two scans separated by 13 days on average, we obtained intra-class correlation values indicating excellent reliability and high contrast, which could be achieved with a different set of parameters depending on the measures of interest and experimental constraints such as acquisition time. Based on this, we provide detailed guidelines covering acquisition through analysis and recommendations for performing NM-MRI experiments with high quality and reproducibility. This work provides a foundation for the optimization and standardization of NM-MRI, a promising MRI approach with growing applications throughout clinical and basic neuroscience. •A detailed NM-MRI volume placement protocol is described.•Guidelines covering acquisition through analysis for NM-MRI are given.•A test-retest study in 10 healthy subjects shows high reproducibility for region-of-interest (ROI) and voxelwise analyses.•~3 minutes of NM-MRI data is needed for high-quality ROI analysis.•~6 minutes of NM-MRI data is needed for high-quality voxelwise analysis.

The objective of this study (NCT01854944) was to assess D2/D3, 5-HT1A, 5-HT2A and serotonin transporter (SERT) occupancies of brexpiprazole in adult subjects with schizophrenia in order to identify the in vivo pharmacologic profile that may be relevant to the antipsychotic, antidepressant, and side effect profiles of the drug. Subjects were grouped into three independent cohorts of four subjects each. All subjects underwent positron emission tomography (PET) scans with two different radiotracers at baseline prior to brexpiprazole administration, and again on Day 10 after daily doses of either 4 mg (Cohorts 1 and 2), or 1 mg (Cohort 3). Cohort 1 received scans with [11C]-(+)-PHNO to measure D2 and D3 receptor occupancy and [11C]CUMI101 to measure 5-HT1A occupancy; Cohort 2 received [11C]MDL100907 for 5-HT2A occupancy and [11C]DASB for SERT occupancy; Cohort 3 underwent scanning with [11C]-(+)-PHNO and [11C]MDL100907. Five female and seven male subjects, aged 42 ± 8 years (range, 28–55 years), participated in this study. Dose dependency was observed at D2 receptors, with occupancies reaching 64 ± 8% (mean +/− SD) following 1 mg/day and 80 ± 12% following 4 mg/day. D3 receptor availability increased following 1 mg brexpiprazole treatment and did not change with 4 mg. Robust and dose-related occupancy was also observed at 5-HT2A receptors. Negligible occupancy (<5%) was observed at 5-HT1A and SERT at 4 mg/day. In summary, brexpiprazole demonstrated in vivo binding to D2 receptors and 5-HT2A receptors at steady state after 10 days of daily administration in a dose dependent manner, while binding to D3, 5-HT1A receptors and SERT was not detectable with the radiotracers used for these targets. This pharmacologic profile is consistent with the observed antipsychotic and antidepressant effects.

Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in non-neurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.

Patients at clinical high-risk (CHR) for psychosis show elevations in [18F]DOPA uptake, an estimate of dopamine (DA) synthesis capacity, in the striatum predictive of conversion to schizophrenia. Intrasynaptic DA levels can be inferred from imaging the change in radiotracer binding at D2 receptors due to a pharmacological challenge. Here, we used methylphenidate, a DA reuptake inhibitor, and [11C]-(+)-PHNO, to measure synaptic DA availability in CHR both in striatal and extra-striatal brain regions. Fourteen unmedicated, nonsubstance using CHR individuals and 14 matched control subjects participated in the study. Subjects underwent two [11C]-(+)-PHNO scans, one at baseline and one following administration of a single oral dose (60 mg) of methylphenidate. [11C]-(+)-PHNO BPND, the binding potential relative to the nondisplaceable compartment, was derived using the simplified reference tissue model with cerebellum as reference tissue. The percent change in BPND between scans, ΔBPND, was computed as an index of synaptic DA availability, and group comparisons were performed with a linear mixed model. An overall trend was found for greater synaptic DA availability (∆BPND) in CHR than controls (p = 0.06). This was driven entirely by ∆BPND in ventral striatum (−34 ± 14% in CHR, −20 ± 12% in HC; p = 0.023). There were no significant group differences in any other brain region. There were no significant differences in DA transmission in any striatal region between converters and nonconverters, although this finding is limited by the small sample size (N = 2). There was a strong and negative correlation between ΔBPND in VST and severity of negative symptoms at baseline in the CHR group (r = −0.66, p < 0.01). We show abnormally increased DA availability in the VST in CHR and an inverse relationship with negative symptoms. Our results suggest a potential early role for mesolimbic dopamine overactivity in CHR. Longitudinal studies are needed to ascertain the significance of the differential topography observed here with the [18F]DOPA literature.

Current treatments for the symptoms of schizophrenia are only effective for positive symptoms in some individuals, and have considerable side effects that impact compliance. Thus, there is a need to investigate the efficacy of other compounds in treating both positive and negative symptoms. We conducted a meta-analysis of English language placebo-controlled clinical trials of naloxone, naltrexone, nalmefene, and buprenorphine in patients with schizophrenia to determine whether opioid antagonists have therapeutic efficacy on positive, negative, total, or general symptoms. We searched online databases Ovid Medline and PsychINFO, PubMed, EMBASE, Scopus, Cochrane library/CENTRAL, Web of Science, and Google Scholar from 1970 through February 2019. Following PRISMA guidelines, Hedges g was calculated for each study. Primary study outcomes were the within-subject change on any symptom assessment scale for positive, negative, total, or general symptoms of schizophrenia between active drug and placebo conditions. Thirty studies were included with 434 total patients. We found a significant effect of all drugs on all scales combined with both a standard random effects model: (g = 0.26; P = 0.02; k = 22; CI = 0.03–0.49) and a more inclusive bootstrap model: (g = 0.26; P = 0.0002; k = 30; CI = 0.11–0.51) and a significant effect on total scales with the bootstrap model (g = 0.25288; P = 0.015; k = 19; CI = 0.04–0.35). We also observed a significant effect of all drugs on all positive scales combined with both the random effects (g = 0.33; P = 0.015; k = 17; CI = 0.07–0.60) and bootstrap models (g = 0.32; P < 0.0001; k = 21; CI = 0.13–1.38). This evidence provides support for further testing in randomized clinical trials of a new class of non-D2-receptor drugs, based on opioid mechanisms, for the treatment of positive and negative symptoms of schizophrenia.

The dopamine (DA) hypothesis of schizophrenia has evolved over the last decade from the stage of circumstantial evidence related to clinical observations and empirical validation from antipsychotic treatment to finally reach more direct testing and validation from imaging studies. These have provided much information that allows us at this point to assemble all the pieces and attempt to synthesize them and integrate them with the other neurotransmitter alterations observed in this illness. Although clearly not sufficient to explain the complexity of this disorder, the DA dysregulation offers a direct relationship to symptoms and to their treatment. We will review here its history, validation, and implications for treatment.