Neural and behavioral correlates of aberrant salience in individuals at risk for psychosis

Correction to the original article published in Schizophrenia Bulletin, Volume 39, Issue 6, 1 November 2013, Pages 1328–1336; https://doi.org/10.1093/schbul/sbs147

Association of stimulants use with dopaminergic alterations in users of cocaine, amphetamine, or methamphetamine: a systematic review and meta-analysis

Importance Stimulant use disorder is common, affecting between 0.3% and 1.1% of the population, and costs more than $85 billion per year globally. There are no licensed treatments to date. Several lines of evidence implicate the dopamine system in the pathogenesis of substance use disorder. Therefore, understanding the nature of dopamine dysfunction seen in stimulant users has the potential to aid the development of new therapeutics. Objective To comprehensively review the in vivo imaging evidence for dopaminergic alterations in stimulant (cocaine, amphetamine, or methamphetamine) abuse or dependence. Data Sources The entire PubMed, EMBASE, and PsycINFO databases were searched for studies from inception date to May 14, 2016. Study Selection Case-control studies were identified that compared dopaminergic measures between stimulant users and healthy controls using positron emission tomography or single-photon emission computed tomography to measure striatal dopamine synthesis or release or to assess dopamine transporter availability or dopamine receptor availability. Data Extraction and Synthesis Demographic, clinical, and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted for stimulants combined, as well as for cocaine and for amphetamine and methamphetamine separately if there were sufficient studies. Main Outcomes and Measures Differences were measured in dopamine release (assessed using change in the D2/D3 receptor availability after administration of amphetamine or methylphenidate), dopamine transporter availability, and dopamine receptor availability in cocaine users, amphetamine and methamphetamine users, and healthy controls. Results A total of 31 studies that compared dopaminergic measures between 519 stimulant users and 512 healthy controls were included in the final analysis. In most of the studies, the duration of abstinence varied from 5 days to 3 weeks. There was a significant decrease in striatal dopamine release in stimulant users compared with healthy controls: the effect size was −0.84 (95% CI, −1.08 to −0.60; P < .001) for stimulants combined and −0.87 (95% CI, −1.15 to −0.60; P < .001) for cocaine. In addition, there was a significant decrease in dopamine transporter availability: the effect size was −0.91 (95% CI, −1.50 to −0.32; P < .01) for stimulants combined and −1.47 (95% CI, −1.83 to −1.10; P < .001) for amphetamine and methamphetamine. There was also a significant decrease in D2/D3 receptor availability: the effect size was −0.76 (95% CI, −0.92 to −0.60; P < .001) for stimulants combined, −0.73 (95% CI, −0.94 to −0.53; P < .001) for cocaine, and −0.81 (95% CI, −1.12 to −0.49; P < .001) for amphetamine and methamphetamine. Consistent alterations were not found in vesicular monoamine transporter, dopamine synthesis, or D1 receptor studies. Conclusions and Relevance Data suggest that both presynaptic and postsynaptic aspects of the dopamine system in the striatum are down-regulated in stimulant users. The commonality and differences between these findings and the discrepancies with the preclinical literature and models of drug addiction are discussed, as well as their implications for future drug development

The Relationship Between Dopamine Synthesis Capacity and Release: Implications for Psychosis

Berry and colleagues report that presynaptic striatal dopamine synthesis capacity (measured with [¹⁸F]FMT PET) is not associated with methylphenidate-induced striatal dopamine release (indexed as a reduction in [¹¹C]raclopride non-displaceable binding-potential) in healthy participants (Berry et al, 2017). The authors should be commended for the quality of this study, in which 40 subjects each received three PET scans within a short time window. The results are pertinent to the interpretation of neuroimaging studies investigating the dopamine hypothesis of schizophrenia

Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system

Previous studies have suggested that risk of psychotic events may be increased in children exposed to methylphenidate (MPH). However, this risk has not been fully examined and the possibility of confounding factors has not been excluded. Patients aged 6-19 years who received at least one MPH prescription were identified using Hong Kong population-based electronic medical records on the Clinical Data Analysis & Reporting System (2001-2014). Using the self-controlled case series design, relative incidence of psychotic events was calculated comparing periods when patients were exposed to MPH with non-exposed periods. Of 20 586 patients prescribed MPH, 103 had an incident psychotic event; 72 (69.9%) were male and 31 (30.1%) female. The mean age at commencement of observation was 6.95 years and the mean follow-up per participant was 10.16 years. On average, each participant was exposed to MPH for 2.17 years. The overall incidence of psychotic events during the MPH exposure period was 6.14 per 10 000 patient-years. No increased risk was found during MPH exposed compared to non-exposed periods (incidence rate ratio (IRR) 1.02 (0.53-1.97)). However, an increased risk was found during the pre-exposure period (IRR 4.64 (2.17-9.92)). Results were consistent across all sensitivity analyses. This study does not support the hypothesis that MPH increases risk of incident psychotic events. It does indicate an increased risk of psychotic events prior to the first prescription of MPH, which may be due to an association between psychotic events and the behavioural and attentional symptoms that led to psychiatric assessment and initiation of MPH treatment

Chronic psychosocial stressors are associated with alterations in salience processing and corticostriatal connectivity

Psychosocial stressors including childhood adversity, migration, and living in an urban environment, have been associated with several psychiatric disorders, including psychotic disorders. The neural and psychological mechanisms mediating this relationship remain unclear. In parallel, alterations in corticostriatal connectivity and abnormalities in the processing of salience, are seen in psychotic disorders. Aberrant functioning of these mechanisms secondary to chronic stress exposure, could help explain how common environmental exposures are associated with a diverse range of symptoms. In the current study, we recruited two groups of adults, one with a high degree of exposure to chronic psychosocial stressors (the exposed group, n = 20), and one with minimal exposure (the unexposed group, n = 22). All participants underwent a resting state MRI scan, completed the Aberrant Salience Inventory, and performed a behavioural task - the Salience Attribution Test (SAT). The exposed group showed reduced explicit adaptive salience scores (cohen's d = 0.69, p = 0.03) and increased aberrant salience inventory scores (d = 0.65, p = 0.04). The exposed group also showed increased corticostriatal connectivity between the ventral striatum and brain regions previously implicated in salience processing. Corticostriatal connectivity in these regions negatively correlated with SAT explicit adaptive salience (r = -0.48, p = 0.001), and positively correlated with aberrant salience inventory scores (r = 0.42, p = 0.006). Furthermore, in a mediation analysis there was tentative evidence that differences in striato-cortical connectivity mediated the group differences in salience scores

Striatal dopamine D₂/₃ receptors in medication-naïve schizophrenia: an [¹²³I] IBZM SPECT study

BACKGROUND: The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been observed to present a significant elevation of dopamine receptor availability compared to healthy controls. Although it is difficult to measure dopamine levels directly in humans, neurochemical imaging techniques such as single-photon emission computed tomography (SPECT) provide indirect indices of in vivo dopamine synthesis and release, and putative synaptic levels. METHODS: We focused on the role of dopamine postsynaptic regulation using [123I] iodobenzamide (IBZM) SPECT. We compared D2/3 receptor availability between 53 healthy controls and 21 medication-naive patients with recent-onset schizophrenia. RESULT: The mean specific striatal binding showed no significant difference between patients and controls (estimated difference = 0.001; 95% CI -0.11 to 0.11; F = 0.00, df = 1, 69; p = 0.99). There was a highly significant effect of age whereby IBZM binding declined with advancing age [estimated change per decade of age = -0.01(binding ratio); 95% CI -0.01 to -0.004; F = 11.5, df = 1, 69; p = 0.001]. No significant correlations were found between the mean specific striatal binding and psychopathological or cognitive rating scores. CONCLUSIONS: Medication-naïve patients with recent-onset schizophrenia have similar D2/3 receptor availability to healthy controls. We suggest that, rather than focusing exclusively on postsynaptic receptors, future treatments should target the presynaptic control of dopamine synthesis and release

Impaired theta phase coupling underlies frontotemporal dysconnectivity in schizophrenia

Frontotemporal dysconnectivity is a key pathology in schizophrenia. The specific nature of this dysconnectivity is unknown, but animal models imply dysfunctional theta phase coupling between hippocampus and medial prefrontal cortex (mPFC). We tested this hypothesis by examining neural dynamics in 18 participants with a schizophrenia diagnosis, both medicated and unmedicated; and 26 age, sex and IQ matched control subjects. All participants completed two tasks known to elicit hippocampal-prefrontal theta coupling: a spatial memory task (during magnetoencephalography) and a memory integration task. In addition, an overlapping group of 33 schizophrenia and 29 control subjects underwent PET to measure the availability of GABAARs expressing the α5 subunit (concentrated on hippocampal somatostatin interneurons). We demonstrate-in the spatial memory task, during memory recall-that theta power increases in left medial temporal lobe (mTL) are impaired in schizophrenia, as is theta phase coupling between mPFC and mTL. Importantly, the latter cannot be explained by theta power changes, head movement, antipsychotics, cannabis use, or IQ, and is not found in other frequency bands. Moreover, mPFC-mTL theta coupling correlated strongly with performance in controls, but not in subjects with schizophrenia, who were mildly impaired at the spatial memory task and no better than chance on the memory integration task. Finally, mTL regions showing reduced phase coupling in schizophrenia magnetoencephalography participants overlapped substantially with areas of diminished α5-GABAAR availability in the wider schizophrenia PET sample. These results indicate that mPFC-mTL dysconnectivity in schizophrenia is due to a loss of theta phase coupling, and imply α5-GABAARs (and the cells that express them) have a role in this process

Disrupted‐in‐schizophrenia 1 functional polymorphisms and D₂/D₃ receptor availability: A [¹¹C]‐(+)‐PHNO imaging study

The disrupted‐in‐schizophrenia 1 (DISC1) protein has been implicated in a range of biological mechanisms underlying chronic mental disorders such as schizophrenia. Schizophrenia is associated with abnormal striatal dopamine signalling, and all antipsychotic drugs block striatal dopamine 2/3 receptors (D_{2/3}Rs). Importantly, the DISC1 protein directly interacts and forms a protein complex with the dopamine D_{2} receptor (D_{2}R) that inhibits agonist‐induced D_{2}R internalisation. Moreover, animal studies have found large striatal increases in the proportion of D_{2}R receptors in a high affinity state (D_{2}^{high}R in DISC1 rodent models. Here, we investigated the relationship between the three most common polymorphisms altering the amino‐acid sequence of the DISC1 protein (Ser704Cys (rs821616), Leu607Phe (rs6675281) and Arg264Gln (rs3738401)) and striatal D_{2/3}R availability in 41 healthy human volunteers, using [{11}^C] ‐(+)‐PHNO positron emission tomography. We found no association between DISC1 polymorphisms and D_{2/3}R availability in the striatum and D_{2}R availability in the caudate and putamen. Therefore, despite a direct interaction between DISC1 and the D_{2}R, none of its main functional polymorphisms impact striatal D_{2/3}R binding potential, suggesting DISC1 variants act through other mechanisms

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHODS: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation

Dopaminergic organization of striatum is linked to cortical activity and brain expression of genes associated with psychiatric illness

Dopamine signaling is constrained to discrete tracts yet has brain-wide effects on neural activity. The nature of this relationship between local dopamine signaling and brain-wide neuronal activity is not clearly defined and has relevance for neuropsychiatric illnesses where abnormalities of cortical activity and dopamine signaling coexist. Using simultaneous PET-MRI in healthy volunteers, we find strong evidence that patterns of striatal dopamine signaling and cortical blood flow (an index of local neural activity) contain shared information. This shared information links amphetamine-induced changes in gradients of striatal dopamine receptor availability to changes in brain-wide blood flow and is informed by spatial patterns of gene expression enriched for genes implicated in schizophrenia, bipolar disorder, and autism spectrum disorder. These results advance our knowledge of the relationship between cortical function and striatal dopamine, with relevance for understanding pathophysiology and treatment of diseases in which simultaneous aberrations of these systems exist