Mesostriatal Dopaminergic Circuit Dysfunction in Schizophrenia: A Multimodal Neuromelanin-sensitive MRI and [18F]-DOPA PET Study.

BACKGROUND: Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin-sensitive MRI (NM-MRI) provides a marker of long-term dopamine function. We examined if midbrain NM-MRI contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia relative to controls and if this correlated with dopamine synthesis capacity. METHODS: N=154 participants (n=74 individuals with schizophrenia and n=80 healthy controls) underwent NM-MRI of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n=38) also received [18F]-DOPA PET to measure dopamine synthesis capacity (Kicer) in the SN-VTA and striatum. RESULTS: SN-VTA NM-CNR was significantly higher in patients with schizophrenia relative to controls (effect size=0.38, p=0.019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA Kicer positively correlated with SN-VTA NM-CNR (r=0.44, p=0.005) and striatal Kicer (r=0.71, p<0.001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal Kicer (r=0.53, p=0.005) and that this relationship appeared strongest between the ventral SN-VTA and associative striatum in schizophrenia. CONCLUSIONS: Our results suggest that neuromelanin levels are higher in patients with schizophrenia relative to controls, particularly in midbrain regions that project to parts of the striatum which receive innervation from the limbic and association cortices. The direct relationship between measures of neuromelanin and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and, thus, potential therapeutic targets.

Perturbed iron biology in the prefrontal cortex of people with schizophrenia.

Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

Disruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness.

Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory performance and white matter (WM) microstructure in hippocampal-prefrontal pathways in schizophrenia-spectrum disorder (SSDs). Here, we investigated these relationships in individuals with first-episode psychosis (FEP) and chronic schizophrenia-spectrum disorders (SSDs) using tractography analysis designed to interrogate the microstructure of WM tracts in the hippocampal-prefrontal pathway. Measures of WM microstructure (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]) were obtained for 47 individuals with chronic SSDs, 28 FEP individuals, 52 older healthy controls, and 27 younger healthy controls. Tractography analysis was performed between the hippocampus and three targets involved in hippocampal-prefrontal connectivity (thalamus, amygdala, nucleus accumbens). Measures of WM microstructure were then examined in relation to episodic memory performance separately across each group. Both those with FEP and chronic SSDs demonstrated impaired episodic memory performance. However, abnormal WM microstructure was only observed in individuals with chronic SSDs. Abnormal WM microstructure in the hippocampal-thalamic pathway in the right hemisphere was associated with poorer memory performance in individuals with chronic SSDs. These findings suggest that disruptions in WM microstructure in the hippocampal-prefrontal pathway may contribute to memory impairments in individuals with chronic SSDs but not FEP.

Clinical characteristics and impacts of HIV infection in people with bipolar disorders.

BACKGROUND: People with bipolar disorders (BD) may be at increased risk of Human Immunodeficiency Virus (HIV) infection but our understanding of the impacts of HIV infection on psychiatric outcomes is poor. This study aimed to examine the prevalence, temporal relationship, and clinical impact of HIV infection in people with BD. METHODS: In this retrospective case-control study, anonymised electronic case records of patients with BD who had been under the care of South London and Maudsley mental health services were used for data extraction. 54 HIV+ people with BD were identified and compared to a matched control group of 54 HIV- people with BD. RESULTS: The prevalence of HIV co-morbidity in the BD population was around 1%. 76% of HIV+ BD men identified as men who have sex with men (MSM). 65% of the HIV+ BD group were diagnosed with BD before becoming HIV+. The HIV+ BD group experienced significantly higher rates of stimulant, GBL/GHB and psychedelic use compared to the HIV- BD group. 85% of the HIV+ BD group were recorded as taking antiretroviral medications. LIMITATIONS: Retrospective and cross-sectional study design, and a relatively small sample size CONCLUSIONS: The prevalence of HIV comorbidity in BD was comparable to the local general population. HIV infection in BD is associated with MSM status and stimulant, GHB/GBL and psychedelics use suggesting that HIV prevention strategies should particularly target these groups. Lower use of antiretroviral medications by people with BD underlines the importance of engaging HIV+ BD people in HIV services.

Use of antidepressants with pharmacogenetic prescribing guidelines in a 10-year depression cohort of adult primary care patients.

OBJECTIVE: To describe the usage patterns of antidepressants with published CYP2D6- and CYP2C19-based prescribing guidelines among depressed primary care patients and estimate the proportion of patients taking antidepressants not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer status. METHODS: Medication use and pharmacogenetic testing results were collected on 128 primary care patients enrolled in a 10-year depression cohort study. At each 12-month interval, we calculated the proportion of patients that: (1) reported use of one or more of the 13 antidepressant medications (i.e. amitriptyline, citalopram, escitalopram, clomipramine, desipramine, doxepin, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine) with published CYP2D6- and CYP2C19-based prescribing guidelines, (2) were taking an antidepressant that was not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer phenotype, and (3) switched medications from the previous 12-month interval. RESULTS: The annual proportion of individuals taking an antidepressant with a CYP2D6- and CYP2C19-based prescribing guidelines ranged from 45 to 84%. The proportion of participants that used an antidepressant that was not recommended for them, based on available CYP2D6 and CYP2C19 metabolizer phenotype, ranged from 18 to 29% and these individuals tended to switch medications more frequently (10%) compared to their counterparts taking medication aligned with their metabolizer phenotype (6%). CONCLUSION: One-quarter of primary care patients used an antidepressant that was not recommended for them based on CYP2D6- and CYP2C19-based prescribing guidelines and switching medications tended to be more common in this group. Studies to determine the impact of CYP2D6 and CYP2C19 genotyping on reducing gene-antidepressant mismatches are warranted.

The ubiquitin proteasome system and schizophrenia.

The ubiquitin-proteasome system is a master regulator of neural development and the maintenance of brain structure and function. It influences neurogenesis, synaptogenesis, and neurotransmission by determining the localisation, interaction, and turnover of scaffolding, presynaptic, and postsynaptic proteins. Moreover, ubiquitin-proteasome system signalling transduces epigenetic changes in neurons independently of protein degradation and, as such, dysfunction of components and substrates of this system has been linked to a broad range of brain conditions. Although links between ubiquitin-proteasome system dysfunction and neurodegenerative disorders have been known for some time, only recently have similar links emerged for neurodevelopmental disorders, such as schizophrenia. Here, we review the components of the ubiquitin-proteasome system that are reported to be dysregulated in schizophrenia, and discuss specific molecular changes to these components that might, in part, explain the complex causes of this mental disorder.

Exploring Heterogeneity on the Wisconsin Card Sorting Test in Schizophrenia Spectrum Disorders: A Cluster Analytical Investigation.

OBJECTIVES: The Wisconsin Card Sorting Test (WCST) is a complex measure of executive function that is frequently employed to investigate the schizophrenia spectrum. The successful completion of the task requires the interaction of multiple intact executive processes, including attention, inhibition, cognitive flexibility, and concept formation. Considerable cognitive heterogeneity exists among the schizophrenia spectrum population, with substantive evidence to support the existence of distinct cognitive phenotypes. The within-group performance heterogeneity of individuals with schizophrenia spectrum disorder (SSD) on the WCST has yet to be investigated. A data-driven cluster analysis was performed to characterise WCST performance heterogeneity. METHODS: Hierarchical cluster analysis with k-means optimisation was employed to identify homogenous subgroups in a sample of 210 schizophrenia spectrum participants. Emergent clusters were then compared to each other and a group of 194 healthy controls (HC) on WCST performance and demographic/clinical variables. RESULTS: Three clusters emerged and were validated via altered design iterations. Clusters were deemed to reflect a relatively intact patient subgroup, a moderately impaired patient subgroup, and a severely impaired patient subgroup. CONCLUSIONS: Considerable within-group heterogeneity exists on the WCST. Identification of subgroups of patients who exhibit homogenous performance on measures of executive functioning may assist in optimising cognitive interventions. Previous associations found using the WCST among schizophrenia spectrum participants should be reappraised. (JINS, 2019, 25, 750-760).

Blood and brain protein levels of ubiquitin-conjugating enzyme E2K (UBE2K) are elevated in individuals with schizophrenia.

A number of recent studies have suggested the ubiquitin proteasome system (UPS) in schizophrenia is dysfunctional. The purpose of this study was to investigate UBE2K, a ubiquitin-conjugating (E2) enzyme within the UPS that has been associated with psychosis symptom severity, in the blood and brain of individuals with schizophrenia. Whole blood and erythrocytes from 128 (71 treatment-resistant schizophrenia, 57 healthy controls) individuals as well as frozen dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) post-mortem samples from 74 (37 schizophrenia, 37 controls) individuals were obtained. UBE2K gene expression was assayed in whole blood and DLPFC samples, whereas protein levels were assayed in erythrocytes and OFC samples. Elevated levels of UBE2K mRNA were observed in whole blood of individuals with schizophrenia (p = 0.03) but not in the DLPFC, while protein levels were raised in erythrocytes and the OFC (p < 0.001 and p = 0.002 respectively). Findings were not better explained by age, smoking, clozapine plasma levels or duration of illness. Although blood and brain samples were derived from independent samples, our findings suggest peripheral protein levels of UBE2K may serve as a surrogate of brain levels and further supports the notion of UPS dysfunction in schizophrenia. Future studies to determine the pathophysiological effects of elevated UBE2K protein levels in the brain of those with schizophrenia are warranted.

Elevated ubiquitinated proteins in brain and blood of individuals with schizophrenia.

Dysregulation of the ubiquitin proteasome system (UPS) has been linked to schizophrenia but it is not clear if this dysregulation is detectable in both brain and blood. We examined free mono-ubiquitin, ubiquitinated proteins, catalytic ubiquitination, and proteasome activities in frozen postmortem OFC tissue from 76 (38 schizophrenia, 38 control) matched individuals, as well as erythrocytes from 181 living participants, who comprised 30 individuals with recent onset schizophrenia (mean illness duration = 1 year), 63 individuals with 'treatment-resistant' schizophrenia (mean illness duration = 17 years), and 88 age-matched participants without major psychiatric illness. Ubiquitinated protein levels were elevated in postmortem OFC in schizophrenia compared to controls (p = <0.001, AUC = 74.2%). Similarly, individuals with 'treatment-resistant' schizophrenia had higher levels of ubiquitinated proteins in erythrocytes compared to those with recent onset schizophrenia (p < 0.001, AUC = 65.5%) and controls (p < 0.001, AUC = 69.4%). The results could not be better explained by changes in proteasome activity, demographic, medication, or tissue factors. Our results suggest that ubiquitinated protein formation may be abnormal in both the brain and erythrocytes of those with schizophrenia, particularly in the later stages or specific sub-groups of the illness. A derangement in protein ubiquitination may be linked to pathogenesis or neurotoxicity in schizophrenia, and its manifestation in the blood may have prognostic utility.

The effects of a muscarinic receptor 1 gene variant on executive and non-executive cognition in schizophrenia spectrum disorders.

Individuals with schizophrenia who are homozygous at the c.267C > A (rs2067477) single nucleotide polymorphism within the muscarinic M1 receptor gene have been reported to perform less well on the Wisconsin Card Sorting Test (WCST). We investigated if rs2067477 genotype variation influenced WCST performance and non-executive cognition cross-diagnostically in a sample of 147 schizophrenia spectrum participants (SSD) and 294 healthy controls. We were unable to detect any significant differences in executive and non-executive cognitive performance across genotype. A broader genetic focus should be considered when investigating the association between the muscarinic system and cognition in SSD.

An Interleukin-1 beta (IL1B) haplotype linked with psychosis transition is associated with IL1B gene expression and brain structure.

We investigated IL1B genetic variation previously associated with risk for transition to psychosis for its association with gene expression in human post-mortem dorsolateral prefrontal cortex (DLPFC) from 74 (37 schizophrenia, 37 control) individuals and brain structure in 92 (44 schizophrenia, 48 control) living individuals. The IL1B A-G-T 'risk for psychosis transition' haplotype (rs16944|rs4848306|rs12621220) was associated with upregulation of IL1B mRNA expression in the DLPFC as well as reduced total grey matter and left middle frontal volumes and enlarged left lateral ventricular volume. Our results suggest IL1B genetic variation may confer psychosis risk via elevated mRNA expression and/or brain structure abnormalities.

Systematic review and critical appraisal of child abuse measurement instruments.

Child abuse is a major public health concern and a strong predictor of adult psychopathology. However, a consensus on how best to measure child abuse is not evident. This review aimed to critically appraise the methodological quality and measurement properties of published child abuse measures, examined the strength of evidence of these instruments for research use using the COnsensus-based Standards for the selection of health Measurement InstrumeNts (COSMIN) checklist and determined which measures were capable of providing information on the developmental timing of abuse. Systematic search of electronic databases identified 52 eligible instruments from 2095 studies. Only 15% (n = 8) of the instruments had strong to moderate levels of evidence for three or more of the nine COSMIN criteria. No instrument had adequate levels of evidence for all criteria, and no criteria were met by all instruments. Our results indicate there is no single instrument that is superior to all others across settings and populations. The availability of measures capable of capturing the effects of child abuse on brain development and associated behavioral phenotypes are limited. Refined instruments with a focus on capturing abuse events during development are warranted in addition to further evaluation of the psychometric properties of these instruments.

Depression, fatigue and neurocognitive deficits in chronic hepatitis C.

Patients with chronic hepatitis C virus (HCV) infection experience a range of symptoms including depression, fatigue and neurocognitive deficits, impairing quality of life. Depression, in particular, may be reactive to increased psychosocial stress, and the physical symptoms of advanced HCV or associated comorbidities. However, even patients at an early stage of HCV infection, with minimal hepatic inflammation or comorbidities, report more depressive symptoms and fatigue than the general population. Similarly, specific neurocognitive deficits occur in early stage HCV infection and are independent of the presence of depression or encephalopathy. Therefore, intracerebral neurobiological changes associated with HCV may potentially explain these symptoms. These changes may arise from infiltration of the brain by peripherally induced cytokines, as well as direct neuropathic effects of HCV viral particles penetrating the blood-brain barrier. These phenomena parallel those reported in human immunodeficiency virus (HIV) infection. HCV-associated intracerebral changes include upregulated inflammatory responses, altered neurotransmitter levels, hormonal dysregulation, and release of neurotoxic substances. These may subsequently lead to abnormal neuronal conduction and function in areas of the brain governing affective responses, emotional processing, motivation, attention and concentration. Although direct-acting antiviral medications lead to high rates of HCV clearance, intracerebral changes may not be subsequently reversed and symptoms of depression, fatigue and neurocognitive deficits may persist. There is an ongoing role for multidisciplinary care and pharmacotherapy to manage these symptoms in HCV patients. Furthermore, there may be opportunities for future therapies to specifically target and ameliorate HCV-associated intracerebral changes.

Graphene foam as a biocompatible scaffold for culturing human neurons.

In this study, we explore the use of electrically active graphene foam as a scaffold for the culture of human-derived neurons. Human embryonic stem cell (hESC)-derived cortical neurons fated as either glutamatergic or GABAergic neuronal phenotypes were cultured on graphene foam. We show that graphene foam is biocompatible for the culture of human neurons, capable of supporting cell viability and differentiation of hESC-derived cortical neurons. Based on the findings, we propose that graphene foam represents a suitable scaffold for engineering neuronal tissue and warrants further investigation as a model for understanding neuronal maturation, function and circuit formation.

Downregulation of plasma SELENBP1 protein in patients with recent-onset schizophrenia.

Upregulation of selenium binding protein 1 (SELENBP1) mRNA expression has been reported in schizophrenia, primarily in the dorsolateral prefrontal cortex. However, peripheral blood studies are limited and results are inconsistent. In this study, we examined SELENBP1 mRNA expression in whole blood and protein expression in plasma from patients with recent-onset schizophrenia (n = 30), treatment-resistant schizophrenia (n = 71) and healthy controls (n = 57). We also examined the effects of SELENBP1 genetic variation on gene and protein expression. We found lower SELENBP1 plasma protein levels in patients with recent-onset schizophrenia (p = 0.042) but not in treatment-resistant schizophrenia (p = 0.81). Measurement of peripheral mRNA levels showed no difference between treatment-resistant schizophrenia and healthy controls (p = 0.234) but clozapine plasma levels (p = 0.036) and duration of illness (p = 0.028) were positively correlated with mRNA levels. Genetic variation was not associated with mRNA or protein expression. Our data represent the first peripheral proteomic study of SELENBP1 in schizophrenia and suggest that plasma SELENBP1 protein is downregulated in patients with recent-onset schizophrenia.

Schizophrenia genetics in the genome-wide era: a review of Japanese studies.

The introduction of the genome-wide association study transformed schizophrenia genetics research and has promoted a genome-wide mindset that has stimulated the development of genomic technology, enabling departures from the traditional candidate gene approach. As result, we have witnessed a decade of major discoveries in schizophrenia genetics and the development of genome-wide approaches to the study of copy number variants. These genomic technologies have primarily been applied in populations of European descent. However, more recently both genome-wide association study and copy number variant studies in Asian populations have begun to emerge. In this invited review, we provide concise summaries of the schizophrenia genome-wide association study and copy number variant literature with specific focus on studies conducted in the Japanese population. When applicable, we compare findings observed in the Japanese population with those found in other populations. We conclude with recommendations for future research in schizophrenia genetics, relevant to Japan and beyond.