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Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked to clozapine. Using proton magnetic resonance spectroscopy (1H-MRS), we examined the ability of glutamate and Glx (glutamate plus glutamine) in the anterior cingulate cortex (ACC) and caudate to predict response to antipsychotic treatment. A total of 89 minimally medicated patients with FEP not meeting symptomatic criteria for remission were recruited across two study sites. 1H-MRS and clinical data were acquired at baseline, 2 and 6 weeks. Response was defined as >20% reduction in Positive and Negative Syndrome Scale (PANSS) Total score from baseline to 6 weeks. In the ACC, baseline glutamate and Glx were higher in Non-Responders and significantly predicted response (P n = 42). Overall accuracy was greatest for ACC Glx (69%) and increased to 75% when symptom severity at baseline was included in the model. Glutamate metabolites in the caudate were not associated with response, and there was no significant change in glutamate metabolites over time in either region. These results add to the evidence linking elevations in ACC glutamate metabolites to a poor antipsychotic response. They indicate that glutamate may have utility in predicting response during early treatment of first episode psychosis. Improvements in accuracy may be made by combining glutamate measures with other response biomarkers.

Background Impaired brain metabolism may be central to schizophrenia pathophysiology, but the magnitude and consistency of metabolic dysfunction is unknown. Methods We searched MEDLINE, PsychINFO and EMBASE between 01/01/1980 and 13/05/2021 for studies comparing regional brain glucose metabolism using 18FDG-PET, in schizophrenia/first-episode psychosis v. controls. Effect sizes (Hedges g) were pooled using a random-effects model. Primary measures were regional absolute and relative CMRGlu in frontal, temporal, parietal and occipital lobes, basal ganglia and thalamus. Results Thirty-six studies (1335 subjects) were included. Frontal absolute glucose metabolism (Hedge's g = −0.74 ± 0.54, p = 0.01; I2 = 67%) and metabolism relative to whole brain (g = −0.44 ± 0.34, p = 0.01; I2 = 55%) were lower in schizophrenia v. controls with moderate heterogeneity. Absolute frontal metabolism was lower in chronic (g = −1.18 ± 0.73) v. first-episode patients (g = −0.09 ± 0.88) and controls. Medicated patients showed frontal hypometabolism relative to controls (−1.04 ± 0.26) while metabolism in drug-free patients did not differ significantly from controls. There were no differences in parietal, temporal or occipital lobe or thalamic metabolism in schizophrenia v. controls. Excluding outliers, absolute basal ganglia metabolism was lower in schizophrenia v. controls (−0.25 ± 0.24, p = 0.049; I2 = 5%). Studies identified reporting voxel-based morphometry measures of absolute 18FDG uptake (eight studies) were also analysed using signed differential mapping analysis, finding lower 18FDG uptake in the left anterior cingulate gyrus (Z = −4.143; p = 0.007) and the left inferior orbital frontal gyrus (Z = −4.239; p = 0.02) in schizophrenia. Conclusions We report evidence for hypometabolism with large effect sizes in the frontal cortex in schizophrenia without consistent evidence for alterations in other brain regions. Our findings support the hypothesis of hypofrontality in schizophrenia.

The liberalisation of cannabis laws, the increasing availability and potency of cannabis has renewed concern about the risk of psychosis with cannabis.The objective of the WFSBP task force was to review the literature about this relationship.Converging lines of evidence suggest that exposure to cannabis increases the risk for psychoses ranging from transient psychotic states to chronic recurrent psychosis. The greater the dose, and the earlier the age of exposure, the greater the risk. For some psychosis outcomes, the evidence supports some of the criteria of causality. However, alternate explanations including reverse causality and confounders cannot be conclusively excluded. Furthermore, cannabis is neither necessary nor sufficient to cause psychosis. More likely it is one of the multiple causal components. In those with established psychosis, cannabis has a negative impact on the course and expression of the illness. Emerging evidence also suggests alterations in the endocannabinoid system in psychotic disorders.Given that exposure to cannabis and cannabinoids is modifiable, delaying or eliminating exposure to cannabis or cannabinoids, could potentially impact the rates of psychosis related to cannabis, especially in those who are at high risk for developing the disorder.

There has been increasing interest in the role of mitochondrial dysfunction in the pathophysiology of schizophrenia. Mitochondrial complex one (MCI) dysfunction may represent a mechanism linking bioenergetic impairment with the alterations in dopamine signalling, glutamatergic dysfunction, and oxidative stress found in the disorder. New lines of evidence from novel approaches make it timely to review evidence for mitochondrial involvement in schizophrenia, with a specific focus on MCI. The most consistent findings in schizophrenia relative to controls are reductions in expression of MCI subunits in post-mortem brain tissue (Cohen's d0.8); reductions in MCI function in post-mortem brains (d0.7); and reductions in neural glucose utilisation (d= 0.3 to 0.6). Antipsychotics may affect glucose utilisation, and, at least in vitro, affect MC1. The findings overall are consistent with MCI dysfunction in schizophrenia, but also highlight the need for in vivo studies to determine the link between MCI dysfunction and symptoms in patients. If new imaging tools confirm MCI dysfunction in the disease, this could pave the way for new treatments targeting this enzyme.

Around a quarter of people who experience a first episode of psychosis (FEP) will develop treatment-resistant schizophrenia (TRS), but there are currently no established clinically useful methods to predict this from baseline. We aimed to explore the predictive potential for clozapine use as a proxy for TRS of routinely collected, objective biomedical predictors at FEP onset, and to externally validate the model in a separate clinical sample of people with FEP. We developed and externally validated two risk prediction models to predict up to 8-year risk of clozapine use from FEP using routinely recorded information including age, sex, ethnicity, triglycerides, alkaline phosphatase levels, and lymphocyte counts in forced-entry logistic regression models. We also produced a least-absolute shrinkage and selection operator (LASSO) based model, additionally including neutrophil count, smoking status, body mass index, and random glucose levels. The models were developed using data from two UK psychosis early intervention services (EIS) and externally validated in another UK EIS. Model performance was assessed via discrimination and calibration. We developed the models in 785 patients, and validated externally in 1,110 patients. Both models predicted clozapine use well at internal validation (forced-entry: C 0.70; 95%CI 0.63,0.76; LASSO: 0.69; 95%CI 0.63,0.77). At external validation, discrimination performance reduced (forced-entry: 0.63; 0.58,0.69; LASSO: 0.64; 0.58,0.69) but recovered after re-estimation of the lymphocyte predictor (C: 0.67; 0.62,0.73). Calibration plots showed good agreement between observed and predicted risk in the forced-entry model. We also present a decision-curve analysis and an online data visualisation tool. The use of routinely collected clinical information including blood-based biomarkers taken at FEP onset can help to predict the individual risk of clozapine use, and should be considered equally alongside other potentially useful information such as symptom scores in large-scale efforts to predict psychiatric outcomes.

IntroductionFDOPA PET has been used extensively to image the human brain in many clinical disorders and has the potential to be used for patient stratification and individualized treatment. However, to reach its full and effective clinical translation, FDOPA PET requires both a robust data infrastructure and analytical protocol that are capable of ensuring high quality data and metadata, accurate biological quantification, and replicable results. In this study we evaluate a digital data repository and automated analytical framework for FDOPA PET neuroimaging that can produce an individualised quantification of dopamine synthesis capacity in the living human brain.MethodsThe imaging platform XNAT was used to store the King’s College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. A fully automated analysis pipeline for imaging processing and data quantification was developed in Python and integrated in XNAT using the Docker technology. Reproducibility was assessed in test-retest datasets both in controls and patients with psychosis. The agreement between the automated analysis estimates and the results derived by the manual analysis were compared. Finally, using a sample of healthy controls (N=115), a sensitivity analysis was performed to explore the impact of experimental and demographic variables on the FDOPA PET measures.ResultsThe final data repository includes 892 FDOPA PET scans organized from 23 different studies, collected at five different imaging sites. After removing commercials studies, the infrastructure consisted of 792 FDOPA PET scans from 666 individuals (female 33.9%, healthy controls 29.1%) collected from four different imaging sites between 2004-2021. The automated analysis pipeline provided results that were in agreement with the results from the manual analysis, with a Pearson’s correlation that ranged from 0.64 to 0.99 for Kicer, and from 0.79 to 1.00 for SUVR. The mean absolute difference between the two pipelines ranges from 3.4% to 9.4% for Kicer, and from 2.5% to 12.4% for SUVR. Moreover, we found good reproducibility of the data analysis by the automated pipeline (in the whole striatum for the Kicer: ICC for the controls = 0.71, ICC for the psychotic patients = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p ), with women showing greater dopamine synthesis capacity than men, while the effects of weight, age, injected radioactivity, and scanner, varied by brain region and parameter of interest.ConclusionsCombining information from different neuroimaging studies has allowed us to test comprehensively the automated pipeline for quantification of dopamine synthesis capacity using FDOPA PET data and to validate its replicability and reproducibility performances on a large sample size. This validation process is a necessary methodological step for the development of the clinical application of FDOPA PET as precision medicine biomarker. The proposed infrastructure is generalisable behind the FDOPA radiotracer.

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.

Q.Clear is a Bayesian penalised likelihood (BPL) reconstruction algorithm available on General Electric (GE) Positron Emission Tomography (PET)-Computed Tomography (CT) and PET-Magnetic Resonance (MR) scanners. This algorithm is regulated by a β value which acts as a noise penalisation factor and yields improvements in signal to noise ratio (SNR) in clinical scans, and in contrast recovery and spatial resolution in phantom studies. However, its performance in human brain imaging studies remains to be evaluated in depth. This pilot study aims to investigate the impact of Q.Clear reconstruction methods using different β value versus ordered subset expectation maximization (OSEM) on brain kinetic modelling analysis of low count brain images acquired in the PET-MR.Six [When comparing a standard OSEM reconstruction of 6 iterations/16 subsets and 5 mm filter with Q.Clear with different β values under low counts, the bias and RC were lower for Q.Clear with β100 for the SN (RC = 2.17), Th (RC = 0.08) and GP (RC = 0.22) and with β200 for the St (RC = 0.14), Cd (RC = 0.18)and Pt (RC = 0.10). The p-values in the 2-way ANOVA model corroborate these findings. ICC values obtained for Th, St, GP, Pt and Cd demonstrate good reliability (0.87, 0.99, 0.96, 0.99 and 0.96, respectively). For the SN, ICC values demonstrate poor reliability (0.43).BP

Importance Antidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random. Objective To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year. Data Sources Data used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies’ websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020. Study Selection Analysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study’s end point. Data Extraction and Synthesis Baseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted. Main Outcomes and Measures Log SDs (blnσ̂)were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference inblnσ̂ between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year. Results In the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (blnσ̂, 1.02; 95% CI, 0.99-1.05;P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (blnσ̂, 1.11; 95% CI, 1.01-1.21;P = .02). Conclusions and Relevance Although this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.

Converging lines of evidence from epidemiological, preclinical, and experimental studies indicate that the endocannabinoid system may be involved in the pathophysiology of schizophrenia and suggest that the cannabinoid CB

Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=-0.33,p = 1.2 ×10

With the ongoing coronavirus disease 2019 (COVID-19) pandemic, psychiatrists find themselves in the clinical situation of being asked by patients, family members and patient advocacy societies to help ensure access to clozapine as a medication critical for ongoing patient care. To provide clozapine prescribing guidance and facilitate regulatory agencies modifying laboratory monitoring and/or dispensing requirements, an expert advisory subgroup of the Treatment Response and Resistance in Psychosis working group developed the following background, recommendations and rationale as a consensus statement.

We compliment the authors and journal for ensuring the “Consensus statement on the use of clozapine during the COVID-19 pandemic” was published in a timely fashion. Coronavirus disease 2019 (COVID-19) rapidly transformed into a pandemic, challenging medicine in ways initially not imagined; this is certainly the case not only for treatmentresistant schizophrenia and for reasons related to clozapine, but also the patient population.

BACKGROUND: Exposure to developmental psychological stressors, adversity and trauma increases the risk of psychosis. Converging evidence indicates that developmental stress and trauma induce long-term changes in dopaminergic functioning which could give rise to a latent vulnerability to mental illness. I will therefore present a synthesis of the existent human and animal literature examining how developmental trauma and stress alters dopaminergic functioning in adulthood. In addition, I will present results of a study using positron emission tomography (PET) of dopamine synthesis capacity and the acute stress response in healthy adults exposed to developmental and adult psychosocial adversity. METHODS: We conducted a systematic review of the animal and human literature using a combination of three superordinate concepts including ‘childhood’, ‘trauma’ and ‘dopamine’ terms. The PET study used [18F]-DOPA in a case-control design (n=17 per group), with one group exposed to high levels of developmental and adult psychosocial adversity and another group exposed to low levels. Acute psychological stress was induced using the Montreal Stress Task. RESULTS: 140 studies were included in our review. Developmental stress and trauma results in long-term, complex changes in dopaminergic function across key cognitive domains including sensitization of the striatal dopaminergic response to stressors and frontal hypodopaminergia. Divergent alterations in dopaminergic function occurred depending on the timing of developmental exposure potentially representing critical periods. Developmental stress exposure potentiates aspects of dopaminergic processing including amplifying threat-related signaling in the ventral (limbic) striatum. This may occur alongside dopaminergic blunting in the amygdala resulting in deficits in fear extinction, impairing the ability to distinguish safe from unsafe environments. In our PET experiment, within people without psychosis long-term psychosocial adversity was associated with reduced baseline dopamine synthesis capacity and de-coupling between striatal dopamine and the acute stress response. Conclusions Developmental trauma exposure is likely to be inducing latent vulnerability to psychosis by producing lasting changes in reward, threat and executive processing. Further studies are needed to investigate the precise mechanisms underlying how trauma-induced changes in dopaminergic function induce vulnerability to psychosis and, in parallel, how dopaminergic processes may confer resilience.

This chapter presents case histories illustrating key aspects of the treatment of schizophrenia based on the authors’ clinical experience of patients that they have treated over the years, although identifying details have been changed. The art of clinical practice includes interpreting and applying evidence to help individual patients who often do not fit into the categories used in clinical trials. The cases show the application of evidence, and also its limitations, in real-world settings. This emphasizes the need for the evidence discussed throughout this book to be considered in the individual context of each patient. You will see variation in the approaches taken by the expert clinicians discussing their cases, reflecting how they interpret and apply evidence in a given clinical context. Each case is followed by a series of learning points and links to other chapters in the book where the issue is considered further.

Clear, accepted definitions of treatment resistance and response are needed so that clinical trials of treatments can be compared, and evidence can be meaningfully interpreted to inform clinical practice. In this chapter, we review the definitions of treatment response and resistance used in clinical trials, highlighting the variability in definitions used across studies, as well as a number of problems with the definitions used, including mixing treatment-intolerant patients with treatment-resistant patients and limited evaluation of the adequacy of treatment in many cases. The chapter then summarizes the work undertaken by the Treatment Response and Resistance in Psychosis working group to produce consensus guidelines and benchmarks to address these issues. Also reviewed are the principles underlying the concept of resistance developed by the working group. Finally, the chapter discusses the implications of these findings for clinical practice.

Schizophrenia and related disorders are common, affecting about 1 in 100 people, and typically begin in late adolescence and early adulthood, when people are in the prime of their lives. They are also major causes of disease burden globally and are amongst the top causes of disability in working-age adults in the world. Carers are significantly affected by the burden of these disorders, which are a leading cause of healthcare costs. Schizophrenia and related disorders are also major causes of premature mortality due to suicide and elevated rates of comorbid conditions, particularly cardiometabolic disorders. It is clear that the stakes are high, and this book aims to help the clinician give their patients the best odds of getting better.

Ethnic minority individuals have an increased risk of developing a psychotic disorder, particularly if they live in areas of ethnic segregation, or low own group ethnic density. The neurobiological mechanisms underlying this ethnic minority associated risk are unknown. We used functional MRI to investigate neural responses to faces of different ethnicity, in individuals of black ethnicity, and a control group of white British ethnicity individuals.In total 20 individuals of black ethnicity, and 22 individuals of white British ethnicity underwent a 3T MRI scan while viewing faces of black and white ethnicity. Own group ethnic density was calculated from the 2011 census. Neighbourhood segregation was quantified using the Index of Dissimilarity method.At the within-group level, both groups showed greater right amygdala activation to outgroup faces. Between groups, the black ethnicity group showed greater right amygdala activation to white faces, compared to the white ethnicity group. Within the black ethnicity group, individuals living in areas of lower own group ethnic density showed greater right amygdala reactivity to white faces (r = -0.61, p = 0.01).This is the first time an increased amygdala response to white faces has been demonstrated in individuals of black ethnicity. In the black ethnicity group, correlations were observed between amygdala response and neighbourhood variables associated with increased psychosis risk. These results may have relevance for our understanding of the increased rates of paranoia and psychotic disorders in ethnic minority individuals.

Recent decades have seen a surge of research interest in the phenomenon of healthy individuals who experience auditory verbal hallucinations, yet do not exhibit distress or need for care. The aims of the present systematic review are to provide a comprehensive overview of this research and examine how healthy voice-hearers may best be conceptualised in relation to the diagnostic versus ‘quasi-‘ and ‘fully-dimensional’ continuum models of psychosis. A systematic literature search was conducted, resulting in a total of 398 article titles and abstracts that were scrutinised for appropriateness to the present objective. Seventy articles were identified for full-text analysis, of which 36 met criteria for inclusion. Subjective perceptual experience of voices, such as loudness or location (i.e., inside/outside head), is similar in clinical and non-clinical groups, although clinical voice-hearers have more frequent voices, more negative voice content, and an older age of onset. Groups differ significantly in beliefs about voices, control over voices, voice-related distress, and affective difficulties. Cognitive biases, reduced global functioning, and psychiatric symptoms such as delusions, appear more prevalent in healthy voice-hearers than in healthy controls, yet less than in clinical samples. Transition to mental health difficulties is increased in HVHs, yet only occurs in a minority and is predicted by previous mood problems and voice distress. Whilst healthy voice-hearers show similar brain activity during hallucinatory experiences to clinical voice-hearers, other neuroimaging measures, such as mismatch negativity, have been inconclusive. Risk factors such as familial and childhood trauma appear similar between clinical and non-clinical voice-hearers. Overall the results of the present systematic review support a continuum view rather than a diagnostic model, but cannot distinguish between ‘quasi’ and ‘fully’ dimensional models. Healthy voice-hearers may be a key resource in informing transdiagnostic approaches to research of auditory hallucinations., Highlights • Subjective perceptual experiences of voices appear similar in clinical and non-clinical groups. • Healthy voice-hearers hear voices less frequently, with less negative content, more perceived control and from an earlier age. • Healthy and clinical voice-hearers differ in beliefs about voices, voice-related distress, and affective difficulties. • Healthy voice-hearers show more cognitive biases, psychiatric symptoms and functional impairments than healthy controls. • Risk factors such as familial and childhood trauma appear similar between clinical and non-clinical voice-hearers.

The human brain can adapt to overcome injury even years after an initial insult. One hypothesis states that early brain injury survivors, by taking advantage of critical periods of high plasticity during childhood, should recover more successfully than those who suffer injury later in life. This hypothesis has been challenged by recent studies showing worse cognitive outcome in individuals with early brain injury, compared with individuals with later brain injury, with working memory particularly affected. We invited individuals who suffered perinatal brain injury (PBI) for an fMRI/diffusion MRI tractography study of working memory and hypothesized that, 30 years after the initial injury, working memory deficits in the PBI group would remain, despite compensatory activation in areas outside the typical working memory network. Furthermore we hypothesized that the amount of functional reorganization would be related to the level of injury to the dorsal cingulum tract, which connects medial frontal and parietal working memory structures. We found that adults who suffered PBI did not significantly differ from controls in working memory performance. They exhibited less activation in classic frontoparietal working memory areas and a relative overactivation of bilateral perisylvian cortex compared with controls. Structurally, the dorsal cingulum volume and hindrance-modulated orientational anisotropy was significantly reduced in the PBI group. Furthermore there was uniquely in the PBI group a significant negative correlation between the volume of this tract and activation in the bilateral perisylvian cortex and a positive correlation between this activation and task performance. This provides the first evidence of compensatory plasticity of the working memory network following PBI.

Background: This work addresses the existing and emerging evidence of overlap within the environmental and genetic profiles of multiple sclerosis (MS) and schizophrenia. Aims: To investigate whether a genetic risk factor for MS (rs703842), whose variation is indicative of vitamin D status in the disorder, could also be a determinant of vitamin D status in chronic psychosis patients. Methods: A cohort of 224 chronic psychosis cases was phenotyped and biologically profiled. The relationship between rs703842 and physiological vitamin D status in the blood plasma was assessed by logistic regression. Deficiency was defined as a blood plasma concentration below 10 ng/µl. Potential environmental confounders of the vitamin D status were considered as part of the analysis. Results: We report suggestive evidence of an association with vitamin D status in established psychosis (ßstandardized=0.51, P=0.04). The logistic model fit significantly benefited from controlling for body mass index, depression and ethnicity (χ2=91.7; 2 degrees of freedom (df); P=1.2×1020). Conclusions: The results suggest that, in addition to lifestyle changes that accompany the onset of illness, vitamin D dysregulation in psychosis has a genetic component that links into MS. Further, comprehensive studies are needed to evaluate this prospect.

The early developments of brain positron emission tomography (PET), including the methodological advances that have driven progress, are outlined. The considerable past achievements of brain PET have been summarized in collaboration with contributing experts in specific clinical applications including cerebrovascular disease, movement disorders, dementia, epilepsy, schizophrenia, addiction, depression and anxiety, brain tumors, drug development, and the normal healthy brain. Despite a history of improving methodology and considerable achievements, brain PET research activity is not growing and appears to have diminished. Assessments of the reasons for decline are presented and strategies proposed for reinvigorating brain PET research. Central to this is widening the access to advanced PET procedures through the introduction of lower cost cyclotron and radiochemistry technologies. The support and expertize of the existing major PET centers, and the recruitment of new biologists, bio-mathematicians and chemists to the field would be important for such a revival. New future applications need to be identified, the scope of targets imaged broadened, and the developed expertize exploited in other areas of medical research. Such reinvigoration of the field would enable PET to continue making significant contributions to advance the understanding of the normal and diseased brain and support the development of advanced treatments.

Background: The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission is fundamental to the development of the disorder. In addition, its potential to mediate neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomic changes in schizophrenia. Here we determine whether changes in brain glutamate are present in subjects at ultra high risk of developing psychosis and whether these changes are related to reductions in cortical gray matter volume.Methods: Twenty-seven individuals with an at-risk mental state and a group of 27 healthy volunteers underwent proton magnetic resonance spectroscopy and volumetric proton magnetic resonance imaging using a 3-Tesla scanner. Glutamate and glutamine levels were measured in anterior cingulate, left hippocampus, and left thalamus. These measures were then related to cortical gray matter volume.Results: At-risk mental state (ARMS) subjects had significantly lower levels of glutamate than control subjects in the thalamus (p Conclusions: This study provides the first evidence that brain glutamate function is perturbed in people with prodromal signs of schizophrenia and that glutamatergic dysfunction is associated with a reduction in gray matter volume in brain regions thought to be critical to the pathogenesis of the disorder. These findings support the hypothesis that drugs affecting the glutamate system may be of benefit in the early stages of psychotic illness.