Overcoming the barriers to identifying and managing treatment-resistant schizophrenia and to improving access to clozapine: A narrative review and recommendation for clinical practice.

Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine remains underused. However, variations in clozapine utilization across geographic and clinical settings suggest that it could be possible to improve its use. In this narrative review and expert opinion, we summarized information available in the literature on the mechanisms of action, effectiveness, and potential adverse events of clozapine. We identified barriers leading to discouragement in clozapine prescription internationally, and we proposed practical solutions to overcome each barrier. One of the main obstacles identified to the use of clozapine is the lack of appropriate training for physicians: we highlighted the need to develop specific professional programs to train clinicians, both practicing and in residency, on the relevance and efficacy of clozapine in TRS treatment, initiation, maintenance, and management of potential adverse events. This approach would facilitate physicians to identify eligible patients and offer clozapine as a treatment option in the early stage of the disease. We also noted that increasing awareness of the benefits of clozapine among healthcare professionals, people with TRS, and their caregivers can help promote the use of clozapine. Educational material, such as leaflets or videos, could be developed and distributed to achieve this goal. The information provided in this article may be useful to improve disease burden and support healthcare professionals, patients, and caregivers navigating the complex pathways to TRS management.

Mitochondrial complex I density is associated with IQ and cognition in cognitively healthy adults: an in vivo [18F]BCPP-EF PET study.

BACKGROUND: Mitochondrial function plays a key role in regulating neurotransmission and may contribute to general intelligence. Mitochondrial complex I (MC-I) is the largest enzyme of the respiratory chain. Recently, it has become possible to measure MC-I distribution in vivo, using a novel positron emission tomography tracer [18F]BCPP-EF, thus, we set out to investigate the association between MC-I distribution and measures of cognitive function in the living healthy brain. RESULTS: Analyses were performed in a voxel-wise manner and identified significant associations between [18F]BCPP-EF DVRCS-1 in the precentral gyrus and parietal lobes and WAIS-IV predicted IQ, WAIS-IV arithmetic and WAIS-IV symbol-digit substitution scores (voxel-wise Pearson's correlation coefficients transformed to Z-scores, thresholded at Z = 2.3 family-wise cluster correction at p < 0.05, n = 16). Arithmetic scores were associated with middle frontal and post-central gyri tracer uptake, symbol-digit substitution scores were associated with precentral gyrus tracer uptake. RAVLT recognition scores were associated with [18F]BCPP-EF DVRCS-1 in the middle frontal gyrus, post-central gyrus, occipital and parietal regions (n = 20). CONCLUSIONS: Taken together, our findings support the theory that mitochondrial function may contribute to general intelligence and indicate that interindividual differences in MC-I should be a key consideration for research into mitochondrial dysfunction in conditions with cognitive impairment.

Corrigendum: The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: a 1H-MRS study in first-episode psychosis patients.

[This corrects the article DOI: 10.3389/fpsyt.2022.967941.].

Histamine-3 Receptor Availability and Glutamate Levels in the Brain: A PET-1H-MRS Study of Patients With Schizophrenia and Healthy Controls.

BACKGROUND: The histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions. METHODS: We employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest. RESULTS: We found significant inverse relationships between tracer uptake and Glu (r = -0.66, P = .02) and Glx (r = -0.62, P = .04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, P = .56, Glx: r = 0.10, P = .75). We also found a significant difference in striatal (F1,20 = 6.00, P = .02) and ACC (F1,19 = 4.75, P = .04) Glx levels between groups. CONCLUSIONS: These results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling.

Immune response to vaccination in people with psychotic disorders relative to healthy controls: prospective study of SARS-CoV-2 vaccination.

This prospective study examines the immune response to SARS-CoV-2 vaccination in patients with psychotic disorders compared with healthy volunteers. Participants were recruited naturalistically as part of the UK's COVID-19 vaccination programme. Prior to receiving their first COVID-19 vaccine, blood samples were provided by participants to examine anti-SARS-CoV-2 immunoglobulins (IgG) at baseline, followed by a repeat assay 1 month after receiving their first vaccine to assess vaccine response. The increase of IgG levels from baseline to 1 month post-vaccination was significantly lower in patients compared with controls, supporting evidence of impaired vaccine response in people with psychotic disorders. When excluding patients treated with clozapine from the analysis, this difference was no longer significant, suggesting that effects may be particularly marked in people taking clozapine.

Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis.

BACKGROUND: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder. METHODS: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation. FINDINGS: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented. INTERPRETATION: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores. FUNDING: German Research Foundation (grant number: 428509362).

Gamma Oscillations and Potassium Channel Modulation in Schizophrenia: Targeting GABAergic Dysfunction.

Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with schizophrenia. Voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels on GABAergic interneurons are critical to the generation of gamma oscillations suggesting that targeting Kv3.1/3.2 could augment GABAergic function and modulate gamma oscillation generation. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on resting state frontal gamma power in people with schizophrenia. We found a significant positive correlation between frontal resting gamma (35-45 Hz) power (n = 22, r = 0.613, P < .002) and positive and negative syndrome scale (PANSS) positive symptom severity. We also found a significant reduction in frontal gamma power (t13 = 3.635, P = .003) from baseline in patients who received AUT00206. This provides initial evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address gamma oscillation abnormalities in schizophrenia.

How to classify antipsychotics: time to ditch dichotomies?

The dichotomies of 'typical/atypical' or 'first/second generation' have been employed for several decades to classify antipsychotics, but justification for their use is not clear. In the current analysis we argue that this classification is flawed from both clinical and pharmacological perspectives. We then consider what approach should ideally be employed in both clinical and research settings.

Schizophrenia: from neurochemistry to circuits, symptoms and treatments.

Schizophrenia is a leading cause of global disability. Current pharmacotherapy for the disease predominantly uses one mechanism - dopamine D2 receptor blockade - but often shows limited efficacy and poor tolerability. These limitations highlight the need to better understand the aetiology of the disease to aid the development of alternative therapeutic approaches. Here, we review the latest meta-analyses and other findings on the neurobiology of prodromal, first-episode and chronic schizophrenia, and the link to psychotic symptoms, focusing on imaging evidence from people with the disorder. This evidence demonstrates regionally specific neurotransmitter alterations, including higher glutamate and dopamine measures in the basal ganglia, and lower glutamate, dopamine and γ-aminobutyric acid (GABA) levels in cortical regions, particularly the frontal cortex, relative to healthy individuals. We consider how dysfunction in cortico-thalamo-striatal-midbrain circuits might alter brain information processing to underlie psychotic symptoms. Finally, we discuss the implications of these findings for developing new, mechanistically based treatments and precision medicine for psychotic symptoms, as well as negative and cognitive symptoms.

Dopaminergic-related Anatomical Pattern of Dorsal Striatum in Schizophrenia.

Striatal dopaminergic overactivity was hypothesized as the core pathophysiology of schizophrenia. However, morphological alterations of striatum in schizophrenia remains exclusive, largely because brain regional heterogeneity limited traditional group-mean based approach. Leveraging third-party brain maps of neurotransmitter and cognition behaviours, we developed a pattern-based representation feature score (ReFS) to investigate structural spatial pattern variation in schizophrenia. Structural ReFS of subcortical regions, particularly the striatum, were linked to schizophrenia diagnosis, symptom severity, and genetic susceptibility. Dopaminergic-ReFS of striatum was increased in schizophrenia patients and reliably reproduced across 13 datasets. The pattern-based ReFS effectively captured the shared genetic pathways underlying both schizophrenia and striatum. The results provide convergent, multimodal suggest the central role of striatal spatial patterns in schizophrenia psychopathologies and and open new avenues to develop individualized treatments for psychotic disorders.

Placebo effects in mental health disorders: protocol for an umbrella review.

INTRODUCTION: Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them through placebo-controlled trials. However, the magnitude of the placebo response in randomised controlled trials to test medications may be substantial, affecting their interpretation. Therefore, improved understanding of the patient, trial and mental disorder factors that influence placebo responses would inform clinical trial design to better detect active treatment effects. There is a growing literature exploring the placebo response within specific mental health disorders, but no overarching synthesis of this research has been produced to date. We present a protocol for an umbrella review of systematic reviews and/or meta-analyses in which we aim to understand the effect size and potential predictors of placebo response within, and across, mental health disorders. METHODS AND ANALYSIS: We will systematically search databases (Medline, PsycINFO, EMBASE+EMBASE Classic, Web of Knowledge) for systematic reviews and/or meta-analyses that report placebo effect size in clinical trials in patients with mental health disorders (initial search date 23 October 2022). Screening of abstracts and full texts will be done in pairs. We will extract data to qualitatively examine how placebo effect size varies across mental health disorders. We also plan to qualitatively summarise predictors of increased placebo response identified either quantitatively (eg, through meta-regression) or qualitatively. Risk of bias will be assessed using the AMSTAR-2 tool. We aim to not only summarise the current literature but also to identify gaps in knowledge and generate further hypotheses. ETHICS AND DISSEMINATION: We do not believe there are any specific ethical considerations relevant to this study. We will publish the results in a peer-reviewed journal.

Sub-Chronic Ketamine Administration Increases Dopamine Synthesis Capacity in the Mouse Midbrain: a Preclinical In Vivo PET Study.

PURPOSE: There is robust evidence that people with schizophrenia show elevated dopamine (DA) synthesis capacity in the striatum. This finding comes from positron emission tomography (PET) studies using radiolabelled l-3,4-dihydroxyphenylalanine (18F-DOPA). DA synthesis capacity also appears to be elevated in the midbrain of people with schizophrenia compared to healthy controls. We therefore aimed to optimise a method to quantify 18F-DOPA uptake in the midbrain of mice, and to utilise this method to quantify DA synthesis capacity in the midbrain of the sub-chronic ketamine model of schizophrenia-relevant hyperdopaminergia. PROCEDURES: Adult male C57Bl6 mice were treated daily with either ketamine (30 mg/kg, i.p.) or vehicle (saline) for 5 days. On day 7, animals were administered 18F-DOPA (i.p.) and scanned in an Inveon PET/CT scanner. Data from the saline-treated group were used to optimise an atlas-based template to position the midbrain region of interest and to determine the analysis parameters which resulted in the greatest intra-group consistency. These parameters were then used to compare midbrain DA synthesis capacity (KiMod) between ketamine- and saline-treated animals. RESULTS: Using an atlas-based template to position the 3.7 mm3 midbrain ROI with a T*-Tend window of 15-140 min to estimate KiMod resulted in the lowest intra-group variability and moderate test-retest agreement. Using these parameters, we found that KiMod was elevated in the midbrain of ketamine-treated animals in comparison to saline-treated animals (t(22) = 2.19, p = 0.048). A positive correlation between DA synthesis capacity in the striatum and the midbrain was also evident in the saline-treated animals (r2 = 0.59, p = 0.005) but was absent in ketamine-treated animals (r2 = 0.004, p = 0.83). CONCLUSIONS: Using this optimised method for quantifying 18F-DOPA uptake in the midbrain, we found that elevated striatal DA synthesis capacity in the sub-chronic ketamine model extends to the midbrain. Interestingly, the dysconnectivity between the midbrain and striatum seen in this model is also evident in the clinical population. This model may therefore be ideal for assessing novel compounds which are designed to modulate pre-synaptic DA synthesis capacity.

Dopamine and schizophrenia from bench to bedside: Discovery of a striatal co-expression risk gene set that predicts in vivo measures of striatal function.

Schizophrenia (SCZ) is characterized by a polygenic risk architecture implicating diverse molecular pathways important for synaptic function. However, how polygenic risk funnels through these pathways to translate into syndromic illness is unanswered. To evaluate biologically meaningful pathways of risk, we used tensor decomposition to characterize gene co-expression in post-mortem brain (of neurotypicals: N=154; patients with SCZ: N=84; and GTEX samples N=120) from caudate nucleus (CN), hippocampus (HP), and dorsolateral prefrontal cortex (DLPFC). We identified a CN-predominant gene set showing dopaminergic selectivity that was enriched for genes associated with clinical state and for genes associated with SCZ risk. Parsing polygenic risk score for SCZ based on this specific gene set (parsed-PRS), we found that greater pathway-specific SCZ risk predicted greater in vivo striatal dopamine synthesis capacity measured by [ 18 F]-FDOPA PET in three independent cohorts of neurotypicals and patients (total N=235) and greater fMRI striatal activation during reward anticipation in two additional independent neurotypical cohorts (total N=141). These results reveal a 'bench to bedside' translation of dopamine-linked genetic risk variation in driving in vivo striatal neurochemical and hemodynamic phenotypes that have long been implicated in the pathophysiology of SCZ.

Dopamine in major depressive disorder: A systematic review and meta-analysis of in vivo imaging studies.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the magnitude and consistency of the findings are unknown. We address this by systematically reviewing in vivo imaging evidence for dopamine measures in MDD and meta-analysing these where there are sufficient studies. METHODS: Studies investigating the dopaminergic system using positron emission tomography or single photon emission computed tomography in MDD and a control group were included. Demographic, clinical and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted. RESULTS: We identified 43 studies including 662 patients and 801 controls. Meta-analysis of 38 studies showed no difference in mean or mean variability of striatal D2/3 receptor availability (g = 0.06, p = 0.620), or combined dopamine synthesis and release capacity (g = 0.19, p = 0.309). Dopamine transporter (DAT) availability was lower in the MDD group in studies using DAT selective tracers (g = -0.56, p = 0.006), but not when tracers with an affinity for serotonin transporters were included (g = -0.21, p = 0.420). Subgroup analysis showed greater dopamine release (g = 0.49, p = 0.030), but no difference in dopamine synthesis capacity (g = -0.21, p = 0.434) in the MDD group. Striatal D1 receptor availability was lower in patients with MDD in two studies. CONCLUSIONS: The meta-analysis indicates striatal DAT availability is lower, but D2/3 receptor availability is not altered in people with MDD compared to healthy controls. There may be greater dopamine release and lower striatal D1 receptors in MDD, although further studies are warranted. We discuss factors associated with these findings, discrepancies with preclinical literature and implications for future research.

Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development.

BACKGROUND: Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation. METHODS: To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS). FINDINGS: Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap. INTERPRETATION: By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes. FUNDING: National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council.

Variability of glucose, insulin, and lipid disturbances in first-episode psychosis: a meta-analysis.

BACKGROUND: First-episode psychosis (FEP) is associated with metabolic alterations. However, it is not known if there is heterogeneity in these alterations beyond what might be expected due to normal individual differences, indicative of subgroups of patients at greater vulnerability to metabolic dysregulation. METHODS: We employed meta-analysis of variance, indexed using the coefficient of variation ratio (CVR), to compare variability of the following metabolic parameters in antipsychotic naïve FEP and controls: fasting glucose, glucose post-oral glucose tolerance test (OGTT), fasting insulin, insulin resistance, haemoglobin A1c (HbA1c), total-cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides. Standardised mean difference in metabolic parameters between groups was also calculated; meta-regression analyses examined physiological/demographic/psychopathological moderators of metabolic change. RESULTS: Twenty-eight studies were analysed (1716 patients, 1893 controls). Variability of fasting glucose [CVR = 1.32; 95% confidence interval (CI) 1.12-1.55; p = 0.001], glucose post-OGTT (CVR = 1.43; 95% CI 1.10-1.87; p = 0.008), fasting insulin (CVR = 1.31; 95% CI 1.09-1.58; p = 0.01), insulin resistance (CVR = 1.34; 95% CI 1.12-1.60; p = 0.001), HbA1c (CVR = 1.18; 95% CI 1.06-1.27; p < 0.0001), total-cholesterol (CVR = 1.15; 95% CI 1.01-1.31; p = 0.03), LDL-cholesterol (CVR = 1.28; 95% CI 1.09-1.50; p = 0.002), and HDL-cholesterol (CVR = 1.15; 95% CI 1.00-1.31; p < 0.05), but not triglycerides, was greater in patients than controls. Mean glucose, glucose post-OGTT, fasting insulin, insulin resistance, and triglycerides were greater in patients; mean total-cholesterol and HDL-cholesterol were reduced in patients. Increased symptom severity and female sex were associated with worse metabolic outcomes. CONCLUSIONS: Patients with FEP present with greater variability in metabolic parameters relative to controls, consistent with a subgroup of patients with more severe metabolic changes compared to others. Understanding determinants of metabolic variability could help identify patients at-risk of developing metabolic syndrome. Female sex and severe psychopathology are associated with poorer metabolic outcomes, with implications for metabolic monitoring in clinical practice.

Reward processing in schizophrenia and its relation to Mu opioid receptor availability and negative symptoms: A [11C]-carfentanil PET and fMRI study.

BACKGROUND: Reward processing deficits are a core feature of schizophrenia and are thought to underlie negative symptoms. Pre-clinical evidence suggests that opioid neurotransmission is linked to reward processing. However, the contribution of Mu Opioid Receptor (MOR) signalling to the reward processing abnormalities in schizophrenia is unknown. Here, we examined the association between MOR availability and the neural processes underlying reward anticipation in patients with schizophrenia using multimodal neuroimaging. METHOD: 37 subjects (18 with Schizophrenia with moderate severity negative symptoms and 19 age and sex-matched healthy controls) underwent a functional MRI scan while performing the Monetary Incentive Delay (MID) task to measure the neural response to reward anticipation. Participants also had a [11C]-carfentanil PET scan to measure MOR availability. RESULTS: Reward anticipation was associated with increased neural activation in a widespread network of brain regions including the striatum. Patients with schizophrenia had both significantly lower MOR availability in the striatum as well as striatal hypoactivation during reward anticipation. However, there was no association between MOR availability and striatal neural activity during reward anticipation in either patient or controls (Pearson's Correlation, controls df = 17, r = 0.321, p = 0.18, patients df = 16, r = 0.295, p = 0.24). There was no association between anticipation-related neural activation and negative symptoms (r = -0.120, p = 0.14) or anhedonia severity (social r = -0.365, p = 0.14 physical r = -0.120, p = 0.63). CONCLUSIONS: Our data suggest reduced MOR availability in schizophrenia might not underlie striatal hypoactivation during reward anticipation in patients with established illness. Therefore, other mechanisms, such as dopamine dysfunction, warrant further investigation as treatment targets for this aspect of the disorder.

The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia.

BACKGROUND: The histamine-3 receptor (H3R) is an auto- and heteroreceptor that inhibits the release of histamine and other neurotransmitters. Post-mortem evidence has found altered H3R expression in patients with psychotic disorders, which may underlie cognitive impairment associated with schizophrenia (CIAS). AIMS: We used positron emission tomography (PET) imaging to compare brain uptake of an H3R selective tracer between patients with schizophrenia and matched controls (healthy individuals). Regions of interest included the dorsolateral prefrontal cortex (DLPFC) and striatum. We explored correlations between tracer uptake and symptoms, including cognitive domains. METHODS: A total of 12 patients and 12 matched controls were recruited to the study and were assessed with psychiatric and cognitive rating scales. They received a PET scan using the H3R-specific radioligand [11C]MK-8278 to determine H3R availability. RESULTS: There was no statistically significant difference in tracer uptake between patients and controls in the DLPFC (t19 = 0.79, p = 0.44) or striatum (t21 = 1.18, p = 0.25). An exploratory analysis found evidence for lower volume of distribution in the left cuneus (pFWE-corrected = 0.01). DLPFC tracer uptake was strongly correlated with cognition in controls (trail making test (TMT) A: r = 0.77, p = 0.006; TMT B: rho = 0.74, p = 0.01), but not in patients (TMT A: r = -0.18, p = 0.62; TMT B: rho = -0.06, p = 0.81). CONCLUSIONS: These findings indicate H3R in the DLPFC might play a role in executive function and this is disrupted in schizophrenia in the absence of major alterations in H3R availability as assessed using a selective radiotracer for H3R. This provides further evidence for the role of H3R in CIAS.