The role of low subcortical iron, white matter myelin, and oligodendrocytes in schizophrenia: a quantitative susceptibility mapping and diffusion tensor imaging study.

Iron-the most abundant magnetic brain substance-is essential for many biological processes, including dopamine and myelin synthesis. Quantitative susceptibility mapping (QSM) MRI has recently linked altered subcortical magnetic susceptibility (χ) to schizophrenia. Since χ is increased by iron and decreased by myelin, abnormal levels of either could underlie these QSM differences.

Reduced Brain Iron and Striatal Hyperdopaminergia in Schizophrenia: A Quantitative Susceptibility Mapping MRI and PET Study.

Objective: Neuroimaging studies have independently associated schizophrenia with low iron and elevated dopamine synthesis. While preclinical research demonstrates that midbrain iron deficiency leads to striatal hyperdopaminergia, this relationship has not been studied in schizophrenia. The authors conducted a case-control study to examine differences in tissue magnetic susceptibility, a marker of brain iron, and correlated these with striatal dopamine synthesis capacity.

Dopamine and Mood in Psychotic Disorders: An 18F-DOPA PET Study.

Importance: There is limited neurobiological or trial evidence guiding treatment of comorbid affective syndromes in psychotic disorders. Given the use of dopamine-blocking antipsychotics, understanding dopamine function across these mood states is warranted.

Objective: To test for differences in dopamine synthesis capacity (Kicer) between affective syndromes across psychotic disorders and for association with psychotic symptom severity.

AI-based prediction of depression symptomatology in first-episode psychosis patients: insights from the EUFEST and RAISE-ETP clinical trials.

Background: Depressive symptoms are highly prevalent in first-episode psychosis (FEP) and worsen clinical outcomes. It is currently difficult to determine which patients will have persistent depressive symptoms based on a clinical assessment. We aimed to determine whether depressive symptoms and post-psychotic depressive episodes can be predicted from baseline clinical data, quality of life, and blood-based biomarkers, and to assess the geographical generalizability of these models.

The effects of dopamine receptor antagonist and partial agonist antipsychotics on the glutamatergic system: double-blind, randomised, placebo-controlled H-MRS cross-over study in healthy volunteers.

Background: Targeting the glutamatergic system is posited as a potentially novel therapeutic strategy for psychotic disorders. While studies in subjects indicate that antipsychotic medication reduces brain glutamatergic measures, they were unable to disambiguate clinical changes from drug effects.

Aims: To address this, we investigated the effects of a dopamine D2 receptor partial agonist (aripiprazole) and a dopamine D2 receptor antagonist (amisulpride) on glutamatergic metabolites in the anterior cingulate cortex (ACC), striatum and thalamus in healthy controls.

Effects of antipsychotics on human cognitive function: causal evidence from healthy volunteers following sustained D2/D3 antagonism, D2/D3 partial agonism and placebo.

Dopamine D2/D3 receptor modulation with antipsychotics is thought to affect cognitive function, but causal evidence in humans is scant, and largely limited to single administrations. Clarifying this is of importance given the widespread use of antipsychotics, and to understand the role of D2/D3 signalling in human cognition. We therefore conducted a double-blind, placebo-controlled crossover study following sustained administration of either a dopamine D2/D3 receptor antagonist (amisulpride at 400 mg daily) or a D2/D3 partial agonist (aripiprazole at 10 mg daily) to two separate samples of healthy humans (total n = 50) for 7 days per condition.

Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel.

Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 10 cells per L (0·5 × 10 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years.

Likelihood-Scheduled Score-Based Generative Modeling for Fully 3D PET Image Reconstruction.

Medical image reconstruction with pretrained score-based generative models (SGMs) has advantages over other existing state-of-the-art deep-learned reconstruction methods, including improved resilience to different scanner setups and advanced image distribution modeling. SGM-based reconstruction has recently been applied to simulated positron emission tomography (PET) datasets, showing improved contrast recovery for out-of-distribution lesions relative to the state-of-the-art. However, existing methods for SGM-based reconstruction from PET data suffer from slow reconstruction, burdensome hyperparameter tuning and slice inconsistency effects (in 3D).

Multidisciplinary consensus on prevention, screening and monitoring of clozapine-associated myocarditis and clozapine rechallenge after myocarditis.

Background: Clozapine is the antipsychotic of choice for people with treatment-resistant schizophrenia (TRS) but is associated with the uncommon but potentially life-threatening adverse effect of myocarditis. However, there are no criteria for diagnosing clozapine-associated myocarditis (CAM) or global guidelines on detection and risk reduction, or for restarting clozapine after CAM.

Aims: To develop criteria for CAM and algorithms for clozapine initiation and clozapine rechallenge after CAM in a multiprofessional consensus process.

Effectiveness of clozapine augmentation with specific doses of other antipsychotics in schizophrenia: a meta-analysis from two nationwide cohorts.

Although clozapine is the most effective medication for treatment-resistant schizophrenia, response is inadequate in over half of people with that condition. There is limited guidance available on effective clozapine augmentation strategies. We studied the comparative effectiveness of specific doses of oral olanzapine, quetiapine, risperidone and aripiprazole augmentation of clozapine treatment on the risk of hospitalization due to a psychotic episode, as a marker for severe relapse, among patients with schizophrenia or schizoaffective disorder.

Glucagon-Like Peptide 1 Receptor Agonists and Mental Health: A Systematic Review and Meta-Analysis.

Importance: People with obesity and diabetes have poorer psychiatric and cognitive outcomes and lower quality of life (QOL) compared with those without. Glucagon-like peptide 1 receptor agonists (GLP1-RAs) are treatments for diabetes and obesity that may also influence psychiatric outcomes.

Objective: To conduct a meta-analysis of randomized placebo-controlled trials to evaluate psychiatric, cognitive, and QOL outcomes with GLP1-RA treatment.

Antipsychotics cause reversible structural brain changes within one week.

Determining the effects of antipsychotics on MRI brain structural metrics without the potential confounding effects related to the natural course of a psychotic illness is challenging. However, it is crucial to understand these effects to interpret the results of cross-sectional and longitudinal studies in medicated patients and, ultimately, to understand better the biological mechanisms driving antipsychotics' effects. In this work, we aim to determine whether exposure to antipsychotics is associated with alterations in brain MRI structural metrics in the absence of disease effects.

INTEGRATE: international guidelines for the algorithmic treatment of schizophrenia.

Schizophrenia is a mental illness involving multiple symptom domains and is often associated with substantial physical health comorbidities. Guidelines exist, but these tend to be country-specific and are often missing a concise yet comprehensive algorithmic approach. From May 1, 2023, to Jan 1, 2025, International Guidelines for Algorithmic Treatment (INTEGRATE) authors from all UN regions collaborated to develop a consensus guideline focused on the pharmacological treatment of schizophrenia.

Effect of the TAAR1 Partial Agonist Ralmitaront on Presynaptic Dopamine Synthesis Capacity Measured Using [F]DOPA PET in Naïve and Cocaine-Treated Mice.

Purpose: Elevated dopamine synthesis capacity is part of the pathophysiology of schizophrenia thought to underlie psychosis. Drugs that reduce this phenomenon could thus be potential treatments for these disorders. In this study, we evaluated the ability of the trace amine-associated receptor 1 (TAAR1) partial agonist ralmitaront to reduce presynaptic dopamine synthesis capacity.

The relationship between cortical synaptic terminal density marker SV2A and glutamate early in the course of schizophrenia: a multimodal PET and MRS imaging study.

Loss of glutamatergic terminals is hypothesised to contribute to excitation-inhibition imbalance in schizophrenia, supported by evidence that the normal positive association between glutamate concentrations and synaptic terminal density is not found in patients with chronic schizophrenia. However, it is unknown whether the relationship between synaptic terminal density and glutamate levels is altered early in the course of illness. To address this, we investigated [C]UCB-J distribution volume ratio (DVR) and glutamatergic markers in healthy volunteers (HV) and in antipsychotic-naïve/free patients with schizophrenia (SCZ) recruited from first-episode psychosis services.

Mitochondria and Cognition: An [F]BCPP-EF Positron Emission Tomography Study of Mitochondrial Complex I Levels and Brain Activation During Task Switching.

Background: Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be noninvasively measured using [F]BCPP-EF positron emission tomography (PET). Neurological conditions associated with mitochondria complex I pathology are also associated with altered blood oxygen level-dependent (BOLD) response and impairments in cognition. In this study, we aimed to investigate the relationship between mitochondrial complex I levels, cognitive function, and associated neural activity during task switching in healthy humans.

The relationship between SV2A levels, neural activity, and cognitive function in healthy humans: A [11C]UCB-J PET and fMRI study.

Synaptic terminal density is thought to influence cognitive function and neural activity, yet its role in cognition has not been explored in healthy humans. We examined these relationships using [11C]UCB-J positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in 25 healthy adults performing cognitive function tasks in the scanner. We found a significant positive association between synaptic terminal density, indicated by [11C]UCB-J PET distribution volume ratio (DVRcs), and neural activity during task switching (PLS-CA, second canonical component, = 0.

Striatal dopamine D2/D3 receptor regulation of human reward processing and behaviour.

Signalling at dopamine D2/D3 receptors is thought to underlie motivated behaviour, pleasure experiences and emotional expression based on animal studies, but it is unclear if this is the case in humans or how this relates to neural processing of reward stimuli. Using a randomised, double-blind, placebo-controlled, crossover neuroimaging study, we show in healthy humans that sustained dopamine D2/D3 receptor antagonism for 7 days results in negative symptoms (impairments in motivated behaviour, hedonic experience, verbal and emotional expression) and that this is related to blunted striatal response to reward stimuli. In contrast, 7 days of partial D2/D3 agonism does not disrupt reward signalling, motivated behaviour or hedonic experience.

Transcriptional and Neurochemical Signatures of Cerebral Blood Flow Alterations in Individuals With Schizophrenia or at Clinical High Risk for Psychosis.

Background: The brain integrates multiple scales of description, from the level of cells and molecules to large-scale networks and behavior. Understanding relationships across these scales may be fundamental to advancing understanding of brain function in health and disease. Recent neuroimaging research has shown that functional brain alterations that are associated with schizophrenia spectrum disorders (SSDs) are already present in young adults at clinical high risk for psychosis (CHR-P), but the cellular and molecular determinants of these alterations remain unclear.

Muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis: protocol for a systematic review and meta-analysis.

Background: Muscarinic receptor agonism and positive allosteric modulation is a promising mechanism of action for treating psychosis, not present in most D2R-blocking antipsychotics. Xanomeline, an M1/M4-preferring agonist, has shown efficacy in late-stage clinical trials, with more compounds being investigated. Therefore, we aim to synthesize evidence on the preclinical efficacy of muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis to provide unique insights and evidence-based information to guide drug development.

Response to clozapine in treatment resistant schizophrenia is related to alterations in regional cerebral blood flow.

PET and SPECT studies in treatment-resistant schizophrenia (TRS) have revealed significant alterations in regional cerebral blood flow (CBF) during clozapine treatment, which may vary according to the clinical response. Here, we used the more recent MRI approach of arterial spin labelling (ASL) to evaluate regional CBF in participants with TRS (N = 36) before starting treatment with clozapine compared to in healthy volunteers (N = 16). We then compared CBF in the TRS group, before and after 12 weeks of treatment with clozapine (N = 24); and examined the relationship of those differences against changes in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores over the treatment period.