Working memory processes and the histamine-3 receptor in schizophrenia: a [C]MK-8278 PET-fMRI study.

Rationale: Working memory impairment is a prominent feature of schizophrenia which predicts clinical and functional outcomes. Preclinical data suggest histamine-3 receptor (H3R) expression in cortical pyramidal neurons may have a role in working memory, and post-mortem data has found disruptions of H3R expression in schizophrenia.

Objectives: We examined the role of H3R in vivo to elucidate its role on working memory impairment in schizophrenia.

Mesostriatal Dopaminergic Circuit Dysfunction in Schizophrenia: A Multimodal Neuromelanin-Sensitive Magnetic Resonance Imaging and [F]-DOPA Positron Emission Tomography Study.

Background: Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin (NM)-sensitive magnetic resonance imaging provides a marker of long-term dopamine function. We examined whether midbrain NM-sensitive magnetic resonance imaging contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia than in healthy control (HC) participants and whether this correlated with dopamine synthesis capacity.

New Drug Treatments for Schizophrenia: A Review of Approaches to Target Circuit Dysfunction.

Schizophrenia is a leading cause of global disease burden. Current drug treatments are associated with significant side effects and have limited efficacy for many patients, highlighting the need to develop new approaches that target other aspects of the neurobiology of schizophrenia. Preclinical, in vivo imaging, postmortem, genetic, and pharmacological studies have highlighted the key role of cortical GABAergic (gamma-aminobutyric acidergic)-glutamatergic microcircuits and their projections to subcortical dopaminergic circuits in the pathoetiology of negative, cognitive, and psychotic symptoms.

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.

The effect of AUT00206, a Kv3 potassium channel modulator, on dopamine synthesis capacity and the reliability of [F]-FDOPA imaging in schizophrenia.

Background: Current treatments for schizophrenia act directly on dopamine (DA) receptors but are ineffective for many patients, highlighting the need to develop new treatment approaches. Striatal DA dysfunction, indexed using [F]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.

The effects of AUT00206, a novel Kv3.1/3.2 potassium channel modulator, on task-based reward system activation: a test of mechanism in schizophrenia.

The pathophysiology of schizophrenia involves abnormal reward processing, thought to be due to disrupted striatal and dopaminergic function. Consistent with this hypothesis, functional magnetic resonance imaging (fMRI) studies using the monetary incentive delay (MID) task report hypoactivation in the striatum during reward anticipation in schizophrenia. Dopamine neuron activity is modulated by striatal GABAergic interneurons.

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study.

N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (V). Hippocampal DVR, but not V, was significantly lower in patients relative to controls (p = 0.

The magnitude and variability of brain structural alterations in bipolar disorder: A double meta-analysis of 5534 patients and 6651 healthy controls.

Background: Bipolar disorder is thought to be associated with structural brain alterations, but findings have been inconsistent. Our double meta-analysis investigated the variability and magnitude of differences in regional brain volumes in patients with bipolar disorder relative to healthy volunteers.

Methods: Databases were systematically searched for MRI studies reporting regional brain volumetric measures in patients with bipolar disorder and controls.

Pre-frontal parvalbumin interneurons in schizophrenia: a meta-analysis of post-mortem studies.

Parvalbumin interneurons are fast-spiking GABAergic neurons that provide inhibitory control of cortical and subcortical circuits and are thought to be a key locus of the pathophysiology underlying schizophrenia. In view of the contradictory results regarding the nature of parvalbumin post-mortem findings in schizophrenia, we conducted a quantitative meta-analysis of the data on parvalbumin cell density and parvalbumin mRNA levels in pre-frontal regions in the brains of patients with schizophrenia (n = 274) compared with healthy controls (n = 275). The results suggest that parvalbumin interneurons are reduced in density in the frontal cortex of patients with schizophrenia (Hedges' g = - 0.

Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology.

Antipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and associated with side-effects and nonadherence in others. We review the in vitro, pre-clinical, clinical and molecular imaging evidence on the mode of action of antipsychotics and their side-effects. This identifies the key role of striatal dopamine D2 receptor blockade for clinical response, but also for endocrine and motor side-effects, indicating a therapeutic window for D2 blockade.

Up: The rise of nitrous oxide abuse. An international survey of contemporary nitrous oxide use.

In recent years the recreational use of inhaled nitrous oxide gas (N2O) is becoming increasingly popular, yet little is known about the characteristics of its users or the effects they experience. This paper presents original research from the 2014 Global Drug Survey (GDS) (n=74,864). GDS runs the largest survey of recreational drug use in the world.

Trends in cannabis-related ambulance presentations from 2000 to 2013 in Melbourne, Australia.

Aims: The current burden of cannabis-related presentations to emergency health services is largely unknown. This paper presents data collected over a 13-year period in metropolitan Melbourne, Australia as part of the Ambo Project, a unique surveillance system that analyses and codes paramedic records for drug-related trends and harms.

Methods: Cannabis-related ambulance attendances involving 15-59 year olds in metropolitan Melbourne were analysed retrospectively from 2000 to 2013 (n=10,531).