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.

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, post-mortem, genetic and pharmacological studies have highlighted the key role of cortical GABA-glutamatergic microcircuits and their projections to subcortical dopaminergic circuits in the pathoetiology of negative, cognitive and psychotic symptoms. Antipsychotics primarily act downstream of the dopaminergic component of this circuit. However, multiple drugs are currently in development that could target other elements of this circuit to treat schizophrenia. These include drugs for GABA or glutamatergic targets, including glycine transporters, d-amino acid oxidase, sodium channels or potassium channels. Other drugs in development are likely to primarily act on pathways that regulate the dopaminergic system such as muscarinic or trace amine receptors or serotonin 2A receptors, whilst phosphodiesterase 10 A inhibitors are being developed to modulate the downstream consequences of dopaminergic dysfunction. Our review considers where new drugs may act on this circuit and their latest clinical trial evidence in terms of indication, efficacy and side-effects. Limitations of the circuit model, including whether there are neurobiologically distinct subgroups of patients, and future directions are also considered. Several drugs based on the mechanisms reviewed have promising clinical data, with the muscarinic agonist KarXT most advanced. If they are approved for clinical use, they have the potential to revolutionise understanding of the pathophysiology and treatment of schizophrenia.

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.

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. GABAergic interneuron firing rates, in turn, are related to conductances in voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels, suggesting that targeting Kv3.1/3.2 could augment striatal function during reward processing. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on striatal activation in patients with schizophrenia, using the MID task. Each participant completed the MID during fMRI scanning on two occasions: once at baseline, and again following either 4 weeks of AUT00206 or placebo treatment. We found a significant inverse relationship at baseline between symptom severity and reward anticipation-related neural activation in the right associative striatum (r = -0.461, p = 0.035). Following treatment with AUT00206, there was a significant increase in reward anticipation-related activation in the left associative striatum (t(13) = 4.23, peak-level p(FWE) < 0.05)), but no significant effect in the ventral striatum. This provides preliminary evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address reward-related striatal abnormalities in schizophrenia.

The effect of AUT00206, a Kv3 potassium channel modulator, on dopamine synthesis capacity and the reliability of [18F]-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 [18F]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.1/3.2 potassium channel modulator, on dopaminergic function in schizophrenia and its relationship with symptom change. Additionally, we investigated the test-retest reliability of [18F]-FDOPA PET in schizophrenia to determine its potential as a biomarker for drug discovery. METHODS: Twenty patients with schizophrenia received symptom measures and [18F]-FDOPA PET scans, before and after being randomised to AUT00206 or placebo groups for up to 28 days treatment. RESULTS: AUT00206 had no significant effect on DA synthesis capacity. However, there was a correlation between reduction in striatal dopamine synthesis capacity (indexed as Kicer) and reduction in symptoms, in the AUT00206 group (r = 0.58, p = 0.03). This was not observed in the placebo group (r = -0.15, p = 0.75), although the placebo group may have been underpowered to detect an effect. The intraclass correlation coefficients of [18F]-FDOPA indices in the placebo group ranged from 0.83 to 0.93 across striatal regions. CONCLUSIONS: The relationship between reduction in DA synthesis capacity and improvement in symptoms in the AUT00206 group provides evidence for a pharmacodynamic effect of the Kv3 channel modulator. The lack of a significant overall reduction in DA synthesis capacity in the AUT00206 group could be due to variability and the low number of subjects in this study. These findings support further investigation of Kv3 channel modulators for schizophrenia treatment. [18F]-FDOPA PET imaging showed very good test-retest reliability in patients with schizophrenia.

New and emerging treatments for schizophrenia: a narrative review of their pharmacology, efficacy and side effect profile relative to established antipsychotics.

Schizophrenia is associated with substantial unmet needs, highlighting the necessity for new treatments. This narrative review compares the pharmacology, clinical trial data and tolerability of novel medications to representative antipsychotics. Cariprazine, brexpiprazole and brilaroxazine are partial dopamine agonists effective in acute relapse. Lumateperone (serotonin and dopamine receptor antagonist) additionally benefits asocial and depressive symptoms. F17464 (D3 antagonist and 5-HT1A partial agonist) has one positive phase II study. Lu AF35700 (dopamine and serotonin receptor antagonist) was tested in treatment-resistance with no positive results. Pimavanserin, roluperidone, ulotaront and xanomeline do not act directly on the D2 receptor at clinical doses. Initial studies indicate pimavanserin and roluperidone improve negative symptoms. Ulotaront and xanomeline showed efficacy for positive and negative symptoms of schizophrenia in phase II trials. BI 409306, BI 425809 and MK-8189 target glutamatergic dysfunction in schizophrenia, though of these only BI 425809 showed efficacy. These medications largely have favourable cardiometabolic side-effect profiles. Overall, the novel pharmacology, clinical trial and tolerability data indicate these compounds are promising new additions to the therapeutic arsenal.

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, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen's d = 0.81; p = 0.15, Cohen's d = 0.49), and negatively associated with total (rho = -0.47, p = 0.04), depressive (rho = -0.67, p = 0.002), and general symptom severity (rho = -0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.

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. The primary outcome measures were variability ratio (VR), coefficient of variability ratio (CVR) and Hedge's g. RESULTS: 118 studies comprising 5534 patients and 6651 controls were included. The variability meta-analysis showed higher variability in amygdala (VR, 1.14; P = .02; CVR, 1.25; P = .005) and hippocampal (VR, 1.16; P = .001; CVR, 1.22; P = <.001) volumes in patients relative to controls. The meta-analysis of volume differences showed higher lateral (g, -0.43; P = <.0001) and third ventricle (g, -0.22; P = .01) volumes in patients; and lower hippocampus (g, 0.41; P = .001), grey matter (g, 0.25; P = .001), white matter (g, 0.23; P = .0002) and total brain volumes (g, 0.20; P = .003) in patients relative to controls. A higher proportion of male subjects was associated with decreased mean volumes of the amygdala, hippocampus and thalamus and increased lateral ventricle volumes. LIMITATIONS: There was significant publication bias and between-study inconsistency for several brain regions. CONCLUSIONS: Bipolar disorder is associated with generalised alterations in white and grey matter brain volumes, particularly marked in the hippocampus volumes, which were smaller but showed greater variability in volumes relative to controls. This suggests that heterogeneity in neurobiological processes involving the hippocampus contribute to clinical heterogeneity in the disorder, and this may be more marked in males than females.

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. We consider how partial D2/3 receptor agonists fit within this framework, and the role of off-target effects of antipsychotics, particularly at serotonergic, histaminergic, cholinergic, and adrenergic receptors for efficacy and side-effects such as weight gain, sedation and dysphoria. We review the neurobiology of schizophrenia relevant to the mode of action of antipsychotics, and for the identification of new treatment targets. This shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies the positive symptoms of psychosis and suggests reduced dopamine release in cortical regions contributes to cognitive and negative symptoms. Current drugs act downstream of the major dopamine abnormalities in schizophrenia, and potentially worsen cortical dopamine function. We consider new approaches including targeting dopamine synthesis and storage, autoreceptors, and trace amine receptors, and the cannabinoid, muscarinic, GABAergic and glutamatergic regulation of dopamine neurons, as well as post-synaptic modulation through phosphodiesterase inhibitors. Finally, we consider treatments for cognitive and negative symptoms such dopamine agonists, nicotinic agents and AMPA modulators before discussing immunological approaches which may be disease modifying. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

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 = - 0.27; p = 0.03) and there is a non-significant reduction in parvalbumin mRNA levels (g = - 0.44; p = 0.12). However, certain methodological issues need to be considered in interpreting such results and are discussed in more detail. A meta-regression was conducted for post-mortem interval and year of publication as covariates which were both non-significant, except in the mRNA meta-analysis where post-mortem interval was found to be significant. Overall our findings provide tentative support for the hypothesis that the GABAergic system is deficient in schizophrenia and that parvalbumin-containing interneurons offer a potential target for treatment. However, further well-controlled studies that examine multiple regions and layers are warranted to determine whether parvalbumin alterations are region or layer specific and to test the robustness of the findings further.

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. The findings confirm N2O as a very common drug of use, in particular in the UK and US (38.6% and 29.4% lifetime prevalence). In the UK N2O was reported to be the eighth most commonly used substance. N2O was generally consumed via gas-filled balloons, at festivals and clubs where use of other substances was common. The vast majority of users use infrequently, and their use is not associated with significant harm. However, there appears to be a subpopulation of heavy users who may be using in a dependent pattern. Analysis of last year N2O users (n=4883), confirms that N2O is associated with hallucinations and confusion (which may be the desired effects) and persistent numbness and accidental injury (27.8%, 23.9%, 4.3% and 1.2% of last year users, respectively). Accidental injury is associated with the highest number of 'hits' per session, suggesting a dose-response relationship. The presence of significant harm is discussed in the light of public education on the risks of N2O use and harm-reduction strategies appropriate to N2O use. Further work needs to be completed to confirm the presence of persistent neurological symptoms in recreational users.

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). Trends and attendance characteristics were compared among cannabis only (CO)-, cannabis and alcohol (CA)- and cannabis with polydrug use (CP)-related attendances. Changes in alcohol and drug involvements in cannabis-related attendances were explored. RESULTS: Rates of cannabis-related ambulance attendances increased significantly over the study period. Increasing rate of attendances per 100,000 population per year changed from 0.6 (2000-2010) to 5.5 (2010-2013). This sharp change was driven by CO- and CP-related attendances (rate of CA-related attendance increased steadily). The highest increasing rate (15.6) was for CO-related attendances among 15-29 years old males (2010-2013). Crystal methamphetamine became the most common illicit co-intoxicant amongst cannabis presentations in 2013. CONCLUSIONS: Relative to the total drug-related burden on ambulance services, cannabis-related presentations appear to be a small but significant and increasing problem. Significant changes in trends across other drug involvement and demographic subgroups suggest a possible shift in the cannabis using population and/or a change in using behaviours. Public health strategies should raise awareness of the increased risk posed by cannabis polydrug use and high attendance subpopulations should be determined.