CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Brain morphometry in 22q11.2 deletion syndrome: an exploration of differences in cortical thickness, surface area, and their contribution to cortical volume.

22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans, with a heterogenous clinical presentation including medical, behavioural and psychiatric conditions. Previous neuroimaging studies examining the neuroanatomical underpinnings of 22q11.2DS show alterations in cortical volume (CV), cortical thickness (CT) and surface area (SA). The aim of this study was to identify (1) the spatially distributed networks of differences in CT and SA in 22q11.2DS compared to controls, (2) their unique and spatial overlap, as well as (3) their relative contribution to observed differences in CV. Structural MRI scans were obtained from 62 individuals with 22q11.2DS and 57 age-and-gender-matched controls (aged 6-31). Using FreeSurfer, we examined differences in vertex-wise estimates of CV, CT and SA at each vertex, and compared the frequencies of vertices with a unique or overlapping difference for each morphometric feature. Our findings indicate that CT and SA make both common and unique contributions to volumetric differences in 22q11.2DS, and in some areas, their strong opposite effects mask differences in CV. By identifying the neuroanatomic variability in 22q11.2DS, and the separate contributions of CT and SA, we can start exploring the shared and distinct mechanisms that mediate neuropsychiatric symptoms across disorders, e.g. 22q11.2DS-related ASD and/or psychosis/schizophrenia.

Correction: Regulation of dopaminergic function: An [18F]-DOPA PET apomorphine challenge study in humans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome.

22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cortical thickness between 1) individuals with 22q11.2DS (n = 62) and neurotypical controls (n = 57) and 2) 22q11.2DS individuals with ASD symptomatology (n = 30) and those without (n = 25). We firstly observed significant differences in surface anatomy between 22q11.2DS individuals and controls for all 3 neuroanatomical features, predominantly in parietotemporal regions, cingulate and dorsolateral prefrontal cortices. We also established that 22q11.2DS individuals with ASD symptomatology were neuroanatomically distinct from 22q11.2DS individuals without ASD symptoms, particularly in brain regions that have previously been linked to ASD (e.g., dorsolateral prefrontal cortices and the entorhinal cortex). Our findings indicate that different clinical 22q11.2DS phenotypes, including those with ASD symptomatology, may represent different neurobiological subgroups. The spatially distributed patterns of neuroanatomical differences associated with ASD symptomatology in 22q11.2DS may thus provide useful information for patient stratification and the prediction of clinical outcomes.

The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.

BACKGROUND: The pathophysiology of psychosis is incompletely understood. Disruption in cortical glutamatergic signalling causing aberrant striatal dopamine synthesis capacity is a proposed model for psychosis, but has not been tested in vivo. We therefore aimed to test the relationship between cortical glutamate concentrations and striatal dopamine synthesis capacity, and psychotic symptoms. METHODS: In this cross-sectional multimodal imaging study, 28 individuals with first-episode psychosis and 28 healthy controls underwent 18F-DOPA PET (measuring striatal dopamine synthesis capacity), and proton magnetic resonance spectroscopy (measuring anterior cingulate cortex glutamate concentrations). Participants were recruited from first-episode psychosis services in London, UK and were required to be in the first episode of a psychotic illness, with no previous illness or treatment episodes. Exclusion criteria for all participants were: history of substantial head trauma, dependence on illicit substances, medical comorbidity (other than minor illnesses), and contraindications to scanning (such as pregnancy). Symptoms were measured using the Positive and Negative Syndrome Scale. The primary endpoint was the relationship between anterior cingulate cortex glutamate concentrations and striatal dopamine synthesis capacity in individuals with their first episode of psychosis as shown by imaging, examined by linear regression. Linear regression was used to examine relationships between measures. FINDINGS: Glutamate concentrations showed a significant inverse relationship with striatal dopamine synthesis capacity in patients with psychosis (R2=0·16, p=0·03, ß -1·71 × 10-4, SE 0·76 × 10-4). This relationship remained significant after the addition of age, gender, ethnicity, and medication status to the model (p=0·015). In healthy controls, there was no significant relationship between dopamine and glutamate measures (R2=0·04, p=0·39). Positive and Negative Syndrome Scale positive psychotic symptoms were positively associated with striatal dopamine synthesis capacity (R2=0·14, p=0·046, ß 2546, SE 1217) and showed an inverse relationship with anterior cingulate glutamate concentrations (R2=0·16, p=0·03, ß -1·71 × 10-4, SE 7·63 × 10-5). No relationships were seen with negative symptoms (positive symptoms, mean [SD] -18·4 (6·6) negative symptoms, mean [SD] -15·4 [6·1]). INTERPRETATION: These observations are consistent with the hypothesis that cortical glutamate dysfunction is related to subcortical dopamine synthesis capacity and psychosis. Although the precise mechanistic relationship between cortical glutamate and dopamine in vivo remains unclear, our findings support further studies to test the effect of modulating cortical glutamate in the treatment of psychosis. FUNDING: Medical Research Council, Wellcome Trust, Biomedical Research Council, South London and Maudsley NHS Foundation Trust, JMAS Sim Fellowship, Royal College of Physicians (Edinburgh) (SJ).

Correction: Regulation of dopaminergic function: an [18F]-DOPA PET apomorphine challenge study in humans.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia.

OBJECTIVE: Treatment resistance is a challenge for the management of schizophrenia. It is not always clear whether inadequate response is secondary to medication ineffectiveness, as opposed to medication underexposure due to non-adherence or pharmacokinetic factors. We investigated the prevalence of subtherapeutic antipsychotic plasma levels in patients identified as treatment-resistant by their treating clinician. METHOD: Between January 2012 and April 2017, antipsychotic plasma levels were measured in 99 individuals provisionally diagnosed with treatment-resistant schizophrenia by their treating clinicians, but not prescribed clozapine. Patients were followed up to determine whether they were subsequently admitted to hospital. RESULTS: Thirty-five per cent of plasma levels were subtherapeutic, and of these, 34% were undetectable. Black ethnicity (P = 0.006) and lower dose (P < 0.001) were significantly associated with subtherapeutic/undetectable plasma levels. Individuals with subtherapeutic/undetectable levels were significantly more likely to be admitted to hospital (P = 0.02). CONCLUSION: A significant proportion of patients considered treatment-resistant have subtherapeutic antipsychotic plasma levels, and this is associated with subsequent admission. The presence of subtherapeutic plasma levels may suggest a need to address adherence or pharmacokinetic factors as opposed to commencing clozapine treatment. While antipsychotic levels are not recommended for the routine adjustment of dosing, they may assist with the assessment of potential treatment resistance in schizophrenia.

Regulation of dopaminergic function: an [18F]-DOPA PET apomorphine challenge study in humans.

Dopaminergic function has a key role in normal brain function, dopaminergic dysfunction being implicated in numerous neuropsychiatric disorders. Animal studies show that dopaminergic stimulation regulates dopaminergic function, but it is not known whether this exists in humans. In the first study (study 1), we measured dopamine synthesis capacity (indexed as Kicer) to identify the relationship between baseline and change in Kicer under resting conditions for comparison with effects of dopaminergic stimulation. In the second study (study 2), we used a within-subjects design to test effects of dopaminergic stimulation on dopamine synthesis capacity. In study 1, eight volunteers received two 18F-DOPA scans on separate days, both at rest. In study 2, 12 healthy male volunteers received two 18F-DOPA positron emission tomographic (PET) scans after treatment with either the dopamine partial agonist apomorphine (0.03 or 0.005 mg kg-1) or placebo. In study 1, no significant correlation was found between baseline and change in dopamine synthesis capacity between scans (r=-0.57, n=8, P=0.17, two-tailed). In study 2, a significant negative correlation was found between baseline dopamine synthesis capacity and percentage change in dopamine synthesis capacity after apomorphine challenge (r=-0.71, n=12, P=0.01, two-tailed). This correlation was significantly different (P<0.01) from the correlation between baseline and change in dopamine synthesis capacity under unstimulated conditions. One-way repeated-measures analysis of variance showed a significant group (study 1/study 2) × time interaction (F(1,18)=11.5, P=0.003). Our findings suggest that regulation of dopamine synthesis capacity by apomorphine depends on baseline dopamine function, consistent with dopamine stimulation stabilizing dopaminergic function. Loss of this autoregulation may contribute to dopaminergic dysfunction in brain disorders such as schizophrenia, substance dependence, and Parkinson's disease.

Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression.

Neuropeptide Y (NPY) has been implicated in depression, emotional processing and stress response. Part of this evidence originates from human single-nucleotide polymorphism (SNP) studies. In the present study, we report that a SNP in the rat Npy promoter (C/T; rs105431668) affects in vitro transcription and DNA-protein interactions. Genotyping studies showed that the C-allele of rs105431668 is present in a genetic rat model of depression (Flinders sensitive line; FSL), while the SNP's T-allele is present in its controls (Flinders resistant line; FRL). In vivo experiments revealed binding of a transcription factor (CREB2) and a histone acetyltransferase (Ep300) only at the SNP locus of the FRL. Accordingly, the FRL had increased hippocampal levels of Npy mRNA and H3K18 acetylation; a gene-activating histone modification maintained by Ep300. Next, based on previous studies showing antidepressant-like effects of physical activity in the FSL, we hypothesized that physical activity may affect Npy's epigenetic status. In line with this assumption, physical activity was associated with increased levels of Npy mRNA and H3K18 acetylation. Physical activity was also associated with reduced mRNA levels of a histone deacetylase (Hdac5). Conclusively, the rat rs105431668 appears to be a functional Npy SNP that may underlie depression-like characteristics. In addition, the achieved epigenetic reprogramming of Npy provides molecular support for the putative effectiveness of physical activity as a non-pharmacological antidepressant.

Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism.

BACKGROUND: Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the catechol O-methyltransferase (COMT) Val158Met polymorphism, the main catabolic pathway of released DA in the prefrontal cortex (PFC). METHOD: PPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. RESULTS: ANOVAs showed that at all prepulse and interval conditions, Val/Val individuals had the lowest PPI, Met/Met the highest, and Val/Met were intermediate. CONCLUSIONS: These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining individual variability of early information processing in healthy subjects and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia.