Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Low prevalence of substance use in people with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS), one of the most common recurrent copy number variant disorders, is associated with dopaminergic abnormalities and increased risk for psychotic disorders. AIMS: Given the elevated prevalence of substance use and dopaminergic abnormalities in non-deleted patients with psychosis, we investigated the prevalence of substance use in 22q11DS, compared with that in non-deleted patients with psychosis and matched healthy controls. METHOD: This cross-sectional study involved 434 patients with 22q11DS, 265 non-deleted patients with psychosis and 134 healthy controls. Psychiatric diagnosis, full-scale IQ and COMT Val158Met genotype were determined in the 22q11DS group. Substance use data were collected according to the Composite International Diagnostic Interview. RESULTS: The prevalence of total substance use (36.9%) and substance use disorders (1.2%), and weekly amounts of alcohol and nicotine use, in patients with 22q11DS was significantly lower than in non-deleted patients with psychosis or controls. Compared with patients with 22q11DS, healthy controls were 20 times more likely to use substances in general (P < 0.001); results were also significant for alcohol and nicotine use separately. Within the 22q11DS group, there was no relationship between the prevalence of substance use and psychosis or COMT genotype. Male patients with 22q11DS were more likely to use substances than female patients with 22q11DS. CONCLUSIONS: The results suggest that patients with 22q11DS are at decreased risk for substance use and substance use disorders despite the increased risk of psychotic disorders. Further research into neurobiological and environmental factors involved in substance use in 22q11DS is necessary to elucidate the mechanisms involved. DECLARATION OF INTEREST: None.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection: In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

The muscarinic M1 receptor modulates associative learning and memory in psychotic disorders.

BACKGROUND: Psychotic disorders are characterized by prominent deficits in associative learning and memory for which there are currently no effective treatments. Functional magnetic resonance imaging (fMRI) studies in psychotic disorders have identified deficits in fronto-temporal activation during associative learning and memory. The underlying pathology of these findings remains unclear. Postmortem data have suggested these deficits may be related to loss of muscarinic M1 receptor mediated signaling. This is supported by an in-vivo study showing improvements in these symptoms after treatment with the experimental M1/4 receptor agonist xanomeline. The current study tests whether reported deficits in fronto-temporal activation could be mediated by loss of M1 receptor signaling in psychotic disorders. METHODS: Twenty-six medication-free subjects diagnosed with a psychotic disorder and 29 age-, gender-, and IQ-matched healthy controls underwent two functional magnetic resonance imaging (fMRI) sessions, one under placebo and one under selective M1 antagonist biperiden, while performing the paired associated learning task. M1 binding potentials (BPND) were measured in the dorsolateral prefrontal cortex (DLPFC) and hippocampus using 123I-IDEX single photon emission computed tomography. RESULTS: In the subjects with psychotic disorders DLPFC hypoactivation was only found in the memory phase of the task. In both learning and memory phases of the task, M1 antagonism by biperiden elicited significantly greater hyperactivation of the parahippocampal gyrus and superior temporal gyrus in subjects with a psychotic disorders compared to controls. Greater hyperactivation of these areas after biperiden was associated with greater hippocampal M1 receptor binding during learning, with no association found with M1 receptor binding in the DLPFC. M1 receptor binding in the DLPFC was related to greater functional sensitivity to biperiden of the cingulate gyrus during the memory phase. CONCLUSION: The current study is the first to show differences in M1 receptor mediated functional sensitivity between subjects with a psychotic disorder and controls during a paired associate learning and memory task. Results point to subjects with psychotic disorders having a loss of M1 receptor reserve in temporal-limbic areas.

Psychosis and autism: magnetic resonance imaging study of brain anatomy.

BACKGROUND: Autism-spectrum disorder is increasingly recognised, with recent studies estimating that 1% of children in South London are affected. However, the biology of comorbid mental health problems in people with autism-spectrum disorder is poorly understood. AIMS: To investigate the brain anatomy of people with autism-spectrum disorder with and without psychosis. METHOD: We used in vivo magnetic resonance imaging and compared 30 adults with autism-spectrum disorder (14 with a history psychosis) and 16 healthy controls. RESULTS: Compared with controls both autism-spectrum disorder groups had significantly less grey matter bilaterally in the temporal lobes and the cerebellum. In contrast, they had increased grey matter in striatal regions. However, those with psychosis also had a significant reduction in grey matter content of frontal and occipital regions. Contrary to our expectation, within autism-spectrum disorder, comparisons revealed that psychosis was associated with a reduction in grey matter of the right insular cortex and bilaterally in the cerebellum extending into the fusiform gyrus and the lingual gyrus. CONCLUSIONS: The presence of neurodevelopmental abnormalities normally associated with autism-spectrum disorder might represent an alternative 'entry-point' into a final common pathway of psychosis.

Influence of muscarinic M1 receptor antagonism on brain choline levels and functional connectivity in medication-free subjects with psychosis: A placebo controlled, cross-over study.

An increasing number of studies implicate the muscarinic cholinergic system in cognitive dysfunction associated with psychosis. This study examined the effect of muscarinic M1 receptor modulation on anterior cingulate cortex (ACC) and striatal choline concentrations and the relation with cognitive performance, as well as functional connectivity of cognitive networks. Thirty medication-free subjects with a psychosis spectrum disorder and 30 gender, age and IQ-matched healthy control subjects underwent 1H-proton magnetic resonance spectroscopy (1H-MRS) twice, once after placebo and once after a single dose of biperiden (M1 receptor antagonist, 4 mg). A subset of 19 psychotic subjects and 28 controls underwent resting-state functional magnetic resonance imaging (rs-fMRI) as well. No significant differences were found in ACC and striatal choline levels, nor in functional connectivity, between the two groups after placebo. Moreover, M1 antagonism did not significantly affect choline levels or functional connectivity. No correlations were found between choline levels and cognition as well as psychotic symptoms. Our findings do not support an association between the cholinergic system and cognition and psychotic symptoms. However, the lack of group differences in choline concentrations and functional connectivity, both after biperiden and placebo, may indicate that there were no severe cholinergic abnormalities present in our sample.

Dopamine in high-risk populations: A comparison of subjects with 22q11.2 deletion syndrome and subjects at ultra high-risk for psychosis.

Striatal dopamine (DA) dysfunction has been consistently reported in psychotic disorders. Differences and similarities in the pathogenesis between populations at clinical and genetic risk for developing psychosis are yet to be established. Here we explored markers of dopamine (DA) function in subjects meeting clinically ultra-high risk criteria for psychosis (UHR) and in subjects with 22q11.2 deletion syndrome (22q11DS), a genetic condition associated with significant risk for developing psychotic disorders. Single Photon Emission Computed Tomography (SPECT) with 123I-labelled iodobenzamide ([123I]IBZM) was used to measure striatal DA D2/3 receptor binding potential (D2R BPND). Also, peripheral DAergic markers were assessed in serum and urine (plasma prolactin (pPRL), plasma homovanillic acid (pHVA) and urine DA(uDA)). No significant difference in striatal D2R BPND was found between UHR and 22q11DS subjects. Compared to UHR subjects, pPRL and pHVA were lower and uDA levels were higher in the 22q11DS subjects. However, after correcting for age and gender, only pPRL as significantly lower in the 22q11DS patients. These results may suggest that there are differences in DAergic markers between subjects with UHR and with 22q11DS that may reflect differences in the pathways to psychosis. However, bigger samples are needed to replicate these findings.

The effect of the muscarinic M1 receptor antagonist biperiden on cognition in medication free subjects with psychosis.

The acetylcholine muscarinic M1 receptor has been implicated in both psychosis and cognition. Post-mortem research has shown reduced muscarinic M1 receptor density in 25% of chronic patients with schizophrenia. It is unknown whether reduced M1 receptor density is related to cognitive symptoms of psychosis. We investigated the role of the M1 receptor in separate cognitive domains in subjects with a psychotic disorder using a muscarinic M1 antagonist as an acute pharmacological challenge. 33 young subjects with a psychotic disorder and 30 gender, age and IQ matched healthy controls were enrolled. All participants completed a comprehensive cognitive test battery twice: once after placebo and once after oral administration of 4mg. biperiden (M1 antagonist). The order of drug administration was counterbalanced. Biperiden significantly negatively influenced both verbal (p< 0.001 and p=0.032) and visual learning and memory (p=0.028) in both groups. A medication x group interaction effect was found for reasoning and problem solving (p=0.005). No main or interaction effects were found for other cognitive domains. These results provide further in-vivo evidence that the M1 receptor is involved in cognitive functioning, particularly verbal and visual memory processes. Lack of differential effects of biperiden between psychotic subjects and healthy controls may suggest that decreased M1 receptor density is only present in chronic, older schizophrenia patients. However, it remains possible that differential effects of biperiden would be present in more severe cognitive impaired subjects with psychosis after several doses of biperiden instead of a single administration.

PRODH rs450046 and proline x COMT Val¹58 Met interaction effects on intelligence and startle in adults with 22q11 deletion syndrome.

RATIONALE: 22q11 deletion syndrome (22q11DS) is associated with an increased risk for psychotic disorders, suggesting a relationship between genotypes and the pathophysiology of psychotic disorders. Two genes in the deleted region, catechol-O-methyl-transferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH), contain polymorphisms associated with neuropsychiatric phenotypes. OBJECTIVES: Here, we explored the association between polymorphisms and full-scale intelligence (FSIQ), startle reactivity (SR) and prepulse inhibition (PPI) in adults with 22q11DS. METHODS: Forty-five adults with 22q11DS were genotyped for PRODH rs450046, rs372055 and COMT Val(158)Met. Plasma proline levels, FSIQ, SR and PPI were measured. RESULTS: Thirty-five percent of the subjects were hyperprolinemic with a median proline value of 456 µmol/L. C allele carriers of PRODH rs450046 had a lower FSIQ compared to T allele carriers, indicating the C allele to be a risk allele (C allele: mean FSIQ 60.2 (sd 8.7); T allele: mean FSIQ 73.7 (sd 11.5); F 1,43 = 7.59; p = 0.009; partial η (2) = 0.15). A significant interaction effect of proline levels and COMT Val(158)Met genotype was found for SR (F 1,16 = 7.9; p = 0.01; partial η (2) = 0.33), but not for PPI and FSIQ. In subjects with hyperprolinemia, the COMT Val(158)Met genotype effect on SR was stronger than in subjects with normal proline levels. CONCLUSIONS: Overall, these data provide further evidence for the risk effect of elevated proline levels combined with the COMT Met allele and support the possibilities of using 22q11DS as a model to investigate genotype effects on psychiatric disorders.

Pharmacological Interventions for the MATRICS Cognitive Domains in Schizophrenia: What's the Evidence?

Schizophrenia is a disabling, chronic psychiatric disorder with a prevalence rate of 0.5-1% in the general population. Symptoms include positive (e.g., delusions, hallucinations), negative (e.g., blunted affect, social withdrawal), as well as cognitive symptoms (e.g., memory and attention problems). Although 75-85% of patients with schizophrenia report cognitive impairments, the underlying neuropharmacological mechanisms are not well understood and currently no effective treatment is available for these impairments. This has led to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, which established seven cognitive domains that are fundamentally impaired in schizophrenia. These domains include verbal learning and memory, visual learning and memory, working memory, attention and vigilance, processing speed, reasoning and problem solving, and social cognition. Recently, a growing number of studies have been conducted trying to identify the underlying neuropharmacological mechanisms of cognitive impairments in schizophrenia patients. Specific cognitive impairments seem to arise from different underlying neuropharmacological mechanisms. However, most review articles describe cognition in general and an overview of the mechanisms involved in these seven separate cognitive domains is currently lacking. Therefore, we reviewed the underlying neuropharmacological mechanisms focusing on the domains as established by the MATRICS initiative which are considered most crucial in schizophrenia.

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis.

Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([18F]-DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [123I]-IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.

Startle reactivity and prepulse inhibition of the acoustic startle response are modulated by catechol-O-methyl-transferase Val(158) Met polymorphism in adults with 22q11 deletion syndrome.

22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22, which includes the gene coding for catechol-O-methyl-transferase (COMT). High dopamine (DA) levels due to COMT haplo-insufficiency may be associated with the increased risk of developing schizophrenia in adults with 22q11DS. Reduced prepulse inhibition (PPI) of the acoustic startle response has been associated with schizophrenia and with disrupted DAergic transmission in the prefrontal cortex (PFC). COMT Val(158)Met polymorphism has been shown to influence PPI. We report the first study in adults with 22q11DS to examine PPI of the acoustic startle response and its modulation by COMT Val(158)Met polymorphism. Startle reactivity (SR) and PPI of the acoustic startle response were measured in 23 adults with 22q11DS and 21 healthy controls. 22q11DS subjects were genotyped for the functional COMT Val(158)Met polymorphism. 22q11DS Met hemizygotes showed reduced SR and PPI compared with 22q11DS Val hemizygotes. The effect of COMT Val(158)Met polymorphism on PPI was no longer significant when controlling for baseline SR. Met hemizygosity in 22q11DS is associated with reduced SR and influences PPI indirectly. Decreased PFC functioning following excessive PFC DA levels may be one of the mechanisms by which the Met genotype in 22q11DS disrupts SR.

White matter integrity in Asperger syndrome: a preliminary diffusion tensor magnetic resonance imaging study in adults.

BACKGROUND: Autistic Spectrum Disorder (ASD), including Asperger syndrome and autism, is a highly genetic neurodevelopmental disorder. There is a consensus that ASD has a biological basis, and it has been proposed that it is a "connectivity" disorder. Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) allows measurement of the microstructural integrity of white matter (a proxy measure of "connectivity"). However, nobody has investigated the microstructural integrity of whole brain white matter in people with Asperger syndrome. METHODS: We measured the fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) of white matter, using DT-MRI, in 13 adults with Asperger syndrome and 13 controls. The groups did not differ significantly in overall intelligence and age. FA, MD and RD were assessed using whole brain voxel-based techniques. RESULTS: Adults with Asperger syndrome had a significantly lower FA than controls in 13 clusters. These were largely bilateral and included white matter in the internal capsule, frontal, temporal, parietal and occipital lobes, cingulum and corpus callosum. CONCLUSIONS: Adults with Asperger syndrome have widespread significant differences from controls in white matter microstructural integrity.

White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents.

Young people with 22q11 Deletion Syndrome (22q11DS) are at substantial risk for developing psychosis and have significant differences in white matter (WM) volume. However, there are few in vivo studies of both WM microstructural integrity (as measured using Diffusion Tensor (DT)-MRI) and WM volume in the same individual. We used DT-MRI and structural MRI (sMRI) with voxel based morphometry (VBM) to compare, respectively, the fractional anisotropy (FA) and WM volume of 11 children and adolescents with 22q11DS and 12 controls. Also, within 22q11DS we related differences in WM to severity of schizotypy, and polymorphism of the catechol-O-methyltransferase (COMT) gene. People with 22q11DS had significantly lower FA in inter-hemispheric and brainstem and frontal, parietal and temporal lobe regions after covarying for IQ. Significant WM volumetric increases were found in the internal capsule, anterior brainstem and frontal and occipital lobes. There was a significant negative correlation between increased schizotypy scores and reduced WM FA in the right posterior limb of internal capsule and the right body and left splenium of corpus callosum. Finally, the Val allele of COMT was associated with a significant reduction in both FA and volume of WM in the frontal lobes, cingulum and corpus callosum. Young people with 22q11DS have significant differences in both WM microstructure and volume. Also, there is preliminary evidence that within 22q11DS, some regional differences in FA are associated with allelic variation in COMT and may perhaps also be associated with schizotypy.