Sex difference in brain CB1 receptor availability in man

none12The endocannabinoid system (ECS) has a widespread neuromodulatory function in the central nervous system and is involved in important aspects of brain function including brain development, cortical rhythms, plasticity, reward, and stress sensitivity. Many of these effects are mediated via the cannabinoid CB1 receptor (CB1R) subtype. Animal studies convincingly show an interaction between the ECS and sex hormones, as well as a sex difference of higher brain CB1R in males. Human in vivo studies of sex difference have yielded discrepant findings. Gender differences in CB1R availability were investigated in vivo in 11 male and 11 female healthy volunteers using a specific CB1R tracer [18F]FMPEP-d2 and positron emission tomography (PET). Regional [18F]FMPEP-d2 distribution volume was used as a proxy for CB1R availability. In addition, we explored whether CB1R availability is linked to neuropsychological functioning. Relative to females, CB1R availability was on average 41% higher in males (p = 0.002) with a regionally specific effect larger in the posterior cingulate and retrosplenial cortices (p = 0.001). Inter-subject variability in CB1R availability was similar in both groups. Voxel-based analyses revealed an inverse association between CB1R availability and visuospatial working memory task performance in both groups (p noneLaurikainen, Heikki; Tuominen, Lauri; Tikka, Maria; Merisaari, Harri; Armio, Reetta-Liina; Sormunen, Elina; Borgan, Faith; Veronese, Mattia; Howes, Oliver; Haaparanta-Solin, Merja; Solin, Olof; Hietala, JarmoLaurikainen, Heikki; Tuominen, Lauri; Tikka, Maria; Merisaari, Harri; Armio, Reetta-Liina; Sormunen, Elina; Borgan, Faith; Veronese, Mattia; Howes, Oliver; Haaparanta-Solin, Merja; Solin, Olof; Hietala, Jarm

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

Changes in brain glutamate on switching to clozapine in treatment-resistant schizophrenia

It has been suggested that the antipsychotic clozapine may modulate brain glutamate, and that this effect could contribute to its efficacy in treatment-resistant schizophrenia (TRS). The aim of this study was to examine the effects of clozapine on brain glutamate in TRS longitudinally. This study examined individuals with TRS before and 12 weeks after switching from a non-clozapine antipsychotic to treatment with clozapine as part of their normal clinical care. Proton magnetic resonance spectroscopy (1H-MRS) measured concentrations, corrected for voxel tissue content, of glutamate (Glucorr), and glutamate plus glutamine (Glxcorr) in the anterior cingulate cortex (ACC) and right caudate nucleus. Symptoms were monitored using the Positive and Negative Syndrome Scale (PANSS). Of 37 recruited patients (27 men, 39.30 years old, 84% clozapine naïve), 25 completed 1H-MRS at both timepoints. 12 weeks of clozapine was associated with a longitudinal reduction in Glucorr in the caudate (n = 23, F = 7.61 P =. 01) but not in the ACC (n = 24, F = 0.02, P =. 59). Percentage reduction in caudate Glucorr was positively correlated with percentage improvement in symptoms (total PANSS score, n = 23, r =. 42, P =. 04). These findings indicate that reductions in glutamate in the caudate nucleus may contribute to symptomatic improvement during the first months of clozapine treatment

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls

Background: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippocampus in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling; however, this has not been tested in vivo. Methods: In this study, we investigated the relationship between hippocampal NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study; 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippocampal NMDAR availability using the PET ligand [18F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy (1H-MRS). Results: A total of 33 individuals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years; mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippocampal DVR and striatal glutamate levels in people with first-episode psychosis (rho = −0.74, p < 0.001) but not in healthy controls (rho = −0.22, p = 0.44). Conclusion: This study show that lower relative NMDAR availability in the hippocampus may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia

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 &lt; 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 &lt; 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 &lt; 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p &lt; 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p &lt; 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

Association between cannabinoid 1 receptor availability and glutamate levels in healthy controls and drug-free patients with first episode psychosis:a multi-modal PET and 1H-MRS study

none5Cannabinoid 1 receptor and glutamatergic dysfunction have both been implicated in the pathophysiology of schizophrenia. However, it remains unclear if cannabinoid 1 receptor alterations shown in drug-naïve/free patients with first episode psychosis may be linked to glutamatergic alterations in the illness. We aimed to investigate glutamate levels and cannabinoid 1 receptor levels in the same region in patients with first episode psychosis. Forty volunteers (20 healthy volunteers, 20 drug-naïve/free patients with first episode psychosis diagnosed with schizophrenia/schizoaffective disorder) were included in the study. Glutamate levels were measured using proton magnetic resonance spectroscopy. CB1R availability was indexed using the distribution volume (VT (ml/cm3)) of [11C]MePPEP using arterial blood sampling. There were no significant associations between ACC CB1R levels and ACC glutamate levels in controls (R = − 0.24, p = 0.32) or patients (R = − 0.10, p = 0.25). However, ACC glutamate levels were negatively associated with CB1R availability in the striatum (R = − 0.50, p = 0.02) and hippocampus (R = − 0.50, p = 0.042) in controls, but these associations were not observed in patients (p > 0.05). Our findings extend our previous work in an overlapping sample to show, for the first time as far as we’re aware, that cannabinoid 1 receptor alterations in the anterior cingulate cortex are shown in the absence of glutamatergic dysfunction in the same region, and indicate potential interactions between glutamatergic signalling in the anterior cingulate cortex and the endocannabinoid system in the striatum and hippocampus.noneBorgan, Faith; Veronese, Mattia; Reis Marques, Tiago; Lythgoe, David J.; Howes, OliverBorgan, Faith; Veronese, Mattia; Reis Marques, Tiago; Lythgoe, David J.; Howes, Olive