Corrigendum: The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: a 1H-MRS study in first-episode psychosis patients.

[This corrects the article DOI: 10.3389/fpsyt.2022.967941.].

Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of SV2A.

BACKGROUND: The synaptic hypothesis is an influential theory of the pathoetiology of schizophrenia (SCZ), which is supported by the finding that there is lower uptake of the synaptic terminal density marker [11C]UCB-J in patients with chronic SCZ than in control participants. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [11C]UCB-J volume of distribution (VT) in antipsychotic-naïve/free patients with SCZ who were recruited from first-episode services compared with healthy volunteers. METHODS: Forty-two volunteers (SCZ n = 21, healthy volunteers n = 21) underwent [11C]UCB-J positron emission tomography to index [11C]UCB-J VT and distribution volume ratio in the anterior cingulate, frontal, and dorsolateral prefrontal cortices; the temporal, parietal and occipital lobes; and the hippocampus, thalamus, and amygdala. Symptom severity was assessed in the SCZ group using the Positive and Negative Syndrome Scale. RESULTS: We found no significant effects of group on [11C]UCB-J VT or distribution volume ratio in most regions of interest (effect sizes from d = 0.0-0.7, p > .05), with two exceptions: we found lower distribution volume ratio in the temporal lobe (d = 0.7, uncorrected p < .05) and lower VT/fp in the anterior cingulate cortex in patients (d = 0.7, uncorrected p < .05). The Positive and Negative Syndrome Scale total score was negatively associated with [11C]UCB-J VT in the hippocampus in the SCZ group (r = -0.48, p = .03). CONCLUSIONS: These findings indicate that large differences in synaptic terminal density are not present early in SCZ, although there may be more subtle effects. When taken together with previous evidence of lower [11C]UCB-J VT in patients with chronic illness, this may indicate synaptic density changes during the course of SCZ.

Treating negative symptoms of schizophrenia: current approaches and future perspectives.

Negative symptoms are core symptoms of schizophrenia which are common throughout the course of the illness. We outline their functional impact, before reviewing the latest research and guidelines on their assessment and treatment. Finally, we discuss conceptual issues related to measurement of negative symptoms and approaches to address these.

The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: A 1H-MRS study in first-episode psychosis patients.

Introduction: Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia. It is unclear whether glutamatergic dysfunction predicts response to treatment or if antipsychotic treatment influences glutamate levels. We investigated the effect of antipsychotic treatment on glutamatergic levels in the anterior cingulate cortex (ACC), and whether there is a relationship between baseline glutamatergic levels and clinical response after antipsychotic treatment in people with first episode psychosis (FEP). Materials and methods: The sample comprised 25 FEP patients; 22 completed magnetic resonance spectroscopy scans at both timepoints. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Results: There was no significant change in glutamate [baseline 13.23 ± 2.33; follow-up 13.89 ± 1.74; t(21) = -1.158, p = 0.260], or Glx levels [baseline 19.64 ± 3.26; follow-up 19.66 ± 2.65; t(21) = -0.034, p = 0.973]. There was no significant association between glutamate or Glx levels at baseline and the change in PANSS positive (Glu r = 0.061, p = 0.777, Glx r = -0.152, p = 0.477), negative (Glu r = 0.144, p = 0.502, Glx r = 0.052, p = 0.811), general (Glu r = 0.110, p = 0.607, Glx r = -0.212, p = 0.320), or total scores (Glu r = 0.078, p = 0.719 Glx r = -0.155, p = 0.470). Conclusion: These findings indicate that treatment response is unlikely to be associated with baseline glutamatergic metabolites prior to antipsychotic treatment, and there is no major effect of antipsychotic treatment on glutamatergic metabolites in the ACC.

The relationship between glutamate, dopamine, and cortical gray matter: A simultaneous PET-MR study.

Prefrontal cortex has been shown to regulate striatal dopaminergic function via glutamatergic mechanisms in preclinical studies. Concurrent disruption of these systems is also often seen in neuropsychiatric disease. The simultaneous measurement of striatal dopamine signaling, cortical gray matter, and glutamate levels is therefore of major interest, but has not been previously reported. In the current study, twenty-eight healthy subjects underwent 2 simultaneous [11C]-( + )-PHNO PET-MRI scans, once after placebo and once after amphetamine in a double-blind randomized cross-over design, to measure striatal dopamine release, striatal dopamine receptor (D2/3R) availability, anterior cingulate glutamate+glutamine (Glx) levels, and cortical gray matter volumes at the same time. Voxel-based morphometry was used to investigate associations between neurochemical measures and gray matter volumes. Whole striatum D2/3R availability was positively associated with prefrontal cortex gray matter volume (pFWE corrected = 0.048). This relationship was mainly driven by associative receptor availability (pFWE corrected = 0.023). In addition, an interaction effect was observed between sensorimotor striatum D2/3R availability and anterior cingulate Glx, such that in individuals with greater anterior cingulate Glx concentrations, D2/3R availability was negatively associated with right frontal cortex gray matter volumes, while a positive D2/3R-gray matter association was observed in individuals with lower anterior cingulate Glx levels (pFWE corrected = 0.047). These results are consistent with the hypothesis that the prefrontal cortex is involved in regulation of striatal dopamine function. Furthermore, the observed associations raise the possibility that this regulation may be modulated by anterior cingulate glutamate concentrations.

Dopamine partial agonists and prodopaminergic drugs for schizophrenia: Systematic review and meta-analysis of randomized controlled trials.

Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=-0.33,p = 1.2 ×10-17), negative (SMD=-0.29,p = 2.2 × 10-31) and total symptoms (SMD =-0.39,p = 1.7 × 10-30) in schizophrenia. There were no significant differences between pooled pro-dopaminergic drugs and placebo in any symptom domain. In subgroup analysis of five studies where patients were selected for negative symptom severity, ar/modafinil was superior to placebo against negative symptoms (SMD=-0.34,p = 0.037). These data favour the clinical use of partial agonists for negative symptoms in schizophrenia, with clinically meaningful effect sizes. Our findings also suggest a benefit for ar/modafinil in patients with predominant negative symptoms. Future trials of other prodopaminergic therapies and dopamine partial agonists in patients with predominant negative symptoms are warranted.

Dopaminergic organization of striatum is linked to cortical activity and brain expression of genes associated with psychiatric illness.

Dopamine signaling is constrained to discrete tracts yet has brain-wide effects on neural activity. The nature of this relationship between local dopamine signaling and brain-wide neuronal activity is not clearly defined and has relevance for neuropsychiatric illnesses where abnormalities of cortical activity and dopamine signaling coexist. Using simultaneous PET-MRI in healthy volunteers, we find strong evidence that patterns of striatal dopamine signaling and cortical blood flow (an index of local neural activity) contain shared information. This shared information links amphetamine-induced changes in gradients of striatal dopamine receptor availability to changes in brain-wide blood flow and is informed by spatial patterns of gene expression enriched for genes implicated in schizophrenia, bipolar disorder, and autism spectrum disorder. These results advance our knowledge of the relationship between cortical function and striatal dopamine, with relevance for understanding pathophysiology and treatment of diseases in which simultaneous aberrations of these systems exist.

Multidisciplinary Management of a Frequent Attender With Pyrexia of Unknown Origin and Psychotic Symptoms.

This case report details the multidisciplinary management of a frequent attender in his early 50s with no fixed abode who presented with pyrexia of unknown origin, complicated by his noncooperation with intervention and treatment because of the development of psychotic symptoms. The case required the involvement of liaison psychiatry, anesthesia, cardiology, radiology, gastroenterology, rheumatology, respiratory, hematology, and social services, highlighting not just multidisciplinary intervention but the benefits of working with a multispeciality team. The patient had previously presented to the emergency department 47 times over an 18-month period. The management during his most recent inpatient stay resulted in the patient living independently and presenting to the hospital only once over the ensuing 7 months.

The clinical significance of duration of untreated psychosis: an umbrella review and random-effects meta-analysis.

The idea that a longer duration of untreated psychosis (DUP) leads to poorer outcomes has contributed to extensive changes in mental health ser-vices worldwide and has attracted considerable research interest over the past 30 years. However, the strength of the evidence underlying this notion is unclear. To address this issue, we conducted an umbrella review of available meta-analyses and performed a random-effects meta-analysis of primary studies. MEDLINE, Web of Science, PsycINFO and EMBASE were searched from inception to September 3, 2020 to identify relevant meta-analyses of studies including patients with schizophrenia spectrum disorders, first-episode psychosis, or affective and non-affective psychosis. Thirteen meta-analyses were included, corresponding to 129 individual studies with a total sample size of 25,657 patients. We detected potential violations of statistical assumptions in some of these meta-analyses. We therefore conducted a new random-effects meta-analysis of primary studies. The association between DUP and each outcome was graded according to a standardized classification into convincing, highly suggestive, suggestive, weak, or non-significant. At first presentation, there was suggestive evidence for a relationship between longer DUP and more severe negative symptoms (beta=-0.07, p=3.6×10-5 ) and higher chance of previous self-harm (odds ratio, OR=1.89, p=1.1×10-5 ). At follow-up, there was highly suggestive evidence for a relationship between longer DUP and more severe positive symptoms (beta=-0.16, p=4.5×10-8 ), more severe negative symptoms (beta=-0.11, p=3.5×10-10 ) and lower chance of remission (OR=2.16, p=3.0×10-10 ), and suggestive evidence for a relationship between longer DUP and poorer overall functioning (beta=-0.11, p=2.2×10-6 ) and more severe global psychopathology (beta=-0.16, p=4.7×10-6 ). Results were unchanged when analysis was restricted to prospective studies. These effect sizes are clinically meaningful, with a DUP of four weeks predicting >20% more severe symptoms at follow-up relative to a DUP of one week. We conclude that DUP is an important prognostic factor at first presentation and predicts clinically relevant outcomes over the course of illness. We discuss conceptual issues in DUP research and methodological limitations of current evidence, and provide recommendations for future research.

Proton Magnetic Resonance Spectroscopy of N-acetyl Aspartate in Chronic Schizophrenia, First Episode of Psychosis and High-Risk of Psychosis: A Systematic Review and Meta-Analysis.

N-acetyl-aspartate (NAA) is a readily measured marker of neuronal metabolism. Previous analyses in schizophrenia have shown NAA levels are low in frontal, temporal and thalamic regions, but may be underpowered to detect effects in other regions, in high-risk states and in first episode psychosis. We searched for magnetic resonance spectroscopy studies comparing NAA in chronic schizophrenia, first episode psychosis and high risk of psychosis to controls. 182 studies were included and meta-analysed using a random-effects model for each region and illness stage. NAA levels were significantly lower than controls in the frontal lobe [Hedge's g = -0.36, p < 0.001], hippocampus [-0.52, p < 0.001], temporal lobe [-0.35, p = 0.031], thalamus [-0.32, p = 0.012] and parietal lobe [-0.25, p = 0.028] in chronic schizophrenia, and lower than controls in the frontal lobe [-0.26, p = 0.002], anterior cingulate cortex [-0.24, p = 0.016] and thalamus [-0.28, p = 0.028] in first episode psychosis. NAA was lower in high-risk of psychosis in the hippocampus [-0.20, p = 0.049]. In schizophrenia, NAA alterations appear to begin in hippocampus, frontal cortex and thalamus, and extend later to many other regions.