Half a century of research on antipsychotics and schizophrenia : A scientometric study of hotspots, nodes, bursts, and trends

Changes over 50 years of research on antipsychotics in schizophrenia have occurred. A scientometric synthesis of such changes over time and a measure of researchers' networks and scientific productivity is currently lacking. We searched Web of Science Core Collection from inception until November 5, 2021, using the appropriate key. Our primary objective was to conduct systematic mapping with CiteSpace to show how clusters of keywords have evolved over time and obtain clusters' structure and credibility. Our secondary objective was to measure research network performance (countries, institutions, and authors) using CiteSpace, VOSviewer, and Bibliometrix. We included 32,240 studies published between 1955 and 2021. The co-cited reference network identified 25 clusters with a well-structured network (Q=0.8166) and highly credible clustering (S=0.91). The main trends of research were: 1) antipsychotic efficacy; 2) cognition in schizophrenia; 3) side effects of antipsychotics. Last five years research trends were: 'ultra-resistance schizophrenia' (S=0.925), 'efficacy/dose-response' (S=0.775), 'evidence synthesis' (S=0.737), 'real-world effectiveness' (S=0.794), 'cannabidiol' (S=0.989), and 'gut microbiome' (S=0.842). These results can inform funding agencies and research groups' future directions.Peer reviewe

Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis.

BACKGROUND Antipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment. METHODS We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change. FINDINGS Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with placebo ranged from -0·23 kg (95% CI -0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from -0·25 kg/m2 (-0·68 to 0·17) for haloperidol to 1·07 kg/m2 (0·90 to 1·25) for olanzapine; for total-cholesterol from -0·09 mmol/L (-0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26-0·86) for clozapine; for LDL cholesterol from -0·13 mmol/L (-0.21 to -0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for brexpiprazole to -0·10 mmol/L (-0·33 to 0·14) for amisulpride; for triglycerides from -0·01 mmol/L (-0·10 to 0·08) for brexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from -0·29 mmol/L (-0·55 to -0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p<0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=-0·35, p=0·035). INTERPRETATION Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. However, the choice of antipsychotic should be made on an individual basis, considering the clinical circumstances and preferences of patients, carers, and clinicians. FUNDING UK Medical Research Council, Wellcome Trust, National Institute for Health Research Oxford Health Biomedical Research Centre

Evaluating sustainability: a retrospective cohort analysis of the Oxfordshire therapeutic community

Background: Therapeutic communities (TCs) could reduce the health care use of people with personality disorder (Davies S, Campling P and Ryan K, Psychiatrist 23:79–83, 1999; Barr W, Kirkcaldy A, Horne A, Hodge S, Hellin K and Göpfert M, J Ment Health 19:412–421, 2010) and in turn reduce the financial and environmental costs of services. Our hypothesis is that 3 years following entry to a TC service, patients have reduced subsequent health care use and associated reductions in financial costs and carbon footprint. Methods: A retrospective 4-year cohort study examined changes in health care use following entry to the Oxfordshire TC service. Comparative analysis was undertaken on a treated (n = 40) and a control group (referred but who declined treatment; n = 45). Financial costs and carbon footprint of health care use were calculated using national tariffs and standard carbon conversion factors. Mean changes in these outcomes were compared over 1, 2 and 3 years and adjusted for costs and carbon footprints in the year prior to joining the TC service. Results: Compared to baseline, the group receiving TC care had greater reductions in financial costs and carbon footprint associated with A&E attendances (p = 0.04) and crisis mental health appointments (p = 0.04) than the control group. There were significantly greater reductions in carbon footprint for all secondary health care use, both physical and mental health care, after 3 years (p = 0.04) in the TC group. Conclusions: TC services may have the potential to reduce the financial cost and carbon footprint of health car

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

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

A leaky umbrella has little value:evidence clearly indicates the serotonin system is implicated in depression

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

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