While dopamine antagonists are an effective treatment for positive psychotic symptoms, they are rarely effective when it comes to treating the cognitive (memory, learning, planning, etc.) and negative (avolition and social withdrawal) symptoms of the disorder. Furthermore, for a sizeable proportion, standard dopamine antagonists are not effective for positive symptoms either. As such, refractory symptoms are a major burden for patients, carers, and clinical services.

To address this, The TUNE-UP (Treating Unmet Needs in Psychiatry) clinic in Oxford was established in September 2023 as an innovative solution aiming to: (A) Undertake an in-depth assessment of cognitive, negative, and positive symptoms; (B) Identify potentially modifiable causative factors contributing to refractory symptoms (e.g., cholinergic burden, sleep disturbances, physical comorbidities, affective symptoms); and (C) Implement management plans including community clozapine initiation where appropriate. We have analysed data from the clinic's initial five months of operation to establish a baseline understanding of our patient population and identify trends in symptoms.

In the first five months of operations, 21 referrals were accepted comprising 80.9% males (mean age 43.3 years, SD 13.7). 3 were referred for cognitive symptoms, 1 for negative and cognitive symptoms, 11 for positive symptoms, 3 for medication optimisation, and 3 for clozapine re-titration. Of those fully assessed (N = 17), mean total symptom scores measured using the Positive and Negative Syndrome Scale (PANSS) were of mild/moderate severity (70.5, SD 18.4). Objective cognitive testing via the Screen for Cognitive Impairment in Psychiatry (SCIP) demonstrated a total mean score of 54.1 (SD 12.1), markedly below what would be expected in a matched control population (76.3). Cognitive scores were lower in those of older age (r = −0.62, p = 0.01). Subjective experience of cognitive impairment was measured using the Subjective Scale to Investigate Cognition in Schizophrenia, poor subjective cognition was associated with more severe negative symptoms (r = 0.57, p = 0.03), but not objective SCIP results (r = 0.12, p = 0.85).

Refractory positive symptoms remain a priority for clinicians, but cognitive and negative symptoms are highly prevalent reinforcing the need for a comprehensive approach. Routine structured assessment of all symptom domains is feasible in clinical practice. Future work should examine the longitudinal impact of various interventions on different symptom domains.

Antipsychotic treatment is associated with metabolic disturbance, with clear differences observed between drugs in the adult population. However, the degree to which metabolic alterations occur with different antipsychotics in children and adolescents is unclear. As such, we aimed to compare and rank antipsychotics based on their metabolic and endocrine side-effects when used in the treatment of schizophrenia in this age population.

We searched MEDLINE, EMBASE, and PsycINFO from inception until October 30, 2022. We included double blinded, randomised controlled trials comparing 12 antipsychotics and placebo in acute treatment of schizophrenia in individuals aged <18 years. We performed random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose, and prolactin concentrations. We performed meta-regressions to examine the relationship between metabolic/endocrine change and age, sex, and ethnicity

Of 6697 citations, we included 15 randomised controlled trials, consisting of 2501 patients. Antipsychotics included in analyses were aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. Median treatment duration was 6 weeks (IQR 6-12). Mean age was 15.13 (SD 0.94) years. Mean differences for weight gain compared with placebo ranged from -2.04 kg (95% CI -4.24 to 0.17) kg for molindone to 4.11 kg (-0.55 to 8.77) for clozapine; for BMI from -0.55 kg/m2 (-1.37 to 0.27) for molindone to 1.92 kg/m2 (0.16 to 3.68) for quetiapine; for total cholesterol from -0.14 mmol/L (-0.70 to 0.41) for risperidone/paliperidone to 0.46 mmol/L (0.00 to 0.90) for quetiapine; for LDL cholesterol from -0.32 mmol (-0.76 to 0.12) for aripiprazole to 0.24 mmol/L (-0.15 to 0.63) for olanzapine; for HDL cholesterol from 0.10 mmol/L (-0.05 to 0.26) for aripiprazole to -0.23 mmol/L (-0.52 to 0.06) for risperidone/paliperidone; for triglycerides from -0.01 mmol/L (-0.21 to 0.34) for molindone to 0.62 mmol/L (0.04 to 1.2) for clozapine; for glucose from -0.33 mmol/L (-0.64 to -0.02) for ziprasidone to 0.81 mmol/L (0.28 to 1.34) for clozapine; for prolactin from -1.92 ng/mL (-15.37 to 11.53) for aripiprazole to 28.10 ng/mL (16.23 to 39.96) for risperidone/paliperidone. Higher baseline age predicted by greater increases in body weight (p = 0.014).

We found significant differences between antipsychotics in terms of metabolic and endocrine side-effects when used in children and adolescents. 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 young people, carers, and clinicians.

Clozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear.

The aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine.

This was a naturalistic study of community patients recommended for clozapine treatment.

Of 158 patients recommended for clozapine treatment, 88 (56%) patients agreed to clozapine initiation and, of these, 58 (66%) were successfully established on clozapine. The success rate for community initiation was 65.4%; which was not significantly different from that for in-patient initiation (58.82%, χ2(1,88) = 0.47, P = 0.49). Following clozapine initiation, there was a significant reduction in median out-patient visits over 1 year (from 24.00 (interquartile range (IQR) = 14.00–41.00) to 13.00 visits (IQR = 5.00–24.00), P < 0.001), and 2 years (from 47.50 visits (IQR = 24.75–71.00) to 22.00 (IQR = 11.00–42.00), P < 0.001), and a 74.71% decrease in psychiatric hospital bed days (z = −2.50, P = 0.01). Service-use costs decreased (1 year: –£963/patient (P < 0.001); 2 years: –£1598.10/patient (P < 0.001). Subanalyses for community-only initiation also showed significant cost reductions (1 year: –£827.40/patient (P < 0.001); 2 year: –£1668.50/patient (P < 0.001) relative to costs prior to starting clozapine. Relative to before initiation, symptom severity was improved in patients taking clozapine at discharge (median Positive and Negative Syndrome Scale total score: initial visit: 80 (IQR = 71.00–104.00); discharge visit 50.5 (IQR = 44.75–75.00), P < 0.001) and at 2 year follow-up (Health of Nation Outcome Scales total score median initial visit: 13.00 (IQR = 9.00–15.00); 2 year follow-up: 8.00 (IQR = 3.00–13.00), P = 0.023).

These findings indicate that community initiation of clozapine is feasible and is associated with significant reductions in costs, service use and symptom severity.

First-episode psychosis (FEP) is associated with metabolic alterations. However, it is not known if there is heterogeneity in these alterations beyond what might be expected due to normal individual differences, indicative of subgroups of patients at greater vulnerability to metabolic dysregulation.

We employed meta-analysis of variance, indexed using the coefficient of variation ratio (CVR), to compare variability of the following metabolic parameters in antipsychotic naïve FEP and controls: fasting glucose, glucose post-oral glucose tolerance test (OGTT), fasting insulin, insulin resistance, haemoglobin A1c (HbA1c), total-cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides. Standardised mean difference in metabolic parameters between groups was also calculated; meta-regression analyses examined physiological/demographic/psychopathological moderators of metabolic change.

Twenty-eight studies were analysed (1716 patients, 1893 controls). Variability of fasting glucose [CVR = 1.32; 95% confidence interval (CI) 1.12–1.55; p = 0.001], glucose post-OGTT (CVR = 1.43; 95% CI 1.10–1.87; p = 0.008), fasting insulin (CVR = 1.31; 95% CI 1.09–1.58; p = 0.01), insulin resistance (CVR = 1.34; 95% CI 1.12–1.60; p = 0.001), HbA1c (CVR = 1.18; 95% CI 1.06–1.27; p < 0.0001), total-cholesterol (CVR = 1.15; 95% CI 1.01–1.31; p = 0.03), LDL-cholesterol (CVR = 1.28; 95% CI 1.09–1.50; p = 0.002), and HDL-cholesterol (CVR = 1.15; 95% CI 1.00–1.31; p < 0.05), but not triglycerides, was greater in patients than controls. Mean glucose, glucose post-OGTT, fasting insulin, insulin resistance, and triglycerides were greater in patients; mean total-cholesterol and HDL-cholesterol were reduced in patients. Increased symptom severity and female sex were associated with worse metabolic outcomes.

Patients with FEP present with greater variability in metabolic parameters relative to controls, consistent with a subgroup of patients with more severe metabolic changes compared to others. Understanding determinants of metabolic variability could help identify patients at-risk of developing metabolic syndrome. Female sex and severe psychopathology are associated with poorer metabolic outcomes, with implications for metabolic monitoring in clinical practice.

Evidence from genetics, post mortem and animal studies suggest that N-Methyl-D-Aspartate Receptor (NMDAR) hypofunction has an important role in the pathophysiology of psychosis. However, it is not known if NMDAR activity is altered in the early stages of psychosis or if this links to symptom severity. Our aim was to investigate NMDAR availability in first-episode psychosis (FEP) and determine if it links to symptom severity. The NMDAR hypofunction hypothesis of schizophrenia was initially proposed in the 1990s on the basis of observations that ketamine and phencyclidine (PCP) induced the full range of schizophrenia-like symptoms (positive, negative and cognitive) when given to healthy participants and also that they worsen symptoms in patients with schizophrenia.

We recruited 40 volunteers, including 21 patients with schizophrenia from early intervention services in London (12 antipsychotic-free and 9 receiving antipsychotic medication) and 19 matched healthy controls. The uptake of an NMDAR selective ligand, [18F]GE179, was measured using positron emission tomography (PET) and indexed using the distribution volume ratio (DVR) and volume of distribution (VT, in millilitres per cubic centimetre) of [18F]GE179 in the hippocampus and additional exploratory regions (anterior cingulate cortex (ACC), thalamus, striatum and temporal lobe). Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS).

A total of 37 individuals were included in the analyses (mean [SD] age of controls, 26.7 [4.5] years; mean [SD] age of patients, 25.3 [4.9] years). There was a significant reduction in hippocampal DVR in the patients with schizophrenia relative to healthy controls (p = 0.02, Cohen's d = 0.81). Although the VT of [18F]GE179 was lower in absolute terms in patients, there was no significant effect of group on VT in the hippocampus (p = 0.15, Cohen's d = 0.49) or the exploratory brain regions. There was a negative association between hippocampal DVR and total PANSS symptoms (rho = –0.47, p = 0.04), depressive symptoms (rho = –0.67, p = 0.002), and general PANSS symptoms (rho = –0.74, p = 0.001).

These results indicate lower hippocampal NMDAR levels in schizophrenia relative to controls with a large effect size, and that lower NMDAR levels are associated with greater levels of symptom severity. These findings are consistent with the role of NMDAR hypofunction in the pathophysiology of schizophrenia; however, further work is required to test specificity and causal relationships.

To conduct a meta-analysis of the effect of ketamine on psychopathology in healthy volunteers and patients with schizophrenia, and the experimental factors affecting this.

Ketamine is increasingly used to treat depression and other psychiatric disorders but can induce schizophrenia-like symptoms. Despite this, the consistency and magnitude of symptoms induced by ketamine, or what factors influence the effects of ketamine on these remain unknown.

MEDLINE, EMBASE and PsychINFO databases were searched for within-subject placebo controlled studies reporting symptoms using the Brief Psychiatric Rating Scale (BPRS) or Positive and Negative Syndrome Scale (PANSS) in response to an acute ketamine challenge in healthy participants or people with schizophrenia. Two independent investigators extracted study-level data for a random-effects meta-analysis. Total, positive and negative BPRS and PANSS scores were extracted. Sub-group analyses were conducted examining the effect of: blinding status, ketamine preparation, infusion method and time between ketamine and placebo condition. Standardized mean change scores were used as effect sizes for individual studies. Standardized mean changes between ketamine and placebo for total, positive and negative BPRS and PANSS were calculated.

Of 7819 citations retrieved, 36 studies involving healthy participants were included. The overall sample included 725 healthy volunteers exposed to both the ketamine and placebo condition. Ketamine induced a significant increase in transient psychopathology in healthy participants, for total (Standardized mean change (SMC) = 1.50 (95% CI = 1.23 to 1.77), p < 0.0001), positive (SMC = 1.55 (95% CI = 1.29 to 1.81), p < 0.0001) and negative (SMC = 1.16, (95% CI = 0.96 to 1.35), p < 0.0001) symptom ratings, relative to the placebo condition. This effect was significantly greater for positive symptoms than negative symptoms (p = 0.004). Bolus followed by constant infusion increased ketamine's effect on positive symptoms relative to infusion alone (p = 0.006). Single-day study design increased ketamine's effect on total symptoms (p = 0.007), but age and gender did not moderate effects. There were insufficient studies for meta-analysis of studies in schizophrenia. Of these studies, two found a significant increase in symptoms with ketamine administration in total and positive symptoms. Only one study found an increase in negative symptom severity with ketamine.

These findings show that acute ketamine administration induces schizophrenia-like symptomatology with large effect sizes but there is a greater increase in positive than negative symptoms, and when a bolus is used. These findings suggest bolus doses should be avoided in its therapeutic use to minimize the risk of inducing transient positive psychotic symptoms.

Ethnic minority individuals have an increased risk of developing a psychotic disorder, particularly if they live in areas of ethnic segregation, or low own group ethnic density. The neurobiological mechanisms underlying this ethnic minority associated risk are unknown. We used functional MRI to investigate neural responses to faces of different ethnicity, in individuals of black ethnicity, and a control group of white British ethnicity individuals.

In total 20 individuals of black ethnicity, and 22 individuals of white British ethnicity underwent a 3T MRI scan while viewing faces of black and white ethnicity. Own group ethnic density was calculated from the 2011 census. Neighbourhood segregation was quantified using the Index of Dissimilarity method.

At the within-group level, both groups showed greater right amygdala activation to outgroup faces. Between groups, the black ethnicity group showed greater right amygdala activation to white faces, compared to the white ethnicity group. Within the black ethnicity group, individuals living in areas of lower own group ethnic density showed greater right amygdala reactivity to white faces (r = −0.61, p = 0.01).

This is the first time an increased amygdala response to white faces has been demonstrated in individuals of black ethnicity. In the black ethnicity group, correlations were observed between amygdala response and neighbourhood variables associated with increased psychosis risk. These results may have relevance for our understanding of the increased rates of paranoia and psychotic disorders in ethnic minority individuals.

Although the benefits of radiotherapy for pituitary adenomas are well-documented, post-irradiation sarcomas of the sella are rarely seen, with only 20 cases (mainly of fibrosarcoma) reported in the medical literature.

We describe a case of post-irradiation sarcoma five years after surgery followed by external-beam irradiation for an extensive and locally invasive growth hormone-secreting tumor. The patient was subsequently given pegvisomant, an antagonist of growth hormone receptor, to control symptoms of growth hormone excess.

The patient underwent transsphenoidal resection of the recurrent tumor, followed by adjuvant chemotherapy. This led to significant relief in the patient's symptoms including radiological evidence of tumor shrinkage, but the tumor regrew when, owing to dose-limiting toxicity, chemotherapy was stopped.

Post-irradiation sarcomas of the pituitary are well-recognized but rare. They should be suspected in patients following sellar irradiation who show abrupt onset of new symptoms and appropriate radiological findings, and such tumors may respond to cytotoxic chemotherapy.