A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia.

Involvement of oxidative stress in the pathophysiology of schizophrenia (SZ) is suggested by studies of peripheral tissue. Nonetheless, it is unclear how such biological changes are linked to relevant, pathological neurochemistry, and brain function. We designed a multi-faceted study by combining biochemistry, neuroimaging, and neuropsychology to test how peripheral changes in a key marker for oxidative stress, glutathione (GSH), may associate with central neurochemicals or neuropsychological performance in health and in SZ. GSH in dorsal anterior cingulate cortex (dACC) was acquired as a secondary 3T 1H-MRS outcome using a MEGA-PRESS sequence. Fifty healthy controls and 46 patients with SZ were studied cross-sectionally, and analyses were adjusted for effects of confounding variables. We observed lower peripheral total GSH in SZ compared to controls in extracellular (plasma) and intracellular (lymphoblast) pools. Total GSH levels in plasma positively correlated with composite neuropsychological performance across the total population and within patients. Total plasma GSH levels were also positively correlated with the levels of Glx in the dACC across the total population, as well as within each individual group (controls, patients). Furthermore, the levels of dACC Glx and dACC GSH positively correlated with composite neuropsychological performance in the patient group. Exploring the relationship between systemic oxidative stress (in particular GSH), central glutamate, and cognition in SZ will benefit further from assessment of patients with more varied neuropsychological performance.

Demographic and clinical correlates of suicidality in adolescents attending a specialist community mental health service: a naturalistic study.

BACKGROUND: Adolescents comprise a unique and often challenging group of patients with diverse presentations to the Mental Health Services; suicidal behavior being one of them. AIMS: The main aim of this naturalistic project was to investigate demographic and clinical correlates of adolescent suicidal and self-harm events, which may be of value to decision-making in clinical practice. METHOD: All adolescents (n = 149) registered and actively managed by a specialist community mental health service in South London were included in the study. Clinical information from their files was used to determine suicidality/self-harm events. The Columbia Classification Algorithm of Suicide Assessment (C-CASA) was utilised for classification purposes. Logistic regression was used to explore the effects of age, sex, diagnosis, medication, substance use (alcohol and/or cannabis) and ethnicity on suicidality/self-harming behaviors. RESULTS: Age, sex and use of psychotropic medication were identified to play a significant role in determining the risk of engaging in self-harming behavior. The risk was higher with increasing age and female sex. Medication seemed to have a protective effect. Reporting a 20% prevalence of non-suicidal self-injury (NSSI) in our population, we highlight the importance of NSSI as a distinct diagnostic category. CONCLUSIONS: Our findings have implications for risk assessment and appropriate decision-making in clinical settings. Results are translatable and relevant to other metropolitan areas.

Promoting careers in academic research to psychiatry residents.

OBJECTIVE: With the shift of interest in psychiatry towards patient-oriented research with clinically relevant outcomes, there is a critical need for well-trained psychiatrist-scientists. The authors report on two developmentally tailored, longitudinal research training curricula designed to use peer mentoring to bridge the gap between physicians and scientists and to promote careers in academic research. METHODS: The authors instituted two independent research training curricula, one for first-year and one for second-to-fourth-year psychiatry residents, spanning two campuses of one institutional residency training program. Each curriculum's participants included psychiatry residents and peer scientific investigators, and both were attended by senior scientists and departmental leaders. The authors developed and administered an anonymous survey at the end of the first cycle of the first-year resident curriculum to assess participant attitudes. RESULTS: The first-year and second-to-fourth-year resident curricula have been implemented for 3 and 2 years, respectively. The authors observed overall participant satisfaction with the first-year curricula, independent of trainee status. Furthermore, first-year psychiatry residents reported increased interest in academic research careers after exposure to the curricula. CONCLUSIONS: Results suggest that it is possible to encourage academic research careers using peer mentoring, an innovative approach that requires minimal funding, causes little disruption to the residents' schedule and engages the gamut of individuals involved in psychiatry care and research: psychiatrists-in-training and young non-clinician scientists-in-training.

Reduced Activity in an Inpatient Liaison Psychiatry Service During the First Wave of the COVID-19 Pandemic: Comparison With 2019 Data and Characterization of the SARS-CoV-2 Positive Cohort.

Background: The COVID-19 pandemic led to changes in the way that healthcare was accessed and delivered in the United Kingdom (UK), particularly during the peak of the first lockdown period (the "first wave") beginning in March 2020. In some patients, COVID-19 is associated with acute neuropsychiatric manifestations, and there is suggestion that there may also be longer term neuropsychiatric complications. Despite this, at the time of writing there are only emerging data on the direct effects of the COVID-19 pandemic on psychiatric care. Methods: In this retrospective study we analyzed referrals to an inpatient liaison psychiatry department of a large acute teaching hospital during the first wave of covid-19 in the UK and compared this data to the same period in 2019. Results: We saw a 40% reduction in the number of referrals in 2020, with an increase in the proportion of referrals for both psychosis or mania and delirium. Almost one third (28%) of referred patients tested positive for COVID-19 at some point during their admission, with 40% of these presenting with delirium as a consequence of their COVID-19 illness. Save delirium, we did not find evidence for high prevalence of new-onset acute mental illness in COVID-19 positive patients. Conclusion: Our data indicate decreased clinical activity in our inpatient psychiatry liaison department during the first wave of the COVID-19 pandemic, although a relative increase in relative increase in referrals for psychosis or mania, suggesting less of a relative decrease in more severe cases of mental illness. The reasons for this are likely multifactorial, including structural changes in the NHS and patient reluctance to present to emergency departments (ED) due to infection fears and Government advice. Our data also supports the literature suggesting the high relative prevalence of delirium in COVID-19, and we support integration of psychiatry liaison teams in acute general hospital wards to optimize delirium management. Finally, consideration should be given to adequate staffing of community and crisis mental health teams to safely manage the mental health of people reluctant to visit EDs.

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.

G-CSF mediated neutrophil augmentation in a unique case of comorbid idiopathic Parkinson's disease and treatment-resistant schizophrenia on clozapine.

Treatment of psychosis in Parkinson's disease (PD) is challenging; pharmacological options are limited, with clozapine considered most effective. The risk of agranulocytosis restricts the use of clozapine, but, where this occurs, cautious re-challenge with granulocyte stimulating factor can be successful. We present a unique case of a patient who developed early-onset PD on a background of antecedent treatment-resistant schizophrenia, who had been treated effectively with clozapine for over 15 years with no adverse events. However, during a hospital admission intended to optimise her Parkinsonian medications, she developed persistent neutropenia necessitating clozapine discontinuation. Numerous attempts to re-challenge with clozapine failed until augmentation with lithium and G-CSF was trialled. Two doses of G-CSF led to a sustained increase in the neutrophil count, allowing the continuation of clozapine therapy in the 1 year of follow up. This illustrates the potential for G-CSF to be used to facilitate clozapine use in a patient population not described previously. Neutrophil augmentation allowed the sustained continuation of this effective therapy, treating her psychotic symptoms without detriment to her movement disorder. We suggest that G-CSF might be considered as a treatment option in other cases where clozapine-associated neutropenia obstructs its use.

Deep Brain Stimulation of the Memory Circuit: Improving Cognition in Alzheimer's Disease.

Deep brain stimulation (DBS) is an effective invasive treatment for a wide range of neurological and psychiatric disorders. Neurosurgically implanted electrodes deliver stimulation of pre-programmed amplitude, frequency, and pulse width within deep brain structures; those settings can be adjusted at a later stage according to individual needs for optimal response. This results in variable effects dependent on the targeted region. An established treatment for movement disorders, the effectiveness of DBS in dementia remains under investigation. Translational studies have uncovered a pro-cognitive effect mediated by changes on cellular as well as network level. Several groups have attempted to examine the benefits of DBS in Alzheimer's disease; differences in inclusion criteria and methodology make generalization of results difficult. This review aims to summarize all completed and ongoing human studies of DBS in Alzheimer's disease. The results are classified by targeted anatomical structure. Future directions, as well as economical and ethical arguments, are explored in the final section.

Decoupling of Brain Temperature and Glutamate in Recent Onset of Schizophrenia: A 7T Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: Converging evidence suggests that cerebral metabolic and cellular homeostasis is altered in patients with recent onset of schizophrenia. As a possible marker of metabolic changes that might link to altered neurotransmission, we used proton magnetic resonance spectroscopy to estimate brain temperature, and we evaluated its relationship to a relevant metabolite, glutamate, within this study population. METHODS: Using proton magnetic resonance spectroscopy at 7T, 20 patients with recent onset (≤24 months after first psychotic symptoms) of schizophrenia and 20 healthy control subjects were studied. We measured levels of N-acetylaspartate and glutamate and estimated brain temperature in a noninvasive manner. RESULTS: Healthy control subjects showed a significant negative correlation between glutamate and brain temperature in the anterior cingulate cortex. In contrast, the physiological correlation between glutamate and brain temperature was lost in patients with recent onset of schizophrenia. CONCLUSIONS: This study supports the hypothesized disrupted relationship between brain metabolism and neurotransmission in patients with recent onset of schizophrenia. The findings include mechanistic implications that are to be followed up in both preclinical and clinical studies.

High prevalence of smoking in Northern Greece.

AIM: To investigate the prevalence of smoking in the general population and in specific population sub-groups in Northern Greece. METHODS: A cross-sectional study was conducted during the period 1999-2001 on a 5% sample (23,840) of those people aged between 21 to 80 out of a total general population of 653,249. 21,854/23,840 general population subjects were interviewed. In addition, we interviewed 9,276 high school students, 1,072 medical students, 597 medical doctors within the National Health System, 825 teachers, and 624 subjects who regularly exercised in a privately-owned gym. A specially modified ICRF study group questionnaire was used. RESULTS: 34.4% of the general population sample were current smokers (47.8% of males and 21.6% of females). Smoking prevalence rates in the population sub-groups were: 29.6% of high school students; 40.7% of medical students; 44.9% of medical doctors; 46.4% of teachers; and 36.9% of the gym group. CONCLUSION: The prevalence of smoking in Northern Greece is high. High school and medical students present with high smoking rates, and the same situation is observed in medical doctors and teachers. An intensification of preventive antismoking measures is required.