Search

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.

Background: Patients with psychotic disorders are at risk of developing mental health and social problems, and physical disorders. To monitor and treat these problems when indicated, an annual routine outcome monitoring program, Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS), was developed. This paper presents the background and content of PHAMOUS, implementation of PHAMOUS, characteristics of the patients screened in 2015, and the outcome of patients with three annual screenings between 2011 and 2015., Methods: PHAMOUS was implemented in four mental health institutions in the Northern Netherlands in 2006. During the PHAMOUS screening, patients are assessed on socio-demographics, psychiatric symptoms, medication, physical parameters, lifestyle, (psycho)social functioning and quality of life, using internationally validated instruments., Results: In 2015, 1955 patients with psychotic disorders were enrolled in the PHAMOUS screening. The majority (72%) was receiving mental healthcare for ten years or longer. A small group was hospitalized (10%) in the past year. Half of the patients were in symptomatic remission. Less than 10% had a paid job. More than half of the patients fulfilled the criteria for metabolic syndrome (54%). The subsample with three annual screenings from 2011 to 2015 (N = 1230) was stable, except the increasing prevalence of high glucose levels and satisfaction with social relationships (Cochran's Q = 16.33, p = .001 resp. Q = 14.79, p = .001)., Conclusion: The annual PHAMOUS screening enables to follow the mental, physical and social health problems of patients, which offers a good basis for shared-decision making with regard to updating the annual treatment plan, next to a wealth of data for scientific research., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Impaired function of prefrontal brain networks may be the source of both negative symptoms and neurocognitive problems in psychotic disorders. Whereas most antipsychotics may decrease prefrontal activation, the partial dopamine D2-receptor agonist aripiprazole is hypothesized to improve prefrontal function. This study investigated whether patients with a psychotic disorder would show stronger activation of prefrontal areas and associated regions after treatment with aripiprazole compared to risperidone treatment. In this exploratory pharmacological neuroimaging study, 24 patients were randomly assigned to either aripiprazole or risperidone. At baseline and after nine weeks treatment they underwent an interview and MRI session. Here we report on brain activation (measured with arterial spin labeling) during performance of two tasks, the Tower of London and the Wall of Faces. Aripiprazole treatment decreased activation of the middle frontal, superior frontal and occipital gyrus (ToL) and medial temporal and inferior frontal gyrus, putamen and cuneus (WoF), while activation increased after risperidone. Activation increased in the ventral anterior cingulate and posterior insula (ToL), and superior frontal, superior temporal and precentral gyrus (WoF) after aripiprazole treatment and decreased after risperidone. Both treatment groups had increased ventral insula activation (ToL) and middle temporal gyrus (WoF), and decreased occipital cortex, precuneus and caudate head activation (ToL) activation. In conclusion, patients treated with aripiprazole may need less frontal resources for planning performance and may show increased frontotemporal and frontostriatal reactivity to emotional stimuli. More research is needed to corroborate and extend these preliminary findings., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Monitoring patients' experiences with antipsychotics may help to improve medication adherence and outcome. We aimed to develop a shorter version of a comprehensive 74-item self-report questionnaire suitable for routine monitoring of desired and undesired effects of antipsychotics., Methods: Included were patients with psychotic disorders from seven mental health care organizations in The Netherlands, using antipsychotic medication, who completed the Subjects' Response to Antipsychotics (SRA-74). Exploratory factor analysis (EFA) and similarity analysis based on mutual information were used to identify the latent factor structure of the SRA. Items were reduced according to their metric properties and clinical relevance upon consensus by an expert panel, using a Delphi procedure of three rounds. We determined the internal consistency of the shorter version using Cronbach's alpha., Results: SRA data of N=1478 patients (mean age of 40 years, 31% females) were eligible for analysis. EFA extracted thirteen factors from the SRA-74, including four factors for desired effects (e.g. recovery of psychosis, cognition and social functioning) and nine factors for undesired effects (e.g. weight gain, flattened affect and increased sleep). Based on this solution 12 items were eliminated for statistical reasons. The expert panel eliminated another 28 items with redundant content, resulting in a 34-item version. The SRA-34 includes 10 desired and 24 clinically relevant undesired effects. Both the subscales for desired and undesired effects have a Cronbach's alpha coefficient of 0.82., Conclusions: The SRA-34 can be used to evaluate desired and undesired effects of antipsychotics in routine clinical practice and research., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Decreased prefrontal activation (hypofrontality) in schizophrenia is thought to underlie negative symptoms and cognitive impairments, and may contribute to poor social outcome. Hypofrontality does not always improve during treatment with antipsychotics. We hypothesized that antipsychotics, which share antagonism at dopamine receptors, with a relatively low dopamine receptor affinity and high serotonin receptor affinity may have a sparing effect on prefrontal function compared to strong dopamine receptor antagonists. We systematically investigated the relation between serotonin and dopamine antagonism of antipsychotics and prefrontal functioning by reviewing neuroimaging studies. The weight of the evidence was consistent with our hypothesis that antipsychotics with low dopaminergic receptor affinity and moderate to high serotonergic affinity were associated with higher activation of the prefrontal cortex. However, clozapine, a weak dopamine and strong serotonin antagonist, was associated with decrease in prefrontal activation. Future studies should further elucidate the link between prefrontal activation and negative symptoms using prospective designs and advanced neuroimaging techniques, which may ultimately benefit the development of treatments for disabling negative symptoms., (Copyright © 2011 Elsevier B.V. All rights reserved.)