Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5?SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.© 2022. The Author(s)

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHODS: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation

Perspectives of professional experts in relation to the development of community-based exercise for young adults with schizophrenia – A qualitative study

Background Exercise plays a crucial role in addressing the increased cardiometabolic morbidity and premature mortality in people with schizophrenia. When delivered in community-based settings, exercise may also reduce loneliness, while promoting overall physical active behaviours. Skilled instructors are essential to deliver effective community-based exercise; however, knowledge about their roles and required training is lacking. We investigated stakeholders’ perspectives on components needed for an educational programme for non-health professional exercise instructors delivering community-based exercise targeting young adults in antipsychotic treatment.Methods We conducted six focus groups comprising a total of 30 individuals representing five different stakeholder groups, namely clinical staff within mental health, physiotherapists, exercise instructors, young adults in antipsychotic treatment, and relatives to young adults in antipsychotic treatment. Data were analysed using qualitative content analysis, as described by Graneheim and Lundman.Results The analysis identified three categories: (i) acknowledging mental illness, (ii) applying a resource-oriented approach, and (iii) promoting exercise as a shared activity, and one overarching theme: instructors as guardians of an inclusive culture.Conclusions An educational programme for exercise instructors delivering community-based exercise to young adults in antipsychotic treatment should focus on securing an inclusive culture that embraces an anti-stigmatising approach. Results of the current study informed the development of an educational programme consisting of an instructor manual, a one-day educational programme for instructors, and a continuous exchange of experiences between instructors.Competing Interest StatementBHE is part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd; and has received lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, Eli Lilly Company, and Lundbeck Pharma A/S. MFA, KR, VS, AR, BSR and JM declare no competing interests.Funding StatementThe study was funded by TrygFonden (Grant No.: 151603)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Regional Ethics Committee of Northern Denmark has confirmed that no formal ethical approval was required (Case No. 2023000206) for the current study.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authorsBackgroundPhysical activity is a key modifiable factor in protecting physical and mental health in people with severe mental illness including schizophrenia. Therefore, early promotion of physical activity is recommended and programmes supporting long-term maintenance of physically active behaviour are warranted. This study aimed to explore the perspectives of professional experts in relation to the development of a sustainable community-based exercise programme tailored to young adults with schizophrenia and intended to promote change and adoption of physical activity. MethodsWe conducted nine semi-structured interviews with 11 clinical and professional experts. Qualitative content analysis, as described by Graneheim and Lundman, was applied to analyse data. ResultsWe identified four categories: (1) living a physical active life with schizophrenia, (2) exercise as promotor of personal recovery, (3) prescribing safe and relevant exercise, and (4) instructors qualifications and formation. ConclusionsWhen developing sustainable community-based exercise programmes tailored to young adults with schizophrenia, developers should ensure instructors qualifications and provide an exercise protocol. In addition, developers should consider providing an inclusive and recovery-oriented exercise environment. Key messagesWhat is already known on this topic O_LIPhysical activity is a key modifiable factor in protecting physical and mental health in people with severe mental illness, including schizophrenia. C_LIO_LISustainable community-based programmes to support adoption of physical activity for young adults with schizophrenia are warranted. C_LI What this study adds O_LIDevelopers of community-based exercise for young adults with schizophrenia must ensure a strategy for identifying and training exercise instructors and the provision of a protocol for delivering safe and clinically relevant exercise. C_LIO_LICommunity-based exercise may have the potential to promote personal recovery and thus considerations regarding the balance between overcoming potential barriers towards participation while promoting a non-clinical exercise environment are provided. C_LI How this study might affect research, practice or policy O_LIThese findings could support and inform the development of community-based programmes promoting physical activity for people with schizophrenia and may be adaptable or inspirable to other psychiatric populations in other geographical settings. C_L

What should be included in an educational programme for non-health professional exercise instructors in charge of community-based exercise targeting young adults in antipsychotic treatment – A focus group study of stakeholder perspectives

Background Exercise plays a crucial role in addressing the increased cardiometabolic morbidity and premature mortality in people with schizophrenia. When delivered in community-based settings, exercise may also reduce loneliness, while promoting overall physical active behaviours. Skilled instructors are essential to deliver effective community-based exercise; however, knowledge about their roles and required training is lacking. We investigated stakeholders’ perspectives on components needed for an educational programme for non-health professional exercise instructors delivering community-based exercise targeting young adults in antipsychotic treatment.Methods We conducted six focus groups comprising a total of 30 individuals representing five different stakeholder groups, namely clinical staff within mental health, physiotherapists, exercise instructors, young adults in antipsychotic treatment, and relatives to young adults in antipsychotic treatment. Data were analysed using qualitative content analysis, as described by Graneheim and Lundman.Results The analysis identified three categories: (i) acknowledging mental illness, (ii) applying a resource-oriented approach, and (iii) promoting exercise as a shared activity, and one overarching theme: instructors as guardians of an inclusive culture.Conclusions An educational programme for exercise instructors delivering community-based exercise to young adults in antipsychotic treatment should focus on securing an inclusive culture that embraces an anti-stigmatising approach. Results of the current study informed the development of an educational programme consisting of an instructor manual, a one-day educational programme for instructors, and a continuous exchange of experiences between instructors.Competing Interest StatementBHE is part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd; and has received lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, Eli Lilly Company, and Lundbeck Pharma A/S. MFA, KR, VS, AR, BSR and JM declare no competing interests.Funding StatementThe study was funded by TrygFonden (Grant No.: 151603)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Regional Ethics Committee of Northern Denmark has confirmed that no formal ethical approval was required (Case No. 2023000206) for the current study.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the author

A machine-learning framework for robust and reliable prediction of short- and long-term treatment response in initially antipsychotic-naive schizophrenia patients based on multimodal neuropsychiatric data

The reproducibility of machine-learning analyses in computational psychiatry is a growing concern. In a multimodal neuropsychiatric dataset of antipsychotic-naïve, first-episode schizophrenia patients, we discuss a workflow aimed at reducing bias and overfitting by invoking simulated data in the design process and analysis in two independent machine-learning approaches, one based on a single algorithm and the other incorporating an ensemble of algorithms. We aimed to (1) classify patients from controls to establish the framework, (2) predict short- and long-term treatment response, and (3) validate the methodological framework. We included 138 antipsychotic-naïve, first-episode schizophrenia patients with data on psychopathology, cognition, electrophysiology, and structural magnetic resonance imaging (MRI). Perinatal data and long-term outcome measures were obtained from Danish registers. Short-term treatment response was defined as change in Positive And Negative Syndrome Score (PANSS) after the initial antipsychotic treatment period. Baseline diagnostic classification algorithms also included data from 151 matched controls. Both approaches significantly classified patients from healthy controls with a balanced accuracy of 63.8% and 64.2%, respectively. Post-hoc analyses showed that the classification primarily was driven by the cognitive data. Neither approach predicted short- nor long-term treatment response. Validation of the framework showed that choice of algorithm and parameter settings in the real data was successfully guided by results from the simulated data. In conclusion, this novel approach holds promise as an important step to minimize bias and obtain reliable results with modest sample sizes when independent replication samples are not available

Heritability of Memory Functions and Related Brain Volumes: A Schizophrenia Spectrum Study of 214 Twins

Abstract Background Memory performance is heritable and shares partial genetic etiology with schizophrenia. How the genetic overlap between memory and schizophrenia is related to intelligence (IQ) and brain volumes has not been formally tested using twin modeling. Methods A total of 214 twins were recruited nationwide by utilization of the Danish registers, including monozygotic and dizygotic twin pairs concordant or discordant for a schizophrenia spectrum disorder and healthy control pairs. Memory/IQ assessments and MRI scans were performed and structural equation modeling was applied to examine the genetic and environmental effects and to quantify associations with schizophrenia liability. Results Significant heritability estimates were found for verbal, visual and working memory. Verbal and visual memory were associated with schizophrenia, and for visual memory the association was due to overlapping genetics. IQ was highly heritable, but only performance IQ was associated with schizophrenia. Genetic factors also contributed to total brain, right superior frontal, left rostral middle frontal and hippocampal volumes. Smaller total brain and hippocampal volumes were associated with schizophrenia, and for the left hippocampus this association was due to overlapping genetic factors. All 3 memory measures were associated with IQ, but only visual memory was associated with total brain and hippocampal volumes. Discussion Specific memory measures and brain volumes were moderately heritable and showed overlap with schizophrenia liability, suggesting partially shared etiological influences. Our findings further suggest that factors impacting IQ also influence memory, whereas memory impairments and brain volume abnormalities appear to represent separate pathological processes in the pathway to schizophrenia

No Effects of Cognitive Remediation on Cerebral White Matter in Individuals at Ultra-High Risk for Psychosis-A Randomized Clinical Trial

Background: Individuals at ultra-high risk for psychosis (UHR) present with subtle alterations in cerebral white matter (WM), which appear to be associated with clinical and functional outcome. The effect of cognitive remediation on WM organization in UHR individuals has not been investigated previously. Methods: In a randomized, clinical trial, UHR individuals aged 18 to 40 years were assigned to treatment as usual (TAU) or TAU plus cognitive remediation for 20 weeks. Cognitive remediation comprised 20 x 2-h sessions of neurocognitive and social-cognitive training. Primary outcome was whole brain fractional anisotropy derived from diffusion weighted imaging, statistically tested as an interaction between timepoint and treatment group. Secondary outcomes were restricted to five predefined region of interest (ROI) analyses on fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. For significant timepoint and treatment group interactions within these five ROIs, we explored associations between longitudinal changes in WM and cognitive functions/clinical symptoms. Finally, we explored dose-response effects of cognitive remediation on WM. Results: A total of 111 UHR individuals were included. Attrition-rate was 26%. The cognitive remediation group completed on average 12 h of neurocognitive training, which was considerably lower than per protocol. We found no effect of cognitive remediation on whole-brain FA when compared to treatment as usual. Secondary ROI analyses revealed a nominal significant interaction between timepoint*treatment of AD in left medial lemniscus (P=0.016) which did not survive control for multiple comparisons. The exploratory test showed that this change in AD correlated to improvements of mental flexibility in the cognitive remediation group (p=0.001). We found no dose-response effect of neurocognitive training on WM. Conclusions: Cognitive remediation comprising 12 h of neurocognitive training on average did not improve global or regional WM organization in UHR individuals. Further investigations of duration and intensity of cognitive training as necessary prerequisites of neuroplasticity-based changes are warranted. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02098408