Sex and Diffusion Tensor Imaging of White Matter in Schizophrenia: A Systematic Review Plus Meta-analysis of the Corpus Callosum

Sex is considered an understudied variable in health research. Schizophrenia is a brain disorder with known sex differences in epidemiology and clinical presentation. We systematically reviewed the literature for sex-based differences of diffusion properties of white matter tracts in schizophrenia. We then conducted a meta-analysis examining sex-based differences in the genu and splenium of the corpus callosum in schizophrenia. Medline and Embase were searched to identify relevant papers. Studies fulfilling the following criteria were included: (1) included individuals with a diagnosis of schizophrenia, (2) included a control group of healthy individuals, (3) included both sexes in the patient and the control groups, (4) used diffusion tensor imaging, and (5) involved analyzing metrics of white matter microstructural integrity. Fractional anisotropy (FA) was used as the measure of interest in the meta-analysis. Of 730 studies reviewed, 75 met the inclusion criteria. Most showed no effect of sex, however, those that did found either that females have lower FA than males, or that the effect of disease in females is larger than that in males. The findings of the meta-analysis in the corpus callosum supported this result. There is a recognized need for studies on schizophrenia with a sufficient sample of female patients. Lack of power undermines the ability to detect sex-based differences. Understanding the sex-specific impact of illness on neural circuits may help inform development of new treatments, and improvement of existing interventions

Brain-wide functional inter-hemispheric disconnection is a potential biomarker for schizophrenia and distinguishes it from depression

Schizophrenia is associated with disconnectivity in the brain although it is still unclear whether changes within or between hemispheres are of greatest importance. In this paper, an analysis of 152 schizophrenia patients compared with 122 healthy controls was carried out. Comparisons were also made with 39 depression patients and 37 controls to examine whether brain-wide changes in inter- or intra-hemispheric functional connectivity are most associated with the disorder and can distinguish it from depression. The authors developed new techniques (first and second order symmetry) to investigate brain-wide changes in patients (45 regions per hemisphere) and their association with illness duration and symptom severity. Functional connectivity between the same regions in left- and right-hemispheres (first order symmetry) was significantly reduced as was that between the same pairs of regions in the left- and right-hemispheres (second order symmetry) or using all possible inter-hemispheric connections in schizophrenia patients. By contrast, no significant changes were found for brain-wide intra-hemispheric links. First order symmetry changes correlated significantly with positive and negative symptom severity for functional connections linked via the anterior commissure and negative symptoms for those linked via the corpus callosum. Support vector machine analysis revealed that inter-hemispheric symmetry changes had 73–81% accuracy in discriminating schizophrenia patients and either healthy controls or depressed patients. In conclusion, reduced brain-wide inter-hemispheric functional connectivity occurs in schizophrenia, is associated with symptom severity, and can discriminate schizophrenia patients from depressed ones or healthy controls. Brain-wide changes in inter-hemispheric connections may therefore provide a useful potential biomarker for schizophrenia

Negative symptoms in schizophrenia: a study in a large clinical sample of patients using a novel automated method

Objectives To identify negative symptoms in the clinical records of a large sample of patients with schizophrenia using natural language processing and assess their relationship with clinical outcomes. Design Observational study using an anonymised electronic health record case register. Setting South London and Maudsley NHS Trust (SLaM), a large provider of inpatient and community mental healthcare in the UK. Participants 7678 patients with schizophrenia receiving care during 2011. Main outcome measures Hospital admission, readmission and duration of admission. Results 10 different negative symptoms were ascertained with precision statistics above 0.80. 41% of patients had 2 or more negative symptoms. Negative symptoms were associated with younger age, male gender and single marital status, and with increased likelihood of hospital admission (OR 1.24, 95% CI 1.10 to 1.39), longer duration of admission (β-coefficient 20.5 days, 7.6–33.5), and increased likelihood of readmission following discharge (OR 1.58, 1.28 to 1.95). Conclusions Negative symptoms were common and associated with adverse clinical outcomes, consistent with evidence that these symptoms account for much of the disability associated with schizophrenia. Natural language processing provides a means of conducting research in large representative samples of patients, using data recorded during routine clinical practice

Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial

Background Negative symptoms of schizophrenia represent deficiencies in emotional responsiveness, motivation, socialisation, speech and movement. When persistent, they are held to account for much of the poor functional outcomes associated with schizophrenia. There are currently no approved pharmacological treatments. While the available evidence suggests that a combination of antipsychotic and antidepressant medication may be effective in treating negative symptoms, it is too limited to allow any firm conclusions. Objective To establish the clinical effectiveness and cost-effectiveness of augmentation of antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia. Design A multicentre, double-blind, individually randomised, placebo-controlled trial with 12-month follow-up Setting Adult psychiatric services, treating people with schizophrenia. Participants Inpatients or outpatients with schizophrenia, on continuing, stable antipsychotic medication, with persistent negative symptoms at a criterion level of severity. Interventions Eligible participants were randomised 1 : 1 to treatment with either placebo (one capsule) or 20 mg of citalopram per day for 48 weeks, with the clinical option at 4 weeks to increase the daily dosage to 40 mg of citalopram or two placebo capsules for the remainder of the study. Main Outcome Measures The primary outcomes were quality of life measured at 12 and 48 weeks assessed using the Heinrich’s Quality of Life Scale, and negative symptoms at 12 weeks measured on the negative symptom subscale of the Positive and Negative Syndrome Scale. Results No therapeutic benefit in terms of improvement in quality of life or negative symptoms was detected for citalopram over 12 weeks or at 48 weeks, but secondary analysis suggested modest improvement in the negative symptom domain, avolition/amotivation, at 12 weeks (mean difference –1.3, 95% confidence interval–2.5 to–0.09). There were no statistically significant differences between the two treatment arms over 48-week follow-up in either the health economics outcomes or costs, and no differences in the frequency or severity of adverse effects, including corrected QT interval prolongation. Limitations The trial under-recruited, partly because cardiac safety concerns about citalopram were raised, with the 62 participants recruited falling well short of the target recruitment of 358. Although this was the largest sample randomised to citalopram in a randomised controlled trial of antidepressant augmentation for negative symptoms of schizophrenia and had the longest follow-up, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. Conclusion Although adjunctive citalopram did not improve negative symptoms overall, there was evidence of some positive effect on avolition/amotivation, recognised as a critical barrier to psychosocial rehabilitation and achieving better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues. The addition of citalopram as a long-term prescribing strategy for the treatment of negative symptoms may merit further investigation in larger studies. Future Work Further studies of the viability of adjunctive antidepressant treatment for negative symptoms in schizophrenia should include appropriate safety monitoring and use rating scales that allow for evaluation of avolition/amotivation as a discrete negative symptom domain. Overcoming the barriers to recruiting an adequate sample size will remain a challenge.</p

Early Psychosis Intervention-Spreading Evidence-based Treatment (EPI-SET) : Protocol for an effectiveness-implementation study of a structured model of care for psychosis in youth and emerging adults

Introduction While early psychosis intervention (EPI) has proliferated in recent years amid evidence of its effectiveness, programmes often struggle to deliver consistent, recovery-based care. NAVIGATE is a manualised model of EPI with demonstrated effectiveness consisting of four components: individualised medication management, individual resiliency training, supported employment and education and family education. We aim to implement NAVIGATE in geographically diverse EPI programmes in Ontario, Canada, evaluating implementation and its effect on fidelity to the EPI model, as well as individual-level outcomes (patient/family member-reported and interviewer-rated), system-level outcomes (captured in provincial administrative databases) and engagement of participants with lived experience. Methods and analysis This is a multisite, non-randomised pragmatic hybrid effectiveness-implementation type III mixed methods study coordinated at the Centre for Addiction and Mental Health (CAMH) in Toronto. Implementation is supported by the Provincial System Support Program, a CAMH-based programme with provincial offices across Ontario, and Extension of Community Healthcare Outcomes Ontario Mental Health at CAMH and the University of Toronto. The primary outcome is fidelity to the EPI model as measured using the First Episode Psychosis Services-Fidelity Scale. Four hundred participants in the EPI programmes will be recruited and followed using both individual-level assessments and health administrative data for 2 years following NAVIGATE initiation. People with lived experience will be engaged in all aspects of the project, including through youth and family advisory committees. Ethics and dissemination Research ethics board approval has been obtained from CAMH and institutions overseeing the local EPI programmes. Study findings will be reported in scientific journal articles and shared with key stakeholders including youth, family members, programme staff and policymakers. Trial registration number NCT03919760; Pre-results

Resting-State Connectivity Biomarkers of Cognitive Performance and Social Function in Individuals With Schizophrenia Spectrum Disorder and Healthy Control Subjects

BACKGROUND: Deficits in neurocognition and social cognition are drivers of reduced functioning in schizophrenia spectrum disorders, with potentially shared neurobiological underpinnings. Many studies have sought to identify brain-based biomarkers of these clinical variables using a priori dichotomies (e.g., good vs. poor cognition, deficit vs. nondeficit syndrome). METHODS: We evaluated a fully data-driven approach to do the same by building and validating a brain connectivity-based biomarker of social cognitive and neurocognitive performance in a sample using resting-state and task-based functional magnetic resonance imaging (n = 74 healthy control participants, n = 114 persons with schizophrenia spectrum disorder, 188 total). We used canonical correlation analysis followed by clustering to identify a functional connectivity signature of normal and poor social cognitive and neurocognitive performance. RESULTS: Persons with poor social cognitive and neurocognitive performance were differentiated from those with normal performance by greater resting-state connectivity in the mirror neuron and mentalizing systems. We validated our findings by showing that poor performers also scored lower on functional outcome measures not included in the original analysis and by demonstrating neuroanatomical differences between the normal and poorly performing groups. We used a support vector machine classifier to demonstrate that functional connectivity alone is enough to distinguish normal and poorly performing participants, and we replicated our findings in an independent sample (n = 75). CONCLUSIONS: A brief functional magnetic resonance imaging scan may ultimately be useful in future studies aimed at characterizing long-term illness trajectories and treatments that target specific brain circuitry in those with impaired cognition and function

Trends in the Study of Motivation in Schizophrenia: A Bibliometric Analysis of Six Decades of Research (1956-2017)

Motivation in schizophrenia has been a key research aim for several decades. Motivation is a very complex process underlying negative symptoms that has been assessed and identified using very different instruments and terminologies. This study provides a comprehensive overview of the growing literature production and highlights an extensive set of variables to better understand the study of motivation. Electronic databases were searched in order to compile relevant studies of motivation in individuals with schizophrenia. The initial search identified 3,248 potentially interesting records, and of these, 161 articles published between 1956 and 2017 were finally included. Information such as year of publication, journal, country, and number of authors was codified. Variables related to sample characteristics, methodological aspects, and motivational terms were also extracted. The results revealed a significant growth trend in literature production, especially since the 2000s, with reward as the main term studied. In addition, questionnaires were identified as the preferred instrument to assess motivation in patients with schizophrenia. Other aspects such as country of publication, authors, journals of publication, and co-citation network analysis were also examined. The discussion offers recommendations for future research

ED to EPI : Protocol for a pragmatic randomised controlled trial of an SMS (text) messaging intervention to improve the transition from the emergency department to early psychosis intervention for young people with psychosis

Introduction While nearly half of all new psychotic disorders are diagnosed in the emergency department (ED), most young people who present to the ED with psychosis do not receive timely follow-up with a psychiatrist, and even fewer with evidence-based early psychosis intervention (EPI) services. We aim to test an intervention delivered using short message service (SMS), a low-cost, low-complexity, youth-friendly approach, to improve transitions from the ED to EPI services. Methods and analysis This is a protocol for a pragmatic randomised, single blind, controlled trial with accompanying economic and qualitative evaluations conducted at the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada. A consecutive series of 186 participants aged 16-29 referred by the ED to CAMH's EPI programme will be recruited for a trial of a two-way intervention involving reminders, psychoeducation and check-ins delivered via SMS. The primary outcome will be attendance at the first consultation appointment within 30 days of study enrolment assessed through chart reviews in the electronic health record. We will also extract routine clinical measures, including the Brief Psychiatric Rating Scale, Clinical Global Impression and Service Engagement Scale, and link with provincial health administrative data to examine system-level outcomes, including ED visits and psychiatric hospitalisations, 6 months and up to 2 years after baseline. We will perform a cost-effectiveness analysis of the primary study outcome and costs incurred, calculating an incremental cost effectiveness ratio. Web-based surveys and qualitative interviews will explore intervention user experience. Patients and families with lived experience will be engaged in all aspects of the project. Ethics and dissemination Research Ethics Board approval has been obtained. Findings will be reported in scientific journal articles and shared with key stakeholders including youth, family members, knowledge users and decision makers. Trial registration number NCT04298450

Porcine Sialoadhesin (CD169/Siglec-1) Is an Endocytic Receptor that Allows Targeted Delivery of Toxins and Antigens to Macrophages

Sialoadhesin is exclusively expressed on specific subpopulations of macrophages. Since sialoadhesin-positive macrophages are involved in inflammatory autoimmune diseases, such as multiple sclerosis, and potentially in the generation of immune responses, targeted delivery of drugs, toxins or antigens via sialoadhesin-specific immunoconjugates may prove a useful therapeutic strategy. Originally, sialoadhesin was characterized as a lymphocyte adhesion molecule, though recently its involvement in internalization of sialic acid carrying pathogens was shown, suggesting that sialoadhesin is an endocytic receptor. In this report, we show that porcine sialoadhesin-specific antibodies and F(ab')2 fragments trigger sialoadhesin internalization, both in primary porcine macrophages and in cells expressing recombinant porcine sialoadhesin. Using chemical inhibitors, double immunofluorescence stainings and dominant-negative constructs, porcine sialoadhesin internalization was shown to be clathrin- and Eps15-dependent and to result in targeting to early endosomes but not lysosomes. Besides characterizing the sialoadhesin endocytosis mechanism, two sialoadhesin-specific immunoconjugates were evaluated. We observed that porcine sialoadhesin-specific immunotoxins efficiently kill sialoadhesin-expressing macrophages. Furthermore, porcine sialoadhesin-specific albumin immunoconjugates were shown to be internalized in macrophages and immunization with these immunoconjugates resulted in a rapid and robust induction of albumin-specific antibodies, this compared to immunization with albumin alone. Together, these data expand sialoadhesin functionality and show that it can function as an endocytic receptor, a feature that cannot only be misused by sialic acid carrying pathogens, but that may also be used for specific targeting of toxins or antigens to sialoadhesin-expressing macrophages