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Mental disorder; Schizophrenia; Treatment-resistant Trastorno mental; Esquizofrenia; Resistentencia al tratamiento Malaltia mental; Esquizofrènia; Resistència al tractament Background: In the European Union, around 5 million people are affected by psychotic disorders, and approximately 30%-50% of people with schizophrenia have treatment-resistant schizophrenia (TRS). Mobile health (mHealth) interventions may be effective in preventing relapses, increasing treatment adherence, and managing some of the symptoms of schizophrenia. People with schizophrenia seem willing and able to use smartphones to monitor their symptoms and engage in therapeutic interventions. mHealth studies have been performed with other clinical populations but not in populations with TRS. Objective: The purpose of this study was to present the 3-month prospective results of the m-RESIST intervention. This study aims to assess the feasibility, acceptability, and usability of the m-RESIST intervention and the satisfaction among patients with TRS after using this intervention. Methods: A prospective multicenter feasibility study without a control group was undertaken with patients with TRS. This study was performed at 3 sites: Sant Pau Hospital (Barcelona, Spain), Semmelweis University (Budapest, Hungary), and Sheba Medical Center and Gertner Institute of Epidemiology and Health Policy Research (Ramat-Gan, Israel). The m-RESIST intervention consisted of a smartwatch, a mobile app, a web-based platform, and a tailored therapeutic program. The m-RESIST intervention was delivered to patients with TRS and assisted by mental health care providers (psychiatrists and psychologists). Feasibility, usability, acceptability, and user satisfaction were measured. Results: This study was performed with 39 patients with TRS. The dropout rate was 18% (7/39), the main reasons being as follows: loss to follow-up, clinical worsening, physical discomfort of the smartwatch, and social stigma. Patients' acceptance of m-RESIST ranged from moderate to high. The m-RESIST intervention could provide better control of the illness and appropriate care, together with offering user-friendly and easy-to-use technology. In terms of user experience, patients indicated that m-RESIST enabled easier and quicker communication with clinicians and made them feel more protected and safer. Patients' satisfaction was generally good: 78% (25/32) considered the quality of service as good or excellent, 84% (27/32) reported that they would use it again, and 94% (30/32) reported that they were mostly satisfied. Conclusions: The m-RESIST project has provided the basis for a new modular program based on novel technology: the m-RESIST intervention. This program was well-accepted by patients in terms of acceptability, usability, and satisfaction. Our results offer an encouraging starting point regarding mHealth technologies for patients with TRS. This work has been supported by the Horizon 2020 Framework Programme of the European Union (grant 643552) and partly funded by CERCA (Centres de Recerca de Catalunya) Programme/Generalitat de Catalunya.

Vertaisarvioitu. Psykoosilääkkeet lievittävät skitsofrenian psykoosioireita ja vähentävät relapsiriskiä. Psykoosilääkityksen pitkäaikaiskäytön hyöty-haittasuhde skitsofrenian hoidossa on osin tuntematon. Etenkin suurten psykoosilääkeannosten pitkäaikaiskäyttö voi altistaa metabolisille, neurologisille, kognitiivisille ja psykologisille haitoille. Psykoosilääkehoidon haittoja voidaan minimoida systemaattisella lääkehoidon ohjauksella, jossa lääkehoito suunnitellaan ja toteutetaan moniammatillisessa yhteistyössä potilaan ja hänen läheistensä kanssa. Lääkehoidon ohjaus voi auttaa käyttämään pienintä vaikuttavaa hoitoannosta sekä parantaa hoitoon sitoutumista ja hoidon tuloksellisuutta. Skitsofrenian psykoosilääkehoidon ohjauskäytäntöjen toteutus edellyttää eri ammattiryhmien kouluttamista, psykoosilääkehoidosta vastaavaa tiimiä ja organisaatiorajat ylittävää moniammatillista työpari- ja verkostotyötä.

Vertaisarvioitu. Kohortti- ja rekisteritutkimuksilla on merkittävä rooli mielenterveyshäiriöiden riskitekijöiden, ennusteen ja hoidon selvittämisessä. Pohjois-Suomen syntymäkohortissa 1966 (Kohortti 66) on tutkittu vuodesta 1990 alkaen mielenterveyshäiriöitä, erityisesti skitsofreniaa ja myös masennusta. Tulosten mukaan skitsofreniaa ennustavat useat varhaiset raskauteen, synnytykseen ja kehitykseen liittyvät tekijät. Skitsofreniaan liittyy muutoksia aivojen rakenteessa ja kognitiivisessa suorituskyvyssä sekä somaattisen terveyden ongelmia. Ennuste on usein epätyydyttävä. Masennuksen osalta on löydetty riskitekijöitä lapsuudesta aikuisuuteen sekä suurentunut somaattisen oheissairastavuuden riski. Kohortissa 66 on tutkittu myös muun muassa persoonallisuushäiriöitä, somatisaatio-oireita, alkoholinkäyttöä ja temperamenttipiirteitä. Tutkimustulokset ovat lisänneet tietoa psykiatristen häiriöiden riskitekijöistä, taudinkulusta ja hoidosta.

Background: As the burden of treatment-resistant schizophrenia (TRS) on patients and society is high it is important to identify predictors of response to medications in TRS. The aim was to analyse whether baseline patient and study characteristics predict treatment response in TRS in drug trials. Methods: A comprehensive search strategy completed in PubMed, Cochrane and Web of Science helped identify relevant studies. The studies had to meet the following criteria: English language clinical trial of pharmacological treatment of TRS, clear definition of TRS and response, percentage of response reported, at least one baseline characteristic presented, and total sample size of at least 15. Meta-regression techniques served to explore whether baseline characteristics predict response to medication in TRS. Results: 77 articles were included in the systematic review. The overall sample included 7546 patients, of which 41% achieved response. Higher positive symptom score at baseline predicted higher response percentage. None of the other baseline patient or study characteristics achieved statistical significance at predicting response. When analysed in groups divided by antipsychotic drugs, studies of clozapine and other atypical antipsychotics produced the highest response rate. Conclusions: This meta-analytic review identified surprisingly few baseline characteristics that predicted treatment response. However, higher positive symptoms and the use of atypical antipsychotics - particularly clozapine -was associated with the greatest likelihood of response. The difficulty involved in the prediction of medication response in TRS necessitates careful monitoring and personalised medication management. There is a need for more investigations of the predictors of treatment response in TRS.

Background: Mobile Therapeutic Attention for Patients with Treatment-Resistant Schizophrenia (m-RESIST) is an EU Horizon 2020-funded project aimed at designing and validating an innovative therapeutic program for treatment-resistant schizophrenia. The program exploits information from mobile phones and wearable sensors for behavioral tracking to support intervention administration. Objective: To systematically review original studies on sensor-based mHealth apps aimed at uncovering associations between sensor data and symptoms of psychiatric disorders in order to support the m-RESIST approach to assess effectiveness of behavioral monitoring in therapy. Methods: A systematic review of the English-language literature, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed through Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases. Studies published between September 1, 2009, and September 30, 2018, were selected. Boolean search operators with an iterative combination of search terms were applied. Results: Studies reporting quantitative information on data collected from mobile use and/or wearable sensors, and where that information was associated with clinical outcomes, were included. A total of 35 studies were identified; most of them investigated bipolar disorders, depression, depression symptoms, stress, and symptoms of stress, while only a few studies addressed persons with schizophrenia. The data from sensors were associated with symptoms of schizophrenia, bipolar disorders, and depression. Conclusions: Although the data from sensors demonstrated an association with the symptoms of schizophrenia, bipolar disorders, and depression, their usability in clinical settings to support therapeutic intervention is not yet fully assessed and needs to be scrutinized more thoroughly.

English summary

IntroductionTreatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. In the European Union, approximately 40% of people with schizophrenia have TRS. Factors such as the persistence of positive symptoms or higher risk of comorbidities leave clinicians with a complex scenario when treating these patients. Intervention strategies based on mHealth have demonstrated their ability to support and promote self-management-based strategies. Mobile therapeutic attention for treatment-resistant schizophrenia(m-RESIST), an innovative mHealth solution based on novel technology and offering high modular and flexible functioning, has been developed specifically for patients with TRS and their caregivers. As intervention in TRS is a challenge, it is necessary to perform a feasibility study before the cost-effectiveness testing stage.Methods and analysisThis manuscript describes the protocol for a prospective multicentre feasibility study in 45 patients with TRS and their caregivers who will be attended in the public health system of three localities: Hospital Santa Creu Sant Pau (Spain), Semmelweis University (Hungary) and Gertner Institute & Sheba Medical Center (Israel). The primary aim is to investigate the feasibility and acceptability of the m-RESIST solution, configured by three mHealth tools: an app, wearable and a web-based platform. The solution collects data about acceptability, usability and satisfaction, together with preliminary data on perceived quality of life, symptoms and economic variables. The secondary aim is to collect preliminary data on perceived quality of life, symptoms and economic variables.Ethics and disseminationThis study protocol, funded by the Horizon 2020 Programme of the European Union, has the approval of the ethics committees of the participating institutions. Participants will be fully informed of the purpose and procedures of the study, and signed inform consents will be obtained. The results will be published in peer-reviewed journals and presented in scientific conferences to ensure widespread dissemination.Trial registration numberNCT03064776; Pre-results.

Onset of alcohol use at an early age increases the risk for later alcohol dependence. We investigated the role of the glucocorticoid receptor (GR) gene (NR3C1) in onset of alcohol use and abuse in 14-year-old adolescents (n = 4534). Several NR3C1 polymorphisms were associated with onset of alcohol drinking or drunkenness at this age. Strongest associations were observed in females, with one marker (rs244465) remaining significant after correction for multiple testing (Padj = 0.0067; odds ratio = 1.7, for drunkenness). Our data provide the first evidence that GR modulates initiation of alcohol abuse and reveal a polymorphism that might contribute to susceptibility to addiction.

Background Progressive brain volume loss in schizophrenia has been reported in previous studies but its cause and regional distribution remains unclear. We investigated progressive regional brain reductions in schizophrenia and correlations with potential mediators. Method Participants were drawn from the Northern Finland Birth Cohort 1966. A total of 33 schizophrenia individuals and 71 controls were MRI scanned at baseline (mean age = 34.7, SD = 0.77) and at follow-up (mean age = 43.4, SD = 0.44). Regional brain change differences and associations with clinical mediators were examined using FSL voxelwise SIENA. Results Schizophrenia cases exhibited greater progressive brain reductions than controls, mainly in the frontal and temporal lobes. The degree of periventricular brain volume reductions were predicted by antipsychotic medication exposure at the fourth ventricular edge and by the number of days in hospital between the scans (a proxy measure of relapse duration) at the thalamic ventricular border. Decline in social and occupational functioning was associated with right supramarginal gyrus reduction. Conclusion Our findings are consistent with the possibility that antipsychotic medication exposure and time spent in relapse partially explain progressive brain reductions in schizophrenia. However, residual confounding could also account for the findings and caution must be applied before drawing causal inferences from associations demonstrated in observational studies of modest size. Less progressive brain volume loss in schizophrenia may indicate better preserved social and occupational functions.

Birth cohort designs are useful in studying adult disease trajectories and outcomes, such as schizophrenia. We review the schizophrenia research performed in the Northern Finland Birth Cohort 1966 (NFBC 1966), which includes 10,934 individuals living in Finland at 16 years of age who have been monitored since each mother’s mid-pregnancy. By the age of 44, 150 (1.4%) had developed schizophrenia. There are 77 original papers on schizophrenia published from the NFBC 1966. The early studies have found various risk factors for schizophrenia, especially related to pregnancy and perinatal phase. Psychiatric and somatic outcomes were heterogeneous, but relatively poor. Mortality in schizophrenia is high, especially due to suicides. Several early predictors of outcomes have also been found. Individuals with schizophrenia have alterations in brain morphometry and neurocognition, and our latest studies have found that the use of high lifetime doses of antipsychotics associated with these changes. The schizophrenia research in the NFBC 1966 has been especially active for 20 years, the prospective study design and long follow-up enabling several clinically and epidemiologically important findings. When compared to other birth cohorts, the research in the NFBC 1966 has offered also unique findings on course and outcome of schizophrenia.