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In the European Union, it is estimated that around 5 million people (0.2-2.6%) suffer from psychotic disorders. Between 30-50% can be considered resistant to treatment, and 10-20% ultra-resistant (Juarez-Reyes et al., 1995; Essock et al., 1996). The standard intervention in patients with resistant schizophrenia is complex, mainly for the presence of persistent positive symptomatology, extensive periods of hospital care and greater risk of multimorbidity, that leads to a scenario with a high degree of suffering for the patients, family and social environment, and a high proportion of costs to the healthcare system (Kennedy et al., 2014). To date, the standard treatment is not enough to achieve remission in resistant schizophrenia patients. Therefore, an improved understanding of treatment refractory schizophrenia and the development of innovative evidence-based interventions adjunctive to pharmacological and psychosocial treatment are necessary. ICT-based programmes are a novel possibility to improve the outcomes of schizophrenia since previous studies have indexed the suitability and promising results of interventions based on m-Health techniques (Granholm et al., 2012; Ben-Zeev et al., 2013). However, new proposals adapted to the specific nature of well-identified clinical subgroups, such as resistant patients, are needed. Intervention in resistant schizophrenia patients should include psychiatric, psychological and medical treatment. Moreover the role of the caregivers in the prognosis of the illness is a key aspect, improving adherence to treatment and identifying early signs of relapse or physical problems. Bearing all these aspects in mind, we propose m-RESIST, as an innovative, secure and sustainable project, which offers an integrated care addressed to empower patients suffering from resistant schizophrenia. m-RESIST intervention, although it is still under development, will integrate three main components: 1) a sensor data analysis module, which will provide passive information about the patients in terms of movement activity, social activity and physiological status, processing data coming from smartphone and wearable devices; 2) a predictive modelling engine, which will enable prediction of clinically significant events, such as hospitalization, risk behaviours and social isolation; and 3) a clinical decision support system (CDSS), which will provide users with necessary information to support health-related and clinical decisionmaking. This CDSS will include psychiatric intervention in three main areas, clinical symptoms management, healthy lifestyle habits and treatment adherence, as well as psychological intervention based in the cognitive behaviour therapy for psychosis. This project highlights the importance of the involvement and participation of the patients and their caregivers in the therapeutic process, whose will have an active and collaborative role with the medical team in the treatment decision-making procedure. m-RESIST system, in order to reduce the severity of episodes and further complications, will ensure the continuation of health care services and also will provide a new tool for a better monitorization of the patients through a personalised and optimised integrated therapeutic process. m-RESIST project is founded by Horizon 2020 Framework Programme of the European Union. PHC26 2014 m-RESIST "Mobile Therapeutic Attention for patients with Treatment Resistant Schizophrenia". The authors listed in this abstract are only a part of the m-RESIST Group. [ABSTRACT FROM AUTHOR]

Highlights from the article: Since almost only whole blood-brain methylation correlation studies have been carried out, we aimed to include other tissue source with high-epithel content like the buccal epithelial sample. For testing tissue specificity, we investigated an epithelial tissue specific CpG site of PTPN7 (cg18384097), to correlate it with methylation levels of the included oral samples (buccal, saliva, mouthwash). The methylation level of S-COMT region showed an inverse correlation to the PTPN7 CpG marker sites (R2=0.85) in mouth-related samples, which correlation indicates a tissue specific methylation pattern, thus cell composition (epithel/leucocyte ratio) has to be considered as an indispensable factor in future studies.

Numerous studies have been using peripheral tissues (e.g., blood or saliva) for DNA methylation analyses in psychiatric epigenetics. The glucocorticoid receptor gene (NR3C1) was among the first ones to show DNA methylation changes due to adverse social environment. Importantly, the NR3C1 gene has several alternative promoters, out of which the 1-F showed increased DNA methylation level at a transcription factor binding site. Afterwards, its co-chaperone molecule, FK506-binding protein 5 (FKBP5) gained interest, showing allele-specific demetylation in its glucocorticoid response element of the 7th intron. This decreased methylation at FKBP5 can lead to NR3C1 resistance, because of an impaired intracellular negative feedback loop. While it is now standard for epigenome-wide DNA methylation analyses to control for cell heterogeneity using cell count estimates derived from the DNA methylation profiles, this important technical variable of cell composition is rarely included in candidate gene analyses. Therefore, we aimed to (1) develop a panel of pyrosequencing assays for cell-specific CG-sites, and (2) evaluate the effect of cell ratio on DNA methylation levels of candidate gene regions in frequently used peripheral tissues, such as Whole Blood (WB), Peripheral Blood Mononuclear Cell (PBMC), as well as non-invasively collected buccal, mouthwash, and saliva samples in two cohorts. Samples were collected from 51 adults participating in a Montreal-based longitudinal cohort, out of which 16 men had been assessed twice. In addition, 38 female patients with borderline personality disorder and 21 control women were recruited at a psychiatric clinic in Budapest. Candidate gene regions of the NR3C1-1F and FKBP5-intron7, as well as tissue-specific CG-sites were assessed by pyrosequencing at both sites. The DNA methylation level of the CG-island in the NR3C1-1F promoter region showed little variance in all of the tissue types we investigated. However, the low CG-density region of FKBP5-intron7 was highly variable across samples, especially in saliva. Notably, methylation level of the epithelial cell marker PTPN7 cg18384097 varied widely among the mouth-related samples in both cohorts (ranging from 9%-95%), even in buccal swab samples, where there was ~ 80% buccal cell ratio on average with 10–12% SD. The effect of epithelial cell composition was substantial on FKBP5-intron7 methylation levels in saliva and mouthwash samples (r=0.5–0.7), but it was less pronounced in buccal swab samples (r=0.2–0.4). Higher ratio of epithelial cells resulted in lower methylation level at the studied FKBP5 CG-sites. Importantly, the stability of the DNA methylation level of this gene region was significant both in saliva and buccal swab samples (r=0.6–0.8, p<0.01). In addition, methylation level of the T lymphocyte marker CD3E cg06164961 also showed correlation with FKBP5-intron7 methylation in blood samples (WB: r=0.5–0.7, PBMC: r=0.3–0.5). Our preliminary results show that cell composition should be taken into account at candidate gene DNA methylation analyses, especially when measuring low CG-density regions in heterogeneous peripheral tissues, such as whole blood or saliva. Using more homogeneous biological samples, e.g., PBMC or purified leukocytes would result in less technical variability. The non-invasively obtained buccal swabs can also yield a relatively homogeneous surrogate sample in psychiatric epigenetics. [ABSTRACT FROM AUTHOR]

In European Union, between 0.2 and 2.6% of the population suffer from psychotic disorders (Wittchen et al., 2011). The largest group is patients with schizophrenia, and around 40% can be considered resistant to pharmacological treatment (Essock et al., 1996; Kennedy et al., 2014). Standard intervention in patients with treatment-resistant schizophrenia (TRS) is difficult due to the persistence of positive symptoms, extensive periods of hospitalization, and higher risk of comorbidities. The full scope of this scenario generates a financial burden on society because of frequent emergency visits, hospitalizations and chronic use of polytherapy (de Silva et al., 2012), as well as a huge impact in the humanistic burden. This concerns patients and caregivers, and involves several dimensions such as quality of life, treatment side effects, caregiver burden, social impairment, suicide, violence, and healthy lifestyle among the most important (Millier et al., 2014 ) In this sense, we have developed the m-RESIST, an intervention programme based on m-Health that offer to TRS patients an holistic approach to: i) integrate psychiatric and psychosocial assistance with other medical health-carers; ii) better monitorization of symptoms through a personalised and optimised therapeutic process; iii) promote acceptance and self-management of disease and co-morbidities; and iv) potentiate involvement of patients and their caregivers in the therapeutic process. Moreover, there are no studies in TRS patients that collect real-time information from patients that allow monitoring, evaluation and intervention in the main areas of the disease, as well as in situations of risk. In this regard, m-RESIST brings an excellent opportunity to access this information, as well as permit an immediate and tailored intervention. This program will have integrated a mobile application that will deliver three possible intervention packages: treatment adherence, healthy lifestyle and symptoms management that include training strategies based on cognitive behaviour therapy for psychosis. Clinical algorithms have been created for each intervention package in order to deliver tailored recommendations to patients, caregivers and clinicians, which will be based on clinical and real-time sensor data. Moreover, a risk level ranking system will be used in order to prioritize actions in risk situations. On-going challenges include a pilot test to assess acceptability, usability and satisfaction of patients, caregivers and clinicians with the m-RESIST intervention program. [ABSTRACT FROM AUTHOR]