Anna Alonso-Solís

Resting-state functional connectivity alterations in the default network of schizophrenia patients with persistent auditory verbal hallucinations

To understand the neural mechanism that underlies treatment resistant auditory verbal hallucinations (AVH), is still an important issue in psychiatric research. Alterations in functional connectivity during rest have been frequently reported in patients with schizophrenia. Though the default mode network (DN) appears to be abnormal in schizophrenia patients, little is known about its role in resistant AVH. We collected resting-state functional magnetic resonance imaging (R-fMRI) data with a 3T scanner from 19 schizophrenia patients with chronic AVH resistant to pharmacological treatment, 14 schizophrenia patients without AVH and 20 healthy controls. Using seed-based correlation analysis, we created spherical seed regions of interest (ROI) to examine functional connectivity of the two DN hub regions (posterior cingulate cortex and anteromedial prefrontal cortex) and the two DN subsystems: dorsomedial prefrontal cortex subsystem and medial temporal lobe subsystem (p<0.0045 corrected). Patients with hallucinations exhibited higher FC between dMPFC ROI and bilateral central opercular cortex, bilateral insular cortex and bilateral precentral gyrus compared to non hallucinating patients and healthy controls. Additionally, patients with hallucinations also exhibited lower FC between vMPFC ROI and bilateral paracingulate and dorsal anterior cingulate cortex. As the anterior cingulate cortex and the insula are two hubs of the salience network, our results suggest cross-network abnormalities between DN and salience system in patients with persistent hallucinations.

Pharmacogenetic study of antipsychotic induced acute extrapyramidal symptoms in a first episode psychosis cohort: role of dopamine, serotonin and glutamate candidate genes

This study investigated whether the risk of presenting antipsychotic (AP)-induced extrapyramidal symptoms (EPS) could be related to single-nucleotide polymorphisms (SNPs) in a naturalistic cohort of first episode psychosis (FEP) patients. Two hundred and two SNPs in 31 candidate genes (involved in dopamine, serotonin and glutamate pathways) were analyzed in the present study. One hundred and thirteen FEP patients (43 presenting EPS and 70 non-presenting EPS) treated with high-potency AP (amisulpride, paliperidone, risperidone and ziprasidone) were included in the analysis. The statistical analysis was adjusted by age, gender, AP dosage, AP combinations and concomitant treatments as covariates. Four SNPs in different genes (DRD2, SLC18A2, HTR2A and GRIK3) contributed significantly to the risk of EPS after correction for multiple testing (P<1 × 10−4). These findings support the involvement of dopamine, serotonin and glutamate pathways in AP-induced EPS.

Altered amplitude of low frequency fluctuations in schizophrenia patients with persistent auditory verbal hallucinations

The aim of this study is to analyze the differences in low frequency fluctuation (LFF) values between schizophrenia patients with and without auditory verbal hallucinations (AVH). Nineteen schizophrenia patients with persistent AVH (HP), fourteen non-hallucinating schizophrenia patients (nHP) and twenty healthy controls (HC) underwent R-fMRI. LFF values were calculated in the slow frequency band (0.01-0.08Hz). By means of group level contrasts, we performed direct voxel-wise group comparisons. Both groups of patients showed decreased amplitude LFF (ALFF) values in the occipital pole and lingual gyrus compared to HC, whereas increased ALFF values were found in the temporal pole and fusifom gyrus. Schizophrenia patients exhibited decreased fractional ALFF (fALFF) values in the precuneus, occipital pole and bilateral occipital cortex, and increased fALFF in the insula compared to HC. There were also differences between patients with and without AVH. (Ok to start with lower case?) fALFF values were higher in the putamen and insular cortex and lower in the frontal pole in HP compared to nHP and HC. ALFF increased in HP patients in the bilateral thalamus and bilateral parahippocampal gyrus, compared to nHP patients and HC. Our results suggest that altered dynamics in low-frequency fluctuations may play a key role in the neurophysiology of auditory hallucinations.

Gray and white matter changes and their relation to illness trajectory in first episode psychosis

Previous works have studied structural brain characteristics in first-episode psychosis (FEP), but few have focused on the relation between brain differences and illness trajectories. The aim of this study is to analyze gray and white matter changes in FEP patients and their relation with one-year clinical outcomes. A sample of 41 FEP patients and 41 healthy controls (HC), matched by age and educational level was scanned with a 3T MRI during the first month of illness onset. One year later, patients were assigned to two illness trajectories (schizophrenia and non-schizophrenia). Voxel-based morphometry (VBM) was used for gray matter and Tract-based spatial statistics (TBSS) was used for white matter data analysis. VBM revealed significant and widespread bilateral gray matter density differences between FEP and HC groups in areas that included the right insular Cortex, the inferior frontal gyrus and orbito-frontal cortices, and segments of the occipital cortex. TBSS showed a significant lower fractional anisotropy (FA) in 8 clusters that included segments of the anterior thalamic radiation, the left body and forceps minor of corpus callosum, the right anterior segment of the inferior fronto-occipital fasciculus and the anterior segments of the cingulum. The sub-groups comparison revealed significant lower FA in the schizophrenia sub-group in two clusters: the anterior thalamic radiation and the anterior segment of left cingulum. These findings are coherent with previous morphology studies. The results suggest that gray and white matter abnormalities are present at early stages of the disease, and white matter differences may distinguish different illness prognosis.

Mobile therapeutic attention for treatment-resistant schizophrenia (m-RESIST): a prospective multicentre feasibility study protocol in patients and their caregivers

Introduction Treatment-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 analysis This 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 dissemination This 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 number NCT03064776; Pre-results.

Volumetric and morphological characteristics of the hippocampus are associated with progression to schizophrenia in patients with first-episode psychosis

BACKGROUND Abnormalities in the hippocampus have been implicated in the pathophysiology of psychosis. However, it is still unclear whether certain abnormalities are a pre-existing vulnerability factor, a sign of disease progression or a consequence of environmental factors. We hypothesized that first-episode psychosis patients who progress to schizophrenia after one year of follow up will display greater volumetric and morphological changes from the very beginning of the disorder. METHODS We studied the hippocampus of 41 patients with a first-episode psychosis and 41 matched healthy controls. MRI was performed at the time of the inclusion in the study. After one year, the whole sample was reevaluated and divided in two groups depending on the diagnoses (schizophrenia vs. non-schizophrenia). RESULTS Patients who progressed to schizophrenia showed a significantly smaller left hippocampus volume than control group and no-schizophrenia group (F=3.54; df=2, 77; P=0.03). We also found significant differences in the morphology of the anterior hippocampus (CA1) of patients with first-episode psychosis who developed schizophrenia compared with patients who did not. CONCLUSIONS These results are consistent with the assumption of hyperfunctioning dopaminergic cortico-subcortical circuits in schizophrenia, which might be related with an alteration of subcortical structures, such as the hippocampus, along the course of the disease. According with these results, hippocampus abnormalities may serve as a prognostic marker of clinical outcome in patients with a first-episode psychosis.

An innovative and integrative m-Health solution for treatment resistant schizophrenia patients

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 multi-morbidity, 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 decision-making. 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. References: 1- Juarez-Reyes, M. G., Shumway, M., Battle, C., Bacchetti, P., Hansen, M. S., & Hargreaves, W. A. (1995). Effects of stringent criteria on eligibility for clozapine among public mental health clients. Psychiatric services, 46(8), 801-806. 2- Essock, S. M., Hargreaves, W. A., Dohm, F. A., Goethe, J., Carver, L., & Hipshman, L. (1996). Clozapine eligibility among state hospital patients. Schizophrenia Bulletin, 22(1), 15-25. 3- Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review.The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014 Mar;29(2):63-76. 4- Granholm, E., Ben-Zeev, D., Link, P. C., Bradshaw, K. R., Holden, J. L. (2012). Mobile Assessment and Treatment for Schizophrenia (MATS): a pilot trial of an interactive text-messaging intervention for medication adherence, socialization, and auditory hallucinations. Schizophrenia bulletin, 38(3), 414-425. 5- Ben-Zeev D, Kaiser SM, Brenner CJBen-Zeev D, Kaiser SM, Brenner CJ, Begale M, Duffecy J, Mohr DC.Mohr DC. Development and usability testing of FOCUS: a smartphone system for self-management of schizophrenia. Psychiatr Rehabil J.Psychiatr Rehabil J. 2013 Dec;36(4):289-96.

P.1.i.009 Default mode network alterations in refractory schizophrenia patients with auditory verbal hallucinations

The purpose of the present study was to study the neuroanatomical alterations in patients with bipolar disorder by structural brain assessment with neuroimaging techniques. Method: We studied 241 adult patients (aged 35−65) who were admitted to an Inpatient Unit between 1st of January of 2011 and 31st of December of 2012 with a diagnosis of bipolar disorder. We made an observational study about neuroanatomical changes, correlating macrostructural alterations assessed by neuroimaging techniques (magnetic resonance imaging), average stay and age. Results: From a sample of 241 inpatients magnetic resonance imaging was done to 38%. Neuroanatomic abnormalities were not observed in 71.7% of cases (66patients), but they appeared in 28.2% (26 patients). The most frequent alterations observed were: decreased prefrontal area volume (69.23%), decreased temporal area volume (50.0%), lateral ventriculomegaly (38.46%), decreased cerebellar volume (25%), decreased corpus callosum (23.7%) and increased basal ganglia (19.2%). Comparative analysis showed no significant differences in relation to the average stay, 17.65 days in the bipolar patients group without neuroanatomical alteration and 18.77 days in the bipolar patients group with alterations. There were significant differences between neuroanatomical alterations and age (c2 = 5480 (p< 0.05). The mean age of the bipolar patients group with neuroanatomical abnormalities is 60.29 years, and in the unaltered bipolar patients group is 43.45 years. The other sociodemographic variables (gender, source sector: urban or rural) show no significant differences between the group of bipolar patients with neuroanatomical abnormalities and the group of bipolar patients without abnormalities. Conclusions: Structural magnetic resonance imaging study shows that brain abnormalities in bipolar disorders are mostly regional, as supported by previously published studies. These neurostructural abnormalities do not involve longer hospitalizations, but they are correlated with older age. These results support the evolution of the disease but involutional changes due to early ‘aging’ of the brain can not be dismissed