Resistant Schizophrenia Patients Research Articles

Negative symptoms and cognitive impairment are associated with distinct motivational deficits in treatment resistant schizophrenia

BackgroundMotivational deficits are a central feature of the negative syndrome in schizophrenia. They have consistently been associated with reduced willingness to expend physical effort in return for monetary rewards on effort based decision making (EBDM) paradigms. Nevertheless, the mechanisms underlying such altered performance are not well characterised, and it remains unclear if they are driven purely by negative symptoms, or also in part by cognitive impairment, antipsychotic treatment or even positive symptoms. Here we investigated the impact of all these factors using a paradigm that has not previously been used to measure EBDM in schizophrenia.MethodsForty treatment resistant schizophrenia (TRS) patients on clozapine and matched controls (N = 80) completed a well validated EBDM task which offers monetary rewards in return for physical effort. Choice and reaction time data was analysed using logistic regressions, as well as Bayesian hierarchical drift diffusion modelling (HDDM). Behavioural parameters were compared between groups and their association with negative symptoms, cognitive function and serum clozapine levels were assessed.ResultsOverall, TRS patients accepted significantly less offers than controls during effort-based decision making, suggesting they were less motivated. They demonstrated reduced sensitivity to increasing rewards, but surprisingly were also less averse to increasing effort. Despite a positive correlation between negative symptoms and cognitive function in TRS, reward sensitivity was associated only with cognitive performance. In contrast, reduced effort aversion correlated with negative symptom severity. Clozapine levels and positive symptoms were not associated with either behavioural parameter.ConclusionMotivational deficits in TRS are characterised by both diminished reward sensitivity and reduced effort aversion during EBDM. Cognitive dysfunction and negative symptom severity account for distinct aspects of these behavioural changes, despite positive associations between themselves. Overall, these findings demonstrate that negative symptoms and cognitive impairment have significant independent contributions to EBDM in TRS, thereby opening the possibility of individualised treatment targeting these mechanisms to improve motivation.

Adiponectin, resistin, Interleukine-4, TGF-β2 levels before and after clozapine treatment in a group of first episode, treatment resistant schizophrenia patients

IntroductionTreatment resistant schizophrenia (TRS) affects at least 15-20% of newly diagnosed patients with schizophrenia. Clozapine treatment for this sub-group of patients should be considered immediately after the failure in response to two antipsychotics (usually risperidone and olanzapine) received in adequate doses and time. Immune changes have been reported in first episode patients with psychosis, although results from various studies remain inconclusive. Very few studies have investigated so far cytokine and adipokine changes in TRS.ObjectivesTo measure Interleukin-4 (IL-4), Tumor Growth Factor-β2 (TGF-β2), adiponectin and resistin in a sample of forty first-episode patients with psychosis (FEP) who proved to be treatment resistant (TRS),after treatment with two atypical antipsychotics ( olanzapine and risperidone) and after clozapine treatment.MethodsSerum levels of adiponectin, resistin, IL-4 and TGF-β2 were measured by enzyme linked immunosorbent assay (ELISA) before and after clozapine treatment. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) before and after clozapine treatment, BMI was calculated in the days of blood sample collection.ResultsWe observed a significant decrease of adiponectin levels after switching from olanzapine/risperidone to clozapine (p<0.0001, Wilcoxon signed rank test W=820.0) and a statistically significant increase of resistin levels after switching to clozapine (p<0.0001, Wicoxon signed rank test W=-658.0). Similarly, a significant increase of TGF-β2 and of IL-4 levels was found after clozapine treatment (p=0.039, Wilcoxon signed rank test test W=-454.0 and p=0.029, Wilcoxon signed rank test W=-386.0, respectively).ConclusionsResistin, IL-4 and TGF-β levels increase after clozapine treatment while adiponectin levels significantly decrease. The findings may of importance, since they may reflect specific immune changes to clozapine responders.Disclosure of InterestNone Declared

PO085 / #1079 TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) FOR SEVERELY ILL SCHIZOPHRENIA PATIENTS: E-POSTER VIEWING

Current pharmacological treatments are effective for treating positive symptoms but have little or no effect to treat negative or cognitive symptoms in schizophrenia. Transcranial direct current stimulation (tDCS) has generated interest in recent years as a potential adjunctive treatment for patients with schizophrenia (1,2,3,4). The aim of this study was to examine the efficacy of frontal cortex tDCS for negative and neurocognitive symptoms in severely ill treatment resistant schizophrenia patients in Niuvanniemi hospital.

Evaluation of IGF-1 as a novel theranostic biomarker for schizophrenia

ObjectiveIn the current study, we aimed to investigate fasting plasma levels of glucose, insulin, growth hormone, IGF-1, and lipid profile in remission schizophrenia patients, treatment resistant schizophrenia patients and healthy controls and to determine whether IGF-1 levels can be used as a theranostic biomarker in schizophrenia. MethodsSixty-two patients under remission from schizophrenia, sixty-five treatment-resistant patients with schizophrenia and sixty-two healthy controls were included in the study. All patients were recruited and evaluated over 11 months. Symptoms at the time of evaluation were assessed twice using BPRS, PANSS, CGI, and GAF scales by an experienced psychiatrist in accordance with Andreaseen's remission criteria and TRIPS group resistance criteria. Blood samples were collected from all participants to determine fasting glucose, LDL, HDL, Triglyceride, Total Cholesterol, fasting, insulin, GH and IGF-1 levels. ResultsFasting blood glucose levels were found to be higher in patients with schizophrenia than in healthy controls. Moreover, LDL levels of the treatment sensitive group were higher than that of the treatment resistant group while they were not significantly different from the healthy controls. IGF-1 levels were lower in the treatment sensitive group than in both treatment resistant and healthy control groups. IGF-1, LDL and age of disease onset were found to be significantly associated with treatment resistance in a regression model. DiscussionIn the present study, remitted patients with schizophrenia could be distinguished from treatment-resistant patients and healthy controls with serum IGF-1, fasting glucose and LDL levels. In addition, we found that smoking and age of disease onset together with IGF-1 levels could significantly predict resistance to treatment.

Betacellulin - A Novel Therapeutic Target for Schizophrenia

Clozapine uniquely relieves psychotic symptoms in 30-50% of treatment resistant (TR) schizophrenia patients; however, the underlying mechanism remains unclear and alternative treatments are needed. Our body of work indicates that clozapine may augment epidermal growth factor (EGF) system signalling. The EGF system ligand betacellulin (BTC) is markedly decreased in schizophrenia patients, particularly in the TR subpopulation suggesting a link between clozapine action and low BTC in this subpopulation.

S1. CLOZAPINE RECHALLENGE FOLLOWING NEUTROPENIA USING GRANULOCYTE COLONY-STIMULATING FACTOR: A QUEBEC CASE SERIES

BackgroundClozapine possesses unique efficacy profile in treatment-resistant schizophrenia but is associated with neutropenia and agranulocytosis, in respectively, 3% and 0.7% of exposed patients. Granulocyte colony-stimulating factor (G-CSF) has been used to allow clozapine continuation or rechallenge in such situation (1,2).MethodsWe aim to describe the use of G-CSF to maintain clozapine despite neutropenia or agranulocytosis in treatment resistant schizophrenia patients in Quebec province, Canada. A national clozapine hematological monitoring database was consulted to identify all patients who have had red event (neutrophil count < 1,5 threshold) since 2004 in Quebec and was cross-referenced with hospital pharmacy software to identify patients who have received at least one dose of G-CSF while been exposed to clozapine All patients with an active cancer diagnosis while taking clozapine and G-CSF were excluded. A group of pharmacists specialized in psychiatry in Quebec was also contacted to ensure selecting all cases in the province. In additional to demographic data and clozapine and G-CSF details, Clinical Global Impression severity scale (CGI-S) was used to evaluate psychopathology severity during four critical turning points: before and after clozapine introduction, after agranulocytosis episode and after clozapine rechallenge. All data were collected retrospectively, using patient’s medical files, from January to July 2019.ResultsEight (8) patients (5 males, 3 females), Caucasian, mean age 48 years old, with clozapine median exposition of 4.8 years, were identified. In 7/8 of those, G-CSF was used according to an “as required strategy”, i.e., whenever the patient’s neutrophil count dropped below a pre-determined threshold, varying according to patient between 0,8 à 1,5. In the other patient, a 3-weekly doses were preventively administered. Despite this, a mean number of 4 red events (ranging from 1 to 10 events) were subsequently observed in those patients, leading to clozapine cessation in 4/8 patients. One other patient responded to G-CSF but the clinical team felt uncomfortable to maintain clozapine in such circumstances. No complication (infection for instance) due to low neutrophil counts was observed nor any significant side effect related to G-CSF. However, in all these cases, while clozapine treatment was associated with clinically significant improvement of psychopathology (mean CGI-S decreased from 5.5 to 3.4), clozapine cessation led to an important psychotic deterioration (mean CGI-S of 6.2) at follow up. Fortunately, in patients successfully rechallenged (3/8), a strong clinical improvement was observed, with return to previous response level observed.DiscussionTo our knowledge, this is the largest case series of clozapine rechallenge using G-CSF and adds to the 39 already described cases in which G-CSF was concomitantly used with clozapine (1,2). While an “as required” strategy was mainly used here, a different prophylactic G-CSF use may have led to higher rates of clozapine maintenance, despite red codes, which provides the impetus for further studies.ReferenceMyles N, Myles H, Clark SR, Bird R, Siskind D. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations. Australian and New Zealand Journal of Psychiatry. 2017;51(10):980–9.Lally J, Malik S, Krivoy A, Whiskey E, Taylor DM, Gaughran FP, et al. The use of granulocyte colony-stimulating factor in clozapine rechallenge: A systematic review. Journal of Clinical Psychopharmacology. 2017;37(5):600–4.

The Effect of Clozapine and Another Antipsychotic Combination Treatment on the Clinical Outcomes of Treatment Resistant Schizophrenia Inpatients

The combination of clozapine with other antipsychotics is a common practice in psychiatry, though the evidence-based knowledge is scarce. This practice is usually used with treatment resistant schizophrenia patients who have a poor response to clozapine monotherapy, therefore a poor prognosis.

Glutamate metabolites in treatment resistant schizophrenia: A meta-analysis and systematic review of 1H-MRS studies

Nearly a third to half of schizophrenia patients are non-responsive to first-line antipsychotics and are labelled treatment resistant schizophrenia (TRS). Neurochemical abnormalities in TRS may not be dopaminergic but possibly glutamate (Glu) related. Studies that have examined glutamatergic abnormalities using proton magnetic resonance spectroscopy (1H-MRS) in TRS, have showed inconsistent results. Hence, we conducted a meta-analysis of 1H-MRS studies comparing levels of Glu-and its metabolites in the brains of TRS and non-treatment resistant schizophrenia (nTRS) patients. Four eligible studies were included in the analysis. Summary effect size for the group difference between TRS (n = 101, including Ultra-TRS) and nTRS (n = 61) in Glu-levels in the anterior cingulate cortex (ACC) as measured with Hedges's g was 0.21 (95% CI: -0.42 to 0.85; p = 0.5) suggesting absence of significant difference. However, on leave one out analysis, one iteration showed significant difference in Glu-levels between the groups (Hedges's g = 0.46; p = 0.02) with higher Glu-levels in TRS implying significant effect of a single study on the effect size. The higher ACC Glu-in TRS was not associated with symptom severity or antipsychotic administration, indicating a possible trait abnormality. The limited number of datasets comparing Glu-metabolites in other brain regions are narratively described. Our analysis is limited by the significant heterogeneity between studies. Further longitudinal, prospective studies are needed to confirm higher Glu-metabolite levels in ACC in TRS and explore this potential trait abnormality.

ABCB1 and DRD3 polymorphism as a response predicting biomarker and tool for pharmacogenetically guided clozapine dosing in Asian Indian treatment resistant schizophrenia patients.

To investigate association of two single nucleotide polymorphisms (SNPs) ABCB1(rs1045462) and DRD3(rs6280) with clozapine response and the dose in treatment resistant schizophrenia (TRS) patients. 200 TRS patients were enrolled in the study during their follow up visit post clozapine initiation. SNP assessment was performed for DRD3 (rs6280) and ABCB1(rs1045462) by sequencing. Blood sample for genotyping was collected with disease and treatment related variables recording on case record form. Patients were classified as responders or nonresponders based upon Andreasen criteria and Positive and Negative Syndrome Scale (PANSS). Mean clozapine dose, the genotype frequency distribution of ABCB1, DRD3 SNPs were significantly different in clozapine responder and non-responder study population (p < 0.05). CT genotype of ABCB1 and AG genotype of DRD3 were observed to be more prevalent in the responder group. TT genotype of ABCB1 and AG genotype of DRD3 were prevalent in the nonresponder group. Clozapine dosing equations for responder and nonresponder TRS populations were developed through logistic regression analysis. 27% variability in clozapine dose was explained by possible combinations of ABCB1 and DRD3 SNP analysis. Differential ABCB1(rs1045462) and DRD3(rs6280) genotype frequencies among the clozapine responders and non-responders explained clear feasibility of response predictor potential along with clozapine dose variability association. Pharmacogenetically guided clozapine dosing is possible if more SNPs are considered together with ABCB1(rs1045462) and DRD3(rs6280) in TRS patients.

Disease Severity in Treatment Resistant Schizophrenia Patients Is Mainly Affected by Negative Symptoms, Which Mediate the Effects of Cognitive Dysfunctions and Neurological Soft Signs.

This post-hoc study was aimed at assessing whether disease severity was higher in a sample of Treatment Resistant Schizophrenia patients (TRS) compared to schizophrenia patients responsive to antipsychotics (non-TRS). Determinants of disease severity were also investigated in these groups. Eligible patients were screened by standardized diagnostic algorithm to categorize them as TRS or non-TRS. All patients underwent the following assessments: CGI-S; PANSS; DAI; NES; a battery of cognitive tests. Socio-demographic and clinical variables were also recorded. TRS patients exhibited significantly higher disease severity and psychotic symptoms, either as PANSS total score or subscales' scores. A preliminary correlation analysis ruled out clinical and cognitive variables not associated with disease severity in the two groups. Hierarchical linear regression showed that negative symptoms were the clinical variable explaining the highest part of variation in disease severity in TRS, while in non-TRS patients PANSS-General Psychopathology was the variable explaining the highest variation. Mediation analysis showed that negative symptoms mediate the effects of verbal fluency dysfunctions and high-level neurological soft signs (NSS) on TRS' disease severity. These results show that determinants of disease severity sharply differ in TRS and non-TRS patients, and let hypothesize that TRS may stem from cognitive disfunctions and putatively neurodevelopmental aberrations.

Clinical evaluation of functional capacity in treatment resistant schizophrenia patients: Comparison and differences with non-resistant schizophrenia patients

Treatment resistant schizophrenia (TRS) is defined by poor or non-response to conventional antipsychotic agents. Functional capacity is defined as the baseline potential of a patient to function in the community, irrespective of actual achievements gained, and has never been studied in TRS. Here, we screened 182 patients with psychotic symptoms and separated them in TRS (n = 28) and non-TRS (n = 32) ones, to evaluate whether they exhibited differential extents and predictive clinical variables of functional capacity. Functional capacity was measured by the UCSD Performance-Based Skills Assessment (UPSA). Psychotic symptoms by PANSS, social functioning by PSP and SLOF, clinical severity of the illness, cognitive functioning, and neurological soft signs (NSS) were assessed. TRS patients had non-significant lower UPSA scores compared to non-TRS (t-test: p > 0.05). In TRS, UPSA score correlated with multiple clinical variables. The highest effect sizes were observed for PANSS negative score (r = −0.67, p < 0.005); SLOF Area1 score (r = 0.66, p < 0.005); NSS severity (r = −0.61, p < 0.005). Multivariate analysis showed that main predictors of UPSA score in TRS patients were PANSS negative score, education years, NSS, Problem Solving performances, and PSP score (F = 11.12, R2 = 0.75, p < 0.0005). These variables were not predictive of UPSA score in non-TRS patients. Hierarchical analysis found that variance in UPSA score mainly depended on negative symptoms, NSS, and problem solving (F = 15.21, R2 = 0.65, p < 0.0005). Path analysis individuated two separate paths to UPSA score. These results delineate a limited and independent group of candidate predictors to be putatively accounted for therapeutic interventions to improve functional capacity, and possibly social functioning, in TRS patients.

Escitalopram augmentation improves negative symptoms of treatment resistant schizophrenia patients – A randomized controlled trial

Serum interleukin (IL)-6 levels in schizophrenia correlate with the severity of negative symptoms. This study aimed to explore the potential immune mechanism of SSRI augmentation in the management of patients with treatment-resistant schizophrenia, assessing changes in IL-6 and CRP amounts. This was a randomized double-blind, placebo-controlled, 8-week study of escitalopram augmentation in 62 schizophrenic patients treated in 2016–2017 at the Shandong Mental Health Center. Twenty-nine healthy controls were also included. Patients received add-on escitalopram or placebo for 8 weeks. Serum IL-6 and CRP were measured at baseline and 8 weeks. The primary outcome was the Positive and Negative Syndrome Scale (PANSS). After 8 weeks of treatment, reductions in total PANSS, negative subscore, and affective subscore were more important in escitalopram treated patients than in the placebo group (all P < 0.05). Escitalopram significantly decreased CRP and IL-6 levels (both P < 0.05). At baseline, IL-6′s effects on negative and cognitive symptoms represented 16.2% and 20.1%, respectively; at week 8, these effects were 22.7% and 20.8% on negative and cognitive symptoms, respectively. CRP had no impact on any PANSS score. Overall, escitalopram augmentation may be a useful addition for schizophrenic patients with persistent negative symptoms. Changes in IL-6 may be associated with negative and cognitive symptoms.

A network-based classification framework for predicting treatment response of schizophrenia patients

Knowledge-based systems including expert systems are one of the core components of clinical decision support systems. Nonetheless, modeling the uncertainty in medical knowledge is one of the main challenges of developing and employing such systems. Among various disorders, mental disorders are especially difficult to model because of their interconnected symptoms that give rise to complex outcomes such as resistance to different treatments. Here, we propose a network-based classification framework to distinguish treatment resistant schizophrenia patients from treatment responsive ones. Within this network-based framework, different antipsychotic medications are considered as external agents that change different properties of a symptoms interaction network where each node of the network represents one symptom. The overall goal of this study is to identify the symptoms that play a major role in responsiveness of the patients to antipsychotic medications. The proposed framework was tested using Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset and compared with three other commonly used feature selection methods: reliefF, Support Vector Machine (SVM) weights, and information gain. According to the results, features selected based on information gain and network analysis provided better classification performance, while the latter also considered the interactions of symptoms and is more interpretable.

T226. CLINICAL PREDICTORS OF FUNCTIONAL CAPACITY IN TREATMENT RESISTANT SCHIZOPHRENIA PATIENTS: COMPARISON WITH RESPONDER PATIENTS, ROLE OF NEGATIVE SYMPTOMS, PROBLEM SOLVING DYSFUNCTIONS, AND NEUROLOGICAL SOFT SIGNS

BackgroundTreatment Resistant Schizophrenia (TRS) patients show more severe impairments in community functioning compared to Antipsychotic Responder Schizophrenia (ARS) patients. The scope of this work was to assess whether TRS patients suffer from more severe alterations in functional capacity, i.e. the baseline potential of a patient to function in the community, and whether factors affecting functional capacity differ between TRS and ARS patients.Methods60 out of 182 eligible patients were included. A multistep diagnostic procedure to separate TRS from ARS was then used. Patients were administered a range of assessment tools including (but not limited to): the PANSS; cognitive performances tests; the Specific Level of Functioning (SLOF); the Neurological Evaluation Scale (NES); the UCSD Performance-Based Skills Assessment (UPSA) extended version. Univariate and multivariate statistics were performed. Significance was set at p<.05.ResultsAfter controlling for covariates, no significant differences in both total and subscales UPSA scores were found between TRS and ARS patients. However, TRS patients constantly scored lower than ARS patients.Stepwise regression was used to determine predictors of UPSA score. The first group encompassed clinical variables. In the whole sample, the final significant model, F(2,57)=18.848, p<.0005, adjusted R2=.37, included: PANSS negative subscale score and NES score. In TRS patients, the final significant model, F(3,24)=16.552, p<.0005, adjusted R2=.63, included PANSS negative scale score, education years, and NES score. In ARS patients, no significant models were found.The second group included cognitive performance variables. In the whole sample, the final significant model, F(2,57)=7.64, p=.001, adjusted R2=.18, included Problem Solving and Verbal Memory. In TRS patients, the final significant model included Problem Solving and VisuoSpatial Memory. In ARS patients, the final significant model included Verbal Memory only.The third group included psychosocial variables. In the whole sample, the final significant model, F(1,58)=18.82, p<.0005, adjusted R2=.23, included SLOF Area5 score only. In TRS patients the final significant model included SLOF Area1 score only, while in ARS patients, no significant models were found.By hierarchical multiple regressions, NES score was found to be predictive of the highest UPSA score variance ratio among schizophrenia patients. The addition of PANSS Negative scale score and Problem Solving (in this order) led to a statistically significant increase in R2. No further models were found to add significant increase in R2. In TRS patients, PANSS Negative scale score was the variable that explained the most variance in UPSA score. The addition of Problem Solving and education years (in this order) led to a statistically significant increase in R2. No further models were found to add significant increase in R2, although NES score showed a trend toward significance.At last, we performed a path analysis to evaluate the type (direct or indirect) and the direction of relationships among these variables and UPSA score. The only variables that were in direct relationship with UPSA score were PANSS Negative Scale score and Problem Solving. SLOF Area5 was in indirect relationship with UPSA score by PANSS Negative Scale score, while NES score relationship with UPSA score was mediated by Problem Solving.DiscussionOur study demonstrated that negative symptoms, altered cognitive performances, and more severe neurological soft signs were the major factors influencing functional capacity in schizophrenia patients. These factors were more relevant in TRS than in ARS patients.

Treatment resistant schizophrenia and neurological soft signs may converge on the same pathology: Evidence from explanatory analysis on clinical, psychopathological, and cognitive variables

Here, we investigated neurological soft signs (NSSs) in treatment resistant schizophrenia (TRS) vs treatment responder schizophrenia (SZ) patients. TRS is a severe condition, affecting approximately one-third of schizophrenia patients and representing a relevant clinical challenge. NSSs are neurological abnormalities reportedly described in schizophrenia patients and linked to dysregulated network connections. We explored the possibility that NSSs may be: i) more severe in TRS patients; ii) differentially associated to clinical/cognitive variables in TRS vs SZ; iii) predictive of having TRS. In addition, we evaluated whether diagnosis may mediate NSSs associations with the above-mentioned variables. Consecutive patients with schizophrenia diagnosis underwent stringent assessment for TRS diagnosis. Demographics and clinical variables were recorded. Psychopathology (by Positive and Negative Syndrome Scale, PANSS), cognitive performances, and NSSs (by Neurological Evaluation Scale, NES) were tested.TRS had higher scores than SZ patients in total NES score and in almost all NES subscales, even after correction for duration of illness and antipsychotic dose (ANCOVA, p<0.05). NSSs significantly correlated with multiple clinical, psychopathological, and cognitive variables (above all: duration of disease and negative symptoms) in TRS but not in SZ patients. Two-way ANOVA showed NSS-x-diagnosis interaction in determining outcomes on multiple cognitive performances, but not in other clinical variables. However, simple main effect analysis detected a significant relationship between high severity NSSs and TRS diagnosis on multiple clinical and cognitive outcomes. Hierarchical regression analysis showed that diagnosis was among a discrete number of predictors yielding significant increases in variance explained on NES total, Sensory Integration and Other Signs subscales' scores. NSSs, together with antipsychotic dose and disease severity, were found to be significantly predictive of TRS diagnosis in a binary logistic regression model. These results suggest a stringent association between NSSs and TRS diagnosis, and may imply that NSSs association with clinical, psychopathological, and cognitive variables may be in part mediated by TRS diagnosis.

Influence of clozapine to modified electroconvulsive therapy in the treatment resistant schizophrenia

IntroductionClozapine is one of the most effective drugs for the treatment resistant schizophrenia (TRS). It was reported that modified electroconvulsive therapy (mECT) may be an effective clozapine augmentation strategy in TRS.ObjectiveThe objective of this study was to investigate the influence of clozapine to mECT in the TRS.MethodsForty-seven patients were recruited in this study, but eight patients were excluded because clozapine was discontinued by reason of side effects. Ultimately, 39 patients were enrolled.ResultsSeventeen patients received mECT before clozapine therapy. Two patients continued mECT after starting clozapine therapy. There was a significant difference between before–after clozapine therapy (χ2 test, P&lt; 0.01). Intermittent mECT was performed for 3 patients before clozapine and for one patient after starting clozapine.DiscussionThis result suggests that clozapine therapy reduces mECT. In Japan, the first-line treatment for TRS is CLO. mECT is recommended for clozapine resistant schizophrenia patients. Prescription of CLO is limited in the part of medical facility because all physicians who prescribe clozapine must be registered with the clozaril patient monitoring service in Japan. It is considered that mECT is more readily selected than clozapine therapy. Therefore, the number of mECT is not reduced generally.ConclusionClozapine therapy reduces the necessity of mECT.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Assessing patient-rated vs. clinician-rated adherence to the therapy in treatment resistant schizophrenia, schizophrenia responders, and non-schizophrenia patients

The present study evaluated consistency, reliability, and determinants of two real-world measures of adherence to prescription in 57 schizophrenia and 61 non-schizophrenia patients. Treatment resistant schizophrenia (TRS) was additionally diagnosed in 28 of the schizophrenia patients. Patients were screened for clinical severity, cognitive functioning, and adherence by 10-item Drug Attitude Inventory (DAI-10) or Adherence-to-Therapy (AtT), a clinician-rated tool developed by our group.DAI-10 and AtT scores showed a significant correlation (p=0.039; ρ=0.21; df=103). Compared to the DAI-10 scale, a higher number of variables were associated with AtT. In schizophrenia and TRS patients, substance abuse was the only significant predictor of lower DAI-10 score (p=0.027, F=5.2, R2=0.07, and p=0.06, F=8.9, R2=0.23, respectively). Lower AtT score was significantly associated with first-generation antipsychotic use (p=0.001, RR: 2.00 [1.40–2.87]), positive symptoms (p=0.02, RR: 1.63 [1.05–2.53]), impaired verbal fluency (p=0.01, RR: 1.88 [0.81–4.32]) or problem solving (p=0.01, RR: 2.14 [0.92–4.98]). AtT, but not DAI-10, score correlated with the score on the Personal and Social Performance scale (p=0.02, F=5.86, R2=0.08).Overall, AtT score was predicted by pharmacological, psychopathological, and cognitive factors, and predictive of psychosocial functioning. Therefore, AtT measure may represent a convenient and practical tool to evaluate schizophrenia patients’ adherence.

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.

Association of birth weight and the development of antipsychotic induced adiposity in individuals with treatment resistant schizophrenia

Though weight gain is a common side effect of antipsychotic treatment, there are no useful predictors of which patients are likely to be affected and to what degree. It has been shown that exposure to adverse conditions during intra-uterine life confers a vulnerability to the development of later life metabolic complications and low birth weight for gestational age has been shown to be a robust marker of such prenatal adversity. We hypothesised that patients with schizophrenia with a lower birth weight will have increased vulnerability to the weight inducing effects of antipsychotic treatment. The relationship between birth weight and total and central adiposity, measured as body mass index (BMI) and waist-to-hip ratio (WHR) respectively, was examined in three groups: drug naïve first episode of psychosis (FEP) patients (n=41), treatment resistant schizophrenia (TRS) patients (n=42) and matched healthy volunteers (n=72). All analyses were controlled for age, gender and duration of treatment exposure. We found that a lower birth weight was associated with higher BMI and WHR only in TRS patients but not in FEP or controls, suggesting that prenatal adversity, as indicated by the surrogate marker of a lower birth weight, confers an increased vulnerability to clozapine induced weight gain.

Clozapine and aripiprazole combination

A 32 years old female with paranoid schizophrenia diagnosed at 20 years old, admitted for psychotic descompensation althought treatment compliance. She had delusional ideas focused on her family with suicidal behaviour and functional impairment, refractory to different antipsychotic treatments so clozapine was initiated. Valproic acid was initiated too because of seizure risk. Clinically, improvement was accomplish at these treatment doses: valproic acid 1000mg per day; clozapine 300mg per day; and aripiprazole 150mg IM per month. Discussion The use of clozapine in resistant schizophrenia patients improves functionality at the long-term and it is specially indicated for suicidal behaviour. Recent studies show that rehospitalization rates for patients treated with clozapine raised 13%. Other studies show that aripiprazole can be off label used as combination therapy in these situations.