Introduction: Negative symptoms (NS) include asociality, avolition, anhedonia, alogia, and blunted affect and are linked to poor prognosis. It has been suggested that they reflect two different factors: diminished expression (EXP) (blunted affect and alogia) and amotivation/pleasure (MAP) (anhedonia, avolition, asociality). The aim of this article was to examine potential sex differences among first-episode schizophrenia (FES) patients and analyze sex-related predictors of two NS symptoms factors (EXP and MAP) and functional outcome. Material and methods: Two hundred and twenty-three FES (71 females and 152 males) were included and evaluated at baseline, six-months and one-year. Repeated measures ANOVA was used to examine the effects of time and sex on NS and a multiple linear regression backward elimination was performed to predict NS factors (MAP-EXP) and functioning. Results: Females showed fewer NS (p = 0.031; Cohen's d=-0.312), especially those related to EXP (p = 0.024; Cohen's d=-0.326) rather than MAP (p = 0.086), than males. In both male and female group, worse premorbid adjustment and higher depressive symptoms made a significant contribution to the presence of higher deficits in EXP at one-year follow-up, while positive and depressive symptoms predicted alterations in MAP. Finally, in females, lower deficits in MAP and better premorbid adjustment predicted better functioning at one-year follow-up (R-2 = 0.494; p < 0.001), while only higher deficits in MAP predicted worse functioning in males (R-2 =0.088; p = 0.012). Conclusions: Slightly sex differences have been found in this study. Our results lead us to consider that early interventions of NS, especially those focusing on motivation and pleasure symptoms, could improve functional outcomes. (c) 2023 The Authors. Published by Elsevier Espana, S.L.U. on behalf of Sociedad Espanola de Psiquiatr & imath;a y Salud Mental (SEPSM). This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:Schizophrenia is a heterogeneous mental health disorder associated with severe disability. Approximately 30% of patients do not respond to pharmacological treatment, a condition known as treatment-resistant schizophrenia (TRS). Emerging digital solutions could help to improve the treatment of this population. Although the importance of characterising the patient journey (PJ) is widely recognised, and previously published in schizophrenia, this has never been done in patients with TRS to identify their specific needs and select digital approaches to fill the healthcare gaps. Therefore, this study aimed to (1) characterise the PJ in patients with TRS, (2) determine the key needs of these patients, and (3) identify digital solutions that could help to address those needs. METHODS:Three focus groups were constituted: (1) patients with TRS (n = 6); (2) informal caregivers (n = 4); and (3) social/healthcare professionals (n = 16). An advisory board (n = 11) was also created. We used the PJ and patient experience (PEx) methodologies, which place the user experience at the centre of the process. A five-step process was used to define the PJ, to identify patient and caregiver archetypes, to determine the needs and preferences of patients and caregivers, and to identify solutions (technological and others) to address those needs. RESULTS:We identified the archetypes of patients with TRS and informal caregivers. Nine stages of the PJ were identified: previous symptomatology; emergency care; hospitalization; therapeutic guidelines; outpatient care; diagnosis; disorder control; exacerbations; and risk behaviours. Six key needs were identified: better care during emergencies; improved understanding of the disorder and adverse events; better communication during diagnosis; better control and monitoring of the disorder; better identification of early warning signs; and immediate professional attention. Twenty-six specific initiatives aimed at improving the PEx and care processes were defined. CONCLUSIONS:This study characterised the PJ in patients with TRS. The findings of this study reveal the key areas of the recovery process that need improvement. Importantly, we developed a set of twenty-six specific initiatives to improve clinical outcomes. The main need identified by participants was for non-pharmacological interventions. TRIAL REGISTRATION:ClinicalTrials.gov NCT05345977.

Background:Treatment-resistant schizophrenia (TRS) is a severe form of schizophrenia associated with low adherence to treatment and poor outcomes. Mobile health (mHealth) interventions may be effective in preventing relapses, increasing treatment adherence, and managing some of the symptoms of schizophrenia. Mobile therapeutic attention for treatment-resistant schizophrenia (m-RESIST) is an innovative mHealth developed specifically for TRS. Objective:We aim to evaluate the effects of m-RESIST on the clinical and functional outcomes and on the perceived quality of life in people with TRS. Methods:A feasibility study without a control group was performed to test the m-RESIST solution on patients with TRS. Participants were recruited from Spain, Israel, and Hungary. This study's population (N=31) followed 3 months of intervention. The m-RESIST was configured by an app, a wearable, and a web-based platform. The severity of symptoms was evaluated by using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Schizophrenia (CGI-SCH) scale. Functionality was assessed by the Global Assessment of Functioning and perceived quality of life was evaluated by the EuroQol visual analogue scale (EQ-VAS). Results:Significant reductions were found in symptoms from pretrial to posttrial on the PANSS total (mean difference -7.2, 95% CI -11.1 to -3.4; P=.001), the PANSS positive (mean difference -1.36, 95% CI -2.6 to -0.1; P=.04), the PANSS negative (mean difference -2.1, 95% CI -3.1 to -1.1; P<.001), and the PANSS general symptoms (mean difference -3.8, 95% CI -6.8 to -0.8; P=.02). In almost one-fifth of the participants (6/31), the overall score for the PANSS decreased by more than 20%, which may be considered a clinically significant change. On the CGI-SCH scale, the sum of total severity of illness decreased significantly (P=.03). A decrease in the sum of positive and negative symptoms of the CGI-SCH score was also found (P=.04 and P=.03, respectively). The sum of depressive or cognitive symptoms did not change. The functionality of participants increased significantly on the Global Assessment of Functioning (P≤.001). The perceived quality of life on the EQ-VAS also improved (mean difference 6.7, 95% CI 0.5 to 12.9; P=.04). Conclusions:To our best knowledge, this was the first study to address the efficacy of the mHealth app m-RESIST on the symptoms and functional capacity and on the quality of life for people with TRS. Our preliminary findings showed that implementing the m-RESIST solution decreased the symptoms and severity of disease, and improved the functionality and perceived quality of life among those with TRS. The change of symptoms on the PANSS total may be clinically significant. Modern technologies such as mHealth interventions may be useful in treating symptoms and functionality even in TRS, which is a major clinical challenge, with usually poor outcomes. These results should be corroborated by performing a controlled trial.

Schizophrenia and psychosis are debilitating conditions with suboptimal treatment options. Deep brain stimulation (DBS) offers promise, but effective treatment targets remain undefined. Examining cases in which DBS either induced or alleviated psychotic symptoms may help identify circuits causally involved in psychosis and suggest candidate targets for intervention. We systematically reviewed the literature to identify all published cases in which DBS modulated (i.e., caused or improved) psychotic symptoms, regardless of target and indication. Authors of original publications were contacted to gather individual case data, allowing DBS electrode reconstruction and stimulation volume modeling. This data was aggregated into standard space and used to characterize anatomical structures most consistently associated with change in symptoms. After screening 332 studies, 36 cases were retained. This included 16 patients who received DBS for treatment-resistant schizophrenia or psychosis (nucleus accumbens, N=7; subgenual cingulate, N=4; substantia nigra pars reticulata, N=3; habenula, N=2) and 18 patients who received DBS for treatment of other conditions and experienced psychotic symptoms as a side effect (anterior nucleus of the thalamus, N=7; centromedian nucleus, N=1; subthalamic nucleus, N=6; nucleus accumbens, N=2; globus pallidus pars interna, N=1; amygdala, N=1). Finally, DBS of the nucleus basalis of Meynert improved visual hallucinations in two additional cases. Although stimulation sites were anatomically heterogeneous, qualitative integration of the empirical anatomical findings with current neurobiological models of schizophrenia revealed two circuits potentially implicated in psychotic symptoms: one centered on the mediodorsal nucleus of the thalamus and its main subcortical afferents, and one involving the nucleus accumbens - ventral tegmental area loop. We propose a preliminary theoretical framework linking these circuits to the emergence and improvement of psychotic symptoms, thereby generating testable hypotheses for future mechanistic and clinical studies. We suggest that disruption of these circuits may respectively relate to impaired filtering of cognitive and limbic representations, and aberrant salience processing.

OBJECTIVE:First episode of psychosis (FEP) is associated with glucose homeostasis abnormalities even before pharmacological intervention. Given inconclusive GWAS results regarding a direct genetic link between schizophrenia and type 2 diabetes mellitus (T2DM), we hypothesized that FEP patients may exhibit altered genetic risk for glycemic traits. We compared polygenic risk scores (PRS) for T2DM (PRST2DM), fasting glucose (PRSFG), and glycated hemoglobin (HbA1c) (PRSHbA1c) between FEP patients and controls, examining their associations with glycemic measures over 24 months. METHODS:We analyzed data from 242 FEP patients and 119 controls, assessing fasting serum glucose and HbA1c at baseline and 24 months. We examined cross-sectional and longitudinal associations between PRS and glycemic measures within each group. RESULTS:FEP patients and controls did not differ significantly in PRS. Significant associations were observed for PRSFG with baseline serum glucose in controls (p = 0.008), PRSFG during follow-up (p = 0.034), PRSHbA1c at 24 months (p = 0.018), and HbA1c longitudinally (p = 0.025). After multiple testing corrections, only the association between PRSFG and baseline serum glucose in controls remained significant (p_adj = 0.023). No associations were found for PRST2DM. CONCLUSIONS: Despite the link between FEP and glycemic disturbances, PRST2DM did not differ between FEP patients and controls. However, PRS for glycemic traits showed associations with glycemic measures in both groups before multiple testing correction, suggesting that genetic predisposition may influence glucose homeostasis in early psychosis. The absence of a direct association between common genetic variants underlying T2DM and early glycemic dysregulation in FEP underscores the importance of considering environmental factors and epigenetic mechanisms.

Approximately 30%-50% of people with schizophrenia worldwide have treatment-resistant schizophrenia (TRS). Currently available standard psychopharmacological and psychological treatments have proven insufficient to achieve full recovery in these patients. Alternative psychological interventions focused on improving emotion regulation, such as the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP), could potentially improve treatment outcomes in this difficult to treat population. The aim of the present case study is to demonstrate how the UP can be adapted for the treatment of TRS. We decided to use UP to treat this particular patient due to the presence of intense unpleasant emotions, aversive reactions, and emotional avoidance strategies. After completing the full treatment protocol, the patient showed significant decreases in scores on the Difficulties in Emotion Regulation Scale (DERS), including total and emotional rejection, life interference, and emotional lack of control. A significant reduction was also observed in anxiety (OASIS) and depressive symptoms (ODSIS). The intervention had a positive impact on auditory hallucinations, with decreased severity, less intense anxiety, and less interference in life. The treatment led to greater control over voices and the patient reported feeling more confident in her relationship with those voices. These results provide preliminary support for the use of UP for the treatment of TRS.

The study of brain gyrification may provide useful information on the cytoarchitecture and connectivity of the brain. One of the methods that have been developed to estimate brain gyrification, known as surface ratio (SR), has not yet been studied in schizophrenia. Here we aimed to assess whether SR could provide new insights on the brain structure of schizophrenia patients and the severity of symptoms. We also computed a more established brain gyrification measure, namely absolute mean curvature (AMC). We analyzed 63 magnetic resonance images, 25 from schizophrenia patients with treatment-resistant auditory verbal hallucinations (SCH-H), 18 from schizophrenia patients without hallucinations (SCH-NH), and 20 from healthy controls (HC). The SR measure revealed that SCH-H patients had a more folded orbitofrontal cortex than SCH-NH patients and HC. Gyrification in this region was also negatively associated with positive symptoms, specifically with the delusions and conceptual disorganization items, only in the SCH-H group. Regarding the AMC measure, we identified two areas where HC showed more gyrification than SCH-H patients, but no relationships arose with symptoms. The hypergyrification of the orbitofrontal cortex displayed by SCH-H patients, as captured by the SR measure, suggests aberrant and/or excessive wiring in these patients, which in turn could give rise to auditory verbal hallucinations. Alternatively, we comment on potential compensatory mechanisms that may better explain the negative association between orbitofrontal gyrification and positive symptomatology. The SR measure captured the most relevant differences and associations, making it a promising biomarker in schizophrenia.

Treatment-resistant schizophrenia (TRS) is a severe form of schizophrenia associated with low adherence to treatment and poor outcomes. Mobile health (mHealth) interventions may be effective in preventing relapses, increasing treatment adherence, and managing some of the symptoms of schizophrenia. Mobile therapeutic attention for treatment-resistant schizophrenia (m-RESIST) is an innovative mobile health (mHealth) solution based on novel technology offering high modular and flexible functioning developed specifically for TRS. To our best knowledge no studies have addressed the efficacy of mHealth applications on the symptoms and functional capacity, and on the quality of life in subjects having TRS. To evaluate the effects of m-RESIST on the clinical and functional outcomes, and on the perceived quality of life among participants having TRS. A feasibility study without a control group was performed to test the m-RESIST solution in TRS patients. Participants were recruited from Spain, Israel and Hungary. Study population (N=31) followed the 3 months of intervention. The m-RESIST was configured by an app, a wearable and a web-based platform. The severity of symptoms was evaluated by using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Schizophrenia (CGI-SCH). Functionality was assessed by the Global Assessment of Functioning (GAF) and perceived quality of life was evaluated by the Analogue Visual Scale of EuroQol 5 dimensions 5 levels questionnaire (EQ-VAS). Significant reductions were found in symptoms from pretrial to post trial on the PANSS total; mean difference -7.2 (P=.001), on the PANSS positive; -1.36 (P =.036) and PANSS negative; -2.1 (P <.001), and also on the PANSS general symptoms; -3.8 (P =.015). In almost one-fifth of the participants (6/31), the overall score for PANSS decreased by more than 20% which may be considered a clinically significant change. On CGI-SCH the sum of total severity of illness decreased significantly (P=.027). A decrease in the sum of positive and negative symptoms of the CGI-SCH-score was also found (P=.037 and P=.03, respectively). The sum of depressive or cognitive symptoms did not change. The functionality of participants increased significantly on the GAF (P =<.001). The perceived quality of life on EQ-VAS improved also (mean difference 6.7, P=.035). To our best knowledge, this was the first study collecting data on the symptoms, functional capacity, and quality of life in TRS by using the mHealth platform (m-RESIST solution). Our novel findings showed that implementing m-RESIS-solution decreased the symptoms and severity of illness, and improved the functionality and perceived quality of life among those having TRS. The change of symptoms on the PANSS total may be clinically significant. Modern technologies like mHealth interventions seem to be useful in treating symptoms and functionality even in TRS which is a major clinical challenge having usually poor outcomes. These results should be corroborated by performing a controlled trial. ClinicalTrials.gov NCT03064776; https://clinicaltrials.gov/ct2/show/record/NCT03064776 International Registered Report Identifier (IRRID): RR2-10.1136/bmjopen-2017-021346

Functioning is a fundamental dimension across all aspects of life, frequently compromised or reduced in individuals with schizophrenia. However, the lack of a commonly agreed definition of functioning in schizophrenia makes it difficult to apply this concept in clinical practice. In this document, we make a detailed analysis of the literature to identify and define functioning and describe how it can be used in clinical practice today. We performed a preliminary literature search in the MEDLINE database (via PubMed) for articles discussing functioning in schizophrenia. The articles retrieved were then read and discussed by a panel of psychiatrists specialising in schizophrenia. The conclusions reached in this meeting formed the basis for a new exhaustive literature search for the purpose of synthesising the evidence published in the past 5 years. In this article, we show the importance a comprehensive, modern, homogeneous definition of functioning in schizophrenia, propose a definition of functioning, and put forward a series of recommendations for assessing functioning in clinical practice. We also review current unmet needs and highlight the need for a standardised tool for evaluating functioning.

Different lines of evidence indicate that the structure and physiology of the basal ganglia and the thalamus is disturbed in schizophrenia. However, it is unknown whether the volume and shape of these subcortical structures are affected in schizophrenia with auditory hallucinations (AH), a core positive symptom of the disorder. We took structural MRI from 63 patients with schizophrenia, including 36 patients with AH and 27 patients who had never experienced AH (NAH), and 51 matched healthy controls. We extracted volumes for the left and right thalamus, globus pallidus, putamen, caudate and nucleus accumbens. Shape analysis was also carried out. When comparing to controls, the volume of the right globus pallidus, thalamus, and putamen, was only affected in AH patients. The volume of the left putamen was also increased in individuals with AH, whereas the left globus pallidus was affected in both groups of patients. The shapes of right and left putamen and thalamus were also affected in both groups. The shape of the left globus pallidus was only altered in patients lacking AH, both in comparison to controls and to cases with AH. Lastly, the general PANSS subscale was correlated with the volume of the right thalamus, and the right and left putamen, in patients with AH. We have found volume and shape alterations of many basal ganglia and thalamus in patients with and without AH, suggesting in some cases a possible relationship between this positive symptom and these morphometric alterations.

To assess the role of age (early onset psychosis-EOP < 18 years vs. adult onset psychosis-AOP) and diagnosis (schizophrenia spectrum disorders-SSD vs. bipolar disorders-BD) on the duration of untreated psychosis (DUP) and prodromal symptoms in a sample of patients with a first episode of psychosis. 331 patients with a first episode of psychosis (7–35 years old) were recruited and 174 (52.6

BACKGROUND:Patients with a first episode of psychosis (FEP) display clinical, cognitive, and structural brain abnormalities at illness onset. Ventricular enlargement has been identified in schizophrenia since the initial development of neuroimaging techniques. Obstetric abnormalities have been associated with an increased risk of developing psychosis but also with cognitive impairment and brain structure abnormalities. Difficulties during delivery are associated with a higher risk of birth asphyxia leading to brain structural abnormalities, such as ventriculomegaly, which has been related to cognitive disturbances.METHODS:We examined differences in ventricular size between 142 FEP patients and 123 healthy control participants using magnetic resonance imaging. Obstetric complications were evaluated using the Lewis-Murray scale. We examined the impact of obstetric difficulties during delivery on ventricle size as well as the possible relationship between ventricle size and cognitive impairment in both groups.RESULTS:FEP patients displayed significantly larger third ventricle size compared with healthy controls. Third ventricle enlargement was associated with diagnosis (higher volume in patients), with difficulties during delivery (higher volume in subjects with difficulties), and was highest in patients with difficulties during delivery. Verbal memory was significantly associated with third ventricle to brain ratio.CONCLUSIONS:Our results suggest that difficulties during delivery might be significant contributors to the ventricular enlargement historically described in schizophrenia. Thus, obstetric complications may contribute to the development of psychosis through changes in brain architecture.

INTRODUCTION:Auditory hallucinations (AH) are one of the most prevalent symptoms of schizophrenia. They might cause several brain alterations, especially changes in the volumes of hippocampus and amygdala, regions related to the relay and processing of auditory cues and emotional memories. MATERIAL AND METHODS:We have recruited 41 patients with schizophrenia and persistent AH, 35 patients without AH, and 55 healthy controls. Using their MRIs, we have performed semiautomatic segmentations of the hippocampus and amygdala using Freesurfer. We have also performed bilateral correlations between the total PSYRATS score and the volumes of affected subregions and nuclei. RESULTS:In the hippocampus, we found bilateral increases in the volume of its hippocampal fissure and decreases in the right fimbria in patients with and without AH. The volume of the right hippocampal tail and left head of the granule cell layer from the dentate gyrus were decreased in patients with AH. In the amygdala, we found its left total volume was shrunk, and there was a decrease of its left accessory basal nucleus in patients with AH. CONCLUSIONS:We have detected volume alterations of different limbic structures likely due to the presence of AH. The volumes of the right hippocampal tail and left head of the granule cell layer from the dentate gyrus, and total volume of the amygdala and its accessory basal nucleus, were only affected in patients with AH. Bilateral volume alterations in the hippocampal fissure and right fimbria seem inherent of schizophrenia and due to traits not contemplated in our research.