A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup.

Psychosis onset is a transdiagnostic event that leads to a range of psychiatric disorders, which are currently diagnosed through clinical observation. The integration of multimodal biological data could reveal different subtypes of psychosis onset to target for the personalization of care. In this study, we tested the existence of subgroups of patients affected by first-episode psychosis (FEP) with a possible immunopathogenic basis. To do this, we designed a data-driven unsupervised machine learning model to cluster a sample of 127 FEP patients and 117 healthy controls (HC), based on the peripheral blood expression levels of 12 psychosis-related immune gene transcripts. To validate the model, we applied a resampling strategy based on the half-splitting of the total sample with random allocation of the cases. Further, we performed a post-hoc univariate analysis to verify the clinical, cognitive, and structural brain correlates of the subgroups identified. The model identified and validated two distinct clusters: 1) a FEP cluster characterized by the high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A and CXCR3); 2) a cluster consisting of an equal number of FEP and HC subjects, which did not show a relative over or under expression of any immune marker (balanced subgroup). None of the subgroups was related to specific symptoms dimensions or longitudinal diagnosis of affective vs non-affective psychosis. FEP patients included in the balanced immune subgroup showed a thinning of the left supramarginal and superiorfrontal cortex (FDR-adjusted p-values < 0.05). Our results demonstrated the existence of a FEP patients' subgroup identified by a multivariate pattern of immunomarkers involved in inflammatory activation. This evidence may pave the way to sample stratification in clinical studies aiming to develop diagnostic tools and therapies targeting specific immunopathogenic pathways of psychosis.

Incidental findings on brain MRI in patients with first-episode and chronic psychosis.

Brain incidental findings (IFs) are unexpected brain abnormalities detected by a structural magnetic resonance (MRI) examination. We conducted a study to assess whether brain IFs are associated with first-episode psychosis (FEP) and chronic psychosis (affective vs. non-affective) compared to healthy controls (HC). Chi-squared analyses were run to compare the frequency of several IFs across groups. Logistic regression analyses were run to explore the association between group and IFs, accounting for sex, age, MRI field strength. We observed a higher frequency of most IFs in both FEP and chronic psychosis groups compared to HC, however most of the chi-squared tests did not reach significance. Patients with FEP and chronic psychosis were 3-4 times more likely to show deep white matter hyperintensities (WMH) than HC. Patients with FEP and affective chronic psychosis were 3-4 times more likely to show ventricular asymmetries than HC. All chronic patients were more likely to show periventricular WMH, liquoral spaces enlargements and ventricular system enlargements respectively. Our results suggest that deep WMH and ventricular asymmetries are associated with both the early and the chronic stages of psychosis, thus representing potential vulnerability factors already present before the onset of the symptoms, possibly due to neurodevelopmental insults.

[Continuity of care and therapeutic adherence in young people at psychosis onset: the integrated intervention model of the Psychiatric Service of Bolzano]. / Continuità e aderenza terapeutica nei giovani all'esordio psicotico: il modello di intervento integrato del Servizio Psichiatrico di Bolzano.

AIM: To report on: 1) the modification process occurred within the Psychiatric Service of Bolzano toward an early, intensive, specific and multimodal system of care for patients experiencing their first psychotic episode and their family members; 2) the 12-month clinical and social course of a sample of patients referred to the "Early Intervention Project". METHODS: Longitudinal naturalist study evaluating the 12-month clinical and outcome of a cohort of first-episode psychosis patients consecutively referred to the "Early Intervention Project" implemented within the Psychiatric Service of Bolzano. Socio-demographic characteristics, housing situation and occupational status, interventions offered (medical intervention, psychotherapy, psychoeducation to family members, social intervention) and hospital admissions were drawn from electronic medical records. Levels of psychopathology and global functioning were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Global assessment of Functioning (GAF), respectively. RESULTS: During the first five years of activity (2012-2017) 116 patients had been referred to the Project. At 12 months 83.6%were still in charge, 7.76% moved to another area, 8.5% have abandoned the intervention. No significant difference in terms of age and gender was found between patients who remained in the project and those who lost contact. All patients had received specific integrated treatment; moreover, 16% had received intensive residential care. Notably, only 13.5% have had a hospital readmission over the 12 months of intervention. The PANSS total, positive and negative scores displayed significant reduction from baseline (BL) to follow-up (FU); in parallel, increase in GAF score from BL to FU was observed. All patients employed at BL were able to keep their job at FU; 17% of all patients unemployed at baseline were employed at FU. DISCUSSION AND CONCLUSION: The "Early Intervention Project" implemented in Bolzano was found to ensure integrated, multidisciplinary and early treatment, as defined by the most recent international guidelines, which produced significant improvement in both clinical and social outcomes in a cohort of first-episode psychosis patients.

Classification of Psychoses Based on Immunological Features: A Machine Learning Study in a Large Cohort of First-Episode and Chronic Patients.

For several years, the role of immune system in the pathophysiology of psychosis has been well-recognized, showing differences from the onset to chronic phases. Our study aims to implement a biomarker-based classification model suitable for the clinical management of psychotic patients. A machine learning algorithm was used to classify a cohort of 362 subjects, including 160 first-episode psychosis patients (FEP), 70 patients affected by chronic psychiatric disorders (schizophrenia, bipolar disorder, and major depressive disorder) with psychosis (CRO) and 132 health controls (HC), based on mRNA transcript levels of 56 immune genes. Models distinguished between FEP, CRO, and HC and between the subgroup of drug-free FEP and HC with a mean accuracy of 80.8% and 90.4%, respectively. Interestingly, by using the feature importance method, we identified some immune gene transcripts that contribute most to the classification accuracy, possibly giving new insights on the immunopathogenesis of psychosis. Therefore, our results suggest that our classification model has a high translational potential, which may pave the way for a personalized management of psychosis.

Altered syntactic abilities in first episode patients: An inner phenomenon characterizing psychosis.

BACKGROUND: Research has consistently shown that language abilities represent a core dimension of psychosis; however, to date, very little is known about syntactic comprehension performance in the early stages of psychosis. This study aims to compare the linguistic abilities involved in syntactic comprehension in a large group of First Episode Psychosis (FEP) patients and healthy controls (HCs). METHODS: A multiple choice test of comprehension of syntax was administered to 218 FEP patients (166 non-affective FEP patients [FEP-NA] and 52 affective FEP patients [FEP-A]) and 106 HCs. All participants were asked to match a sentence they listen with one out of four vignettes on a pc screen. Only one vignette represents the stimulus target, while the others are grammatical or non-grammatical (visual) distractors. Both grammatical and non-grammatical errors and performance in different syntactic constructions were considered. RESULTS: FEP committed greater number of errors in the majority of TCGB language domains compared to HCs. Moreover, FEP-NA patients committed significantly more non-grammatical (z = -3.2, p = 0.007), locative (z = -4.7, p < 0.001), passive-negative (z = -3.2, p = 0.02), and relative (z = -4.6, p < 0.001) errors compared to HCs as well as more passive-affirmative errors compared to both HCs (z = -4.3, p < 0.001) and FEP-A (z = 3.1, p = 0.04). Finally, we also found that both FEP-NA and FEP-A committed more grammatical (FEP-NA: z = -9.2, p < 0.001 and FEP-A: z = -4.4, p < 0.001), total (FEP-NA: z = -8.2, p < 0.001 and FEP-A: z = 3.9, p =  0.002), and active-negative (FEP-NA: z = -5.8, p < 0.001 and FEP-A: z = -3.5, p = 0.01) errors compared to HCs. CONCLUSIONS: This study shows that the access to syntactic structures is already impaired in FEP patients, especially in those with FEP-NA, ultimately suggesting that language impairments represent a core and inner feature of psychosis even at early stages.

Dimensional structure of first episode psychosis.

AIM: Current diagnostic systems, DSM-5 and ICD-10, still adopt a categorical approach to classify psychotic disorders. The present study was aimed at investigating the structure of psychotic symptomatology in both affective and non-affective psychosis from a dimensional approach. METHODS: Participants with a first episode psychosis (FEP) were recruited from a cluster-randomized controlled trial (GET-UP PIANO TRIAL), offered to all Community Mental Health Centres (CMHCs) located across two northern Italian regions. After clinical stabilization, patients were assessed with a comprehensive set of psychopathological measures including the Positive and Negative Syndrome Scale, the Hamilton Depression Rating Scale and the Bech-Rafaelsen Mania Rating Scale. A two-step cluster analysis was performed. RESULTS: Overall, 257 FEP patients (male, n = 171, 66.5%; mean age = 24.96 ± 4.56) were included in the study. The cluster analysis revealed a robust four-cluster solution: delusional-persecutory (n = 82; 31.9%), depressed (n = 95; 37%), excited (n = 26; 10.1%) and negative-disorganized (n = 54; 21%), thus suggesting a quadripartite structure with both affective and non-affective dimensions. Among non-affective dimensions, negative and disorganization symptoms constituted a unique construct apart from positive symptoms. CONCLUSIONS: Symptom dimensions may represent a useful tool for dissecting the indistinct and non-specific psychopathology of FEP in order to better target specific interventions.

Non literal language comprehension in a large sample of first episode psychosis patients in adulthood.

To date no data still exist on the comprehension of figurative language in the early phases of psychosis. The aim of this study is to investigate for the first time the comprehension of metaphors and idioms at the onset of the illness. Two-hundred-twenty eight (228) first episode psychosis (FEP) patients (168 NAP, non-affective psychosis; 60 AP, affective psychosis) and 70 healthy controls (HC) were assessed. Groups were contrasted on: a) type of stimulus (metaphors vs idioms) and b) type of response (OPEN = spontaneous explanations vs CLOSED = multiple choice answer). Moreover, a machine learning (ML) approach was adopted to classifying participants. Both NAP and AP had a poorer performance on OPEN metaphors and idioms compared to HC, with worse results on spontaneous interpretation of idioms than metaphors. No differences were observed between NAP and AP in CLOSED tasks. The ML approach points at CLOSED idioms as the best discriminating variable, more relevant than the set of pre-frontal and IQ scores. Deficits in non-figurative language may represent a core feature of psychosis. The possibility to identify linguistic features discriminating FEP may support the early recognition of patients at risk to develop psychosis, guiding provision of personalized and timely interventions.

Family Burden, Emotional Distress and Service Satisfaction in First Episode Psychosis. Data from the GET UP Trial.

Background: Literature has documented the role of family in the outcome of chronic schizophrenia. In the light of this, family interventions (FIs) are becoming an integral component of treatment for psychosis. The First Episode of Psychosis (FEP) is the period when most of the changes in family atmosphere are observed; unfortunately, few studies on the relatives are available. Objective: To explore burden of care and emotional distress at baseline and at 9-month follow-up and the levels of service satisfaction at follow-up in the two groups of relatives (experimental treatment EXP vs. treatment as usual TAU) recruited in the cluster-randomized controlled GET UP PIANO trial. Methods: The experimental treatment was provided by routine public Community Mental Health Centers (Italian National Health Service) and consisted of Treatment as Usual plus evidence-based additional treatment (Cognitive Behavioral Therapy for psychosis for patients, Family Intervention for psychosis, and Case Management). TAU consisted of personalized outpatient psychopharmacological treatment, combined with non-specific supportive clinical management and informal support/educational sessions for families. The outcomes on relatives were assessed by the Involvement Evaluation Questionnaire (IEQ-EU), the General Health Questionnaire (GHQ-12), and the Verona Service Satisfaction Scale (VSSS-EU). Differences within and between groups were evaluated. Results: At baseline, 75 TAU and 185 EXP caregivers were assessed. In the experimental group 92% of relatives participated in at least 1 family session. At follow-up both groups experienced improvement in all IEQ and GHQ items, but caregivers belonging to the EXP arm experienced a significantly greater change in 10 IEQ items (mainly pertaining to the "Tension" dimension) and in GHQ items. Due to the low sample size, a significant effectiveness was only observed for 2 IEQ items and 1 GHQ-12 item. With respect to VSSS data at follow-up, caregivers in the EXP arm experienced significantly greater satisfaction in 8 items, almost all pertaining to the dimensions "Relatives' Involvement" and "Professionals' Skills and Behavior." Conclusions: The Family intervention for psychosis delivered in the GET UP PIANO trial reduced family burden of illness and improved emotional distress and satisfaction with services. These results should encourage to promote FIs on caregivers of first-episode psychosis patients.

Predictors and moderators of treatment outcome in patients receiving multi-element psychosocial intervention for early psychosis: results from the GET UP pragmatic cluster randomised controlled trial.

BackgroundThe GET UP multi-element psychosocial intervention proved to be superior to treatment as usual in improving outcomes in patients with first-episode psychosis (FEP). However, to guide treatment decisions, information on which patients may benefit more from the intervention is warranted.AimsTo identify patients' characteristics associated with (a) a better treatment response regardless of treatment type (non-specific predictors), and (b) a better response to the specific treatment provided (moderators).MethodSome demographic and clinical variables were selected a priori as potential predictors/moderators of outcomes at 9 months. Outcomes were analysed in mixed-effects random regression models. (Trial registration: ClinicalTrials.gov, NCT01436331)ResultsAnalyses were performed on 444 patients. Education, duration of untreated psychosis, premorbid adjustment and insight predicted outcomes regardless of treatment. Only age at first contact with the services proved to be a moderator of treatment outcome (patients aged ⩾35 years had greater improvement in psychopathology), thus suggesting that the intervention is beneficial to a broad array of patients with FEP.ConclusionsExcept for patients aged over 35 years, no specific subgroups benefit more from the multi-element psychosocial intervention, suggesting that this intervention should be recommended to all those with FEP seeking treatment in mental health services.

Feasibility and Effectiveness of a Multi-Element Psychosocial Intervention for First-Episode Psychosis: Results From the Cluster-Randomized Controlled GET UP PIANO Trial in a Catchment Area of 10 Million Inhabitants.

Integrated multi-element psychosocial interventions have been suggested to improve the outcomes of first-episode psychosis (FEP) patients, but they have been studied primarily in experimental settings and in nonepidemiologically representative samples. Thus, we performed a cluster-randomized controlled trial, comparing an integrated multi-element psychosocial intervention, comprising cognitive behavioral therapy, family intervention, and case management, with treatment as usual (TAU) for FEP patients in 117 community mental health centers (CMHCs) in a large area of northern Italy (10 million inhabitants). The randomized units (clusters) were the CMHCs, and the units of observation the patients (and, when available, their family members). The primary hypotheses were that add-on multicomponent intervention: (1) results in greater improvements in symptoms, as assessed with positive and negative syndrome scale and (2) reduces in-hospital stay, based on days of hospitalization over the 9-month follow-up. Four hundred and forty-four FEP patients received the intervention or TAU and were assessed at baseline and 9 months. Based on the retention rates of patients (and families) in the experimental arm, multi-element psychosocial interventions can be implemented in routine mental health services. Regarding primary outcomes, patients in the experimental arm showed greater reductions in overall symptom severity, while no difference could be found for days of hospitalization. Among the secondary outcomes, greater improvements were detected in the experimental arm for global functioning, emotional well-being, and subjective burden of delusions. No difference could be found for service disengagement and subjective burden of auditory hallucinations. These findings support feasibility and effectiveness of early interventions for psychosis in generalist mental health services.

Suicide in elderly South Tyroleans in various residential settings at the time of death: a psychological autopsy study.

BACKGROUND: Completed suicide is more frequent among older adults than any other age group. Data on suicide in nursing homes and other residential facilities are inconsistent. This work aims to describe the characteristics of elderly suicide victims in different residential settings compared to young suicide victims. METHODS: Data on people who died by suicide in the South Tyrol (Alto Adige) region of Italy between 2000 and 2009 were gathered from the local Provincial Mortality Register. Further detailed information was collected via questionnaires to mental health departments and psychological services, family physicians and relatives of the deceased. RESULTS: A total of 525 cases of suicide were recorded, with a linearly decreasing trend during the study period. About one-third of the suicides occurred in those aged 60 years and over. Suicide in the elderly was associated with low education level (odds ratio (OR) = 7.1, P < 0.001), living in a one-person household (OR = 2.4, P < 0.01), not having economic troubles (OR = 6.1, P < 0.01), having seen a doctor in the past month (OR = 2.4, P < 0.01) and living in a residential facility (OR = 2.6, P < 0.05). Twenty-four (17.9%) suicide victims aged 60 years and over were in a residential facility/hospital at the time of the death. They were more likely to be women, not married, and to die by jumping from a height. CONCLUSIONS: The suicide risk should be carefully assessed in the elderly who live alone or are institutionalized or hospitalized. Efforts are warranted to reduce seniors' access to high places in hospitals and facilities.

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial.

BACKGROUND: Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services. METHODS/DESIGN: The Psychosis early Intervention and Assessment of Needs and Outcome (PIANO) trial is part of a larger research program (Genetics, Endophenotypes and Treatment: Understanding early Psychosis - GET UP) which aims to compare, at 9 months, the effectiveness of a multi-component psychosocial intervention versus treatment as usual (TAU) in a large epidemiologically based cohort of patients with FEP and their family members recruited from all public community mental health centers (CMHCs) located in two entire regions of Italy (Veneto and Emilia Romagna), and in the cities of Florence, Milan and Bolzano. The GET UP PIANO trial has a pragmatic cluster randomized controlled design. The randomized units (clusters) are the CMHCs, and the units of observation are the centers' patients and their family members. Patients in the experimental group will receive TAU plus: 1) cognitive behavioral therapy sessions, 2) psycho-educational sessions for family members, and 3) case management. Patient enrollment will take place over a 1-year period. Several psychopathological, psychological, functioning, and service use variables will be assessed at baseline and follow-up. The primary outcomes are: 1) change from baseline to follow-up in positive and negative symptoms' severity and subjective appraisal; 2) relapse occurrences between baseline and follow-up, that is, episodes resulting in admission and/or any case-note records of re-emergence of positive psychotic symptoms. The expected number of recruited patients is about 400, and that of relatives about 300. Owing to the implementation of the intervention at the CMHC level, the blinding of patients, clinicians, and raters is not possible, but every effort will be made to preserve the independency of the raters. We expect that this study will generate evidence on the best treatments for FEP, and will identify barriers that may hinder its feasibility in 'real-world' clinical settings, patient/family conditions that may render this intervention ineffective or inappropriate, and clinical, psychological, environmental, and service organization predictors of treatment effectiveness, compliance, and service satisfaction.