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Treatment Resistant Schizophrenia (TRS) is the persistence of significant symptoms despite adequate antipsychotic treatment. Although consensus guidelines are available, this condition remains often unrecognized and an average delay of 4-9 years in the initiation of clozapine, the gold standard for the pharmacological treatment of TRS, has been reported. We aimed to determine through a machine learning approach which domain of the Positive and Negative Syndrome Scale (PANSS) 5-factor model was most associated with TRS.In a cross-sectional design, 128 schizophrenia patients were classified as TRS (n = 58) or non-TRS (n = 60) after a structured retrospective-prospective analysis of treatment response. The random forest algorithm (RF) was trained to analyze the relationship between the presence/absence of TRS and PANSS-based psychopathological factor scores (positive, negative, disorganization, excitement, and emotional distress). As a complementary strategy to identify the variables most associated with the diagnosis of TRS, we included the variables selected by the RF algorithm in a multivariate logistic regression model.according to the RF model, patients with higher disorganization, positive, and excitement symptom scores were more likely to be classified as TRS. The model showed an accuracy of 67.19%, a sensitivity of 62.07%, and a specificity of 71.43%, with an area under the curve (AUC) of 76.56%. The multivariate model including disorganization, positive, and excitement factors showed that disorganization was the only factor significantly associated with TRS. Therefore, the disorganization factor was the variable most consistently associated with the diagnosis of TRS in our sample.

Background: Major Depressive Episodes (MDEs) may characterise many psychiatric disorders. Its pharmacotherapy is laid with unmet needs, rendering the testing of new drugs necessary. Objective: To compare the effects of vortioxetine with those of other antidepressants (OADs) in a 1-year naturalistic setting. Methods: We included 126 adult patients with anMDE in the course of major depressive (MDD), bipolar (BD), or schizophrenia spectrum disorders (SSOPDs), with or without substance use disorder (SUD), who received 5-20 mg/day oral vortioxetine, and compared them with 100 patients receiving OADs at baseline and after 1, 3, 8, and 12 months on their scores on the MADRS, the CGIS, the 24-item BPRS, the YMRS, the Hamilton Anxiety Rating Scale, a Visual Analogue Scale for craving, the Columbia-Suicide Severity Rating Scale, and the WHOQOL-BREF. Results: Patients on vortioxetine improved similarly to those on OADs on all measures, independently from having or not a comorbid SUD. However, they improved with time better than their OADcounterparts if affected by BD or SSOPDs, but not MDD, on the CGI-S, BPRS depression, anxiety, and manic symptoms. SUD hampered the response of anxiety to treatment. Men improved on depression with time better than women. Conclusion: MDEs responded to vortioxetine similarly to OADs by improving in depression, general psychopathology, anxiety, suicidal thinking, and quality-of-life, independently from SUD comorbidity. MDEs of patients with BD or SSOPDs on vortioxetine responded better than that of patients on OADs. Clinical Trial Registration No. 17354N.

Aim Early age at schizophrenia onset (EOS) has been associated with a worse clinical course, although previous studies reported substantial heterogeneity. Despite the relevance of the subject, the relationship between the age of onset and treatment resistant schizophrenia (TRS) is less clear. Methods We screened 197 non-affective psychotic patients. Of these, 99 suffered from schizophrenia and were putative TRS and were included in a prospective 4-to-8-week trial to assess their response to antipsychotics. According to status (TRS/nonTRS) and age-at-onset (early: ≤18 years, EOS; adult: >18 years, adult onset schizophrenia [AOS]) patients were subdivided in EOS-TRS, EOS-nonTRS, AOS-TRS, AOS-nonTRS. Multiple clinical variables were measured and compared by analysis of covariance (ANCOVA), using age as a covariate. Two-way analysis of variance (ANOVA) was used to assess whether significant differences were attributable to TRS status or age-at-onset. Results The rate of TRS patients was significantly higher in EOS compared to AOS. At the ANCOVA, EOS-TRS had significantly worse clinical, cognitive, and psychosocial outcomes compared to the other groups. Overall, EOS-TRS were more impaired than EOS-nonTRS, while significant differences with AOS-TRS were less consistent, albeit appreciable. Two-way ANOVA demonstrated that, in the majority of the investigated variables, the significant differences among groups were attributable to the TRS status effect rather than to age-at-onset or combined effects. Conclusions These results suggest that refractoriness to antipsychotics may be strongly linked to the early onset of psychotic symptoms, possibly as a result of common neurobiology.

Age-at-onset (AAO) affects psychiatric disorder outcome; substance (SUDs) or alcohol use disorders (AUDs) may influence their onset. Affective temperaments may affect early AAO and drug-use proneness.

Background: Treatment-resistance in schizophrenia is 30–40%. Its neurobiology remains unclear; to explore it, we conducted a combined spectrometry/tractography/cognitive battery and psychopathological rating study on patients with treatment-resistant schizophrenia (TRS), dividing the sample into early-onset (N = 21) and adult-onset TRS (N = 20). Previous studies did not differentiate between early- (onset 13–18 years) and adult-onset (>18 years at formal diagnosis of schizophrenia) TRS. Methods: We evaluated cross-sectionally 41 TRS patients (26 male and 15 female) and 20 matched healthy controls (HCs) with psychopathological and cognitive testing prior to participating in brain imaging scanning using magnetic resonance spectroscopy and diffusion tensor imaging to determine the relationship between their symptoms and their glutamate levels and white matter integrity. Results: TRS patients scored lower than HCs on all cognitive domains; early-onset patients performed better than adult-onset patients only on the Symbol Coding domain. TRS correlated with symptom severity, especially negative symptoms. Glutamate levels and glutamate/creatine were increased in anterior cingulate cortex. Diffusion tensor imaging showed low fractional anisotropy in TRS patients in specific white matter tracts compared to HCs (bilateral anterior thalamic radiation, cortico-spinal tract, forceps minor, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and right uncinate fasciculus). Conclusions: We identified specific magnetic resonance spectroscopy and diffusion tensor imaging alterations in TRS patients. Adult-onset TRS differed little from early-onset TRS on most measures; this points to alterations being present since the outset of schizophrenia and may constitute a biological signature of treatment-resistance.

Background: The Covid 19 pandemic might have impacted response to drug treatment in major depressive episode (MDE). We compared responses to three different antidepressant drugs, i.e., vortioxetine, sertraline, and trazodone, in outpatients with MDE during Major Depressive Disorder (MDD), Bipolar Disorder (BD), or schizophrenia and related psychoses (SSOPDs) during two time periods, i.e., prior to suffering Covid-19–related trauma and after suffering such trauma. Methods: We conducted an observational study on clinically stabilised for at least 6 months outpatients with MDE during the course of MDD (N=58), BD (N=33), or SSOPDs (N=51). Patients, whose baseline assessments of Montgomery-Åsberg Rating Scale (MADRS), Hamilton Anxiety Rating Scale (Ham-A), Brief Psychiatric Rating Scale (BPRS), Visual Analogue Scale for Craving (VAS-crav) and World Health Organization Quality of Life, Brief version (WHOQOL-BREF) were available, were recruited at the time they suffered Covid-19–related traumas. Fifty patients, prior to the pandemic, when they were clinically stable, were treated with 15 mg/die vortioxetine, 44 with 450 mg/die trazodone, and 48 with 150 mg/die sertraline. After experiencing a major Covid-19–related personal trauma, patients showed clinical worsening which required dosage adjustment (20 mg/day vortioxetine; 600 mg/day trazodone, and 200 mg/day sertraline) and, for a part of them, a month of hospitalisation. Scores on the MADRS, Ham-A, BPRS, VAS-crav and WHOQOL-BREF were compared drug-wise and gender-wise with Student’s t test for continuous variables and χ2 for categorical variables. Result: The sample consisted of 142 outpatients (age, mean 39.63 ± 16.84; 70 men and 72 women); women were older than men (mean age 43.18 ± 17.61 vs. 35.98 ± 15.30; p=0.01). The two genders did not differ on other variables). For all treatments, symptoms worsening was observed at the time of trauma, followed by slow recovery with treatment readjustment. Trauma-related worsening in patients on vortioxetine was less intense than patients on the other two antidepressants and recovery was faster. All drugs were associated with an improvement in QoL. The vortioxetine group showed a lower hospitalisation rate (24%) than sertraline (35.4%) and trazodone (38.6%), but this was not significant (p=0.27). Conclusion: All drugs improved symptoms after Covid-19 trauma in patients with MDE, with vortioxetine showing a small advantage. No differences between vortioxetine, sertraline and trazodone were found as concerns the need for hospitalisation.

Background Schizophrenia (SCZ) is a debilitating mental illness characterized by a highly complex, heterogeneous, non-mendelian genetic background. Recent progress in dissecting genetic architecture of SCZ has accelerated over the last decade due to new advanced technologies. Genome-Wide Association Studies (GWAS) on extremely large samples of patients identified and replicated hundreds of Single-Nucleotide Polymorphism (SNPs), each exhibiting only a modest effect. The analysis of genomic Copy Number Variations (CNVs) clarified the role of rare structural variants conferring significant risk by disrupting multiple genes involved in neurodevelopmental pathways, and linked to SCZ. In this scenario, the aim of our study is to carry out a genetic characterization of a cohort of patients affected by SCZ, in order to assess the risk of recurrence, to elucidate putative pathogenetic mechanisms and, whenever possible, to conceive tailored interventions and therapies. Methods 34 patients (8 women and 26 men) affected by SCZ and admitted to Day Hospital at Psychiatric Division for Treatment Resistant Psychosis of the University of Naples Federico II were recruited, and underwent: i) psychopathological evaluation and assessment of clinical response to antipsychotics; ii) genetic counseling; iii) further diagnostic investigation by using Comparative Genomic Hybridization (CGH) + Single Nucleotide Polymorphism (SNP) microarray with 2x400k Agilent’s platform “GenetiSure” for detecting unbalanced chromosomal abnormalities and regions of homozygosity (ROHs). Results Structural pathogenetic rearrangements resulted in 9 (27%) patients. Those identified were the following: 15q13.3 deletion, 16p13.11 duplication, 22q11.22 deletion (TOP3B), 22q11.22 (PRODH, DGCR5, DGCR6), RBFOX1 deletion, TCF4 deletion, derivative X chromosome (X;Y translocation). Potentially pathogenic rearrangements, involving genes associated with psychiatric disorders or implicated in neurodevelopment, resulted in 15 patients (44%). No relevant CNVs were detected in 10 patients (29%), although they showed the presence of ROHs that may contain susceptibility loci, since many neurodevelopmental genes map onto or near these specific regions. Certain of these rearrangements occur in many patients, and certain patients showed likewise multiple rearrangements. Discussion The analysis of CNVs and SNPs allowed us to characterize the genetic disease structure in the whole cohort of patients and helped to refine the diagnosis in a few cases, thereby ascertaining an underlying specific genetic condition. A further extension of the study, in terms of sample size and more accurate investigations (i.e genetic mapping of ROHs) is underway. According to literature, rare risk-associated CNVs account for 2% of SCZ cases, but their higher prevalence (27%) in our sample may be influenced by a larger percentage of Treatment Resistant and more severely ill patients (since they were recruited in a highly specialized Unit for Treatment Resistant Psychosis). Therefore, our future purpose is to demonstrate a robust genetic modulation of Treatment Resistant endophenotypes of SCZ. Moreover, we believe that the role of genetic counseling in psychiatric services should be emphasized, and that genetic testing in this field should not be restricted to suspected childhood neuropsychiatric disorders. According to the neurodevelopmental hypothesis of SCZ, that suggests a brain development disruption in early life (due to genetic and early environmental factors), prompting to a subsequent later emergence of the disease in adulthood, even chronic complex adult mental illness, such as SCZ, deserves detailed investigations and a more exhaustive genetic evaluation.

Background Clozapine is the gold standard for Treatment Resistant Schizophrenia (TRS) and its use is strongly recommended after failure of two/three antipsychotics. Nonetheless, prescribing trends do not appear to follow the global guidelines and switching to clozapine is often delayed or improper. Reasons for clozapine underuse are quite understood, whereas little is known on clozapine misuse. In fact, more stringent operative criteria to define TRS should be used in clinical practice, taking advantage of standardized assessment tools in order to avoid false TRS positive. In these perspectives, we studied the patterns of clozapine prescription in a sample of TRS and non-TRS patients, in order to identify psychopathological variables associated with lifetime exposure to clozapine. Methods 198 consecutive patients have been screened for eligibility criteria from 2016 until 2019 at Treatment Resistant Psychosis Centre of the University of Naples “Federico II”. Only stabilized schizophrenic patients aged between 18 and 65 were enrolled. All relevant clinical-demographic data were recorded. TRS diagnosis was based on TRRIP working group operational criteria and clear pseudo-resistance factors were excluded. Patients were subdivided into two groups: those having received or currently under clozapine treatment (eCLZ) and those never treated by clozapine (nCLZ). Patients were assessed for psychotic symptoms (PANSS), cognitive performances (BACS), neurological soft signs (NES), functional capacity (UPSA), social functioning (PSP and SLOF scales), and severity of illness (CGI-S). Results Among the patients included (92), eCLZ were 50 (54.3%), of which 20% being non-TRS. Compared to nCLZ, eCLZ had a significantly earlier age at onset, more hospitalizations, higher daily antipsychotic doses; eCLZ patients had significantly higher scores on the CGI-S, PANSS total, PANSS Negative, General Psychopathology and PAUSS subscale and, according to the Five Factor PANSS Model, higher score on Negative and Disorganization Factors; eCLZ had also more impaired Working Memory performances, higher NES Total score, lower PSP and all SLOF areas scores, except Area4. Then we use univariate and multivariate analysis to delineate predictors of clozapine exposure and to evaluate whether these factors may organize in proximal (independent) and distal (mediated) associations. We found five independently associated variables that mediate all the other ones: high antipsychotic doses, higher disease severity, suicide attempts, impaired working memory, more severe Stereotyped Thinking. Discussion While it is expected that some TRS patients might not receive clozapine, the observation that non-TRS patients had been exposed to clozapine may surprise. A possible explanation may be the lack of systematized procedure to diagnose TRS, which is often merely coincident with a nonspecific lack of response to antipsychotics. Due to mediation analysis, we further gained insights into the hierarchy of these variables’ impact on clozapine prescription and we finally compose a complex network of proximal and distal factors predicting clozapine exposure in schizophrenic patients. The above-mentioned independent variables significantly associated with clozapine exposure let intend that eCLZ patients may belong to a subset of more severely ill ones, beyond reaching the response threshold. Earlier onset patients may suffer from a more severe disease, be more prone to suicide attempts, and less responsive to antipsychotics. This result needs to be replicated in wider samples, and this relevant therapeutic issue should be further debated in order to gather robust evidence to support or discourage clozapine off-label use and misuse.

Background Earlier age at schizophrenia onset has been associated with worse prognosis, greater symptom severity, social withdrawal, poorer cognitive performances, however much heterogeneity and inconsistency in findings have been reported in these studies. Treatment Resistant Schizophrenia (TRS) is defined as the persistence of significant symptoms despite at least two adequate treatment trials, each for a minimum duration and dosage. Patients affected by TRS display worse cognitive functioning, social performances and a greater prevalence of Neurological Soft Signs compared to non-TRS. To date, no studies have explored whether early onset TRS patients differ in multiple clinical, cognitive, and social outcomes compared to early onset non-TRS patients and to adult onset patients. The objective of this study is to investigate the relationship of the condition of non-response to antipsychotic agents with age at onset of the first psychotic episode Methods We recruited 99 non-affective psychotic patients, that were referred to our academic outpatient unit for supposed resistance to antipsychotics. The diagnosis of TRS was made by a structured diagnostic flowchart, according to published guidelines. Patients underwent a wide set of clinical and cognitive evaluations by trained raters. According to the age of the first episode of psychosis, patients were subdivided in early onset (EO, 20 years). Clinical and demographic variables were compared by Student’s t and Chi square tests. Then, patients were subdivided in EO-TRS, EO-nonTRS, AO-TRS, AO-nonTRS and their clinical outcomes were compared by ANCOVA, using age as a covariate. The 2way ANOVA was used to assess whether significant differences among groups were attributable to Diagnosis (TRS vs. non-TRS), Age at Onset (EO vs. AO), or combined effects. Results Compared to AO schizophrenia patients, EO had more relevant cognitive impairments (although limited to discrete domains), more severe neurological soft signs, more severe psychotic symptoms, mostly in the disorganized and autistic trait domains, and exhibited more severe social and functional impairments. The rate of TRS patients was significantly higher in the EO group and the rate of non-TRS was significantly higher in the AO group (X=6.31, df=1, p=0.012). At the ANCOVA, EO-TRS patients had significantly longer duration of disease, more severe disease, and were under higher antipsychotic doses. Neurological soft signs were more relevant in the group of EO-TRS, while Visuospatial memory and verbal memory were more impaired in this group compared to the others. Also, this subgroup of patients exhibited the highest scores on PANSS total and subscales, and more impaired psychosocial functioning at the PSP, the UPSA, and the SLOF. Notably, in many cases, EO-TRS were more impaired than EO-nonTRS, while significant differences with AO-TRS were less consistent. 2way ANOVA demonstrated that in the majority of the investigated variables the significant differences among groups were attributable to a Diagnosis effect rather than to Age at Onset or combined effects. Discussion The study confirmed previous observations in patients subdivided into EO vs. AO ones. However, EO patients were more frequently TRS. The group of EO-TRS had the most severe and impaired outcomes. These results were mostly dependent on the condition of non-response to antipsychotic agents rather than to the earlier age at onset of psychotic symptoms. The neurobiology of TRS may cause both the most severe clinical course and the earlier age at onset of these patients. Heterogeneity in previous reports on EO schizophrenia may stem from fluctuating relative rates of TRS/non-TRS patients included in some studies compared to others.

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.

Background Negative symptoms (NSs) are more severe in Treatment Resistant Schizophrenia (TRS) than Antipsychotic Responder Schizophrenia (ARS) patients. NSs are predictors of outcomes of neurological soft signs and functional capacity in TRS but not in ARS patients. The scope of this work is to clarify whether NSs effects are integral to or independent from the TRS diagnosis in our sample of patients. Methods 70 out of 206 eligible putative TRS and ARS patients were included (enrollment still ongoing). Patients were tested by the Neurological Evaluation Scale (NES); the CGI-S; the PANSS; the Heinrichs’ Quality of Life Scale (QLS); the UCSD Performance-Based Skills Assessment (UPSA); the Personal and Social Performance (PSP) scale and Specific Level of Functioning (SLOF). Patients were subdivided in NSHigh (severe NSs) and NSLow (mild NSs) based on ROC curve-derived cut-off. Results At the Student’s t test, NSHigh had significantly lower scores than NSLow patients on: Verbal Fluency; QLS score; PSP score; UPSA Financial, Communication, and Family Skills; UPSA total score; all SLOF areas (except Area4). NSHigh patients had significantly higher scores than NSLow patients on CGI-S; PANSS Positive and General Psychopathology Subscale scores; and NES score. Distribution of NS patients was significantly different between TRS/ARS diagnostic groups, as NSHigh patients were significantly more frequent in the TRS group (Pearson chi square: □1=5.51, p=.001). Notably, mean PANSS Negative Subscale scores were significantly higher in TRS compared to ARS patients (Student’s t: F1,58=2.84, p=.006). Since multiple variables found to be significantly different in NSHigh vs. NSLow patients were also significantly different between TRS and ARS patients, the question arises whether the significant differences found between diagnostic groups may depend on the higher percentage of patients with more severe NSs in the TRS group. Therefore, a two-way ANOVA was carried out with dichotomous NS and Diagnosis variables as the independent variables. Outcomes on multiple clinical variables were significantly different among groups. A NS*Diagnosis interaction effect was found for NES score (F1,58=4.32, p=.042, Visuospatial Memory, UPSA Transportation skills, and SLOF Area1. In all these cases, NSHigh/TRS patients performed significantly worse than the other patient groups; in the case of NES score, NSHigh/TRS patients score significantly higher than the other groups. Independent effect of either NSs or Diagnosis were also found for multiple variables, suggesting that NSs and Diagnosis may interact but their effects are not completely overlapping. To have a more deepen comprehension of NS effects on diagnosis, we carried out a moderator regression analysis and an ANCOVA analysis that further confirmed the finding that NSs’ mediate Diagnosis effects on a number of clinical outcomes. Given that NSs largely affect clinical variables, we asked which distinct symptom may exert the greater impact on each of these variables. Therefore, we carried out a including the seven PANSS Negative Subscale items as the independent variables. The items that explained the highest variance in clinical variables were mostly Stereotyped Thinking (N7), Passive Social Withdrawal (N4), and Difficulty in Abstract Thinking (N5). Discussion These data suggest that NSs are both independent determinants and moderators of TRS/ARS diagnosis effect on multiple psychopathology, cognitive, and psychosocial factors. More impaired functions attributed to non-response to antipsychotics may depend on more severe NSs. However, only a subset of NSs appears to exert this action, possibly related to the multidimensional construct of these symptoms.