Longitudinal outcomes of a work inclusion program in mental health departments in the city of Milan.

BACKGROUND: Work functioning impairment is a key diagnostic and prognostic criterion in patients with psychiatric disorders and work inclusion is a major goal of their therapeutic pathway. Since 2009, the Regional Innovative Program (PIR) TR106, promoted by ASST Fatebenefratelli-Sacco of Milan in collaboration with other Departments of Mental Health and Addictions (DSMDs) in the town of Milan (Italy), has been developing the employment inclusion of psychiatric patients. AIMS: The objective of this study is to evaluate its outcomes over 8 years of observation. METHOD: We reported the results of a retrospective epidemiologic analysis on 2,142 interventions on 1,066 patients recruited, investigating PIR TR106 outcomes per year focusing on different subgroups. We focused on 'positive', 'negative', and 'other' outcomes. RESULTS: We preliminary calculated job maintenance interventions (5%, 107) and excluded these interventions from the overall. We observed 29 job firing (1.4%) and 15 job resignations (0.7%) as negative results (equal to 2.2% of the total) and 388 job hiring (16.6%), 647 traineeships (31.8%), and 413 work formation (20.3%) as positive outcomes (equal to 68.75%). In other outcomes (29.1%) we found 305 dismissals from PIR TR 106 (15%) and transitory outcomes (14.1%).Job hiring increased from 8.9% in 2012 to 23.8 % in 2019 (p < .001), while the dismissals diminished from 26.7% to 13.3% (p < .001). The effectiveness of traineeships in terms of job hiring increased in the ratio of annual job hiring versus job traineeship (+48.8%). The majority of hired patients (15.1%) were affected by a psychotic disorder. A significant hiring increase was observed in patients with psychotic disorders and personality disorders (p < .005). CONCLUSIONS: PIR-TR106 represents a territorial employment inclusion program with progressively increasing effectiveness and specificity, as suggested by changes in outcomes during the 8-year observation. The adaptive capacity and sustainability of the intervention are worth further investigation.

The Italian version of the Brief Assessment of Cognition in Affective Disorders: performance of patients with bipolar disorder and healthy controls.

OBJECTIVES: Cognitive deficits in Bipolar Disorder (BD) are significant enough to have an impact on daily functioning. Therefore, appropriate tools must be used to improve our understanding of the nature and severity of cognitive deficits in BD. In this study, we aimed to compare the cognitive profiles of patients with BD and healthy controls (HC) applying the Italian version of the Brief Assessment of Cognition in Affective Disorders (BAC-A). METHODS: This cross-sectional study included 127 patients with BD and 134 HC. The participants' cognitive profiles were evaluated using the Italian version of the BAC-A, which assesses verbal memory, working memory, motor speed, verbal fluency, attention & processing speed, executive functions, and two new measures of affective processing. The BAC-A raw scores were corrected using the normative data for the Italian population. In addition, we explored whether intelligence quotient (IQ) and specific clinical variables would predict the BAC-A affective, non-affective, and total composite scores of patients with BD and HC. RESULTS: HC performed better than patients with BD in all BAC-A subtests (all p < .001), except for subtests of the Affective Interference Test. (p ≥ .05). The effect sizes varied in magnitude and ranged between d = 0.02 and d = 1.27. In patients with BD, lower BAC-A composite scores were predicted by a higher number of hospitalizations. There was a significant association between IQ and BAC-A composite scores in both bipolar patients and HC. CONCLUSIONS: The Italian BAC-A is sensitive to the cognitive impairments of patients with BD in both affective and non-affective cognitive domains.

Successful clozapine rechallenge after myopericarditis: a case report.

Clozapine-induced myocarditis and pericarditis are uncommon adverse effects of clozapine treatment. However, in most cases, they lead to clozapine discontinuation. Here, we describe a case of successful clozapine rechallenge after clozapine-induced myopericarditis. The patient, a 31-year-old male with treatment-resistant schizophrenia (TRS), developed dyspnea on exertion and chest pain on day 19 after the start of clozapine titration. An electrocardiogram (ECG) showed widespread, mild, convex ST interval elevation. While troponin levels were mildly elevated, the echocardiogram was unremarkable. A myopericarditis diagnosis was formulated, and clozapine was stopped, with a progressive resolution of clinical, laboratory and ECG abnormalities. After 6 months, a rechallenge with clozapine was attempted. A very slow titration scheme was adopted, along with close monitoring of clinical, laboratory and ECG parameters. Clozapine target dose was reached without the occurrence of any abnormality. Given the unique role of clozapine in the management of TRS, clozapine rechallenge may be considered after pericarditis, even with troponin levels elevation. Further studies are needed to update current clinical guidelines.

The Influence of 5-HTTLPR, BDNF Rs6265 and COMT Rs4680 Polymorphisms on Impulsivity in Bipolar Disorder: The Role of Gender.

Impulsivity has been proposed as an endophenotype for bipolar disorder (BD); moreover, impulsivity levels have been shown to carry prognostic significance and to be quality-of-life predictors. To date, reports about the genetic determinants of impulsivity in mood disorders are limited, with no studies on BD individuals. Individuals with BD and healthy controls (HC) were recruited in the context of an observational, multisite study (GECOBIP). Subjects were genotyped for three candidate single-nucleotide polymorphisms (SNPs) (5-HTTLPR, COMT rs4680, BDNF rs6265); impulsivity was measured through the Italian version of the Barratt Impulsiveness Scale (BIS-11). A mixed-effects regression model was built, with BIS scores as dependent variables, genotypes of the three polymorphisms as fixed effects, and centers of enrollment as random effect. Compared to HC, scores for all BIS factors were higher among subjects with euthymic BD (adjusted ß for Total BIS score: 5.35, p < 0.001). No significant interaction effect was evident between disease status (HC vs. BD) and SNP status for any polymorphism. Considering the whole sample, BDNF Met/Met homozygosis was associated with lower BIS scores across all three factors (adjusted ß for Total BIS score: −10.2, p < 0.001). A significant 5-HTTLPR x gender interaction was found for the SS genotype, associated with higher BIS scores in females only (adjusted ß for Total BIS score: 12.0, p = 0.001). Finally, COMT polymorphism status was not significantly associated with BIS scores. In conclusion, BD diagnosis did not influence the effect on impulsivity scores for any of the three SNPs considered. Only one SNP­the BDNF rs6265 Met/Met homozygosis­was independently associated with lower impulsivity scores. The 5-HTTLPR SS genotype was associated with higher impulsivity scores in females only. Further studies adopting genome-wide screening in larger samples are needed to define the genetic basis of impulsivity in BD.

A longitudinal analysis of a work inclusion model for psychiatric patients in the Mental Health Departments of the city of Milan.

BACKGROUND: Work functioning impairment is a key diagnostic and transnosographic criterion for psychiatric disorders in both DSM-5 and ICD-11. Occupational inclusion is a fundamental aspect of the care path for patients attending the territorial services provided by the Italian Mental Health and Addiction Departments (DSMDs). Since 2009, the Regional Innovative Programme (PIR) TR106, promoted by the Fatebenefratelli-Sacco hospital of Milan, Italy, in collaboration with six other metropolitan DSMDs, was created to promote integration for people suffering from mental health problems in the city of Milan. METHOD: Here we present the results of a retrospective epidemiologic analysis on 2,142 interventions on 1,066 patients, conducted between 2012 and 2019. RESULTS: Most of the interventions were conducted with people with psychotic disorders (39%), followed by personality disorders (25.2%) and affective disorders (22.2%). The age range of 25 to 54 years represented 91.5% of the whole sample, mainly in the 35 to 44 years range (36.4%). Significant age group-related changes in interventions were observed in the observation period, with a reduction in the interventions provided to subjects of the 35 to 44 age group, and an increase in the 25 to 34 age group. CONCLUSIONS: PIR TR106 provided the most accurate assessment and data collection so far for the city of Milan. Our data characterised psychiatric groups in order to develop specific treatment plans and work inclusion interventions.

The association of childhood trauma, lifetime stressful events and general psychopathological symptoms in euthymic bipolar patients and healthy subjects.

BACKGROUND: Psychopathological symptoms during euthymia in Bipolar Disorder (BD) affect quality of life and predispose to the occurrence of new acute episodes, however only few studies investigated potential risk-factors. This study aims to explore the association between childhood trauma (CT), lifetime stressful events (SLEs) and psychopathological symptoms in BD patients during euthymia and controls (HC). METHODS: A total of 261 participants (93 euthymic patients with BD, 168 HC) were enrolled. Generalized linear models and multiple logistic models were used to assess the association among the Symptom Check List-90-R (SCL-90-R), the Infancy Trauma Interview, the Paykel Life Events Scale. RESULTS: The rate of participants reporting CT was higher in BD (n=47; 53%) than HC (n=43; 30%) (p=0.001). The experience of neglect was strongly related to BD (OR 6.5; p=0.003). CT was associated to higher scores on the SCL-90-R subscales (all the subscales except Phobia). No effects of the interaction between CT and diagnosis were found on SCL-90-R. Finally, there was a main effect of CT on lifetime SLEs (p<.001), that was not associated with diagnosis (p=0.833), nor with the interaction between CT and diagnosis (p=0.624). LIMITATIONS: The cross-sectional design does not allow causal inferences; the exclusion of subjects reporting medical or psychiatric comorbidity limits generalizability. CONCLUSIONS: CT was associated both to psychopathological symptoms during euthymia and the lifetime SLEs, thus it may represent a vulnerability factor influencing the course of BD. Overall, these data contribute to overcome the limited evidences documenting the influence of environmental factors on euthymic phase in BD.

Brain Morphology of Cannabis Users With or Without Psychosis: A Pilot MRI Study.

Cannabis is the illicit drug most commonly used worldwide, and its consumption can both induce psychiatric symptoms in otherwise healthy subjects and unmask a florid psychotic picture in patients with a prior psychotic risk. Previous studies suggest that chronic and long-term cannabis exposure may exert significant negative effects in brain areas enriched with cannabinoid receptors. However, whether brain alterations determined by cannabis dependency will lead to a clinically significant phenotype or to a psychotic outbreak at some point of an abuser's life remains unclear. The aim of this study was to investigate morphological brain differences between chronic cannabis users with cannabis-induced psychosis (CIP) and non-psychotic cannabis users (NPCU) without any psychiatric conditions and correlate brain deficits with selective socio-demographic, clinical and psychosocial variables. 3T magnetic resonance imaging (MRI) scans of 10 CIP patients and 12 NPCU were acquired. The type of drug, the frequency, and the duration, as well socio-demographic, clinical and psychosocial parameters of dependency were measured. CIP patients had extensive grey matter (GM) decreases in right superior frontal gyrus, right precentral, right superior temporal gyrus, insula bilaterally, right precuneus, right medial occipital gyrus, right fusiform gyrus, and left hippocampus in comparison to chronic cannabis users without psychosis. Finally, in CIP patients, the results showed a negative correlation between a domain of the Brief Psychiatric Rating Scale (BPRS), BPRS-Activity, and selective GM volumes. Overall, the results suggest that cannabis-induced psychosis is characterized by selective brain reductions that are not present in NPCU. Therefore, neuroimaging studies may provide a potential ground for identifying putative biomarkers associated with the risk of developing psychosis in cannabis users.

The Role of the Subplate in Schizophrenia and Autism: A Systematic Review.

The subplate (SP) represents a transitory cytoarchitectural fetal compartment containing most subcortical and cortico-cortical afferents, and has a fundamental role in the structural development of the healthy adult brain. There is evidence that schizophrenia and autism may be determined by developmental defects in the cortex or cortical circuitry during the earliest stages of pregnancy. This article provides an overview on fetal SP development, considering its role in schizophrenia and autism, as supported by a systematic review of the main databases. The SP has been described as a cortical amplifier with a role in the coordination of cortical activity, and sensitive growth and migration windows have crucial consequences with respect to cognitive functioning. Although there are not enough studies to draw final conclusions, improved knowledge of the SP's role in schizophrenia and autism spectrum disorders may help to elucidate and possibly prevent the onset of these two severe disorders.

The brief assessment of cognition in affective disorders: Normative data for the Italian population.

BACKGROUND: To date there are no validated tests in Italian to assess cognitive functions in Bipolar Disorder. Therefore, this study aimed to provide normative data for the Italian version of the Brief Assessment of Cognition in Affective Disorders (BAC-A), a battery targeting neuro- and affective-cognition in affective disorders. METHODS: Data were collected from 228 healthy participants (age range: 18-67; mean age: 34.68 ± 12.15 years) across eight recruiting sites. The influence of age, sex and education was measured and adjusted for using multivariate stepwise regression models. Normative values were established by means of the Equivalent Score approach. RESULTS: Most of the BAC-A subtests showed patterns of association with age (inversely associated with overall cognitive performance), education (positively associated with Verbal Memory and Fluency, Digit Sequencing and Affective Processing subtests) and sex (females performed better than males in the Affective Interference Test but worse in the Emotion Inhibition Task, Digit Sequencing and Tower of London). LIMITATIONS: The sample size was not sufficiently large for developing stratified norms, using 10-years ranges. Moreover, the participants included in the study were, on average, highly educated. CONCLUSIONS: The normative data of the BAC-A provided in this study can serve as a cognitive functioning reference for Italian-speaking participants within the age range of the study sample. This can increase the applicability of this test in both clinical and research settings. The reliability and validity of the Italian BAC-A need to be further investigated.

Temperament and character influence on depression treatment outcome.

BACKGROUND: personality features have been repeatedly associated with depression treatment outcome in Major Depressive Disorder (MDD), however conclusive results are still lacking. Moreover, as for Bipolar Disorder (BD), results are only few and preliminary. AIM: the aim of the present study was to perform an exploratory investigation of the influence of personality traits as assessed by the Temperament and Character Inventory (TCI), on principal depression treatment outcomes (non remission, non response and resistance). METHODS: 743 mood disorders patients (455 MDD (61.24%) and 288 BD (38.76%)) were recruited in the context of 6 European studies. Generalized logit models were performed to test the effects of TCI dimensions on treatment outcomes, considering possible confounders such as age, gender and education. Positive results were controlled for comorbidities (anxiety and substance use disorders) as well. RESULTS: MDD Non-Remitters showed high Harm Avoidance (HA) and Self Transcendence (ST) (p = 0.0004, d = 0.40; p = 0.007, d = 0.36 respectively) and low Persistence (P) and Self Directedness (SD) (p = 0.05; d = 0.18; p = 0.002, d = 0.40, respectively); MDD Non-Responders showed a slightly different profile with high HA and low Reward Dependence (RD) and SD; finally, MDD Resistants showed low RD, P and Cooperativeness (C). In BD patients, only higher HA in non response was observed. LIMITATIONS: the retrospective cross-sectional design, the TCI assessment regardless of the mood state and the small number of bipolar patients represent the main limitations. CONCLUSION: specific TCI personality traits are associated with depression treatment outcome in MDD patients. The inclusion of such personality traits, together with other socio-demographic and clinical predictors, could ameliorate the accuracy of the prediction models available to date.

Temperament and Character Inventory in Bipolar Disorder versus Healthy Controls and Modulatory Effects of 3 Key Functional Gene Variants.

BACKGROUND: Bipolar disorder (BD) has been associated with temperamental and personality traits, although the relationship is still to be fully elucidated. Several studies investigated the genetic basis of temperament and character, identifying catechol-O-methyltransferase (COMT), brain derived neurotrophic factor (BDNF), and serotonin transporter (5-HTT) gene variants as strong candidates. METHODS: In the GECO-BIP study, 125 BD patients and 173 HC were recruited. Subjects underwent to a detailed assessment and the temperament and character inventory 125 items (TCI) was administrated. Three functional genetic variants within key candidate genes (COMT rs4680, BDNF rs6265, and the serotonin-transporter-linked polymorphic region (5-HTTLPR)) were genotyped. Univariate and multivariate analyses were performed. RESULTS: Compared to HC, BD patients showed higher scores in novelty seeking (NS; p = 0.001), harm avoidance (HA; p < 0.001), and self transcendence (St; p < 0.001), and lower scores in self directness (p < 0.001) and cooperativeness (p < 0.001) TCI dimensions. Concerning the genetic analyses, COMT rs4680 was associated with NS in the total sample (p = 0.007) and in the male subsample (p = 0.022). When performing the analysis in the HC and BD samples, the association was confirmed only in HC (p = 0.012), and in the HC male subgroup in particular (p = 0.004). BDNF rs6265 was associated with St in the BD group (p = 0.017). CONCLUSION: COMT rs4680 may modulate NS in males in the general population. This effect was not detected in BD patients, probably because BD alters the neurobiological basis of some TCI dimensions. BDNF rs6265 seems to modulate St TCI dimension only in BD patients, possibly modulating the previously reported association between rs6265 and BD treatment response. Further studies are needed to confirm our findings.

Association between low-activity allele of cathecolamine-O-methyl-transferase (COMT) and Borderline Personality Disorder in an Italian population.

The objective of the present study was to test the association between Borderline Personality Disorder (BPD) and the cathecolamine-O-methyl-transferase (COMT) low-activity (Met158) single nucleotide polymorphism (SNP). In this case-control study, DNA was obtained from venous blood of 19 BPD patients and 36 healthy subjects. COMT-Val158Met single-nucleotide polymorphism was genotyped by predesigned SNP assay. The COMT Met158 allele was over-represented in patients with BPD in comparison to normal subjects (68.4% vs 44.4%, respectively; Fisher exact test, p = .02). In terms of genotype, the Met158Met subjects were more frequent in patients versus controls (47.4% vs 22.2%, respectively), whereas the high-activity genotype Val158Val was under-represented (10.5% vs 33.3%, respectively). The allele encoding for the COMT with low enzymatic efficiency was found to be over-represented in BPD, possibly resulting in excessive synaptic dopaminergic activity and ultimately affecting externalizing behaviours, such as impulsivity and aggressiveness.

Childhood abuse is associated with structural impairment in the ventrolateral prefrontal cortex and aggressiveness in patients with borderline personality disorder.

Volume reduction and functional impairment in areas of the prefrontal cortex (PFC) have been found in borderline personality disorder (BPD), particularly in patients with a history of childhood abuse. These abnormalities may contribute to the expression of emotion dysregulation and aggressiveness. In this study we investigated whether the volume of the PFC is reduced in BPD patients and whether a history of childhood abuse would be associated with greater PFC structural changes. Structural MRI data were obtained from 18 BPD patients and 19 healthy individuals matched for age, sex, handedness, and education and were analyzed using voxel based morphometry. The Child Abuse Scale was used to elicit a past history of abuse; aggression was evaluated using the Buss-Durkee Hostility Inventory (BDHI). The volume of the right ventrolateral PFC (VLPFC) was significantly reduced in BPD subjects with a history of childhood abuse compared to those without this risk factor. Additionally, right VLPFC gray matter volume significantly correlated with the BDHI total score and with BDHI irritability and negativism subscale scores in patients with a history of childhood abuse. Our results suggest that a history of childhood abuse may lead to increased aggression mediated by an impairment of the right VLPFC.

Electrophysiological changes of cardiac function during antidepressant treatment.

Some antidepressant agents can cause electrophysiological changes of cardiac function leading to ventricular arrhythmias and sudden death. However, antidepressants have also protective effects on the heart through their capacity to modulate cardiac autonomic-mediated physiological responses. Heart rate variability and QTc length are two strictly linked parameters that allow us to appreciate the effects of different drugs on cardiac physiology. Heart rate variability reflects functioning of the autonomic nervous system and possibly also regulation by the limbic system. Autonomic regulation of cardiac activity influences also cardiac repolarization and QT length, both directly and via its effects on heart rate. In this review we present the methodologies adopted to study the effect of antidepressant drugs on QT length and heart rate variability and we summarize data on electrophysiological changes related to antidepressant treatment. Clinical implications for the choice of different antidepressants in different clinical populations are discussed.