The mediating role of reflective functioning in the association between childhood trauma and suicide attempt.

BACKGROUND: Childhood trauma is intimately related with suicidal behaviour. Patients who have suffered childhood trauma develop impaired Reflective Functioning (RF), which refers to the capacity to understand ourselves and others in terms of intentional mental states. An improvement in RF has been associated with a reduction in suicidal attempts, but the mediating role of RF between childhood trauma and suicidal behaviour has not been addressed so far. OBJECTIVE: We aim to examine the potential mediating effect of RF among childhood trauma and suicide attempts. METHOD: We included 748 patients who had attempted suicide at least once. They were asked to complete the Reflective Functioning Questionnaire (RFQ-8), the Columbia-Suicide Severity Rating scale (CSSRS), and the Childhood Trauma Questionnaire-Short Form (CTQ-SF). We conducted linear regressions by simple mediating model to examine the role of RF in the indirect association between childhood trauma and the number of suicide attempts. RESULTS: Our results show significant indirect effects through hypo and hypermentalizing between Emotional Abuse (EA) and Sexual Abuse (SA) in childhood and the number of suicide attempts in lifetime. These results indicate that ineffective RF significantly mediates the association between childhood trauma and suicidality. CONCLUSION: This is the first study supporting the mediational role of RF in the relationship between EA and SA, and the number of suicide attempt in lifetime. These findings have important implications for reducing suicide rates and preventing future re-attempts. Further studies analysing this mediating role and focusing efforts on increasing RF-based interventions are required.

Pattern of long-term weight and metabolic changes after a first episode of psychosis: Results from a 10-year prospective follow-up of the PAFIP program for early intervention in psychosis cohort.

BACKGROUND: People with psychosis are at higher risk of cardiovascular events, partly explained by a higher predisposition to gain weight. This has been observed in studies on individuals with a first-episode psychosis (FEP) at short and long term (mainly up to 1 year) and transversally at longer term in people with chronic schizophrenia. However, there is scarcity of data regarding longer-term (above 3-year follow-up) weight progression in FEP from longitudinal studies. The aim of this study is to evaluate the longer-term (10 years) progression of weight changes and related metabolic disturbances in people with FEP. METHODS: Two hundred and nine people with FEP and 57 healthy participants (controls) were evaluated at study entry and prospectively at 10-year follow-up. Anthropometric, clinical, and sociodemographic data were collected. RESULTS: People with FEP presented a significant and rapid increase in mean body weight during the first year of treatment, followed by less pronounced but sustained weight gain over the study period (Δ15.2 kg; SD 12.3 kg). This early increment in weight predicted longer-term changes, which were significantly greater than in healthy controls (Δ2.9 kg; SD 7.3 kg). Weight gain correlated with alterations in lipid and glycemic variables, leading to clinical repercussion such as increments in the rates of obesity and metabolic disturbances. Sex differences were observed, with women presenting higher increments in body mass index than men. CONCLUSIONS: This study confirms that the first year after initiating antipsychotic treatment is the critical one for weight gain in psychosis. Besides, it provides evidence that weight gain keep progressing even in the longer term (10 years), causing relevant metabolic disturbances.

Association and epistatic analysis of white matter related genes across the continuum schizophrenia and autism spectrum disorders: The joint effect of NRG1-ErbB genes.

BACKGROUND: Schizophrenia-spectrum disorders (SSD) and Autism spectrum disorders (ASD) are neurodevelopmental disorders that share clinical, cognitive, and genetic characteristics, as well as particular white matter (WM) abnormalities. In this study, we aimed to investigate the role of a set of oligodendrocyte/myelin-related (OMR) genes and their epistatic effect on the risk for SSD and ASD. METHODS: We examined 108 SNPs in a set of 22 OMR genes in 1749 subjects divided into three independent samples (187 SSD trios, 915 SSD cases/control, and 91 ASD trios). Genetic association and gene-gene interaction analyses were conducted with PLINK and MB-MDR, and permutation procedures were implemented in both. RESULTS: Some OMR genes showed an association trend with SSD, while after correction, the ones that remained significantly associated were MBP, ERBB3, and AKT1. Significant gene-gene interactions were found between (i) NRG1*MBP (perm p-value = 0.002) in the SSD trios sample, (ii) ERBB3*AKT1 (perm p-value = 0.001) in the SSD case-control sample, and (iii) ERBB3*QKI (perm p-value = 0.0006) in the ASD trios sample. DISCUSSION: Our results suggest the implication of OMR genes in the risk for both SSD and ASD and highlight the role of NRG1 and ERBB genes. These findings are in line with the previous evidence and may suggest pathophysiological mechanisms related to NRG1/ERBBs signalling in these disorders.

Classification of first-episode psychosis using cortical thickness: A large multicenter MRI study.

Machine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between predictions and clinical variables. 428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20,484 vertices) were extracted. Linear Support Vector Machine was used for classification within a repeated nested cross-validation framework. Vertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy of 66.2% and an Area Under the Curve of 72%. By stratifying our sample for MRI scanner, we increased generalizability across sites. Temporal brain areas resulted as the most influential in the classification. The predictive decision scores significantly correlated with age at onset, duration of treatment, and positive symptoms. In conclusion, although far from the threshold of clinical relevance, temporal cortical thickness proved to classify between FEP subjects and healthy individuals. The assessment of site-dependent variables permitted an increase in the across-site generalizability, thus attempting to address an important machine learning limitation.

Sexual Regional Dimorphism of Post-Adolescent and Middle Age Brain Maturation. A Multi-center 3T MRI Study.

Sex-related differences are tied into neurodevelopmental and lifespan processes, beginning early in the perinatal and developmental phases and continue into adulthood. The present study was designed to investigate sexual dimorphism of changes in gray matter (GM) volume in post-adolescence, with a focus on early and middle-adulthood using a structural magnetic resonance imaging (MRI) dataset of healthy controls from the European Network on Psychosis, Affective disorders and Cognitive Trajectory (ENPACT). Three hundred and seventy three subjects underwent a 3.0 T MRI session across four European Centers. Age by sex effects on GM volumes were investigated using voxel-based morphometry (VBM) and the Automated Anatomical Labeling atlas regions (ROI). Females and males showed overlapping and non-overlapping patterns of GM volume changes during aging. Overlapping age-related changes emerged in bilateral frontal and temporal cortices, insula and thalamus. Both VBM and ROI analyses revealed non-overlapping changes in multiple regions, including cerebellum and vermis, bilateral mid frontal, mid occipital cortices, left inferior temporal and precentral gyri. These findings highlight the importance of accounting for sex differences in cross-sectional analyses, not only in the study of normative changes, but particularly in the context of psychiatric and neurologic disorders, wherein sex effects may be confounded with disease-related changes.

The synergetic effect of childhood trauma and recent stressful events in psychosis: associated neurocognitive dysfunction.

BACKGROUND: A higher incidence of childhood trauma (CT) has been reported in first episode of psychosis (FEP). There is, however, a lack of knowledge about the synergetic effect between CT and recent stressful events (RSE). METHODS: Information on specific types of CT (under 17 years) and RSE (within the past 3 years) was available for 290 FEP patients and 52 healthy controls (HC). Cognitive function at baseline was assessed through a comprehensive neuropsychological test battery. RESULTS: While 45.2% of FEP patients and 25% of HC reported at least one CT event, 62.7% of FEP and 21.2% of HC reported an RSE. Meanwhile, 36.2% of FEP patients and 9.6% of HC encountered both childhood and recent stressful events. The patients that just reported CT showed normality in all but the verbal memory cognitive domain; those with additive CT and RSE presented worse general cognitive function, specifically on working memory, processing speed, and executive function. RSE and general cognitive dysfunction were significant determinants of psychosis onset. CONCLUSIONS: These results support a synergetic influence of trauma and stressful events on brain function and allow a better understanding of mediators for psychotic disorders useful in the design of specific strategies based on stress-targeted therapies.

The prognostic role of catatonia, hallucinations, and symptoms of schizophrenia in acute and transient psychosis.

OBJECTIVES: To examine the prospective temporal stability of acute and transient psychotic disorders (ATPDs) and analyze whether there are clinical, psychopathological, or sociodemographic characteristics that predict ATPD diagnostic stability. METHOD: We conducted a prospective, 2-year, observational study of patients presenting a first-episode ATPD. A multivariate logistic regression model was developed to identify independent variables associated with ATPD diagnostic stability. Well-established predictive factors of diagnostic stability, as well as all the psychopathological features included in the ICD-10 Diagnostic Criteria for Research (DCR) descriptions of ATPD, were analyzed. RESULTS: Sixty-eight patients with a first episode of ATPD completed the study with a diagnostic stability rate as high as 55.9% (n = 38) at the end of the follow-up period. Multivariate analysis revealed that diagnostic stability was independently significantly associated with the baseline presence of motility disturbances (OR = 6.86, 95% CI = 1.10-42.62; P = 0.039), the absence of hallucinations (OR = 5.75, 95% CI = 1.51-21.98; P = 0.010), and the absence of schizophrenic features (OR = 7.13, 95% CI = 1.38-36.90; P = 0.019). CONCLUSION: A symptom checklist assessing these psychopathological features would enable early identification of those subjects whose initial ATPD diagnosis will remain stable over time.

Stopping cannabis use benefits outcome in psychosis: findings from 10-year follow-up study in the PAFIP-cohort.

OBJECTIVE: To examine the long-term (up to 10 years) patterns related to cannabis use in a sample of patients with first episode of psychosis (FEP) and the effect that consumption might have on clinical, functioning, and neurocognition at long-term. METHODS: Cannabis use was described in 209 FEP patients. Patients were divided into three groups according to cannabis use: persistent users, ex-users, and never-users. Groups were longitudinally (baseline and 10-year follow-up) compared on clinical, functional, and cognitive variables. RESULTS: Clinical differences at 10-year follow-up were observed between persistent cannabis users and the other two groups (ex-users and never-users), showing persistent users more severe symptoms (BPRS: x2  = 15.583, P ≤ 0.001; SAPS: x2  = 12.386, P = 0.002) and poorer functionality (DAS: x2  = 6.067, P = 0.048; GAF: x2  = 6.635, P = 0.033). Patients who stopped cannabis use prior to the reassessment showed a similar pattern to those who had never consumed. CONCLUSION: The use of cannabis could negatively affect the evolution of the psychotic disorder. Perhaps the negative effects caused by cannabis use could be reversed with the cessation of consumption. It is necessary to make an effort in the intervention toward an early withdrawal from the use of cannabis, since this could play an important role in the prognosis of the disease.

Personality traits, theory of mind and their relationship with multiple suicide attempts in a sample of first episode psychosis patients: One-year follow-up study.

BACKGROUND: High rates of suicidal behaviour (SB) have been found in first episode psychosis (FEP) patients. It has been suggested that the presence of multiple suicide attempts (mSA) increases the risk of later SA and the risk of eventual death by suicide. OBJECTIVE: Our main objective was to study the baseline factors associated with the presence of mSA during the first year after FEP. In addition, a second aim was to find out whether there were any differences between single and multiple suicide attempters in the timing of the first SA after FEP. METHOD: A total of 65 FEP patients were evaluated. The presence of SAs were recorded at two different times after FEP. Bivariate and multivariate analyses were performed to explore the relationship between SA with sociodemographic and clinical variables. RESULTS: Multiple linear regression showed that mSA was associated with the presence of increased symptom severity (B = 0.35; t = 3.67; p < 0.01) and errors in first-order false-belief task (B = 0.48; t = 2.11; p = 0.04). There were significant differences in the timing of first SA after FEP between multiple and single suicide attempters. CONCLUSIONS: Theory of mind impairments along with more severe symptoms during the first contact with mental health services for psychotic symptoms appeared to be important predictors of mSA. On the other hand, multiple suicide attempters tend to make a first SA after FEP earlier than single suicide attempters. These results could contribute to the implementation of preventive suicidal programs, however they must be confirmed by additional research.

[Evaluation of verbal inhibitory control with the Stroop Test in early episodes of psychosis with the experience of traumatic events in infancy]. / Evaluacion del control inhibitorio verbal con el test de Stroop en primeros episodios de psicosis con experiencia de trauma en la infancia.

INTRODUCTION: Data from clinical experience highlight the high prevalence of traumatic experiences in subjects with schizophrenia spectrum disorder. However, much is left to examine about the effect of traumatic experiences in the development and severity of psychosis. The Stroop Test assess the verbal response inhibition, an executive function which allows to stop an automatic response and makes possible the inhibition of new behaviours, depending on the situation. AIM: To examine the relationship between subjective experience of trauma, verbal response inhibition in the Stroop Test, and severity of the diagnosis at six months from the onset of the disease, in patients with first episode psychosis. PATIENTS AND METHODS: Data were obtained from a longitudinal intervention program of first-episode of psychosis (PAFIP) conducted at the University Hospital Marques de Valdecilla, Spain. The variables of interest in the present study were the Stroop Test and the Childhood Trauma Questionnaire as part of the neuropsychological assessment of PAFIP. RESULTS: Statistically significant differences were obtained in verbal response inhibition, being more subjects with high response inhibition when the said trauma was of low intensity. CONCLUSIONS: These data support the relationship between intensity of the traumatic experience in childhood and response inhibition dysfunction in people with first episode psychosis, although we cannot conclude a more severe diagnosis at six months from the onset of psychosis in people with traumatic experiences more intense.

TITLE: Evaluacion del control inhibitorio verbal con el test de Stroop en primeros episodios de psicosis con experiencia de trauma en la infancia.Introduccion. Los datos aportados por la experiencia clinica evidencian la elevada prevalencia de experiencias traumaticas en sujetos que desarrollan psicosis. No obstante, queda mucho por examinar sobre el efecto de las experiencias traumaticas en su desarrollo y gravedad. El test de Stroop mide la inhibicion cognitiva verbal, una funcion ejecutiva que permite frenar una respuesta automatizada y posibilita la inhibicion de comportamientos alternativos a los ya aprendidos, en funcion de las demandas. Objetivo. Examinar la relacion entre la experiencia subjetiva de trauma, el control inhibitorio verbal medido con el test de Stroop y la gravedad del diagnostico a los seis meses desde el inicio de la enfermedad en sujetos con un primer episodio psicotico. Pacientes y metodos. La muestra estuvo formada por 119 pacientes del «Programa Asistencial para Fases Iniciales de Psicosis¼ del Hospital Universitario Marques de Valdecilla. Las variables de interes fueron el test de Stroop y el Childhood Trauma Questionnaire como parte del protocolo de evaluacion neuropsicologica de dicho programa. Resultados. Se obtuvieron diferencias estadisticamente significativas en control inhibitorio verbal y se encontro un mayor numero de sujetos con alto control inhibitorio cuando el trauma referido fue de baja intensidad. Conclusiones. Estos datos confirman la relacion entre intensidad de la experiencia traumatica en la infancia y alteracion del control inhibitorio verbal en personas con primer episodio psicotico, aunque no permiten concluir una mayor gravedad del diagnostico a los seis meses del inicio de la psicosis en personas con experiencias traumaticas de mayor intensidad.

Predicting suicidal behaviour after first episode of non-affective psychosis: The role of neurocognitive functioning.

BACKGROUND: Suicide has been recognised as one of the major causes of premature death in psychosis. However, predicting suicidal behaviour (SB) is still challenging in the clinical setting and the association of neurocognition with SB in psychosis remains poorly understood. This study aimed to investigate the role of neurocognitive performance as predictor of SB. Also, we sought to explore differences in the evolution of clinical and neurocognitive functioning between participants with/without history of suicide attempts (SA) over follow-up period. METHODS: The sample of the study is composed by 517 patients. Sociodemographic, clinical, functional and neurocognitive measures were evaluated at baseline as well as 1-year and 3 years after first episode of psychosis. Bivariate and multivariate analyses explored the influence of these variables as putative baseline predictors of SB. Repeated measures analyses of variance tested differences in clinical and neurocognitive outcomes at 1- and 3-year follow-up. RESULTS: Global cognitive functioning (GCF) (OR = 1.83, 95% CI = 1.25-2.67) and severe depressive symptoms (OR = 1.17, 95% CI = 1.07-1.28) predicted SB. Longitudinal analyses revealed that patients with SB at follow-up presented with higher levels of remission in terms of positive psychotic symptoms and depression. In addition, those with a history of SB had worse GCF and visual memory than those without such antecedents. CONCLUSIONS: GCF was found to be the most robust predictor of SB along with severe depressive symptomatology. Hence, poorer cognitive performance in FEP appears to emerge as a risk factor for suicidal behaviour from early stages of the illness and a comprehensive neurocognitive assessment may contribute to risk assessment.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

BACKGROUND: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. METHODS: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. RESULTS: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. CONCLUSIONS: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: ßstd = -0.052; P = 0.021; right: ßstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

Manual motor speed dysfunction as a neurocognitive endophenotype in euthymic bipolar disorder patients and their healthy relatives. Evidence from a 5-year follow-up study.

BACKGROUND: Few studies have examined Manual Motor Speed (MMS) in bipolar disorder (BD). The aim of this longitudinal, family study was to explore whether dysfunctional MMS represents a neurocognitive endophenotype of BD. METHODS: A sample of 291 subjects, including 131 BD patients, 77 healthy first-degree relatives (BD-Rel), and 83 genetically-unrelated healthy controls (HC), was assessed with the Finger-Tapping Test (FTT) on three occasions over a 5-year period. Dependence of FTT on participants´ age was removed by means of a lineal model of HC samples, while correcting simultaneously the time and learning effect. Differences between groups were evaluated with an ANOVA test. RESULTS: The patients' performance was significantly worse than that of HC over time (p≤0.006), and these deficits remained when non-euthymic BD patients (n=9) were excluded from analysis. Some significant differences between BD patients and BD-Rel (p≤0.037) and between BD-Rel and HC (p≤0.033) were found, but they tended to disappear as time progressed (p≥0.057). Performance of the BD-Rel group was intermediate to that of BD and HC. Most sociodemographic and clinical variables did not affect these results in patients. (p≥0.1). However, treatment with carbamazepine and benzodiazepines may exert a iatrogenic effect on MMS performance (p≤0.006). LIMITATIONS: Only right-handed subjects were included in this study. Substantial attrition over time was detected. CONCLUSIONS: There were significant differences between the patients´ MMS performance and that of healthy relatives and controls, regardless of most clinical and sociodemographic variables. Dysfunctional MMS could be considered an endophenotype of BD. Further studies are needed to rule out possible iatrogenic effects of some psychopharmacological treatments.