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.

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.

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.

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.

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 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.

Normative data of the Magical Ideation Scale from childhood to adulthood in an Italian cohort.

The assessment of schizotypy allows to identify people at risk to develop psychosis. For this purpose, psychometric tools have been developed, such as the Magical Ideation Scale (MIS). This scale investigates attenuated forms of thought transmission experiences, thought withdrawal and aberrant beliefs, related to positive schizotypy. This study aims at providing an Italian version of the MIS and its normative data in the general population from childhood to adulthood, being the first study evaluating subjects under 17year-old. The Italian MIS version was translated by three independent operators and administered to 1378 non-clinical participants, stratified into four age groups (i.e., 8-13, 14-17, 18-24 and 25-34). The unidimensionality of the scale was supported, and its internal consistency was satisfactory (i.e., ordinal Cronbach's αs ranging from 0.86 to 0.90 in different age groups), as well as test-retest reliability (i.e., 1-month ICC of 0.82 in a retested sub-sample). Normative data for the age groups were provided. Specific gender and age-related differences in MIS score were found, i.e. females scored higher than males in the 25-34 age group, which in general, as a group, scored lower than all the other age groups. This study provided evidence of reliability for the Italian version of the MIS in childhood and adolescence, for the first time, as well as in adulthood, showing specific gender and age effects in the early adult cohort.

Embelin binds to human neuroserpin and impairs its polymerisation.

Neuroserpin (NS) is a serpin inhibitor of tissue plasminogen activator (tPA) in the brain. The polymerisation of NS pathologic mutants is responsible for a genetic dementia known as familial encephalopathy with neuroserpin inclusion bodies (FENIB). So far, a pharmacological treatment of FENIB, i.e. an inhibitor of NS polymerisation, remains an unmet challenge. Here, we present a biophysical characterisation of the effects caused by embelin (EMB a small natural compound) on NS conformers and NS polymerisation. EMB destabilises all known NS conformers, specifically binding to NS molecules with a 1:1 NS:EMB molar ratio without unfolding the NS fold. In particular, NS polymers disaggregate in the presence of EMB, and their formation is prevented. The NS/EMB complex does not inhibit tPA proteolytic activity. Both effects are pharmacologically relevant: firstly by inhibiting the NS polymerisation associated to FENIB, and secondly by potentially antagonizing metastatic processes facilitated by NS activity in the brain.

Reliability and normative data of the Perceptual Aberration Scale in an Italian juvenile general population sample.

Psychometric tools, such as the Perceptual Aberration Scale (PAS), have been developed to identify people at risk to develop psychosis. This paper aims at providing an Italian version of the Perceptual Aberration Scale and its normative data for the general juvenile Italian population. The Italian version of the PAS was produced using three independent translators. It was administered to 1089 non-clinical participants, stratified into three age-groups, i.e., 8-13, 14-17 and 18-24. The Italian version of the PAS displayed good internal consistency in each age-group evaluated (i.e. Alpha Coefficients: 0.90 for the 8-13 age-group, 0.84 for the 14-17 age-group, and 0.87 for the 18-24 age-group) and the assumption of unidimensionality was corraborate. Furthermore, normative data for the three groups were collected (i.e. cut-offs: 25 for the 8-13 age-group, 21 for the 14-17 age-group and 20 for the 18-24 age-group) and an age-related difference, as the 18-24 group scored lower than the younger groups, was found. The Italian version of the PAS proved to be a reliable psychometric tool to investigate perceptual aberration during childhood, adolescence and young adulthood.

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.

Antidepressants: their effects on cardiac channels, QT prolongation and Torsade de Pointes.

The cardiovascular side effects of older antidepressants, such as tricyclic antidepressants, are well established and are known to be linked to their capacity to inhibit cardiac and vascular ion channels. Newer compounds, such as selective serotonin reuptake inhibitors, mirtazapine and venlafaxine, have been reported to have a more benign cardiovascular profile, although they also share antagonistic properties with regard to voltage-dependent ion channels in different tissues. The electrophysiological effects that antidepressants exert on ion channels may affect the cardiac action potential (AP), lengthening both depolarization and repolarization phases, widening the QRS complex, prolonging the QT interval or causing Brugada-like electrocardiogram patterns. Lengthening of the depolarization phase can slow conduction through the His-Purkinje system and myocardium, while slowing repolarization can lead to early after depolarizations and Torsade de Pointes (TdP). In this review, we discuss data from experimental animal models regarding the effects of antidepressants on the cardiac AP, as well as antidepressant-induced QT prolongation in humans and sudden death in patients treated with antidepressants. It appears that although various experimental studies may lead to an understanding of the mechanisms involved in the modulation of cardiac electrical activity, there are significant discrepancies between in vitro data describing the action of antidepressants on the AP, data from clinical trials on QT prolongation by antidepressants and risk of TdP. The role of genetic polymorphisms of potassium-channel-encoding genes in determining the individual risk of cardiac arrhythmias and the limits of QT use as a marker of risk are discussed. Extensive pharmacokinetic and pharmacodynamic studies are required to determine the doses and plasma ranges of each drug that are associated with the greatest risk of arrhythmic complications.

QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy.

BACKGROUND: Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment. METHOD: We examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional antidepressant (citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the antipsychotic.Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test. RESULTS: Mean QTc intervals significantly increased in Group 2 (24 +/- 21 ms) however this was not the case in Group 1 (-1 +/- 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05). CONCLUSIONS: No significant prolongation of the QT interval was found following monotherapy with an antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation. Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and antidepressant agents.

Anatomical MRI study of borderline personality disorder patients.

Hippocampal volume reduction has been reported in patients with borderline personality disorder (BPD), and is hypothesized to be associated with traumatic childhood experiences. We extended this investigation to explore additional brain regions and other potential clinical correlates of structural brain changes in BPD. Ten unmedicated BPD subjects and 20 healthy controls were assessed for current and past Axis I and II comorbidities and histories of childhood abuse. All had magnetic resonance imaging (MRI) studies with a 1.5 T GE Signa Imaging System, performing three-dimensional-gradient echo imaging (SPGR) with the following parameters: TR=25 ms, TE=5 ms, and slice-thickness=1.5 mm. Compared with healthy controls, BPD subjects had significantly smaller right and left hippocampal volumes, most marked in subjects with childhood abuse, and significantly increased right and left putamen volumes, especially in subjects with substance use disorders. No significant differences between groups were found for caudate, amygdala, temporal lobes, dorsolateral prefrontal cortex and total brain volumes. This study replicated prior findings of diminished hippocampal volumes in subjects with BPD. Also, increased putamen volumes were found in BPD, a finding that has not been previously reported. Early traumatic experiences may play a role in hippocampal atrophy, whereas substance use disorders may contribute to putamen enlargement.