The Italian version of the Reflective Functioning Questionnaire: Validity data for adults and its association with severity of borderline personality disorder.

INTRODUCTION: Impairments in the ability to understand others and the self in terms of internal mental states (reflective functioning [RF] or mentalizing) are thought to play a key role in the development of borderline personality disorder (BPD). The first aim of this study was to validate the Italian version of the Reflective Functioning Questionnaire (RFQ), a brief self-report measure of RF, by examining its factor structure with Principal Component Analyses (PCA), and correlations with constructs that should be theoretically related to RF. In addition, we investigated whether the RFQ could empirically distinguish between healthy controls and carefully diagnosed BPD patients using Research Operating Curve methods, and was related to severity of borderline pathology as measured with the Shedler-Westen Assessment Procedure (SWAP), an observer-rated measure of BPD pathology. METHODS: An Italian translation of the RFQ was administered to a sample of 154 healthy controls and a clinical sample of 59 BPD patients diagnosed with the Structured Clinical Interview for DSM-IV Axis II disorders. Clinical severity of BPD was assessed with the SWAP. Normal controls completed self-report inventories of constructs related to RF (mindfulness, empathy, Theory of Mind, alexithymia, and autistic traits). RESULTS: PCA confirmed the a priori factor structure in the Italian translation of the RFQ, showing two subscales that measure certainty and uncertainty about mental states, with satisfactory reliability and construct validity. These dimensions also distinguished BPD patients from healthy controls (p < 0.05). ROC analyses showed that the uncertainty subscale discriminated BPD patients from healthy individuals (area under the curve = 78%, cut of 4.5 points, sensitivity = 73%, specificity = 68%). Within the patient group, regression analyses showed uncertainty about mental states to have a significant unique contribution in predicting BPD severity (p < 0.05), explaining 12% of the variance. CONCLUSIONS: Results largely supported the reliability and validity of the Italian version of the RFQ. These findings also provide further evidence for the role of impairments in mentalizing and reinforce the rationale for offering mentalization-based interventions to individuals with this disorder.

Assessing mentalization in psychotherapy: first validation of the Mentalization Imbalances Scale.

The aim of this study was to provide data on the preliminary validation of a clinician-report multidimensional assessment measure of mentalization (Mentalization Imbalances Scale, MIS). A random national sample of psychotherapists (N=190) completed the MIS to identify mentalization imbalances, and the Personality Disorder Checklist to assess the personality disorders (PDs) of randomly selected patients currently in their care. Factor analysis confirmed the presence of six factors that represented different imbalances of mentalization: cognitive, affective, automatic, external, imbalance toward others, and imbalance toward self. We found several significant relationships between patients' mentalization imbalances and personality pathology. Paranoid, schizoid, and schizotypal PDs were predicted by an imbalance toward self, an imbalance the patients shared with histrionic, avoidant, and obsessive compulsive PDs, whereas dependent, borderline, and histrionic PDs were related to an imbalance toward others. Cognitive imbalance was related to schizoid, narcissistic, and obsessive compulsive PDs, whereas affective imbalance predicted antisocial, borderline, narcissistic and histrionic PDs. Automatic imbalance was related to schizotypal, antisocial, and borderline PDs. MIS represents a reliable and valid measure that can help clinicians at understanding patients' specific difficulties of mentalization.

Repetitive TMS on Left Cerebellum Affects Impulsivity in Borderline Personality Disorder: A Pilot Study.

The borderline personality disorder (BPD) is characterized by a severe pattern of instability in emotional regulation, interpersonal relationships, identity and impulse control. These functions are related to the prefrontal cortex (PFC), and since PFC shows a rich anatomical connectivity with the cerebellum, the functionality of the cerebellar-PFC axis may impact on BPD. In this study, we investigated the potential involvement of cerebello-thalamo-cortical connections in impulsive reactions through a pre/post stimulation design. BPD patients (n = 8) and healthy controls (HC; n = 9) performed an Affective Go/No-Go task (AGN) assessing information processing biases for positive and negative stimuli before and after repetitive transcranial magnetic stimulation (rTMS; 1 Hz/10 min, 80% resting motor threshold (RMT) over the left lateral cerebellum. The AGN task consisted of four blocks requiring associative capacities of increasing complexity. BPD patients performed significantly worse than the HC, especially when cognitive demands were high (third and fourth block), but their performance approached that of HC after rTMS (rTMS was almost ineffective in HC). The more evident effect of rTMS in complex associative tasks might have occurred since the cerebellum is deeply involved in integration and coordination of different stimuli. We hypothesize that in BPD patients, cerebello-thalamo-cortical communication is altered, resulting in emotional dysregulation and disturbed impulse control. The rTMS over the left cerebellum might have interfered with existing functional connections exerting a facilitating effect on PFC control.

Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis.

A large array of studies have investigated peripheral oxytocin (OT) and vasopressin (ADH) as potential biomarkers of psychiatric disorders, with highly conflicting and heterogenous findings. We searched Web of KnowledgeSM and Scopus® for English original articles investigating OT and/or ADH levels in different biological fluids (plasma/serum, saliva, urine and cerebrospinal fluid) across several psychiatric disorders. Sixty-four studies were included. We conducted 19 preliminary meta-analyses addressing OT alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 7 psychiatric disorders and ADH alterations in plasma/serum, saliva, urine and cerebrospinal fluid of 6 psychiatric disorders compared to controls. Hedge's g was used as effect size measure, together with heterogeneity analyses, test of publication biases and quality control. None of them (except serum OT in anorexia nervosa) revealed significant differences. There is no convincing evidence that peripheral ADH or OT might be reliable biomarkers in psychiatric disorders. However, the lack of significant results was associated with high methodological heterogeneity, low quality of the studies, small sample size, and scarce reliability of the methods used in previous studies, which need to be validated and standardized.

Diagnostic Stability of ICD/DSM First Episode Psychosis Diagnoses: Meta-analysis.

BACKGROUND: Validity of current International Classification of Disease/Diagnostic and Statistical Manual of Mental Disorders (ICD/DSM) first episode psychosis diagnoses is essential in clinical practice, research, training and public health. METHOD: We provide a meta-analytical estimate of prospective diagnostic stability and instability in ICD-10 or DSM-IV first episode diagnoses of functional psychoses. Independent extraction by multiple observers. Random effect meta-analysis conducted with the "metaprop," "metaninf," "metafunnel," "metabias," and "metareg" packages of STATA13.1. Moderators were tested with meta-regression analyses. Heterogeneity was assessed with the I 2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and Egger's test. FINDINGS: 42 studies and 45 samples were included, for a total of 14 484 first episode patients and an average follow-up of 4.5 years. Prospective diagnostic stability ranked: schizophrenia 0.90 (95% CI 0.85-0.95), affective spectrum psychoses 0.84 (95% CI 0.79-0.89), schizoaffective disorder 0.72 (95% CI 0.61-0.73), substance-induced psychotic disorder 0.66 (95% CI 0.51-0.81), delusional disorder 0.59 (95% CI 0.47-0.71), acute and transient psychotic disorder/brief psychotic disorder 0.56 (95% CI 0.62-0.60), psychosis not otherwise specified 0.36 (95% CI 0.27-0.45, schizophreniform disorder 0.29 (95% CI 0.22-0.38). Diagnostic stability within schizophrenia spectrum psychoses was 0.93 (95% CI 0.89-0.97); changes to affective spectrum psychoses were 0.05 (95% CI 0.01-0.08). About 0.10 (95% CI 0.05-0.15) of affective spectrum psychoses changed to schizophrenia spectrum psychosis. Across the other psychotic diagnoses there was high diagnostic instability, mostly to schizophrenia. INTERPRETATION: There is meta-analytical evidence for high prospective diagnostic stability in schizophrenia spectrum and affective spectrum psychoses, with no significant ICD/DSM differences. These results may inform the development of new treatment guidelines for early psychosis and impact drug licensing from regulatory agencies.

Disorder, not just state of risk: meta-analysis of functioning and quality of life in people at high risk of psychosis.

BACKGROUND: The nosology of the psychosis high-risk state is controversial. Traditionally conceived as an 'at risk' state for the development of psychotic disorders, it is also conceptualised as a clinical syndrome associated with functional impairment. AIMS: To investigate meta-analytically the functional status of patients at high clinical risk for psychosis and its association with longitudinal outcomes. METHOD: Three meta-analyses compared level of functioning (n = 3012) and quality of life (QoL) (n = 945) between a high-risk group, a healthy control group and group with psychosis, and baseline functioning in people in the high-risk group who did or did not have a transition to psychosis at follow-up (n = 654). RESULTS: People at high risk had a large impairment in functioning (P<0.001) and worse QoL (P = 0.001) than the healthy control group, but only small to moderately better functioning (P = 0.012) and similar QoL (P = 0.958) compared with the psychosis group. Among the high-risk group, those who did not develop psychosis reported better functioning (P = 0.001) than those who did. CONCLUSIONS: Our results indicate that the high-risk state is characterised by consistent and large impairments of functioning and reduction in QoL similar to those in other coded psychiatric disorders.

Neurofunctional maps of the 'maternal brain' and the effects of oxytocin: a multimodal voxel-based meta-analysis.

Several studies have tried to understand the possible neurobiological basis of mothering. The putative involvement of oxytocin, in this regard, has been deeply investigated. Performing a voxel-based meta-analysis, we aimed at testing the hypothesis of overlapping brain activation in functional magnetic resonance imaging (fMRI) studies investigating the mother-infant interaction and the oxytocin modulation of emotional stimuli in humans. We performed two systematic literature searches: fMRI studies investigating the neurofunctional correlates of the 'maternal brain' by employing mother-infant paradigms; and fMRI studies employing oxytocin during emotional tasks. A unimodal voxel-based meta-analysis was performed on each database, whereas a multimodal voxel-based meta-analytical tool was adopted to assess the hypothesis that the neurofunctional effects of oxytocin are detected in brain areas implicated in the 'maternal brain.' We found greater activation in the bilateral insula extending to the inferior frontal gyrus, basal ganglia and thalamus during mother-infant interaction and greater left insular activation associated with oxytocin administration versus placebo. Left insula extending to basal ganglia and frontotemporal gyri as well as bilateral thalamus and amygdala showed consistent activation across the two paradigms. Right insula also showed activation across the two paradigms, and dorsomedial frontal cortex activation in mothers but deactivation with oxytocin. Significant activation in areas involved in empathy, emotion regulation, motivation, social cognition and theory of mind emerged from our multimodal meta-analysis, supporting the need for further studies directly investigating the neurobiology of oxytocin in the mother-infant relationship.

Effectiveness of a single education and counseling intervention in reducing anxiety in women undergoing hysterosalpingography: a randomized controlled trial.

Hysterosalpingography (HSG) is generally considered a stressful and painful procedure; we aimed to evaluate whether a single education and counseling intervention could reduce women's distress and pain after undergoing HSG for infertility. Patients were randomized into control group (n = 108) and intervention group (n = 109). All patients filled the following questionnaires before and after HSG: Zung self-rating anxiety scale (Z-SAS), Zung self-rating depression scale (Z-SDS), and an ad hoc questionnaire designed to evaluate HSG procedure knowledge. Pain was scored using a visual analog scale. The intervention consisted in a 45-minute individualised session 48 h before HSG. We observed a reduction of anxiety and depression scores in the intervention arm compared to the control group. After controlling for potential confounding variables, intervention was an independent predictor of the difference of Z-SAS score before and after HSG. This is the first randomised controlled trial to assess the potential effectiveness of a single education and counseling intervention to lower anxiety in a diagnostic setting.

Is cannabis neurotoxic for the healthy brain? A meta-analytical review of structural brain alterations in non-psychotic users.

AIMS: Despite growing research in the field of cannabis imaging, mostly in those with a psychotic illness, the possible neurotoxic effects of smoked cannabis on the healthy brain have yet to be fully understood. There appears to be a need to evaluate the existing imaging data on the neuroanatomical effects of cannabis use on non-psychotic populations. METHODS: We conducted a meta-analytical review to estimate the putative neurotoxic effect of cannabis in non-psychotic subjects who were using or not using cannabis. We specifically tested the hypothesis that cannabis use can alter grey and white matter in non-psychotic subjects. RESULTS: Our systematic literature search uncovered 14 studies meeting the inclusion criteria for the meta-analysis. The overall database comprised 362 users and 365 non-users. At the level of the individual studies there is limited and contrasting evidence supporting a cannabis-related alteration on the white and grey matter structures of non-psychotic cannabis users. However, our meta-analysis showed a consistent smaller hippocampus in users as compared to non-users. Heterogeneity across study designs, image acquisition, small sample sizes and limited availability of regions of interest to be included in the meta-analysis may undermine the core findings of this study. CONCLUSIONS: Our results suggest that in the healthy brain, chronic and long-term cannabis exposure may exert significant effects in brain areas enriched with cannabinoid receptors, such as the hippocampus, which could be related to a neurotoxic action.

Prevalence of self-reported childhood abuse in psychosis: a meta-analysis of retrospective studies.

There is extensive clinical literature reporting traumatic childhood experiences in patients with psychosis. A quantitative meta-analysis addressing the prevalence of self-reported childhood sexual (CSA), physical (CPA) and emotional abuse (CEA) in psychotic patients has yet to be done. We conducted, a systematic literature search to identify retrospective studies addressing self-reported childhood abuse in patients with DSM/ICD psychosis. Demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors. Quantitative meta-analysis of CSA, CPA, CEA in the sample of patients was performed. Statistical heterogeneity and publication bias were assessed and meta-regressions performed to control for different moderators. Twenty-three studies were retrieved and included a total of 2017 psychotic patients. The prevalence of self-reported CSA, CPA, CEA were respectively of 26%, 39% and 34%. Age, publication year, gender and substance abuse moderated CSA, while age, clinical setting and substance abuse moderated CPA. Results indicated that CEA was moderated by gender and publication year of the study. According to our meta-analysis, psychotic patients have a consistently high self-report of childhood traumatic events which are sexual, physical and emotional in nature. It is our opinion that clinicians should be trained and skilled to carefully investigate childhood abuse in psychosis.

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.

Psychological correlates of decision-making during prenatal diagnosis: a prospective study.

OBJECTIVE: Decision-making during prenatal diagnosis has not been extensively studied. We aimed to determine psychological correlates and level of decisional conflict following prenatal diagnosis. METHOD: A total of 159 pregnant women were consecutively enrolled. All participants completed three questionnaires (the Hospital Anxiety and Depression scale, the Berlin Social Support scales and the Decisional Conflict scale) at three time points (T1 - waiting period between prenatal testing and disclosure of the results; T2 - decision phase within 3 days from test result disclosure; T3 - digestion period within 3 weeks from disclosure). RESULTS: Women with fetal anomaly who terminate pregnancy were significantly more anxious and depressed than controls at each time point. Additionally, women with a normal fetus who terminate pregnancy presented higher level of anxiety and depression compared with controls at T2. Women who terminated pregnancy showed increased uncertainty scores at T2 and T3. Anxious and depressed individuals at T2 (decision period) were more uncertain about their choice at T3 compared to women with normal levels of anxiety and depression. CONCLUSION: The decision to terminate pregnancy, irrespective of test results, may determine emotional distress and psychiatric morbidity. Women who were anxious and depressed at decision appeared to be more uncertain about their choices as time passed by. A careful assessment of women during prenatal diagnosis should be useful to identify women who may benefit from psychological support.

Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk.

CONTEXT: A substantial proportion of people at clinical high risk of psychosis will develop a psychotic disorder over time. However, the risk of transition to psychosis varies between centers, and some recent work suggests that the risk of transition may be declining. OBJECTIVE: To quantitatively examine the literature to date reporting the transition risk to psychosis in subjects at clinical high risk. DATA SOURCES: The electronic databases were searched until January 2011. All studies reporting transition risks in patients at clinical high risk were retrieved. STUDY SELECTION: Twenty-seven studies met the inclusion criteria, comprising a total of 2502 patients. DATA EXTRACTION: Transition risks, as well as demographic, clinical, and methodologic variables, were extracted from each publication or obtained directly from its authors. DATA SYNTHESIS: There was a consistent transition risk, independent of the psychometric instruments used, of 18% after 6 months of follow-up, 22% after 1 year, 29% after 2 years, and 36% after 3 years. Significant moderators accounting for heterogeneity across studies and influencing the transition risks were the age of participants, publication year, treatments received, and diagnostic criteria used. There was no publication bias, and a sensitivity analysis confirmed the robustness of the core findings. CONCLUSIONS: The state of clinical high risk is associated with a very high risk of developing psychosis within the first 3 years of clinical presentation, and the risk progressively increases across this period. The transition risk varies with the age of the patient, the nature of the treatment provided, and the way the syndrome and transition to psychosis are defined.

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.

The functional neuroanatomy of autism.

Autism is a neurodevelopmental syndrome characterized by impaired social and executive functions. Functional magnetic resonance imaging (fMRI) is a non-invasive technique that allows investigation of the neural networks underlying cognitive impairments in autism. In this article, brain imaging studies investigating the functional brain anatomy of autism are reviewed. Face recognition, theory of mind and executive functions have all been explored in functional neuroimaging studies involving autistic patients. The available literature suggests an involvement of abnormal functional mechanisms in face recognition, mentalization and executive functions in adults with high-functioning autism or Asperger's syndrome, possibly due to brain maturation abnormalities, and resulting in dysfunctional reciprocal cortico-subcortical connections. Future functional neuroimaging research should investigate subgroups of autistic children and adolescents longitudinally and attempt to integrate genetic, cognitive and empirical approaches. Such studies will be instrumental in furthering understanding of the pathophysiology of autism and in exploring the importance of dimensional measures of the broader phenotype currently defined as autism.

Anatomical MRI findings in mood and anxiety disorders.

OBJECTIVE: In vivo structural magnetic resonance imaging (MRI) studies have evaluated the brain anatomy of various psychiatric disorders, allowing the investigation of putative abnormal brain circuits possibly involved in the patophysiology of psychiatric disorders. Here we reviewed the structural MRI literature in mood and anxiety disorders. METHODS: All anatomical MRI studies evaluating mood and anxiety disorder patients were identified through a comprehensive Medline search conducted for the period from 1966 to January 2002, and a manual search of bibliographic cross-referencing complemented the Medline search. RESULTS: Differential patterns of anatomical brain abnormalities appear to be involved in subtypes of mood disorders, with hippocampus and basal ganglia being abnormal in unipolar disorder, and amygdala and cerebellum in bipolar disorders, suggesting that these two mood disorders are biologically distinct. As for anxiety disorders, orbital frontal regions and basal ganglia have been reported to be anatomically abnormal in obsessive-compulsive disorder, temporal lobe was found to be abnormally reduced in panic disorder, and abnormal hippocampus shrinkage was shown in posttraumatic stress disorder. CONCLUSIONS: The structural MRI findings reviewed here suggest abnormalities in specific brain regions participating in proposed neuroanatomic models possibly involved in the pathophysiology of mood disorders and anxiety disorders. Nonetheless, available MRI studies have suffered from limitations related to relatively small patient samples and involvement of medicated patients, and were largely cross-sectional investigations. Therefore, longitudinal MRI studies involving more sizeable samples of drug-free patients, patients at first episode of illness or at high risk for mood or anxiety disorders, associated to genetic studies, are likely to be extremely valuable to separate state from trait brain abnormalities and to characterize further the pathophysiology of these disorders.