Abnormalities in functional connectivity in borderline personality disorder: Correlations with metacognition and emotion dysregulation.

A few studies reported functional abnormalities at rest in borderline personality disorder (BPD), but their relationship with clinical aspect is unclear. We aimed to assess functional connectivity (FC) in BPD patients and its association with BPD clinical features. Twenty-one BPD patients and 14 healthy controls (HC) underwent a multidimensional assessment and resting-state fMRI. Independent component analysis was performed to identify three resting-state networks: default mode network (DMN), salience network (SN), and executive control network (ECN). FC differences between BPD and HC were assessed with voxel-wise two-sample t-tests. Additionally, we investigated the mean FC within each network and the relationship between connectivity measures and BPD clinical features. Patients showed significant lower mean FC in the DMN and SN, while, at the local level, a cluster of lower functional connectivity emerged in the posterior cingulate cortex of the DMN. The DMN connectivity was positively correlated with the anger-state intensity and expression, while the SN connectivity was positively correlated with metacognitive abilities and a negative correlation emerged with the interpersonal aggression. The dysfunctional connectivity within these networks might explain clinical features of BPD patients.

Development and Validation of the Health of the Nation Outcome Scales-Residential Facility (HoNOS-RF).

The Health of the Nation Outcome Scale (HoNOS) (Lora et al. Epidemiol Psichiatr Soc 10(3):198-212, 2001) is widely used. However, clinicians have expressed concerns about its ability to describe severe mentally ill patients, as it does not consider some relevant clinical aspects. This study aims to develop and validate the HoNOS-Residential Facility (HoNOS-RF) in order to pursue a thorough assessment of patients admitted to psychiatric residential facilities (RFs). The final version of the HoNOS-RF was administered to 409 patients admitted to four RFs. Exploratory factor analysis, Cronbach' alpha (α), Intraclass Correlation Coefficients (ICC) were used to assess construct validity, internal consistency and reliability, respectively. Concurrent criterion validity was assessed through correlations with the Brief Psychiatric Rating Scale-Expanded Version (BPRS-E) (Roncone et al. Acta Psychiatric Scand 100(3):229-36, 1999), Personal and Social Performance Scale (PSP) (Morosini et al. Acta Psychiatric Scand 101(4): 323-29, 2000), and comparisons across diagnostic groups. The final version of the HoNOS-RF consisted of 31 items, grouped into the following eight factors (overall explaining 55% of the total variability): personal and interpersonal functioning; environment; behavior and burden of care; cognitive function; somatic problems; anxiety-depression symptoms; psychotic symptoms; and other psychiatric symptoms. The scale showed high internal consistency (α = .807), and the correlations with PSP and BPRS-E ranged from adequate to moderate. The ICCs were in the excellent range for almost all items. These findings support the validity and the reliability of the HoNOS-RF, thus it may be a useful tool for the assessment of patients admitted to RFs, as it addresses clinical aspects that were mostly not included in the original version.

Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: results and lessons of an underpowered randomised clinical trial.

BACKGROUND: As lithium treatment might be effective in reducing the risk of deliberate self-harm (DSH) in adult patients with unipolar affective disorders, we designed a pragmatic randomised trial to assess its efficacy in more than 200 patients with treatment-resistant depression. However, we randomised 56 patients only. The aim of this report is therefore twofold: first, to disseminate the results of this underpowered study which may be incorporated into future meta-analytical reviews; second, to analyse some critical aspects of the study which might explain failure to reach the target sample size. METHODS: We carried out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode were allocated to add lithium to usual care (intervention arm) versus usual care alone (control arm). Suicide completion and acts of DSH during the 12 months of follow-up constituted the composite primary outcome. RESULTS: Of 58 patients screened for inclusion, 29 were allocated to lithium plus usual care and 27 were assigned to usual care without lithium. Six patients in the lithium plus usual care group and seven in the usual care group committed acts of DSH during the follow-up phase. The survival probability did not differ between the two treatment arms (Chi2 = 0.17, p =0.676). With regard to changes in the severity of depressive symptomatology from baseline to endpoint, no significant differences were detected. CONCLUSIONS: The present study failed to achieve the minimum sample size needed to detect a clinically meaningful difference between the two treatment arms. Consequently, the finding that lithium, in addition to usual care, did not exert a positive effect in terms of reduction of DSH after 12 months of follow-up is likely due to the lack of sufficient statistical power to detect a difference, if a difference existed. The dissemination of the results of this underpowered study will inform future meta-analytical reviews on lithium and suicide-related outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00927550.

Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: a protocol for a randomised, independent, pragmatic, multicentre, parallel-group, superiority clinical trial.

BACKGROUND: Data on therapeutic interventions following deliberate self harm (DSH) in patients with treatment-resistant depression (TRD) are very scant and there is no unanimous consensus on the best pharmacological option for these patients. There is some evidence that lithium treatment might be effective in reducing the risk of completed suicide in adult patients with unipolar affective disorders, however no clear cut results have been found so far. The primary aim of the present study is to assess whether adding lithium to standard therapy is an effective treatment strategy to reduce the risk of suicidal behaviour in long term treatment of people with TRD and previous history of DSH. METHODS/DESIGN: We will carry out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode will be allocated to add lithium to current therapy (intervention arm) or not (control arm). Following randomisation, treatment is to be taken daily for 1 year unless some clear reason to stop develops. Suicide completion and acts of DSH during the 12 months of follow-up will constitute the composite primary outcome. To preserve outcome assessor blindness, an independent adjudicating committee, blind to treatment allocation, will anonymously review all outcome events. DISCUSSION: The results of this study should indicate whether lithium treatment is associated with lower risk of completed suicide and DSH in adult patients with treatment resistant unipolar depression, who recently attempted suicide. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00927550.

Structural brain features of borderline personality and bipolar disorders.

A potential overlap between bipolar disorder (BD) and borderline personality disorder (BPD) has been recently proposed. We aimed to assess similarities and differences of brain structural features in BD and BPD. Structural magnetic resonance imaging (MRI) was performed in 26 inpatients with BPD, 14 with BD, and 40 age-and sex-matched healthycontrols (HC). Voxel-based morphometry analysis with Statistical Parametric Mapping (SPM) was used to localize and quantify gray (GM) and white matter (WM) abnormalities in BD and BPD compared to HC and to identify those specifically affected in each patient group. Region of interest (ROI)-based analyses were also performed for confirmation. GM density changes in BD are significantly more diffuse and severe than in BPD, as demonstrated in both SPM- and ROI-based analyses. The topography of GM alterations showed some regions of overlap, but each disorder had specific regions of abnormality (involving both cortical and subcortical structures in BD, confined mainly to fronto-limbic regions in BPD). WM density changes were less pronounced in both conditions and involved completely different regions. Although BPD and BD show a considerable overlap of GM changes, the topography of alterations is more consistent with the separate conditions hypothesis and with the vulnerability of separate neural systems.

Volumetric and topographic differences in hippocampal subdivisions in borderline personality and bipolar disorders.

Hippocampal abnormalities may be implicated in the pathophysiology of mental disorders with affective symptoms such as borderline personality disorder (BPD) and bipolar disorder (BD). We aimed to investigate hippocampal morphology in BPD and BD patients, compared to 1:1 age- and sex-matched healthy controls (HC) using a three-dimensional mapping method. Manual tracing of the hippocampi on magnetic resonance imaging (MRI) images was performed on 26 patients with BPD (age: 38±11; sex (f): 16 (61%)) and 15 with BD (age: 44±9; sex (f): 5 (33%)) and their age- and sex-matched HC (for BPD: n=26; age: 38±11; sex (f): 16 (61%); for BD: n=15; age: 44±9; sex (f): 5 (33%)). Compared to their reference groups, BPD patients showed smaller hippocampal volume bilaterally. The BD group showed significantly smaller right hippocampal volumes. In the surface maps, alterations were localized to different hippocampal sectors for the two groups: the CA1 regions and subiculum, bilaterally, in BPD, and the right dentate gyrus in the BD group. These differences persisted after controlling for alcohol and substance abuse. BPD and BD groups may exhibit distinct patterns of volumetric MRI changes in hippocampal subdivisions that might be related to the clinical phenomenology of each disorder.

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia.

BACKGROUND: One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. METHODS/DESIGN: The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. DISCUSSION: The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.

3' UTR (AGG)n repeat of glial cell line-derived neurotrophic factor (GDNF) gene polymorphism in schizophrenia.

Association studies on gene polymorphisms of neurotransmitter systems have hypothesized an involvement of dopamine receptors in susceptibility to schizophrenia. However, structural and morphological abnormalities in different brain regions of schizophrenic patients support neurodevelopmental etiology for schizophrenia and neurotrophic factor genes could be candidates for genetic studies. The glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic and potential differentiation factor for dopaminergic systems. We have performed, in an Italian sample, an association study on 3' UTR (AGG)n repeat in GDNF gene. Our results have evidenced a difference in the allele frequencies between patients and controls (CLUMP (T1) chi2 = 17.365, df = 9, P = 0.043) and the (AGG)n > or = 15 alleles (Fisher Exact Test (two side) chi2 = 11.818, df = 1, P = 0.0003) were more present in the controls group. Similarity, the carriers of (AGG)n > or = 15 (OR = 0.176 95% CI: 0.060-0.520) were more present in the same group. These results support that the (AGG)n > or = 15 alleles could be protective factors against schizophrenia and thus they suggest a possible involvement of GDNF gene in the genetic liability to illness.