Aberrant Cerebello-Cerebral Connectivity in Remitted Bipolar Patients 1 and 2: New Insight into Understanding the Cerebellar Role in Mania and Hypomania.

Bipolar disorder (BD) is a major mental illness characterized by periods of (hypo) mania and depression with inter-episode remission periods. Functional studies in BD have consistently implicated a set of linked cortical and subcortical limbic regions in the pathophysiology of the disorder, also including the cerebellum. However, the cerebellar role in the neurobiology of BD still needs to be clarified. Seventeen euthymic patients with BD type1 (BD1) (mean age/SD, 38.64/13.48; M/F, 9/8) and 13 euthymic patients with BD type 2 (BD2) (mean age/SD, 41.42/14.38; M/F, 6/7) were compared with 37 sex- and age-matched healthy subjects (HS) (mean age/SD, 45.65/14.15; M/F, 15/22). T1 weighted and resting-state functional connectivity (FC) scans were acquired. The left and right dentate nucleus were used as seed regions for the seed based analysis. FC between each seed and the rest of the brain was compared between patients and HS. Correlations between altered cerebello-cerebral connectivity and clinical scores were then investigated. Different patterns of altered dentate-cerebral connectivity were found in BD1 and BD2. Overall, impaired dentate-cerebral connectivity involved regions of the anterior limbic network specifically related to the (hypo)manic states of BD. Cerebello-cerebral connectivity is altered in BD1 and BD2. Interestingly, the fact that these altered FC patterns persist during euthymia, supports the hypothesis that cerebello-cerebral FC changes reflect the neural correlate of subthreshold symptoms, as trait-based pathophysiology and/or compensatory mechanism to maintain a state of euthymia.

Effect of affective temperament on illness characteristics of subjects with bipolar disorder and major depressive disorder.

BACKGROUND: Affective temperaments represent the stable, biologically determined substrates of mood disorders. The relationship between affective temperaments and bipolar disorder (BD) or major depressive disorder (MDD) has been described. However, the strength of such relationship should be tested while considering other factors influencing the diagnosis of BD/MDD. Literature also lacks a comprehensive description of the interplay between affective temperament and characteristics of mood disorders. The aim of the present study is to address these issues. METHODS: This is a multicentric observational study including 7 Italian university sites. Five-hundred-fifty-five euthymic subjects with BD/MDD were enrolled and further divided in those with hyperthymic (Hyper, N = 143), cyclothymic (Cyclo, N = 133), irritable (Irr, N = 49), dysthymic (Dysth, N = 155), and anxious (Anx N = 76) temperaments. Linear, binary, ordinal and logistic regressions were performed to assess the association between affective temperaments and i) diagnosis of BD/MDD; ii) characteristics of illness severity and course. RESULTS: Hyper, Cyclo and Irr were more likely to be associated with BD, together with earlier age of onset and presence of a first-degree relative with BD. Anx and Dysth were more associated with MDD. Differences in association between affective temperaments and characteristics of BD/MDD were observed for hospital admissions, phase-related psychotic symptoms, length and type of depression, comorbidity and pharmacological intake. LIMITATIONS: Small sample size, cross-sectional design, recall biases. CONCLUSION: Specific affective temperaments were associated to certain characteristics of illness severity and course of BD or MDD. Evaluation of affective temperaments might help a deeper understanding of mood disorders.

Anti-purkinje cell and natural autoantibodies in a group of psychiatric patients. Evidences for a correlation with the psychopathological status.

Phenomena of autoimmunity are frequent among psychiatric patients, but we don't know yet if they should be considered primary and linked to the pathophisiology of the disorder, or aspecific and associated to a general immune system activation. Paraneoplastic Cerebellar Degeneration (PCD) represents a well known model of specific autoimmunity. In order to better understand the abovementioned issues, we used this condition to compare a set of immune dysfunctions found in a group of psychiatric patients. For this reason we tested sera from 48 psychiatric patients (24 schizophrenics, 17 bipolars and 7 obsessive-compulsive), 22 PCD patients and 52 healthy controls for the presence of anti-Purkinje autoantibodies and of some natural autoantibodies (ANAs, AMAs, APCAs, ASMAs). Psychopatological status of the psychiatric patients was assessed with BPRS, SANS, SAPS, HAM-D, CGI-S. In the psychiatric group anti-Purkinje autoantibodies were identified in 11/48 (22,9%) patients, while they were present in 22/22 (100%) PCD patients and in 0/52 (0%) healthy controls. Among all anti-Purkinje autoantibody positive patients (in the PCD and psychiatric samples), only those belonging to the psychiatric sample, but not those with PCD, were frequently found positive also for natural autoantibodies, that are considered good markers of aspecific immune activation. In these patients, both anti-Purkinje and natural autoantibodies were found associated with acute/positive psychopathological symptoms. These results seem to point out that some phenomena of auto-immunity described in psychiatric patients could be aspecific, unrelated to the pathophysiology of the concomitant mental disorders and could be more frequent during phases of acute/positive symptoms.

Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study).

Background: Treatment-resistant Depression (TRD) represents a widespread disorder with significant direct and indirect healthcare costs. esketamine, the S-enantiomer of ketamine, has been recently approved for TRD, but real-world studies are needed to prove its efficacy in naturalistic settings. Objectives: Evaluate the effectiveness and safety of esketamine nasal spray in a clinical sample of patients with TRD from several Italian mental health services. Methods: REAL-ESK study is an observational, retrospective and multicentric study comprising a total of 116 TRD patients treated with esketamine nasal spray. Anamnestic data and psychometric assessment (MADRS, HAMD-21, HAM-A) were collected from medical records at baseline (T0), one month (T1) and three month (T2) follow-ups. Results: A significant reduction of depressive symptoms was found at T1 and T2 compared to T0. A dramatic increase in clinical response (64.2 %) and remission rates (40.6 %) was detected at T2 compared to T1. No unexpected safety concerns were observed, side effects rates were comparable to those reported in RCTs. No differences in efficacy have been found among patients with and without psychiatric comorbidities. Limitations: The open design of the study and the absence of a placebo or active comparator group are limitations. The study lacks an inter-rater reliability evaluation of the assessments among the different centres. Side effects evaluation did not involve any specific scale. Conclusions: Our findings support the safety and tolerability of esketamine in a real-world TRD sample. The later response and the non-inferiority in effectiveness in patients with comorbidities represent novel and interesting findings.

Theory of Mind as a mediator variable between neurocognition and functioning in young individuals in treatment with secondary services for non-psychotic disorders.

A large body of studies provides evidence for a link between neurocognition, theory of mind (ToM) and functioning in psychotic spectrum disorders (PSDs), with ToM mediating the effect that neurocognition has on functioning. These three constructs and the related mediation effect may characterize different psychiatric syndromes other than PSDs. Structural equation modelling (SEM) was applied to baseline data from a longitudinal study of 138 young individuals with a recent-onset psychiatric disorder. Using SEM, we tested the hypothesis that ToM mediates the effect of neurocognition on functioning independent of the level of psychosis risk and the diagnostic category. In the mediation model the bootstrapping estimate revealed a significant indirect effect that was the association of social cognition with neurocognition and with functional outcome. ToM was significantly associated with neurocognition and the path from neurocognition to functioning was no longer significant as soon as the mediator (ToM) was entered into the mediation model consistent with a complete mediation effect through ToM. This mediation was independent of the psychosis-risk status and the psychiatric diagnoses. Our results provide useful information on a young psychiatric sample, in which specific therapeutic interventions have the potential to significantly limit functional disability.

Impaired conflict resolution and vigilance in euthymic bipolar disorder.

Difficulty attending is a common deficit of euthymic bipolar patients. However, it is not known whether this is a global attentional deficit or relates to a specific attentional network. According to the attention network approach, attention is best understood in terms of three functionally and neuroanatomically distinct networks-alerting, orienting, and executive control. In this study, we explored whether and which of the three attentional networks are altered in euthymic Bipolar Disorder (BD). A sample of euthymic BD patients and age-matched healthy controls completed the Attention Network Test for Interactions and Vigilance (ANTI-V) that provided not only a measure of orienting, executive, and alerting networks, but also an independent measure of vigilance (tonic alerting). Compared to healthy controls, BD patients have impaired executive control (greater interference), reduced vigilance (as indexed by a decrease in the d' sensitivity) as well as slower overall reaction times and poorer accuracy. Our results show that deficits in executive attention and sustained attention often persist in BD patients even after complete remission of affective symptoms, thus suggesting that cognitive enhancing treatments programmed to improve these deficits could contribute to improve their functional recovery.

Capgras-like syndrome in a patient with an acute urinary tract infection.

Delusional misidentification syndromes are a group of delusional phenomena in which patients misidentify familiar persons, objects, or themselves, believing that they have been replaced or transformed. In 25%-40% of cases, misidentification syndromes have been reported in association with organic illness. We report an acute episode of Capgras-like delusion lasting 8 days, focused on the idea that people were robots with human bodies, in association with an acute urinary infection. To our knowledge, this is the first case report associating urinary tract infection with Capgras-like syndrome. Awareness of the prevalence of delusional misidentification syndromes associated with acute medical illness should promote diligence on the part of clinicians in recognizing this disorder.

Symptomatic subsyndromal depression in hospitalized hypertensive patients.

BACKGROUND: Clinicians generally agree on the association between depression and hypertension. Less clear is if the nature of the link is direct or indirect and if this should be considered confined only to syndromal forms or if it concerns also subsyndromal affective presentations. This study investigated the nature of the association between hypertension and subsyndromal depression in hospitalized hypertensive patients. METHODS: 196 hypertensive and 96 non hypertensive inpatients underwent a SCID interview, to exclude patients positive for any Axis I or Axis II diagnosis. Symptomatic Subsyndromal Depression (SSD) was identified according to criteria proposed by Judd. Psychopathological assessment was performed with Anxiety Sensitivity Index (ASI) and Hopkins Symptom Checklist-90 (SCL-90). Clinical assessments included blood pressure measurement, evaluation of general health conditions and screening cardiovascular risk factors (smoke, alcohol, body weight, sedentary life style). RESULTS: Hypertensives met more frequently criteria for SSD. They also scored higher on ASI and SCL-90. However, those with more severe physical conditions, if compared with more healthy patients, did not show increased psychopathological severity. Similarly, psychopathological symptom severity did not differ among hypertensives positive for other cardiovascular risk factors, commonly more frequent among depressed subjects. LIMITATIONS: Further analyses are needed to explore the potential advantage obtained on blood pressure control by treating SSD. CONCLUSIONS: Hospitalized hypertensives, more frequently satisfied criteria for Symptomatic Subsyndromal Depression. These milder affective forms are probably directly linked to the presence of hypertension, rather than being indirectly associated to physical impairment or to higher prevalence of other cardiovascular risk factors.

A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder.

S-adenosyl-L-methionine (SAMe) is a natural substance which constitutes the most important methyl donor in transmethylation reactions in the central nervous system. Several clinical trials have shown that SAMe possesses an antidepressant activity. This multicentre study was carried out to confirm both efficacy and safety of SAMe in the treatment of major depression. SAMe was given intramuscularly (i.m.) at a dose of 400 mg/d, double-blind, vs. 150 mg/d oral Imipramine (IMI) in patients with a diagnosis of major depressive episode, with a baseline score on the 21-item Hamilton Depression Rating Scale (HAMD) of >or=18. A total of 146 patients received SAMe whereas 147 received IMI for a period of 4 wk. The two main efficacy measures were endpoint HAMD score and percentage of responders to Clinical Global Impression (CGI) at week 4. Secondary efficacy measures were the final Montgomery-Asberg Depression Rating Scale (MADRS) scores and the response rate intended as a fall in HAMD scores of at least 50% with respect to baseline. The analysis of safety and tolerability was conducted in all treated patients. SAMe and IMI did not differ significantly on any efficacy measure, either main or secondary. Adverse events were significantly less in patients treated with SAMe compared to those treated with IMI. These data show 400 mg/d i.m. SAMe to be comparable to 150 mg/d oral IMI in terms of antidepressive efficacy, but significantly better tolerated. These findings suggest interesting perspectives for the use of SAMe in depression.