PREDOMINANT POLARITY AND THE POLARITY INDEX OF DRUGS USED IN MAINTENANCE TREATMENT OF BIPOLAR DISORDER

Objective: Predominant polarity (PP) is an important variable in maintenance treatment of Bipolar Disorder (BD). This study aimed at determining the role of Polarity Index (PI), a metric indicating antimanic versus antidepressive prophylactic potential of drugs, in clinical decision-making. Method: 257/604 (43%) of patients with BD-I or II fulfilled criteria for manic (MPP) or depressive PP (DPP). The PI, representing Number Needed to Treat (NNT) for prevention of depression and NNT for mania prevention ratio, was calculated for patients’ current treatment. MPP and DPP groups were compared regarding sociodemographic, clinical and therapeutic characteristics. Results: 143 patients (55.6%) fulfilled criteria for DPP and 114 (44.4%) for MPP. Total PI, Antipsychotics’ PI and Mood Stabilizers PI were higher, indicating a stronger antimanic action, in MPP. MPP presented higher prevalence of BD-I, male gender, younger age, age at onset and at first hospitalization, more hospitalizations, primary substance misuse and psychotic symptoms. DP correlated with BD-II, depressive onset, primary life events, melancholia and suicide attempts. Conclusion: The results confirm the usefulness of the PI. In this large sample, clinical differences among these groups justify differential treatment approach. The PI appears to be a useful operationalization of what clinicians do for maintenance therapy in BD

MOOD SYMPTOMS IN STABILIZED PATIENTS WITH SCHIZOPHRENIA: A BIPOLAR TYPE WITH PREDOMINANT PSYCHOTIC FEATURES?

Background: Schizophrenia (SZ) and bipolar disorder (BD) are traditionally distinguished on the basis of progressive deterioration and long-term outcome, but a more dimensional approach is warranted. There are limited data on the occurrence of manic symptoms in patients with schizophrenia. The aim of the current study was to search for patterns in the clinical symptomatology, which may suggest the presence of one or several mood disorders under the label of schizophrenia. Subjects and methods: Hundred-seventy-five patients diagnosed with schizophrenia according to DSM-5 were included in the study. The psychometric assessment included the Positive and Negative Syndrome Scale, Young Mania Rating Scale, The Montgomery- Åsberg Depression Rating Scale and the Calgary Depression Scale. The statistical analysis included MANOVA, Pearson Correlation coefficient and principal components analysis. Results: Significant subthreshold manic symptoms were present in 25.14% of patients. Mood symptoms correlated with positive symptoms. The PCA revealed a complex structure with 15 factors (one positive, negative, somatic, anxiety, neurocognitive, disorganization and manic, five depressive and three psychomotor/excitement/hostility/violence). Conclusion: Psychotic mood disorders are often phenotypically indistinguishable from schizophrenia, so it is likely that psychotic affective patients have been misdiagnosed with schizophrenia. The current study suggests that there seem to be patients with mania misdiagnosed as \u27schizophrenics\u27 because of the presence of psychotic features, a condition better described as \u27schizophreniform bipolar disorder\u27

Revisiting loxapine: a systematic review

Loxapine is an antipsychotic used in psychiatry for over 40 years with a well-established profile. Loxapine is a dibenzoxazepine tricyclic antipsychotic agent, available for oral, intramuscular and inhalatory administration. In the light of the recent approval by the regulatory agencies of inhaled loxapine for use in the acute treatment of mild-to-moderate agitation in adults affected with schizophrenia or bipolar disorder, this article aims to critically review the available literature on loxapine, irrespective of its formulation. This review examines the efficacy and tolerability of the various formulations of loxapine in the treatment of agitation and aggression in patients affected with schizophrenia, bipolar disorder and other psychiatric conditions. A comprehensive and systematic literature search of PubMed/MEDLINE was conducted, and relevant pharmacodynamic and pharmacokinetic data was included. The findings from the literature were critically reviewed and synthesized. The available data suggests that the antipsychotic efficacy of loxapine is similar to the efficacy of other typical or atypical antipsychotics, with an adverse effects profile comparable to that of the typical antipsychotics at high doses for chronic treatment. As an acute treatment in agitation associated with schizophrenia or bipolar disorder, inhaled loxapine was developed as an innovative and rapid option which appears to be efficacious and tolerable

Gut microbial dysbiosis occurring during pulmonary fungal infection in rats is linked to inflammation and depends on healthy microbiota composition

While the effect of gut microbiota and/or inflammation on a distant body site, including the lungs (gut–lung axis), has been well characterized, data about the influence of lung microbiota and lung inflammation on gut homeostasis (lung–gut axis) are scarce. Using a well-characterized model of pulmonary infection with the fungus Aspergillus fumigatus, we investigated alterations in the lung and gut microbiota by next-generation sequencing of the V3–V4 regions of total bacterial DNA. Pulmo- nary inflammation due to the fungus A. fumigatus caused bacterial dysbiosis in both lungs and gut, but with different characteristics. While increased alpha diversity and unchanged bacterial composition were noted in the lungs, dysbiosis in the gut was characterized by decreased alpha diversity indices and modified bacterial composition. The altered homeostasis in the lungs allows the immigration of new bacterial species of which 41.8% were found in the feces, indicating that some degree of bacterial migration from the gut to the lungs occurs. On the contrary, the dysbiosis occurring in the gut during pulmonary infection was a consequence of the local activity of the immune system. In addition, the alteration of gut microbiota in response to pulmonary infection depends on the bacterial composition before infection, as no changes in gut bacterial microbiota were detected in a rat strain with diverse gut bacteria. The data presented support the existence of the lung–gut axis and provide additional insight into this mechanism. IMPORTANCE Data regarding the impact of lung inflammation and lung microbiota on GIT are scarce, and the mechanisms of this interaction are still unknown. Using a well-characterized model of pulmonary infection caused by the opportunistic fungus Aspergillus fumigatus, we observed bacterial dysbiosis in both the lungs and gut that supports the existence of the lung–gut axis. KEYWORDS fungal lung infection, gastrointestinal microbiota, lung microbiota, lung-gut axis, rats B acteria inhabit every part of the human body, but most of them are found in the gut. Gut microbiota are responsible for many functions, including nutrient metabolism, immunomodulation, maintenance of host physiology, and protection against pathogen overgrowth (1). To date, numerous scientific studies confirm the important role of gut bacteria in health and disease. This microbial community impacts not only local immunity but also a distant body site, such as the lungs. Disturbances in gut bacterial composition have been linked to asthma (2), chronic obstructive pulmonary disease (3), cystic fibrosis (4), and lung cancer (5). Furthermore, pulmonary involvement was noted in inflammatory gastrointestinal disease characterized by microbial dysbiosis (6), Month XXXX Volume 0 Issue 0 10.1128/spectrum.01990-23 1 Editor Agostinho Carvalho, University of Minho, Braga, Portugal Address correspondence to Maja Tolinacki, [email protected]. The authors declare no conflict of interest. See the funding table on p. 15. Received 11 May 2023 Accepted 25 July 2023 Published 25 August 2023 Copyright © 2023 Popovic et al. This is an open- access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Downloaded from https://journals.asm.org/journal/spectrum on 09 October 2023 by 147.91.199.205. supporting the existence of a gut–lung axis. The gut bacterial microbiota or some of their constituents impact the immune response in the lungs against viruses (7–9), bacteria (10–13), fungi (14), and allergic airway inflammation (15) mainly through the effect of the gut microbiota (or their metabolites) on the immune cell activity. While the gut–lung axis is well characterized, the influence of the lung microbiota as well as lung inflammation on gut homeostasis has attracted much more attention in recent years. The first indication of the lung–gut axis was a higher prevalence (compared to healthy subjects) of gastrointestinal symptoms in patients with asthma (16) and chronic obstructive pulmonary disease (17). The existence of gastrointestinal symptoms in patients with pulmonary virus infection has also been documented (18). Gastrointesti- nal symptoms (abdominal pain, nausea, vomiting, and diarrhea) were noted in 11.6% of children with influenza infection (18), and a later study showed a decrease in alpha diversity in the feces of influenza-infected patients compared to healthy controls (19). Fecal bacterial samples from patients with COVID-19 infection were shown to cluster separately from those in healthy controls as well, but in the majority of these patients, SARS-Cov-2 could be detected in the feces (20). Experimental studies in mice confirmed the occurrence of gut dysbiosis following respiratory influenza virus infection (21–25) and respiratory syncytial virus infection (24), despite the fact that the virus has not been detected in the gut (21, 22, 24, 25). It has been shown that the alteration of gut microbiota is a consequence of infection with live virus particles, as administration of an attenuated influenza vaccine had no effect on the microbiota (24). Bacterial dysbiosis in the gut also occurs following pulmonary bacterial infection. A decrease in alpha diversity indices and differential relative abundance of fecal microbiota were noted in patients with pulmonary tuberculosis (26, 27) and in mice infected with Mycobacterium tuberculosis (28) and Klebsiella pneumoniae (29). Even administration of the major component of the outer membrane of Gram-negative bacteria, lipopolysac- charide, to the lungs caused gut bacteria dysbiosis (30). In addition to pulmonary infections caused by viruses or bacteria, alteration of the gut microbiota was noted in mice exposed to hyperoxia (31) and in patients with lung cancer (compared to healthy individuals) (32) indicating that pulmonary inflammation/injury affects the gut microbiota regardless of its origin. Despite a growing body of evidence for interaction between the lungs and gut, there is still a lot of work to be done to understand this crosstalk. There are virtually no data regarding gut microbiota changes during pulmonary infection caused by fungi. Our previous study showed an alteration in immune-mediated homeostasis of the gut in a rat model of sublethal pulmonary infection with A. fumigatus (33). Using the same experimental model of infection in Dark Agouti (DA) rat strain, we aimed to investigate changes in the lung and gut microbiota by next-generation sequencing of the V3–V4 regions of total bacterial DNA in these two organs. Possible mechanisms of lung–gut communication were also investigated. In addition, to examine whether gut dysbiosis is a general characteristic during pulmonary fungal infection, we analyzed feces from infected Albino Oxford (AO) rats, a strain that develop quantitatively different immune response to fungus A. fumigatus (34) and whose gut microbiota was previously shown to respond differently to oral cadmium administra- tion (35) compared to DA rats

Deconstructing major depressive episodes across unipolar and bipolar depression by severity and duration: a cross-diagnostic cluster analysis on a large, international, observational study

A cross-diagnostic, post-hoc analysis of the BRIDGE-II-MIX study was performed to investigate how unipolar and bipolar patients suffering from an acute major depressive episode (MDE) cluster according to severity and duration. Duration of index episode, Clinical Global Impression-Bipolar Version-Depression (CGI-BP-D) and Global Assessment of Functioning (GAF) were used as clustering variables. MANOVA and post-hoc ANOVAs examined between-group differences in clustering variables. A stepwise backward regression model explored the relationship with the 56 clinical-demographic variables available. Agglomerative hierarchical clustering with two clusters was shown as the best fit and separated the study population (n = 2314) into 65.73% (Cluster 1 (C1)) and 34.26% (Cluster 2 (C2)). MANOVA showed a significant main effect for cluster group (p < 0.001) but ANOVA revealed that significant between-group differences were restricted to CGI-BP-D (p < 0.001) and GAF (p < 0.001), showing greater severity in C2. Psychotic features and a minimum of three DSM-5 criteria for mixed features (DSM-5-3C) had the strongest association with C2, that with greater disease burden, while non-mixed depression in bipolar disorder (BD) type II had negative association. Mixed affect defined as DSM-5-3C associates with greater acute severity and overall impairment, independently of the diagnosis of bipolar or unipolar depression. In this study a pure, non-mixed depression in BD type II significantly associates with lesser burden of clinical and functional severity. The lack of association for less restrictive, researched-based definitions of mixed features underlines DSM-5-3C specificity. If confirmed in further prospective studies, these findings would warrant major revisions of treatment algorithms for both unipolar and bipolar depression

Clinical and neurocognitive predictors of functional outcome in depressed patients with partial response to treatment: one year follow-up study

Background: Cognitive dysfunction represents a distinct biological and clinical dimension in major depression disorders (MDD) and cognitive performance strongly affects psychosocial functioning in patients diagnosed with MDD. Objective: To assess which neurocognitive variables at baseline predict the functional outcome of MDD patients in a 1-year follow-up study as assessed by Functioning Assessment Short Test (FAST) and whether the improvement observed on affective and cognitive symptoms in our 12 week-prospective observational study after treatment with selective serotonin reuptake inhibitors (SSRIs) and selective noradrenalin reuptake inhibitors (SNRIs) can affect the following long-term psychosocial functional outcome at 1 year in the same MDD patients. Methods: We recruited a total of 31 patients (8 males; 23 females) with MDD who had previously completed a pharmacological treatment with SSRIs (n = 22) or SNRIs (n = 9) for 12 weeks, and then continued the same pharmacological treatment for 1 year. After an average 1-year follow-up, they were interviewed with the FAST to assess functional outcome. Multivariate analyses were applied to identify clinical and neurocognitive predictors of functional outcome. Results: Total Montreal Cognitive Assessment (MoCA), Digit Span forward (Span F) and backward (Span B), and 15 Rey words immediate recall (Rey I) scores significantly correlated with FAST. However, after performing regression models only Rey immediate recall score was useful to predict long-term functional outcome (Pearson correlation coefficient R= -0.68, p < 0.001) in four specific subdomains of FAST. When considering changes in affective and cognitive symptoms at the end of the 12 weeks of pharmacological treatment with SSRI or SNRIs (T1-T0) by multiple regression analysis, we found that Span F-test predicted scores in the FAST leisure domain, whereas, changes in Span F, Frontal Assessment Battery (FAB) and Rey I predicted psychosocial functioning in the specific 'cognitive' subdomains of FAST. Conclusion: Our data suggest that long-term psychosocial functioning can be influenced by neurocognitive performance at baseline, with verbal memory playing a key role in overall functioning. Furthermore, improvement in verbal memory can predict functional outcome at one year in MDD patients with a recent history of partial response to antidepressants

Aggressiveness in depression: a neglected symptom possibly associated with bipolarity and mixed features

OBJECTIVE: To evaluate aggressiveness during a major depressive episode (MDE) and its relationship with bipolar disorder (BD) in a post hoc analysis of the BRIDGE-II-MIX study. METHOD: A total of 2811 individuals were enrolled in this multicenter cross-sectional study. MDE patients with (MDE-A, n = 399) and without aggressiveness (MDE-N, n = 2412) were compared through chi-square test or Student's t-test. A stepwise backward logistic regression model was performed. RESULTS: MDE-A group was more frequently associated with BD (P < 0.001), while aggressiveness was negatively correlated with unipolar depression (P < 0.001). At the logistic regression, aggressiveness was associated with the age at first depressive episode (P < 0.001); the severity of mania (P = 0.03); the diagnosis of BD (P = 0.001); comorbid borderline personality disorder (BPD) (P < 0.001) but not substance abuse (P = 0.63); no current psychiatric treatment (P < 0.001); psychotic symptoms (P = 0.007); the marked social/occupational impairment (P = 0.002). The variable most significantly associated with aggressiveness was the presence of DSM-5 mixed features (P < 0.001, OR = 3.815). After the exclusion of BPD, the variable of lifetime suicide attempts became significant (P = 0.013, OR = 1.405). CONCLUSION: Aggressiveness seems to be significantly associated with bipolar spectrum disorders, independently from BPD and substance abuse. Aggressiveness should be considered as a diagnostic criterion for the mixed features specifier and a target of tailored treatment strategy

The implications of hypersomnia in the context of major depression: Results from a large, international, observational study

According to the DSM-5, 'reduction in the need for sleep' is the only sleep-related criteria for mixed features in depressive episodes. We aimed at studying the prevalence, clinical correlates and the role of hypersomnia in a sample of acutely depressed patients. Secondarily, we factors significantly increasing the odds of hypersomnia were studied. We conducted a post-hoc analysis of the BRIDGE-II-Mix study. Variables were compared between patients with hypersomnia (SLEEP+) and with insomnia (SLEEP-) with standard bivariate tests. A stepwise backward logistic regression model was performed with SLEEP+ as dependent variable. A total of 2514 subjects were dichotomized into SLEEP+ (n = 423, 16.8%) and SLEEP- (n = 2091, 83.2%). SLEEP+ had significant higher rates of obese BMI (p < 0.001), BD diagnosis (p = 0.027), severe BD (p < 0.001), lifetime suicide attempts (p < 0.001), lower age at first depression (p = 0.004) than SLEEP-. Also, SLEEP+ had significantly poorer response to antidepressants (AD) such as (hypo)manic switches, AD resistance, affective lability, or irritability (all 0<0.005). Moreover, SLEEP+ had significantly higher rates of mixed-state specifiers than SLEEP- (all 0 < 0.006). A significant contribution to hypersomnia in our regression model was driven by metabolic-related features, such as 'current bulimia' (OR = 4.21) and 'overweight/obese BMI (OR = 1.42)'. Globally, hypersomnia is associated with poor outcome in acute depression. Hypersomnia is strongly associated with mixed features and bipolarity. Metabolic aspects could influence the expression of hypersomnia, worsening the overall clinical outcome. Along with commonly used screening tools, detection of hypersomnia has potential, costless discriminative validity in the differential diagnosis unipolar and bipolar depression

P3‐209: Impact of Biomarkers On Diagnostic Confidence in Clinical Assessment of Patients with Suspected Alzheimer's Disease and High Diagnostic Uncertainty: An EADC Study

Background: NIA-AA and IWG diagnostic criteria for Alzheimer's Disease (AD) include core structural, functional, and CSF biomarkers. The impact of core biomarkers in clinical settings is still unclear. This study aimed at measuring the impact of core biomarkers on the diagnostic confidence of uncertain AD cases in a routine memory clinic setting. // Methods: 356 patients with mild dementia (MMSE = 20) or Mild Cognitive Impairment possibly due to AD were recruited in 17 European Alzheimer's Disease Consortium (EADC) memory clinics. The following variables were collected: age; sex; MMSE; neuropsychological evaluation including long term memory, executive functions, language and visuospatial abilities. Core biomarkers were collected following local practices: Scheltens’s visual assessment of medial temporal atrophy (MTA) on MR scan; visual assessment of hypometabolism/hypoperfusion on FDG-PET/SPECT brain scan; CSF Aß1-42, tau and phospho-tau levels. At diagnostic workup completion, an estimate of confidence that cognitive complaints were due to AD was elicited from clinicians on a structured scale ranging from 0 to 100. Only cases with uncertain diagnoses (confidence between 15% and 85%) were retained for analysis. Generalized linear models were used to describe the relationship between the collected measures and the diagnostic confidence of AD. // Results: Neuropsychological assessment was carried out in almost all cases (98% of the cases). Medial temporal atrophy ratings were done in 40% of cases, assessment of cortical hypometabolism/hypoperfusion in 34%, and CSF Aß and tau levels in 26%. The markers that better explained the variability of diagnostic confidence were CSF Aß1-42 level (R2=0.46) and hypometabolism/hypoperfusion (R2=0.45), followed by CSF tau level (R2=0.35), MTA assessment (R2=0.32) and. All figures were highly significant, at p<<0.001. The diagnostic confidence variability due to neuropsychological tests for different domains was lower: MMSE (R2=0.29); long term memory (R2=0.23); executive functions (R2=0.05); language (R2=0.02); visuospatial abilities (R2=0.04) even if significant (p<0.01). // Conclusions: The use of core biomarkers in the clinical assessment of subjects with suspected AD and high diagnostic uncertainty is still limited. However, when assessed, these biomarkers show a higher impact on diagnostic confidence of AD than the most widespread clinical measures