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Objective: Evidence on the clinical and metabolic characterization of mixed features (MFs) in bipolar disorder (BD) is limited. We performed a cross-sectional study analyzing clinical and metabolic correlates of MFs in people with bipolar depression or mania/hypomania., Methods: We included people with BD consecutively admitted for inpatient treatment from May 2020 to July 2023 as part of the Northern Milan Area Cohort (NOMIAC) project. The SCID-5 was used to confirm the diagnosis and assess DSM-5 specifiers. Young Mania Rating Scale and Montgomery-Åsberg Depression Rating Scale were used to measure symptom severity. Information on socio-demographic, clinical, and metabolic conditions - including obesity, diabetes, hypertension, dyslipidemia, and hypothyroidism - were collected. Multiple logistic regression models were used to compare clinical and metabolic correlates between subjects with and without DSM-5 MFs., Results: We included 163 inpatients with BD (111 admitted for a manic/hypomanic episode and 52 for a major depressive episode), 39 of whom with MFs. The overall logistic regression model showed that MFs were associated with anxious distress (z = 2.44; p = 0.015) and obesity (z = 2.39; p = 0.017), also being less frequent among moderately/markedly ill people as compared with those borderline/mildly ill (z = -2.71; p = 0.007). Additional analyses corroborated the association between MFs and these characteristics in people with a depressive episode, though not in those with mania/hypomania., Conclusion: Notwithstanding some limitations, our study provides additional insight into the characterization of individuals with MFs, highlighting that anxious distress and symptom severity, along with obesity, may represent core features helpful for the assessment and management of MFs in BD., Competing Interests: Declaration of competing interest The authors have no competing interests to report., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Schizophrenia spectrum disorders (SSDs) are associated with immune-inflammatory activation. Recently, complete blood count (CBC)-based inflammation indexes such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR) have emerged as reproducible and cost-effective inflammation markers in mental disorders. In this study, we aimed at investigating the relationship of NLR, MLR, and PLR with symptom severity in people with SSDs, testing interactions with relevant clinical variables., Methods: We included inpatients with SSDs aged 18-65 consecutively hospitalized from May 2020 to March 2024. Socio-demographic and clinical data were recorded. CBC-based ratios were estimated from routinely collected blood samples. Structural equation modelling (SEM) was performed to test relationships involving symptom severity constructs and CBC-based ratios, accounting for substance use disorder, antipsychotic treatment, and obesity., Results: Two hundred sixty-six participants met inclusion criteria. The SEM analysis uncovered a significant relationship of MLR with positive (coeff.: 0.19, p=0.048) and negative (coeff.: 0.27, p=0.004) symptoms, also showing a significant link of substance use disorder and antipsychotic treatment with symptom severity as well as of antipsychotic treatment with obesity., Conclusions: Notwithstanding the cross-sectional design and the somewhat limited sample representativeness, this study showed a significant relationship between the MLR - but not the NLR or the PLR - and the severity of both positive and negative symptoms, testing at the same time the interactions with other clinical variables. Considering the insufficiency and inconsistency of data in this field, further research is needed to validate our findings and elucidate the underlying mechanisms driving the observed relationships between the MLR and SSD symptoms., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The role of anterior pituitary hormones - i.e., adrenocorticotropic hormone (ACTH), luteinizing and follicle stimulating hormones (LH and FSH), growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) - in early schizophrenia and psychoses unclear. We thus performed a systematic review and meta-analysis on the blood concentrations of ACTH, LH and FSH, GH, PRL, and TSH in drug-naïve people with first-episode psychosis (FEP) as compared with healthy controls., Methods: We searched Embase, MEDLINE, and PsycInfo for articles indexed until September 2022. Data quality was appraised. Random-effects meta-analyses were carried out, generating pooled standardized mean differences (SMDs). Between-study heterogeneity was estimated using the I 2 statistic. Sensitivity and meta-regression analyses were performed., Results: Twenty-six studies were included. Drug-naïve people with FEP, compared to healthy subjects, had higher blood concentrations of ACTH (k = 7; N = 548; SMD = 0.62; 95%CI: 0.29 to 0.94; p < 0.001; I 2 = 60.9%) and PRL (k = 17; N = 1757; SMD = 0.85; 95%CI: 0.56 to 1.14; p < 0.001; I 2 = 85.5%) as well as lower levels of TSH (k = 6; N = 677; SMD = -0.34; 95%CI: -0.54 to -0.14; p = 0.001; I 2 = 29.1%). Meta-regressions did not show any moderating effect of age (p = 0.78), sex (p = 0.21), or symptom severity (p = 0.87) on PRL concentrations in drug-naïve FEP. Available data were not sufficient to perform meta-analyses on FSH, LH, and GH., Conclusions: Drug-naïve people with FEP have altered ACTH, PRL, and TSH blood concentrations, supporting the hypothesis that an abnormal anterior pituitary hormone secretion may be involved in the onset of schizophrenia and psychoses. Further research is needed to elucidate the role of pituitary hormones in FEP., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The brain-derived neurotrophic factor (BDNF) has received considerable attention as a potential biomarker of major depressive disorder (MDD) and antidepressant response. We conducted an overview of meta-analyses investigating the relationship of BDNF with MDD, related clinical features, and antidepressant treatment. Based on a systematic screening on main electronic databases, 11 systematic reviews with meta-analyses were included. Available evidence suggests that people with MDD have peripheral and central BDNF levels lower than non-depressed individuals. A negative correlation between blood BDNF and symptom severity emerged, while no association with suicidality was detected. Moreover, an increase in blood BDNF levels after antidepressant treatment, proportional to symptom improvement, was reported. BDNF levels seem to be increased in both treatment responders and remitters, remaining stable in non-responders. Conversely, no variations of BDNF concentrations after non-pharmacological interventions (electroconvulsive therapy, repetitive transcranial magnetic stimulation, and physical activity) were found. The findings of this overview appear consistent with the neurotrophic hypothesis of depression, suggesting that BDNF may play a role in both MDD pathophysiology and pharmacological treatment response., Competing Interests: Declarations of interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Pteridines, such as neopterin, biopterin, and tetrahydrobiopterin (BH 4 ), may be involved in depression pathophysiology owing to their links to immune-inflammatory response, oxidative and nitrosative stress, and monoaminergic transmission. Nonetheless, studies assessing pteridines in depression are inconsistent. We conducted a systematic review and meta-analysis of observational studies comparing blood pteridine concentrations between subjects with depression and healthy controls (HCs)., Methods: We searched Embase, MEDLINE, and PsycInfo for articles indexed through November 2021. Study quality was appraised, evaluating age and gender comparability between groups, sample representativeness, and methods to assess depression. Random-effects meta-analyses were carried out, generating pooled standardized mean differences (SMDs). Heterogeneity across studies was estimated using the I 2 statistic., Results: Twenty-four studies, involving 3075 subjects, were included. Individuals with depression showed blood neopterin concentrations higher than HCs (k = 19; SMD = 0.36; p < 0.001) with moderate heterogeneity across studies (I 2  = 58.2%). No moderating role of age, gender, or type of blood sample was found. Sensitivity analyses showed no impact of inconsistency and quality of studies on findings. Neopterin concentrations were higher among individuals with major depressive disorder compared to HCs (SMD = 0.44; p < 0.001). This held true also when considering only drug-free subjects (SMD = 0.68; p = 0.003). No differences in biopterin concentrations were found between subjects with depression and HCs (k = 5; SMD = -0.35; p = 0.086), though this result was limited by inconsistency of findings (I 2  = 77.9%) and quality of studies. Finally, no sufficient data were available for a meta-analysis on BH 4 ., Conclusions: As a whole, our work partly supports the hypothesis of an imbalance of pteridine metabolism in depression., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There is accumulating evidence that individuals with schizophrenia show altered levels of thyroid hormones. However, a qualitative and quantitative synthesis of findings in this field has not been performed so far. Therefore, we aimed to perform a systematic review and meta-analysis of studies investigating the levels of thyroid-stimulating hormone (TSH), free thyroxine (fT4), total thyroxine (tT4), free triiodothyronine (fT3) and total triiodothyronine (tT3) in multiple-episode schizophrenia (MES) and first-episode psychosis (FEP). Electronic databases were searched from their inception until 30th May 2020 by two independent reviewers. Random-effects meta-analyses and meta-regression analyses were performed. Altogether, 19 studies were included. Persons with FEP had significantly lower TSH levels (5 studies, g = -0.26, 95%CI: -0.47 to -0.06, p = 0.013, I 2  = 21.3%), higher fT4 levels (3 studies, g = 0.58, 95%CI: 0.15-1.01, p = 0.008, I 2  = 64.6%) and lower tT3 levels (2 studies, g = -0.60, 95%CI: -0.82 to -0.37, p < 0.001, I 2  = 0%) compared to controls. Elevated TSH levels were found in persons with MES (13 studies, g = 0.20, 95%CI: 0.02-0.39, p = 0.031, I 2  = 50.0%). Our findings imply that the levels of TSH might be decreased in persons with FEP and increased in those with MES. Other alterations need to be confirmed by additional studies. These findings imply the need to monitor the levels of TSH and thyroid hormones from the onset of psychosis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has had a severe psychosocial impact on healthcare workers (HCWs). This systematic review and meta-analysis aimed at evaluating the association between individual features and depressive symptoms reported by HCWs during the pandemic. We searched Medline, Embase, and PsycInfo up to 23 June 2020. We included cross-sectional studies testing the association between individual correlates and depressive symptoms in HCWs during the SARS-CoV-2 outbreak. Fourteen studies met inclusion criteria, involving 14,173 HCWs (3,070 with depressive symptoms). Women (OR = 1.50; 95 %CI: 1.28-1.76; I 2 = 40.0 %), individuals with suspected/confirmed COVID-19 (OR = 2.10; 95 %CI: 1.64-2.69; I 2 = 0 %), and those with an infected family member or friend (OR = 1.67; 95 %CI: 1.37-2.04; I 2 = 0%) were more likely to report depressive features, which, instead, were less frequent among doctors (compared with nurses) (OR = 0.80; 95 %CI: 0.66-0.98; I 2 = 48.2 %) and HCWs who felt adequately protected (OR = 0.48; 95 %CI: 0.32-0.72; I 2 = 36.3 %). Our study provided timely evidence on the correlates of depressive symptoms among HCWs during the pandemic. Early screening is crucial to develop tailored health interventions, redesigning the response to COVID-19., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Several drugs previously tested in clinical trials and approved for different indications have been repurposed for bipolar disorder. We carried out a systematic meta-review of meta-analyses of randomized placebo-controlled trials investigating repurposed drugs as adjunctive treatments for mania and bipolar depression. We performed a critical appraisal using 'A MeaSurement Tool to Assess systematic Reviews' Version 2 (AMSTAR 2). We synthesized results on efficacy, tolerability, and safety, assessing evidence quality according to the 'Grading of Recommendations, Assessment, Development and Evaluations' (GRADE) approach. Our systematic search identified nine eligible studies investigating 12 drugs, four for mania and eight for bipolar depression. The quality of reporting was heterogeneous according to AMSTAR 2. In mania, allopurinol (for symptoms reduction and remission at 4-8 weeks) and tamoxifen (for response and symptoms reduction at 4-6 weeks) showed higher efficacy than placebo, with low and very low quality of evidence, respectively. Concerning bipolar depression, modafinil/armodafinil (for response, remission, and symptoms reduction at 6-8 weeks) and pramipexole (for response and symptoms reduction at 6 weeks) were superior to placebo, despite the low quality of evidence. Results on the efficacy of celecoxib and N-acetylcysteine were of low quality and limited to certain outcomes. Overall, the lack of evidence of high and moderate quality does not allow us to draw firm conclusions on the clinical utility of repurposed drugs as adjunctive treatments for mania and bipolar depression, highlighting the need for additional research., (Copyright © 2021 Elsevier Ltd. All rights reserved.)