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Abstract Background Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium’s clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations. Content This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors’ preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections. Conclusions Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium’s ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately.

Abstract Background Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

BackgroundShared biological factors may play a role in both the cognitive deficits and the increased prevalence of metabolic syndrome observed in individuals with Schizophrenia (SCZ). These factors could entail disturbances in tryptophan (Trp) to both melatonin (MLT) and kynurenine (Kyn) metabolic pathways, as well as inflammation and alterations in the gut microbiome composition.MethodsThe present research project aims to investigate this hypothesis by recruiting 170 SCZ patients from two different recruitment sites, assessing their cognitive functions and screening for the presence of metabolic syndrome. Additionally, we plan to assess the impact of a 3-month cognitive remediation therapy on 30 of these patients. We will analyze clinical data alongside serum biomarkers and gene expression related to the Trp- to MLT and Kyn metabolic pathways, markers of inflammatory and composition of the gut microbiome. The association between Trp-MLT-Kyn levels, expression levels of selected genes, inflammatory markers and clinical phenotypes will be analyses in the context of general linear models.DiscussionThis project has the potential to identify some typical SCZ symptomatic clusters that will be more stringently associated with variations in the Trp-MLT-Kyn/inflammatory system and with a better response to cognitive remediation therapy. Moreover, in a future perspective, it may highlight a group of patients who may benefit from a pharmacological treatment aiming at reinstating the physiological Trp to MLT and Kyn system. Therefore, it has the potential to move research toward a personalized approach for SCZ management.

BackgroundAffective temperament, defined as the fundamental predisposition from which normal affective states originate or as the constitutional core of personality, play a crucial role in mood disorders, particularly bipolar disorders. Understanding the relationship between temperaments, treatment adherence, and self-care is crucial for effective management and improved clinical results.ObjectivesThis study aims to (1) assess the correlation between affective temperaments and treatment adherence, (2) investigate the relationship between affective temperaments and self-care abilities, (3) identify predictors of treatment adherence, and (4) explore the moderating effect of self-care on the relationship between treatment adherence and depressive temperament in individuals with bipolar disorder.MethodsA cross-sectional study was conducted with 231 individuals diagnosed with bipolar disorder (BD) type I (N=160) and type II (N=71). The participants were evaluated using the following psychometric tools: Temperament Evaluation of Memphis, Pisa, and San Diego (TEMPS) to assess affective temperaments, Personal and Social Performance Scale (PSP) to evaluate social functioning and self-care abilities, and Morisky Medication Adherence Scale (MMAS) to measure treatment adherence. The study involved statistical analyses to examine correlations, identify predictors, and explore moderating effects.ResultsThe findings revealed significant correlations between affective temperaments and both treatment adherence and self-care abilities. Specifically, hyperthymic temperament was positively associated with higher treatment adherence, whereas cyclothymic and depressive temperaments were linked to lower adherence. Self-care abilities were found to mediate the relationship between depressive temperament and treatment adherence, suggesting that improved self-care can enhance adherence in individuals with depressive temperament.ConclusionsAffective temperaments significantly influence treatment adherence and self-care abilities in individuals with bipolar disorder. The mediating role of self-care highlights the importance of developing targeted interventions to improve self-care practices, thereby enhancing treatment adherence and overall well-being. Personalized treatment strategies based on temperament assessments could lead to better clinical outcomes and quality of life for individuals with bipolar disorder.

Assisted reproductive technology (ART) is an emerging field in medicine that incorporates complex procedures and has profound ethical, moral, social, religious, and economic implications not just for the individuals who have access to this method but also for society. In this narrative review, we summarise multiple aspects of ART procedures and the possible consequences on the mother and newborn. Moreover, we provide an overview of the possible long-term consequences of ART procedures on the health of newborns, although longitudinal evidence is particularly scant. Users should be informed that ART procedures are not risk-free to prepare them for the possible negative outcomes that may occur in the perinatal period or even in childhood and adulthood. Indeed, risk estimates point to increased liability for major nonchromosomal birth defects; cardiovascular, musculoskeletal, and urogenital (in male newborns) defects; and any other birth defects. Less certainty is present for the risk of neuropsychiatric sequelae in children conceived through ART. Thus, its application should be accompanied by adequate counselling and psychological support, possibly integrated into specific multidisciplinary clinical programmes.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Abstract Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Schizophrenia (SCZ) and schizoaffective disorder (SAD) are severe and complex psychiatric disorders whose liability threshold is modulated by the interplay of biological, mainly genetic, and environmental factors. Consistent evidence has pointed to the role of serum brain-derived neurotrophic factor (BDNF) as a plausible illness biomarker in SCZ spectrum disorders. There is no consensus, however, on the temporal trajectory of this decline. Here, we present a secondary analysis of the Longitudinal Assessment of BDNF in Sardinian Psychotic patients (LABSP) study, focusing on the impact of antipsychotic therapy, particularly long-acting injectable (LAI), on the longitudinal trajectory of serum BDNF levels and analyzing the effect of BDNF genetic variants. LABSP patients were assessed every 6 months for a series of measures, including the assessment of BDNF serum levels over 24 months. Blood samples for each patient were taken at the same time of the day (between 8:00 and 10:00 a.m.). BDNF serum levels were determined using the BDNF ELISA Kit. Four tag single nucleotide polymorphisms (SNPs) within the BDNF gene (rs1519480, rs11030104, rs6265 [Val66Met], and rs7934165) were selected using standard parameters and analyzed with polymerase chain reaction (PCR). Mixed-effects linear regression models (MLRMs) were used to analyze longitudinal data. Twenty-four patients out of 105 LABSP (22.9%) patients received therapy with LAI. Analysis with MLRM showed a significant effect of LAI treatment associated with increasing serum BDNF levels (Z=2.2, p=0.02). However, oral antipsychotics did not significantly impact the longitudinal trajectory of serum BDNF levels (Z=0.15, p=0.9). There was no moderating effect of variants within the BDNF gene on the identified association. We identified a significant longitudinal increase in serum BDNF in SCZ and SAD patients treated with LAI antipsychotic therapy. The significant impact of this preparation of antipsychotic treatment on serum BDNF, despite the limited sample size, points to a moderate to large magnitude of effect that should be investigated in future prospective studies.

Major depressive disorder (MDD) is the most common psychiatric disease worldwide with a huge socio-economic impact. Pharmacotherapy represents the most common option among the first-line treatment choice; however, only about one third of patients respond to the first trial and about 30% are classified as treatment-resistant depression (TRD). TRD is associated with specific clinical features and genetic/gene expression signatures. To date, single sets of markers have shown limited power in response prediction. Here we describe the methodology of the PROMPT project that aims at the development of a precision medicine algorithm that would help early detection of non-responder patients, who might be more prone to later develop TRD. To address this, the project will be organized in 2 phases. Phase 1 will involve 300 patients with MDD already recruited, comprising 150 TRD and 150 responders, considered as extremes phenotypes of response. A deep clinical stratification will be performed for all patients; moreover, a genomic, transcriptomic and miRNomic profiling will be conducted. The data generated will be exploited to develop an innovative algorithm integrating clinical, omics and sex-related data, in order to predict treatment response and TRD development. In phase 2, a new naturalistic cohort of 300 MDD patients will be recruited to assess, under real-world conditions, the capability of the algorithm to correctly predict the treatment outcomes. Moreover, in this phase we will investigate shared decision making (SDM) in the context of pharmacogenetic testing and evaluate various needs and perspectives of different stakeholders toward the use of predictive tools for MDD treatment to foster active participation and patients’ empowerment. This project represents a proof-of-concept study. The obtained results will provide information about the feasibility and usefulness of the proposed approach, with the perspective of designing future clinical trials in which algorithms could be tested as a predictive tool to drive decision making by clinicians, enabling a better prevention and management of MDD resistance.

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.

Abstract Several pieces of evidence show that gut microbiota can impact psychiatric disorders. However, no mechanism behind the relationship has been identified. Host genetics and their diets have a significant impact on the gut microbiota. More advanced studies are needed to find the mechanism and develop new therapeutic strategies.

Abstract Background Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking. Methods Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment. Results In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed. Conclusions Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment.

Background and Objectives: Traumatic events adversely affect the clinical course of obsessive–compulsive disorder (OCD). Our study explores the correlation between prolonged interpersonal trauma and the severity of symptoms related to OCD and anxiety disorders. Materials and Methods: The study follows a cross-sectional and observational design, employing the International Trauma Questionnaire (ITQ) to examine areas linked to interpersonal trauma, the Hamilton Anxiety Rating Scale (HAM-A), and the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) to assess anxious and obsessive–compulsive symptoms, respectively. Descriptive analysis, analysis of variance (ANOVA), and logistic regression analyses were conducted. Results: We recruited 107 OCD-diagnosed patients, categorizing them into subgroups based on the presence or absence of complex post-traumatic stress disorder (cPTSD). The ANOVA revealed statistically significant differences between the two groups in the onset age of OCD (p = 0.083), psychiatric familial history (p = 0.023), HAM-A, and Y-BOCS (p < 0.0001). Logistic regression indicated a statistically significant association between the presence of cPTSD and Y-BOCS scores (p < 0.0001). Conclusions: The coexistence of cPTSD in OCD exacerbates obsessive–compulsive symptoms and increases the burden of anxiety. Further advancements in this field are crucial for mitigating the impact of early trauma on the trajectory of OCD and associated anxious symptoms.

Bipolar disorder (BD) is a highly disabling condition with a chronic and relapsing nature. Despite the substantial socioeconomic burden associated with BD, there are still significant research gaps in risk stratification, diagnostic accuracy, and treatment selection, all key components of precision psychiatry. One possible strategy to increase the validity of precision psychiatry approaches in BD is to increase our knowledge of disorder-associated gut microbiota perturbations. To this end, we systematically reviewed the evidence on gut microbiota alterations in relation to precision psychiatry approaches on BD. We performed a systematic review on PubMed/MEDLINE and Web of Science to identify original articles investigating the possible clinical applications of microbiota analyses for pragmatic precision psychiatry in BD. A pearl growing strategy was employed to enlarge the scope of this review. The primary search strategy yielded one paper and an additional one was identified through reference tracking. The included studies were observational, with one study of good quality. The identified results justify the efforts devolved in this area of research and underscore the need to expand these investigations through additional larger and properly designed studies.

Abstract Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

Abstract Background Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p

Abstract Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p

Obsessive–compulsive disorder (OCD) represents a frequent and highly disabling mental disorder. Past attempts to characterize different disease subgroups focused on the time of onset (late vs. early onset), presence of insight (poor insight), and post-infectious forms (pediatric acute-onset neuropsychiatric syndrome, PANS). Each subgroup may be associated with a differing impact on cognition, functioning, sleep quality, and treatment response profile. Certain lines of evidence suggest brain-derived neurotrophic factor (BDNF) levels may differ between individuals living with OCD as compared with controls, but there is a lack of evidence on the variation of BDNF levels in OCD subgroups. Lastly, the potential of assessing inflammatory states, electroencephalogram, and polysomnography to characterize these subtypes has been hardly explored. Estimates of drug-resistance rates indicate that 20% and up to 65% of affected adults and up to 35% of the pediatric population may not benefit from pharmacological treatments. At least part of the variability in treatment response could depend on the underlying biological heterogeneity. In the present project, we aim to increase the accuracy in characterizing the phenotypical and biological signature for the different OCD subtypes through clinical, cognitive, and sleep markers, along with other possible markers that may be biologically plausible.

Background and PurposeComorbidity between diabetes and depression, and diabetes and eating disorders (ED) conveys significant diagnostic, clinical and therapeutic implications. The present study was conducted on a sample of adult outpatients affected by Type 1 Diabetes (T1DM) to assess lifetime prevalence of ED; current prevalence of depression and Disturbed Eating Behaviors (DEB) and their impact on glycemic control. We hypothesized that patients with depression would have higher rates of lifetime ED and current DEB. We hypothesized a significant and independent association between DEB and the prevalence of depression.Materials and MethodsThe study was carried out using a cross-sectional design in a sample of 172 diabetic patients with T1DM aged from 17 to 55 years. Lifetime prevalence of ED according to DSM-5 criteria was assessed by means of the Module H modified of the Structured Clinical Interview for DSM-IV Axis I Disorder (SCID-I). The following questionnaires were used: Beck Depression Inventory–IA version (BDI-IA) and Diabetes Eating Problems Survey—Revised (DEPS-R), to assess respectively the current presence of depression and DEB. Socio-demographic, clinical, and laboratory data were also collected.ResultsHigh rates of depression (35.5%) and DEB (19.2%) were observed in our sample of 172 adult outpatients with T1DM. Lifetime history of ED was present in 20.9% of the sample and was more frequently diagnosed in patients with current depression (34.4% vs. 13.9%, p = 0.002). Higher levels of DEB at DEPS-R significantly increased the odds of depression (adjOR: 1.09; 95% CI: 1.03–1.15; p = 0.003). The presence of DEB was associated with poor glycemic control. On the other hand, no association was found between depression and metabolic compensation.ConclusionAdult patients with T1DM and depression should be screened for ED and DEB. Treating DEB could positively impact both mood and glycemic control in this population. Further studies should be carried out on a larger patient population using a longitudinal design and an accurate method of evaluation to explore the complex relationship between diabetes, depression, ED, and DEB. Future research should investigate treatment strategies for DEB in T1DM patients and their impact on both psychopathological and metabolic outcomes.

Background and Objectives: Alterations in hot cognition and in the tryptophan metabolism through serotonin (5-HT) and kynurenine (KYN) pathways have been associated with an increased risk of suicidal behavior. Here, we aim at probing the association between Stroop test performances and tryptophan pathway components in a sample of individuals with bipolar disorder (BD). Materials and Methods: We explored the association between the Emotion Inhibition Subtask (EIS) performances of the Brief Assessment of Cognition for Affective Disorders (BAC-A) and plasmatic levels of 5-hydroxytriptophan (5-HTP), 5-HT, KYN, 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KYNA) among subjects reporting lifetime suicide ideation (LSI) vs. non-LSI and subjects reporting lifetime suicide attempts (LSA) vs. non-LSA. Results: In a sample of 45 subjects with BD, we found a statistically significant different performance for LSA vs. non-LSA in the color naming (CN) and neutral words (NW) EIS subtasks. There was a significant association between CN performances and plasma 5-HTP levels among LSI and LSA subjects but not among non-LSI or non-LSA. Conclusions: In our sample, patients with LSA and LSI presented lower performances on some EIS subtasks compared to non-LSA and non-LSI. Moreover, we found an inverse correlation between plasma 5-HTP concentration and some EIS performances in LSA and LSI but not among non-LSA or non-LSI. This may represent an interesting avenue for future studies probing this complex association.

Abstract Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

Abstract Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen’s kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [− 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

Abstract Background Since its introduction in modern medicine, naturalistic observations emerged about possible uses of lithium treatment for conditions different from recurring affective disorders, for which it is still a first-line treatment option. Some evidence about the antiviral properties of lithium began in the early 1970s, when some reports found a reduction of labial-herpetic recurrences. The present review aims to present most of the pre-clinical and clinical evidence about lithium’s ability to inhibit DNA and RNA viruses, including Coronaviridae, as well as the possible pathways and mechanisms involved in such antiviral activity. Main body Despite a broad number of in vitro studies, the rationale for the antiviral activity of lithium failed to translate into methodologically sound clinical studies demonstrating its antiviral efficacy. In addition, the tolerability of lithium as an antiviral agent should be addressed. In fact, treatment with lithium requires continuous monitoring of its serum levels in order to prevent acute toxicity and long-term side effects, most notably affecting the kidney and thyroid. Yet lithium reaches heterogeneous but bioequivalent concentrations in different tissues, and the anatomical compartment of the viral infection might underpin a different, lower need for tolerability concerns which need to be addressed. Conclusions Lithium presents a clear antiviral activity demonstrated at preclinical level, but that remains to be confirmed in clinical settings. In addition, the pleiotropic mechanisms of action of lithium may provide an insight for its possible use as antiviral agent targeting specific pathways.

Abstract Background and hypothesis Schizophrenia spectrum disorders are among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Furthermore, we examined whether genetic variation within the BDNF gene could moderate these relationships. Study design Every 6 months, 105 patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and social measures. We performed a targeted analysis of four tag single nucleotide polymorphisms within the BDNF gene that were selected and analyzed using polymerase chain reaction. Longitudinal data were analyzed using mixed-effects linear regression models. Study results We observed a declining longitudinal trajectory of BDNF levels in psychotic patients in general, and in relation to the severity of depressive and negative symptoms. BDNF serum levels also declined in patients scoring lower in cognitive measures such as attention and speed of information processing and verbal fluency. The rs7934165 polymorphism moderated the significant association between verbal fluency and BDNF levels. Conclusions These findings in patients from real-world settings suggest a plausible role of peripheral BDNF levels as a marker of illness burden in schizophrenia spectrum disorders.

The persistence of depressive morbidity is frequent in bipolar disorder, and the pharmacological management of this symptomatology often lacks effectiveness. This systematic review aimed to summarize the results of the naturalistic observational studies on the pharmacological treatment of bipolar depression published through April 2022. The certainty of evidence was evaluated according to the GRADE approach. In sum, 16 studies on anticonvulsants, 20 on atypical antipsychotics, 2 on lithium, 28 on antidepressants, and 9 on other compounds were found. Lamotrigine, quetiapine, aripiprazole, and ketamine were the most investigated compounds. Overall, the results support the recommendations regarding the effectiveness of lamotrigine and quetiapine. In contrast to the current recommendations, aripiprazole was shown to be effective and generally well tolerated. Additionally, SSRIs were shown to be effective, but, since they were associated with a possibly higher switch risk, they should be used as an adjunctive therapy to mood stabilizers. Lithium was only studied in two trials but was shown to be effective, although the serum concentrations levels were not associated with clinical response. Finally, ketamine showed divergent response rates with a low certainty of evidence and, so far, unclear long-term effects. Heterogeneity in diagnosis, sample sizes, study designs, reporting of bias, and side effects limited the possibility of a head-to-head comparison.

Abstract Background Bipolar disorder (BD) is characterized by recurrent episodes of depression and mania/hypomania alternating with intervals of well-being. The neurobiological underpinnings of BD are still veiled although there is evidence pointing to a malfunction of the circadian clock system that is regulated by the neuromodulator melatonin (MLT). Small sample size studies in BD patients have shown that changes in the levels of MLT are associated with shifts in illness status. Moreover, mood stabilizers (including lithium and valproic acid) influence the MLT system. Of interest, MLT also modulates intestinal microbiota, and recent work suggests an important role of microbiota alterations in neuropsychiatric disorders, including BD. This study is designed to explore whether the possible patterns of associations between changes in the levels of MLT and its precursors and BD mood phases are modulated by variants within the genes encoding for the elements of the MLT system and/or by the microbiota composition. Methods We will conduct a 2-year follow-up study in 50 BD patients during the three different mood phases of the disease. For each phase, we will perform a blood withdrawal for the analysis of MLT levels and of variants of the genes related to the MLT pathway between 8 and 10 a.m. after an overnight fasting, a stool specimen collection for the analysis of microbiota composition, and a detailed psychometric assessment for depression, mania, impulsivity and cognitive abilities. We will also recruit 50 healthy age-matched controls in whom we will perform a blood withdrawal between 8 and 10 a.m. after an overnight fasting, a stool specimen collection, and a psychometric assessment to exclude the presence of psychiatric disorders. Discussion In this cross sectional (case–control vs. BD comparisons) and longitudinal (24 months) study, we expect to clarify the link between the MLT system, microbiota and BD psychopathology. We expect to identify some typical BD symptomatic clusters that will be more strictly associated with variations in the MLT system. In a personalized medicine perspective, this subgroup of BD patients may benefit from a pharmacological therapy targeting the MLT system. Trial registration This study protocol was approved by the Ethics Committee of the University Hospital Agency of Cagliari (PG/2019/6277)

Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses.

The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine (KYN) pathways in 44 patients with BD and 45 healthy controls. We assessed whether variants that were differentially associated with metabolite levels based on the diagnostic status improved the prediction accuracy of BD using penalized regression approaches. We identified several genetic variants that were significantly associated with metabolites (5-HT, 5-hydroxytryptophan (5-HTP), TRP, and quinolinic acid (QA) or metabolite ratios (5-HTP/TRP and KYN/TRP) and for which the diagnostic status exerted a significant effect. The inclusion of genetic variants led to increased accuracy in the prediction of the BD diagnostic status. Specifically, we obtained an accuracy of 0.77 using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictors retained as informative in this model included body mass index (BMI), the levels of TRP, QA, and 5-HT, the 5-HTP/TRP ratio, and genetic variants associated with the levels of QA (rs6827515, rs715692, rs425094, rs4645874, and rs77048355) and TRP (rs292212) or the 5-HTP/TRP ratio (rs7902231). In conclusion, our study identified statistically significant associations between metabolites of TRP via the 5-HT and KYN pathways and genetic variants at the genome-wide level. The discriminative performance of penalized regression models incorporating clinical, genetic, and metabolic predictors warrants a follow-up analysis of this panel of determinants.

Abstract Background Lithium has been used clinically for 70 years, mainly to treat bipolar disorder. Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries, encouraging this update about its safe clinical use. We conducted a nonsystematic review of recent research reports and developed consensus among international experts on the use of lithium to treat major mood disorders, aiming for a simple but authoritative guide for patients and prescribers. Main text We summarized recommendations concerning safe clinical use of lithium salts to treat major mood disorders, including indications, dosing, clinical monitoring, adverse effects and use in specific circumstances including during pregnancy and for the elderly. Conclusions Lithium continues as the standard and most extensively evaluated treatment for bipolar disorder, especially for long-term prophylaxis.

Severe mental disorders (SMD) are highly prevalent psychiatric conditions exerting an enormous toll on society. Therefore, prevention of SMD has received enormous attention in the last two decades. Preventative approaches are based on the knowledge and detailed characterization of the developmental stages of SMD and on risk prediction. One relevant biological component, so far neglected in high risk research, is microbiota. The human microbiota consists in the ensemble of microbes, including viruses, bacteria, and eukaryotes, that inhabit several ecological niches of the organism. Due to its demonstrated role in modulating illness and health, as well in influencing behavior, much interest has focused on the characterization of the microbiota inhabiting the gut. Several studies in animal models have shown the early modifications in the gut microbiota might impact on neurodevelopment and the onset of deficits in social behavior corresponding to distinct neurosignaling alterations. However, despite this evidence, only one study investigated the effect of altered microbiome and risk of developing mental disorders in humans, showing that individuals at risk for SMD had significantly different global microbiome composition than healthy controls. We then offer a developmental perspective and provided mechanistic insights on how changes in the microbiota could influence the risk of SMD. We suggest that the analysis of microbiota should be included in the comprehensive assessment generally performed in populations at high risk for SMD as it can inform predictive models and ultimately preventative strategies.

Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine – glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.

Treatment of psychiatric disorders relies heavily on a trial and error approach, often prolonging the time required to obtain symptomatic improvements. The identification of reliable predictors of treatment response is instrumental to enact an individualized approach. Alexithymia represents a personality trait reflecting an intrinsic difficulty in recognizing the emotional components of subjective experiences. Thus, its modulating role on treatment outcome has gathered substantial attention during the past years. In the present paper, we aimed at exploring the available evidence for Alexithymia role in influencing the treatment outcome on a wide range of psychiatric conditions by means of a systematic review.Data SourceWe performed a systematic review in Medline and Scopus, augmented by tracking the reference list of the pertinent articles.Inclusion CriteriaTo be included in this review, research studies had to assess alexithymia impact on a treatment intervention delivered to manage a primary psychiatric disorder.Study Evaluation and Data SynthesisAfter removing duplicates, titles were screened first, then abstracts, and last full texts were read, eventually leading to the inclusion or exclusion of the papers according to the criteria established before the online search. Then results of the search were downloaded in.xml format and uploaded in Rayyan, a free web software, that helps expedite the initial screening of abstracts and titles using a process of semi-automation while incorporating a high level of usability. After uploading, screening of the literature was performed in blind by two investigators. Disagreement between reviewers was resolved by joint discussion with a third senior investigator. The quality of evidence was assessed using the Newcastle Ottawa Scale. Thereafter, the data considered relevant was extracted and synthetized in this paper.ResultsOur search yielded a total of 30 articles dealing with a wide range of psychiatric conditions and exploring both pharmacological and psychotherapeutic interventions. Several lines of evidence suggest a complex role for alexithymia in influencing the psychiatric treatment outcome, further underscoring the need for additional research in this area to better address the existing knowledge gaps.

Background and Objectives: Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia. Despite its superior efficacy profile as compared with other antipsychotics, clozapine remains underutilized. Clozapine monitoring systems clearly describe the proposed management of clozapine-induced neutropenia; however, no specific mention is made of how to interpret neutrophilic leukocytosis, despite that being a relatively frequent finding. Prescribers unfamiliar with this molecule may misjudge its clinical significance, potentially leading to untimely treatment interruption. Here, we systematically review the literature on the risk of neutrophilic leukocytosis during clozapine treatment, and describe eight additional cases among our patient cohort. Materials and Methods: We performed a systematic review of the literature on PubMed and Embase using the PRISMA 2020 guidelines, and selected all original reports describing either (1) the prevalence of neutrophilic leukocytosis during clozapine treatment, or (2) the clinical significance of neutrophilic leukocytosis. We described eight additional cases of neutrophilic leukocytosis during clozapine treatment while attending an outpatient psychiatric clinic. Results: Our research ultimately yielded the selection of 13 articles included in this systematic review. The case series highlighted the presence of stable and clinically unremarkable neutrophilia during a follow-up ranging from one to ten years. Conclusions: Existing evidence indicates that leukocytosis associated with clozapine treatment can be considered as an asymptomatic and benign condition, suggesting that no change in clozapine treatment is needed upon its detection.

The gut microbiota is constituted by more than 40,000 bacterial species involved in key processes including high order brain functions. Altered composition of gut microbiota has been implicated in psychiatric disorders and in modulating the efficacy and safety of psychotropic medications. In this work we characterized the composition of the gut microbiota in 38 patients with schizophrenia (SCZ) and 20 healthy controls (HC), and tested if SCZ patients with different response to antipsychotics (18 patients with treatment resistant schizophrenia (TRS), and 20 responders (R)) had specific patterns of gut microbiota composition associated with different response to antipsychotics. Moreover, we also tested if patients treated with typical antipsychotics (n = 20) presented significant differences when compared to patients treated with atypical antipsychotics (n = 31). Our findings showed the presence of distinct composition of gut microbiota in SCZ versus HC, with several bacteria at the different taxonomic levels only present in either one group or the other. Similar findings were observed also depending on treatment response and exposure to diverse classes of antipsychotics. Our results suggest that composition of gut microbiota could constitute a biosignatures of SCZ and TRS.

Background and Objectives: Predominant polarity (PP) may be a useful course specifier in at least a significant proportion of patients with Bipolar Disorder (BD), being associated with several clinically relevant correlates. Emerging evidence suggests that the concept of PP might influence the selection of maintenance treatments, based on a drug polarity index (PI) which measures the greater antidepressive vs. antimanic preventive efficacy of mood stabilizers over long-term maintenance treatment. In this study, we aimed to validate the PI in a large sample of Italian BD patients with accurate longitudinal characterization of the clinical course, which ensured a robust definition of the PP. Materials and Methods: Our sample is comprised of 653 patients with BD, divided into groups based on the predominant polarity (manic/hypomanic predominant polarity—MPP, depressive predominant polarity—DPP and no predominant polarity). Subsequently we calculated the mean total polarity index for each group, and we compared the groups. Results: When we examined the mean PI of treatments prescribed to individuals with DPP, MPP and no predominant polarity, calculated using two different methods, we failed to find significant differences, with the exception of the PI calculated with the Popovic method and using the less stringent criterion for predominant polarity (PP50%). Conclusions: Future prospective studies are needed in order to determine whether the predominant polarity is indeed one clinical factor that might guide the clinician in choosing the right mood stabilizer for BD maintenance treatment.

Abstract Background Admixture analysis of age at onset (AAO) has helped delineating the clinical profile of early onset (EO) bipolar disorder (BD). However, there is scarce evidence comparing the distributional properties of AAO as well as the clinical features of EO BD type 1 (BD1) with EO BD type 2 (BD2). To this end, we studied 515 BD patients (224 BD1, 279 BD2, and 12 BD not otherwise specified [NOS]) diagnosed according to DSM-IV-TR criteria. Methods AAO was defined as the first reliably diagnosed hypo/manic or depressive episode according to diagnostic criteria. We used normal distribution mixture analysis to identify subgroups of patients according to AAO. Models were chosen according to the Schwarz’s Bayesian information criteria (BIC). Clinical correlates of EO were analysed using univariate tests and multivariate logistic regression models. Results A two normal components model best fitted the observed distribution of AAO in BD1 (BIC = −1599.3), BD2 (BIC = −2158.4), and in the whole sample (BIC = −3854.9). A higher number of EO BD2 patients had a depression-(hypo)mania-free interval (DMI) course, while a higher rate of (hypo)mania-depression-free interval (MDI) course was found in EO BD1. EO BD2 had also a higher rate of comorbidity with alcohol dependence compared to EO BD1. The latter finding was confirmed by multivariate logistic regression analysis. Conclusions In conclusion, both BD1 and BD2 had bimodal AAO distributions, but EO subgroups had a diagnostic-specific clinical delineation.

Abstract Background Concerns about potential adverse effects of long-term exposure to lithium as a mood-stabilizing treatment notably include altered renal function. However, the incidence of severe renal dysfunction; rate of decline over time; effects of lithium dose, serum concentration, and duration of treatment; relative effects of lithium exposure vs. aging; and contributions of sex and other factors all remain unclear. Methods Accordingly, we acquired data from 12 collaborating international sites and 312 bipolar disorder patients (6142 person-years, 2669 assays) treated with lithium carbonate for 8–48 (mean 18) years and aged 20–89 (mean 56) years. We evaluated changes of estimated glomerular filtration rate (eGFR) as well as serum creatinine, urea–nitrogen, and glucose concentrations, white blood cell count, and body-mass index, and tested associations of eGFR with selected factors, using standard bivariate contrasts and regression modeling. Results Overall, 29.5% of subjects experienced at least one low value of eGFR ( 55; risk of ≥2 low values was 18.1%; none experienced end-stage renal failure. eGFR declined by 0.71%/year of age and 0.92%/year of treatment, both by 19% more among women than men. Mean serum creatinine increased from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL, glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6 kg/m2. By multivariate regression, risk factors for declining eGFR ranked: longer lithium treatment, lower lithium dose, higher serum lithium concentration, older age, and medical comorbidity. Later low eGFR was also predicted by lower initial eGFR, and starting lithium at age ≥ 40 years. Limitations Control data for age-matched subjects not exposed to lithium were lacking. Conclusions Long-term lithium treatment was associated with gradual decline of renal functioning (eGFR) by about 30% more than that was associated with aging alone. Risk of subnormal eGFR was from 18.1% (≥2 low values) to 29.5% (≥1 low value), requiring about 30 years of exposure. Additional risk factors for low eGFR were higher serum lithium level, longer lithium treatment, lower initial eGFR, and medical comorbidity, as well as older age.

Abstract Background The purpose of the study was to evaluate in a sample of insulin-treated diabetic patients, with type 1 or type 2 diabetes, the psychometric characteristics of the Italian version of the DEPS-R scale, a diabetes-specific self-report questionnaire used to analyze disordered eating behaviors. Methods The study was performed on 211 consecutive insulin-treated diabetic patients attending two specialist centers. Lifetime prevalence of eating disorders (EDs) according to DSM-IV and DSM-5 criteria were assessed by means of the Module H of the Structured Clinical Interview for DSM IV Axis I Disorder and the Module H modified, according to DSM-5 criteria. The following questionnaires were administered: DEPS-R and the Eating Disorder Inventory – 3 (EDI-3). Test/retest reproducibility was assessed on a subgroup of 70 patients. The factorial structure, internal consistency, test-retest reliability and concurrent validity of DEPS-R were assessed. Results Overall, 21.8% of the sample met criteria for at least one DSM-5 diagnosis of ED. A “clinical risk” of ED was observed in 13.3% of the sample. Females displayed higher scores at DEPS-R, a higher percentage of at least one diagnosis of ED and a higher clinical risk for ED. A high level of reproducibility and homogeneity of the scale were revealed. A significant correlation was detected between DEPS-R and the 3 ED risk scales of EDI-3. Conclusions The data confirmed the overall reliability and validity of the scale. In view of the significance and implications of EDs in diabetic patients, it should be conducted a more extensive investigation of the phenomenon by means of evaluation instruments of demonstrated validity and reliability.

Abstract Objectives To present a new case of adverse cutaneous reaction during lithium treatment and to update the systematic review and meta-analysis of the incidence of this adverse reaction. Methods We conducted a systematic search (performed in September 2016) for peer-reviewed articles in English indexed in Medline (2011-present). Meta-analytical estimates were obtained using the “Metafor” package. Case presentation Ms. H., a 31-year-old Caucasian woman with BD1, was admitted to the inpatient unit for a full-blown psychotic episode and treated with carbamazepine 400 mg q.d., lithium carbonate 450 mg q.d., and risperidone 4 mg q.d. with clinical improvement. After 12 days from the start of psychopharmacological treatment, she manifested a cutaneous reaction that motivated the stop of carbamazepine treatment, as well as the increase in lithium carbonate dose (750 mg q.d.). Risperidone dose remained unvaried. Since the skin lesion persisted after 8 days from withdrawal of carbamazepine, the private practitioner stopped also lithium carbonate treatment (de-challenge), maintaining risperidone treatment. The cutaneous reaction resolved spontaneously after six days from withdrawal of lithium carbonate. Subsequently, the worsening of psychopathological conditions motivated a new admission during which lithium carbonate was reintroduced (16 days after its suspension) (re-challenge). On the following day, we observed an itching erythematous maculopapular rash involving the trunk, the four limbs, and the oral mucosa. Conclusions Our case of an erythematous maculopapular rash during lithium treatment was the first to present a challenge–de-challenge–re-challenge sequence that suggests causality. Although meta-analysis does not point to an increased rate of adverse skin reaction during lithium treatment, clinicians should not neglect to monitor cutaneous symptoms during lithium treatment.

Abstract Background Severe mental illness (SMI) has considerable excess morbidity and mortality, a proportion of which is explained by cardiovascular diseases, caused in part by antipsychotic (AP) induced QT-related arrhythmias and sudden death by Torsade de Point (TdP). The implementation of evidence-based recommendations for cardiac function monitoring might reduce the incidence of these AP-related adverse events. To investigate clinicians’ adherence to cardiac function monitoring before and after starting AP, we performed a retrospective assessment of 434 AP-treated SMI patients longitudinally followed-up for 5 years at an academic community mental health center. Methods We classified antipsychotics according to their risk of inducing QT-related arrhythmias and TdP (Center for Research on Therapeutics, University of Arizona). We used univariate tests and multinomial or binary logistic regression model for data analysis. Results Univariate and multinomial regression analysis showed that psychiatrists were more likely to perform pre-treatment electrocardiogram (ECG) and electrolyte testing with AP carrying higher cardiovascular risk, but not on the basis of AP pharmacological class. Univariate and binomial regression analysis showed that cardiac function parameters (ECG and electrolyte balance) were more frequently monitored during treatment with second generation AP than with first generation AP. Conclusions Our data show the presence of weaknesses in the cardiac function monitoring of AP-treated SMI patients, and might guide future interventions to tackle them.

Futurists have anticipated that novel autonomous technologies, embedded with machine learning (ML), will substantially influence healthcare. ML is focused on making predictions as accurate as possible, while traditional statistical models are aimed at inferring relationships between variables. The benefits of ML comprise flexibility and scalability compared with conventional statistical approaches, which makes it deployable for several tasks, such as diagnosis and classification, and survival predictions. However, much of ML-based analysis remains scattered, lacking a cohesive structure. There is a need to evaluate and compare the performance of well-developed conventional statistical methods and ML on patient outcomes, such as survival, response to treatment, and patient-reported outcomes (PROs). In this article, we compare the usefulness and limitations of traditional statistical methods and ML, when applied to the medical field. Traditional statistical methods seem to be more useful when the number of cases largely exceeds the number of variables under study and a priori knowledge on the topic under study is substantial such as in public health. ML could be more suited in highly innovative fields with a huge bulk of data, such as omics, radiodiagnostics, drug development, and personalized treatment. Integration of the two approaches should be preferred over a unidirectional choice of either approach.

Major depressive disorder (MDD) is a common severe psychiatric illness, exhibiting sub-optimal response to existing pharmacological treatments. Although its etiopathogenesis is still not completely understood, recent findings suggest that an altered composition of the gut microbiota might play a role. Here we aimed to explore potential differences in the composition of the gut microbiota between patients with MDD and healthy controls (HC) and to identify possible signatures of treatment response by analyzing two groups of MDD patients characterized as treatment-resistant (TR) or responders (R) to antidepressants. Stool samples were collected from 34 MDD patients (8 TR, 19 R and 7 untreated) and 20 HC. Microbiota was characterized using the 16S metagenomic approach. A penalized logistic regression analysis algorithm was applied to identify bacterial populations that best discriminate the diagnostic groups. Statistically significant differences were identified for the families of Paenibacillaceae and Flavobacteriaceaea, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis among others. The phyla Proteobacteria, Tenericutes and the family Peptostreptococcaceae were more abundant in TR, whereas the phylum Actinobacteria was enriched in R patients. Moreover, a number of bacteria only characterized the microbiota of TR patients, and many others were only detected in R. Our results confirm that dysbiosis is a hallmark of MDD and suggest that microbiota of TR patients significantly differs from responders to antidepressants. This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD, suggesting a role in response to antidepressants.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Cohorts are instrumental for epidemiologically oriented observational studies. Cohort studies usually observe large groups of individuals for a specific period of time to identify the contributing factors to a specific outcome (for instance an illness) and create associations between risk factors and the outcome under study. In collaborative projects, federated data facilities are meta-database systems that are distributed across multiple locations that permit to analyze, combine, or harmonize data from different sources making them suitable for mega- and meta-analyses. The harmonization of data can increase the statistical power of studies through maximization of sample size, allowing for additional refined statistical analyses, which ultimately lead to answer research questions that could not be addressed while using a single study. Indeed, harmonized data can be analyzed through mega-analysis of raw data or fixed effects meta-analysis. Other types of data might be analyzed by e.g., random-effects meta-analyses or Bayesian evidence synthesis. In this article, we describe some methodological aspects related to the construction of a federated facility to optimize analyses of multiple datasets, the impact of missing data, and some methods for handling missing data in cohort studies.