Association of Klotho with Neuropsychiatric Disorder: A Meta-Analysis.

Neuropsychiatric disorders are mainly concerned with the behavioural, emotional and cognition symptoms that may be due to disturbed cerebral functions or extracerebral disease. Klotho protein is an antiaging protein that is mostly associated with cognitive changes in these disorders and thus this meta-analysis is conducted in order to find Klotho proteins association with these disorders. We searched related topics in pubmed, by using the key word i.e. Klotho and related disorder from neuropsychiatry e.g. Klotho levels and schizophrenia, Klotho levels and parkinsonism etc. Total 82 studies were found till 9th February 2021 after extensive search and 10 studies were selected for further analysis. The meta-analysis of studies was performed using the Random effect model. The forest plot represented each study in the meta-analysis, so as to make the comparison of SMD value across studies. The meta-analysis outcome demonstrated that overall schizophrenia had higher klotho levels as compared with bipolar disorder, psychosocial stress, parkinsonism, multiple sclerosis, depression, Alzheimer's disease, and healthy controls, followed by MS. The meta-analysis also found that bipolar disorder and Alzheimer's disease were associated with low klotho levels as compared to schizophrenia. The results indicate a significant association of the klotho levels and schizophrenia. Further studies are needed to characterize the potential biological roles of klotho levels in psychiatric disorders.

An e-Health Psychoeducation Program for Managing the Mental Health of People with Bipolar Disorder during the COVID-19 Pandemic: A Randomized Controlled Study.

Background: Social rhythm dysregulation has been identified as a determining factor in bipolar disorder (BD) relapses. It directly impacts individuals' quality of life (QoL). This study aims to present preliminary data on the efficacy of an e-health psychoeducational intervention for BD for improving clinical outcomes. Methods: This study used an open-label, crossover, randomized controlled trial design. The inclusion criteria consisted of a BD diagnosis, affiliation with the Consultation Psychiatry and Psychosomatic Center at the University Hospital in Cagliari, Italy, age over 18, and the obtaining of informed consent. Anxiety and depressive symptoms, QoL, and social and biological rhythms were measured using standardized instruments validated in Italian. Results: A total of 36 individuals were included in the experimental group (EG) and 18 in the control group (CG). The final sample consisted of 25 in the EG and 14 in the CG. A statistically significant improvement in QoL was found in the EG post-treatment (p = 0.011). Significant correlations were found between QoL and the dysregulation of biorhythms in the EG at T0 (p = 0.0048) and T1 (p = 0.0014). Conclusions: This study shows that, during extreme distress, an e-health group psychoeducation intervention for people with BD could significantly improve the perception of QoL. The results must be confirmed by studies conducted with larger-sized samples.

Impact of Serotonin Deficiency on Circadian Dopaminergic Rhythms.

Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain-including those involving serotonin and dopamine-exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.

Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.

OBJECTIVE: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.

Neurophysiological profiles of patients with bipolar disorders as probed with transcranial magnetic stimulation: A systematic review.

AIM: Bipolar disorder (BD) has a significant impact on global health, yet its neurophysiological basis remains poorly understood. Conventional treatments have limitations, highlighting the need for a better understanding of the neurophysiology of BD for early diagnosis and novel therapeutic strategies. DESIGN: Employing a systematic review approach of the PRISMA guidelines, this study assessed the usefulness and validity of transcranial magnetic stimulation (TMS) neurophysiology in patients with BD. METHODS: Databases searched included PubMed, MEDLINE, Embase, and PsycINFO, covering studies from January 1985 to January 2024. RESULTS: Out of 6597 articles screened, nine studies met the inclusion criteria, providing neurophysiological insights into the pathophysiological basis of BD using TMS-electromyography and TMS-electroencephalography methods. Findings revealed significant neurophysiological impairments in patients with BD compared to healthy controls, specifically in cortical inhibition and excitability. In particular, short-interval cortical inhibition (SICI) was consistently diminished in BD across the studies, which suggests a fundamental impairment of cortical inhibitory function in BD. This systematic review corroborates the potential utility of TMS neurophysiology in elucidating the pathophysiological basis of BD. Specifically, the reduced cortical inhibition in the SICI paradigm observed in patients with BD suggests gamma-aminobutyric acid (GABA)-A receptor-mediated dysfunction, but results from other TMS paradigms have been inconsistent. Thus, complex neurophysiological processes may be involved in the pathological basis underlying BD. This study demonstrated that BD has a neural basis involving impaired GABAergic function, and it is highly expected that further research on TMS neurophysiology will further elucidate the pathophysiological basis of BD.

Psychometric Assessment of an Item Bank for Adaptive Testing on Patient-Reported Experience of Care Environment for Severe Mental Illness: Validation Study.

BACKGROUND: The care environment significantly influences the experiences of patients with severe mental illness and the quality of their care. While a welcoming and stimulating environment enhances patient satisfaction and health outcomes, psychiatric facilities often prioritize staff workflow over patient needs. Addressing these challenges is crucial to improving patient experiences and outcomes in mental health care. OBJECTIVE: This study is part of the Patient-Reported Experience Measure for Improving Quality of Care in Mental Health (PREMIUM) project and aims to establish an item bank (PREMIUM-CE) and to develop computerized adaptive tests (CATs) to measure the experience of the care environment of adult patients with schizophrenia, bipolar disorder, or major depressive disorder. METHODS: We performed psychometric analyses including assessments of item response theory (IRT) model assumptions, IRT model fit, differential item functioning (DIF), item bank validity, and CAT simulations. RESULTS: In this multicenter cross-sectional study, 498 patients were recruited from outpatient and inpatient settings. The final PREMIUM-CE 13-item bank was sufficiently unidimensional (root mean square error of approximation=0.082, 95% CI 0.067-0.097; comparative fit index=0.974; Tucker-Lewis index=0.968) and showed an adequate fit to the IRT model (infit mean square statistic ranging between 0.7 and 1.0). DIF analysis revealed no item biases according to gender, health care settings, diagnosis, or mode of study participation. PREMIUM-CE scores correlated strongly with satisfaction measures (r=0.69-0.78; P<.001) and weakly with quality-of-life measures (r=0.11-0.21; P<.001). CAT simulations showed a strong correlation (r=0.98) between CAT scores and those of the full item bank, and around 79.5% (396/498) of the participants obtained a reliable score with the administration of an average of 7 items. CONCLUSIONS: The PREMIUM-CE item bank and its CAT version have shown excellent psychometric properties, making them reliable measures for evaluating the patient experience of the care environment among adults with severe mental illness in both outpatient and inpatient settings. These measures are a valuable addition to the existing landscape of patient experience assessment, capturing what truly matters to patients and enhancing the understanding of their care experiences. TRIAL REGISTRATION: ClinicalTrials.gov NCT02491866; https://clinicaltrials.gov/study/NCT02491866.

Seroprevalence and sociodemographic characteristics of Toxoplasma gondii infection in patients with psychiatric disorders in Malaysia.

Toxoplasma gondii is a neurotropic protozoan parasite that affects neuronal processing in the brain. This study aimed to investigate the prevalence of T. gondii infection in psychiatric disorder patients. We also investigated the potential association between sociodemographic, clinical manifestation, and behavior of Toxoplasma-seropositive patients with psychiatric disorders. Commercial ELISAs (IgG, IgM, and IgG avidity) using serum and PCR using buffy coat were performed on samples from 54 individuals in each of the following groups: patients diagnosed with depressive disorder, bipolar disorder, and schizophrenia, as well as psychiatrically healthy subjects (control group). They were recruited from the Hospital Universiti Sains Malaysia in Kelantan, Malaysia. Of 54 patients with depressive disorder, 24/54 (44.4 %) were seropositive for IgG, and four (16.7 %) were IgG+/IgM+. Among the latter, a high avidity index indicating a past infection was observed in half of the samples (50.0 %), and the other half (50.0 %) showed a low avidity index, indicating a possible recent infection. Meanwhile, 30/54 (55.6 %) patients with bipolar disorder were seropositive for IgG+, five (16.7 %) were IgG+/IgM+, and four of them had a high avidity index, and one had a low avidity index. Patients with schizophrenia showed 29/54 (53.7 %) seropositive for IgG, two of them (6.9 %) were IgG+/IgM+; one of latter had a high avidity index, and one had a low avidity index. Of 54 people in the control group, 37.0 % (20/54) were seropositive for T. gondii IgG antibodies. However, no significant difference was observed in seroprevalence between the control group and each patient group. No PCR-positive results were documented. A Chi-Square and multiple logistic regression showed that age (p = 0.031), close contact with cats/pets (p = 0.033) and contact with soil (p = 0.012) were significantly associated with Toxoplasma seropositivity in patients with psychiatric disorders. Additional research is needed to elucidate the causal relationships and underlying mechanisms.

The effect of physical exercises program on social functioning, alexithymia, and sense of coherence among patients with bipolar disorders: A randomized control trial.

BACKGROUND: Despite evidence that physical exercises have been helpful in the treatment of various psychiatric disorders, it is unclear whether these data can be generalized to bipolar disorder. The use of physical exercises is challenging and hopeful among patients with bipolar disorders. Few studies have examined the efficacy of physical exercise for patients with bipolar disorders. OBJECTIVE: Investigate the effect of applying physical exercises program on social functioning, alexithymia, and sense of coherence among patients with bipolar disorders. METHODS: This study followed a randomized control trial design "pre and post-test." Patients were randomly allocated to intervention (n = 25) and control groups (Waiting list) (n = 25). The Social Functioning Scale, Toronto Alexithymia Scale, and Sense of Coherence scales were applied in the study. Pre-test and post-tests were administered to investigate the effect of applying the physical exercises program between December 2022 to March 2023. RESULTS: A statistically significant increase in the mean sense of coherence and social functioning scores among the study group. Mean alexithymia scores were significantly decreased among the study group between pre, immediately after, and after a three-month follow-up period. CONCLUSION: Physical exercises are an adjunctive treatment modality that is helpful for patients with bipolar disorders. Nurse educators and service providers should reconsider the physical health care requirements for patients with bipolar disorders to equip them to manage the common comorbidities in people with mental illness.

Role of the Cerebellum in Bipolar Disorder: A Systematic Literature Review.

The aim of this systematic literature review was to investigate the role of the cerebellum in the affective symptoms observed in patients with bipolar disorder. The present systematic literature review included clinical studies conducted from 2013-2023 among adult populations with bipolar I and II disorders, along with their specifiers. With regard to cerebellar pathology, it was found that those with bipolar disorder performed worse than their healthy counterparts in their ability to comprehend the mental states of others and in identifying negative mental states. Additionally, individuals with bipolar disorder had reduced gray matter loss in regions such as lobules I-IX, crus I, and crus II, different functional activation patterns of the thalamus, striatum, and hippocampus on functional magnetic resonance imaging (fMRI), and increased cortical thickness. Cerebro-cerebellar functional connectivities were altered in patients with bipolar disorder. The effects of lamotrigine and lithium on cerebellar volume and abnormalities are also discussed in this paper. The present systematic literature review illustrates the emerging involvement of the cerebellum in bipolar disorder and its affective symptoms and paves the way for future research and a better understanding of bipolar disorder.

Implementing cognitive screenings for outpatients with bipolar disorder following optimised treatment in a specialised mood disorder clinic.

Bipolar disorder (BD) is often accompanied by persistent cognitive impairment. However, screening for cognitive impairment in the clinic is challenged by a lack of consensus on screening procedures. This study assesses cognitive impairment prevalence and screening feasibility in alignment with the International Society for Bipolar Disorder Targeting Cognition Task Force recommendations. Between January 2022 and May 2023, 136 newly diagnosed BD outpatients were assessed with the Screen for Cognitive Impairment in Psychiatry after 15-20 months of specialised care at the Copenhagen Affective Disorder Clinic. Cognitive impairment patterns and associations with cognitive complaints, perceived stress, and functioning were examined. Most screened patients (73 %) achieved full or partial remission, with 51 % being cognitively normal, 38 % showing global impairments, and 11 % displaying selective impairments. Among remitted patients, 56 % were cognitively normal, while 31 % and 13 % exhibited global or selective impairments, respectively. Both objectively impaired patient groups reported more subjective cognitive difficulties than those who were cognitively normal. The globally impaired group also demonstrated poorer functioning, more depressive symptoms and lower quality of life than cognitively normal patients. Across all patients, lower cognitive performance correlated with more cognitive complaints, lower functioning, lower quality of life, and more depressive symptoms. Cognitive screenings were relatively easily implementable, involving only a 1.5 h session including mood ratings, feedback and cognitive strategy discussion. The study highlights the clinical relevance and feasibility of cognitive screenings in BD patients, emphasizing the need for tailored interventions given frequent cognitive impairment in clinically stable individuals.

Longitudinal changes in resting-state functional connectivity as markers of vulnerability or resilience in first-degree relatives of patients with bipolar disorder.

BACKGROUND: There is a significant contribution of genetic factors to the etiology of bipolar disorder (BD). Unaffected first-degree relatives of patients (UR) with BD are at increased risk of developing mental disorders and may manifest cognitive impairments and alterations in brain functional and connective dynamics, akin to their affected relatives. METHODS: In this prospective longitudinal study, resting-state functional connectivity was used to explore stable and progressive markers of vulnerability i.e. abnormalities shared between UR and BD compared to healthy controls (HC) and resilience i.e. features unique to UR compared to HC and BD in full or partial remission (UR n = 72, mean age = 28.0 ± 7.2 years; HC n = 64, mean age = 30.0 ± 9.7 years; BD patients n = 91, mean age = 30.6 ± 7.7 years). Out of these, 34 UR, 48 BD, and 38 HC were investigated again following a mean time of 1.3 ± 0.4 years. RESULTS: At baseline, the UR showed lower connectivity values within the default mode network (DMN), frontoparietal network, and the salience network (SN) compared to HC. This connectivity pattern in UR remained stable over the follow-up period and was not present in BD, suggesting a resilience trait. The UR further demonstrated less negative connectivity between the DMN and SN compared to HC, abnormality that remained stable over time and was also present in BD, suggesting a vulnerability marker. CONCLUSION: Our findings indicate the coexistence of both vulnerability-related abnormalities in resting-state connectivity, as well as adaptive changes possibly promoting resilience to psychopathology in individual at familial risk.

Study of the different sleep disturbances during the prodromal phase of depression and mania in bipolar disorders.

BACKGROUND: One of the challenges in bipolar disorder (BD) lies in early detection of the illness and its recurrences, to improve prognosis. Sleep disturbances (SD) have been proposed as reliable predictive markers of conversion. While preliminary studies have explored the relationship between SD and the onset of mood episodes, the results remain heterogeneous and a few have specifically examined patients' perception of prodromal symptoms and their progression until the episode occurs. Identifying prodromes represents a crucial clinical challenge, as it enables early intervention, thereby reducing the severity of BD. Therefore, the objective of this study is to better characterize and evaluate the progressive nature of SD as prodromal symptoms of mood episodes, and patients' perception of it. METHODS: Patients diagnosed with BD, either hospitalized or seeking treatment for a (hypo)manic or depressive episode benefited from standardized questionnaires, structured interviews, and self-report questionnaires to evaluate SD prior to the current episode, as well as sociodemographic and clinical information. RESULTS: Out of the 41 patients included, 59% spontaneously reported SD prior to the episode, appearing 90 days before depression and 35 days before mania (pre-indexed/spontaneous reports: 51.22% insomnia complaints, 4.88% hypersomnolence complaints, 7.32% parasomnias, 2.44% sleep movements). After inquiry about specific SD, the percentage of patients reporting prodromal SD increased significantly to 83%, appearing 210 days before depression and 112.5 days before mania (post-indexed reports: 75.61% presented with insomnia complaints appearing 150 days before depression and 20 days before mania, 46.34% had hypersomnolence complaints appearing 60 days before depression, 43.9% had parasomnias appearing 210 days before depression and 22.5 days before mania, 36.59% had sleep movements appearing 120 days before depression and 150 days before mania). Of note, bruxism appeared in 35% of patients before mania, and restless legs syndrome in 20% of patients before depression. CONCLUSION: This study highlights the very high prevalence of SD prior to a mood episode in patients with BD with differences between depressive and manic episodes. The more systematic screening of sleep alterations of the prodromal phase improved the recognition and characterization of different symptoms onset by patients. This underscores the need for precise questioning regarding sleep patterns in patients, to better identify the moment of transition toward a mood episode, referred to as "Chronos syndrome". The study emphasizes the importance of educating patients about the disorder and its sleep prodromal symptoms to facilitate early intervention and prevent recurrences.

Effects of seasonality in emergency admissions for mental disorders: two years of clinical experience.

OBJECTIVES: This retrospective study, conducted in Turin, Italy, between January 2021 and February 2023, investigates the impact of seasonal heatwaves on emergency department (ED) admissions for mental disorders. METHODS: Through the analysis of data from 2,854 patients, this research found a significant link between the occurrence of heatwaves, especially from June to August, and an elevated rate of ED admissions for psychiatric conditions. RESULTS: The data indicate a clear seasonal pattern, with admissions peaking during the hot months and diminishing in the colder months. Particularly, the study delineates an enhanced correlation between heatwaves and admissions for severe psychiatric disorders, such as bipolar disorder, major depression, personality disorders, and schizophrenia, accounting for 1,868 of the cases examined. This correlation was most pronounced among individuals aged 50-59 years. CONCLUSIONS: The results of this study highlight a critical association between the incidence of seasonal heatwaves and an uptick in ED visits for psychiatric disorders, with a distinct impact on severe cases. It underscores the urgency for healthcare systems to anticipate seasonal fluctuations in psychiatric ED admissions and to allocate resources effectively to support patients during peak periods.

Lower levels of TRAF1 in Brodmann's area 24, but not 46, in bipolar disorders are not detectable in major depressive disorders.

INTRODUCTION: Multiple lines of research implicate inflammation-related pathways in the molecular pathology of mood disorders, with our data suggesting a critical role for aberrant cortical tumour necrosis factor α (TNF)-signaling in the molecular pathology of bipolar disorders (BPD) and major depressive disorders (MDD). METHODS: To extend our understanding of changes in TNF-signaling pathways in mood disorders we used Western blotting to measure levels of tumour necrosis factor receptor associated factor 1 (TRAF1) and transmembrane TNF receptor superfamily member 1B (tmTNFRSF1B) in Brodmann's areas (BA) 24 and 46 from people with BPD and MDD. These proteins are key rate-limiting components within TNF-signaling pathways. RESULTS: Compared to controls, there were higher levels of TRAF1 of large effect size (η = 0.19, Cohen's d = 0.97) in BA 24, but not BA 46, from people with BPD. Levels of TRAF1 were not altered in MDD and levels of tmTNFRSF1B were not altered in either disorder. LIMITATIONS: The cases studied had been treated with psychotropic drugs prior to death which is an unresolvable study confound. Cohort sizes are relatively small but not untypical of postmortem CNS studies. CONCLUSIONS: To facilitate post-synaptic signaling, TRAF1 is known to associate with tmTNFRSF1B after that receptor takes its activated conformation which occurs predominantly after it binds to transmembrane TNF (tmTNF). Simultaneously, when tmTNFRSF1B binds to tmTNF reverse signaling through tmTNF is activated. Hence our findings in BA 24 argues that bidirectional TNF-signaling may be an important component of the molecular pathology of BPD.

Prescriptions of psychotropic and somatic medications among patients with severe mental disorders and healthy controls in a naturalistic study.

PURPOSE: Psychotropic and somatic medications are both used in treating severe mental disorders (SMDs). Realistic estimates of the prevalence of use across medication categories are needed. We obtained this in a clinical cohort of patients with SMD and healthy controls (HCs). MATERIALS AND METHODS: Prescriptions filled at Norwegian pharmacies the year before and after admittance to the Thematically Organized Psychosis (TOP) study were examined in 1406 patients with SMD (mean age 32.5 years, 48.2% women) and 920 HC (34.1 years, 46.2% women). Using data from the Norwegian Prescription Database (NorPD), the number of users in different anatomical therapeutic chemical (ATC) categories was compared using logistic regression. Population estimates were used as reference data. RESULTS: Use of antipsychotics (N05A), antiepileptics (N03A), antidepressants (N06A), anxiolytics (N05B), hypnotics and sedatives (N05C), anticholinergics (N04A), psychostimulants, attention deficit hyperactivity disorder and nootropic agents (N06B) and drugs for addiction disorders (N07B) was significantly more prevalent in patients with SMD than HC. Use of diabetes treatment (A10), antithrombotic drugs (B01), beta blockers (C07), lipid modifiers (C10), and thyroid and endocrine therapeutics (H03) was also more prevalent in patients with SMD, but with two exceptions somatic medication use was comparable to the general population. Among HC, there was low prevalence of use for most medication categories. CONCLUSION: Patients were using psychiatric medications, but also several types of somatic medications, more often than HC. Still, somatic medication use was mostly not higher than in the general population. The results indicate that HC had low use of most medication types.

Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes (CYP2C19 or CYP2D6), the serotonin transporter (SLC6A4), and the serotonin receptor 2A subtype (HTR2A). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC0-24; p = 0.025), trough concentrations (Ctrough; p = 0.013), and elimination half-lives (t1/2; p < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia (p = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores (p = 0.017). Escitalopram maximum concentration, AUC0-24, CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

Incidence and predictors of metabolic syndrome onset in individuals with bipolar disorders: A longitudinal study from the FACE-BD cohort.

INTRODUCTION: Metabolic syndrome (MetS) is a cluster of components including abdominal obesity, hyperglycemia, hypertension, and dyslipidemia. MetS is highly prevalent in individuals with bipolar disorders (BD) with an estimated global rate of 32.6%. Longitudinal data on incident MetS in BD are scarce and based on small sample size. The objectives of this study were to estimate the incidence of MetS in a large longitudinal cohort of 1521 individuals with BD and to identify clinical and biological predictors of incident MetS. METHODS: Participants were recruited from the FondaMental Advanced Center of Expertise for Bipolar Disorder (FACE-BD) cohort and followed-up for 3 years. MetS was defined according to the International Diabetes Federation criteria. Individuals without MetS at baseline but with MetS during follow-up were considered as having incident MetS. A logistic regression model was performed to estimate the adjusted odds ratio and its corresponding 95% confidence interval (CI) for an association between each factor and incident MetS during follow-up. We applied inverse probability-of-censoring weighting method to minimize selection bias due to loss during follow-up. RESULTS: Among individuals without MetS at baseline (n = 1521), 19.3% developed MetS during follow-up. Multivariable analyses showed that incident MetS during follow-up was significantly associated with male sex (OR = 2.2, 95% CI = 1.7-3.0, p < 0.0001), older age (OR = 2.14, 95% CI = 1.40-3.25, p = 0.0004), presence of a mood recurrence during follow-up (OR = 1.91, 95% CI = 1.22-3.00, p = 0.0049), prolonged exposure to second-generation antipsychotics (OR = 1.56, 95% CI = 0.99, 2.45, p = 0.0534), smoking status at baseline (OR = 1.30, 95% CI = 1.00-1.68), lifetime alcohol use disorders (OR = 1.33, 95% CI = 0.98-1.79), and baseline sleep disturbances (OR = 1.04, 95% CI = 1.00-1.08), independently of the associations observed for baseline MetS components. CONCLUSION: We observed a high incidence of MetS during a 3 years follow-up (19.3%) in individuals with BD. Identification of predictive factors should help the development of early interventions to prevent or treat early MetS.

Comparing stigma between French people experiencing schizophrenia versus bipolar disorders.

BACKGROUND: Among the multiple challenges that people experiencing mental illness in general, and schizophrenia or bipolar disorders in particular, have to face, stigma appears to be one of the most difficult to tackle. In France, the body of research about stigma regarding people experiencing schizophrenia or bipolar disorders is growing, but not as much as in other western countries. AIMS: In this context, our study aims to explore and compare stigma in French people experiencing schizophrenia or bipolar disorders, along with their respective mental healthcare system experience, in order to better address them within public health policies. METHODS: 20 French mental health service users experiencing schizophrenia and 20 experiencing bipolar disorders answered the Stigma Scale, which assesses three dimensions of stigma (discrimination, difficulties of divulgation and lack of positive aspects). A semi-structured interview was used to collect information about the experience of the mental healthcare system (level of information, access to diagnosis, treatment, access to psychoeducation, etc.). RESULTS: People experiencing schizophrenia and people experiencing bipolar disorders are different populations in terms of social impairment. However, they share a comparable negative experience of the mental healthcare system and a comparable level of information about their illness, to the exception of diagnosis divulgation, as people experiencing bipolar disorders have a better access to their diagnosis. People experiencing schizophrenia perceive a higher actual discrimination than people experiencing bipolar disorders. CONCLUSIONS: Public health policies should take into account the strong perception of actual discrimination of people experiencing schizophrenia, with capitalizing on what seems beneficial for people experiencing bipolar disorders.

Interpersonal sensitivity and childhood trauma in patients with major depressive disorder, bipolar I, and II disorder.

Childhood trauma and interpersonal sensitivity impact the development of mood disorders. In this study, we investigate the association between childhood trauma and interpersonal sensitivity in patients with mood disorders. A total 775 patients (major depressive disorder [MDD, n = 241], bipolar I disorder [BD I, n = 119], and bipolar II disorder [BD II, n = 415]) and 734 controls. For evaluation, we used the Childhood Trauma Questionnaire-Short Form (CTQ) and Interpersonal Sensitivity Measure (IPSM). We examined between-group differences for each subscale in the CTQ and IPSM. Patients with BD II had significantly higher IPSM total scores than patients with MDD, BD I, or controls. The CTQ total score was related to the IPSM total score in all participants and subgroups. Among the CTQ subscales, emotional abuse showed the highest correlation with the IPSM total score, while separation anxiety and fragile inner self showed higher positive correlations with CTQ than the other subscales of IPSM in all patient groups and the control group, respectively. The findings reveal that childhood trauma and interpersonal sensitivity are positively correlated among patients with MDD, BD I, and BD II, and that interpersonal sensitivity is higher in patients with BD II than those with BD I or MDD. Childhood trauma is associated with interpersonal sensitivity, and each trauma type has a different impact on mood disorders. We expect that this study will encourage future research on interpersonal sensitivity and childhood trauma in mood disorders to improve treatment approaches.

Altered Sex Differences in Hippocampal Subfield Volumes in Schizophrenia.

BACKGROUND AND HYPOTHESIS: The hippocampus is a heterogenous brain structure that differs between the sexes and has been implicated in the pathophysiology of psychiatric illnesses. Here, we explored sex and diagnostic group differences in hippocampal subfield volumes, in individuals with schizophrenia spectrum disorder (SZ), bipolar disorders (BD), and healthy controls (CTL). STUDY DESIGN: One thousand and five hundred and twenty-one participants underwent T1-weighted magnetic resonance imaging (SZ, n = 452, mean age 30.7 ±â€…9.2 [SD] years, males 59.1%; BD, n = 316, 33.7 ±â€…11.4, 41.5%; CTL, n = 753, 34.1 ±â€…9.1, 55.6%). Total hippocampal, subfield, and intracranial volumes were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple regression models were fitted to examine sex-by-diagnostic (sub)group interactions in volume. In SZ and BD, separately, associations between volumes and clinical as well as cognitive measures were examined between the sexes using regression models. STUDY RESULTS: Significant sex-by-group interactions were found for the total hippocampus, dentate gyrus, molecular layer, presubiculum, fimbria, hippocampal-amygdaloid transition area, and CA4, indicating a larger volumetric deficit in male patients relative to female patients when compared with same-sex CTL. Subgroup analyses revealed that this interaction was driven by males with schizophrenia. Effect sizes were overall small (partial η < 0.02). We found no significant sex differences in the associations between hippocampal volumes and clinical or cognitive measures in SZ and BD. CONCLUSIONS: Using a well-powered sample, our findings indicate that the pattern of morphological sex differences in hippocampal subfields is altered in individuals with schizophrenia relative to CTL, due to higher volumetric deficits in males.