A Tradeoff in the Neural Code across Regions and Species.

Many evolutionary years separate humans and macaques, and although the amygdala and cingulate cortex evolved to enable emotion and cognition in both, an evident functional gap exists. Although they were traditionally attributed to differential neuroanatomy, functional differences might also arise from coding mechanisms. Here we find that human neurons better utilize information capacity (efficient coding) than macaque neurons in both regions, and that cingulate neurons are more efficient than amygdala neurons in both species. In contrast, we find more overlap in the neural vocabulary and more synchronized activity (robustness coding) in monkeys in both regions and in the amygdala of both species. Our findings demonstrate a tradeoff between robustness and efficiency across species and regions. We suggest that this tradeoff can contribute to differential cognitive functions between species and underlie the complementary roles of the amygdala and the cingulate cortex. In turn, it can contribute to fragility underlying human psychopathologies.

Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: From animal to clinical studies.

Orexins (also known as hypocretins) are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system and bind two different G protein-coupled receptors (OX1R and OX2R). Since its discovery in 1998, the orexin system has gained the interest of the scientific community as a potential therapeutic target for the treatment of different pathological conditions. Considering previous basic science research, a dual orexin receptor antagonist, suvorexant, was the first orexin agent to be approved by the US Food and Drug Administration to treat insomnia. In this review, we discuss and update the main preclinical and human studies involving the orexin system with several psychiatric and neurodegenerative diseases. This system constitutes a nice example of how basic scientific research driven by curiosity can be the best route to the generation of new and powerful pharmacological treatments.

A critical role of Ca2+/calmodulin-dependent protein kinase II in coupling between evening and morning circadian oscillators in the suprachiasmatic nucleus.

Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) is widely expressed in the brain and is involved in various functions, including memory formation, mood and sleep. We previously reported that CaMKIIα is involved in the circadian molecular clock. Mice lacking functional CaMKIIα (K42R mice) exhibited a gradual increase in activity time (α decompression) of running-wheel (RW) activity due to a lengthened circadian period (τ) of activity offset under constant darkness (DD). In the present study, to investigate the functional roles of CaMKIIα in behavioural rhythms, we measured RW and general movements simultaneously under prolonged DD. Tau became longer as the relative intensity of behaviour activity within an activity time shifted from activity onset towards activity offset. In some K42R mice, α was gradually expanded with a marked reduction of RW activity, while general movements persisted without noticeable decline, which was followed by an abrupt shortening of α (α compression) with differential phase shifts of the activity onset and offset and recovery of RW activity. These results suggest that an internal coupling between the oscillators controlling activity onset and offset is bidirectional but with different strengths. The α compression occurred recurrently in 38% of K42R mice examined with an average interval of 37 days in association with attenuation of RW activity but never in the wild-type (WT) mice. Consistent with behavioural rhythms, the circadian period of the PER2::LUC rhythm in the cultured suprachiasmatic nucleus (SCN) slice was significantly longer in K42R than in WT. These findings are best interpreted by assuming that a loss of functional CaMKIIα attenuates the coupling between the onset and offset oscillators.

Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions.

Mitochondria-endoplasmic reticulum contacts (MERCs) mediate a close and continuous communication between both organelles that is essential for the transfer of calcium and lipids to mitochondria, necessary for cellular signalling and metabolic pathways. Their structural and molecular characterisation has shown the involvement of many proteins that bridge the membranes of the two organelles and maintain the structural stability and function of these contacts. The crosstalk between the two organelles is fundamental for proper neuronal function and is now recognised as a component of many neurological disorders. In fact, an increasing proportion of MERC proteins take part in the molecular and cellular basis of pathologies affecting the nervous system. Here we review the alterations in MERCs that have been reported for these pathologies, from neurodevelopmental and neuropsychiatric disorders to neurodegenerative diseases. Although mitochondrial abnormalities in these debilitating conditions have been extensively attributed to the high energy demand of neurons, a distinct role for MERCs is emerging as a new field of research. Understanding the molecular details of such alterations may open the way to new paths of therapeutic intervention.

Gut bacteriome and mood disorders in women with PCOS.

STUDY QUESTION: How does the gut bacteriome differ based on mood disorders (MDs) in women with polycystic ovary syndrome (PCOS), and how can the gut bacteriome contribute to the associations between these two conditions? SUMMARY ANSWER: Women with PCOS who also have MDs exhibited a distinct gut bacteriome with reduced alpha diversity and a significantly lower abundance of Butyricicoccus compared to women with PCOS but without MDs. WHAT IS KNOWN ALREADY: Women with PCOS have a 4- to 5-fold higher risk of having MDs compared to women without PCOS. The gut bacteriome has been suggested to influence the pathophysiology of both PCOS and MDs. STUDY DESIGN, SIZE, DURATION: This population-based cohort study was derived from the Northern Finland Birth Cohort 1966 (NFBC1966), which includes all women born in Northern Finland in 1966. Women with PCOS who donated a stool sample at age 46 years (n = 102) and two BMI-matched controls for each case (n = 205), who also responded properly to the MD criteria scales, were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 102 women with PCOS and 205 age- and BMI-matched women without PCOS were included. Based on the validated MD criteria, the subjects were categorized into MD or no-MD groups, resulting in the following subgroups: PCOS no-MD (n = 84), PCOS MD (n = 18), control no-MD (n = 180), and control MD (n = 25). Clinical characteristics were assessed at age 31 years and age 46 years, and stool samples were collected from the women at age 46 years, followed by the gut bacteriome analysis using 16 s rRNA sequencing. Alpha diversity was assessed using observed features and Shannon's index, with a focus on genera, and beta diversity was characterized using principal components analysis (PCA) with Bray-Curtis Dissimilarity at the genus level. Associations between the gut bacteriome and PCOS-related clinical features were explored by Spearman's correlation coefficient. A P-value for multiple testing was adjusted with the Benjamini-Hochberg false discovery rate (FDR) method. MAIN RESULTS AND THE ROLE OF CHANCE: We observed changes in the gut bacteriome associated with MDs, irrespective of whether the women also had PCOS. Similarly, PCOS MD cases showed a lower alpha diversity (Observed feature, PCOS no-MD, median 272; PCOS MD, median 208, FDR = 0.01; Shannon, PCOS no-MD, median 5.95; PCOS MD, median 5.57, FDR = 0.01) but also a lower abundance of Butyricicoccus (log-fold changeAnalysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC)=-0.90, FDRANCOM-BC=0.04) compared to PCOS no-MD cases. In contrast, in the controls, the gut bacteriome did not differ based on MDs. Furthermore, in the PCOS group, Sutterella showed positive correlations with PCOS-related clinical parameters linked to obesity (BMI, r2=0.31, FDR = 0.01; waist circumference, r2=0.29, FDR = 0.02), glucose metabolism (fasting glucose, r2=0.46, FDR < 0.001; fasting insulin, r2=0.24, FDR = 0.05), and gut barrier integrity (zonulin, r2=0.25, FDR = 0.03). LIMITATIONS, REASONS FOR CAUTION: Although this was the first study to assess the link between the gut bacteriome and MDs in PCOS and included the largest PCOS dataset for the gut microbiome analysis, the number of subjects stratified by the presence of MDs was limited when contrasted with previous studies that focused on MDs in a non-selected population. WIDER IMPLICATIONS OF THE FINDINGS: The main finding is that gut bacteriome is associated with MDs irrespective of the PCOS status, but PCOS may also modulate further the connection between the gut bacteriome and MDs. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant Agreement (MATER, No. 813707), the Academy of Finland (project grants 315921, 321763, 336449), the Sigrid Jusélius Foundation, Novo Nordisk Foundation (NNF21OC0070372), grant numbers PID2021-12728OB-100 (Endo-Map) and CNS2022-135999 (ROSY) funded by MCIN/AEI/10.13039/501100011033 and ERFD A Way of Making Europe. The study was also supported by EU QLG1-CT-2000-01643 (EUROBLCS) (E51560), NorFA (731, 20056, 30167), USA/NIH 2000 G DF682 (50945), the Estonian Research Council (PRG1076, PRG1414), EMBO Installation (3573), and Horizon 2020 Innovation Grant (ERIN, No. EU952516). The funders did not participate in any process of the study. We have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Effectiveness of exercise rehabilitation interventions on depressive symptoms in older adults post hip fracture: a systematic review and meta-analysis.

This study determines the effectiveness of exercise rehabilitation interventions on depressive symptoms in older adults after hip fracture. Ovid MEDLINE, Embase, Global Health, APAPsych, CENTRAL, CIHAHL, PEDro and Open Grey were searched from database inception to June 10, 2022 for definitive, pilot or feasibility randomised controlled trials of rehabilitation interventions (versus any comparator) which reported depressive symptoms among older adults post hip fracture. Nonrandomised trials and those not published in English were excluded. Selection, quality appraisal (Cochrane Risk of Bias 2) and extraction in duplicate. Results were synthesised narratively and with meta-analysis (Hedge's g for intervention effect, I2 for heterogeneity). Eight trials (1146 participants) were included. Interventions were predominantly face-to-face exercise rehabilitation (range three to 56 sessions) at home versus usual care. Three trials were assigned overall low risk of bias, three some concerns and two high risk. The pooled effect of rehabilitation on depressive symptoms at intervention end favoured the intervention group (Hedges's g -0.43; 95% CI: -0.87, 0.01; four trials). Three trials demonstrated no between group difference following adjustment for baseline depressive symptoms. One trial found lower odds of depression when the intervention additionally included falls prevention, nutrition consultation and depression management. There is a potential benefit of exercise rehabilitation interventions on depressive symptoms after hip fracture. A mechanism for benefit may relate to baseline symptom severity, exercise frequency, frequency of health professional contacts, addition of a psychological component or of the quality of the underlying trials. To appropriately inform clinical guidelines, further appropriately powered trials with follow-up are warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: CRD42022342099.

Hospital-Initiated Smoking Cessation Among Patients Admitted with Behavioral Health Conditions.

BACKGROUND: Smoking rates among people living with behavioral health conditions (BHC) range from 30 to 65% and are 2-4 times higher than rates found in the general population. Starting tobacco treatment during a hospital stay is effective for smoking cessation, but little is known regarding treatment response among inpatients with BHC. OBJECTIVE: This study pooled data across multiple clinical trials to determine the relative success in quitting among participants with BHC compared to other study participants. PARTICIPANTS: Adults who smoke (≥ 18 years old) from five hospital-based smoking cessation randomized clinical trials. DESIGN: A retrospective analysis using data from the electronic health record to identify participants with primary diagnoses related to BHC. Recruitment and data analysis were conducted from 2011 to 2016. We used propensity score matching to pair patients with BHC to those with similar characteristics and logistic regression to determine differences between groups. MEASURES: The main outcome was self-reported 30-day abstinence 6 months post-discharge. RESULTS: Of 6612 participants, 798 patients had a BHC-related primary diagnosis. The matched sample included 642 pairs. Nearly 1 in 3 reported using tobacco medications after hospitalization, with no significant difference between patients with and without BHC (29.3% vs. 31.5%; OR (95% CI) = 0.90 (0.71, 1.14), p = 0.40). Nearly 1 in 5 patients with BHC reported abstinence at 6 months; however, their odds of abstinence were 30% lower than among people without BHC (OR (95% CI) = 0.70 (0.53,0.92), p = 0.01). CONCLUSION: When offered tobacco treatment, hospitalized patients with BHC were as likely as people without BHC to accept and engage in treatment. However, patients with BHC were less likely to report abstinence compared to those without BHC. Hospitals are a feasible and promising venue for tobacco treatment among inpatients with BHC. More studies are needed to identify treatment approaches that help people with BHC achieve long-term abstinence.

Effect of RANKL on Lower Depressive Symptoms In Hemodialysis Patients.

Depression and osteoporosis are common diseases in dialysis patients. In addition, patients with osteoporosis are more susceptible to depression. Contrary to previous anti-osteoporosis agents, denosumab and romosozumab could be used in dialysis patients and have similar action mechanisms for blocking RANKL. RANKL causes bone resorption after binding RANKL, but binding with OPG leads to suppress of bone resorption. In recent mice study, inhibition of RANKL with denosumab improved depressive-like phenotype. Besides, it was found that OPG was associated with depression. Therefore, this study aimed to investigate the association of depressive symptoms with RANKL and OPG in hemodialysis patients. We conducted a cross-sectional study with a total of 172 hemodialysis patients. The participants were measured for plasma RANKL, OPG, MMP-2, and MMP-9 levels. Logistic regression analysis was performed to evaluate the effect of RANKL and OPG on the presence of depressive symptoms. The depressive symptoms were observed in 90 (52.3%) subjects. RANKL tertile 3 had negative association with BDI score (ß - 4.527, 95% CI - 8.310 to - 0.743) in univariate analysis, and this association persisted even after multivariate adjustments (ß - 5.603, 95% CI - 9.715 to -1.491) in linear regression. In logistic regression between RANKL tertiles and depressive symptoms, RANKL tertile 3 had significantly lower unadjusted OR (0.40, 95% CI 0.19-0.86), and multivariate-adjusted OR (0.31, 95% CI 0.12-0.82) for depressive symptoms. OPG was not significantly associated with depressive symptoms. Higher plasma RANKL concentrations were significantly associated with lower depressive symptoms in HD patients.Trial registration WHO registry, No. KCT0003281, date: January 12, 2017.

Use of virtual reality in bipolar disorder: a systematic review.

Virtual reality (VR) is a technology that allows to interact with recreated digital environments and situations with enhanced realism. VR has shown good acceptability and promise in different mental health conditions. No systematic review has evaluated the use of VR in Bipolar Disorder (BD). This PRISMA-compliant systematic review searched PubMed and Web of Science databases (PROSPERO: CRD42023467737) to identify studies conducted in individuals with BD in which VR was used. Results were systematically synthesized around four categories (cognitive and functional evaluation, clinical assessment, response to VR and safety/acceptability). Eleven studies were included (267 individuals, mean age = 36.6 years, 60.7% females). Six studies using VR to carry out a cognitive evaluation detected impairments in neuropsychological performance and delayed reaction times. VR was used to assess emotional regulation. No differences in well-being between VR-based and physical calm rooms were found. A VR-based stress management program reduced subjective stress, depression, and anxiety levels. VR-based cognitive remediation improved cognition, depressive symptoms, and emotional awareness. 48.7% of the individuals with BD considered VR-based cognitive remediation 'excellent', whereas 28.2% considered it 'great'. 87.2% of individuals did not report any side effects. 81.8% of studies received a global quality rating of moderate. Emerging data point towards a promising use of VR in BD as an acceptable assessment/intervention tool. However, multiple unstudied domains as comorbidity, relapse and prodromal symptoms should be investigated. Research on children and adolescents is also recommended. Further research and replication of findings are required to disentangle which VR-interventions for which populations and outcomes are effective.

Characterizing the distinct imaging phenotypes, clinical behavior, and genetic vulnerability of brain maturational subtypes in mood disorders.

BACKGROUND: Mood disorders are characterized by great heterogeneity in clinical manifestation. Uncovering such heterogeneity using neuroimaging-based individual biomarkers, clinical behaviors, and genetic risks, might contribute to elucidating the etiology of these diseases and support precision medicine. METHODS: We recruited 174 drug-naïve and drug-free patients with major depressive disorder and bipolar disorder, as well as 404 healthy controls. T1 MRI imaging data, clinical symptoms, and neurocognitive assessments, and genetics were obtained and analyzed. We applied regional gray matter volumes (GMV) and quantile normative modeling to create maturation curves, and then calculated individual deviations to identify subtypes within the patients using hierarchical clustering. We compared the between-subtype differences in GMV deviations, clinical behaviors, cell-specific transcriptomic associations, and polygenic risk scores. We also validated the GMV deviations based subtyping analysis in a replication cohort. RESULTS: Two subtypes emerged: subtype 1, characterized by increased GMV deviations in the frontal cortex, cognitive impairment, a higher genetic risk for Alzheimer's disease, and transcriptionally associated with Alzheimer's disease pathways, oligodendrocytes, and endothelial cells; and subtype 2, displaying globally decreased GMV deviations, more severe depressive symptoms, increased genetic vulnerability to major depressive disorder and transcriptionally related to microglia and inhibitory neurons. The distinct patterns of GMV deviations in the frontal, cingulate, and primary motor cortices between subtypes were shown to be replicable. CONCLUSIONS: Our current results provide vital links between MRI-derived phenotypes, spatial transcriptome, genetic vulnerability, and clinical manifestation, and uncover the heterogeneity of mood disorders in biological and behavioral terms.

Identification of latent classes in mood and anxiety disorders and their transitions over time: a follow-up study in the adult general population.

BACKGROUND: Mood and anxiety disorders are heterogeneous conditions with variable course. Knowledge on latent classes and transitions between these classes over time based on longitudinal disorder status information provides insight into clustering of meaningful groups with different disease prognosis. METHODS: Data of all four waves of the Netherlands Mental Health Survey and Incidence Study-2 were used, a representative population-based study of adults (mean duration between two successive waves = 3 years; N at T0 = 6646; T1 = 5303; T2 = 4618; T3 = 4007; this results in a total number of data points: 20 574). Presence of eight mood and anxiety DSM-IV disorders was assessed with the Composite International Diagnostic Interview. Latent class analysis and latent Markov modelling were used. RESULTS: The best fitting model identified four classes: a healthy class (prevalence: 94.1%), depressed-worried class (3.6%; moderate-to-high proportions of mood disorders and generalized anxiety disorder (GAD)), fear class (1.8%; moderate-to-high proportions of panic and phobia disorders) and high comorbidity class (0.6%). In longitudinal analyses over a three-year period, the minority of those in the depressed-worried and high comorbidity class persisted in their class over time (36.5% and 38.4%, respectively), whereas the majority in the fear class did (67.3%). Suggestive of recovery is switching to the healthy class, this was 39.7% in the depressed-worried class, 12.5% in the fear class and 7.0% in the high comorbidity class. CONCLUSIONS: People with panic or phobia disorders have a considerably more persistent and chronic disease course than those with depressive disorders including GAD. Consequently, they could especially benefit from longer-term monitoring and disease management.

Neurocognitive correlates of metabolic dysregulation in individuals with mood disorders: a systematic review and meta-analysis.

Individuals with mood disorders are predisposed to metabolic dysfunction, while those with metabolic dysregulation such as diabetes and obesity experience more severe depressive symptoms. Both metabolic dysfunction and mood disorders are independently associated with cognitive deficits. Therefore, given their close association, this study aimed to explore the association between metabolic dysfunction in individuals with mood disorders in relation to cognitive outcomes. A comprehensive search comprised of these three domains was carried out; a random-effects meta-analysis pooling mean cognitive outcomes was conducted (PROSPERO ID: CRD42022295765). Sixty-three studies were included in this review; 26 were synthesized in a quantitative meta-analysis. Comorbid metabolic dysregulation was associated with significantly lower global cognition among individuals with mood disorders. These trends were significant within each mood disorder subgroup, including major depressive disorder, bipolar disorder, and self-report depression/depressive symptoms. Type 2 diabetes was associated with the lowest cognitive performance in individuals with mood disorders, followed by peripheral insulin resistance, body mass index ⩾25 kg/m2, and metabolic syndrome. Significant reduction in scores was also observed among individual cognitive domains (in descending order) of working memory, attention, executive function, processing speed, verbal memory, and visual memory. These findings demonstrate the detrimental effects of comorbid metabolic dysfunction in individuals with mood disorders. Further research is required to understand the underlying mechanisms connecting mood disorders, metabolism, and cognition.

Choroid plexus volume is increased in mood disorders and associates with circulating inflammatory cytokines.

Depressed patients exhibit altered levels of immune-inflammatory markers both in the peripheral blood and in the cerebrospinal fluid (CSF) and inflammatory processes have been widely implicated in the pathophysiology of mood disorders. The Choroid Plexus (ChP), located at the base of each of the four brain ventricles, regulates the exchange of substances between the blood and CSF and several evidence supported a key role for ChP as a neuro-immunological interface between the brain and circulating immune cells. Given the role of ChP as a regulatory gate between periphery, CSF spaces and the brain, we compared ChP volumes in patients with bipolar disorder (BP) or major depressive disorder (MDD) and healthy controls, exploring their association with history of illness and levels of circulating cytokines. Plasma levels of inflammatory markers and MRI scans were acquired for 73 MDD, 79 BD and 72 age- and sex-matched healthy controls (HC). Patients with either BD or MDD had higher ChP volumes than HC. With increasing age, the bilateral ChP volume was larger in patients, an effect driven by the duration of illness; while only minor effects were observed in HC. Right ChP volumes were proportional to higher levels of circulating cytokines in the clinical groups, including IFN-γ, IL-13 and IL-17. Specific effects in the two diagnostic groups were observed when considering the left ChP, with positive association with IL-1ra, IL-13, IL-17, and CCL3 in BD, and negative associations with IL-2, IL-4, IL-1ra, and IFN-γ in MDD. These results suggest that ChP could represent a reliable and easy-to-assess biomarker to evaluate the brain effects of inflammatory status in mood disorders, contributing to personalized diagnosis and tailored treatment strategies.

Chronic treatment with the antipsychotic lurasidone modulates the neuroinflammatory changes associated with the vulnerability to chronic mild stress exposure in female rats.

Stress exposure is a key risk factor for the developmentof depressive-like conditions. However, despite the higher incidence of Major Depressive Disorder in the female population, classical stress-based experimental paradigms have primarily focused on males. In the present study, we used the well-established chronic mild stress (CMS) paradigm to investigate the development of anhedonia, a cardinal symptom of affective disorders, in the female animals and we also studied the potential effect of the antipsychotic drug lurasidone in normalizing the alterations brought about by stress exposure. We found that three weeks of CMS exposure produced a significant reduction of sucrose intake in 50% of the animals (vulnerable, CMS-V), whereas the others were resilient (CMS-R). The development of an anhedonic phenotype in CMS-V was associated with a significant elevation of different immune markers, such as Complement C3 and C4, and inflammatory cytokines, including INFß and Il1ß in dorsal and ventral hippocampus. Interestingly, sub-chronic treatment with the antipsychotic drug lurasidone was able to revert the anhedonic phenotype while normalizing most of the molecular alterations found in rats vulnerable to CMS exposure. This study extends the ability of lurasidone to normalize the anhedonic phenotype in CMS rats also to females. Moreover, we provide novel evidence on lurasidone's potential effectiveness in treating mental disorders characterized by immune-inflammatory dysfunction.

Behavioral as well as hippocampal transcriptomic and microglial responses differ across sexes in adult mouse offspring exposed to a dual genetic and environmental challenge.

INTRODUCTION: A wide range of positive, negative, and cognitive symptoms compose the clinical presentation of schizophrenia. Schizophrenia is a multifactorial disorder in which genetic and environmental risk factors interact for a full emergence of the disorder. Infectious challenges during pregnancy are a well-known environmental risk factor for schizophrenia. Also, genetic variants affecting the function of fractalkine signaling between neurons and microglia were linked to schizophrenia. Translational animal models recapitulating these complex gene-environment associations have a great potential to untangle schizophrenia neurobiology and propose new therapeutic strategies. METHODS: Given that genetic variants affecting the function of fractalkine signaling between neurons and microglia were linked to schizophrenia, we compared the outcomes of a well-characterized model of maternal immune activation induced using the viral mimetic polyinosinic:polycytidylic acid (Poly I:C) in wild-type versus fractalkine receptor knockout mice. Possible behavioral and immune alterations were assessed in male and female offspring during adulthood. Considering the role of the hippocampus in schizophrenia, microglial analyses and bulk RNA sequencing were performed within this region to assess the neuroimmune dynamics at play. Males and females were examined separately. RESULTS: Offspring exposed to the dual challenge paradigm exhibited symptoms relevant to schizophrenia and unpredictably to mood disorders. Males displayed social and cognitive deficits related to schizophrenia, while females mainly presented anxiety-like behaviors related to mood disorders. Hippocampal microglia in females exposed to the dual challenge were hypertrophic, indicative of an increased surveillance, whereas those in males showed on the other end of the spectrum blunted morphologies with a reduced phagocytosis. Hippocampal bulk-RNA sequencing further revealed a downregulation in females of genes related to GABAergic transmission, which represents one of the main proposed causes of mood disorders. CONCLUSIONS: Building on previous results, we identified in the current study distinctive behavioral phenotypes in female mice exposed to a dual genetic and environmental challenge, thus proposing a new model of neurodevelopmentally-associated mood and affective symptoms. This paves the way to future sex-specific investigations into the susceptibility to developmental challenges using animal models based on genetic and immune vulnerability as presented here.

Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder.

INTRODUCTION: Cariprazine treats acute manic and depressive episodes in bipolar I disorder (BP-I), but its efficacy in preventing relapse of mood episode remains unknown. METHODS: In this phase 3b, double-blind, placebo-controlled study, patients with BP-I with acute manic or depressive episodes (each with/without mixed features), were treated with cariprazine 3.0 mg/day during a 16-week open-label treatment period; those who achieved stable remission within 8 weeks and remained stable for at least another 8 weeks were randomized to receive cariprazine 1.5 or 3.0 mg per day or placebo in the double-blind treatment period for up to 39 weeks. The primary efficacy endpoint was time to relapse of any mood episode. Adverse events (AEs) were assessed. RESULTS: Patients (440/896) enrolled in the open-label treatment period achieved stability criteria and were randomized to receive cariprazine 3.0 mg/day (n = 148), cariprazine 1.5 mg/day (n = 147), or placebo (n = 145) in the double-blind treatment period. Relapse rates were 17.9%, 16.8%, and 19.7% in the cariprazine 3.0 mg/day, cariprazine 1.5 mg/day, and placebo groups, respectively. Neither dose of cariprazine was more effective than placebo on the primary outcome (3.0 mg/day: HR = 0.89, [95% CI: 0.5, 1.5]; 1.5 mg/day: HR = 0.83, 95% CI [0.5, 1.4]). The most frequently reported AEs (≥5%) were akathisia, headache, insomnia, and nausea in the open-label treatment period and increased weight and insomnia in the double-blind treatment period. In the open-label and double-blind treatment periods, 7.5% and 1.6% of patients experienced an AE leading to discontinuation. CONCLUSION: Cariprazine was not superior to placebo in the prevention of relapses in this study. Relapse rates were unusually low in the placebo group. Cariprazine was well-tolerated.

Early warning signals observed in motor activity preceding mood state change in bipolar disorder.

INTRODUCTION: Alterations in motor activity are well-established symptoms of bipolar disorder, and time series of motor activity can be considered complex dynamical systems. In such systems, early warning signals (EWS) occur in a critical transition period preceding a sudden shift (tipping point) in the system. EWS are statistical observations occurring due to a system's declining ability to maintain homeostasis when approaching a tipping point. The aim was to identify critical transition periods preceding bipolar mood state changes. METHODS: Participants with a validated bipolar diagnosis were included to a one-year follow-up study, with repeated assessments of the participants' mood. Motor activity was recorded continuously by a wrist-worn actigraph. Participants assessed to have relapsed during follow-up were analyzed. Recognized EWS features were extracted from the motor activity data and analyzed by an unsupervised change point detection algorithm, capable of processing multi-dimensional data and developed to identify when the statistical property of a time series changes. RESULTS: Of 49 participants, four depressive and four hypomanic/manic relapses among six individuals occurred, recording actigraphy for 23.8 ± 0.2 h/day, for 39.8 ± 4.6 days. The algorithm detected change points in the time series and identified critical transition periods spanning 13.5 ± 7.2 days. For depressions 11.4 ± 1.8, and hypomania/mania 15.6 ± 10.2 days. CONCLUSION: The change point detection algorithm seems capable of recognizing impending mood episodes in continuous flowing data streams. Hence, we present an innovative method for forecasting approaching relapses to improve the clinical management of bipolar disorder.

Stable neural underpinnings of emotional cognition subgroups in patients newly diagnosed with bipolar disorder: A prospective fMRI study.

OBJECTIVES: This study aimed to investigate the neural underpinnings of emotional cognition subgroups in recently diagnosed patients with bipolar disorder (BD) and change over time over a 15-month follow-up period. METHODS: Patients and healthy controls (HC) underwent emotional and nonemotional cognitive assessments and functional magnetic resonance imaging (fMRI) at the baseline (BD n = 87; HC n = 65) and at 15-month follow-up (BD n = 44; HC n = 38). Neural activity during emotion reactivity and regulation in response to aversive pictures was assessed during fMRI. Patients were clustered into subgroups based on their emotional cognition and, with HC, were compared longitudinally on cognition and neural activity during emotion reactivity and regulation. RESULTS: Patients were optimally clustered into two subgroups: Subgroup 1 (n = 40, 46%) was characterized by heightened emotional reactivity in negative social scenarios, which persisted over time, but were otherwise cognitively intact. This subgroup exhibited stable left amygdala hyper-activity over time during emotion reactivity compared to subgroup 2. Subgroup 2 (n = 47, 54%) was characterized by global emotional cognitive impairments, including stable difficulties with emotion regulation over time. During emotion regulation across both time points, this group exhibited hypo-activity in the left dorsolateral prefrontal cortex. Additionally, patients in subgroup 2 had poorer nonemotional cognition, had more psychiatric hospital admissions and history of psychotic episodes than those in subgroup 1. CONCLUSIONS: Broad impairments in emotional cognition in approximately half of BD patients and associated nonemotional cognitive deficits may originate from insufficient recruitment of prefrontal resources, contributing to poorer clinical outcomes.

Biomarkers of cognitive and memory decline in psychotropic drug users.

Psychotropic drugs are vital in psychiatry, aiding in the management of mental health disorders. Their use requires an understanding of their pharmacological properties, therapeutic applications, and potential side effects. Ongoing research aims to improve their efficacy and safety. Biomarkers play a crucial role in understanding and predicting memory decline in psychotropic drug users. A comprehensive understanding of biomarkers, including neuroimaging, biochemical, genetic, and cognitive assessments, is essential for developing targeted interventions and preventive strategies. In this narrative review, we performed a comprehensive search on PubMed and Google using review-specific terms. Clinicians should use a multifaceted approach, including neurotransmitter analysis, neurotrophic factors, miRNA profiling, and cognitive tasks for early intervention and personalized treatment. Anxiolytics' mechanisms involve various neurotransmitter systems and emerging targets. Research on biomarkers for memory decline in anxiolytic users can lead to early detection and intervention, enhancing clinical practices and aligning with precision medicine. Mood stabilizer users can benefit from early detection of memory decline through RNA, neurophysiological, and inflammatory biomarkers, promoting timely interventions. Performance-enhancing drugs may boost athletic performance in the short term, but their long-term health risks and ethical issues make their use problematic. Long-term use of psychotropic performance enhancers in athletes shows changes in biomarkers of cognitive decline, necessitating ongoing monitoring and intervention strategies. Understanding these genetic influences on memory decline helps pave the way for personalized approaches to prevent or mitigate cognitive deterioration, emphasizing the importance of genetic screening and early interventions based on an individual's genetic profile. Future research should focus on refining these biomarkers and protective measures against cognitive deterioration. Overall, a comprehensive understanding of biomarkers in psychotropic drug users is essential for developing targeted interventions and preventive strategies.

Oxytocin: physiology, pharmacology, and clinical application for labor management.

Oxytocin is a peptide hormone that plays a key role in regulating the female reproductive system, including during labor and lactation. It is produced primarily in the hypothalamus and secreted by the posterior pituitary gland. Oxytocin can also be administered as a medication to initiate or augment uterine contractions. To study the effectiveness and safety of oxytocin, previous studies have randomized patients to low- and high-dose oxytocin infusion protocols either alone or as part of an active management of labor strategy along with other interventions. These randomized trials demonstrated that active management of labor and high-dose oxytocin regimens can shorten the length of labor and reduce the incidence of clinical chorioamnionitis. The safety of high-dose oxytocin regimens is also supported by no associated differences in fetal heart rate abnormalities, postpartum hemorrhage, low Apgar scores, neonatal intensive care unit admissions, and umbilical artery acidemia. Most studies reported no differences in the cesarean delivery rates with active management of labor or high-dose oxytocin regimens, thereby further validating its safety. Oxytocin does not have a predictable dose response, thus the pharmacologic effects and the amplitude and frequency of uterine contractions are used as physiological parameters for oxytocin infusion titration to achieve adequate contractions at appropriate intervals. Used in error, oxytocin can cause patient harm, highlighting the importance of precise administration using infusion pumps, institutional safety checklists, and trained nursing staff to closely monitor uterine activity and fetal heart rate changes. In this review, we summarize the physiology, pharmacology, infusion regimens, and associated risks of oxytocin.