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Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

The aim of this study was to determine the technological properties (chemical, mechanical and physical) of Eschweilera sp. woods using near infrared spectroscopy (NIRS). NIR spectroscopy proved to be efficient for chemical analysis (extractives, lignin and carbohydrates) and physical-mechanical testing (moisture content, basic density - BD, modulus of elasticity - MOE and modulus of rupture - MOR) of wood, providing a powerful tool for use in sustainable forest management activities in the Amazon. Wood samples from three trees of each Eschweilera species were collected from the Experimental Station of Tropical Forestry/INPA/Brazil. Specimens were extracted from the cross-sectional area (20 × 20 × 30 mm) in the direction sapwood-heartwood. NIR spectra (4.000-10.000 cm-1) were then obtained from the samples (moisture 12%) using Fourier-transform spectrometry. The Partial Least Squares (PLS) regression prediction models for the chemical, mechanical and physical properties of Amazonian woods were used for quantification. The results for total extractives (both in toluene and ethanol) and hot water solubility showed a maximum extractive concentration of 7.66% and 3.13% for E. odora (yellow matá-matá), including several compounds with low molecular weight, such as resins, gums, terpenes, alkaloids, flavonoids, and tannins. The highest concentration of phenolic substances (tannins) was found in E. Truncata (black matá-matá, 10.00%). The macrocomponents (primary metabolism) of Eschweilera species were in the range of 44.20-46.33% for cellulose and 28.89-31.21% for lignin. Mineral compounds (ash) were quantified in concentrations < 0.70%. The predictive results for the physical and mechanical properties of matá-matá wood are in the standard range for tropical woods. The higher calorific value (HCV) varied from 4.993-5.033 cal g-1 and the BD from 0.78-0.88 g m-3. Regarding moisture, the highest content was observed in E. truncata (13.46%). Values for mechanical resistance were in the range of 14,253-17,447 MPa for MOE and 146.04-175.73 MPa for MOR, with the greatest strength attributed to E. truncata wood. The values obtained for the wood technological properties of E. coriacea (white matá-matá), E. odora (yellow matá-matá) and E. truncata (black matá-matá) were compatible with those obtained by destructive determination of tropical species and also for other species of the genus Eschweilera.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Transcranial direct current stimulation (tDCS) has been proposed as a new treatment in major depressive disorder (MDD). This is a fully remote, multisite, double-blind, placebo-controlled, randomized superiority trial of 10-week home-based tDCS in MDD. Participants were 18 years or older, with MDD in current depressive episode of at least moderate severity as measured using the Hamilton Depression Rating Scale (mean = 19.07 ± 2.73). A total of 174 participants (120 women, 54 men) were randomized to active (n = 87, mean age = 37.09 ± 11.14 years) or sham (n = 87, mean age = 38.32 ± 10.92 years) treatment. tDCS consisted of five sessions per week for 3 weeks then three sessions per week for 7 weeks in a 10-week trial, followed by a 10-week open-label phase. Each session lasted 30 min; the anode was placed over the left dorsolateral prefrontal cortex and the cathode over the right dorsolateral prefrontal cortex (active tDCS 2 mA and sham tDCS 0 mA, with brief ramp up and down to mimic active stimulation). As the primary outcome, depressive symptoms showed significant improvement when measured using the Hamilton Depression Rating Scale: active 9.41 ± 6.25 point improvement (10-week mean = 9.58 ± 6.02) and sham 7.14 ± 6.10 point improvement (10-week mean = 11.66 ± 5.96) (95% confidence interval = 0.51-4.01, P = 0.012). There were no differences in discontinuation rates. In summary, a 10-week home-based tDCS treatment with remote supervision in MDD showed high efficacy, acceptability and safety. ClinicalTrials.gov registration: NCT05202119., Competing Interests: Competing interests: C.H.Y.F. reports the following competing interests: research grant funding on behalf of the University of East London from Flow Neuroscience (no. R102696); research grant funding from NIMH (no. R01MH134236), the Baszucki Brain Research Fund Milken Institute (no. BD0000009), the Rosetrees Trust (no. CF20212104), the International Psychoanalytic Society (no. 158102845), the MRC (no. G0802594), NARSAD and the Wellcome Trust. She is Associate Editor of Psychoradiology and Section Editor of the Brain Research Bulletin. A.H.Y. reports the following competing interests: paid lectures and advisory boards for the following companies with therapies used in affective and related disorders: Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema Pharma, Compass, AstraZeneca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, LivaNova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, Sage, Novartis and Neurocentrx. He is principal investigator for the following studies: the Restore-Life VNS registry study funded by LivaNova; ESKETINTRD3004: ‘An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression’; The Effects of Psilocybin on Cognitive Function in Healthy Participants; The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD); A Double-Blind, Randomized, Parallel-Group Study with Quetiapine Extended Release as Comparator to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy (Janssen); An Open-label, Long-term, Safety and Efficacy Study of Aticaprant as Adjunctive Therapy in Adult and Elderly Participants with Major Depressive Disorder (MDD) (Janssen); A Randomized, Double-blind, Multicentre, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants with Major Depressive Disorder (MDD) with Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy; A Study of Disease Characteristics and Real-life Standard of Care Effectiveness in Patients with Major Depressive Disorder (MDD) With Anhedonia and Inadequate Response to Current Antidepressant Therapy Including an SSRI or SNR (Janssen). He is UK Chief Investigator for the following studies: Novartis MDD study no. MIJ821A12201; Compass; and the COMP006 and COMP007 studies. Grant funding (past and present) includes: NIMH (USA); CIHR (Canada); NARSAD (USA); the Stanley Medical Research Institute (USA); MRC (UK); the Wellcome Trust (UK); the Royal College of Physicians of Edinburgh; the British Medical Association (UK); the VGH & UBC Foundation (Canada); WEDC (Canada); the CCS Depression Research Fund (Canada); the Michael Smith Foundation for Health Research (Canada); NIHR (UK). Janssen (UK) and EU Horizon 2020. He is the Editor of the Journal of Psychopharmacology and Deputy Editor of BJPsych Open. He has no shareholdings in pharmaceutical companies. S.S. reports the following competing interests: research grant funding on behalf of the University of Texas Health Science Center at Houston from Flow Neuroscience; paid advisory boards for the following companies: Worldwide Clinical Trials and Inversago; and Vicore Pharma. He is a full-time employee of Intra-Cellular Therapies. He has received grants and research support from NIMH (USA) (no. 1R21MH119441-01A1), NIMH (no. 1R21MH129888-01A1), NICHD (no. 1R21HD106779-01A1), SAMHSA (no. 6H79FG000470-01M003) and Fizer foundation. He has received research funding as a principal investigator or study/subinvestigator from or participated as consultant/speaker for Flow Neuroscience, COMPASS Pathways, LivaNova, Janssen, Relmada and the Psychiatry Education Forum. Intra-Cellular Therapies or National Institutes of Health (NIH) or SAMHSA or any other organizations had no role in study design and conduct; the collection, management, analysis and interpretation of the data; the preparation, review or approval of the manuscript; and the decision to submit the manuscript for publication. The study’s content is solely the responsibility of the authors and does not necessarily represent the official views of the Intra-Cellular Therapies or NIH or SAMHSA. R.M-V. has received consulting fees from Eurofarma Pharmaceuticals, Abbott and BioStrategies group; has research contracts with Boerhinger Ingelheim and Janssen Pharmaceuticals; and has received speaker fees from Otsuka, EMS and Cristalia. He is a member of the scientific boards of Symbinas Pharmaceuticals and Allergan. He is also the principal investigator for the following grants: NIH (nos. R21HD106779 and R21MH129888), Milken Institute (no. BD-0000000081). D.M. and L.H. work for Biomedical Statistical Consulting; they provide statistical support to MCRA and received payments from Flow Neuroscience. A.-R.G.-N., G.S., H.H., J.C.S., M.R., N.L., P.J.L., P.O., R.D.W. and S.S.K. declare no competing interests., (© 2024. The Author(s).)

Background: Fatigue is a multidimensional condition that may overlap with depression. Initial studies found that fatigue responds in only a limited way to standard monoaminergic antidepressants and mood stabilizers but does respond positively to intravenous (IV) racemic (R,S)-ketamine (ketamine). However, IV ketamine's use is limited by cost and access barriers. To date, no study has evaluated intranasal (IN) ketamine in individuals with fatigue. This study sought to evaluate the anti-fatigue effects of a single 50 mg dose of IN ketamine in individuals with major depressive disorder (MDD) or bipolar depression (BDep), both with and without comorbid alcohol use disorder (AUD)., Methods: Twenty-eight individuals with primary diagnoses of MDD or BDep I/II currently experiencing a depressive episode with active suicidality were enrolled; approximately 60 % had comorbid AUD. Changes in the NIH-Brief Fatigue Inventory (NIH-BFI) were assessed at baseline and at 4, 24, and 48 h post-treatment., Results: The group x time interaction for NIH-BFI score was significant (F = 3.44, p = 0.022), favoring IN ketamine over placebo. IN ketamine was well-tolerated with minimal adverse effects., Limitations: Limitations include the limited sample size, short duration, and single, fixed dose., Conclusions: IN ketamine appears to induce rapid anti-fatigue effects in individuals with severe MDD and BDep both with and without comorbid AUD. This suggests that IN ketamine holds potential as an alternative, rapid-acting, anti-fatigue option for different medical conditions., Competing Interests: Declaration of competing interest Dr. Machado-Vieira has received consulting fees from Eurofarma Pharmaceuticals, Abbott, and BioStrategies group; has research contracts with Boerhinger Ingelheim and Janssen Pharmaceuticals; has received speaker fees from Otsuka, EMS, and Cristalia; and is a member of the scientific boards of Symbinas Pharmaceuticals and Allergan. Dr. Machado-Vieira is also the PI for the following grants: NIH (R21HD106779 and R21MH129888), Milken Institute (BD-0000000081), Dr Machado-Vieira was PI for the Janssen 54135419TRD4005 study. Dr. Soares has served on the Advisory Board of Alkermes; as a Consultant for Boehringer, Johnson and Johnson, Livanova, and Sunovian; and received research grants from Compass Pathways, Mind Med, and Relmada. Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise., (Copyright © 2024. Published by Elsevier B.V.)

Psychedelic substances such as psilocybin have recently gained attention for their potential therapeutic benefits in treating depression and other mental health problems. However, individuals with bipolar disorder (BD) have been excluded from most clinical trials due to concerns about manic switches or psychosis. This study aimed to systematically examine the effects of recreational psychedelic use in individuals with BD. Using the Timeline Followback (TLFB) method, we assessed mood symptoms, substance use, and other mental health-related variables in the month before and three months following participants' most recent psychedelic experience. Results showed a significant reduction in depressive symptoms and cannabis use, an increase in the number of days without mental health symptoms, and an increase in the number of days with hallucinogen use. Importantly, no significant changes in (hypo)manic, psychotic, or anxiety symptoms were observed. These findings suggest that psychedelics may hold potential as a safe and effective treatment for BD, though further research, including randomized controlled trials, is needed., Competing Interests: Declaration of competing interest This research did not receive any external funding from the public, commercial, or not-for-profit sectors. No conflicts of interest to disclose with regards to this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: There is a robust relationship between depression and substance use in youth, with higher levels of substance use associated with greater depressive symptomatology. However, previous research has examined individual substances, without consideration of psychiatric comorbidities. Here, we investigate patterns of substance use among depressed and/or suicidal youth within the context of psychiatric comorbidities., Methods: 945 youth with depression and/or suicidality from the Texas Youth Depression and Suicide Research Network (TX-YDSRN) were assessed for current use of alcohol, nicotine, cannabis, and other drugs and comorbid psychiatric diagnoses. We used latent class analysis to identify patterns of past-year substance use, then examined if demographics or psychiatric disorders predicted class membership., Results: We identified three patterns of substance use: non-use (63.4 %), moderate likelihood of using alcohol, nicotine and cannabis (23.8 %), and high likelihood of using all substances (12.7 %). Compared to non-users, individuals in the moderate and high likelihood classes were more likely to be older. Individuals in the high likelihood class were more likely to have a substance use disorder, ADHD, and higher suicidality scores., Limitations: We cannot ascertain the causal or temporal ordering of substance use and psychiatric diagnoses due to the cross-sectional nature of the study., Conclusions: Using a brief, self-report measure of substance use, we identified three classes of substance users differing in probability of past-year use, which were predicted by older age and some psychiatric comorbidities. While research on universal screening of substance use in youth remains limited, we discuss who may benefit from such screening among depressed youth., Competing Interests: Declaration of competing interest Drs. Mitchell and Wakefield serve as Executive Committee Members of the Texas Child Mental Health Care Consortium. Dr. Jha has received contract research grants from Acadia Pharmaceuticals, Neurocrine Bioscience, Navitor/Supernus and Janssen Research & Development; honorarium to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network and as Guest Editor for Psychiatric Clinics of North America from Elsevier; consultant fees from Eleusis Therapeutics US, Inc., Janssen Global Services, Janssen Scientific Affairs, Boehringer Ingelheim, and Guidepoint Global; fees to serve on Data Safety and Monitoring Board for Worldwide Clinical Trials (Eliem and Inversargo), Vicore Pharma and IQVIA (Click); and honoraria for educational presentations from North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, H.C. Wainwright & Co., and Global Medical Education. Dr. Soares has served as a consultant to Boehringer Ingelheim, Livanova, Sunovian, and Johnson & Johnson. He has served on the advisory board of Alkermes and received research grants from Compass Pathways, Mind Med, and Relmada Therapeutics Inc. Dr. Trivedi has provided consulting services to Acadia Pharmaceuticals, Alkermes Inc., Alto Neuroscience Inc., Axsome Therapeutics, BasePoint Health management LLC, Biogen MA Inc., Cerebral Inc., Circular Genomics Inc., Compass Pathfinder Limited, Daiichi Sankyo Inc., GH Research, GreenLight VitalSign6 Inc., Heading Health, Janssen Pharmaceutical, Legion Health, Merck Sharp & Dohme Corp., Mind Medicine Inc., Myriad Neuroscience, Naki Health Ltd., Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka America Pharmaceutical Inc., Otsuka Europe LTD, Otsuka Pharmaceutical Development & Commercialization Inc., Praxis Precision Medicines Inc., PureTech LYT Inc., Relmada Therapeutics Inc., SAGE Therapeutics, Signant Health, Sparian Biosciences, Titan Pharmaceuticals, Takeda Pharmaceuticals Inc., WebMD. He has received grant/research funding from NIMH, NIDA, NCATS, American Foundation for Suicide Prevention, Patient-Centered Outcomes Research Institute (PCORI), Blue Cross Blue Shield of Texas, SAMHSA, and the DoD. Additionally, he has received editorial compensation from Elsevier and Oxford University Press. No other authors have interests to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bipolar disorder (BD) has been linked to accelerated aging processes, with many studies suggesting that drugs used to treat BD may modulate pathways related to aging. This systematic review aimed to determine whether FDA-approved pharmacotherapies for BD have reported effects on aging biomarkers across clinical and preclinical studies. We conducted searches in PubMed and PsychINFO and followed PRISMA guidelines. Out of 6400 records identified, 19 studies met the inclusion criteria. Most preclinical studies tested the effects of BD drugs, especially lithium, on lifespan and telomere biology in cell and animal models. Clinical studies predominantly focused on lithium, evaluating aging markers like telomere length, telomerase, mitochondrial DNA copy number, and epigenetic age acceleration in individuals with BD. Findings indicate that chronic lithium treatment is associated with modulatory effects on aging biomarkers, particularly increased telomere length and telomerase activity. Conversely, some negative results were also reported. Limited evidence suggests potential aging-modulating properties of other mood stabilizers like valproic acid and lamotrigine, evidencing that further investigation is required. Despite variability across studies, the overall findings support the notion that pharmacotherapies used in BD present many effects of aging biomarkers. However, the field is still developing, with a clear emphasis on lithium and a lack of standardized methods to evaluate aging biomarkers in clinical samples. Further research exploring the anti-accelerated aging effects of BD drugs beyond lithium, their mechanisms of action, and potential synergistic effects is warranted., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gabriel R. Fries reports financial support was provided by National Institute of Mental Health and Milken Institute, and Tatiana Barichello reports financial support was provided by the National Institute on Aging, the Texas Alzheimer's Research and Care Consortium, and The National Football League Players Association. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy, axial diffusivity, mean diffusivity and radial diffusivity) for 25 WM tracts were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of suicide attempt ( n =652; mean age=35.4±14.7; female=71.8%), individuals with a psychiatric diagnosis but no STB (i.e., clinical controls; n =1871; mean age=34±14.8; female=59.8%), and individuals with no mental disorder diagnosis and no STB (i.e., healthy controls; n =642; mean age=29.6±13.1; female=62.9%). We also compared these measures among individuals with recent suicidal ideation ( n =714; mean age=36.3±15.3; female=66.1%), clinical controls ( n =1184; mean age=36.8±15.6; female=63.1%), and healthy controls ( n =1240; mean age= 31.6±15.5; female=61.0%). We found subtle but statistically significant effects, such as lower fractional anisotropy associated with a history of suicide attempt, over and above the effect of psychiatric diagnoses. These effects were strongest in the corona radiata, thalamic radiation, fornix/stria terminalis, corpus callosum and superior longitudinal fasciculus. Effect sizes were small (Cohen's d < 0.25). Recent suicidal ideation was not associated with alterations in WM microstructure. This large-scale coordinated mega-analysis revealed subtle regional and global alterations in WM microstructure in individuals with a history of suicide attempt. Longitudinal studies are needed to confirm whether these alterations are a risk factor for suicidal behaviour., Competing Interests: Conflicts of interest ALvH receives consultancy fees from the Augeo foundation. CAZ is a full-time US government employee. He is listed as a co-inventor on a patent for the use of ketamine and its metabolites in major depression and suicidal ideation. Dr. Zarate has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. HPB has consulted to the Milken Institute. MW is a member of the following advisory boards and gave presentations to the following companies: Bayer AG, Germany; Boehringer Ingelheim, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with MDD, unrelated to this investigation. MW did not receive any financial compensation from the companies mentioned above. IA received speakers honorarium from Lundbeck. IBH is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. AC reports being currently an employee of the Regeneron Genetics Center, and may own Regeneron stock or stock options. JCS acknowledge to be related with the next companies ALKERMES (Advisory Board), BOEHRINGER Ingelheim (Consultant), COMPASS Pathways (Research Grant), JOHNSON & JOHNSON (Consultant), LIVANOVA (Consultant), RELMADA (Research Grant), SUNOVION (Research Grant),Mind Med (Research Grant). PMP received payment or honoraria for lectures and presentations in educational events for Sandoz, Daiichi Sankyo, Eurofarma, Abbot, Libbs, Instituto Israelita de Pesquisa e Ensino Albert Einstein, Instituto D’Or de Pesquisa e Ensino. All other authors report no biomedical financial interests, disclosures or potential conflicts of interest.

Although specific risk factors for brain alterations in bipolar disorders (BD) are currently unknown, obesity impacts the brain and is highly prevalent in BD. Gray matter correlates of obesity in BD have been well documented, but we know much less about brain white matter abnormalities in people who have both obesity and BD. We obtained body mass index (BMI) and diffusion tensor imaging derived fractional anisotropy (FA) from 22 white matter tracts in 899 individuals with BD, and 1287 control individuals from 20 cohorts in the ENIGMA-BD working group. In a mega-analysis, we investigated the associations between BMI, diagnosis or medication and FA. Lower FA was associated with both BD and BMI in six white matter tracts, including the corpus callosum and thalamic radiation. Higher BMI or BD were uniquely associated with lower FA in three and six white matter tracts, respectively. People not receiving lithium treatment had a greater negative association between FA and BMI than people treated with lithium in the posterior thalamic radiation and sagittal stratum. In three tracts BMI accounted for 10.5 to 17% of the negative association between the number of medication classes other than lithium and FA. Both overweight/obesity and BD demonstrated lower FA in some of the same regions. People prescribed lithium had a weaker association between BMI and FA than people not on lithium. In contrast, greater weight contributed to the negative associations between medications and FA. Obesity may add to brain alterations in BD and may play a role in effects of medications on the brain., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Objectives: To compare the prevalence of physical morbidities between older aged patients with bipolar disorder (OABD) and non-psychiatric comparisons (NC), and to analyze sex differences in prevalence., Methods: OABD was defined as bipolar disorder among adults aged ≥50 years. Outcomes analyzed were the prevalence of diseases affecting the cardiovascular, respiratory, gastrointestinal, genitourinary, renal, musculoskeletal, and endocrine systems. The analysis used cross-sectional data of OABD participants (n = 878; mean age 60.9 ± 8.0 years, n = 496 (56%) women) from the collaborative Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) dataset and NC participants recruited at the same sites (n = 355; mean age 64.4 ± 9.7 years, n = 215 (61%) women)., Results: After controlling for sex, age, education, and smoking history, the OABD group had more cardiovascular (odds ratio [95% confidence interval]: 2.12 [1.38-3.30]), renal (5.97 [1.31-43.16]), musculoskeletal (2.09 [1.30-3.43]) and endocrine (1.90 [1.20-3.05]) diseases than NC. Women with OABD had more gastrointestinal (1.56 [0.99-2.49]), genitourinary (1.72 [1.02-2.92]), musculoskeletal (2.64 [1.66-4.37]) and endocrine (1.71 [1.08-2.73]) comorbidities than men with OABD, when age, education, smoking history, and study site were controlled., Conclusions: This replication GAGE-BD study confirms previous findings indicating that OABD present more physical morbidities than matched comparison participants, and that this health burden is significantly greater among women., Competing Interests: Declaration of competing interest VB-M has received honoraria from Angelini, unrelated to the present work. JBL has received grant funding from NIH, AHA, and Merck. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The environment preservation has been an important motivation to find alternative, functional, and biodegradable materials to replace polluting petrochemicals. The production of nonbiodegradable face masks increased the concentration of microplastics in the environment, highlighting the need for sustainable alternatives, such as the use of local by-products to create efficient and eco-friendly filtering materials. Furthermore, the use of smart materials can reduce the risk of contagion and virus transmission, especially in the face of possible mutations. The development of novel materials is necessary to ensure less risk of contagion and virus transmission, as well as to preserve the environment. Taking these factors into account, 16 systems were developed with different combinations of precursor materials (holocellulose, polyaniline [ES-PANI], graphene oxide [GO], silver nanoparticles [AgNPs], and activated carbon [AC]). Adsorption tests of the spike protein showed that the systems containing GO and AC were the most efficient in the adsorption process. Similarly, plate tests conducted using the VSV-IN strain cultured in HepG2 cells showed that the system containing all phases showed the greatest reduction in viral titer method. In agreement, the biocompatibility tests showed that the compounds extracted from the systems showed low cytotoxicity or no significant cytotoxic effect in human fibroblasts. As a result, the adsorption tests of the spike protein, viral titration, and biocompatibility tests showed that systems labeled as I and J were the most efficient. In this context, the present research has significantly contributed to the technological development of antiviral systems, with improved properties and increased adsorption efficiency, reducing the viral titer and contributing efficiently to public health. In this way, these alternative materials could be employed in sensors and devices for filtering and sanitization, thus assisting in mitigating the transmission of viruses and bacteria. RESEARCH HIGHLIGHTS: Sixteen virus adsorbent systems were developed with different combinations of precursor materials (holocellulose, polyaniline (ES-PANI), graphene oxide (GO), silver nanoparticles (AgNPs), and activated carbon (AC)). The system that included all of the nanocomposites holocellulose, PANI, GO, AgNPs, and AC showed the greatest reduction in viral titration. The biocompatibility tests revealed that all systems caused only mild or moderate cytotoxicity toward human fibroblasts., (© 2024 Wiley Periodicals LLC.)

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Fear conditioning is encoded by strengthening synaptic connections between the neurons activated by a conditioned stimulus (CS) and those activated by an unconditioned stimulus (US), forming a memory engram, which is reactivated during memory retrieval. In temporal associations, activity within the prelimbic cortex (PL) plays a role in sustaining a short-term, transient memory of the CS, which is associated with the US after a temporal gap. However, it is unknown whether the PL has only a temporary role, transiently representing the CS, or is part of the neuronal ensembles that support the retrieval, i.e., whether PL neurons support both transient, short-term memories and stable, long-term memories. We investigated neuronal ensembles underlying temporal associations using fear conditioning with a 5-s interval between the CS and US (CFC-5s). Controls were trained in contextual fear conditioning (CFC), in which the CS-US overlaps. We used Robust Activity Marking (RAM) to selectively manipulate PL neurons activated by CFC-5s learning and Targeted Recombination in Active Populations (TRAP2) mice to label neurons activated by CFC-5s learning and reactivated by memory retrieval in the amygdala, medial prefrontal cortex, hippocampus, perirhinal cortices (PER) and subiculum. We also computed their co-reactivation to generate correlation-based networks. The optogenetic reactivation or silencing of PL encoding ensembles either promoted or impaired the retrieval of CFC-5s but not CFC. CFC-5s retrieval reactivated encoding ensembles in the PL, PER, and basolateral amygdala. The engram network of CFC-5s had higher amygdala and PER centralities and interconnectivity. The same PL neurons support learning and stable associative memories., (© 2024. The Author(s).)

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia ( p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores ( p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Mastitis diagnosis can be made by detecting Staphylococcus aureus (S. aureus), which requires high sensitivity and selectivity. Here, we report on microfluidic genosensors and electronic tongues to detect S. aureus DNA using impedance spectroscopy with data analysis employing visual analytics and machine learning techniques. The genosensors were made with layer-by-layer films containing either 10 bilayers of chitosan/chondroitin sulfate or 8 bilayers of chitosan/sericin functionalized with an active layer of cpDNA S. aureus. The specific interactions leading to hybridization in these genosensors allowed for a low limit of detection of 5.90 × 10 -19  mol/L. The electronic tongue had four sensing units made with 6-bilayer chitosan/chondroitin sulfate films, 10-bilayer chitosan/chondroitin sulfate, 8-bilayer chitosan/sericin, and 8-bilayer chitosan/gold nanoparticles modified with sericin. Despite the absence of specific interactions, various concentrations of DNA S. aureus could be distinguished when the impedance data were plotted using a dimensionality reduction technique. Selectivity of S. aureus DNA was confirmed using multidimensional calibration spaces, based on machine learning, with accuracy up to 89 % for the genosensors and 66 % for the electronic tongue. Hence, with these computational methods one may opt for the more expensive genosensors or the simpler and cheaper electronic tongue, depending on the sensitivity level required to diagnose mastitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Although individuals with a family history of alcohol use disorder (AUD) have a superior antidepressant response to ketamine, outcomes in patients with current AUD remain unclear. This study sought to investigate whether intranasal (IN) racemic ( R,S )-ketamine had antisuicidal and antidepressant effects in unipolar and bipolar depression and whether comorbid AUD conferred superior antisuicidal outcomes for patients., Methods: This was a double-blind, randomized, placebo-controlled trial (May 2018 to January 2022) of single administration, fixed-dose (50 mg) IN ( R,S )-ketamine (or saline comparator) in unmedicated inpatients meeting Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Text Revision, criteria for a current major depressive episode (bipolar or unipolar), with current suicidal ideation (SI) and past attempt. Patients with and without comorbid AUD were enrolled. Change in Scale for Suicide Ideation score was the primary outcome measure, and change in Montgomery-Åsberg Depression Rating Scale score was the secondary outcome measure., Results: No significant group × time effect was noted for SI ( F = 1.1, P = .36). A statistical trend toward superior improvement in suicidality was observed in participants with comorbid AUD. The group × time interaction was significant for improvements in depression ( F = 3.06, P = .03) and largely unaffected by comorbid AUD or primary mood disorder type. Within the ketamine group, a significant correlation was observed between improvement in depressive symptoms and SI for patients without comorbid AUD ( r =0.927, P = .023) that was absent in patients with AUD ( r = 0.39, P = .44)., Conclusion: IN ketamine induced rapid antidepressant effects compared to placebo but did not significantly alter SI scores. The treatment was well tolerated. Continued investigation with IN ketamine as a practical alternative to current formulations is warranted., Trial Registration: ClinicalTrials.gov identifier: NCT03539887., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Purpose: Self-management and lifestyle interventions are a key factor in treatment outcomes for persons with bipolar disorder (BD). A virtual environment (VE), due to it's ability to provide flexibility of involvement in its platform, may be an alternative to face-to-face treatment to provide support for self-management. The purpose of this study is to explore how a VE, developed for chronic illness self-management, may be modified to promote self-management and lifestyle changes in those with BD., Method: This study used a qualitative description design with focus groups. Data were collected via minimally structured interviews and analyzed using thematic content analysis. A total of seven focus groups were conducted, and the sample consisted of 30 adults with BD. Age range was 21-77 years with 21 females, seven males, and two non-binary individuals., Results: Five themes emerged from the findings: Self-management and lifestyle interventions with regards to (1) mental health; (2) holistic health; (3) role of peers; (4) involvement of the family; (5) technological aspects of the VE., Conclusions: Focus group participants suggested that the VE may be an efficacious way to enhance self-management and promote lifestyle interventions in those with BD. Research is needed to adapt such platforms to the need of the patients and examine its' effect on health outcomes., Competing Interests: Declaration of competing interest The authors have no declarations of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset., Design/methods: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601)., Results: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning., Conclusions: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning., (© 2024 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at >700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD., (© 2024. The Author(s).)

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects., (© 2024. The Author(s).)

Rates of youth depression and suicide are rising worldwide and represent public health crises. The present study examined the relationship between trauma history and symptoms of depression, suicidal ideation, and anxiety among suicidal and depressed youth. A diverse group of 1000 8-20-year-olds enrolled in the statewide Texas Youth Depression and Suicide Research Network (TX-YDSRN) reported their trauma history (Traumatic Events Screening Inventory for Children) and symptoms of depression (Patient Health Questionnaire for adolescents; PHQ-A), anxiety (Generalized Anxiety Disorder scale; GAD-7), and suicidality (Concise Health Risk Tracking scale; CHRT-SR). Nearly half of the sample reported exposure to multiple categories of traumatic experiences. Number of trauma exposure categories significantly predicted PHQ-A and GAD-7 scores. Exposure to interpersonal trauma and to sexual trauma were significantly associated with PHQ-A, GAD-7, and CHRT-SR scores. The number of trauma exposure categories was associated with increased levels of anxiety and depression; however, only exposure to interpersonal or sexual trauma was associated with more suicidality. Clinicians should assess trauma exposure in patients seeking psychiatric care, especially for interpersonal and sexual trauma, which may be predictive of increased risk for suicidality in depressed youth. Future work should disentangle the effects of specific trauma types from multiple trauma exposure., Competing Interests: Declaration of Competing Interest Dr. Blader reports having received consultant and speakers’ honoraria from Supernus Pharmaceuticals. Dr. Brown has received consulting fees from Sage and Biogen Pharmaceuticals. Dr. Soares has served as an advisor or consultant for Asofarma, Boehringer Ingelheim, Johnson & Johnson, Livanova, Pfizer, Pulvinar Neuro LLC, Relmada, Sanofi, and Sunovian. He has received research grants from Alkermes, Allergan, and Compass and holds less than U.S. $5,000 in Atai Life Sciences stock. Dr. Wakefield serves as an Executive Committee Member of the Texas Child Mental Health Care Consortium. Dr. Trivedi has received research funding from NIMH, NIDA, NCATS, the American Foundation for Suicide Prevention, the Patient-Centered Outcomes Research Institute, and the Blue Cross Blue Shield of Texas. He has served as a consultant or advisor for ACADIA Pharmaceuticals, Alkermes Inc., Alto Neuroscience Inc, Applied Clinical Intelligence, LLC, Axsome Therapeutics, Biogen MA Inc, Boegringer Ingelheim, Cerebral Inc., Circular Genomics Inc., Compass Pathfinder Limited, Daiichi Sankyo Inc, GH Research, GreenLight VitalSign6 Inc, Heading Health, Health Care 16 Global Village, Janssen Pharmaceutical, Legion Health, Lundbeck Research USA, Merck Sharp & Dohme Corp., Mind Medicine Inc., Myriad Neuroscience, Naki Health Ltd, Navitor, Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka America Pharmaceutical Inc, Perception Neuroscience Holdings, Pharmerit International, Policy Analysis Inc., Praxis Precision Medicines Inc, Relmada Therapeutics Inc., Rexahn Pharmaceuticals, Inc., SAGE Therapeutics, Signant Health, Sparian Biosciences, Titan Pharmaceuticals, Takeda Pharmaceuticals Inc, WebMD. He has received grant/research funding from NIMH, NIDA, NCATS, American Foundation for Suicide Prevention, Patient-Centered Outcomes Research Institute (PCORI), and Blue Cross Blue Shield of Texas. Additionally, he has received editorial compensation from Engage Health Media, and Oxford University Press. Dr. Goodman, Mr. Elmore, Ms. Mayes, Dr. Minhajuddin, Dr. Slater, Dr. Liberzon, Dr. Baronia, Ms. Bivins, Dr. LaGrone, Ms. Jackson, and Dr. Martin have no disclosures to report., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In trace fear conditioning, the prelimbic cortex exhibits persistent activity during the interval between the conditioned and unconditioned stimuli, which maintains a conditioned stimulus representation. Regions cooperating for this function or encoding the conditioned stimulus before the interval could send inputs to the prelimbic cortex, supporting learning. The basolateral amygdala has conditioned stimulus- and unconditioned stimulus-responsive neurons, convergently activated. The prelimbic cortex could directly project to the basolateral amygdala to associate the transient memory of the conditioned stimulus with the unconditioned stimulus. We investigated the neuronal circuit supporting temporal associations using contextual fear conditioning with a 5-s interval, in which 5 s separates the contextual conditioned stimulus from the unconditioned stimulus. Injecting retrobeads, we quantified c-Fos in prelimbic cortex- or basolateral amygdala-projecting neurons from 9 regions after contextual fear conditioning with a 5-s interval or contextual fear conditioning, in which the conditioned and unconditioned stimuli overlap. The contextual fear conditioning with a 5-s interval activated ventral CA1 and perirhinal cortex neurons projecting to the prelimbic cortex and prelimbic cortex neurons projecting to basolateral amygdala. Both fear conditioning activated ventral CA1 and lateral entorhinal cortex neurons projecting to basolateral amygdala and basolateral amygdala neurons projecting to prelimbic cortex. The perirhinal cortex → prelimbic cortex and ventral CA1 → prelimbic cortex connections are the first identified prelimbic cortex afferent projections participating in temporal associations. These results help to understand time-linked memories, a process required in episodic and working memories., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Alzheimer's disease (AD) and other classes of dementia are important public health problems with overwhelming social, physical, and financial effects for patients, society, and their families and caregivers. The pathophysiology of AD is poorly understood despite the extensive number of clinical and experimental studies. The brain's lipid-rich composition is linked to disturbances in lipid homeostasis, often associated with glucose and lipid abnormalities in various neurodegenerative diseases, including AD. Moreover, elevated low-density lipoprotein (LDL) cholesterol levels may be related to a higher probability of AD. Here, we hypothesize that lipids, and electronegative LDL (L5) in particular, may be involved in the pathophysiology of AD. Although changes in cholesterol, triglyceride, LDL, and glucose levels are seen in AD, the cause remains unknown. We believe that L5-the most electronegative subfraction of LDL-may be a crucial factor in understanding the involvement of lipids in AD pathology. LDL and L5 are internalized by cells through different receptors and mechanisms that trigger separate intracellular pathways. One of the receptors involved in L5 internalization, LOX-1, triggers apoptotic pathways. Aging is associated with dysregulation of lipid homeostasis, and it is believed that alterations in lipid metabolism contribute to the pathogenesis of AD. Proposed mechanisms of lipid dysregulation in AD include mitochondrial dysfunction, blood-brain barrier disease, neuronal signaling, inflammation, and oxidative stress, all of which lead ultimately to memory loss through deficiency of synaptic integration. Several lipid species and their receptors have essential functions in AD pathogenesis and may be potential biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Akyol, Akyol, Chou, Chen, Liu, Selek, Soares and Chen.)

Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L -glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABA A receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.

Background: American youth are seriously impacted by depression and suicide. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) Participant Registry Study was initiated in 2020 to develop predictive models for treatment outcomes in youth with depression and/or suicidality. This report presents the study rationale, design and baseline characteristics of the first 1000 participants., Methods: TX-YDSRN consists of the Network Hub (coordinating center), 12 medical school "Nodes" (manage/implement study), each with 1-5 primary care, inpatient, and/or outpatient Sub-Sites (recruitment, data collection). Participants are 8-20-year-olds who receive treatment or screen positive for depression and/or suicidality. Baseline data include mood and suicidality symptoms, associated comorbidities, treatment history, services used, and social determinants of health. Subsequent assessments occur every two months for 24 months., Results: Among 1000 participants, 68.7 % were 12-17 years, 24.6 % were ≥ 18 years, and 6.7 % were < 12. Overall, 36.8 % were non-Hispanic Caucasian, 73.4 % were female, and 79.9 % had a primary depressive disorder. Nearly half of the sample reported ≥1 suicide attempt, with rates similar in youth 12-17 years old (49.9 %) and those 18 years and older (45.5 %); 29.9 % of children <12 reported at least one suicide attempt. Depression and anxiety scores were in the moderate-severe range for all age groups (Patient Health Questionnaire for Adolescents [PHQ-A]: 12.9 ± 6.4; Generalized Anxiety Disorder [GAD-7]: 11.3 ± 5.9)., Limitations: The sample includes youth who are receiving depression care at enrollment and may not be representative of non-diagnosed, non-treatment seeking youth., Conclusions: The TX-YDSRN is one of the largest prospective longitudinal cohort registries designed to develop predictive models for outcome trajectories based on disorder heterogeneity, social determinants of health, and treatment availability., Competing Interests: Declaration of competing interest Dr. Trivedi has provided consulting services to Alkermes Inc., Axsome Therapeutics, Biogen MA Inc., Cerebral Inc., Circular Genomics Inc., Compass Pathfinder Limited, GH Research Limited, Heading Health Inc., Janssen, Legion Health Inc., Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc., Merck Sharp & Dhome LLC, Naki Health, Ltd., Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka American Pharmaceutical Inc., Otsuka Canada Pharmaceutical Inc., Otsuka Pharmaceutical Development & Commercialization Inc., Praxis Precision Medicines Inc., SAGE Therapeutics, Sparian Biosciences Inc., Takeda Pharmaceutical Company Ltd., WebMD. He sits on the Scientific Advisory Board of Alto Neuroscience Inc., Cerebral Inc., Compass Pathfinder Limited, Heading Health, GreenLight VitalSign6 Inc., Legion Health Inc., Merck Sharp & Dohme Corp, Orexo US Inc., Signant Health. He holds stock in Alto Neuroscience Inc., Cerebral Inc., Circular Genomics Inc., GreenLight VitalSign6 Inc., Legion Health Inc. Additionally, he has received editorial compensation from American Psychiatric Association, and Oxford University Press. Dr. Blader reports having received consultant and speakers' honoraria from Supernus Pharmaceuticals. Dr. Brown has received consulting fees from Sage and Biogen Pharmaceuticals. Dr. Hughes reports receiving research funding to her institution from NIH and the American Foundation for Suicide Prevention (AFSP). She reports receiving support from the Society of Clinical Child and Adolescent Psychology, the Jed Foundation, and Mental Health in Mind, International AB, and consulting on quality improvement interventions for depression and suicidal/self-harm behavior. She receives book royalties from Guilford Press. Dr. Kennard receives royalties from Guilford, Press, Inc.; and serves on the board of trustees for the Jerry M. Lewis, III, MD Research Foundation. Dr. Soares has served as an advisor or consultant for Asofarma, Boehringer Ingelheim, Johnson & Johnson, Livanova, Pfizer, Pulvinar Neuro LLC, Relmada, Sanofi, and Sunovian. He has received research grants from Alkermes, Allergan, and Compass and holds less than U.S. $5000 in Atai Life Sciences stock. Dr. Soutullo reports for the period 2018–2022 non-personal research funds from Lundbeck and Janssen; is a consultant/advisory board member of Editorial Médica Panamericana, EUNETHYDIS (European Network on Hyperkinetic Disorder), NeuroTech Solutions Ltd. (Israel), Limbix Health DSMB (United States), MEDEA (Spain), Tech Innosphere Engineering LTD (Germany), and Shire/now part of Takeda (Spain); received speaker's bureau fees from Bial (Portugal), Cuquerella Medical Consulting (Spain), Medice (Germany), Rubio (Spain), Tecnofarma (Peru), and Shire/now part of Takeda (Spain), and royalties from Editorial Médica Panamericana (Spain). Dr. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He is a consultant for Brainsway and Biohaven Pharmaceuticals. He owns stock less than $5000 in NView. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, and Jessica Kingsley. Dr. Wakefield serves as an Executive Committee Member of the Texas Child Mental Health Care Consortium. Drs. Minhajuddin, Slater, Baronia, DeFelippis, Farmer, Garza, Liberzon, Martin, and Mrs. Mayes have no declarations to report., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: By 2030, over 50% of individuals living with bipolar disorder (BD) are expected to be aged ≥50 years. However, older age bipolar disorder (OABD) remains understudied. There are limited large-scale prospectively collected data organized in key dimensions capable of addressing several fundamental questions about BD affecting this subgroup of patients., Methods: We developed initial recommendations for the essential dimensions for OABD data collection, based on (1) a systematic review of measures used in OABD studies, (2) a Delphi consensus of international OABD experts, (3) experience with harmonizing OABD data in the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD, n ≥ 4500 participants), and (4) critical feedback from 34 global experts in geriatric mental health., Results: We identified 15 key dimensions and variables within each that are relevant for the investigation of OABD: (1) demographics, (2) core symptoms of depression and (3) mania, (4) cognition screening and subjective cognitive function, (5) elements for BD diagnosis, (6) descriptors of course of illness, (7) treatment, (8) suicidality, (9) current medication, (10) psychiatric comorbidity, (11) psychotic symptoms, (12) general medical comorbidities, (13) functioning, (14) family history, and (15) other. We also recommend particular instruments for capturing some of the dimensions and variables., Conclusion: The essential data dimensions we present should be of use to guide future international data collection in OABD and clinical practice. In the longer term, we aim to establish a prospective consortium using this core set of dimensions and associated variables to answer research questions relevant to OABD., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Although mitochondrial dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. An emerging paradigm suggests mitochondria play an important non-energetic role in adaptation to stress, impacting cellular resilience and acting as a source of systemic allostatic load. Known as mitochondrial allostatic load, this (phenomenon) occurs when mitochondria are unable to recalibrate and maintain cell homeostasis. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls. We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. In this study, 14 BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. Ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. After adjusting for confounding variables, such as age, sex, body mass index (BMI), and smoking status, patients with BD presented lower MHI compared to non-psychiatry controls, as well as higher ccf-mtDNA levels that negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, MHI and ccf-mtDNA were also examined in relation to several MQC-related proteins, such as Fis-1, Opa-1, and LC3. Our results showed that MHI correlated negatively with Fis-1 and positively with Opa-1 and LC3. Accordingly, ccf-mtDNA had a positive correlation with Fis-1 and a negative correlation with Opa-1 and LC3. Furthermore, we found a noteworthy inverse correlation between illness severity and MHI, with lower MHI and higher ccf-mtDNA levels in subjects with a longer illness duration, worse functional status, and higher depressive symptoms. Our findings indicate that mitochondrial allostatic load contributes to BD, suggesting mitochondria represent a potential biological intersection point that could contribute to impaired cellular resilience and increased vulnerability to stress and mood episodes. Ultimately, by linking mitochondrial dysfunction to disease progression and poor outcomes, we might be able to build a predictive marker that explains how mitochondrial function and its regulation contribute to BD development and that may eventually serve as a treatment guide for both old and new therapeutic targets., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Transcranial direct current stimulation (tDCS) has been used as treatment for depression, but its effects are heterogeneous. We investigated, in a subsample of the clinical trial Escitalopram versus Electrical Direct Current Therapy for Depression Study (ELECTTDCS), whether white matter areas associated with depression disorder were associated with tDCS response. Baseline diffusion tensor imaging data were analyzed from 49 patients (34 females, mean age 41.9) randomized to escitalopram 20 mg/day, tDCS (2 mA, 30 min, 22 sessions), or placebo. Antidepressant outcomes were assessed by Hamilton Depression Rating Scale-17 (HDRS) after 10-week treatment. We used whole-brain tractography for extracting white matter measures for anterior corpus callosum, and bilaterally for cingulum bundle, striato-frontal, inferior occipito-frontal fasciculus and uncinate. For the rostral body, tDCS group showed higher MD associated with antidepressant effects (estimate = -5.13 ± 1.64, p = 0.002), and tDCS significantly differed from the placebo and the escitalopram group. The left striato-frontal tract showed higher FA associated with antidepressant effects (estimate = -2.14 ± 0.72, p = 0.003), and tDCS differed only from the placebo group. For the right uncinate, the tDCS group lower AD values were associated with higher HDRS decrease (estimate = -1.45 ± 0.67, p = 0.031). Abnormalities in white matter MDD-related areas are associated with tDCS antidepressant effects. Suggested better white matter microstructure of the left prefrontal cortex was associated with tDCS antidepressant effects. Future studies should investigate whether these findings are driven by electric field diffusion and density in these areas., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

In fear conditioning with time intervals between the conditioned (CS) and unconditioned (US) stimuli, a neural representation of the CS must be maintained over time to be associated with the later US. Usually, temporal associations are studied by investigating individual brain regions. It remains unknown, however, the effect of the interval at the network level, uncovering functional connections cooperating for the CS transient memory and its fear association. We investigated the functional network supporting temporal associations using a task in which a 5-s interval separates the contextual CS from the US (CFC-5s). We quantified c-Fos expression in forty-nine brain regions of male rats following the CFC-5s training, used c-Fos correlations to generate functional networks, and analyzed them by graph theory. Control groups were trained in contextual fear conditioning, in which CS and US overlap. The CFC-5s training additionally activated subdivisions of the basolateral, lateral, and medial amygdala; prelimbic, infralimbic, perirhinal, postrhinal, and intermediate entorhinal cortices; ventral CA1 and subiculum. The CFC-5s network had increased amygdala centrality and higher amygdala internal and external connectivity with the retrosplenial cortex, thalamus, and hippocampus. Amygdala and thalamic nuclei were network hubs. Functional connectivity among these brain regions could support CS transient memories and their association., (© 2023. Springer Nature Limited.)

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at > 700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold-changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical predictor in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

In temporal associations, a conditioned stimulus (CS) is separated by a time interval from the unconditioned stimulus (US), which activates the prelimbic cortex (PL) to maintain a CS representation over time. However, it is unknown whether the PL participates, besides the encoding, in the memory consolidation, and thus directly, with activity-dependent changes or indirectly, by modulation of activity-dependent changes in other brain regions. We investigated brain regions supporting the consolidation of associations with intervals and the influence of PL activity in this consolidation process. For this, we observed in Wistar rats the effect of pre-training PL inactivation by muscimol in CREB (cAMP response element-binding protein) phosphorylation, which is essential for memory consolidation, in subdivisions of the medial prefrontal cortex (mPFC), hippocampus, and amygdala 3 h after the training in the contextual fear conditioning (CFC) or CFC with 5-s interval (CFC-5s), fear associations without or with an interval between the CS and US, respectively. Both the CFC-5s and CFC training increased phosphorylation of CREB in the PL and infralimbic cortex (IL); lateral (LA) and basolateral (BLA) amygdala; dorsal CA1 (dCA1); dorsal (dDG), and ventral dentate gyrus, and the CFC-5s training in the central amygdala (CEA). PL activity was necessary for the CREB phosphorylation in the PL, BLA, CEA, dCA1, and dDG only in animals trained in the CFC-5s. The cingulate cortex, ventral CA1, and ventral subiculum did not have learning-induced phosphorylation of CREB. These results suggest that the mPFC, hippocampus, and amygdala support the consolidation of associations with or without intervals and that PL activity influences consolidation in the dorsal hippocampus and amygdala in temporal associations. Thereby, the PL contributes directly and indirectly by modulation to memory consolidation. The time interval engaged the PL early in recent memory consolidation. Results expanded PL's role beyond the time interval and remote memory consolidation., (© 2023 Wiley Periodicals LLC.)

Early detection of potential side effects (SE) is a critical and challenging task for drug discovery and patient care. In-vitro or in-vivo approach to detect potential SEs is not scalable for many drug candidates during the preclinical stage. Recent advances in explainable machine learning may facilitate detecting potential SEs of new drugs before market release and elucidating the critical mechanism of biological actions. Here, we leverage multi-modal interactions among molecules to develop a biologically informed graph-based SE prediction model, called HHAN-DSI. HHAN-DSI predicted frequent and even uncommon SEs of the unseen drug with higher or comparable accuracy against benchmark methods. When applying HHAN-DSI to the central nervous system, the organs with the largest number of SEs, the model revealed diverse psychiatric medications' previously unknown but probable SEs, together with the potential mechanisms of actions through a network of genes, biological functions, drugs, and SEs., Competing Interests: Competing Interests Statement We do not have a competing interest to disclose.

In this work, 13 thiosemicarbazones (1a - m) and 16 thiazoles (2a - p) were obtained, which were properly characterized by spectroscopic and spectrometric techniques. The pharmacokinetic properties obtained in silico revealed that the derivatives are in accordance with the parameters established by lipinski and veber, showing that such compounds have good bioavailability or permeability when administered orally. In assays of antioxidant activity, thiosemicarbazones showed moderate to high antioxidant potential when compared to thiazoles. In addition, they were able to interact with albumin and DNA. Screening assays to assess the toxicity of compounds to mammalian cells revealed that thiosemicarbazones were less toxic when compared to thiazoles. In relation to in vitro antiparasitic activity, thiosemicarbazones and thiazoles showed cytotoxic potential against the parasites Leishmania amazonensis and Trypanosoma cruzi. Among the compounds, 1b, 1j and 2l stood out, showing inhibition potential for the amastigote forms of the two parasites. As for the in vitro antimalarial activity, thiosemicarbazones did not inhibit Plasmodium falciparum growth. In contrast, thiazoles promoted growth inhibition. This study shows in a preliminary way that the synthesized compounds have antiparasitic potential in vitro., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Acute inflammation is associated with sickness behavior characterized by reduced motivation for pleasurable activities in humans. The current study investigated the effect of an experimentally induced inflammatory stimulus on motivational reward in people who remitted from depression., Methods: This randomized, double-blind crossover study involved 12 participants, 5 with remitted major depressive disorder (rMDD) and 7 healthy controls (HC), who received an injection of typhoid vaccine and placebo (or vice-versa) intramuscularly at least one week apart. At baseline and between 4 and 6 h post-injection on both days, participant mood was measured using the profile of mood states (POMS), and injection blood samples were collected for cytokines measurement. All participants completed the Effort Expenditure for Rewards Task (EEfRT), a behavioral paradigm measuring effort-based decision-making before and 4 h post-both injections. Generalized linear mixed modeling was used to evaluate group differences in choosing the hard over easy task to obtain a monetary reward., Results: Typhoid vaccine increased IL-6 in all participants. On the EEfRT, a significant interaction between treatment condition (typhoid vs. placebo) and participant group (HC vs. rMDD) was found (p = .004). Analyses of simple effects within treatment conditions found that after placebo, HCs were more likely to choose the harder task than rMDD (OR = 3.21; p = .013). However, after the typhoid vaccine, no differences were found between rMDD and HC (p = .397). Analyses within participant groups found that the probability of choosing a hard task was higher after placebo for HC (OR = 1.37; p = .045), but not different within rMDD (p = .241). For HC at baseline, mood was significantly lower following injection with typhoid vaccine, relative to placebo (b = -1.03, p < .001); however, this effect should be considered coincidental, given that mood rating was taken prior to injection. For rMDD patients 4-6 h post-injection, mood was significantly lower following typhoid vaccine, relative to placebo (b = -0.981, p < .001 b = -0.77, p < .001). Finally, for HC receiving placebo, mood was significantly lower 4-6 h post-injection, relative to baseline (b = -1.76, p < .001)., Conclusions: Our preliminary findings suggest persistent deficits in motivational reward processing function despite clinical improvement in remitted depressed patients., Competing Interests: Declaration of competing interest Dr. Selvaraj has received honoraria from British Medical Journal Publishing Group and Psychiatry Education Forum. He has received research support from Flow Neuroscience and study/sub investigator for clinical research, Compass Pathways, LivaNova, Janssen and Relmada. He received consultant fee for DSMB from Vicore pharma and worldwide clinical trials/Inversago. Dr. Soares has received grants/research support from BMS, Forrest, J&J, Merck, Compass pathways, Relmada, Stanley Medical Research Institute, NIH, and has been a speaker for Pfizer and Abbott. All other authors have no conflicts of interest to report., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n = 50), BD individuals with (n = 77, BD/SA) and without (n = 67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n = 48) and BD/non-SA (n = 47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F = 5.424, p = 0.005), with the highest GrimAgeAccel in BD/SA (p = 0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p = 0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

The search for brain morphology findings that could explain behavioral disorders has gone through a long path in the history of psychiatry. With the advance of brain imaging technology, studies have been able to identify brain morphology and neural circuits associated with the pathophysiology of mental illnesses, such as bipolar disorders (BD). Promising results have also shown the potential of neuroimaging findings in the identification of outcome predictors and response to treatment among patients with BD. In this chapter, we present brain imaging structural and functional findings associated with BD, as well as their hypothesized relationship with the pathophysiological aspects of that condition and their potential clinical applications.