Development of a harmonized sociodemographic and clinical questionnaire for mental health research: A Delphi-method-based consensus recommendation.

OBJECTIVE: Harmonized tools are essential for reliable data sharing and accurate identification of relevant factors in mental health research. The primary objective of this study was to create a harmonized questionnaire to collect demographic, clinical and behavioral data in diverse clinical trials in adult psychiatry. METHODS: We conducted a literature review and examined 24 questionnaires used in previously published randomized controlled trials in psychiatry, identifying a total of 27 domains previously explored. Using a Delphi-method process, a task force team comprising experts in psychiatry, epidemiology and statistics selected 15 essential domains for inclusion in the final questionnaire. RESULTS: The final selection resulted in a concise set of 22 questions. These questions cover factors such as age, sex, gender, ancestry, education, living arrangement, employment status, home location, relationship status, and history of medical and mental illness. Behavioral factors like physical activity, diet, smoking, alcohol and illicit drug use were also included, along with one question addressing family history of mental illness. Income was excluded due to high confounding and redundancy, while language was included as a measure of migration status. CONCLUSION: The recommendation and adoption of this harmonized tool for the assessment of demographic, clinical and behavioral data in mental health research can enhance data consistency and enable comparability across clinical trials.

Gender-specific aspects of socialisation and risk of cardiovascular disease among community-dwelling older adults: a prospective cohort study using machine learning algorithms and a conventional method.

BACKGROUND: Gender influences cardiovascular disease (CVD) through norms, social relations, roles and behaviours. This study identified gender-specific aspects of socialisation associated with CVD. METHODS: A longitudinal study was conducted, involving 9936 (5,231 women and 4705 men) initially healthy, community-dwelling Australians aged 70 years or more from the ASPirin in Reducing Events in the Elderly (ASPREE) study and ASPREE Longitudinal Study of Older Persons, with a median follow-up time of 6.4 years. Variable categorisation, variable selection (using machine learning (ML) models; Elastic Net and extreme gradient boosting) and Cox-regression were employed separately by binary gender to identity socialisation factors (n=25 considered) associated with CVD. RESULTS: Different socialisation factors were identified using the ML models. In the Cox model, for both genders, being married/partnered was associated with a reduced risk of CVD (men: HR 0.76, 95% CI 0.60 to 0.96; women: HR 0.67, 95% CI 0.58 to 0.95). For men, having 3-8 relatives they felt close to and could call on for help (HR 0.76, 95% CI 0.58 to 0.99; reference <3 relatives), having 3-8 relatives they felt at ease talking with about private matters (HR 0.70, 95% CI 0.55 to 0.90; reference <3 relatives) or playing games such as chess or cards (HR 0.82, 95% CI 0.67 to 1.00) was associated with reduced risk of CVD. For women, living with others (HR 0.71, 95% CI 0.55 to 0.91) or having ≥3 friends they felt at ease talking with about private matters (HR 0.74, 95% CI 0.58 to 0.95; reference <3 friends) was associated with a lower risk of CVD. CONCLUSIONS: This study demonstrates the need to prioritise gender-specific social factors to improve cardiovascular health in older adults.

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity.

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.

Machine Learning in Electroconvulsive Therapy: A Systematic Review.

ABSTRACT: Despite years of research, we are still not able to reliably predict who might benefit from electroconvulsive therapy (ECT) treatment. As we exhaust what is possible using traditional statistical analysis, ECT remains a good candidate for machine learning approaches due to the large data sets with data captured through electroencephalography (EEG) and other objective measures. A systematic review of 6 databases led to the full-text examination of 26 articles using machine learning approaches in examining data predicting response to ECT treatment. The identified articles used a wide variety of data types covering structural and functional imaging data (n = 15), clinical data (n = 5), a combination of clinical and imaging data (n = 2), EEG (n = 3), and social media posts (n = 1). The clinical indications in which response prediction was assessed were depression (n = 21) and psychosis (n = 4). Changes in multiple anatomical regions in the brain were identified as holding a predictive value for response to ECT. These primarily centered on the limbic system and associated networks. Clinical features predicting good response to ECT in depression included shorter duration, lower severity, higher medication dose, psychotic features, low cortisol levels, and positive family history. It has also been possible to predict the likelihood of relapse of readmission with psychosis after ECT treatment, including a better response if higher transfer entropy was calculated from EEG signals. A transdisciplinary approach with an international consortium collecting a wide range of retrospective and prospective data may help to refine and extend these outcomes and translate them into clinical practice.

A randomized controlled trial to compare the effects of time-restricted eating versus Mediterranean diet on symptoms and quality of life in bipolar disorder.

BACKGROUND: The primary objective of this randomized controlled trial (RCT) is to establish the effectiveness of time-restricted eating (TRE) compared with the Mediterranean diet for people with bipolar disorder (BD) who have symptoms of sleep disorders or circadian rhythm sleep-wake disruption. This work builds on the growing evidence that TRE has benefits for improving circadian rhythms. TRE and Mediterranean diet guidance will be offered remotely using self-help materials and an app, with coaching support. METHODS: This study is an international RCT to compare the effectiveness of TRE and the Mediterranean diet. Three hundred participants will be recruited primarily via social media. Main inclusion criteria are: receiving treatment for a diagnosis of BD I or II (confirmed via DIAMOND structured diagnostic interview), endorsement of sleep or circadian problems, self-reported eating window of ≥ 12 h, and no current mood episode, acute suicidality, eating disorder, psychosis, alcohol or substance use disorder, or other health conditions that would interfere with or limit the safety of following the dietary guidance. Participants will be asked to complete baseline daily food logging for two weeks and then will be randomly allocated to follow TRE or the Mediterranean diet for 8 weeks, during which time, they will continue to complete daily food logging. Intervention content will be delivered via an app. Symptom severity interviews will be conducted at baseline; mid-intervention (4 weeks after the intervention begins); end of intervention; and at 6, 9, and 15 months post-baseline by phone or videoconference. Self-rated symptom severity and quality of life data will be gathered at those timepoints, as well as at 16 weeks post baseline. To provide a more refined index of whether TRE successfully decreases emotional lability and improves sleep, participants will be asked to complete a sleep diary (core CSD) each morning and complete six mood assessments per day for eight days at baseline and again at mid-intervention. DISCUSSION: The planned research will provide novel and important information on whether TRE is more beneficial than the Mediterranean diet for reducing mood symptoms and improving quality of life in individuals with BD who also experience sleep or circadian problems. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06188754.

The contribution of alexithymia, childhood maltreatment, impulsivity, C-reactive protein, lipid profile, and thyroid hormones to aggression and psychological distress (depression and anxiety) in schizophrenia.

There are individual effects of alexithymia, childhood maltreatment, impulsivity, and some biological markers on aggression and psychological distress in schizophrenia. However, the combined effects of these psychological and biological markers have not yet been fully studied. This study therefore aimed to investigate the influence of these psychological and biological markers on aggression and psychological distress (e.g., depression and anxiety) in inpatients with schizophrenia (n = 355). Participants completed self-report and clinician-rated scales, and blood samples were collected. There were no significant differences between patients with and without alexithymia regarding biological markers. Patients with childhood maltreatment exhibited higher levels of free triiodothyronine (FT3) and C-reactive protein (CRP), as well as lower total cholesterol (TC) levels, compared to non-traumatized individuals. Aggression was positively predicted by psychological distress, alexithymia, childhood maltreatment, impulsivity, CRP, and FT3, and negatively by TC and low-density lipoprotein cholesterol. Negative symptoms, childhood maltreatment, alexithymia, aggression, and CRP positively, and high-density lipoprotein cholesterol negatively emerged as predictors of psychological distress. The study highlights the connections between childhood maltreatment, alexithymia, impulsivity, and potentially related biological dysregulation in explaining aggression and negative mood states as a bio-psychological model of aggression and mood in schizophrenia.

The neglected association between schizophrenia and bone fragility: a systematic review and meta-analyses.

Schizophrenia is associated with increased risk of medical comorbidity, possibly including osteoporosis, which is a public health concern due to its significant social and health consequences. In this systematic review and meta-analysis, we aimed to determine whether schizophrenia is associated with bone fragility. The protocol for this review has been registered with PROSPERO (CRD42020171959). The research question and inclusion/exclusion criteria were developed and presented according to the PECO (Population, Exposure, Comparison, Outcome) framework. Schizophrenia was identified from medical records, DSM-IV/5 or the ICD. The outcomes for this review were bone fragility [i.e., bone mineral density (BMD), fracture, bone turnover markers, bone quality]. A search strategy was developed and implemented for the electronic databases. A narrative synthesis was undertaken for all included studies; the results from eligible studies reporting on BMD and fracture were pooled using a random effects model to complete a meta-analysis. The conduct of the review and reporting of results adhered to PRISMA guidelines. Our search yielded 3103 studies, of which 29 met the predetermined eligibility criteria. Thirty-seven reports from 29 studies constituted 17 studies investigating BMD, eight investigating fracture, three investigating bone quality and nine investigating bone turnover markers. The meta-analyses revealed that people with schizophrenia had lower BMD at the lumbar spine [standardised mean difference (SMD) -0.74, 95% CI -1.27, -0.20; Z = -2.71, p = 0.01] and at the femoral neck (SMD -0.78, 95% CI -1.03, -0.53; Z = -6.18, p ≤ 0.001). Also observed was a higher risk of fracture (OR 1.43, 95% CI 1.27, 1.61; Z = 5.88, p ≤ 0.001). Following adjustment for publication bias, the association between schizophrenia and femoral neck BMD (SMD -0.63, 95% CI -0.97, -0.29) and fracture (OR 1.32, 95% CI 1.28, 1.35) remained. Significantly increased risk of bone fragility was observed in people with schizophrenia. This association was independent of sex, participant number, methodological quality and year of publication.

New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview.

Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. SIGNIFICANCE STATEMENT: Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer.

Current Pharmacotherapies for Smoking Cessation and Promising Emerging Drugs.

OBJECTIVE: Pharmacotherapy is commonly used during quit attempts and has shown an increase in the likelihood of achieving abstinence. However, with established pharmacotherapies, abstinence rates following a quit attempt remain low, and relapse is common. This review aims to investigate the efficacy and harm profiles of current and emerging pharmacotherapies. METHODS: Literature review of current and emerging pharmacotherapies for smoking cessation and tobacco use disorder. RESULTS: Emerging pharmacotherapies include new formulations of existing therapies, drug repurposing and some new treatments. New treatments are welcome and may incorporate different mechanisms of action or different safety and tolerability profiles compared to existing treatments. However, emerging pharmacotherapies have yet to demonstrate greater efficacy compared to existing treatments. The emergence of Electronic Nicotine Delivery Systems (ENDS) or 'vaping' is a feature of the current debate around tobacco use disorder. ENDS appear to facilitate switching but not quitting and are controversial as a harm minimisation strategy. LIMITATIONS: Studies included a broad range of therapies and trial designs that should be compared with their differences taken into consideration. CONCLUSION: Strategies to successfully quit smoking vary between individuals and may extend beyond pharmacotherapy and involve complex psychosocial factors and pathways.

A Brief Workplace Training Program to Support Help-Seeking for Mental Ill-Health: Protocol for the Helipad Cluster Randomized Controlled Trial.

BACKGROUND: Most people with mental health problems do not seek help, with delays of even decades in seeking professional help. Lack of engagement with professional mental health services can lead to poor outcomes and functional impairment. However, few effective interventions have been identified to improve help-seeking in adults, and those that exist are not widely implemented to deliver public health impact. Co-designing interventions with people with lived experience of mental ill-health and other relevant stakeholders is critical to increase the likelihood of uptake and engagement with these programs. OBJECTIVE: This study aims to (1) test the effectiveness of a co-designed help-seeking program on increasing professional help-seeking intentions in employees in a workplace setting; (2) determine whether the program reduces mental illness stigma and improves help-seeking intentions and behavior, mental health literacy, mental health symptoms, and work and activity functioning relative to the control condition; (3) explore factors that facilitate broader implementation of the co-designed program; and (4) explore the cost-effectiveness of the co-designed program compared to the control condition over 6 months. METHODS: A 2-arm cluster randomized controlled trial will be conducted (target sample: N=900 from 30 to 36 workplaces, with n=25 to 35 participants per workplace). The trial will compare the relative effectiveness of an enhanced interactive program (intervention condition) with a standard psychoeducation-alone program (active control condition) on the primary outcome of professional help-seeking intentions as measured by the General Help-Seeking Questionnaire. Secondary outcomes include the impact on mental illness stigma; mental health literacy; help-seeking attitudes and behavior; work and activity functioning; quality of life; and symptoms of mental ill-health including depression, anxiety, and general psychological distress. RESULTS: Facilitators of and risks to the trial are identified and addressed in this protocol. Recruitment of workplaces is scheduled to commence in the first quarter of 2024. CONCLUSIONS: If effective, the program has the potential to be ready for rapid dissemination throughout Australia, with the potential to increase appropriate and efficient service use across the spectrum of evidence-based services. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12623000270617p; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385376. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/55529.

Depressive symptoms and cognitive decline in older adults.

OBJECTIVES: Few studies have examined the impact of late-life depression trajectories on specific domains of cognitive function. This study aims to delineate how different depressive symptom trajectories specifically affect cognitive function in older adults. DESIGN: Prospective longitudinal cohort study. SETTING: Australia and the United States of America. PARTICIPANTS: In total, 11,035 community-dwelling older adults with a mean age of 75 years. MEASUREMENTS: Depressive trajectories were modelled from depressive symptoms according to annual Centre for Epidemiological Studies Depression Scale 10 (CES-D-10) surveys. Four trajectories of depressive symptoms were identified: low ("nondepressed"), consistently mild ("subthreshold depression"), consistently moderate ("persistent depression"), and initially low but increasing ("emerging depression"). Global cognition (Modified Mini-Mental State Examination [3MS]), verbal fluency (Controlled Oral Word Association Test [COWAT]), processing speed (Symbol Digit Modalities Test [SDMT]), episodic memory (Hopkins Verbal Learning Test - Revised [HVLT-R]), and a composite z-score were assessed over a subsequent median 2 years. RESULTS: Subthreshold depression predicted impaired performance on the SDMT (Cohen's d -0.04) and composite score (-0.03); emerging depression predicted impaired performance on the SDMT (-0.13), HVLT-R (-0.09), 3 MS (-0.08) and composite score (-0.09); and persistent depression predicted impaired performance on the SDMT (-0.08), 3 MS (-0.11), and composite score (-0.09). CONCLUSIONS: Depressive symptoms are associated with later impaired processing speed. These effects are small. Diverse depression trajectories have different impacts on cognitive function.

Prior psychiatric morbidity and differential psychopharmacological treatment patterns: Exploring the heterogeneity of bipolar disorder in a nationwide study of 9594 patients.

OBJECTIVES: Individuals with bipolar disorders (BD) have heterogenic pre-onset illness courses and responses to treatment. The pattern of illness preceding the diagnosis of BD may be a marker of future treatment response. Here, we examined associations between psychiatric morbidity preceding the diagnosis of BD and pharmacological treatment patterns in the 2 years following diagnosis. METHODS: In this register-based study, we included all patients with a diagnosis of BD attending Danish Psychiatric Services between January 1, 2012 and December 31, 2016. We examined the association between a diagnosis of substance use disorder, psychosis (other than schizophrenia or schizoaffective disorder), unipolar depression, anxiety/OCD, PTSD, personality disorder, or ADHD preceding BD and pharmacological treatment patterns following the diagnosis of BD (lithium, valproate, lamotrigine, antidepressants, olanzapine, risperidone, and quetiapine) via multivariable Cox proportional hazards regression adjusted for age, sex, and year of BD diagnosis. RESULTS: We included 9594 patients with a median age of 39 years, 58% of whom were female. Antidepressants, quetiapine, and lamotrigine were the most commonly used medications in BD and were all linked to prior depressive illness and female sex. Lithium was used among patients with less diagnostic heterogeneity preceding BD, while valproate was more likely to be used for patients with prior substance use disorder or ADHD. CONCLUSION: The pharmacological treatment of BD is linked to psychiatric morbidity preceding its diagnosis. Assuming that these associations reflect well-informed clinical decisions, this knowledge may inform future clinical trials by taking participants' prior morbidity into account in treatment allocation.

Transdiagnostic Associations between Anger Hostility and Chemokine Interferon-gamma Inducible Protein 10.

Objective: Many psychiatric disorders are linked to low grade systemic inflammation as measured by systemic cytokine levels. Exploration of cytokines and immune activity and their role in psychiatric symptoms may inform pathobiology and treatment opportunities. The aim of this study is to explore if there are associations between cytokines and psychiatric symptom clusters. Comparison between patients regularly using and those not using psychotropic medication is also conducted. Methods: This was a cross sectional naturalistic study with 132 participants from a general open inpatient psychiatric ward at the Nordland Hospital Trust, Norway. Serum levels of 28 different cytokines were assessed. Psychiatric symptoms the last week were assessed by a self-rating scale (Symptom check list, SCL-90-R) and grouped in defined clusters. Multiple linear regression model was used for statistical analyses of associations between levels of cytokines and symptoms, adjusting for possible confounding factors. Results: We found a positive association (p = 0.009) between the chemokine interferon-gamma inducible protein 10 (CXCL 10; IP-10) and the anger hostility cluster. No associations were found between the other symptom clusters and cytokines. IP-10 and the anger hostility cluster were positively associated (p = 0.002) in the subgroup of patients using psychotropic medication, not in the subgroup not using psychotropic medication. Conclusion: Our analyses revealed a significant positive association between the symptom cluster anger hostility in SCL-90-R and the chemokine IP-10 in the subgroup of patients using psychotropic medications.

Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial.

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.

Cost-utility analysis of adjunct repetitive transcranial magnetic stimulation for treatment resistant bipolar depression.

OBJECTIVE: To evaluate the cost-effectiveness of repetitive transcranial magnetic stimulation (rTMS) as an adjunct to standard care from an Australian health sector perspective, compared to standard care alone for adults with treatment-resistant bipolar depression (TRBD). METHODS: An economic model was developed to estimate the cost per disability-adjusted life-year (DALY) averted and quality-adjusted life-year (QALY) gained for rTMS added to standard care compared to standard care alone, for adults with TRBD. The model simulated the time in three health states (mania, depression, residual) over one year. Response to rTMS was sourced from a meta-analysis, converted to a relative risk and used to modify the time in the depressed state. Uncertainty and sensitivity tested the robustness of results. RESULTS: Base-case incremental cost-effectiveness ratios (ICERs) were $72,299 per DALY averted (95 % Uncertainty Interval (UI): $60,915 to $86,668) and $46,623 per QALY gained (95 % UI: $39,676 - $55,161). At a willingness to pay (WTP) threshold of $96,000 per DALY averted, the base-case had a 100 % probability of being marginally cost-effective. At a WTP threshold of $64,000 per QALY gained, the base-case had a 100 % probability of being cost-effective. Sensitivity analyses decreasing the number of sessions provided, increasing the disability weight or the time spent in the depression state for standard care improved the ICERs for rTMS. CONCLUSIONS: Dependent on the outcome measure utilised and assumptions, rTMS would be considered a very cost-effective or marginally cost-effective adjunct to standard care for TRBD compared to standard care alone.

Staging 2.0: refining transdiagnostic clinical staging frameworks to enhance reliability and utility for youth mental health.

Globally, 75% of depressive, bipolar, and psychotic disorders emerge by age 25 years. However, these disorders are often preceded by non-specific symptoms or attenuated clinical syndromes. Difficulties in determining optimal treatment interventions for these emerging mental disorders, and uncertainties about accounting for co-occurring psychopathology and illness trajectories, have led many youth mental health services to adopt transdiagnostic clinical staging frameworks. In this Health Policy paper, an international working group highlights ongoing challenges in applying transdiagnostic staging frameworks in clinical research and practice, and proposes refinements to the transdiagnostic model to enhance its reliability, consistent recording, and clinical utility. We introduce the concept of within-stage heterogeneity and describe the advantages of defining stage in terms of clinical psychopathology and stage modifiers. Using examples from medicine, we discuss the utility of categorising stage modifiers into factors associated with progression (ie, potential predictors of stage transition) and extension (ie, factors associated with the current presentation that add complexity to treatment selection). Lastly, we suggest how it is possible to revise the currently used transdiagnostic staging approach to incorporate these key concepts, and how the revised framework could be applied in clinical and research practice.

Anti-manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine.

BACKGROUND: Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. AIM: The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). METHODS: Wistar rats were given 14 days of m-amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low-frequency stimulation (LFS) or continuous high-frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field tests and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. RESULTS: M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. CONCLUSION: These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.