Internet-delivered transdiagnostic psychological treatments for individuals with depression, anxiety or both: a systematic review with meta-analysis of randomised controlled trials.

OBJECTIVE: Depression and anxiety are major public health problems. This study evaluated the effects of internet-delivered transdiagnostic psychological treatments for individuals with depression, anxiety, or both. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Medline (Ovid), Cochrane Library (Wiley), the Web of Science Core Collection (Clarivate), and PsycInfo (EBSCO) were searched on 24 May 2021, with an update on 6 February 2023. ELIGIBILITY CRITERIA: Randomised controlled trials of internet-delivered transdiagnostic psychological treatments, open to both participants with primary depression and participants with primary anxiety. This review concerned all treatment frameworks, both guided and unguided formats and all age groups. DATA EXTRACTION AND SYNTHESIS: In random-effects meta-analysis, we estimated pooled effects on depression symptoms and anxiety in terms of Hedges' g with 95% CIs. Absolute and relative heterogeneity was quantified as the τ2 and I 2. RESULTS: We included 57 trials with 21 795 participants. Nine trials (16%) recruited exclusively from routine care, and three (5%) delivered treatment via video. For adults, large within-group reductions were seen in depression (g=0.90; 95% CI 0.81 to 0.99) and anxiety (g=0.87; 95% CI 0.78 to 0.96). Compared with rudimentary passive controls, the added effects were moderate (depression: g=0.52; 95% CI 0.42 to 0.63; anxiety: g=0.45; 95% CI 0.34 to 0.56) and larger in trials that required all participants to meet full diagnostic criteria for depression or an anxiety disorder. Compared with attention/engagement controls, the added effects were small (depression: g=0.30; 95% CI 0.07 to 0.53; anxiety: g=0.21; 95% CI 0.01 to 0.42). Heterogeneity was substantial, and the certainty of the evidence was very low. Two trials concerned adolescents and reported mixed results. One trial concerned older adults and reported promising results. CONCLUSION: Internet-delivered transdiagnostic treatments for depression and anxiety show small-to-moderate added effects, varying by control condition. Research is needed regarding routine care, the video format, children and adolescents and older adults. PROSPERO REGISTRATION NUMBER: CRD42021243172.

Influencing factors of length of stay among repeatedly hospitalized patients with mood disorders: a longitudinal study in China.

BACKGROUND: Patients with mood disorders usually require repeated and prolonged hospitalization, resulting in a heavy burden on healthcare resources. This study aims to identify variables associated with length of stay(LOS) of repeatedly hospitalized patients with mood disorders and to provide information for optimizing psychiatry management and healthcare resource allocation. METHODS: Electronic medical records (EMRs) of repeatedly hospitalized patients with mood disorders from January 2010 to December 2018 were collected and retrospectively analyzed. Chi-square and t-test were adopted to investigate the differences in characteristics between the two groups of short LOS and long LOS. Generalized estimating equation (GEE) was conducted to investigate potential factors influencing LOS. RESULTS: A total of 2,009 repeatedly hospitalized patients with mood disorders were enrolled, of which 797 (39.7%) had a long LOS and 1,212 (60.3%) had a short LOS. Adverse effects of treatment, continuous clinical manifestation, chronic onset type, suicide attempt, comorbidity and use of antidepressants were positively associated with long LOS among all repeatedly hospitalized patients with mood disorders (P < 0.050). For patients with depression, factors associated with long LOS consisted of age, monthly income, adverse effects of treatment, continuous clinical manifestation, suicide attempt and comorbidity (P < 0.050). Whereas, for patients with bipolar disorder (BD), adverse effects of treatment, four or more hospitalizations and use of antidepressants contributed to the long LOS (P < 0.050). Influencing factors of LOS also vary among patients with different effectiveness of treatment. CONCLUSION: The LOS in repeatedly hospitalized patients with mood disorders was influenced by multiple factors. There were discrepancies in the factors affecting LOS in patients with different diagnoses and effectiveness of treatment, and specific factors should be addressed when evaluating the LOS.

Sociodemographic and clinical risk factors for suicidal ideation and suicide attempt in functional/dissociative seizures and epilepsy: a large cohort study.

BACKGROUND: People with functional/dissociative seizures (FDS) are at elevated suicidality risk. OBJECTIVE: To identify risk factors for suicidality in FDS or epilepsy. METHODS: Retrospective cohort study from the UK's largest tertiary mental healthcare provider, with linked national admission data from the Hospital Episode Statistics. Participants were 2383 people with a primary or secondary diagnosis of FDS or epilepsy attending between 01 January 2007 and 18 June 2021. Outcomes were a first report of suicidal ideation and a first hospital admission for suicide attempt (International Classification of Diseases, version 10: X60-X84). Demographic and clinical risk factors were assessed using multivariable bias-reduced binomial-response generalised linear models. FINDINGS: In both groups, ethnic minorities had significantly reduced odds of hospitalisation following suicide attempt (OR: 0.45-0.49). Disorder-specific risk factors were gender, age and comorbidity profile. In FDS, both genders had similar suicidality risk; younger age was a risk factor for both outcomes (OR: 0.16-1.91). A diagnosis of depression or personality disorders was associated with higher odds of suicidal ideation (OR: 1.91-3.01). In epilepsy, females had higher odds of suicide attempt-related hospitalisation (OR: 1.64). Age had a quadratic association with both outcomes (OR: 0.88-1.06). A substance abuse disorder was associated with higher suicidal ideation (OR: 2.67). Developmental disorders lowered the risk (OR: 0.16-0.24). CONCLUSIONS: This is the first study systematically reporting risk factors for suicidality in people with FDS. Results for the large epilepsy cohort complement previous studies and will be useful in future meta-analyses. CLINICAL IMPLICATIONS: Risk factors identified will help identify higher-risk groups in clinical settings.

Comorbid physical health burden of serious mental health disorders in 32 European countries.

BACKGROUND: Mental health disorders (MHDs) are associated with physical health disparities, but underlying excess risk and health burden have not yet been comprehensively assessed. OBJECTIVE: To assess the burden of comorbid physical health conditions (PHCs) across serious MHDs in Europe. METHODS: We estimated the relative prevalence risk of PHCs associated with alcohol use disorders (AUD), bipolar disorder (BD), depressive disorders (DD) and schizophrenia (SZ) across working-age populations of 32 European countries in 2019 based on a targeted literature review. Excess physical health burden was modelled using population-attributable fractions and country-level prevalence data. FINDINGS: We screened 10 960 studies, of which 41 were deemed eligible, with a total sample size of over 18 million persons. Relative prevalence of PHCs was reported in 54%, 20%, 15%, 5% and 7% of studies, respectively, for SZ, DD, BD, AUD or mixed. Significant relative risk estimates ranged from 1.44 to 3.66 for BD, from 1.43 to 2.21 for DD, from 0.81 to 1.97 for SZ and 3.31 for AUD. Excess physical health burden ranged between 27% and 67% of the total, corresponding to 84 million (AUD), 67 million (BD), 66 million (DD) and 5 million (SZ) PHC diagnoses in Europe. A 1% reduction in excess risk assuming causal inference could result in two million fewer PHCs across investigated MHDs. CONCLUSIONS: This is the first comprehensive study of the physical health burden of serious MHDs in Europe. The methods allow for updates, refinement and extension to other MHDs or geographical areas. CLINICAL IMPLICATIONS: The results indicate potential population health benefits achievable through more integrated mental and physical healthcare and prevention approaches.

Nudges and Prompts Increase Engagement in Self-Guided Digital Health Treatment for Depression and Anxiety: Results From a 3-Arm Randomized Controlled Trial.

BACKGROUND: Accessible and effective approaches to mental health treatment are important because of common barriers such as cost, stigma, and provider shortage. The effectiveness of self-guided treatment is well established, and its use has intensified because of the COVID-19 pandemic. Engagement remains important as dose-response relationships have been observed. Platforms such as Facebook (Meta Platform, Inc), LinkedIn (Microsoft Corp), and X Corp (formerly known as Twitter, Inc) use principles of behavioral economics to increase engagement. We hypothesized that similar concepts would increase engagement in self-guided digital health. OBJECTIVE: This 3-arm randomized controlled trial aimed to test whether members of 2 digital self-health courses for anxiety and depression would engage with behavioral nudges and prompts. Our primary hypothesis was that members would click on 2 features: tips and a to-do checklist. Our secondary hypothesis was that members would prefer to engage with directive tips in arm 2 versus social proof and present bias tips in arm 3. Our tertiary hypothesis was that rotating tips and a to-do checklist would increase completion rates. The results of this study will form a baseline for future artificial intelligence-directed research. METHODS: Overall, 13,224 new members registered between November 2021 and May 2022 for Evolution Health's self-guided treatment courses for anxiety and depression. The control arm featured a member home page without nudges or prompts. Arm 2 featured a home page with a tip-of-the-day section. Arm 3 featured a home page with a tip-of-the-day section and a to-do checklist. The research protocol for this study was published in JMIR Research Protocols on August 15, 2022. RESULTS: Arm 3 had significantly younger members (F2,4564=40.97; P<.001) and significantly more female members (χ24=92.2; P<.001) than the other 2 arms. Control arm members (1788/13,224, 13.52%) completed an average of 1.5 course components. Arm 2 members (865/13,224, 6.54%) clicked on 5% of tips and completed an average of 1.8 course components. Arm 3 members (1914/13,224, 14.47%) clicked on 5% of tips, completed 2.7 of 8 to-do checklist items, and completed an average of 2.11 course components. Completion rates in arm 2 were greater than those in arm 1 (z score=3.37; P<.001), and completion rates in arm 3 were greater than those in arm 1 (z score=12.23; P<.001). Engagement in all 8 components in arm 3 was higher than that in arm 2 (z score=1.31; P<.001). CONCLUSIONS: Members engaged with behavioral nudges and prompts. The results of this study may be important because efficacy is related to increased engagement. Due to its novel approach, the outcomes of this study should be interpreted with caution and used as a guideline for future research in this nascent field. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/37231.

Assessing the Alignment of Large Language Models With Human Values for Mental Health Integration: Cross-Sectional Study Using Schwartz's Theory of Basic Values.

BACKGROUND: Large language models (LLMs) hold potential for mental health applications. However, their opaque alignment processes may embed biases that shape problematic perspectives. Evaluating the values embedded within LLMs that guide their decision-making have ethical importance. Schwartz's theory of basic values (STBV) provides a framework for quantifying cultural value orientations and has shown utility for examining values in mental health contexts, including cultural, diagnostic, and therapist-client dynamics. OBJECTIVE: This study aimed to (1) evaluate whether the STBV can measure value-like constructs within leading LLMs and (2) determine whether LLMs exhibit distinct value-like patterns from humans and each other. METHODS: In total, 4 LLMs (Bard, Claude 2, Generative Pretrained Transformer [GPT]-3.5, GPT-4) were anthropomorphized and instructed to complete the Portrait Values Questionnaire-Revised (PVQ-RR) to assess value-like constructs. Their responses over 10 trials were analyzed for reliability and validity. To benchmark the LLMs' value profiles, their results were compared to published data from a diverse sample of 53,472 individuals across 49 nations who had completed the PVQ-RR. This allowed us to assess whether the LLMs diverged from established human value patterns across cultural groups. Value profiles were also compared between models via statistical tests. RESULTS: The PVQ-RR showed good reliability and validity for quantifying value-like infrastructure within the LLMs. However, substantial divergence emerged between the LLMs' value profiles and population data. The models lacked consensus and exhibited distinct motivational biases, reflecting opaque alignment processes. For example, all models prioritized universalism and self-direction, while de-emphasizing achievement, power, and security relative to humans. Successful discriminant analysis differentiated the 4 LLMs' distinct value profiles. Further examination found the biased value profiles strongly predicted the LLMs' responses when presented with mental health dilemmas requiring choosing between opposing values. This provided further validation for the models embedding distinct motivational value-like constructs that shape their decision-making. CONCLUSIONS: This study leveraged the STBV to map the motivational value-like infrastructure underpinning leading LLMs. Although the study demonstrated the STBV can effectively characterize value-like infrastructure within LLMs, substantial divergence from human values raises ethical concerns about aligning these models with mental health applications. The biases toward certain cultural value sets pose risks if integrated without proper safeguards. For example, prioritizing universalism could promote unconditional acceptance even when clinically unwise. Furthermore, the differences between the LLMs underscore the need to standardize alignment processes to capture true cultural diversity. Thus, any responsible integration of LLMs into mental health care must account for their embedded biases and motivation mismatches to ensure equitable delivery across diverse populations. Achieving this will require transparency and refinement of alignment techniques to instill comprehensive human values.

Effect of metacognitive therapy on depression in patients with chronic disease: a protocol for a systematic review and meta-analysis.

BACKGROUND: Chronic diseases have a high prevalence worldwide, and patients with chronic diseases often suffer from depression, leading to a poor prognosis and a low quality of life. Metacognitive therapy is a transdiagnostic psychotherapy intervention focused on thinking patterns, with the advantages of reliable implementation effect, short intervention period and low cost. It can help patients change negative metacognition, alleviate depression symptoms, and has a higher implementation value compared with other cognitive interventions. Therefore, metacognitive therapy may be an effective way to improve the mental health of patients with chronic diseases. METHODS AND ANALYSIS: CNKI, Wanfang Database, VIP Database for Chinese Technical Periodicals, Sinomed, PubMed, SCOPUS, Embase, The Cochrane Library, Web of Science and PsycINFO will be used to select the eligible studies. As a supplement, websites (eg, the Chinese Clinical Registry, ClinicalTrials.gov) will be searched and grey literature will be included. The heterogeneity and methodological quality of the eligible studies will be independently screened and extracted by two experienced reviewers. All the data synthesis and analysis (drawing forest plots, subgroup analysis and sensitive analysis) will be conducted using RevMan 5.4.1. ETHICS AND DISSEMINATION: This article is a literature review that does not include patients' identifiable information. Therefore, ethical approval is not required in this protocol. The findings of this systematic review and meta-analysis will be published in a peer-reviewed journal as well as presentations at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42023411105.

Recent advances in the crosstalk between the brain-derived neurotrophic factor and glucocorticoids.

Brain-derived neurotrophic factor (BDNF), a key neurotrophin within the brain, by selectively activating the TrkB receptor, exerts multimodal effects on neurodevelopment, synaptic plasticity, cellular integrity and neural network dynamics. In parallel, glucocorticoids (GCs), vital steroid hormones, which are secreted by adrenal glands and rapidly diffused across the mammalian body (including the brain), activate two different groups of intracellular receptors, the mineralocorticoid and the glucocorticoid receptors, modulating a wide range of genomic, epigenomic and postgenomic events, also expressed in the neural tissue and implicated in neurodevelopment, synaptic plasticity, cellular homeostasis, cognitive and emotional processing. Recent research evidences indicate that these two major regulatory systems interact at various levels: they share common intracellular downstream pathways, GCs differentially regulate BDNF expression, under certain conditions BDNF antagonises the GC-induced effects on long-term potentiation, neuritic outgrowth and cellular death, while GCs regulate the intraneuronal transportation and the lysosomal degradation of BDNF. Currently, the BDNF-GC crosstalk features have been mainly studied in neurons, although initial findings show that this crosstalk could be equally important for other brain cell types, such as astrocytes. Elucidating the precise neurobiological significance of BDNF-GC interactions in a tempospatial manner, is crucial for understanding the subtleties of brain function and dysfunction, with implications for neurodegenerative and neuroinflammatory diseases, mood disorders and cognitive enhancement strategies.

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

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

Tardive Dysphoria With Selective-Serotonin Reuptake Inhibitors Treated Successfully With Atypical Antidepressants: A Case Series From Tertiary Hospital Setting.

Tardive dysphoria (TDp) is a phenomenon characterized by the delayed onset or worsening of depressive symptoms following the discontinuation or alteration of antidepressant medications. TDp is a recently defined, under-recognized, and understudied condition. We present a series of five TDp cases exploring the diverse presentations, management strategies, and associated medical conditions. In all the cases, TDp manifested after prolonged use of selective serotonin reuptake inhibitors (SSRIs). All cases were successfully managed with atypical antidepressants. These cases offer insight into TDp, providing clinicians and researchers with examples of atypical trajectories in depressive symptomatology.

Implementation of the Mind Youth Questionnaire (MY-Q) for routine health-related quality of life screening of adolescents with type 1 diabetes in a large tertiary care center.

OBJECTIVES: Prevalence of diabetes distress and mental health comorbidities among adolescents with type 1 diabetes (T1D) is high. Despite recommendations for routine psychosocial risk assessment, there is little guidance for their implementation. This study aims to describe the implementation and baseline outcomes of the Mind Youth Questionnaire (MY-Q), a validated psychosocial screening tool for health-related quality of life (QoL) including mood, among adolescents living with T1D. METHODS: Adolescents aged 13-18 years completed the MY-Q from October 1, 2019-April 1, 2023. Baseline characteristics, MY-Q results including categories flagged positive (noting possible areas of concern), debrief duration, and frequency of social work or mental health referral were collected and analyzed using descriptive statistics. RESULTS: A total of 343 adolescents (mean age 15.3 years; 52 % female) completed a baseline MY-Q. Median overall MY-Q debrief time (IQR) was 10.0 min (6.0, 20.0). About 290 (84.5 %) adolescents had at least one of seven categories flagged, most commonly "Family" (61 %). About 30 % of adolescents had "Mood" flagged, and 2.9 % of adolescents were referred to mental health following debrief. CONCLUSIONS: Without the need for additional resources, implementation of the MY-Q in a pediatric tertiary care diabetes clinic successfully identified QoL issues and mental health concerns among adolescents with T1D.

Essential oils for clinical aromatherapy: A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Aromatherapy, a holistic healing practice utilizing the aromatic essences of plant-derived essential oils, has gained significant attention for its therapeutic potential in promoting overall well-being. Use of phytoconstituent based essential oil has played a significant role in the evolving therapeutic avenue of aromatherapy as a complementary system of medicine. AIM OF THE STUDY: This comprehensive review article aims to explore the usage of essential oils for aromatherapy, shedding light on their diverse applications, scientific evidence, and safety considerations. Furthermore, the growing interest in using essential oils as complementary therapies in conjunction with conventional medicine is explored, underscoring the significance of collaborative healthcare approaches. MATERIALS AND METHODS: Literature search was performed from databases like PubMed, ScienceDirect, Scopus, and Bentham using keywords like Aromatherapy, Aromatic Plants, Essential oils, Phytotherapy, and complementary medicine. The keywords were used to identify literature with therapeutic and mechanistic details of herbal agents with desired action. RESULTS: The integration of traditional knowledge with modern scientific research has led to a renewed interest in essential oils as valuable tools in contemporary healthcare. Various extraction methods used to obtain essential oils are presented, emphasizing their impact on the oil's chemical composition and therapeutic properties. Additionally, the article scrutinizes the factors influencing the quality and purity of essential oils, elucidating the significance of standardization and certification for safe usage. A comprehensive assessment of the therapeutic effects of essential oils is provided, encompassing their potential as antimicrobial, analgesic, anxiolytic, and anti-inflammatory agents, among others. Clinical trials and preclinical studies are discussed to consolidate the existing evidence on their efficacy in treating diverse health conditions, both physical and psychological. Safety considerations are of paramount importance when employing essential oils, and this review addresses potential adverse effects, contraindications, and best practices to ensure responsible usage. CONCLUSIONS: This comprehensive review provides valuable insights into the exploration of essential oils for aromatherapy, emphasizing their potential as natural and potent remedies for a wide range of ailments. By amalgamating traditional wisdom and modern research, this article aims to encourage further investigation into the therapeutic benefits of essential oils while advocating for their responsible and evidence-based incorporation into healthcare practices.

Development of a self-report screening instrument for emotional dysregulation: the Reactivity, Intensity, Polarity and Stability questionnaire, screening version (RIPoSt-SV).

BACKGROUND: Emotional dysregulation (ED) refers to the inability to manage emotional experiences or expressions hindering goal-oriented behavior. Moderate impairment on at least two domains among temper control, affective lability, and emotional over-reactivity has been proposed to identify ED in adults with attention-deficit/hyperactivity disorder (ADHD). No screening measure designed for use in diverse psychiatric samples exists. We aimed to develop a self-report screening tool for ED based on the 40-item version of the Reactivity, Intensity, Polarity, and Stability questionnaire (RIPoSt-40). METHODS: 150 adult outpatients with non-psychotic conditions were enrolled between February and July 2023 at the Second Psychiatry Unit of Pisa University Hospital. Clinically significant ED (CSED) was defined based on the previously suggested approach for ADHD. Differences between patients with and without CSED were tested. To develop our screening instrument, a decision tree algorithm was trained by hyperparameter tuning through 5-fold cross-validation in 120 subjects and tested on the remaining 30. RESULTS: 75 subjects met criteria for CSED (50 %). CSED was associated with lower age and higher prevalence of psychiatric conditions, including minor mood disorders, ADHD, cannabis use disorders, and eating disorders. We identified a decision tree consisting of six items from RIPoSt-40 that effectively detected CSED, with accuracy, sensitivity, specificity, positive and negative predictive values of 80 % or higher in both the training and testing sets. LIMITATIONS: Tertiary-level; no consensus on criteria; sample size. CONCLUSION: The screening version of the Reactivity, Intensity, Polarity, and Stability questionnaire (RIPoSt-SV) demonstrates promise as a valuable tool for ED screening in clinical settings.

Neuropathic pain, mood, and stress-related disorders: A literature review of comorbidity and co-pathogenesis.

Neuropathic pain can be caused by multiple factors, and its prevalence can reach 10% of the global population. It is becoming increasingly evident that limited or short-lasting response to treatments for neuropathic pain is associated with psychological factors, which include psychiatric comorbidities known to affect quality of life. It is estimated that 60% of patients with neuropathic pain also experience depression, anxiety, and stress symptoms. Altered mood, including stress, can be a consequence of several painful conditions but can also favor pain chronicization when preexisting. Despite the apparent tight connection between clinical pain and mood/stress disorders, the exact physiological mechanisms remain unclear. This review aims to provide an overview of state-of-the-art research on the mechanisms of pain related to the pathophysiology of depression, anxiety, and stress disorders.

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

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

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.

A retrospective analysis of iv ketamine outcome on hospitalizations in an unselected psychiatric sample.

OBJECTIVE: This study aims to explore the outcome with iv ketamine treatment in a real-world clinical setting, primarily measured as posttreatment days hospitalized. METHODS: The psychiatric medical records of 46 patients having received iv ketamine on a psychiatric treatment indication between 2015-2018 were retrospectively examined. Analysis comparing the number and duration of hospital admissions before and after ketamine treatment as well as logistic regression analysis to investigate clinical predictors of effectiveness, were performed. To assess patients' severity of depressed symptoms records were screened for MADRS-S scores. RESULTS: No significant difference between pre- and posttreatment hospital days (p=0.170), or number of hospitalizations (p=0.740) were found. The response rate was 31% and remission rate 21%. None of the predictors showed statistical significance in the logistic model. CONCLUSION: Iv ketamine treatment showed effectiveness in reducing depressive symptoms even with complex patients in a real-world clinical setting. However, this did not translate to a reduction in hospitalization. Highlighting the multifaceted challenges posed when implementing iv ketamine treatment in clinical practice.

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

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

Gut bacteriome and mood disorders in women with PCOS.

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

Is behavioural activation an effective treatment for depression in children and adolescents? An updated systematic review and meta-analysis.

Behavioural Activation (BA)-a brief therapy based on the scheduling of enjoyable, purposeful and rewarding activities-is an effective and cost-effective treatment for depression in adults that shows promise for children and adolescents. We provide an update on a previous systematic review of evidence on BA-delivered in-person, telephone, or online-for depression and comorbid anxiety in children and adolescents. We conducted systematic literature searches in 6 databases up to February 2024. We included all study designs evaluating BA with participants up to 18 years old with diagnosable depression, as established by a validated screening tool or diagnostic manual. We used the Moncrieff Scale and the Cochrane Risk of Bias tool to assess study quality. We summarised the findings of all study types with a narrative synthesis and of randomised controlled trials (RCTs) with a meta-analysis. Overall, 24 studies (6 RCTs, 18 pre-post evaluations, n = 2,758) met our inclusion criteria. A meta-analysis of 4 RCTs (n = 156) showed that BA has a small effect of 0.24 (Hedge's adjusted g) in reducing depression symptoms compared to a waiting-list control, usual care and other therapies. Online and telephone-facilitated BA was shown to be feasible in 3 studies and effective in 1. Outcomes on comorbid anxiety were mixed. No economic evaluations met our inclusion criteria. BA shows sufficient promise as an intervention for reducing depression symptoms in children and adolescents to justify the need for further RCTs, providing that five conditions are met: studies are powered to detect a minimal clinically important difference; BA materials are fit-for-purpose to produce clinically meaningful change; follow-ups are longer than 6 months; primary outcomes are child-reported; and intervention costs, resource use and adverse events are reported.