Background: Major depressive disorder (MDD) affects approximately 1 in 6 adults during their lifetime, yet antidepressant selection relies predominantly on trial-and-error, with response rates of only 42% to 53%. While machine learning (ML) models have shown promise in predicting treatment outcomes, most focus on single treatments rather than comparative selection across therapeutic alternatives, limiting their clinical utility for the medication choice decisions that clinicians face in practice. Objective: This systematic review evaluates ML approaches that examine 2 or more pharmacological interventions for predicting treatment outcomes in MDD, with a focus on their capacity to facilitate comparative treatment selection between medications or medication classes for individual patients. Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched PubMed, Scopus, and Web of Science for studies published from 2015 to 2025. We included studies involving adults with MDD that used ML models to predict treatment outcomes across 2 or more pharmacological treatments and reported medication-specific prediction outcomes. Risk of bias was assessed using PROBAST-AI (Prediction Model Risk of Bias Assessment Tool for Artificial Intelligence). We conducted a narrative synthesis organized by modeling strategies, data integration approaches, validation methodologies, and performance patterns. Results: From 5370 initial records, 19 studies met the inclusion criteria, with dataset sample sizes ranging from 49 to 77,226 participants. Studies employed 3 distinct modeling strategies: drug-specific supervised models trained independently for each medication, subtype- or trajectory-based approaches using clustering methods to identify differential response patterns, and a unified differential prediction framework generating calibrated cross-treatment predictions. Performance varied substantially, with area under the curve values ranging from 0.59 to 0.95 and classification accuracies between 62% and 95.4%, though high performance was concentrated in studies with small samples, high-dimensional neurobiological features, and internal-only validation. Only 7 studies conducted external validation, which generally yielded more conservative performance estimates. Feature informativeness was more consistently associated with performance variation than algorithm complexity. Most studies did not formally distinguish between prognostic features predicting general outcomes and predictive features identifying differential medication responses, and none applied formal explainability techniques. Conclusions: ML for comparative antidepressant selection remains in an early stage of development. Only 1 study implemented a unified framework directly supporting patient-level treatment ranking. Key barriers to clinical translation include insufficient distinction between prognostic and predictive markers, limited cross-trial validation, near-absent calibration reporting, and absent explainability. Future research should prioritize unified comparative frameworks with calibrated predictions, rigorous external validation on diverse cohorts, explicit modeling of heterogeneous treatment effects, and integration of explainability into model development.
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iCARE Self-Guided Digital Intervention for Postpartum Depression in Danish Mothers: Formative Research Using User-Centered Design
<strong>Background:</strong> Postpartum depression (PPD) is a major public health concern. Despite advancements in treatment, many barriers to accessing care remain. There has been a growing interest in digital interventions for the prevention and treatment of PPD. However, for mothers with mild and moderate symptoms of depression, there is a limited offer of self-guided internet-based interventions developed with user input and with considerations on how to integrate the intervention into stepped care models for PPD. <strong>Objective:</strong> The aim of this study was (1) to describe the process of the design and development of iCARE, a self-guided digital psychological intervention for mothers with mild and moderate symptoms of PPD in Denmark, (2) present the program’s theory illustrated by a logic model, and (3) explore its initial usability and prospective acceptability. <strong>Methods:</strong> Applying user-centered design methods, the intervention development followed six steps: (1) a literature review to identify evidence‑based therapeutic components of self‑guided interventions for PPD, (2) interviews with women with lived experience of PPD and group discussions with mental health experts and home‑visiting providers to identify user needs, (3) iterative design and content development with stakeholder feedback in collaboration with the Department of Digital Psychiatry, (4) prototype testing using think‑aloud usability sessions and interviews with 5 mothers, (5) a group cognitive walkthrough with mental health experts, and (6) final refinement and implementation of the iCARE program with developers and designers. <strong>Results:</strong> Initial interviews with mothers and maternal health care providers emphasized the importance of a digital intervention offering timely psychoeducation, coping strategies, and pathways to in-person care while addressing the diversity of expressions of PPD symptoms. Stakeholders recommended a flexible program, multimodal content, and integration into maternal care systems with community health nurses supporting engagement and participation. The prototype was designed to be user-centered, engaging, and with multiple interactive features. It included components on psychoeducation, cognitive exercises grounded in cognitive behavioral therapy, acceptance and commitment principles, and mood-monitoring. The prototype was designed to be user-centered and engaging, with interactive features and components on psychoeducation, cognitive exercises grounded in cognitive behavioral and acceptance and commitment principles, and mood-monitoring. Prototype testing indicated high prospective acceptability and led to refinements across 6 themes: appropriateness of content; motivation and engagement; inclusivity and gender representation; clarity of instructions and data use; understanding of therapeutic method; and usability, layout, and navigation. <strong>Conclusions:</strong> iCARE is a self-guided internet-based psychological intervention for mothers with mild and moderate symptoms of PPD in Denmark. It was developed with user input by using qualitative methods, user-centered design, and psychological theory. Further research is needed to evaluate the feasibility and effectiveness of the program in a randomized controlled trial and its integration into maternal health care models such as universal PPD screening and home-visiting.
Assessing directional connections between symptoms, cognition, insight, and real-life functioning in schizophrenia: a partial ancestor graphs analysis
IntroductionSchizophrenia is a severe chronic mental disorder causing significant global disability. Understanding the intricate relationships between symptoms, cognitive functions, and real-life outcomes is essential for developing effective interventions. Prior research, while informative, could not often determine the direction of the association between these illness-related factors. This study aimed to investigate the possible causal connections within the interrelationships of these variables. MethodsThis cross-sectional study included 215 clinically stable patients diagnosed with schizophrenia. Comprehensive assessments covered psychopathology, neurocognition, social cognition, metacognition, clinical insight, and real-life functioning. Causal relationships were explored using Partial Ancestral Graphs, a causal discovery framework that accounts for mediators and confounders. The Greedy Fast Causal Inference algorithm was employed with 1,000 bootstrap replications to assign edge orientations.ResultsA central neurocognitive–metacognitive–functional system of directed connection emerged: visual learning was linked to attention/vigilance and working memory. Working memory showed a direct relationship with metacognition, which, in turn, was connected to real-life functioning. Two partly independent contributions to real-life functioning were also identified: conceptual disorganization and experiential negative symptoms, which were directly related to expressive deficits. Positive symptoms, depressive symptoms, and social cognition occupied peripheral positions, showing no significant connection with other variables. Unawareness and misattribution of symptoms showed an indeterminate association disconnected from the main network.DiscussionThe findings show a set of directed associations that start with neurocognitive abilities, pass through working memory and metacognition, and terminate in real-life functioning. Independently, conceptual disorganization and expressive negative symptoms also exert direct influences. These directed systems of connections provide operational guidance for clinical practice, highlighting critical targets for interventions such as cognitive remediation focused on working memory, metacognitive therapies, and strategies addressing disorganization and avolition, all aimed at improving real-life outcomes in schizophrenia.
From cats to cortex: T. gondii and psychosis, depression, and anxiety
This review examines whether cat ownership, via exposure to the neurotropic parasite T. gondii, contributes to vulnerability for psychotic, depressive, and anxiety symptoms. T. gondii establishes lifelong latent infection in the brain and muscle, where it can modulate dopaminergic signaling, neuroinflammation, and tryptophan–kynurenine metabolism, providing a biologically plausible pathway to altered cognition, mood, and behavior. Epidemiological and meta-analytic data indicate small-to-moderate associations between T. gondii seropositivity and schizophrenia, with more variable but suggestive links to depression and anxiety. Evidence for cat ownership as an independent risk factor is inconsistent: some cohorts and recent meta-analyses report elevated odds of schizophrenia-related outcomes in those exposed to cats, whereas rigorously controlled studies frequently find attenuated or null effects. Methodological limitations, alternative explanations, and cultural implications are discussed, and priorities for mechanism-informed, longitudinal and interventional research are outlined.
Brain Histamine Map Links Genetic Factors to Mental Health and Psychiatric Disorders
A study headed by researchers at King’s College London and the University of Porto has mapped the histamine system in the brain. Histamine, a molecule more commonly associated with allergies, plays a separate but poorly understood role in brain function. The new study addresses this gap, building the first multiscale map of the histamine system which spans from genetics to behavior and related mental health conditions.
The findings provide a new framework for understanding how this often-overlooked chemical system contributes to brain function and could point towards new treatment strategies for histamine-related conditions such as depression, ADHD, and schizophrenia. The study was funded by the National institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre.
Daniel Martins, MD, PhD, visiting senior research fellow at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) King’s College London, said, “This work provides a crucial foundation for future research. By integrating molecular biology, brain imaging, and computational analysis, it offers a new perspective on how neurotransmitter systems are organized across the human brain. As neuroscience moves toward more integrated and personalized models of mental health, understanding systems like histamine may prove essential for unlocking new approaches to diagnosis and treatment.”
Martins is first and corresponding author of the team’s published paper in Nature Mental Health, which is titled “Mapping histamine pathway networks in the human brain across cognition and psychiatric disorders.” In their paper the team concluded, “This study provides an integrated characterization of the histaminergic system in the human brain, leveraging transcriptomic, neuroimaging, and functional datasets to delineate its molecular organization and relevance to brain function underlying cognition and psychiatric disorders.”
Histamine is a neurotransmitter, a molecule crucial for neurons to communicate with one another, the authors explained. “Neuronal histamine plays a crucial role in the regulation of brain function, serving as a neuromodulator with widespread influence across multiple neurotransmitter systems.” However, neuroscience research has classically focused on understanding other neurotransmitter systems such as dopamine and serotonin.
As the investigators noted, the organization of histamine in the human brain remains incompletely characterized. However, they explained, dysregulation of the histaminergic system has been implicated in a number of neuropsychiatric conditions, including anxiety, depression, schizophrenia, and autism spectrum disorder (ASD), as well as neurodegenerative diseases including Alzheimer’s, Parkinson’s, and Huntington’s diseases. “Therefore, targeting the brain histamine system has garnered significant attention as a potential new therapeutic strategy for treating these disorders, with pharmacological interventions aimed at modulating histamine receptor activity showing promise in preclinical models.”
Histamine acts through four known histamine receptors, which are responsible for how the signal will influence receiver neurons. Each of these histamine receptors, (histamine receptor H1 (encoded by HRH1), H2 (HRH2), H3 (HRH3) and H4 (HRH4)), mediates distinct functions. For their newly reported study, Martins and colleagues carried out what they described as multimodal analysis, integrating transcriptomic, neuroimaging, developmental and functional datasets to map the architecture of the histaminergic system.
To build a comprehensive map of how histamine acts in the brain, researchers first combined genetic and molecular data with physical maps of the brain.
This revealed which brain regions receive more input from the brain’s histamine system, and which parts show greater capacity to respond to histamine. These molecular data were then linked with positron emission tomography imaging of histamine receptors in living individuals, as well as functional neuroimaging databases that map brain regions to specific cognitive processes and mental health conditions. This type of scan shows how different parts of the brain are working by tracking a tiny amount of radioactive tracer in real time.
Their results found that different histamine receptors were found on brain cells that either turn activity up (excitation) or turn it down (inhibition). “The findings reveal that histaminergic genes exhibit distinct cellular and regional expression profiles, closely aligning with known histaminergic neuroanatomy and function,” they wrote. “At the single-cell level, histamine receptor H1 and histamine receptor H2 were enriched in excitatory neurons, whereas histamine receptor H3 showed preferential expression in inhibitory populations.” This suggests histamine may be important in maintaining the balance between excitation and inhibition, a fundamental property of healthy brain function.
Brain regions with higher histamine-related gene expression were consistently associated with processes such as emotional regulation, stress and fear responses, decision-making, impulsivity, reward, sleep, and memory.
The parts of the brain where histamine-related genes were most active also overlapped significantly with brain regions known to be affected in several psychiatric conditions, including attention-deficit/hyperactivity disorder, major depressive disorder, schizophrenia, and anorexia nervosa. This is in keeping with previous hypotheses linking histamine to these disorders. “By linking histaminergic gene expression to brain-cell types, neurotransmitter systems, cognitive domains and psychiatric disorders, these correlational findings generate several hypotheses concerning histamine’s critical role in brain organization, neurodevelopment and mental health, which further experimental mechanistic work should prioritize and build onto investigate causal relationships,” the investigators concluded.
Martins said, “Current psychiatric treatments largely target neurotransmitters such as serotonin and dopamine, yet histamine interacts closely with these systems and influences their activity. By providing a detailed map of histamine-related pathways, this work suggests new opportunities for developing treatments that target this system more directly, particularly for symptoms such as cognitive dysfunction, fatigue, and impaired motivation.
While these findings do not establish a direct causal role, they suggest that histamine signalling may contribute to regional vulnerability in these disorders. This aligns with a growing view in psychiatry that mental health conditions arise from disruptions across interacting brain systems rather than a single chemical imbalance.”
This new map paints a neural picture of a previously lesser-studied molecule. It opens up future avenues of research into exactly what histamine is doing in various cell types and parts of the brain.
“We want to emphasise that these findings are hypothesis-generating and based on large-scale datasets that capture patterns rather than direct mechanisms,” commented senior author Steve Williams, PhD, professor of neuroimaging at IoPPN King’s College London. Future studies will focus on testing how histamine signaling changes in living individuals, for example through pharmacological interventions or longitudinal imaging approaches.
Co-author Daniel Van Wamelen, PhD, clinical senior lecturer in neuroscience at IoPPN, King’s College London and one of the authors on the paper said: “This kind of work is already taking place at King’s College London, for example in the iMarkHD project. In this project we use Positron Emission Tomography scans to study a specific histamine receptor (called H3) in people with Huntington’s disease, an inherited condition that affects the brain. The goal is to see how histamine activity changes in different parts of the brain over time, and how these changes relate to symptoms such as apathy, depression, and anxiety.”
The post Brain Histamine Map Links Genetic Factors to Mental Health and Psychiatric Disorders appeared first on GEN – Genetic Engineering and Biotechnology News.
<![CDATA[Anti-inflammatory drugs ease anhedonia and depressive symptoms in high-CRP depression, spotlighting CRP-guided treatment and lifestyle strategies while calling for stronger RCTs.]]>
The dual-burden of professional and academic stress: a cross-sectional mapping of mental health status and coping efficacy among postgraduate students in Nairobi, Kenya
BackgroundPostgraduate students face a dual burden of intense academic rigour and professional responsibilities, a dynamic particularly pronounced in growing economic hubs such as Nairobi, Kenya. While global literature highlights rising psychological distress in higher education, there is limited evidence on how specific coping mechanisms mediate mental health outcomes among postgraduates at private African universities. Understanding these dynamics is critical for institutional psychosocial support systems.ObjectivesThis study aimed to assess the mental health status (depression, anxiety, and stress) of postgraduate students at Strathmore University. Grounded in Lazarus and Folkman’s Transactional Model of Stress and Coping Mechanisms.MethodsAdopting a quantitative cross-sectional descriptive design, data were collected from 242 actively enrolled postgraduate students using a random stratified sampling technique. Mental health status was measured using the Depression, Anxiety, and Stress Scale (DASS-21), and coping mechanisms were evaluated via the Coping Orientation to Problems Experienced (COPE) inventory. Data analysis utilised descriptive statistics, Spearman’s rank correlation, and multiple linear regression models.FindingsResults indicated significant psychological strain, with participants reporting difficulty winding down and high levels of anticipatory anxiety (DASS means ranged from 2.23/to 2.73 on a scale of 0-3. Regression analysis showed that coping strategies accounted for 40.2% of the variation in mental health. Notably, emotion-focused coping (β = 0.307, p <.001) and avoidant coping (β = 0.344, p <.001) had significant positive effects on mental well-being in this context. Conversely, problem-focused coping (β = -0.189, p = .002) had a significant negative effect, suggesting that direct action-oriented strategies may exacerbate distress for students facing stressors beyond their immediate control.ConclusionThe study finds that postgraduate mental health is profoundly influenced by the “plasticity” of coping strategies. While active problem-solving is traditionally encouraged, for the Kenyan postgraduate master’s student, adaptive emotion-focused and strategic avoidant strategies currently offer greater psychological relief. Universities must move from generic support to “fit-for-purpose” interventions that destigmatise mental health services and promote adaptive emotional regulation to ensure academic and professional success.
<![CDATA[Large meta-analysis finds GLP-1 drugs don’t raise depression or suicidality and modestly boost quality of life and eating control in diabetes/obesity.]]>
Surf Therapy: A Powerful Low-Intensity Approach in Global Youth Mental Health Care
By Mai El Shoush, Partnerships Campaign Manager, Stavros Niarchos Foundation (SNF) Global Center for Child and Adolescent Mental Health at the Child Mind Institute
In Conversation with Waves for Change
The world’s oceans have long been profound forces that shape coastlines, cultures, and scientific discovery. And today, through targeted programs, they also serve as therapeutic environments transforming youth mental health worldwide.
As global health systems continue to explore solutions that minimize resource constraints while addressing child and adolescent mental health demands, innovative approaches like surf therapy are demonstrating remarkable effectiveness as low-intensity initiatives. From the beaches of California to the coastal communities of South Africa, Australia, Hawai’i, the United Kingdom, and Senegal, these programs are creating accessible entry points for young people.
Wave for Change (W4C) — a South Africa-based organization and valued implementation partner of the Stavros Niarchos Foundation (SNF) Global Center at the Child Mind Institute — has developed an evidence-based Surf Therapy program for youth in underserved communities. We spoke with their chief development officer Paula Yarrow and senior grant manager Jill Sloan about the award-winning program. As a highly regarded Cape Town‑based NGO that uses surfing as a therapeutic tool to support youth mental health, W4C offers safe spaces, evidence‑based emotional regulation tools, community mentorship, and a pathway to resilience for young people growing up in challenging environments.
The partnership includes the identification of workforce gaps and training needs for frontline workers such as NGOs, to further expand evidence-based support and brief interventions through culturally appropriate, low-intensity psychological therapy approaches. The context-specific training materials are expected to be piloted later in the year in South Africa and are intended to improve access to quality mental health care for young people.
W4C launched Surf Therapy in 2009, which has since helped more than 10,000 adolescents experiencing high-stress environments gain valuable coping skills across its hubs in the Western and Eastern Cape as well as Cape Town. Participants learn how to build positive social networks and develop self-regulation skills to support healthy emotional and behavioral responses to stress, with coaches themselves aged between 18-25. The program creates a fun, culturally relevant environment through the Take 5 model — a framework W4C has designed to be adapted for a range of sports, arts, and cultural initiatives. The model has been utilized by several leading global organizations, including UNICEF.
Waves for Change also played a key role in the founding of the International Surf Therapy Organization (ISTO), connecting practitioners, clinicians, and researchers to advance science research, raise awareness, and support surf therapy.
How does Waves for Change use evidence-based Surf Therapy and capacity building as a solution to fill the gap in youth mental health care?
Approximately 90 percent of the world’s adolescents live in low- and middle-income countries (LMICs). In the most underserved communities, adolescents may experience repeated exposure to violence, unmet basic needs, and limited access to safe spaces or trusted caregivers. Typically, there are very few mental health services that are accessible to such youth.
The more Adverse Childhood Experiences (ACEs) a child or adolescent has whilst growing up, the more likely they are to develop toxic stress — an ongoing stress state without respite. This can often lead to mental health conditions such as anxiety, depression, substance misuse, and cognitive impairment. This can also result in the development of physical health conditions such as heart disease as they grow into adulthood.
The main problem we’ve identified is that there aren’t enough trained workforces (e.g., sports coaches, youth facilitators) that are able to deliver simple, fun, structured play-based sessions with consistency at scale. Our work provides a response to this issue within the adolescent mental health promotion and illness prevention arena. Additionally, our initiatives significantly increase the number of individuals — coaches, teachers, mentors or others — who are already in contact with young adolescents and can provide them with mental health support to foster their immediate and longer-term mental health.
How has Waves for Change adapted the organization’s Surf Therapy program to develop the Take 5 model?
Waves for Change’s Take 5 training model has been incubated, tested, and rigorously evaluated within W4C’s award-winning Surf Therapy program. Take 5 distils the key components of our Surf Therapy program, providing coaches with the essential skills they need to build and sustain caring relationships with children. And it uses a simple teaching routine that creates consistently engaging, fun, structured programs for children and adolescents that suit their language, culture, and context.
Take 5 is low intensity and cost-effective — tailored for high-stress environments and the unique mental wellness needs of adolescents living in multidimensional poverty, conflict, or crisis.
How has partnering with young people to research and co-develop programs made the work more impactful?
In research studies we’ve conducted, adolescent participants (ages 10-16) reported experiencing between 6-8 adverse events every year, including violence and abuse. When asked what sorts of spaces they wanted to see at Waves for Change, the adolescents identified core components such as access to a safe space where they could have fun, be heard, and learn skills to cope. These components now form the bedrock of our Surf Therapy program. We initially worked with 9-12-year-olds and have since developed the follow-on programme for adolescents up to age 16 who have graduated the Surf Therapy programme. This is called Surf Club and is available to all Surf Therapy graduates.
Waves for Change also conducts pre- and post-intervention surveys with participants to monitor the impact of our work. Our coaches (ages 18-25) are at the frontline of delivering our services. A key role they play is to listen with care and respect to the adolescents’ concerns, and to share them with our Child Protection team for review and follow-up when needed.
What makes your partnership with the SNF Global Center at the Child Mind Institute unique?
Working with the Child Mind Institute allows Waves for Change to collaborate with and learn from colleagues doing similar work in the adolescent mental health space across South Africa, the United Kingdom, and Brazil. The partnership offers an opportunity to learn about approaches that have been successful in other health systems. It has also allowed Waves for Change to share detailed information about the training and supervision protocol used to develop key competencies in the coach workforce that leads Surf Therapy in South Africa. This has helped the Child Mind Institute to develop a comprehensive guide for other similar workforces.
Can you expand on the importance of partnerships in strengthening youth mental health care and community empowerment?
Partnerships allow for the consolidation of skills and resources so that a greater impact can be achieved. For example, at Waves for Change, we work with over 70 referral partners every year to identify young adolescents who can benefit from our Surf Therapy program. We are also partnering with the Department of Cultural Affairs and Sport to use our Take 5 model to train MOD and YearBeyond coaches and mentors, who are already reaching large numbers of children and young adolescents through their work. And we’re contributing to building the broader ecosystem of mental health support for adolescents and children by training large national NGOs, government agencies, and humanitarian organizations with our Take 5 model.
How can non-profits further help foster strong peer networks and inclusive safe spaces?
Some of the key lessons we have learnt are the following:
- In the field of youth mental health, make youth the leaders on program implementation
- Provide youth with skills, opportunities, supervision, and support so that they can grow and develop further
- Maintain a strong culture of protection, respect, and communication so that all participants feel safe, welcome, accepted, and heard
Read more about W4C’s Surf Therapy from Youth Liaison Officer, Azola Sibanda and Training Manager Jamie-Lee Davids
The post Surf Therapy: A Powerful Low-Intensity Approach in Global Youth Mental Health Care appeared first on Child Mind Institute.
Exercise as a multiscale recalibration of stress-related homeostatic balance
Chronic stress disrupts homeostasis in the brain and body, leading to anxiety, depression, and cardiovascular and metabolic dysfunction. Although exercise can counter these effects, the mechanisms are scattered across fields and not yet integrated. This review proposes a multi-scale framework. Exercise is not only stress-relieving; it is also a controllable challenge that can recalibrate the system when repeated bouts are matched by sufficient recovery and bioenergetic support. We propose that repeated exercise engages a stress response–adaptation–recovery cycle, in which peripheral signals from skeletal muscles, liver, adipose tissue and gut convey body metabolic state to the brain and are consolidated into durable plasticity only when mitochondrial capacity, substrate availability, and redox balance permit recovery. These signals pass through the blood-brain barrier and engage plasticity switches, including neurotrophic signals, epigenetic modification and metabolic coupling, thus stabilizing the neural circuits of threat appraisal, reward processing and contextual memory. By integrating these dimensions, we clarify how exercise can transform short-term physical stress into lasting resilience and provide direction for future research.