Warneford Hospital

Transcranial magnetic stimulation (TMS) is a novel approved therapy for treatment-resistant depression. Little is known about its neurocognitive mechanisms of action. The existing literature has focused on resting-state neuroimaging. It therefore remains unknown what information processing changes TMS induces during treatment that drive mood change. Here we tested the hypothesis that transcranial magnetic stimulation (TMS) treatment changes emotional bias, increasing the focus on positive (versus negative) information processing. 49 patients with major depression received 20 daily sessions of open-label intermittent theta-burst TMS to left dorsolateral prefrontal cortex. Emotional bias was measured using behavioural and functional magnetic resonance imaging tasks of emotional face processing, both at baseline and after eight days of treatment. We tested whether early changes in these measures after the first week predicted clinical outcome at the end of treatment (4 weeks). As predicted, an increase in behavioural and neural measures of positive bias after one week predicted clinical response after four weeks of treatment. Behaviourally, response to TMS treatment was associated with a bias towards interpreting ambiguous facial expressions as positive. Neurally, clinical improvement was related to increased neuroimaging response for the contrast of positive versus negative emotional faces in rostral anterior cingulate cortex (rACC), and a positive bias in task-related functional connectivity between rACC and posterior default mode network. These early neurocognitive changes predicted clinical outcomes after four weeks of treatment, beyond early symptom reduction. Thus, clinical response to TMS treatment was linked to increases in positive bias in emotional processing early during treatment which might represent a neurocognitive mechanism of TMS depression treatment, potentially neurally distinct from antidepressant drugs.

Abstract Neuroimaging has revealed that major depression is underpinned by dysfunctional brain networks, with symptom variability stemming from altered interactions within and between brain regions. While the effect of depression severity is well-studied, the effect of depression duration (chronicity) is relatively neglected, despite its clinical significance. This study examined how severity, chronicity, and their interaction affect brain network connectivity and grey matter volume. Forty-six patients (31 females, mean age 40.5) were assessed using whole-brain network modeling and voxel-based morphometry (VBM). Severity was measured via the Hamilton Depression Rating Scale, and chronicity was defined as an episode lasting over 24 months. The key finding was that chronicity moderated the impact of severity on functional connectivity between the Central Executive Network (CEN) and the precuneus (part of the Default Mode Network, DMN). Chronic versus non-chronic patients showed opposite patterns. Non-chronic patients showed stronger CEN-Default Mode Precuneus connectivity at low severity and weaker at high severity; chronic patients showed the reverse. This study reveals a novel impact of chronicity on CEN-DMN interactions, a neglected moderator of brain-symptom severity correlations in depression.

Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision. To investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns. This was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025. Treatment complexity was assessed as number of different antidepressant classes in prescriptions filled in 4.5 years. Sustained-use 360 groups were defined as 360 or more cumulative days (in 4.5 years) of a single antidepressant. Participants with genome-wide genotypes were contrasted across mutually exclusive sustained-use 360 groups. Associations of 44 self-reported phenotypes and polygenic scores (PGSs) for 15 traits with sustained-use 360 subgroups. Genome-wide association studies (GWASs) were conducted for selective serotonin reuptake inhibitor (SSRI) or SSRI/serotonin-norepinephrine reuptake inhibitor sustained use contrasted to other participants. Of 12 074 participants (9041 [75%] female with a mean [SD] age of 41.8 [14.6] years; 3022 [25%] male with a mean [SD] age of 47.7 [14.6] years) with 1 or more prescriptions and lifetime MDD, 8898 had genotyping data. High treatment complexity was significantly associated with 37 of 44 self-reported phenotypes (eg, higher rates of smoking, recurrent MDD, suicidal ideation, chronic pain, and circadian and atypical depression subtypes) and higher PGSs for psychiatric traits (MDD PGS: β, 0.04; 95% CI, 0.03-0.06; P = 1.2 × 10-8; ADHD PGS: β, 0.03; 95% CI, 0.02-0.05; P = 2.1 × 10-5 ; bipolar disorder PGS: β, 0.03; 95% CI, 0.01-0.04. P = 1.2 × 10-4 ; neuroticism PGS: β, 0.02; 95% CI, 0.01-0.04; P = 1.3 × 10-3). A total of 5453 (61%) met criteria for an exclusive antidepressant sustained-use 360 group. These groups had distinct phenotypic profiles, including associations with body mass index, suicidal ideation, and co-occurring conditions. GWASs identified novel loci, including an immune-related gene SLAMF3/LY9, for which single-nucleotide variant rs4656934 was associated with reduced odds of sustained SSRI use (G allele; odds ratio, 0.81; 95% CI, 0.75-0.87; P = 3.5 × 10-8). This study found that phenotypic factors were associated with sustained antidepressant use and treatment complexity. PGSs for traits studied were associated with treatment complexity but showed little association with sustained-use 360 groups. These findings support further research to guide treatment selection and to identify patients at risk of difficult-to-treat depression, informing precision psychiatry and early intervention in MDD.

Randomized controlled trials (RCTs) are the foundation of current clinical treatment guidelines. However, they may not reflect real-world populations, due to strict eligibility criteria. We determined the proportion of individuals with major depressive disorder (MDD) receiving maintenance antidepressant treatment in routine care who would be ineligible for RCTs, and compared their outcomes with those who were eligible. Utilizing specialized health care registers in Finland (2004-2018) and Sweden (2006-2021), we identified adults diagnosed with non-psychotic MDD (ICD-10: F32, F33) who were stabilized on maintenance antidepressant monotherapy. Through multidisciplinary expert consensus on latest meta-analytic evidence, we derived a standardized list of RCT inclusion and exclusion criteria. These criteria were systematically applied to classify individuals as RCT-eligible or RCT-ineligible. We then used Cox proportional models to derive hazard ratios (HRs) of a composite primary outcome of hospitalization due to any psychiatric reason or suicide attempt, and all-cause mortality, during a 6-month follow-up. Secondary outcomes were treatment changes (i.e., discontinuation, switch or augmentation) and psychiatric sick leave ≥2 weeks. A total of 73,720 individuals in Finland and 135,092 in Sweden were included. More than one third of patients with MDD (33.5% in Finland and 35.3% in Sweden) were found to be ineligible for RCTs. The most common reasons for ineligibility were comorbidities (serious somatic disease, other psychiatric disorders, or substance use disorder). RCT-ineligible individuals had more than twice the risk of the composite primary outcome compared to eligible individuals (HR=2.44, 95% CI: 2.15-2.76 in Finland; HR=2.61, 95% CI: 2.37-2.87 in Sweden). Approximately one third of the composite primary outcome was attributable to RCT-ineligibility factors (32.5%, 95% CI: 27.9-37.1 for Finland; 36.2%, 95% CI: 32.6-39.8 for Sweden). Risk of treatment change was slightly but significantly higher in ineligible individuals. Findings were consistent in a wide range of sensitivity analyses. We conclude that more inclusive eligibility criteria for RCTs, and their integration with real-world data, are needed to improve the generalizability of antidepressant trial evidence and MDD clinical treatment guidelines.

Parents experience significant stress when their baby receives a prenatal diagnosis that will require surgical treatment. This study aimed to explore parents' experiences of a neonatal surgical pathway and develop recommendations for support. Twenty-four parents completed surveys and nine parents were subsequently interviewed regarding their experiences of the neonatal surgical pathway. Themes were identified using reflexive thematic analysis. Parents highlighted the importance of preparation, empathetic communication and involvement in their baby's care. Different levels of support that parents would find useful ranged from parent-to-parent mentoring, a space to discuss feelings in medical consultations, ensuring physical health needs were met, and access to embedded psychological support. The findings show that beyond the immediate stress of having an unwell child, the way in which the wider medical system holds parents in their distress has a major impact on parents' wellbeing. Recommendations to improve support are provided at universal, targeted and specialist levels. For example, it is advised that all parents receive preparation throughout different stages of the treatment journey through antenatal counselling, ward tours, and the opportunity to speak to former patients. Efforts should be made to solicit parents' feelings and concerns to enable them to feel heard and cared for. A number of parents may experience heightened levels of distress, for whom access to specialist psychological support may be indicated.

BackgroundData repositories are critical to advancing open science, ensuring data persistence, and promoting reuse for novel scientific discoveries. In dementia research, platforms such as Dementias Platform Australia, Dementias Platform UK, and the Alzheimer's Disease Data Initiative, have emphasized making data Findable, Accessible, Interoperable, and Reusable (FAIR). However, the decentralized nature of these platforms requires researchers to navigate multiple sites, compile metadata manually, and face challenges in comparing and accessing studies across platforms.MethodTo address these challenges, we developed the Global Ageing and Dementia Study Explorer (GLADSE), an open‐source R Shiny application. The tool collects and standardizes commonly used metadata from partner platforms, including applying the C‐SURV data model themes and domains, to provide rich, detailed and comparable information. The application was built using R Shiny modules under the golem framework, ensuring modularity for scalability and ease of maintenance. GLADSE offers an interactive dashboard with multiple functionalities, including platform and study overviews, filters, visualization plots, and report generation. Additionally, it can be embedded via iframe within partner platform websites, with optional user authentication. A metadata submission tool was developed separately to encourage data custodians to contribute new datasets.ResultGLADSE centralizes metadata exploration, enabling users to identify and compare relevant datasets without navigating multiple platforms. Its modular design allows seamless updates and future expansions. The tool improves data accessibility by featuring diverse metadata and presenting it in an interactive interface. Early feedback highlights its effectiveness in improving data discovery and enabling cross‐platform collaboration, including federated analysis. By integrating global resources, the tool maximizes the utility of existing research infrastructure and facilitates global partnerships.ConclusionGLADSE advances dementia research making data FAIR and fostering collaboration across dementia platforms. Planned future developments, such as incorporating measurement‐level metadata standardised using the C‐SURV ontology will enhance the utility of study filters and visualization plots. Expanding to include detailed imaging and genomic metadata will further strengthen its utility. By proposing a solution to the decentralized data platforms and promoting global collaboration, GLADSE maximizes the value of public investments in research infrastructures, supports critical progress in understanding, preventing, and treating dementia, a pressing public health challenge.

To assess the effects of and related evidence certainty of interventions for attention deficit/hyperactivity disorder (ADHD) across an individual's lifespan, and to develop a continuously updated web platform for people with lived experience of ADHD as a method to disseminate living evidence synthesis for shared decision making. Umbrella review and platform for shared decision making. Six databases from inception to 19 January 2025. Study authors were contacted for additional information when necessary. Systematic reviews that used meta-analyses of randomised controlled trials were eligible if they compared a drug or non-drug intervention with a passive control in individuals with a diagnosis of ADHD. Primary outcomes were severity of ADHD symptoms, analysed by rater type (clinician-rated, parent-rated, teacher-rated, or self-rated) and time point (short term (12 weeks, or study endpoint), medium term (26 weeks), and long term (52 weeks)),acceptability (participants dropping out for any reason), and tolerability (participants dropping out owing to any side effects). Secondary outcomes included daily functioning, quality of life, comorbid symptoms, and key side effects (decreased sleep and appetite). Eligible meta-analyses were re-estimated with a standardised statistical approach. Methodological quality was assessed using AMSTAR-2. Evidence certainty was evaluated using an algorithmic version of the GRADE framework, adapted for drug and non-drug interventions. 115 of 414 full text articles were deemed eligible and 299 were excluded; the eligible articles comprised 221 unique combinations of participants, interventions, comparators, and outcomes. For each combination, the most recent and methodologically robust meta-analysis was selected for re-estimation, which gave 221 re-estimated meta-analyses in total, derived from 47 meta-analytic reports. In the short term, alpha-2 agonists, amphetamines, atomoxetine, methylphenidate, and viloxazine showed medium to large effect sizes in reducing the severity of ADHD symptoms in children and adolescents, with moderate to high certainty evidence. Methylphenidate showed consistent benefits across raters (standardised mean difference >0.75, 95% confidence interval (CI) 0.56 to 1.03; moderate or high certainty evidence). These interventions showed lower tolerability than the placebo, but this effect was not significant for methylphenidate and atomoxetine. In adults, atomoxetine, cognitive behavioural therapy, methylphenidate (and, when restricting analyses to high quality trials, amphetamines) showed at least moderate certainty evidence of efficacy on ADHD symptoms, with medium effect sizes. Methylphenidate, amphetamines, and atomoxetine had worse tolerability than placebo (methylphenidate, risk ratio 0.50, 95% CI 0.36 to 0.69; amphetamines, 0.40, 0.22 to 0.72; atomoxetine, 0.45, 0.35 to 0.58). Some non-drug interventions (acupuncture and cognitive behavioural therapy in children and adolescents, and mindfulness in adults) showed large effect sizes for ADHD symptoms, but with low certainty evidence. No high certainty, long term evidence was found for any intervention. An online platform showing effects and evidence certainty of each intervention across age groups, time points, and outcomes (https://ebiadhd-database.org/) was developed. This review provides updated evidence to inform patients, practitioners, and guideline developers how best to manage ADHD symptoms. The online platform should facilitate the implementation of shared decision making in daily practice. Open Science Framework https://osf.io/ugqy6/.

Lithium is an effective treatment for mood disorders. However, its mechanism of action concerning its effect on impulsivity and emotional processing is still unclear. The current study aimed to investigate the effect of a 5-day lithium treatment on decision-making, reward-seeking and emotional processing in healthy volunteers. We conducted a double-blind, placebo-controlled, cross-over design study involving sixteen participants aged 18-50 years. Participants received lithium 800mg once daily followed by matching placebo or vice versa for five days in a random order. Impulsivity and emotional processing were assessed on day six using the Cambridge Gambling Task and the Emotional Testing Battery, respectively. There were significant interactions with large effect sizes between treatment and order for delay aversion (F1,14 = 13.79, p = 0.002, partial η2 = 0.496) and reward-seeking (F1,14 = 34.065, p = < 0.001, partial η2 = 0.709), but the post-hoc tests suggested only moderate, inconclusive effects at either visit. There was a significant interaction between treatment, emotion and order with a large effect size for the facial expression recognition task. The post-hoc analyses found that during the first visit, relative to placebo, lithium-treated participants showed a higher accuracy in recognising disgust and lower misclassification rates and response bias in recognising sad facial expressions, but higher accuracy and response bias in recognising fear during the second visit. We found a significant interaction between treatment and valence with a large effect size for emotional encoding of self-referent words. Post-hoc analysis showed that lithium was associated with a longer reaction time to encode negative self-referent words than placebo. Short-term lithium treatment in healthy participants produced a positive emotional bias in facial expression recognition and emotional encoding of self-referent words, but no significant effects on impulsivity and reward seeking. The early induction of positive bias in emotional processing may contribute to lithium's effectiveness in mood disorders.

ABSTRACTWhile preclinical studies suggest that Phosphodiesterase 5 (PDE5) inhibition may reduce cognitive impairment, findings from observational studies on whether PDE5 inhibitors reduce Alzheimer's disease (AD) risk have been inconsistent. We performed a two‐sample cis‐Mendelian Randomisation (MR) analysis to estimate the causal effect of PDE5 inhibition on AD risk. The analysis was performed across four different genome‐wide association studies (GWAS) of AD to enhance reliability through triangulation. Additionally, a sex‐stratified MR analysis using data from UK Biobank was performed to assess potential sex‐specific effects. No evidence of a causal association between PDE5 inhibition and AD risk was found in the main analyses. Similar findings were obtained in the sex‐stratified analysis. Our study uses genetic data to triangulate the evidence and suggests that PDE5 inhibitors are unlikely to decrease the risk of AD. Further research is needed to thoroughly understand the impact of PDE5 inhibitors on the risk of Alzheimer's disease.

BACKGROUNDThe apolipoprotein E (APOE) gene includes the strongest protective (ε2) and risk (ε4) variants for sporadic Alzheimer's disease (AD), but underlying mechanisms remain unclear. We studied APOE genotype effects on the cerebrospinal fluid (CSF) proteome.METHODSUsing untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A–T–), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across APOE genotypes using linear regression and characterized biological pathways.RESULTSFive hundred forty‐nine of 978 proteins (56%) differed between ε2/ε3 (n = 32 individuals) or ε4 carriers (n = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood–brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism.DISCUSSIONCombining two cohorts enabled analysis of the rare APOE ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity.HighlightsApolipoprotein E (APOE) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD).Combining cohorts enabled analysis of rare APOE ε2–associated protection in AD.The rare ε2 genotype may confer protection through improved neuronal plasticity.APOE ε4 carriers show increased blood–brain barrier dysfunction and glucose metabolism.These findings offer new insights into genotype‐specific mechanisms in early AD.