Faculty Bibliography

Serotonergic psychedelics and 3,4-methylendioxtmethamphetamine (MDMA) are promising treatments for mental disorders with a continuously evolving evidence base. We searched Pubmed/Scopus/clinical trial registries up to 08july2025 for double-blind randomized controlled trials (RCTs) testing MDMA or serotonergic psychedelics in patients with mental disorders. Primary outcomes were change in disease-specific symptoms and all-cause discontinuation. Standardized mean differences (SMD) and relative risk (RR) were estimated using random-effects meta-analysis. Risk of bias (RoB) was assessed with Cochrane's RoB-tool version 2 and certainty of evidence with GRADE. The review is maintained as living systematic review (https://ebipsyche-database.org/). We included 30 RCTs (1480 participants; female=45.8 %; with psychological support=83.3 %; high RoB=83.3 %). In post-traumatic stress disorder (PTSD), MDMA reduced PTSD symptoms compared to any control (k = 11; SMD=-0.85 [-1.09; -0.60]; I²=0 %; GRADE=low). In major depressive disorder (MDD), psilocybin/ayahuasca/LSD reduced depressive symptoms (k = 8; SMD=-0.62 [-0.97; -0.28]; I²=55 %; GRADE=very low). In anxiety disorders, both MDMA and serotonergic psychedelics reduced anxiety symptoms (SMD_MDMA=-1.18 [-2.04; -0.32]; I²=0 %; k = 2; GRADE=low and SMD_serotonergic=-0.88 [-1.70; -0.06]; I²=54 %;k = 5; GRADE=very low). In alcohol use disorder, neither psilocybin nor LSD reduced abstinence rates (k = 6; RR=1.42 [0.89; 2.26]; I²=7 %; GRADE=very low). In attention-deficit hyperactivity disorder (ADHD), LSD did not reduce ADHD symptoms (k = 1; SMD=0.22 [-0.32; 0.76]; GRADE=very low). Moderate certainty in evidence was only found for MDMA on PTSD symptoms when compared to placebo. MDMA/serotonergic psychedelics were not associated with higher risk of all-cause discontinuation (RR_MDMA=0.74 [0.32; 1.72]; RR_serotonergic=0.81 [0.56; 1.15]). Overall, MDMA/serotonergic psychedelics are promising for the treatment of PTSD, MDD, and anxiety disorders with moderate to large effect sizes. Pragmatic trials, long-term, head-to-head trials exploring the role of psychological support, aiming to identify predictors of response, and accounting for expectancy and functional unblinding are needed. Studies addressing these limitations will likely be required for regulatory approval of psychedelic drugs.

IMPORTANCE/UNASSIGNED:Individuals with attention-deficit/hyperactivity disorder (ADHD) may present with psychosis or bipolar disorder (BD) following treatment with stimulants. The extent to which this occurs is currently unclear. OBJECTIVE/UNASSIGNED:To meta-analytically quantify the occurrence of psychosis or BD after exposure to stimulants in individuals with ADHD and assess possible moderating factors. DATA SOURCES/UNASSIGNED:PubMed, Web of Science, Ovid/PsycINFO, and Cochrane Central Register of Reviews were searched from inception until October 1, 2024, without language restrictions. STUDY SELECTION/UNASSIGNED:Studies of any design with DSM or International Classification of Diseases-defined ADHD populations exposed to stimulants, where psychosis or BD outcomes were evaluated. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses and MOOSE Meta-analysis of Observational Studies in Epidemiology guidelines were followed, the protocol was registered, and the Newcastle-Ottawa scale and Cochrane risk of bias-2 tool were used for quality appraisal. Random-effects meta-analysis, subgroup analyses, and meta-regressions were conducted. MAIN OUTCOMES AND MEASURES/UNASSIGNED:For the proportion of individuals developing psychotic symptoms, psychotic disorders, and BD, effect sizes are reported as percentages with 95% CIs. For the comparison between amphetamines and methylphenidate, effect sizes are presented as odds ratios with 95% CIs. RESULTS/UNASSIGNED:Sixteen studies (N = 391 043; mean [range] age, 12.6 [8.5-31.1] years; 288 199 [73.7%] male) were eligible. Among individuals with ADHD prescribed stimulants, 2.76% (95% CI, 0.73-9.88; k = 10; n = 237 035), 2.29% (95% CI, 1.52-3.40; k = 4; n = 91 437), and 3.72% (95% CI, 0.77-16.05; k = 4; n = 92 945) developed psychotic symptoms, a psychotic disorder, and BD, respectively. Heterogeneity across the studies was significant (I2 > 95%). Psychosis occurrence risk was significantly higher in individuals exposed to amphetamines than to methylphenidate (odds ratio [OR], 1.57, 95% CI, 1.15-2.16; k = 3, n = 231 325). Subgroup analyses showed significantly higher prevalence of psychotic symptoms in studies from North America and in those with longer follow-up periods. Increased psychosis occurrence was associated with a higher proportion of female participants, smaller sample sizes, and higher dose of stimulants. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This systematic review and meta-analysis found a nonnegligible occurrence of psychotic symptoms, psychotic disorders, or BD in individuals with ADHD treated with stimulants. Amphetamines were associated with higher occurrence compared to methylphenidate. The included studies cannot establish causality, highlighting the need for further research, including randomized clinical trials and mirror-image studies comparing individuals exposed and not exposed to stimulants. Nonetheless, clinicians should inform patients about the increased occurrence of psychosis or BD when discussing stimulant pharmacotherapy and systematically monitor for these conditions throughout treatment.

INTRODUCTION/UNASSIGNED:Comorbidity between disorders is pervasive, and its relationship to the main conditions under investigation needs to be addressed for robust causal inference. However, many clinical etiologic studies still fail to capitalize on the theoretical advancements and improved recommendations regarding covariate adjustment in this context. Specifically, studies often lack explicit causal assumptions about the role of comorbidity in exposure-outcome relationships, potentially leading to inappropriate accounting for comorbid conditions and resulting in biased effect estimates. This study aims to explore common causal structures involving comorbidity and provide guidance for handling it in etiologic research. METHODS/UNASSIGNED:We use Directed Acyclic Graphs (DAGs) to depict six causal scenarios involving comorbidity as a confounder, mediator, collider, or consequence of the exposure or outcome, illustrated with real-world clinical examples. Simulations were conducted across 5,000 iterations for each scenario, assessing the impact of conditioning on comorbidity under four effect measures (risk difference, odds ratio, risk ratio, and mean difference). Bias was evaluated by comparing adjusted and unadjusted effect estimates to the true values. RESULTS/UNASSIGNED:The impact of conditioning on comorbidity varied by its causal role. Adjusting for comorbidity mitigated bias when it acted as a confounder but introduced bias when it was a mediator or collider. In instances where comorbidity was a consequence of either the exposure or outcome, the decision to adjust depended on the research objectives and could vary across effect measures. DISCUSSION/UNASSIGNED:Explicit causal assumptions are essential for selecting appropriate analytical strategies in etiologic research. This study provides practical guidance on analytical handling of the measures of comorbidity, highlighting the need for study design and analysis to align with research objectives. Future work should address more complex causal structures and other methodological challenges.

Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high-frequency oscillations (HFOs, defined as 250-500Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1-500Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2^-/-, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.

Interoceptive accuracy, the ability to correctly perceive internal body signals such as heartbeats, has been empirically and theoretically linked to stress. However, issues with the measurement of both interoceptive accuracy and stress have led to lack of clarity regarding this relationship. This systematic review and meta-analysis aimed to clarify whether interoceptive accuracy is associated with different facets of stress, including - physical, cognitive and self-reported stressors and the physiological stress response. A systematic search identified 2014 abstracts. Twenty-eight authors were contacted to request data for eligible studies, which yielded a final sample of 20 studies. Results revealed a positive association between heartbeat counting task (HCT) performance and acute physical stressors, and a negative association between HCT performance and physiological stress responses. No significant relationships were observed between stress and interoceptive accuracy assessed by the heartbeat discrimination task. While these findings offer tentative support for stress-interoceptive accuracy associations, they must be interpreted with caution given substantial heterogeneity in stress measures, limited use of interoception tasks beyond the HCT, and ongoing concerns regarding task validity. Implications for future research and methodological recommendations are discussed.

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially-expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of cell proliferation. We found that the expression of sFRP3, a Wnt signaling inhibitor, is altered in a seizure-dependent manner and might be regulated by ΔFosB, a seizure-induced transcription factor. Increasing sFRP3 expression prevented NSC depletion and improved spatial discrimination, suggesting that the loss of sFRP3 might mediate seizure-driven impairment in cognition in AD model mice, and perhaps also in AD.Significance statement There is increased incidence of seizures in individuals with Alzheimer's disease (AD), but it is unclear how seizures contribute to cognitive decline. Here, we uncover a molecular mechanism by which seizures in AD induce expression of a long-lasting transcription factor in the hippocampal dentate gyrus that suppresses expression of sFRP3, an inhibitor of neural stem cell division, accelerating the depletion of a finite pool of neural stem cells and dysregulating adult hippocampal neurogenesis. We found that restoring sFRP3 expression prevents accelerated use and depletion of neural stem cells and improves performance in an adult neurogenesis-dependent cognitive task. Our findings have implications for AD, epilepsy, and other neurological disorders that are accompanied by seizures.

BACKGROUND/UNASSIGNED:Complementary and integrative health (CIH) services enhance physiological and psychological wellbeing, while potentially reducing medical costs. Despite these benefits, use of inpatient CIH services remains poorly characterized, impeding efforts to develop equitable and effective healthcare. OBJECTIVE/UNASSIGNED:This retrospective case-control study examined characteristics of patients likely to receive CIH referrals and consults. METHOD/UNASSIGNED:Electronic health records were analyzed from patients hospitalized at a large metropolitan academic medical center from September 2022 to February 2024. RESULTS/UNASSIGNED:values <0.001). Among those referred, 72% received at least one CIH consult, with lower odds of completing a consult for male patients. CONCLUSION/UNASSIGNED:Disparities underscore the need for equitable CIH services access in healthcare systems. Future research will test how to broaden services to male patients, those with non-English language preference, and less medical complexity, to ensure greater benefit from holistic healthcare.

Adverse childhood experiences (ACE) are common risk factors for many psychiatric disorders. Their underlying biological mechanisms may involve oxidative stress (OS), which has deleterious effects on cells through its own actions and through its interactions with inflammation and the stress axes, particularly in the brain. In order to assess the role of OS in the association between ACE and psychopathology, we performed a systematic review of animal and human research (PROSPERO CRD42023378418 and CRD42022378376), funded by the Swiss National Science Foundation (grant number 204033). PubMed, Web of Science, PsycInfo, Scopus and Embase were searched from inception until 31 October 2024. We included 130 studies involving animal models exposed to stressor-paradigms recognized as ACE analogs before they reached adulthood, or human participants with a history of ACE and assessment of psychopathology, and reporting outcomes on OS-related markers. Animal studies overall show increased OS and psychopathology after stress, thus supporting the hypothesis that OS mediates the relationship between ACE and psychopathology. Human studies are heterogeneous and less conclusive. Although the association between ACE exposure and OS, in animals and humans, was likely affected by the nature, the timing, and the intensity of the exposure, these parameters were only evaluated in a small fraction of studies. Similarly, though some studies hinted at sex differences in the OS response to ACE in animals, the majority of studies did not address this issue. Further research, using longitudinal designs and more thorough examination of ACE history in participants, is therefore needed.

The development of racial identity in Black boys is a critical aspect of their overall mental health and well-being. This article explores the unique societal and cultural challenges faced by Black boys in the context of identity formation and mental health outcomes. It critiques the one size fits all approach in clinical settings and advocates for an equitably tailored approach that emphasizes cultural competence, cultural responsiveness, and the importance of understanding the lived experiences of Black youth. By integrating these elements into clinical practice, mental health professionals can provide more effective and compassionate care promoting their mental health and resilience.