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.

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.

In youth, lithium is an effective medication for mood disorders, particularly for mixed and manic episodes of bipolar disorder, and is generally well-tolerated. In some clinical contexts, lithium is used off-label to manage other conditions. We conducted a scoping review of studies on the efficacy/effectiveness and safety/tolerability of lithium for treating youths with psychiatric conditions other than mood disorders or neurological disorders. We searched EMBASE, MEDLINE, PsycINFO, PubMed, and ClinicalTrials.gov up to March 31, 2025, with no restrictions on language or document type. We included studies of any design involving children and adolescents (mean age up to 18) treated with lithium, either as monotherapy or in combination with other psychotropic agents. We assessed study quality using the appropriate NHLBI tools and visually summarized the results with a heat map displaying sample size by study design and conditions, as well as the timeline of included studies' publication years. From 2687 records initially identified, after de-duplication removal and screening, 367 full-text reports were assessed, and 41 studies were included in the review, grouped by type of psychiatric or neurological disorder, most of which had a small sample. Among the assessed studies, 60 % of were considered of "fair" quality and 40 % of "poor" quality. Overall, although the clinical use of lithium beyond bipolar disorder in youth is increasing, the underlying evidence base remains limited. More rigorous research based on RCTs and observational studies with designs aimed at reducing confounding are needed to guide clinical practice.

Stimulants such as methylphenidate (MPH) are the first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD). Although stimulants are effective at a group level, individual response varies, which advocates for tailored treatment approaches. Prior studies suggested that neurobiological measures following a single dose of stimulants are indicative of longer-term clinical response. To expand these findings, we tested whether an association between acute and longer-term treatment response can also be identified using measures commonly used in clinic. Sixty adults with ADHD completed clinico-neuropsychological measures, including the Barkley Adult ADHD Rating Scale-IV (BAARS-IV) and the Quantitative behavior (Qb) test, following a single dose of MPH (20 mg) and placebo. These measures were repeated after two-month MPH treatment to ascertain response. We tested associations between single-dose and longer-term response using univariate and multivariable (Lasso) regression approaches. We also ran correlations between predicted and true outcome measures. Univariate regressions showed significant associations between single-dose and two-month improvement in BAARS hyperactivity/impulsivity and Qb scores (all p < 0.001 but Qb activity, p = 0.006). Multivariable models including acute response and baseline clinicodemographic measures yielded significant correlations between predicted and actual values for all BAARS-IV and Qb scores at follow-up, except for BAARS inattention and Qb activity. Most had large/very large effect size (up to r = 0.69). These findings suggest that specific clinico-neuropsychological changes following a single dose of MPH may be indicative of longer-term treatment response, especially when combined with pre-treatment clinico-demographic characteristics. Once validated in larger and more heterogeneous samples, these results may support more informed and individualized treatment approaches for ADHD.

Autism and attention-deficit hyperactivity disorder (ADHD) are among the most common neurodivergent neurotypes worldwide. Epidemiological evidence shows that sleep and circadian disturbances, such as difficulty initiating and maintaining sleep, and delayed sleep-wake phase, are highly prevalent in autistic children, children with ADHD, and those with both neurotypes. Despite scientific advancements, a comprehensive framework integrating sleep and circadian mechanisms with targeted interventions for autism and ADHD remains underdeveloped. In this Review we examine sleep and circadian rhythm differences in autistic children and adolescents, and in those with ADHD or both neurotypes, focusing on the underlying biological mechanisms. We discuss recent advances in the genetic and molecular links between sleep, circadian rhythms, and neuroplasticity, alongside the influence of these systems on physiology and therapeutic strategies. Both pharmacological and non-pharmacological interventions are considered, with an emphasis on the need for an integrated support model that accounts for the dynamic interplay between sleep and circadian rhythms in these populations. We identify key gaps in the current evidence base, particularly in relation to non-pharmacological interventions, and outline future research directions. Although most randomised controlled trials in children and adolescents have focused on behavioural sleep interventions, we also discuss emerging findings from trials using alternative approaches, such as targeted light therapy in adults, with implications for paediatric populations. Finally, we emphasise the importance of incorporating the perspectives of autistic children and adolescents and those with ADHD, as well as their parents and caregivers, into research designs.

Attention-deficit/hyperactivity disorder (ADHD) was once thought to be solely a childhood condition. Now it is well established that it can persist into adulthood, with an estimated worldwide prevalence of around 2.5%. Additionally, up to 70% of individuals with childhood-onset ADHD continue to experience impairing symptoms as adults, even if they no longer meet the criteria for a formal diagnosis. The validity of adult ADHD initially faced strong criticism. Today, empirical research supports its descriptive validity (identifying characteristic signs and symptoms), predictive validity (concerning specific outcomes, courses, and responses to treatment), and concurrent validity (evidence related to its underlying causes and biological mechanisms). Despite this progress, unresolved questions and ongoing debates about adult ADHD persist. This paper summarizes current empirical evidence, alongside uncertainties and controversies, regarding the definition, epidemiology, diagnosis, etiology, neurobiology, and management of ADHD in adults. Crucially, we also include perspectives from individuals with lived experience of this condition, highlighting their views on unmet needs and priorities for improving care. Key uncertainties and controversies on adult ADHD include: a) the possibility of late-onset ADHD; b) the significance of emotional dysregulation as a core symptom; c) the definition and characterization of functional impairment; d) the persistence of comorbid psychiatric and somatic conditions after accounting for confounders; e) the relevance of executive dysfunction in the definition of the condition; f) the use of objective diagnostic measures; g) the long-term effects of treatments; and h) the role of non-pharmacological interventions. Further research on adult ADHD is urgently needed. Funding for studies on this condition lags behind that for childhood ADHD and other mental disorders in adulthood. Hopefully, efforts by clinicians, researchers and other stakeholders will ultimately help ensure that adults with ADHD are better understood, supported, and empowered to thrive.

Improving meaningful outcomes is the main goal of clinical care for mental disorders. Traditionally, the focus in clinical research and practice has been on outcome domains that refer to symptom severity or service use (e.g., hospitalization), relate to categorical diagnoses, and favour clinician-rated measures. More recently, self-rated and dimensional as well as transdiagnostic outcome domains have gained traction, and functioning, quality of life and well-being/life satisfaction, along with the construct of personal recovery, have become a stronger focus. These key multidimensional outcome domains need to be properly defined and assessed. Further, the concepts of "functional" and "personal" recovery need to be differentiated. "Functional recovery" is defined by observed functioning across the domains of self-care, social interactions, leisure time activities, and educational or vocational activities. "Personal recovery" involves the subjective sense of living a personally meaningful life, irrespective of whether symptoms continue, or ongoing/intermittent support is needed. Despite the multi-stakeholder relevance of these outcome domains, no comprehensive account of how to measure them is available. To fill this gap, we provide here an overview of the main tools to assess functioning, quality of life/well-being/life satisfaction, and personal recovery outcomes across mental disorders in adults, aiming to also identify additional needs that should be addressed. We identified tools that can be used in clinical and research practice to assess people with the following mental health conditions: anxiety disorders, bipolar disorder, dementias, eating disorders, major depressive disorder, obsessive-compulsive and related disorders, personality disorders, post-traumatic stress disorder, schizophrenia, and substance use disorders. Both transdiagnostic and disorder-specific measures are described. Suggested tools were selected keeping feasibility and scalability needs in mind. The incorporation of these measures in both research and clinical care will enrich patient assessment as well as treatment planning and evaluation, increasing the likelihood of enhanced outcomes in people living with mental disorders.

The use of complementary, alternative and integrative medicine (CAIM) is highly prevalent among autistic individuals, with up to 90% reporting having used CAIM at least once in their lifetime. However, the evidence base for the effects of CAIM for autism remains uncertain. Here, to fill this gap, we conducted an umbrella review of meta-analyses exploring the effects of CAIM in autism across the lifespan and developed a web platform to disseminate the generated results. Five databases were searched (up to 31 December 2023) for systematic reviews with meta-analyses exploring the effects of CAIM in autism. Independent pairs of investigators identified eligible papers and extracted relevant data. Included meta-analyses were reestimated using a consistent statistical approach, and their methodological quality was assessed with AMSTAR-2. The certainty of evidence generated by each meta-analysis was appraised using an algorithmic version of the GRADE framework. This process led to the identification of 53 meta-analytic reports, enabling us to conduct 248 meta-analyses exploring the effects of 19 CAIMs in autism. We found no high-quality evidence to support the efficacy of any CAIM for core or associated symptoms of autism. Although several CAIMs showed promising results, they were supported by very low-quality evidence. The safety of CAIMs has rarely been evaluated, making it a crucial area for future research. To support evidence-based consideration of CAIM interventions for autism, we developed an interactive platform that facilitates access to and interpretation of the present results ( https://ebiact-database.com ).