Background: Increased levels of emotion dysregulation and impulsive behavior are overlapping symptoms in adult Attention-Deficit/Hyperactivity Disorder (aADHD) and Borderline Personality Disorder (BPD), both symptom domains reflecting on inhibitory control, although from different angles. Our aims were to describe their differences in the above conditions, investigate their associations with childhood traumatization, and to explore the potential mediation of emotion dysregulation and impulsivity between childhood traumas and personality functioning. Methods: Young adults between 18 and 36 years diagnosed with aADHD (n = 100) and BPD (n = 63) were investigated with structured clinical interviews, while age-matched healthy controls (n = 100) were screened for psychiatric disorders. Patients with aADHD-BPD comorbidity were excluded from further analyses. The Difficulties in Emotion Regulation Scale, the Barratt Impulsiveness Scale, the Level of Personality Functioning Scale, and the Childhood Trauma Questionnaire-Short Form were administered to investigate trait measures and childhood traumatization, respectively. Behavioral impulsivity and delay aversion were assessed using selected tests of the Cambridge Neuropsychological Test Automated Battery, and a computerized decision-making paradigm based on the Rogers decision-making task, respectively. Results: Significantly higher levels of emotion dysregulation and impulsivity were present both in the aADHD and BPD groups, however with different profiles. Waiting and stopping impulsivity was selectively higher among aADHD patients compared to healthy controls. The BPD group reported higher levels of emotion dysregulation in all domains, and demonstrated increased delay aversion among uncertain conditions in decision-making. Higher levels of childhood trauma were associated with emotion dysregulation, trait impulsivity, and delay aversion across groups. Emotion regulatory capacity played a significant mediating role between childhood traumatization and the level of personality functioning. Conclusions: Inhibitory control profiles of the aADHD and BPD groups were divergent. Childhood traumatization was associated with lower levels of personality functioning in adulthood, independently of diagnosis, an effect mediated more by emotion dysregulation, rather than impulsivity. These findings have various clinical implications for the treatment of aADHD and BPD, including psychoeducation, pharmacological interventions, and psychotherapy targeting specific symptom domains.

While the currently prevailing theory of ADHD postulates a neurobiological background and core deficits of behavioural inhibition and executive functioning as the basis of ADHD symptoms, our current conceptualisation also acknowledges the essential contributory role of psychosocial, ecological, and cognitive factors. Considering the multifactorial background of ADHD, its treatment equally needs to be multifactorial involving, besides pharmacotherapy, skill development and psychotherapy as well, especially if we postulate the increasing contribution of social factors in the background of the increasing burden of ADHD. Pharmacotherapies, including stimulants and non-stimulant ADHD medications applied as first-line treatments have a positive effect on core behavioural symptoms, however, they often do not sufficiently remediate several other symptoms and comorbid disorders, which are consequences of ADHD, especially considering that ADHD persists into adulthood and is present over the whole life span. Furthermore, pharmacological treatment is not sufficient to substitute for the skills needed to manage symptoms and adapt well to the environment. As part of a multimodal treatment approach, psychological therapies for ADHD target, besides core ADHD symptoms, other associated features including emotional dysregulation, personality development, neurocognitive dysfunction, depression, anxiety, and sleep problems. Insufficiently treated ADHD may contribute to psychological and personality developmental problems in children, as well as increased health costs and decreased productivity warranting multimodal treatment to address the areas not sufficiently targeted by ADHD-specific pharmacotherapy.

Background: Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs). Methods: Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone). Results: Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment. Conclusions: Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.

Attention-deficit/hyperactivity disorder (ADHD) persists into adulthood in up to 60% of cases, affecting 2.5-6.8% of adults worldwide, with high comorbidity rates of mood, anxiety, and substance use disorders, and significant functional impairments, such as reduced quality of life, increased mortality, and economic burden. This review synthesizes etiological factors, including neuroimaging evidence of fronto-striatal and default mode network disruptions, high heritability up to 70-80% driven by common, polygenic and rare variants, and environmental risk factors. Treatment emphasizes multimodal approaches, with stimulants as first-line pharmacotherapy due to their superior efficacy over non-stimulants like atomoxetine and viloxazine. Novel agents in development, such as centanafadine triple reuptake inhibitor and solriamfetol target core symptoms and comorbidities, showing promising phase III results. Despite the high effect sizes of pharmacological treatment for ADHD, obstacles such as acceptance and adherence remain challenging. Neuromodulatory interventions, including transcranial direct current stimulation (tDCS) and neurofeedback, demonstrate moderate effects on inattention and executive function. Psychotherapeutic options, particularly cognitive-behavioral therapy (CBT)-based interventions, improve symptom management and emotional regulation, often as adjuncts to medication. The review highlights the need for personalized strategies addressing adherence, comorbidity, and long-term outcomes, emphasizing integrated care to mitigate ADHD's lifelong impact.

Schizophrenia is a complex psychiatric disorder of complex etiology. Despite decades of antipsychotic drug development and treatment, the mechanisms underlying cellular drug effects remain incompletely understood. Induced pluripotent stem cell (iPSC)-based disease and pharmacological modelling offer new avenues for drug development. In this study, we explored the development of two- and three-dimensional neural progenitor cultures and the impact of different antipsychotics in a schizophrenia model. Four human iPSC lines, including two carrying a de novo ZMYND11 gene mutation associated with schizophrenia, were differentiated into hippocampal neural progenitor cells (NPCs), cultured either in monolayers or as 3D spheroids. While in monolayers the proliferation of the NPCs was similar, spheroids showed significant differences in scattered cell number and outgrowth size between schizophrenia mutant and wild-type NPCs. Since there is only limited information about the effects of antipsychotic agents on neural progenitor cell proliferation and differentiation, we investigated the effects of three molecules, representing three subgroups of antipsychotics, in the 2D and 3D NPC models. Our findings suggest that cell adhesion may play a crucial role in the molecular disease pathways of schizophrenia, highlighting the value of spheroid models for mechanistic and drug development studies. These studies may significantly help our understanding of the effects of schizophrenia on neural development and the response of progenitors to antipsychotic medications.

Aims DiGeorge syndrome (DGS) due to 22q11.2 microdeletion is characterized by a high degree of phenotypic variability. This study aimed to elucidate the molecular and cellular mechanisms underlying this variability and exacerbation of cardiovascular manifestations by developing a human induced pluripotent stem cell (hiPSC)-based model using a three-generation family. Methods and results We established hiPSC lines and their cardiovascular derivatives from a family carrying the identical 22q11.2 deletion but displaying a wide spectrum of cardiovascular involvement, allowing for a direct comparison of genetics and phenotypes at the cellular level. Genetic analyses revealed no de novo mutation in the DG region genes in patients, and no correlation between the cumulative number of genetic variants and the severity of DGS. However, we observed the presence of gene variants that may modulate predisposition to the disease with possible role in cardiovascular development. Cardiomyocytes from DGS-hiPSC with prominent cardiac symptoms exhibited altered expression of connexin-43, suggesting disruptions in early cardiac morphogenesis compared to asymptomatic relatives. Endothelial cells differentiated from symptomatic DGS-hiPSC showed impaired migration and disrupted tubular morphology with dysregulation of angiogenesis and vascular integrity pathways at the transcriptomic level. To bridge in vitro and transcriptomics findings with in vivo relevance, we performed deep clinical phenotyping for each participant and applied gene-to-phenotype correlation algorithms using large-scale clinical registry data. Conclusion Our results demonstrate that hiPSC-derived cardiovascular cells from DGS patients recapitulate disease-specific morphological and functional abnormalities, enabling identification of genotype-phenotype relationships that underlie clinical heterogeneity. Translational Perspective By modelling DGS with patient-derived hiPSC from a uniquely multigenerational family, our study reveals how shared genetic microdeletions can result in divergent pathophysiological outcomes at the cellular level. This work establishes that individualised hiPSC models faithfully reflect cardiac and vascular anomalies observed in patients and delineate the cellular and transcriptional mechanisms underlying these differences. These results facilitate early identification of pathogenic mechanisms, potentially enabling more refined risk assessment and personalised monitoring strategies for DGS patients - both for cardiovascular manifestations and potentially for extra-cardiac features.