Medicine and Pharmacology

Abstract: Fibromyalgia (FM) is a chronic, widespread musculoskeletal pain syndrome of still unknown etiology, characterized by allodynia and hyperalgesia. It affects between 2% and 8% of the population and is significantly more prevalent in women than in men. It is attributed to physiological, endocrine, immunological, and neurobiological variations that influence both pain development and the response to pharmacological treatments. have Limited efficacy and a high incidence of adverse effects of current pharmacological treatments for FM have increased interest in the use of alternative therapies with medicinal plants. Non-polar extracts such as the essential oil of Salvia rosmarinus are included in herbal formulations suggesting its potential antinociceptive properties for nociplastic pain. However, the evidence regarding the analgesic efficacy and mechanisms of action according to sex remains unexplored. The objective in this study was to investigate the efficacy of a non-polar extract of S. rosmarinus, whose GC-MS profile is described, and to explore the involvement of gonadal hormone receptors in an experimental model of FM in male and female rats. The extract (10, 30 and 300 mg/kg, i.p.) or Gabapentin (30 mg/kg, i.p., as reference drug) were evaluated 30 minutes after their administration by using the Von Frey filaments and thermal acetone test for tactile and mechanical allodynia, respectively, and Randall Sellito test for mechanical hyperalgesia carried out for a period of 240 minutes. To determine the involvement of gonadal hormone receptors, reserpinized female rats were pretreated with the selective estrogen receptor β antagonist (ERβ, PHTPP, 25 µg/rat) 24 hours before the extract, while male rats received non-steroidal antiandrogen pretreatment with flutamide (10 mg/kg/day) for 14 days, followed by behavioral testing. The extract produced a dose-dependent antiallodynic and antihyperalgesic effect, with greater efficacy in females compared to males as this effect was significant starting at a dose of 30 mg/kg, while in males only the highest dose was significant. Blockade of ERβ receptors inhibited the antinociceptive effect in females, while androgen blockade facilitated the effect in males. The results of this study suggest that non-polar metabolites of S. rosmarinus are involved in its antinociceptive efficacy mediated by sex-dependent gonadal hormonal mechanisms for FM-type pain relief.

Abstract: Background/Objectives: The burden of Major Depressive Disorder (MDD) calls for assessing the needs and design of innovative add-on interventions. Generative artifi-cial-intelligence (AI) tools are increasingly used in everyday life. Evidence remains limited on how needs assessment and co-participatory design can inform AI chatbot trials for MDD. Methods: This study reports a mixed-methods design. Phase 1 comprised a needs assessment of 511 psychiatric outpatient attendees in Hong Kong. Phase 2 involved a participatory co-design and test-run experiences with 10 lived-experience experts with MDD and 8 multidisciplinary clinical professionals. This process developed the CARES-MDD, a generative AI-chatbot grounded in evidence-based Cogni-tive-Behavioral-Therapy content as an adjunct to standard care. Results: In Phase 1, 66.2% reported using generic AI chatbots for emotional concerns; privacy, anticipated negative evaluation, and concern about burdening others were recurring themes in the qualitative data. 24/7 accessibility, non-judgmental, and localized empathy were the main themes of a desired mental health AI chatbot. In Phase 2, CARES-MDD was co-designed and as-sessed against a 7-domain consensus rubric measuring perceived usefulness and ac-ceptability. Overall, CARES-MDD received favorable expert rubric ratings. Content analysis identified positive and negative experiences which established parameters for future trial methodology. Conclusions: This study identifies needs and yields the co-design of the CARE-MDD purposed as adjunct support for MDD in psychiatric care in Hong Kong, providing the parameters to inform future controlled trials.

Abstract: Objective: To synthesize comparative evidence on antidepressant efficacy, sleep effects, and sexual dysfunction in depression with comorbid insomnia, and to propose a symptom-priority framework for antidepressant selection.Data Sources: PubMed/MEDLINE and Google Scholar were searched through August 2026 (antidepressant, insomnia, sleep architecture, sexual dysfunction, major depressive disorder, and individual drug names); reference lists and guidelines were hand-searched.Study Selection: Randomized trials, network meta-analyses, systematic reviews, large effectiveness cohorts (e.g., STAR*D), and major guidelines on efficacy or sleep/sexual-function effects were prioritized; 43 sources were included.Data Extraction: Data on comparative efficacy, sleep effects, and treatment-emergent sexual dysfunction were extracted and synthesized narratively by drug class and agent; no formal risk-of-bias scoring was applied.Results: Because most antidepressants are comparably efficacious on average, selection in depression with insomnia hinges largely on differential sleep and sexual-function effects. Activating agents (fluoxetine, paroxetine, venlafaxine, bupropion) disrupt sleep continuity and suppress REM sleep, while sedating agents (mirtazapine, trazodone, doxepin) shorten sleep latency and increase slow-wave sleep; agomelatine promotes sleep via circadian resynchronization, not sedation. Adjunctive Z-drugs raise remission rates by about 25% over monotherapy, and CBT for insomnia is an effective adjunct. SSRIs and venlafaxine carry sexual-dysfunction rates of roughly one-quarter to three-quarters, versus no significant difference from placebo for bupropion, agomelatine, mirtazapine, and nefazodone.Conclusions: Because average efficacy differences are small, sleep and sexual-function profiles are actionable axes for antidepressant selection in depression with insomnia. Clinicians should match drug choice to the patient's most disabling symptoms, monitor both domains explicitly, and actively treat residual insomnia.

Abstract: Background/Objectives: Response to psychotropic medications is highly variable: approximately 40% of patients with major depressive disorder fail to respond to initial antidepressant treatment, and antipsychotics and mood stabilizers show comparably wide inter-individual variability in efficacy and tolerability. Genetic studies explain only a fraction of this variation, and the absence of valid biomarkers forces trial-and-error prescribing. Pharmacometabolomics — the application of global metabolite profiling to drug response — has emerged as a complementary “omics” strategy capturing the integrated effects of genome, environment, gut microbiome, and disease state on efficacy and toxicity. This review synthesizes evidence that pharmacometabolomics can predict psychotropic treatment response, characterize adverse metabolic effects, and contribute to precision psychiatry, focusing on antidepressants, antipsychotics, and mood stabilizers. Methods: This narrative review synthesized seminal conceptual and methodological literature, proof-of-concept and replication pharmacometabolomic studies in depressed, psychotic, and bipolar populations, lipidomic and metabolomic investigations of antipsychotic-induced metabolic adversity, ketamine/esketamine translational studies, and pharmacometabolomics-informed pharmacogenomic investigations, prioritizing highly cited primary literature. Results: Pretreatment metabolic profiles (“metabotypes”) distinguish responders from non-responders to sertraline and placebo, and baseline glycine, sphingolipid, and tryptophan-pathway metabolites predict citalopram/escitalopram outcomes, with a glycine dehydrogenase polymorphism identified through pharmacometabolomics-informed pharmacogenomics. Ketamine and esketamine produce detectable changes in glutamate, tryptophan, and urea-cycle metabolites within two hours that correlate with antidepressant response days later. Risperidone normalizes partially disturbed energy, neurotransmitter, and phospholipid pathways in schizophrenia, and lipidomic signatures track antipsychotic-associated weight gain, free-fatty-acid surges, and diabetes risk. Gut microbial metabolism of psychotropics contributes additional, individually variable layers of drug activation and toxicity visible in the metabolome, and regulatory frameworks for biomarker qualification are emerging. Conclusions: Pharmacometabolomics provides mechanism-based, dynamically measurable biomarkers of psychotropic treatment response and adverse effects, and its integration with pharmacogenomics and systems pharmacology offers a credible route to precision psychiatry. Prospective validation, standardized analytical platforms, and multi-omics integration remain the principal barriers to clinical translation.

Abstract: Background: Symptoms overlap and heterogeneity observed in psychiatric disorders pose a challenge to accurate diagnosis and patient stratification. In low-resource settings such as Nigeria, utilizing available structured clinical data with unsupervised machine learning can reveal latent subtypes, potentially improving diagnosis and treatment. Aims: This study aims to identify meaningful psychiatric subtypes in a Nigerian cohort using clustering of mental state and patient history data. Method: Data from 664 patients with 38 clinical variables were analyzed. Mental state domain included mood, thought content, perception, and insight, while history domain covered psychosocial background, family history, substance use, and past psychiatric episodes. After preprocessing, imputation and one-hot encoding, KMeans clustering was applied independently to the two domains. The optimal cluster number (k = 4) was chosen based on the Elbow Method and silhouette scores for clinical interpretability and model robustness. Cluster stability was assessed with Adjusted Rand Index and Normalized Mutual Information. Chi-square tests evaluated cluster-diagnosis correlation. Results: Mental state clustering demonstrated high stability (ARI = 0.9944; NMI = 0.9912), while history clustering showed moderate agreement (ARI = 0.4490; NMI = 0.5465). Correlation analysis between clusters identified four patient profiles with distinct clinical features: (1) a Social Stressor profile marked by reactive symptoms to acute social triggers without prior history, likely benefiting from psychosocial support; (2) a Psychiatric Chronicity profile of episodic or long-term disorders requiring ongoing management; (3) a Minimal Risk Factor profile representing mostly first-episode cases without clear risk factors, needing careful monitoring; and (4) a Complex Multi-Risk profile involving overlapping personal, familial, and medical risks requiring comprehensive multidisciplinary care. These profiles were significantly associated with diagnosis (p < 0.001). Conclusions:Unsupervised clustering revealed clinically relevant psychiatric subtypes in an underrepresented population, highlighting opportunities for tailored interventions. Further studies should validate these findings and explore their predictive value for treatment outcomes.

Abstract: Delusions occur in disorders with markedly different etiologies, including schizophrenia, medication-induced psychosis, postpartum psychosis, neurodegenerative disease, and metabolic encephalopathy. This convergence poses a basic clinical problem: the phenomenology of a delusion may provide limited information about the mechanism that produced it or the prognosis that follows. This article examines five routes to a fixed false belief using the ARCH × Φ framework, in which biological execution depends on the conjunction of architecture (A), drive (D), context (C), and a permissive phase or gating state (Φ). The central proposal is that, in a conjunctive system, severe disruption of different required components can converge on a common clinical endpoint. A second distinction separates current execution from the persistent neural substrate that constrains future execution. Transient state disturbances may therefore produce severe but reversible psychosis, whereas developmental mis-writing or progressive substrate loss may produce persistent or worsening illness. Schizophrenia, corticosteroid psychosis, postpartum psychosis, Alzheimer's disease, and homocystinuria illustrate distinct versions of this problem. The framework is presented as a mechanistic organizing hypothesis rather than a completed theory of delusion; several mappings remain inferential, and the homocystinuria case identifies a failure mode not represented by the original equation. Its value lies in making clinically relevant distinctions among convergent symptoms and in generating falsifiable predictions across molecular, circuit, and clinical levels.

Abstract: Background/Objectives: Major depressive disorder is a highly prevalent psychiatric condition associated with substantial functional impairment. Despite available phar-macological and psychotherapeutic interventions, a considerable proportion of indi-viduals do not achieve adequate symptom improvement, contributing to the persistent clinical burden of treatment-resistant depression (TRD). To expand therapeutic options for this population, our team developed a virtual reality–based therapy (VRT) inte-grating experiential and relational components. As part of VRT, participants engaged in dialogues with an avatar, animated in real time by the therapist, representing a person meaningfully associated with their depressive experiences. This pilot clinical trial examined the short-term efficacy of VRT compared with treatment as usual (TAU) in individuals with TRD. Methods: This two-arm, parallel-group trial compared VRT in 20 individuals with TRD with TAU in 10 individuals. The primary outcome was depressive symptom severity. Secondary outcomes included anxious symptom severity, self-esteem, quality of life, and functioning. Primary and secondary outcomes were analyzed using linear mixed models with maximum-likelihood estimation for missing data, with time-by-treatment interactions used to determine whether changes over time differed significantly between VRT and TAU. Results: Post-therapy, VRT produced large effects on depressive symptoms relative to TAU, as assessed by both self-reported (d = 2.61, p < 0.01) and clinician-rated scores (d = 2.10, p < 0.01). Large ef-fects favoring VRT were also observed for anxiety (d = 1.86, p < 0.01), self-esteem (d = 2.07, p < 0.01), quality of life (self-report: d = 2.37; clinician-rated: d = 2.21; both p < 0.01), and functioning (d = 1.27, p < 0.01). Conclusion: These preliminary findings suggest that VRT may represent a promising therapeutic approach for individuals with TRD. Larger controlled trials are warranted to confirm its efficacy and evaluate the durability of treatment effects over time.

Abstract: The general factor of psychopathology, p, orders people on a broad dimension of psychiatric burden and predicts impairment, developmental risk, and other adverse outcomes. Debate has focused on which latent-variable structure best recovers p, but comparative fit cannot resolve that question cleanly because bifactor models possess high fitting propensity. This article identifies a prior problem at measurement. Many psychiatric instruments convert directionally opposite manifestations into the same severity value. Major-depression criteria and the PHQ-9, for example, count insomnia or hypersomnia, appetite loss or overeating, and psychomotor retardation or agitation toward the same syndrome and severity score. Human data show that the discarded direction can carry biological signal: depressed patients with increased versus decreased appetite show different endocrine, inflammatory, metabolic, and neural profiles despite comparable overall depressive severity, and genetic analyses likewise distinguish directionally defined neurovegetative symptoms. I formalize the consequence as a non-injective measurement map. If two distinct latent states map to the same observed score vector on a rectified coordinate, no covariance model or downstream factor score can recover the information that the instrument removed. This result does not imply that p is artifactual or useless; it implies that magnitude is not generally sufficient for representation. Developmental neuroscience provides biological plausibility for signed latent disturbances because opposing structural changes can be dissociated experimentally, but the formal result does not depend on any particular developmental mechanism. I propose tests based on bipolar rescoring, held-out prediction, treatment-by-direction interactions, and etiologically anchored contrasts. The appropriate remedy is not necessarily a different factor model. It is measurement that preserves which way a clinically relevant system deviated.

Abstract: Autism spectrum disorder is characterized by substantial heterogeneity in developmental trajectories, therapeutic engagement, and intervention responsiveness. Although early intervention is widely emphasized, developmental timing is often interpreted primarily in chronological terms. This Hypothesis and Theory article proposes adaptive neurodevelopmental window accessibility (ANWA) as a hypothesis-generating translational construct for studying timing-sensitive intervention responsiveness in autism. ANWA is defined as the dynamic, context-dependent degree to which an autistic child is currently accessible to therapeutic learning, given the interaction among developmental timing, biological burden, adaptive reserve or energetic capacity, regulatory availability, contextual support fit, therapeutic engagement accessibility, and neuroplastic responsiveness. ANWA is not proposed as a fixed critical period, a universal sensitive period, a measure of developmental readiness alone, or a validated clinical tool for determining treatment timing. The manuscript clarifies the conceptual novelty of ANWA by distinguishing it from critical periods, sensitive periods, neuroplasticity, developmental readiness, early intervention timing, therapeutic engagement, biological burden, treatment response, and intervention intensity. It also proposes candidate latent domains, observable indicators, feasible clinical measures, testable hypotheses, falsifiability criteria, and a staged validation roadmap. A hierarchical dynamic model is proposed in which biological burden, energetic capacity, regulatory state, therapeutic engagement accessibility, and contextual support fit may moderate the relationship between intervention exposure and responsiveness. ANWA remains theoretical and requires empirical validation. It should not be used to deny intervention, determine service eligibility, assign responsibility to children or families, or imply that developmental opportunity has been permanently missed. Its value is to support future longitudinal research into when, how, and under which modifiable conditions therapeutic input becomes more accessible, tolerable, and developmentally usable.

Abstract: Background: Cannabis use is common among individuals with psychiatric disorders, but its relationship with anhedonia and reward-processing deficits remains unclear. Anhedonia is multidimensional, encompassing anticipatory and consummatory pleasure, motivation, reward learning, and neurobiological signatures such as blunted striatal dopamine release and reduced reward-related activation in mesocorticolimbic regions. THC, the primary psychoactive constituent of cannabis, acts directly on CB1 receptors within this circuitry. However, findings on how THC-specific cannabis use affects anhedonia and reward-related outcomes across psychiatric populations are inconsistent, varying by dose, frequency, and use pattern. This systematic review synthesizes current literature on THC-specific cannabis use and anhedonia or reward-related outcomes across psychiatric disorders. Methods: Following PRISMA 2020 guidelines, Medline, PsycINFO, and Embase were searched through March 2026. Eligible studies included experimental, quasi-experimental, and observational designs assessing cannabis exposure in populations with clinical or subclinical psychiatric disorders or symptoms, reporting at least one subjective, behavioral, or neurobiological measure of anhedonia or reward processing (e.g., anticipatory/consummatory pleasure, effort-based motivation, reward responsiveness, or neural reward activity). Results: Twenty studies met inclusion criteria, spanning psychosis-spectrum disorders (13 studies, N = 53,043), MDD/depressive symptoms (8 studies, N = 4,657), bipolar disorder (1 study, N = 103), and anxiety symptoms (1 study, N = 153). In schizophrenia and first-episode psychosis, longitudinal studies consistently linked cannabis use to reduced intrinsic motivation and blunted neural reward sensitivity, while cross-sectional findings were mixed. Among clinical high-risk youth, cannabis use was inversely associated with baseline social anhedonia but did not predict subsequent change. In MDD, cannabis use disorder—rather than general use—predicted greater odds of anhedonia onset over 3–6-year follow-up; five of seven moderate-to-high-quality studies found significant associations. Abstinence/treatment findings were mixed: a 28-day abstinence paradigm reduced self-reported anhedonia, while reduced cannabis use during CBT/MET was linked to reduced ventral striatal reward activation despite depressive symptom improvement. The bipolar study found no association with physical anhedonia; the anxiety study found greater cannabis severity linked to anticipatory but not consummatory anhedonia. Conclusions: Evidence most consistently implicates CUD in worsening motivational and anticipatory reward deficits in schizophrenia and MDD. Findings for bipolar and anxiety disorders are limited. Methodological heterogeneity underscores the need for longitudinal, mechanistic studies clarifying causal pathways and disorder-specific vulnerabilities.

Abstract: Autism spectrum disorder is characterized by substantial heterogeneity in developmental trajectories, biological profiles, adaptive functioning, regulatory capacity, family-contextual factors, and response to intervention. Although evidence-informed interventions may benefit many autistic children, therapeutic response remains variable, limited, or fluctuating in a significant proportion of cases. This variability highlights the need for stratification frameworks that can better characterize when, how, and under what conditions an autistic child becomes accessible to therapeutic input. This Hypothesis and Theory manuscript proposes the Therapeutic Engagement Index (TEI) as a hypothesis-generating stratification construct for understanding variability in therapeutic accessibility and intervention responsiveness in autism. TEI is situated within FIAP^® — Framework for Integrated Autism Precision Care — and is conceptualized as a multidimensional framework integrating regulatory availability, attentional and interactional access, responsiveness to therapeutic support, persistence and adaptive effort, contextual transfer, and relational/motivational engagement. The manuscript further clarifies the concept of functional bottlenecks as multidimensional constraints that may limit access to intervention despite the availability of therapeutic support. These bottlenecks may involve regulatory instability, sensory overload, fatigue, sleep disruption, anxiety, communication barriers, family-contextual stress, or mismatch between intervention demands and the child’s adaptive capacity. TEI is not presented as a validated clinical scale, diagnostic instrument, predictive model, or intervention protocol. Rather, it is proposed as a research-oriented conceptual architecture requiring feasibility testing, inter-rater reliability assessment, construct validation, longitudinal evaluation, and empirical testing in clinical and community contexts. Similarly, TEI-Precision is framed as a conceptual translational architecture for future human-supervised digital implementation, not as an implemented digital health platform, autonomous artificial intelligence system, or validated decision-support tool. By operationalizing TEI domains, clarifying illustrative engagement profiles, and outlining a staged validation roadmap, this manuscript aims to support future research on precision autism care, therapeutic responsiveness, biological burden, and responsible digital health translation.

Abstract: Concurrent cognitive activity during emotional-memory retrieval may alter subjective memory characteristics, particularly imagery vividness and emotional intensity, possibly through competition for limited working-memory resources. Experimental dual-task paradigms have used visuospatial, motor, articulatory, and other cognitively demanding tasks. However, deliberate covert rehearsal of structured, emotionally neutral linguistic material during emotional-memory retrieval appears to have received comparatively limited theoretical attention. This article introduces Linguistic Dual-Task Integration (LDTI), a hypothesis-generating neurocognitive framework proposing that repetitive covert rehearsal of emotionally neutral linguistic material during intentional emotional-memory activation may constitute a form of concurrent verbal working-memory engagement. Rather than treating language solely as a vehicle for communication or cognitive restructuring, LDTI examines covert linguistic rehearsal as an active cognitive task that may influence the conditions under which emotional memories are retrieved and processed. The framework integrates working-memory research with theoretical perspectives on inner speech, executive control, attentional prioritization, and autobiographical memory. It hypothesizes that neutral linguistic rehearsal may recruit verbal working-memory resources while emotionally salient autobiographical representations remain active, thereby altering proximal characteristics of retrieval. Executive stabilization and altered attentional priority are treated as secondary hypotheses, whereas autobiographical integration is positioned as a distal possibility. Whether any observed effects reflect linguistic organization, phonological or articulatory interference, expectancy, or generic cognitive load is a central empirical question. LDTI is not presented as a validated psychotherapeutic intervention and makes no claim of clinical efficacy or superiority over established trauma-focused treatments. Instead, it specifies falsifiable predictions, competing explanations, boundary conditions, and a staged research agenda for investigating covert neutral linguistic rehearsal during emotional-memory processing.

Abstract: Background: Artificial Intelligence (AI) chatbots and their underlying technology arguably has potential but are associated with risks for the users. There are few reports of delusions developed during intense use of chatbots in people with preexisting mental illness in the medical literature. Here, we report a case of delusions developed de novo during intense use of ChatGPT in a high-functioning individual without personal- or family history of mental illness. Case presentation: A man in his twenties with no personal- or family history of mental illness started using ChatGPT intensely when working on his master’s thesis during university studies. He gradually transitioned to communicating with the chatbot about deeply personal issues initially seeking advice on self-development. Over the course of eight weeks of intense use of ChatGPT he developed a severe manic episode with delusions of grandeur and reference. The delusions revolved around the tariffs imposed by the United States in April 2025. Specifically, the young man became convinced that he, as member of an international resistance movement, had developed a method to predict the stock market that would protect Europe against the imposed tariffs, false beliefs that were consistently consolidated by ChatGPT. He contacted several politicians with his ideas. As his behaviour became increasingly erratic, he was admitted voluntarily to a psychiatric ward. Psychiatric evaluation revealed that the patient had no history of physical illness or drug use, and a physical examination showed no sign of current physical disorder. At the psychiatric ward, he was treated with benzodiazepines against his will and the mania and delusions gradually resolved after discharge. Seven months after discharge the patient was without any psychiatric symptoms and was employed in a full-time job. Conclusions: This case supports the notion that chatbots driven by generative artificial intelligence can lead to development of severe delusions.

Abstract: The therapist’s lived experience remains comparatively underrepresented in psychotherapy research despite its importance for clinical understanding and therapeutic decision-making. Drawing on a psychodynamic-phenomenological perspective, this qualitative study examines how the therapist’s experience can function as a source of clinical knowledge through the comparative analysis of two anonymized psychotherapeutic cases. The psychotherapies were conducted within a psychodynamic framework, while their subsequent analysis employed phenomenological reflection on the therapist’s embodied, affective, and relational participation in the therapeutic encounter. Although both patients presented with prominent anxiety accompanied by control, perfectionism, and inhibition, they generated markedly different therapeutic fields. In the first case, organized predominantly around narcissistic vulnerability and shame, the therapist experienced fragile proximity, subtle discouragement, and recurrent loss of emotional contact. In the second, organized around guilt, harsh superego functioning, and fear of criticism, the therapist’s experience was characterized by vigilance, careful pacing, and the need to contain affect without intensifying self-attack. These contrasting experiential configurations revealed distinct transferential-countertransferential organizations that were not immediately evident from symptom presentation alone. The findings support the integration of psychodynamic concepts with phenomenological reflection and suggest that the therapist’s first-person perspective constitutes a meaningful source of qualitative clinical knowledge, enriching contemporary first-person approaches to psychotherapy research.

Abstract: Autistic individuals often demonstrate substantial within-person variability in regulation, participation, recovery, learning readiness, and responsiveness to intervention across time and contexts. Although sleep disruption, fatigue, autonomic regulation, physiological stress, sensory demands, and recovery processes may contribute to this variability, no validated multidimensional instrument currently measures the dynamic biological and functional resources potentially available for adaptive developmental work. This Hypothesis and Theory article proposes a hypothesis-generating measurement framework for the future development of an Energetic Capacity Index (ECI) in autism. It distinguishes three scientifically separate levels: Energetic Capacity, the underlying translational construct; Estimated Energetic Capacity, a provisional research estimate derived from repeated multimodal observations; and the Energetic Capacity Index, a candidate measurement instrument requiring independent development and validation. A provisional measurement architecture is outlined across candidate domains of physiological regulation, restorative recovery, functional endurance, adaptive availability, and contextual demand. The proposed framework integrates repeated multimodal observations, including caregiver-reported, clinician-observed, behavioral, contextual, and, where feasible, physiological indicators while explicitly rejecting reliance on any single biomarker or isolated observation. The manuscript presents a staged development pathway encompassing conceptual operationalization, feasibility, reliability, construct discrimination, responsiveness, longitudinal sensitivity, fairness, external validation, and responsible digital implementation. The ECI is not presented as a validated scale, biomarker, diagnostic instrument, severity score, predictive algorithm, or clinical decision-support tool. Its scientific contribution will ultimately depend on whether future empirical studies demonstrate operational feasibility, coherent measurement properties, meaningful within-person variability, incremental explanatory value, fairness, and reproducibility across independent populations and settings. Rather than introducing a validated measurement instrument, this work establishes a transparent scientific roadmap for the responsible development of a future multidimensional measure of Energetic Capacity in autism.

Abstract: (1) Background: The peripartum period increases vulnerability to mental disorders. Data from specialized psychiatric settings in Southeast Europe remain limited. This study assessed prevalence and distribution of perinatal mental health disorders, diagnostic changes, hospitalizations, obstetric complications, and breastfeeding among women treated at the Perinatal and Reproductive Psychiatry Unit in Belgrade, Serbia. (2) Methods: Retrospective review of medical records from 287 patients (2015–2024), including socio-demographics, ICD-10 diagnoses, hospitalizations, obstetric complications, and breastfeeding data. (3) Results: Mean age was 33.1 ± 5.6 years. Mood disorders (F30–F39) were most common (39.6% before, 42.2% during, 32.1% after pregnancy), followed by neurotic and stress-related disorders (F40–F48). Postpartum F50–F59 diagnoses (especially F53) rose significantly (p < 0.001). Hospitalizations peaked before pregnancy (35.2%) and were rare during pregnancy (3.1%) and postpartum (0.3%). Leading obstetric complications were emergency cesarean (1.9%) and fetal loss (1.4%). Only 41.3% of women with data breastfed (mean 4.7 months). (4) Conclusions: Mood disorders predominate in specialized perinatal care. Results highlight the need for sys-tematic screening, specialized outpatient services, and multidisciplinary support to improve outcomes for women in Serbia.

Abstract: Immune-inflammatory dysregulation plays a central role in the pathophysiology of schizophrenia (SCZ). Interleukin-33 (IL-33), a pleiotropic alarmin cytokine of the IL-1 family, modulates neuroimmune communication, glial activation, and tissue repair, yet its involvement in psychotic disorders remains poorly characterized. This study examined serum IL-33 concentrations in 21 patients experiencing an acute psychotic relapse and 21 age- and sex-matched healthy controls (HC). Using a longitudinal design, we measured serum IL-33 by ELISA at 12:00 h and 24:00 h on the day after admission and the day before discharge in patients, alongside comprehensive clinical assessment with the Positive and Negative Syndrome Scale (PANSS). Patients with SCZ exhibited significantly lower IL-33 levels than HC at all time points (p < 0.05). Notably, IL-33 concentrations increased significantly at midnight from admission to discharge (p = 0.028), paralleling clinical improvement in PANSS positive and general psychopathology scores. A robust inverse correlation between age and IL-33 levels was observed in both patients and controls (p < 0.05), independent of sex, smoking status, sampling time, and antipsychotic dosage. These findings provide the first longitudinal evidence that IL-33 is reduced during acute psychotic episodes and rises in association with clinical recovery, supporting its role as a state-dependent biomarker. Our results highlight the involvement of alarmin signalling in the neuroimmune dysregulation underlying psychotic relapse and underscore the importance of age as a critical covariate in immunopsychiatric research.

Abstract: Background: Suicide represents a major global public health challenge, and suicide attempts are among the strongest predictors of subsequent suicide. Despite their importance, Portugal lacks comprehensive national epidemiological evidence on suicide attempts presenting to emergency departments, limiting the development of targeted prevention strategies and informed public health policy. Objective: To examine temporal trends and describe the sociodemographic and clinical characteristics of emergency department presentations for suicide attempts in Portugal between 2018 and 2024.Design: Population-based cross-sectional study. Methods: We conducted a population-based analysis of mandatory nationwide emergency department records from 2018 to 2024. Suicide attempts were identified using ICD-10 diagnostic codes. Age-standardized rates were calculated using the WHO World Standard Population. Temporal trends were evaluated using Joinpoint log-linear regression to estimate annual percentage changes (EAPCs) and corresponding 95% confidence intervals (CIs), overall and by sex. Results: A total of 158,937 emergency department presentations for suicide attempts were identified, representing 0.25% of all emergency department visits during the study period. Age-standardized rates remained relatively stable, decreasing from 85.80 to 76.38 per 100,000 population (EAPC = −3.9%, 95% CI: −14.1% to 7.5%). Self-poisoning was the predominant method, accounting for 98.7% of all presentations. The highest burden was observed among individuals aged 15–29 years and ≥65 years, and most cases were managed in second-level Ministry of Health (MINSA) facilities. Substantial regional variation in presentation rates was observed across the country. Conclusions: Emergency department presentations for suicide attempts remained largely stable in Portugal between 2018 and 2024 despite considerable regional disparities. The concentration of presentations among adolescents and young adults and older adults, together with the predominance of self-poisoning, highlights the need for age-specific suicide prevention strategies, strengthened emergency department surveillance, and interventions aimed at reducing access to commonly used lethal means.

Abstract: Background: Psychotropic medications are frequently prescribed off-label in individuals with intellectual disability (ID) and other neurodevelopmental disorders to manage challenging behaviors (CBs), often in the absence of a clearly defined psychiatric condition. Although antipsychotics and benzodiazepines may reduce acute behavioral dysregulation, long-term use is associated with significant adverse effects and may contribute to functional suppression rather than adaptive regulation. Increasing attention has therefore been directed toward integrated treatment models combining behavioral interventions with systematic psychopharmacological review and deprescribing strategies. Case presentation: We report the case of a 26-year-old woman with ID, severe CBs, and a history of long-term psychotropic polypharmacy admitted to a high-intensity behavioral residential care setting. At admission, the patient presented with severe aggression, self-injurious behavior, property destruction, mutism, psychomotor slowing, and marked social disengagement while receiving haloperidol, diazepam, and valproate. A multidisciplinary intervention based on Applied Behavior Analysis (ABA) and functional assessment was implemented within a “Tandem Treatment” framework integrating behavioral intervention with gradual psychotropic deprescribing. Behavioral procedures included functional communication training, differential reinforcement, environmental modulation, and structured skill acquisition programs. Over the course of treatment, antipsychotic medication was discontinued and benzodiazepines were progressively reduced without behavioral deterioration or rebound phenomena. Concurrently, severe challenging behaviors showed a marked and sustained reduction, while adaptive functioning, participation in daily activities, sleep regulation, social responsiveness, and quality-of-life indicators improved substantially. Conclusions: This case suggests that, in selected individuals with ID and severe CBs, integrated behavioral treatment may support the safe reduction of psychotropic medications while improving adaptive and clinical outcomes. The findings highlight the importance of function-based behavioral assessment, multidisciplinary coordination, and data-driven psychopharmacological monitoring in the management of complex neurodevelopmental conditions. Further controlled studies are needed to clarify the role of integrated deprescribing models in this population.

Abstract: Background/Objectives: Hypoxic brain damage and adverse childhood experiences (ACEs) are strongly associated with neurodevelopmental disorders, adverse behavioral outcomes, and increased risk of bipolar disorder. This case study evaluates the neurological sequelae of severe childhood trauma and recurrent hypoxia in a man in his mid-20s with a history of extreme violent criminal and sexual behavior, with the aim of clarifying the neurological factors associated with his actions. Methods: Multimodal neuroimaging was performed in a subject with recurrent childhood strangulation-induced hypoxia and sexual, physical, and emotional abuse. Assessments included positron emission tomography (PET) with Z-mapping for metabolic analysis, diffusion tensor imaging (DTI) for white matter integrity, and MRI quantitative volumetrics (QV) for structural evaluation. Results: PET revealed hypometabolism in the left temporal insular cortex and left dorsal posterior cingulate gyrus, a decreased neocortical-to-cerebellar metabolic ratio, and hypermetabolism in the right temporal cortex. DTI showed profound decreases in fractional anisotropy (FA) in the anterior corpus callosum consistent with hypoxic injury. DTI also showed decreased FA in left dorsal anterior cingulate consistent with adverse childhood events. MRI QV demonstrated bilateral putamen enlargement, consistent with multiple hypoxic episodes and bipolar disorder, as well as significant asymmetry, with the left putamen smaller than the right, suggesting relative left-right putamen asymmetry secondary to traumatic brain injury. Conclusions: Multimodal neuroimaging identified marked metabolic, white matter, and volumetric abnormalities consistent with severe childhood hypoxia, childhood abuse, bipolar disorder, and traumatic brain injury. Objective abnormalities in networks involved in impulse control and aggression provide neurobiological context relevant to mitigation considerations in aberrant homicidal behavior.