Annarita Vignapiano

Dextromethorphan is extensively O-demethylated by cytochrome P450 2D6 (CYP2D6) to dextrorphan, and the two molecules do not share a target profile. Dextrorphan is the more potent N-methyl-D-aspartate (NMDA) channel blocker; the parent compound is the more potent serotonin transporter inhibitor; their sigma-1 affinities are comparable, so differences in sigma-1 engagement depend on exposure rather than intrinsic affinity. CYP2D6 activity therefore does not scale exposure to a fixed pharmacology; it determines which pharmacology is expressed. This review develops that principle and extends it to a three-agent system. From published unbound concentrations and functional potencies, we calculate a model-derived fractional-target-engagement index. Under the base-case inputs, CYP2D6 inhibition raises the serotonergic index approximately fourfold while reducing the NMDA channel index; deterministic sensitivity analysis shows that the direction is robust to one-at-a-time 0.5-fold to 2-fold perturbations but not to all joint extreme assumptions. Quinidine and bupropion are analyzed as mechanistically distinct proofs of concept, and quinidine-derived exposure estimates are not treated as quantitative surrogates for the dextromethorphan–bupropion steady state. The framework is then applied to the untested question of whether a boosted dextromethorphan combination and esketamine are redundant or complementary. The agents share an NMDA channel mechanism, while CYP2B6 pathway overlap remains a hypothesis-generating observation rather than evidence of clinically relevant competition. No controlled data on the three-agent combination exist, and no therapeutic recommendation is made.

Background: We investigated, in an exploratory cross-sectional design, whether EDS-R score at admission showed adjusted cross-sectional associations with FT3, LDH, and ALT in patients with anorexia nervosa (AN) in residential treatment. Methods: A total of 164 patients with AN (first admission per patient) (AN-R: n = 122; AN-BP: n = 42; mean BMI 15.7 ± 1.7 kg/m²; 98.2% female) admitted consecutively to a specialist residential unit were included. Biochemical parameters were assessed within 48 h of admission using fully automated, internationally standardised analytical methods. FT3 was measured by electrochemiluminescence immunoassay (ECLIA) on automated immunoassay platforms, in accordance with standard immunometric procedures. ALT and LDH were measured by kinetic enzymatic (UV) methods following IFCC recommendations, using high-throughput clinical chemistry analysers. All analyses were performed in the core laboratory (Corelab) of the ASL Salerno hospital network, with internal and external quality control programmes in place. Exercise dependence severity was measured using the EDS-R Multivariable OLS and logistic regression analyses were conducted, adjusting for age, BMI, disease duration, and AN subtype. Results: Among 16 biochemical parameters examined, FT3 and LDH showed the largest Spearman correlations with EDS-R score, though neither survived Bonferroni correction for 16 simultaneous tests (threshold: p < 0.0031) (FT3: ρ = −0.224, p = 0.007; LDH: ρ = +0.244, p = 0.006). In multivariable regression, EDS-R score was independently associated with lower FT3 (β = −0.040, 95% CI [−0.072, −0.008], p = 0.016, n = 144) and higher LDH (β = +14.56, 95% CI [3.78, 25.35], p = 0.009, n = 124), while BMI was not significant in either model. By contrast, BMI was the sole significant predictor of ALT (β = −0.078, 95% CI [−0.136, −0.021], p = 0.008, n = 154), with the EDS-R score being non-significant (β = 0.019, p = 0.604). Binary logistic regression confirmed an association between EDS-R score and low-T3 syndrome (FT3 < 2.30 pg/mL): OR = 1.290 (95% CI [1.043–1.596], p = 0.019). Conclusions: In this exploratory cross-sectional study, EDS-R score showed adjusted associations with lower FT3 and higher LDH, but not ALT, at residential admission in AN, independent of BMI, age, AN subtype, and illness duration. These hypothesis-generating, cross-sectional findings cannot be interpreted as establishing prediction, causation, biomarker validity, or clinical utility. Prospective replication is required before any clinical implications can be considered.

Background: Sleep disturbances are a clinically relevant and transdiagnostic dimension of eating disorders (EDs), particularly during adolescence and young adulthood. Although early improvements in insomnia severity during residential treatment have been described, the longitudinal trajectory of sleep disturbances, habitual sleep timing, and eating disorder psychopathology across a six-month residential stay has not been systematically characterised. Methods: This prospective real-world observational study enrolled 30 female adolescents and young adults (aged 14–22 years) in a small exploratory cohort, predominantly with anorexia nervosa (AN; 83.3%) and a minority with bulimia nervosa (BN; 16.7%), all with clinically significant insomnia at admission (Insomnia Severity Index [ISI] > 14). All sleep outcomes were based on subjective self-report; no objective sleep assessment (actigraphy or polysomnography) was available. Participants were consecutively recruited from the Regional Residential Centre for Eating Disorders “Mariconda”, ASL Salerno, Italy. Of 38 consecutive admissions assessed for eligibility, 8 were excluded (ISI ≤ 14 at admission: n = 5; incomplete baseline data: n = 3), yielding a final enrolled sample of n = 30. All 30 participants completed the six-month residential programme; no drop-outs occurred. ISI was assessed monthly (T0–T6); PSQI and EDE-Q were assessed at T0, T3, and T6; diary-derived sleep timing (sleep midpoint) was assessed monthly (T0–T6), while diary-derived sleep continuity parameters (SOL, WASO, TST, SE%) were available at T0, T1, T3, and T6. Linear mixed-effects models (LMM) and bootstrap-resampled paired analyses were used. Results: ISI declined progressively from 21.1 ± 2.5 at baseline to 7.4 ± 2.7 at month 6 (Δ = −13.7; 95% CI [−14.4, −13.1]; p < 0.001). By month 6, 56.7% of participants had achieved remission (ISI < 8) and 100% had met response criteria (ΔISI ≤ −8). Sleep midpoint advanced progressively by 86 min over six months (from ~04:41 to ~03:16 after midnight), with no significant association with BMI or pharmacological treatment in linear mixed-effects models. EDE-Q global scores decreased from 4.57 ± 0.49 to 2.06 ± 0.58. Changes in ISI were not correlated with changes in EDE-Q at month 3 (r = 0.042, p = 0.826) but were significantly correlated at month 6 (r = 0.480, p = 0.007). All pharmacological regimens remained stable throughout the six-month observation period. The association between improvement in insomnia severity and eating-disorder psychopathology was not evident at month 3 but emerged at month 6, suggesting that these domains may change at different rates during residential treatment. Given the exploratory nature of the analyses, p-values are reported without adjustment for multiple comparisons and should be considered hypothesis-generating. Conclusions: Across six months of residential treatment, progressive improvements were observed in insomnia severity, subjective sleep continuity, habitual sleep timing, BMI, and eating-disorder psychopathology. In the absence of a control group, spontaneous remission, regression to the mean, and non-specific components of care, including the routinely administered Passiflora incarnata L. adjunct, cannot be individually distinguished as contributors to the observed changes, and these findings should be interpreted within the constraints of an uncontrolled observational design relying on subjective sleep measures. Controlled studies are needed to determine whether these changes are directly attributable to treatment or primarily reflect concurrent weight restoration and clinical improvement.

Background: Anorexia nervosa (AN) is associated with extensive biochemical alterations at the time of clinical presentation. Despite distinct behavioural profiles, it remains unclear whether the restricting (AN-R) and binge–purge (AN-BP) subtypes differ in their biochemical profile at residential admission, a question with direct implications for clinical monitoring protocols. Methods: We conducted a retrospective cross-sectional study of 177 consecutive AN inpatients (AN-R: n = 130; AN-BP: n = 47; 98.3% female; mean BMI 15.8 ± 2.0 kg/m²; mean age 19.2 ± 5.5 years; 53.7% adolescents) admitted to a specialist residential unit (2018–2026). Thirty-five biochemical parameters were assessed. Unadjusted comparisons used Mann–Whitney U tests with rank-biserial effect sizes; multivariable logistic regression adjusted for BMI, age, and illness duration. Results: Overall, 98.3% of patients presented at least one biochemical anomaly (mean 4.4 ± 2.6 per patient). The most frequently abnormal parameters were LDH elevation (75.0%), vitamin D insufficiency (73.0%), low T3 syndrome (defined as low free triiodothyronine [FT3]) (58.0%), FT4 suppression (53.5%), ALT elevation (35.1%), and leucopenia (32.3%). AN subtype predicted none of these outcomes in unadjusted or multivariable analyses (all p > 0.10). The odds of presenting ≥3 simultaneous anomalies were not significantly associated with subtype, BMI, or illness duration in multivariable analysis. In contrast, older age independently predicted greater odds of low T3 syndrome (OR = 1.14 per year, 95% CI [1.00, 1.30], p = 0.045) and leucopenia (OR = 1.22 [1.06, 1.39], p = 0.004). No differences were observed between adolescents and adults in unadjusted comparisons. Conclusions: Despite their distinct behavioural profiles, no statistically significant biochemical differences were detected between AN-R and AN-BP at residential admission. These findings support routine standardised biochemical screening in all patients with anorexia nervosa admitted to residential care, regardless of behavioural subtype. Older age may identify a subgroup warranting closer endocrine and haematological monitoring.

Disorder. Together, these studies point toward continuous, ecologically valid observation as a complement to episodic clinical evaluation.Digital therapeutics and care-pathway implementation. A third, more intervention-oriented cluster spans individual platforms to health-system deployment. Del Vecchio et Information ecosystems. Two contributions step outside the clinical-tool paradigm to examine the informational environment patients encounter. Alpua and Yoldaş assess the reliability of YouTube content on functional neurological disorder, while Alimour and Alrabeei propose a reconceptualization of emerging, digitally mediated psychopathologies under conditions of information saturation, both relevant to any eHealth strategy, since the tools described elsewhere in this topic do not operate in an informational vacuum. These contributions are a reminder that digital innovation extends beyond clinical tools to the informational environment patients navigate on their own. Synthesis and open questions. Read together, these contributions confirm a field moving unevenly across the innovation pipeline. Instrumented, objective assessment is maturing fastest, since these approaches can be validated against existing scales without long-term outcome data. Digital therapeutics and system-level implementation are earlier stage, dominated by protocols, feasibility studies, and single-site evaluations rather than multisite controlled trials. Several contributions are case reports or small feasibility studies; cross-study comparability is limited by heterogeneous outcome measures and platforms; and few address data governance, interoperability, or the equity implications of tools presupposing smartphone or wearable access. The future of digital psychiatry will depend not only on new technologies, but on AI's ability to integrate heterogeneous clinical, behavioral, and physiological data into transparent, reliable decision-support systems. Precision psychiatry and eHealth will earn their place in routine care only to the extent that they are held to the same evidentiary standard as any other clinical intervention.

Background: Celiac disease (CeD) requires lifelong adherence to a strict gluten-free (GF) diet. During the COVID-19 pandemic, the prevailing clinical assumption was that food supply disruptions and dietary management difficulties would be the primary sources of patient distress. This exploratory cross-sectional study directly tested this assumption in an Italian CeD cohort. Methods: COVIMPACT is an exploratory observational, web-based study conducted in Italy (data collected: July–September 2024; participants retrospectively reported their experiences during the COVID-19 pandemic period 2020–2022). Participants with a confirmed CeD diagnosis were recruited through patient associations and online networks. A structured 26-item questionnaire addressed socio-demographic, nutritional, psychological, and healthcare-access domains. Descriptive statistics, chi-square bivariate analyses (Cramér’s V as effect size), and binary logistic regression were performed using R (v4.1) and Python. Results: Among 118 participants (78% female; median age 36 years; IQR 12–42), 27% reported self-perceived psychological distress. Against expectation, difficulties in accessing GF products and changes in gluten consumption showed no clear associations with distress. Instead, social exclusion showed the strongest association (Firth OR = 5.55, 95% CI: 1.80–17.09, p = 0.003), while reduced physical activity (Firth OR = 5.28, 95% CI: 1.86–14.99, p = 0.002, full model; Firth OR = 5.54, p = 0.001, reduced model) and negative economic impact (Firth OR = 3.77, 95% CI: 0.89–15.97, p = 0.071, trend) were additional associated factors. Female sex showed a non-significant trend (Firth OR = 4.21, p = 0.082). All estimates carry wide confidence intervals (EPV = 4.1) and should be treated as hypothesis-generating. Conclusions: These preliminary findings suggest that social exclusion and physical inactivity may be more strongly associated with self-perceived distress than dietary challenges in contexts where GF food access is structurally protected. Results are exploratory, hypothesis-generating, and should not be generalised beyond this selected Italian cohort.

Background: Histamine H3 receptor-targeting compounds modulate histaminergic tone and downstream monoaminergic/arousal circuits and have been proposed to exert potential antidepressant-like effects in preclinical models. Methods: We conducted a systematic review and meta-analysis of rodent studies evaluating H3-related interventions on depression-like behavior. We screened 60 records, assessed 12 studies qualitatively (four CORE, eight sensitivity), and included nine studies in random-effects meta-analyses (REML). Primary outcomes were the forced swim test (FST) and tail suspension test (TST); effect sizes were summarized as Hedges’ g (positive values indicate reduced immobility). Results: In the primary ALL analysis, H3-related interventions improved FST outcomes (g = 1.40, 95% CI 0.83–1.97; k = 7) and were also associated with improved TST outcomes, albeit with substantial heterogeneity (g = 2.27, 95% CI 0.80–3.73; k = 5). CORE-only analyses were directionally consistent but less precise (FST: g = 1.11, 95% CI −0.06–2.27; k = 3; TST: g = 2.95, 95% CI 0.87–5.02; k = 2). Sucrose preference was reported in one study and indicated improvement (g = 1.61, 95% CI 0.29–2.92). Conclusions: H3-related interventions show an antidepressant-like signal in rodent FST and TST, with greater heterogeneity for TST, highlighting the need for more standardized and adequately powered preclinical studies.

Background: Addictive disorders are characterized by the dysregulation of neural circuits involved in reward processing, salience attribution, emotional regulation, and cognitive control. Traditional neuroimaging paradigms based on static or two-dimensional stimuli show limited ecological validity and may fail to capture the contextual complexity of real-world addictive triggers. Immersive virtual reality (VR) offers a novel approach to simulate realistic, multisensory environments capable of eliciting craving and emotional responses. Although several reviews have examined VR in addictive disorders, most combined immersive and non-immersive tools and did not restrict inclusion to studies with brain-based outcomes. Methods: This systematic review with narrative synthesis was conducted in PubMed/MEDLINE and APA PsycINFO for studies published up to 30 December 2025. This systematic review followed PRISMA 2020 and was prospectively registered in PROSPERO; due to heterogeneity, findings were synthesized narratively. Eligible studies included human participants with substance-related or behavioral addictions and employed immersive VR paradigms (e.g., head-mounted display–based environments) combined with neuroimaging or neurophysiological measures (EEG, fMRI, fNIRS, PET, or DTI). Risk of bias was assessed using ROB-2 or ROBINS-I, and overall certainty of evidence was evaluated with the GRADE framework. Results: Ten studies met the inclusion criteria, encompassing over 1450 participants with alcohol, nicotine, methamphetamine, opioid use disorders, and internet gaming disorder. Immersive VR was associated with craving-related neural responses across modalities, involving prefrontal, insular, limbic, and striatal networks. EEG studies reported spectral power changes associated with craving and attentional salience, while fMRI, fNIRS, and PET studies demonstrated activation and modulation of executive control and reward-related circuits. Preliminary longitudinal and interventional studies indicate that repeated VR exposure may induce neurobiological changes consistent with therapeutic modulation. Conclusions: Immersive VR combined with neuroimaging supports the use of immersive VR as an ecologically grounded framework to probe addiction-related brain circuits; however, larger trials and standardized reporting are needed to strengthen clinical translation. Future studies should prioritize adequately powered randomized designs, harmonized VR cue-reactivity paradigms, and transparent neuroimaging reporting to enable reproducibility and cumulative inference.

Background: Creative Expressive Therapies, including Art Therapy and Dance/Movement Therapy (DMT), are increasingly integrated as adjunctive interventions in the treatment of complex psychiatric conditions. However, comparative evidence regarding their differential effects across diagnostic groups remains limited. Methods: This exploratory quasi-experimental 2 × 2 factorial study compared Art Therapy and DMT, delivered as adjuncts to treatment as usual, in patients with first-episode psychosis (FEP) and eating disorders (EDs) (N = 36). Participants received ten weekly group sessions. Changes in perceived well-being, emotional tension regulation, and physical tension regulation were assessed at baseline and post-intervention using self-report measures. Data were analyzed using repeated-measures ANOVA and linear mixed-effects models. Results: Significant pre–post improvements were observed across all outcome domains, indicating a transdiagnostic effect of Creative Expressive Therapies. Differential response patterns emerged according to clinical profile and therapeutic modality. DMT was associated with relatively greater improvements in physical tension regulation in patients with EDs, whereas Art Therapy showed relatively greater effects on emotional tension regulation in patients with FEP. Conclusions: Within the limitations of an exploratory, non-randomized design and the use of non-validated outcome measures, the findings suggest modality-specific patterns of response to Creative Expressive Therapies. These results should be considered hypothesis-generating and support further investigation through adequately powered randomized controlled trials employing validated clinical and neurobiological outcomes.

Background: Anorexia nervosa (AN) and obsessive–compulsive disorder (OCD) share core features of cognitive rigidity, anxiety, and altered reward processing. Pharmacological options remain limited, and combined modulation of serotonergic and dopaminergic systems may provide new therapeutic directions. This naturalistic study explored the combined use of lurasidone and fluvoxamine in individuals with restrictive AN (AN-r) and comorbid OCD. Methods: Forty-five female inpatients with AN-r and OCD were followed for six months. Participants received either lurasidone + fluvoxamine (n = 14) or heterogeneous SSRI/antipsychotic regimens (n = 31). Primary outcomes were the Recovery Assessment Scale (RAS) and Body Uneasiness Test Global Severity Index (BUT-GSI). Secondary outcomes included the Eating Disorder Examination-Questionnaire (EDE-Q) and Eating Disorder Inventory-3 (EDI-3). Bayesian repeated-measures ANOVAs were conducted, reporting BF₁₀, BFInclusion, and P(M│data) values, with multiple imputation applied to manage missing data. Results: Analyses indicated time-related changes across primary outcomes (RAS and BUT-GSI), with moderate-to-strong evidence (BF¹⁰ = 4.2–18.6) supporting overall improvement during treatment. Secondary and exploratory measures showed weaker or inconsistent trends (BF₁₀ < 3). No evidence emerged for group-by-time interactions exceeding anecdotal strength. Conclusions: Within the constraints of this small, all-female inpatient cohort, the findings illustrate directional, time-related changes compatible with global rehabilitation effects rather than drug-specific efficacy. The study demonstrates the feasibility—and methodological challenges—of applying Bayesian longitudinal modeling to incomplete clinical datasets. Future randomized or adaptive trials incorporating objective endpoints and data-quality pipelines are warranted to test whether serotonergic–dopaminergic–σ-1 synergy provides genuine clinical benefit in the AN–OCD spectrum.