Non-suicidal self-injury (NSSI) often emerges during adolescence and young adulthood. A prior open-label pilot study suggested that N-acetylcysteine (NAC) may reduce NSSI frequency in young individuals.

This study investigated potential NSSI-related biological markers for NAC in young adults with a history of NSSI using a placebo-controlled, randomised clinical trial of two NAC dosage regimens.

Forty-three individuals (assigned female at birth) aged 16–24 years and with a history of NSSI were randomly assigned to either low-dose NAC (3600 mg/day), high-dose NAC (5400 mg/day) or placebo treatment for 4 weeks. Participants underwent blood draws, magnetic resonance imaging with spectroscopy and clinical assessments before and after treatment. Primary outcomes included brain glutathione (GSH), blood reduced to oxidised GSH ratio and brain glutamate. Secondary outcomes included antioxidant protein levels, brain gamma-aminobutyric acid concentrations, functional connectivity (between amygdala and insula) and clinical outcomes. Pharmacokinetics, tolerability and correlations among measures were also explored.

For 39 participants who completed study assessments at follow-up, weekly NSSI and depression symptoms improved similarly across both treatment and placebo groups, with no significant group differences in primary or secondary outcomes at follow-up. Some significant correlations emerged.

The study did not support the proposed biological signatures of NAC in young adults with NSSI, although exploratory findings suggested potential biological correlates of clinical improvement. Further research is necessary to explore neurobiologically based treatments for young adults with NSSI.

Treatment-resistant schizophrenia (TRS) develops in ˜30% of patients, resulting in higher hospitalization rates, morbidity, mortality, and suicidality, and increased costs (Pompili et al CNS NDDT 2017; 16 870-884). Despite inconsistent findings of its efficacy, antipsychotic polypharmacy (APP) is frequently prescribed in an attempt to treat refractory symptoms (Correll ClinNorthAm 2012; 35 661-681). While marketed APs all act through the modulation of 5HT/DA transmission, clozapine, the only drug approved for TRS, seems to act on multiple receptor systems (Brunello et al NPP 1995; 13 177-213). The need to modulate non-monoaminergic targets is supported by findings of excessive glutamatergic activity, rather than increased dopamine synthesis, in patients with TRS (Demjaha et al BioPsy 2014; 75 11-3). Evenamide, devoid of biological activity at >150 CNS targets, is able to normalize excessive glutamate release without affecting basal levels. Evenamide has demonstrated benefits in several animal models of psychosis (monotherapy and add-on to AP). Benefit of evenamide as add-on was demonstrated in a phase 2, open-label trial (Anand et al IJNPP 2023; 174 216-229) and in a phase 2/3 randomized, double-blind study in patients not responding adequately to SGAs.

Evaluate the efficacy, safety, and tolerability of evenamide 30 mg bid as add-on treatment in patients with documented TRS receiving AP treatment but not adequately benefitting from a stable therapeutic dose.

This is a prospective, potentially pivotal, phase 3, randomized, double-blind, placebo-controlled, 1-year international study, with a primary efficacy endpoint at 12 weeks and long-term efficacy endpoints at 26 and 52 weeks. Eligible patients must have a diagnosis of TRS according to the TRRIP consensus guidelines (Howes et al AmJPsy 2017; 174 216-229). During the 6-week screening period and throughout the study, adherence to background AP(s) and evenamide will be confirmed through measurements of plasma levels. Selection criteria include CGI-S of mildly to severely ill (3-6); BPRS total score ≥45, with a score ≥18 on core symptoms of psychosis, and PANSS total score ≥70. An Independent Eligibility Committee will determine patients’ eligibility. Patients improving ≥20% on the BPRS or ≥1 category on the CGI-S during the screening period will be excluded. Efficacy (PANSS, CGI-S/C, Q-LES-Q-SF, PSP scales) and safety (vital signs, ECG, lab tests, physical/neurological/eye exams, ESRS-A, CDSS, C-SSRS) will be evaluated at regular intervals.

Results from this study will determine whether addition of evenamide 30 mg bid to APs is associated with clinically important benefit in TRS patients.

Positive results would support the role of glutamate modulators for the optimal treatment of TRS.

R. Anand Consultant of: AbbVie, Acadia, BiolineRx, Domain, Enkam,Erydel, Forest, Janssen, Hoffman La Roche, Lundbeck, Noema, Ono, Pfizer, UCB, Shire, Sigma-Tau, Takeda, Teva, A. Turolla Employee of: Newron Pharmaceuticals SpA, G. Chinellato Employee of: Newron Pharmaceuticals SpA, R. Giuliani Employee of: Newron Pharmaceuticals SpA, F. Sansi Employee of: Newron Pharmaceuticals SpA, R. Hartman Employee of: Newron Pharmaceuticals SpA

Treatment of schizophrenia remains a challenge despite the development of numerous antipsychotics (AP) (Pompili et al CNS NDDT 2017; 16 870-884). The various strategies to address patients’ unmet needs, such as AP polypharmacy or switching AP, do not seem to provide adequate benefit. A reason for this may reside in the similarity of mechanisms of action of most APs. However, the monoaminergic systems targeted by these drugs are not always disrupted in schizophrenia, as it is widely accepted that patients who fail to respond to AP have glutamatergic, but not dopaminergic dysfunctions (Moghaddam et al NPP 2012; 37 4-15). Evenamide normalizes excessive glutamate release without affecting its basal levels, and it does not interact with >150 CNS targets. It has been shown to be effective in animal models of psychosis as monotherapy and add-on to AP. Previous trials indicate that evenamide benefits patients with schizophrenia with inadequate response and have shown clinically important benefits lasting up to 1-year in TRS (Anand et al IJNPP 2023; 26 523-528).

Study 008A, a phase 2/3 international, randomized, double-blind, placebo-controlled, 4-week trial, assessed the efficacy and safety of evenamide 30 mg bid as add-on in patients poorly responding to an SGA.

Outpatients with a diagnosis of schizophrenia, still symptomatic (PANSS 70-85; CGI-S 4-6) despite treatment with an SGA at a therapeutic dose (confirmed through plasma levels) for an adequate period, were enrolled. Efficacy was assessed on the PANSS, CGI-S, and LOF through the comparison of changes from baseline to Day 29 between evenamide and placebo groups using a MMRM analysis. Moreover, the proportion of patients reaching a clinically important improvement on the PANSS and CGI-C were compared between groups using a logistic regression model (chi-square test). Safety measures comprised: TEAEs, vital signs, labs, ECG/EEG, seizure checklist, physical/neurological/eye examinations, C-SSRS, ESRS-A, CDSS.

291 patients were randomized in the study in 11 countries (EU, Asia and LATAM), and 280 completed the study. The low attrition rate (<4%), and proportion of patients with TEAEs (~25% in both groups) indicate that evenamide was well tolerated. A statistically significant greater improvement was found on the PANSS total score and on the CGI-S in the evenamide compared to the placebo group. Furthermore, a significantly higher proportion of patients treated with evenamide, compared to those receiving placebo, experienced clinically meaningful benefit measured on the PANSS (≥20% improvement) and CGI-C (at least much improved).

This is the first randomized, placebo-controlled trial to demonstrate the clinical benefit of adding a NCE modulating glutamate in patients with schizophrenia who did not experience adequate response from treatment with a SGA.

R. Anand Consultant of: AbbVie, Acadia, BiolineRx, Domain, Enkam, Erydel, Forest, Janssen, Hoffman La Roche, Lundbeck, Noema, Ono, Pfizer, UCB, Shire, Sigma-Tau, Takeda, Teva, A. Turolla Employee of: Newron Pharmaceuticals SpA, G. Chinellato Employee of: Newron Pharmaceuticals SpA, R. Giuliani Employee of: Newron Pharmaceuticals SpA, F. Sansi Employee of: Newron Pharmaceuticals SpA, R. Hartman Consultant of: Newron Pharmaceuticals SpA.

Using a ‘transdiagnostic’ paradigm for psychopathology, we review the evidence-base for the different treatment interventions for anger, aggression and violence (AAV). We aim to more accurately link the range of psychopathology associated with AAV to underlying brain structures and functional neurocircuitry. Building upon these findings, we propose a working model that may have greater clinical utility than reliance upon a purely ‘disorder-based’ paradigm for addressing AAV. This will permit greater understanding of when anger (which has also conferred evolutionary survival advantages) can become maladaptive and destructive. This comprehensive, ‘interventionist’ model will hopefully lead to better clinical conceptualization of AAV, especially since most AAV presents more commonly in the context of interpersonal/situational stressors and to non-forensically trained clinicians.

1. 1. To identify biological, cognitive, disorder-based, developmental and personality predispositions to AAV

2. 2. To link neuroanatomical and functional brain circuitry with onset and maintainence of AAV

3. 3. To identify how pharmacological and non pharmacological interventions work, and ‘where’ in the brain,

4. 4. To review the evidence-base supporting various treatment interventions

Database review of PUBMED, PsychINFO, Google Scholar and treatment guidelines dating back 15 years (review articles, treatment guidelines, meta-analyses and randomized controlled trials).

This will be visually depicted in an electronic slide (or >1 slide, if permitted) to identify:

1. 1) The inter-relationship between contextal factors, the psychopathology of AAV and undelying brain ‘circutry’

2. 2) The specific nature of the impulsive anger, ‘reactive’ aggression and violence response ‘cycle’ and where in this cycle various interventions can be effectively utlized

3. 3) Which patient populations respond best to which types of interventions

1. 1. AAV are hyperarousal states, with outcomes that can be successfully managed

2. 2. The evidence-base for the role of medications is more limited

3. 3. The evidence-base for the role of various psychotherapies is greater, with specific therapies being particularly useful across psychiatric disorders and populations

4. 4. Psychodynamic approches remain curently underutilized and underappreciated

5. 5. Both medications and therapy influence brain neuroplasticity separately and synergistically

None Declared

In recent years, dopamine D3 receptor (DRD3) has gained extensive attention in substance use disorders (SUDs) in terms of their anatomical localization and role in drug-related processes. Animal studies have shown that DRD3 agonists modulate addictive behaviour. In addition, cariprazine (CAR), a novel antipsychotic with a partial agonist effect on DRD3, may be a treatment option for patients diagnosed with schizophrenia (SCZ) with comorbid SUD.

Therefore, the main goal of the present work was to summarize literature data about DRD3 and CAR in SUDs.

A systematic review was conducted in August 2024. The full-text search was performed without filtering from four databases (PubMed, ScienceDirect, Web of Science, Cochrane Registry). In the first search “dopamine receptor D3” AND “substance use” OR “addiction” OR “dependence” OR “misuse” were used as the key search terms, and in the second search “cariprazine” AND “substance use” OR “addiction” OR “dependence” OR “misuse” were used. Duplicated studies, non-relevant articles, review articles, and animal and cell studies were excluded.

In the first search, 40 articles were identified; however, 15 were excluded. In the second search, 21 articles were identified; however, 12 were excluded. Findings based on the 25 included articles show that DRD3 modulators, which are mostly agonists of the receptors, may have a positive effect on both psychotic symptoms and substance use frequency- and drug-seeking behavioral reduction. Our findings based 9 included articles demonstrate that CAR is a more effective and safe medication for SCZ with comorbid SUD than other atypical antipsychotics. It could also be suggested that in other psychiatric conditions where substance abuse is occurring CAR is also a good treatment option.

Based on past and current research, it’s crucial to systematically evaluate the role of DRD3 for developing new therapeutic perspectives in SUDs, though more research is needed to confirm the efficacy and safety of DRD3 modulators and CAR as medications for SUDs. Furthermore, the present review suggests that CAR may be the optimal antipsychotic for treating SCZ with comorbid SUDs.

None Declared

Sepsis, a life-threatening organ dysfunction resulting from a dysregulated host response to infections, poses a critical threat. Cardiac surgery itself induces a robust inflammatory response, further exacerbated by cardiopulmonary bypass, causing notable clinical and physiological changes. Identifying sepsis early in the post-operative period with elevated septic markers becomes challenging, with delayed antibiotic intervention ultimately posing a fatal risk for the patient.

We performed a prospective observational cross-sectional study aimed at identifying sepsis markers that include total leucocyte count, absolute neutrophil count, platelet count, serum albumin, chest X-ray, blood, urine, and tracheal cultures, procalcitonin, c-reactive protein, serum lactate >2.5 mmol/l along with clinical parameters (fever, hypotension, tachycardia) on post-operative days 1, 3, 5, and 10 in paediatric patients undergoing cardiac surgery with prolonged cardiopulmonary bypass time >100 min.

Total leucocyte count, absolute neutrophil count, and platelet counts were not significant enough to detect early sepsis, especially in patients with prolonged cardiopulmonary bypass time. Chest X-ray was significant from post-operative day 3 onwards. Procalcitonin was significant from day 5, and C-reactive protein was significant only from day 10. Among the clinical parameters, fever, hypotension, tachycardia, and elevated lactate levels were significant from post-operative day 1 in the patients developing sepsis.

Neonates and infants faced a higher sepsis risk than older children. Longer cardiopulmonary bypass and aortic clamp times correlated with increased sepsis likelihood. Clinical factors outweighed laboratory indicators for early sepsis detection post-cardiac surgery, prompting prompt investigation and intervention.