Anhedonia, defined as the diminished ability to experience or anticipate pleasure, is a core symptom of major depressive disorder (MDD) and bipolar depression (BD), and associated with depression severity, suicidality and poor treatment outcomes. Conventional antidepressants demonstrate limited efficacy against anhedonia. Esketamine nasal spray (ESK-NS) - a novel NMDA receptor antagonist approved for treatment-resistant depression - has demonstrated rapid antidepressant effects, though its specific impact on anhedonia remains underexplored. This multicenter, observational, real-world study included 253 treatment-resistant patients (199 with unipolar depression/TRD; 54 with bipolar depression/B-TRD). All participants received repeated administrations of ESK-NS adjunctive to their current medication regimen. Anhedonia was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia subscale at baseline, after one month (T1), and three months (T2). Response was defined as a ≥50 % reduction in MADRS anhedonia subscale score from baseline. Adverse effects were systematically monitored. Significant improvements in anhedonia were observed in both TRD and B-TRD groups, and these effects were distinct from overall depressive symptom reduction (p < 0.001). Response rates at T2 were 51.92 % in B-TRD and 38 % in TRD patients. Drop-out rates were 12.96 % in B-TRD and 14 % in TRD, primarily due to inefficacy or side effects. Safety profiles were comparable between groups, with minimal incidence of manic switches (B-TRD 5.6 %, TRD 2.0 %, p = 1.000). Repeated administration of ESK-NS effectively reduces anhedonia in both unipolar and bipolar depression patients in real-world settings, suggesting a targeted, transdiagnostic anti-anhedonic effect beyond general antidepressant action.

Background: Dual disorders (DDs) involve the coexistence of a substance use disorder (SUD) with another mental illness, often from the psychotic and affective categories. They are quite common in clinical practice and present significant challenges for both diagnosis and treatment. This study explores the effectiveness of brexpiprazole, a third-generation antipsychotic, in an Italian sample of individuals diagnosed with schizophrenia spectrum disorder and a comorbid SUD. Methods: Twenty-four patients, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and enrolled in several Italian hospitals, underwent a psychometric assessment at baseline (T0) and one month (T1) after starting brexpiprazole treatment administered at a mean dosage of 2 mg/day. Results: Brexpiprazole demonstrated significant reductions in psychopathological burden (Positive and Negative Syndrome Scale/PANSS total score: p < 0.001). Positive (p = 0.003) and negative (p = 0.028) symptoms, substance cravings (VAS craving: p = 0.039), and aggression (MOAS scale: p = 0.003) were notably reduced. Quality of life improved according to the 36-item Short Form Health Survey (SF-36) subscales (p < 0.005). Conclusions: This study provides initial evidence supporting brexpiprazole’s efficacy and safety in this complex patient population, with positive effects not only on psychopathology and quality of life, but also on cravings. Further studies involving larger cohorts of subjects and extended follow-up periods are needed.

Background: Dual disorders (DD) entail the coexistence of a substance use disorder (SUD) and another mental health condition, often within psychotic and affective disorders. This study aims to evaluate lurasidone, an innovative atypical antipsychotic, in individuals diagnosed with schizophrenia spectrum disorder and concurrent comorbidities of alcohol use disorder/substance use disorder (AUD/SUD). Methods: A cohort of 23 subjects diagnosed with schizophrenia spectrum disorder and comorbid AUD/SUD underwent psychometric assessments at baseline (T0) and one-month (T1) post-lurasidone initiation. Results: Lurasidone exhibited significant reductions in psychopathological burden, evidenced by decreased total PANSS scores (Z = 2.574, p = 0.011). Positive symptoms, substance craving (VAS Craving; Z = 3.202, p = 0.001), and aggressivity (MOAS scale; Z = 2.000, p = 0.050) were notably reduced. Clinical Global Impression (CGI) scores significantly improved (Z = 2.934, p = 0.003). Quality of life enhancements were observed in SF-36 subscales (energy, emotional well-being, and social functioning) (p < 0.05) and Q-LES-Q-SF scale (Z = −2.341, p = 0.021). A safety analysis indicated lurasidone’s good tolerability, with only 8.7% reporting discontinuation due to side effects. Conclusions: This study offers initial evidence supporting lurasidone’s efficacy and safety in dual diagnoses, highlighting positive effects on psychopathology, substance craving, and quality of life. These findings emphasize the need for tailored, comprehensive treatment strategies in managing the complexities of this patient population.

Novel psychoactive substances (NPS) are increasingly used by young individuals for their psychoactive effects and have been frequently associated with the emergence of psychotic symptoms and schizophrenia spectrum disorders. However, it remains unclear whether NPS use directly increases the risk of psychosis onset or whether individuals with a predisposition to psychosis are more likely to engage in NPS use. This systematic review aims to explore the relationship between NPS consumption and the risk of developing psychotic symptoms. Out of 4477 identified studies, 95 met the inclusion criteria. FINDINGS: indicate that synthetic cannabinoids are the most frequently implicated substances, showing a strong association with acute psychosis and, in some cases, with persistent or relapsing psychotic disorders. The presence of Schneiderian First Rank Symptoms in some cases highlights a phenomenological overlap with schizophrenia, suggesting a possible risk of transition. Synthetic cathinones, phenethylamines, and other NPS classes were also linked to a broad range of psychotic manifestations, including disturbances in thought content and perceptual abnormalities. Although many episodes appeared transient, a notable proportion evolved into persistent psychotic states, supporting the hypothesis that NPS may either unmask latent vulnerabilities or directly contribute to the development of chronic psychotic disorders. These results underline the critical importance of systematically assessing NPS use in individuals presenting with first-episode psychosis and call for increased clinical and public health awareness regarding the psychiatric risks associated with these substances.

Introduction: Treatment-Resistant Depression (TRD) affects approximately 30–50% of patients with Major Depressive Disorder (MDD) who fail to respond to at least two adequate antidepressant trials. This condition presents substantial clinical and functional challenges, and no universally accepted treatment algorithm currently exists. Emerging therapeutic strategies, particularly glutamatergic modulators and psychedelics, have shown promising results in managing TRD. Methods: We conducted a narrative review using PubMed and Scopus with the query “(treatment resistant depression OR TRD) AND (glutamatergic OR glutamate OR psychedelic OR psilocybin OR antipsychotic augmentation) NOT (review OR animal OR mouse).” After applying inclusion/exclusion criteria, 60 articles were selected. Results: The most frequently studied treatments (43 studies) are glutamatergic agents, particularly intravenous ketamine and intranasal esketamine, which have consistently demonstrated rapid and clinically meaningful reductions in depressive symptoms. Augmentation with atypical antipsychotics also showed effectiveness for partial responders. Psychedelic-assisted therapies yielded sustained antidepressant benefits and modulated biomarkers such as BDNF and inflammatory markers. Discussion and Conclusion: The findings support a potential paradigm shift away from traditional monoaminergic-based treatments toward more personalized, mechanism-driven strategies for managing TRD. Ketamine and esketamine offer rapid-onset relief suitable for acute high-risk cases, while augmentation strategies remain valuable for partial responders. Psychedelic interventions, although still experimental, hold promise as adjunctive options. Furthermore, biomarkers and early response predictors may help guide individualized treatment decisions.

Background: Piperazines, synthetic compounds known for their stimulant and hallucinogenic effects, have gained prominence among novel psychoactive substances (NPS) and are frequently associated with adverse psychiatric outcomes, including psychosis. Methods: A systematic review of the literature available up to 23 May 2024 was conducted, using the PubMed, Scopus, and Web of Science databases, in addition to the related gray literature, utilizing the following search strategy: “piperazines” AND (“psychosis” OR “hallucination” OR “delusion” OR “schizophrenia” OR “delusional” OR “schizoaffective”) NOT review NOT animal. Data collection adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The research methods were registered with PROSPERO (CRD42024549204). Results: Out of a total of 4547 articles identified, 4 met the inclusion criteria. We observed an important relationship between piperazine abuse and the onset of acute psychotic episodes, marked by symptoms such as paranoia, auditory, and visual hallucinations. Conclusion: The complex polyreceptor action mechanism of piperazines may explain these psychopathological effects, similar to those observed with other NPS. Although studies confirm a link between piperazine use and psychosis, data on long-term outcomes are limited. Recovery is common following cessation and treatment. Further research into the effects of piperazine abuse and the development of specific treatment protocols for substance-induced psychosis is necessary.