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Keywords = antipsychotic treatment

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34 pages, 640 KiB  
Review
Future Pharmacotherapy for Bipolar Disorders: Emerging Trends and Personalized Approaches
by Giuseppe Marano, Francesco Maria Lisci, Gianluca Boggio, Ester Maria Marzo, Francesca Abate, Greta Sfratta, Gianandrea Traversi, Osvaldo Mazza, Roberto Pola, Gabriele Sani, Eleonora Gaetani and Marianna Mazza
Future Pharmacol. 2025, 5(3), 42; https://doi.org/10.3390/futurepharmacol5030042 - 4 Aug 2025
Abstract
Background: Bipolar disorder (BD) is a chronic and disabling psychiatric condition characterized by recurring episodes of mania, hypomania, and depression. Despite the availability of mood stabilizers, antipsychotics, and antidepressants, long-term management remains challenging due to incomplete symptom control, adverse effects, and high relapse [...] Read more.
Background: Bipolar disorder (BD) is a chronic and disabling psychiatric condition characterized by recurring episodes of mania, hypomania, and depression. Despite the availability of mood stabilizers, antipsychotics, and antidepressants, long-term management remains challenging due to incomplete symptom control, adverse effects, and high relapse rates. Methods: This paper is a narrative review aimed at synthesizing emerging trends and future directions in the pharmacological treatment of BD. Results: Future pharmacotherapy for BD is likely to shift toward precision medicine, leveraging advances in genetics, biomarkers, and neuroimaging to guide personalized treatment strategies. Novel drug development will also target previously underexplored mechanisms, such as inflammation, mitochondrial dysfunction, circadian rhythm disturbances, and glutamatergic dysregulation. Physiological endophenotypes, such as immune-metabolic profiles, circadian rhythms, and stress reactivity, are emerging as promising translational tools for tailoring treatment and reducing associated somatic comorbidity and mortality. Recognition of the heterogeneous longitudinal trajectories of BD, including chronic mixed states, long depressive episodes, or intermittent manic phases, has underscored the value of clinical staging models to inform both pharmacological strategies and biomarker research. Disrupted circadian rhythms and associated chronotypes further support the development of individualized chronotherapeutic interventions. Emerging chronotherapeutic approaches based on individual biological rhythms, along with innovative monitoring strategies such as saliva-based lithium sensors, are reshaping the future landscape. Anti-inflammatory agents, neurosteroids, and compounds modulating oxidative stress are emerging as promising candidates. Additionally, medications targeting specific biological pathways implicated in bipolar pathophysiology, such as N-methyl-D-aspartate (NMDA) receptor modulators, phosphodiesterase inhibitors, and neuropeptides, are under investigation. Conclusions: Advances in pharmacogenomics will enable clinicians to predict individual responses and tolerability, minimizing trial-and-error prescribing. The future landscape may also incorporate digital therapeutics, combining pharmacotherapy with remote monitoring and data-driven adjustments. Ultimately, integrating innovative drug therapies with personalized approaches has the potential to enhance efficacy, reduce adverse effects, and improve long-term outcomes for individuals with bipolar disorder, ushering in a new era of precision psychiatry. Full article
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13 pages, 269 KiB  
Review
From Genotype to Guidelines: Rethinking Neutropenia Risk in Clozapine Use
by Amir Agustin Estil-las, William C. Sultan, Carla Sultan, Martena Grace, Mark Elias and Kristal Arraut
Psychiatry Int. 2025, 6(3), 93; https://doi.org/10.3390/psychiatryint6030093 (registering DOI) - 4 Aug 2025
Viewed by 24
Abstract
Clozapine, a second-generation antipsychotic known for its effectiveness in treating resistant schizophrenia, is often linked with serious hematological side effects, particularly neutropenia and agranulocytosis. This review investigates the underlying pathophysiological mechanisms of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA), outlines associated risk factors, and [...] Read more.
Clozapine, a second-generation antipsychotic known for its effectiveness in treating resistant schizophrenia, is often linked with serious hematological side effects, particularly neutropenia and agranulocytosis. This review investigates the underlying pathophysiological mechanisms of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA), outlines associated risk factors, and evaluates current clinical management strategies. Clozapine’s pharmacological profile, marked by its antagonism of dopamine D4 and serotonin receptors, contributes to both its therapeutic advantages and hematological toxicity. Epidemiological data show a prevalence of CIN and CIA at approximately 3.8% and 0.9%, respectively, with onset typically occurring within the first six months of treatment. Key risk factors include older age, Asian and African American ethnicity, female sex, and certain genetic predispositions. The development of CIN and CIA may involve bone marrow suppression and autoimmune mechanisms, although the exact processes remain partially understood. Clinical presentation often includes nonspecific symptoms such as fever and signs of infection, necessitating regular hematological monitoring in accordance with established guidelines. Management strategies include dosage adjustments, cessation of clozapine, and the administration of granulocyte colony-stimulating factors (G-CSF). Advances in pharmacogenomics show promise for predicting susceptibility to CIN and CIA, potentially improving patient safety. This review emphasizes the importance of vigilant monitoring and personalized treatment approaches to reduce the risks associated with clozapine therapy. Full article
15 pages, 1548 KiB  
Case Report
Catatonia in a Possible Case of Moderate Neuroleptic Malignant Syndrome: A Case Report
by Daniel Ungureanu, Patricia-Ștefania Mitrea, Silvina Iluț, Aurora Taloș and Cătălina-Angela Crișan
Reports 2025, 8(3), 134; https://doi.org/10.3390/reports8030134 - 2 Aug 2025
Viewed by 87
Abstract
Background and Clinical Significance: Neuroleptic malignant syndrome (NMS) is a life-threatening condition usually caused by the exposure to antipsychotics. This case report presents a catatonia syndrome that may have developed in the context of a moderate NMS. Case Presentation: An 18-year-old [...] Read more.
Background and Clinical Significance: Neuroleptic malignant syndrome (NMS) is a life-threatening condition usually caused by the exposure to antipsychotics. This case report presents a catatonia syndrome that may have developed in the context of a moderate NMS. Case Presentation: An 18-year-old male patient presented with a treatment-resistant catatonia syndrome that debuted 2 weeks prior to the presentation (creatin kinase levels = 4908 U/L, maximum temperature = 38.9°C, white blood count = 13.20 × 109/L, Bush–Francis Catatonia Rating Scale = 30 points). Possible organic causes of catatonia were ruled out, according to the negative results obtained. The patient’s condition improved under benzodiazepine treatment and he was later discharged. After discharge, the catatonia was attributed to a possible NMS with moderate severity. The diagnosis was supported by NMS Diagnosis Criteria Score = 85 points and the presence of Levenson’s triad. Conclusions: This case highlights the concomitant manifestation of both catatonia and NMS in the same patient and the difficulty of establishing a correct diagnosis involving both entities. Full article
(This article belongs to the Section Mental Health)
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21 pages, 301 KiB  
Review
Targeting Psychotic and Cognitive Dimensions in Clinical High Risk for Psychosis (CHR-P): A Narrative Review
by Michele Ribolsi, Federico Fiori Nastro, Martina Pelle, Eleonora Esposto, Tommaso B. Jannini and Giorgio Di Lorenzo
J. Clin. Med. 2025, 14(15), 5432; https://doi.org/10.3390/jcm14155432 - 1 Aug 2025
Viewed by 132
Abstract
Schizophrenia (SCZ) is a debilitating disorder with substantial societal and economic impacts. The clinical high risk of psychosis (CHR-P) state generally precedes the onset of SCZ, offering a window for early intervention. However, treatment guidelines for CHR-P individuals remain contentious, particularly regarding antipsychotic [...] Read more.
Schizophrenia (SCZ) is a debilitating disorder with substantial societal and economic impacts. The clinical high risk of psychosis (CHR-P) state generally precedes the onset of SCZ, offering a window for early intervention. However, treatment guidelines for CHR-P individuals remain contentious, particularly regarding antipsychotic (AP) medications. Although several studies have examined the effects of APs on reducing the risk of conversion to psychosis, the novelty of this narrative review lies in its focus on differentiating APs’ effects on positive and negative symptoms, as well as cognitive functioning, in CHR-P individuals. Evidence suggests that APs may be cautiously recommended for attenuated positive symptoms to stabilize individuals for psychological interventions, but their use in treating negative symptoms is generally discouraged due to limited efficacy and potential side effects. Similarly, the effects of APs on cognitive abilities remain underexplored, with results indicating a lack of significant neurocognitive outcomes. In conclusion, APs’ use in CHR-P patients requires careful consideration due to limited evidence and potential adverse effects. Future research should focus on individual symptom domains and treatment modalities to optimize outcomes in this critical population. Until then, a cautious approach emphasizing non-pharmacological interventions is advisable. Full article
(This article belongs to the Section Mental Health)
68 pages, 2838 KiB  
Review
Unravelling the Viral Hypothesis of Schizophrenia: A Comprehensive Review of Mechanisms and Evidence
by Mădălina Georgeta Sighencea and Simona Corina Trifu
Int. J. Mol. Sci. 2025, 26(15), 7429; https://doi.org/10.3390/ijms26157429 - 1 Aug 2025
Viewed by 324
Abstract
Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a [...] Read more.
Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a wide array of neurotropic viruses, including influenza viruses, herpesviruses (HSV-1 and 2, CMV, VZV, EBV, HHV-6 and 8), hepatitis B and C viruses, HIV, HERVs, HTLV, Zika virus, BoDV, coronaviruses (including SARS-CoV-2), and others. These pathogens can contribute to schizophrenia through mechanisms such as direct microinvasion, persistent central nervous system infection, immune-mediated neuroinflammation, molecular mimicry, and the disturbance of the blood–brain barrier. Prenatal exposure to viral infections can trigger maternal immune activation, resulting in cytokine-mediated alterations in the neurological development of the foetus that persist into adulthood. Genetic studies highlight the role of immune-related loci, including major histocompatibility complex polymorphisms, in modulating susceptibility to infection and neurodevelopmental outcomes. Clinical data also support the “mild encephalitis” hypothesis, suggesting that a subset of schizophrenia cases involve low-grade chronic neuroinflammation. Although antipsychotics have some immunomodulatory effects, adjunctive anti-inflammatory therapies show promise, particularly in treatment-resistant cases. Despite compelling associations, pathogen-specific links remain inconsistent, emphasising the need for longitudinal studies and integrative approaches such as viromics to unravel causal relationships. This review supports a “multi-hit” model in which viral infections interfere with hereditary and immunological susceptibilities, enhancing schizophrenia risk. Elucidating these virus–immune–brain interactions may facilitate the discovery of biomarkers, targeted prevention, and novel therapeutic strategies for schizophrenia. Full article
(This article belongs to the Special Issue Schizophrenia: From Molecular Mechanism to Therapy)
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16 pages, 365 KiB  
Article
Sex-Specific Differences in Antidepressant and Antipsychotic Treatment Outcomes and Serum Levels in Children and Adolescents
by Maike Scherf-Clavel, Stefanie Fekete, Manfred Gerlach, Christoph U. Correll, Paul Plener, Jörg M. Fegert, Andreas Karwautz, Peter Heuschmann, Tobias Banaschewski, Wolfgang Briegel, Christian Fleischhaker, Tobias Hellenschmidt, Hartmut Imgart, Michael Kaess, Michael Kölch, Karl Reitzle, Tobias J. Renner, Christian Rexroth, Gerd Schulte-Körne, Frank Theisen, Susanne Walitza, Christoph Wewetzer, Franca Keicher, Stefan Unterecker, Sebastian Walther, Marcel Romanos, Karin M. Egberts, Timo Vloet and Regina Taurinesadd Show full author list remove Hide full author list
Pharmaceutics 2025, 17(8), 983; https://doi.org/10.3390/pharmaceutics17080983 - 30 Jul 2025
Viewed by 300
Abstract
Introduction: Sex-specific differences in psychopharmacological treatment have gained increasing attention in adults, with studies showing that women often have higher serum concentrations of psychotropic drugs due to biological differences. However, despite recognition of these differences in adults, reference ranges for therapeutic drug monitoring [...] Read more.
Introduction: Sex-specific differences in psychopharmacological treatment have gained increasing attention in adults, with studies showing that women often have higher serum concentrations of psychotropic drugs due to biological differences. However, despite recognition of these differences in adults, reference ranges for therapeutic drug monitoring (TDM) in general, but even more sex-specific therapeutic windows for psychotropic drugs, are lacking in children and adolescents, who may metabolize and respond to medications differently. Aim: The study aimed to investigate sex-specific differences in antidepressant (AD) and antipsychotic (AP) -treatment outcomes, and pharmacokinetics in childhood/adolescence. In particular, we examined differences in AD and AP serum levels and clinical effects, including adverse drug effects (ADEs) and therapeutic effectiveness. Methods: This study is part of the multicenter “TDM-VIGIL” pharmacovigilance project, which prospectively followed patients aged 6–18 years treated with AD and AP across 18 child psychiatric centers in German-speaking countries from 2014 to 2018. Clinical data, including drug concentrations (AD: fluoxetine, mirtazapine, (es)citalopram, sertraline; AP: aripiprazole, quetiapine, olanzapine, risperidone), were collected using an internet-based registry, and treatment outcomes and ADEs were assessed during routine visits. Statistical analyses were performed to examine sex differences in pharmacokinetics and clinical responses, adjusting for age, weight, and other confounders. Results: A total of 705 patients (66.5% girls, 24.7% <14 years, mean age of 14.6 years) were included. Female patients were slightly older, had lower body weight, and were more often diagnosed with depression and anorexia nervosa, while boys were more frequently diagnosed with hyperkinetic disorders and atypical autism. We found no sex differences in the serum concentrations of investigated drugs when adjusted for age and weight. In fluoxetine treatment in patients diagnosed with mood (affective) disorders, female sex was associated with the probability for very good therapy response (p = 0.04), as well as with moderate treatment response (p = 0.02) compared to no treatment response. Discussion: Our findings suggest that sex may not affect serum levels of investigated AD and AP in children/adolescents. However, treatment outcome of fluoxetine was associated with sex, with higher probability for a better outcome in female patients diagnosed with mood (affective) disorders. Full article
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16 pages, 1238 KiB  
Article
Mortality Risk of Colistin vs. Non-Colistin Use in Cancer Patients with Multidrug-Resistant Gram-Negative Bacterial Infections: Stratified by Resistance Profile and Concomitant Medications
by Soo Hyeon Lee, Yongwon Choi, Chang-Young Choi, Yeo Jin Choi and Sooyoung Shin
Medicina 2025, 61(8), 1361; https://doi.org/10.3390/medicina61081361 - 28 Jul 2025
Viewed by 350
Abstract
Background and Objectives: Cancer patients are particularly susceptible to infections caused by multidrug-resistant Gram-negative bacteria (MDR GNB) due to chemotherapy- or radiation therapy-induced immunosuppression. Colistin is often prescribed as a last-resort agent for MDR GNB infection, but its clinical benefit in oncology patients [...] Read more.
Background and Objectives: Cancer patients are particularly susceptible to infections caused by multidrug-resistant Gram-negative bacteria (MDR GNB) due to chemotherapy- or radiation therapy-induced immunosuppression. Colistin is often prescribed as a last-resort agent for MDR GNB infection, but its clinical benefit in oncology patients remains unclear. This study aims to evaluate the mortality risk associated with colistin versus non-colistin regimens in cancer patient with MDR GNB infections, stratified by resistance profiles, infection sites, and concomitant medication use. Materials and Methods: A retrospective cohort study was conducted in adult cancer patients with MDR GNB infections that are resistant to at least three antibiotic classes and identified from at least two anatomical sites at a tertiary care hospital in Korea. Propensity score-matched in a 1:3 ratio either to the colistin group or non-colistin group and multivariate Cox hazard regression analyses were used to evaluate mortality in cancer patients with MDR GNB infections, primarily Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Results: A total of 85 patients (29 patients in the colistin and 56 patients in the non-colistin group) were included in the analysis. Overall, colistin use did not show a statistically significant mortality benefit compared to non-colistin regimens (hazard ratio (HR) 0.93, 95% CI 0.47–1.87). However, the subgroup analysis revealed that colistin had a potential association with significantly lower mortality in pneumonia patients with aminoglycoside-resistant infections (HR 0.04, 95% CI 0.002–0.69). Concomitant use of antipsychotics and benzodiazepines in selected resistance profiles also correlated with improved outcomes. In contrast, a potential association was found between concomitant macrolide use and increased mortality in patients with fluoroquinolone- or penicillin-resistant profiles. Conclusions: Colistin may offer survival benefits in selected high-risk cancer patients with MDR GNB pneumonia. Treatment outcomes are influenced by resistance profiles, infection sites, and concomitant medications, indicating the significant importance of individualized antimicrobial therapy and antimicrobial stewardship in oncology patients. Full article
(This article belongs to the Section Pharmacology)
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21 pages, 1563 KiB  
Systematic Review
Anhedonia and Negative Symptoms in First-Episode Psychosis: A Systematic Review and Meta-Analysis of Prevalence, Mechanisms, and Clinical Implications
by Valerio Ricci, Alessandro Sarni, Marialuigia Barresi, Lorenzo Remondino and Giuseppe Maina
Healthcare 2025, 13(15), 1796; https://doi.org/10.3390/healthcare13151796 - 24 Jul 2025
Viewed by 336
Abstract
Background: Anhedonia, defined as the diminished capacity to experience pleasure, represents a core negative symptom in first-episode psychosis (FEP) with profound implications for functional outcomes and long-term prognosis. Despite its clinical significance, comprehensive understanding of anhedonia prevalence, underlying mechanisms, and optimal intervention [...] Read more.
Background: Anhedonia, defined as the diminished capacity to experience pleasure, represents a core negative symptom in first-episode psychosis (FEP) with profound implications for functional outcomes and long-term prognosis. Despite its clinical significance, comprehensive understanding of anhedonia prevalence, underlying mechanisms, and optimal intervention strategies in early psychosis remains limited. Objectives: To systematically examine the prevalence and characteristics of anhedonia in FEP patients, explore neurobiological mechanisms, identify clinical correlates and predictive factors, and evaluate intervention efficacy. Methods: Following PRISMA 2020 guidelines, we conducted comprehensive searches across PubMed, Embase, PsycINFO, and Web of Science databases from January 1990 to June 2025. Studies examining anhedonia and negative symptoms in FEP patients (≤24 months from onset) using validated assessment instruments were included. Quality assessment was performed using appropriate tools for study design. Results: Twenty-one studies comprising 3847 FEP patients met inclusion criteria. Anhedonia prevalence ranged from 30% at 10-year follow-up to 53% during acute phases, demonstrating persistent motivational deficits across illness trajectory. Factor analytic studies consistently supported five-factor negative symptom models with anhedonia as a discrete dimension. Neuroimaging investigations revealed consistent alterations in reward processing circuits, including ventral striatum hypofunction and altered network connectivity patterns. Social anhedonia demonstrated stronger associations with functional outcomes compared to other domains. Epigenetic mechanisms involving oxytocin receptor methylation showed gender-specific associations with anhedonia severity. Conventional antipsychotic treatments showed limited efficacy for anhedonia improvement, while targeted psychosocial interventions demonstrated preliminary promise. Conclusions: Anhedonia showed high prevalence (30–53%) across FEP populations with substantial clinical burden (13-fold increased odds vs. general population). Meta-analysis revealed large effect sizes for anhedonia severity in FEP vs. controls (d = 0.83) and strong negative correlations with functional outcomes (r =·−0.82). Neuroimaging demonstrated consistent ventral striatum dysfunction and altered network connectivity. Social anhedonia emerged as the strongest predictor of functional outcomes, with independent suicide risk associations. Conventional antipsychotics showed limited efficacy, while behavioral activation approaches demonstrated preliminary promise. These findings support anhedonia as a distinct treatment target requiring specialized assessment and intervention protocols in early psychosis care. Full article
(This article belongs to the Section Medication Management)
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11 pages, 227 KiB  
Article
Long-Acting Injectable Antipsychotic Use in Children and Adolescents in Comparison to Adults
by Iris Anja Levy, Joseph Lipton, Yoav Kohen and Alex Gizunterman
J. Clin. Med. 2025, 14(14), 5086; https://doi.org/10.3390/jcm14145086 - 17 Jul 2025
Viewed by 294
Abstract
Objective: The aim of the study was to assess the effectiveness and safety of long-acting injectable anti-psychotic treatment (LAIA) amongst children and adolescents. Given the difficulty of performing an randomized controlled trial (RCT), we suggested comparing children and adolescents to young adults who [...] Read more.
Objective: The aim of the study was to assess the effectiveness and safety of long-acting injectable anti-psychotic treatment (LAIA) amongst children and adolescents. Given the difficulty of performing an randomized controlled trial (RCT), we suggested comparing children and adolescents to young adults who were treated with LAIAs, and extrapolating data regarding efficacy and safety. Method: We compared data from medical files of adult inpatients treated with LAIAs to children and adolescent inpatients treated with LAIAs, between January 2014 and April 2021. Results: clinical global impression (CGI) scale score and rate of side effects (79% vs. 92%, p-value = 0.106) were not different between children and adolescents and young adults treated with LAIAs. There were no significant differences found between the groups in most demographic and clinical parameters such as gender distribution, legal status (voluntary or involuntary hospitalization), first hospitalizations and subsequent hospitalizations. Significant differences were found in duration of hospitalizations (144 days vs.50 days, p-value < 0.001), the indication for recommending LAIA treatment, diagnosis, the distribution of specific LAIAs and the rates of patients treated for side effects of anti-psychotic treatment. Conclusions: Results suggest that LAIA treatment may be as effective amongst children and adolescents as it is for adults. More research should be done to assess safety and efficacy of LAIA treatment in children and adolescents in the short and long term. Full article
(This article belongs to the Special Issue Clinical Features and Management of Psychosis)
18 pages, 556 KiB  
Article
Clinical Outcomes in Patients with Schizophrenia Treated with Long-Acting Injectable vs. Oral Antipsychotics: A Naturalistic Study
by Francesca Bardi, Lorenzo Moccia, Georgios D. Kotzalidis, Gianluca Boggio, Andrea Brugnami, Greta Sfratta, Delfina Janiri, Gabriele Sani and Alessio Simonetti
Healthcare 2025, 13(14), 1709; https://doi.org/10.3390/healthcare13141709 - 16 Jul 2025
Viewed by 585
Abstract
Background/Objectives: Long-acting injectable antipsychotics (LAIs) represent a significant advancement in the treatment of schizophrenia (SCZ), particularly for improving adherence and long-term outcomes. This study aimed to assess the clinical outcomes of patients receiving atypical LAIs compared to those on various oral antipsychotics [...] Read more.
Background/Objectives: Long-acting injectable antipsychotics (LAIs) represent a significant advancement in the treatment of schizophrenia (SCZ), particularly for improving adherence and long-term outcomes. This study aimed to assess the clinical outcomes of patients receiving atypical LAIs compared to those on various oral antipsychotics over a one-year follow-up in a naturalistic setting. Methods: Sixty patients with SCZ were subdivided in two groups, those receiving LAIs (n = 25) and those receiving oral antipsychotics (n = 35). The groups were comparable for age, gender, educational attainment, employment status, marital status, smoking habits, and baseline SCZ severity, with no differences in baseline chlorpromazine equivalent dosages. Results: Over the follow-up period, patients in the LAI group discontinued treatment less frequently (χ2 = 4.72, p = 0.030), showed fewer suicide attempts (χ2 = 5.63, p = 0.018), fewer hospitalizations (χ2 = 4.95, p = 0.026), and fewer relapses (χ2 = 6.61, p = 0.010). Significant differences also emerged on the Drug Attitude Inventory (DAI-10) scores (F = 8.76, p = 0.005) and Body Mass Index (BMI) values (F = 8.32, p = 0.007), with the LAI group showing more favorable outcomes. Conclusions: LAIs, compared to oral antipsychotics, may promote treatment adherence, as shown by decreased hospitalization; furthermore, their use is related with better outcomes, like fewer relapses and less suicide attempts in individuals with SCZ in real-world settings. Full article
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29 pages, 4862 KiB  
Article
Repurposed Antipsychotics as Potential Anticancer Agents: Clozapine Efficacy and Dopaminergic Pathways in Neuroblastoma and Glioblastoma
by Catarina Moura, Maria João Gouveia and Nuno Vale
Life 2025, 15(7), 1097; https://doi.org/10.3390/life15071097 - 12 Jul 2025
Viewed by 467
Abstract
Neuro-oncology focuses on the diagnosis and treatment of brain tumors, which, despite their rarity, are associated with high mortality due to their invasiveness and limited treatment options. Emerging evidence suggests that dopamine (DA), a neurotransmitter crucial for cognitive and emotional processes, and its [...] Read more.
Neuro-oncology focuses on the diagnosis and treatment of brain tumors, which, despite their rarity, are associated with high mortality due to their invasiveness and limited treatment options. Emerging evidence suggests that dopamine (DA), a neurotransmitter crucial for cognitive and emotional processes, and its receptors may influence tumor growth and the tumor microenvironment. This study aimed to evaluate the potential anticancer effects of repurposed antipsychotic dopamine-targeting drugs (Clozapine, CLZ; Pimozide, PIM; Olanzapine, OLZ; and Risperidone, RIS) and antiemetic drugs (Domperidone, DOM; Droperidol, DRO) on neuroblastoma (SH-SY5Y) and glioblastoma (A172) cell lines, and to assess whether their efficacy is modulated by oxidative stress and DA synthesis. The drugs were first tested individually, followed by co-treatment with tyrosine (Tyr), a dopamine precursor, and hydrogen peroxide (H2O2), an inducer of oxidative stress. Additionally, drug activity was evaluated in the simultaneous presence of H2O2 and Tyr. CLZ exhibited the highest cytotoxicity in both cell lines, suggesting strong anticancer potential and also synergism among the different combinations, particularly in SH-SY5Y. Liquid chromatography of the extracellular medium showed greater Tyr consumption in SH-SY5Y compared to A172 cells, indicating a higher dependence on extracellular Tyr to mitigate drug- and/or stress-induced cytotoxicity. In summary, several of the repurposed antipsychotics demonstrated cytotoxic effects on central nervous system tumor cells, with CLZ showing the most promising activity, even under oxidative stress conditions. These findings support further investigation into dopamine-targeting drugs as potential therapeutic agents in neuro-oncology. Full article
(This article belongs to the Section Pharmaceutical Science)
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9 pages, 191 KiB  
Perspective
Clozapine and Regulatory Inertia: Revisiting Evidence, Risks, and Reform
by Carlos De las Cuevas
Healthcare 2025, 13(14), 1668; https://doi.org/10.3390/healthcare13141668 - 10 Jul 2025
Viewed by 313
Abstract
In the United States, the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program was implemented to ensure safe prescription and monitoring; however, its administrative complexity has often resulted in unintended barriers to access. Clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), [...] Read more.
In the United States, the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program was implemented to ensure safe prescription and monitoring; however, its administrative complexity has often resulted in unintended barriers to access. Clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), yet its use continues to be constrained by outdated regulatory frameworks, cultural inertia, and clinical hesitancy. This perspective article revisits the pharmacokinetic foundations of clozapine, re-examines its association with fatal outcomes, and critiques the persistence of obsolete monitoring systems such as the U.S. REMS program. Drawing on recent consensus publications endorsed by over 120 international clozapine experts, this article outlines the proposed changes to the U.S. prescription information and contextualizes them within broader global practices. This article argues that many barriers to clozapine use stem not from evidence, but from regulatory conservatism and the perpetuation of clinical myths. The dismantling of the REMS program in early 2025 represents a pivotal moment, yet further reforms are urgently needed to align regulatory guidance with contemporary science. Ultimately, this article is a call to rediscover the clinical value of clozapine and to translate decades of knowledge into regulatory and clinical action. Full article
12 pages, 1766 KiB  
Article
Negative Impact of Olanzapine on ICU Delirium Resolution: An Emulated Clinical Trial
by Ajna Hamidovic and John Davis
Pharmaceuticals 2025, 18(7), 1019; https://doi.org/10.3390/ph18071019 - 9 Jul 2025
Viewed by 338
Abstract
Introduction: Delirium is a common and debilitating clinical complication among ICU patients. Despite the prevalence of this condition, there are insufficient data to support or refute the routine use of atypical antipsychotics since the existing evidence remains sparse and inconclusive. The objective [...] Read more.
Introduction: Delirium is a common and debilitating clinical complication among ICU patients. Despite the prevalence of this condition, there are insufficient data to support or refute the routine use of atypical antipsychotics since the existing evidence remains sparse and inconclusive. The objective of the present study was to evaluate whether pre-ICU administration of the atypical antipsychotic olanzapine is associated with a differential time to delirium resolution relative to the control condition. Methods: In this emulated clinical trial, we utilized the MIMIC-IV v3.1 database, which contains deidentified health records from approximately 65,000 ICU patients, to derive a cohort of patients with a positive delirium screening within 24 h of ICU admission. We exluded patients who received any antipsychotic other than olanzapine prior to ICU admission. We performed propensity score matching using logistic regression and nearest-neighbor matching (1:1, caliper = 0.2) to balance covariates between the olanzapine and control groups. The primary outcome was time to delirium resolution, defined as the first negative delirium assessment. A Cox proportional hazards model, adjusted for multiple covariates and incorporating age as a time-dependent variable, was used to examine the association between olanzapine use and delirium resolution. Interaction terms were included to evaluate effect modification by age and gender. Results: A total of 5070 patients with a positive delirium screening within 24 h and no exposure to other antipsychotics met the eligibility criteria; 421 olanzapine users were matched to 421 controls using propensity score matching. Covariate balance was achieved (all standardized mean differences < 0.1), and no multicollinearity was detected (all VIFs < 2). Pre-ICU olanzapine use was associated with a 27% decrease in the likelihood of delirium resolution (HR = 0.73; 95% CI: 0.63–0.86; p < 0.001). A significant interaction with age indicated that the negative impact of olanzapine on delirium resolution increased with advancing age (HR = 1.0024 per unit of age × log(time), p = 0.023), translating to a 2.4% increase in the risk of prolonged delirium resolution for every 10-year increase in age per log(time). There was no modification of the association according to gender. Discussion: The negative effect of olanzapine on ICU delirium resolution, particularly among the elderly, presented in this study is in line with the results of our earlier study showing a negative effect (i.e., prolonged ICU stay) among patients receiving quetiapine relative to both control and haloperidol conditions. Distinctly strong anticholinergic effects of both olanzapine and quetiapine relative to the other antipsychotic agents may be driving the identified negative outcomes. Conclusions: Results of this emulated clinical trial do not support the use of olanzapine for the treatment of ICU delirium because the agent prolongs time to resolution of the condition. Full article
(This article belongs to the Section Pharmacology)
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31 pages, 5415 KiB  
Review
Psychopharmacological Therapy Positively Modulates Disease Activity in Inflammatory Bowel Disease: A Systematic Review
by Federica Di Vincenzo, Antonio Maria D’Onofrio, Angelo Del Gaudio, Elena Chiera, Gaspare Filippo Ferrajoli, Francesco Pesaresi, Alessio Simonetti, Marianna Mazza, Georgios Demetrios Kotzalidis, Mauro Pettorruso, Giovanni Martinotti, Loris Riccardo Lopetuso, Antonio Gasbarrini, Gabriele Sani, Gionata Fiorino, Franco Scaldaferri and Giovanni Camardese
Int. J. Mol. Sci. 2025, 26(13), 6514; https://doi.org/10.3390/ijms26136514 - 6 Jul 2025
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Abstract
Depression, anxiety, and perceived stress are common comorbidities in patients with inflammatory bowel disease (IBD) and may negatively influence the disease course. Likewise, severe IBD may contribute to the development or worsening of psychiatric symptoms. Despite the established relevance of the gut–brain axis [...] Read more.
Depression, anxiety, and perceived stress are common comorbidities in patients with inflammatory bowel disease (IBD) and may negatively influence the disease course. Likewise, severe IBD may contribute to the development or worsening of psychiatric symptoms. Despite the established relevance of the gut–brain axis and frequent use of psychotropic medications in IBD patients, limited evidence exists regarding the effects of psychiatric treatments on gastrointestinal disease activity. Therefore, the aim of this systematic review is to evaluate the effectiveness of psychiatric therapies on gastrointestinal symptoms and disease activity in patients with IBD. The work was conducted in accordance with PRISMA guidelines. Searches were performed across PubMed, Web of Science, and Scopus up to July 2024. Eligible studies evaluated the effectiveness of psychiatric medications—including antidepressants, antipsychotics, anxiolytics, sedative-hypnotics, mood stabilizers, anticonvulsants, and others—on at least one gastrointestinal outcome in patients with IBD. Outcomes included changes in commonly used clinical and endoscopic scores for Crohn’s disease (CD) and ulcerative colitis (UC), number of bowel movements, stool consistency, presence of blood in stool, severity of abdominal pain, as well as in surrogate markers of disease activity following treatment. Out of 8513 initially identified articles, 22 studies involving 45,572 IBD patients met the inclusion criteria. Antidepressants, particularly bupropion, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, and duloxetine, were associated with improvements in IBD activity scores, including Crohn’s Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn’s Disease (SES-CD) for CD, Mayo score and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for UC. Case reports highlighted potential benefits of pregabalin and lithium carbonate, respectively, showed by the reduction in clinical and endoscopic score of disease activity for pregabalin and improvement of UC symptoms for lithium carbonate, while topiramate showed limited efficacy. Clonidine and naltrexone determined the reductions in clinical and endoscopic score of disease activity, including CDAI and Crohn’s disease endoscopy index severity score (CDEIS) for CD and Disease Activity Index (DAI) for UC. Despite the limited data and study heterogeneity, antidepressants, naltrexone, and clonidine were associated with improvements in IBD activity. Larger, prospective studies are needed to confirm the therapeutic potential of psychiatric medications in modulating IBD activity and to guide integrated clinical management. Full article
(This article belongs to the Section Molecular Immunology)
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Systematic Review
Dopamine Partial Agonists in Pregnancy and Lactation: A Systematic Review
by Alexia Koukopoulos, Delfina Janiri, Miriam Milintenda, Sara Barbonetti, Georgios D. Kotzalidis, Tommaso Callovini, Lorenzo Moccia, Silvia Montanari, Marianna Mazza, Lucio Rinaldi, Alessio Simonetti, Mario Pinto, Giovanni Camardese and Gabriele Sani
Pharmaceuticals 2025, 18(7), 1010; https://doi.org/10.3390/ph18071010 - 6 Jul 2025
Viewed by 687
Abstract
Background/Objectives: Dopamine partial agonists are drugs initially developed to treat schizophrenia, seeking a double effect of increased dopaminergic transmission in the prefrontal cortex and decrease in the accumbens/striatum. Of these drugs, aripiprazole, brexpiprazole, and cariprazine are currently marketed and used in schizophrenia [...] Read more.
Background/Objectives: Dopamine partial agonists are drugs initially developed to treat schizophrenia, seeking a double effect of increased dopaminergic transmission in the prefrontal cortex and decrease in the accumbens/striatum. Of these drugs, aripiprazole, brexpiprazole, and cariprazine are currently marketed and used in schizophrenia spectrum and mood disorders. It is debated whether patients with psychiatric disorders becoming pregnant should discontinue or continue their antipsychotic treatment despite some risks for the fetus, i.e., whether it is worse to have an untreated disorder or treating it with drugs. The safety of drugs for mother and baby extend from pregnancy to the postpartum, when breastfeeding assumes great importance. We set to investigate the use of dopamine partial agonists in pregnancy and lactation. Methods: On 23 June 2025, we used suitable strategies for identifying cases and studies of cariprazine, aripiprazole, brexpiprazole, dopamine partial agonists in pregnancy, perinatal period, and/or lactation on PubMed, CINAHL, PsycInfo/PsycArticles, Scopus, and ClinicalTrials.gov. We used the PRISMA Statement in developing our review. We included case reports and clinical studies. We excluded reports without pregnancy or focused on other drugs than the above. We reached consensus on eligibility with Delphi rounds among all authors. Results: Our searches produced 386 results on the above databases. We included 24 case reports/series and 15 studies. Most studies showed no negative pregnancy outcomes. There were serious concerns about the use of dopamine D2/D3 partial agonists during lactation. Conclusions: The use of dopamine partial agonists during pregnancy appears to be safe, but during breastfeeding they should be better avoided. Full article
(This article belongs to the Special Issue Pharmaceutical Strategy for Mood Disorders)
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