Lithium has remained one of the most established treatments for mood disorders for more than seven decades. Evidence supports its effectiveness in the management of acute manic episodes and in the prevention of relapse in bipolar disorder during maintenance therapy. In addition to its mood-stabilizing properties, lithium is distinguished by a clinically relevant anti-suicidal effect, supported by current evidence showing reduced rates of suicidal behavior in patients with recurrent mood disorders. Different salts, including carbonate and sulfate, are available as Immediate-Release (IR) and Sustained-Release (SR) formulations. SR formulations are associated with slower absorption and delayed peak concentrations, smaller peak-trough fluctuations, and fewer peak-related adverse effects, while achieving a comparable overall exposure to IR formulations. Among SR options, lithium sulfate deserves specific consideration because formulation-dependent properties may favor more predictable absorption and a steadier serum concentration profile. This review summarizes current evidence regarding lithium use across the lifespan, with particular focus on the pharmacokinetic characteristics and clinical implications of different lithium formulations. We discuss practical aspects relevant to routine care, including laboratory and therapeutic drug monitoring, clinically relevant food and drug interactions, toxicity management, switching strategies, and treatment considerations in vulnerable populations, including those with impaired renal function, older adults, children and adolescents, and women during pregnancy and the postpartum period. Overall, SR formulations may offer practical advantages in individualized long-term treatment by improving tolerability and facilitating once-daily administration, although the currently available evidence remains limited by the lack of large direct comparative trials and the predominance of observational studies.

Trazodone, an antidepressant, has only been approved for use in major depressive disorder (MDD), but has demonstrated potent therapeutic potential in various conditions, such as insomnia and anxiety. It targets multiple serotonergic, adrenergic, and histaminergic receptors. Given this multimodal and multifunctional profile, we aimed to provide a comprehensive overview of the pharmacodynamic and pharmacokinetic properties of trazodone and its clinical applications across various conditions. Trazodone demonstrates sedative and anxiolytic effects even at a low dose (25–75 mg) and a full antidepressant effect at higher doses (150–300 mg). The availability of trazodone in immediate-release, extended-release, intravenous, and intramuscular formulations enables flexible and personalized treatment based on the patient’s symptoms, medical history, tolerability, and clinical settings. Clinical evidence also demonstrates that trazodone is effective and well-tolerated across various conditions, including MDD, treatment-resistant depression, insomnia (off-label), neurological disorders, dementia, and delirium, highlighting its versatility. Additionally, the low risk of sexual dysfunction, limited withdrawal symptoms, and weight-neutral effects make it suitable for use in patients with comorbid conditions. Trazodone is a multimodal and multifunctional antidepressant that exhibits a broad range of therapeutic effects in MDD and other comorbid conditions. Further research on the pharmacokinetic and pharmacodynamic relationship of trazodone, its parenteral use in acute settings, and the development of prescribing algorithms for predicting treatment responses may enhance its therapeutic outcomes in patients with MDD.

Background: Adverse Drug Reactions (ADRs) are a significant public concern because of their impact on healthcare systems. Spontaneous reporting of ADRs is crucial for monitoring drug safety and recognizing possible risk factors. The objective of this study was to characterize ADR reports from the Allergy and Clinical Immunology Unit of the G. Martino University Hospital, Messina, Italy. Methods: A retrospective analysis was conducted, including all ADRs spontaneously reported from patients attending the clinic because of at least one previous ADR, from June 2022 to June 2024. Results: A total of 388 reports were collected, mainly from females (71.1%) and adult patients (84.3%). ADRs were mostly immediate, from antibiotics and anti-inflammatory drugs (61.5%), with a high prevalence of cutaneous and respiratory disorders. Delayed reactions were mostly from endocrine therapies, vaccines, and antiepileptics. Anaphylactic shock was present only in 13 ADR reports (3.35%). A higher risk of developing serious ADRs was found in elderly patients aged ≥65 years (p = 0.012). An original finding was that a positive history of allergies (p = 0.023) and past medical history of ADRs (p = 0.045) were negatively correlated to the occurrence of a serious ADR, probably because patients had been previously followed in an allergy setting and alerted about ADRs. Conclusions: This study underlines the role of ADR follow-up in allergy settings to identify preventable traits and related risk factors; appropriate ADR reporting and collaboration between allergists and pharmacovigilance centers can be a winning strategy for ADR prevention.

Background/Objectives: The recent approval of the first intranasal calcitonin gene-related peptide receptor antagonist (CGRP-RA), zavegepant, has increased the relevance of this drug class in treating acute migraine. However, introducing an alternative delivery method may result in a different real-world safety profile. Thus, the aim of this study was to assess adverse events (AEs) related to zavegepant through a retrospective pharmacovigilance disproportionality analysis. Methods: We analyzed Individual Case Safety Reports (ICSRs) presenting zavegepant as the suspected drug, submitted to the Food and Drug Administration (FDA) Adverse Event Monitoring System (AEMS) database between 1 January 2023 and 31 December 2025. ICSRs were assessed by using descriptive and disproportionality analyses. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were used as disproportionality measures. Results were deemed significant if the ROR 95% CI lower bound was >1 and ≥3 ICSRs were available for each drug–event pair. Results: A total of 509 zavegepant-related ICSRs were identified. Most ICSRs involved female patients (n = 353; 69.4%), with a median (quartile 1, Q1–quartile 3, Q3) age of 45 (34–56) years. The Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Terms with the highest RORs were nasal discomfort (n = 62; ROR = 298.85; 95%CI [228.91, 390.17]), rhinalgia (10; 126.09; [67.34, 236.09]), dysgeusia (147; 94.72; [78.19, 114.75]), pharyngeal ulceration (3; 79.20; [25.42, 246.75]), and upper-airway cough syndrome (16; 62.87; [38.19, 103.49]). Conclusions: These results suggest a safety profile for zavegepant consistent with previous knowledge regarding CGRP-RAs. However, nasal and/or oropharyngeal AEs, plausibly related to intranasal exposure, may affect perceived tolerability and timely use, warranting further investigation.

INTRODUCTION/OBJECTIVE:Strong evidence suggests that inflammation can affect the activity of Cytochrome P450 (CYP) isoforms responsible for the metabolism of numerous psychiatric drugs. This is likely of particular importance in conditions such as Major Depressive Disorder (MDD), where a relevant percentage of patients report non-response to treatment. Thus, the existing knowledge on the impact of inflammation on medications used in MDD, and metabolised via these pathways (e.g., antidepressants and antipsychotics), needs to be further evaluated. METHODS:In this systematic review, the PubMed, Scopus, and Web of Science databases were screened, and published articles between January 1st, 2010, and May 25th, 2025, were retrieved. The research strategy was based on combinations of key terms related to pharmacokinetics, inflammation, and antidepressants or antipsychotics. A total of five observational and cohort studies were included, along with ten case series or case reports that investigated the topic in human subjects. RESULTS/DISCUSSION:The available evidence appears unbalanced and severely limited for antidepressants. The single study available suggests limited changes in the pharmacokinetics of citalopram and venlafaxine in inflammatory conditions. By contrast, the available data for antipsychotics suggest variable effects of inflammation on their pharmacokinetics. In particular, clozapine is associated with substantial increases in plasma concentrations. Overall, the relationship between inflammation and the pharmacokinetics of psychiatric drugs appears to be complex. Furthermore, much of the available data is plagued by limitations, such as small sample sizes and retrospective designs, as well as poor characterisation of patients' genetic and immunological profiles. CONCLUSION:Considering the current, very limited evidence base, especially for antidepressants, the necessity for larger prospective studies remains pressing. Further studies should incorporate pharmacogenetics and immunological profiling to better support clinical practice recommendations.

INTRODUCTION:This is an update of a prior review of clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions (DDIs) between antidepressants and antiseizure medications (ASMs). AREA COVERED:Articles published between 1 January 2010 and 30 November 2025 were identified through structured searches in PubMedⓇ, Web of Science, SCOPUS, and Google Scholar using antidepressant- and ASM-related terms. Some antidepressants, including fluoxetine, paroxetine, fluvoxamine, are moderate to strong inhibitors of various cytochrome P450 (CYP) isoenzymes and may cause clinically relevant interactions with ASMs metabolized by these pathways. First-generation ASMs with enzyme-inducing properties (e.g. carbamazepine, phenobarbital, and phenytoin) or enzyme-inhibiting effects (e.g. valproic acid) may alter the PK profile of several antidepressants, potentially leading to reduced therapeutic efficacy or dose-dependent toxicity. The introduction of second- and third-generation ASMs has substantially improved the safety of combined pharmacotherapy. Potential PD DDIs between antidepressants and ASMs are less clearly defined and remain largely theoretical. EXPERT OPINION:Antidepressants and ASMs are associated with a considerable risk of clinically significant DDIs. A thorough understanding of the underlying PK and PD mechanisms, combined with complementary strategies including therapeutic drug monitoring, consultation of interaction databases, and careful clinical monitoring, is essential to anticipate, prevent, and effectively manage adverse DDIs.

Monoclonal antibodies (mAbs) have revolutionized the treatment of multiple myeloma (MM), demonstrating remarkable effectiveness, despite potential adverse events (AEs). This study aims to identify unexpected signals of disproportionate reporting (SDRs) for cardiovascular (CV) and respiratory AEs associated with mAbs in MM treatment. From January 2015 to December 2023, reports involving suspected drugs (daratumumab, elotuzumab, elranatamab, isatuximab, belantamab mafodotin, teclistamab, and talquetamab) were analyzed in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Descriptive analysis was followed by disproportionality analyses first comparing mAbs to all other drugs (reference group, RG1), and subsequently conducting a sensitivity analysis against other MM drugs (RG2). Out of 13,496,241 reports, 31,052 (0.2

The European Clozapine Task Force is a group of psychiatrists and pharmacologists practicing in 18 countries under European Medicines Agency (EMA) regulation, who are deeply concerned about the underuse of clozapine in European countries. Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia, a large proportion of them do not have access to this treatment. Concerns about clozapine-induced agranulocytosis and stringent blood monitoring rules are major barriers to clozapine prescribing and use. There is a growing body of evidence that the incidence of clozapine-induced agranulocytosis is very low after the first year of treatment. Maintaining lifelong monthly blood monitoring after this period contributes to unjustified discontinuation of clozapine. We leverage recent and replicated evidence on the long-term safety of clozapine to call for the revision and updating of the EMA's blood monitoring rules, thus aiming to overcome this major barrier to clozapine prescribing and use. We believe the time has come for relaxing the rules without increasing the risks for people using clozapine in Europe.

Introduction: The combination of BRAF and MEK inhibitors (BRAF/MEKi) has significantly improved survival in melanoma patients with BRAF V600 mutations. However, these agents can cause cardiovascular (CV) toxicity, compromising efficacy. This study evaluated the CV adverse events (cAEs) associated with BRAF/MEKi using the U.S. FDA Adverse Event Reporting System (FAERS) to identify new signals of disproportionate reporting (SDRs). Methods: Descriptive and disproportionality analyses were conducted on reports listing dabrafenib (D), vemurafenib (V), encorafenib (E), trametinib (T), cobimetinib (C), or binimetinib (B) as suspects in monotherapy or combination therapy (D + T, V + C, E + B), with melanoma as the indication and at least one cAE. Standardized MedDRA Queries (SMQs) related to cAEs, including bradyarrhythmias and tachyarrhythmias, cardiac failure, cardiomyopathy, thrombotic events, ischaemic heart disease, and myocarditis/pericarditis, were analyzed. Results: Of the 14,077,067 reports retrieved, 18,370 (0.1%) were linked to BRAF/MEKi, with 1591 (8.7%) reporting cAEs, primarily in combination therapy (n = 1268). Disproportionality analysis identified 64 clinically relevant SDRs, most of which were unexpected. Notable findings included bradyarrhythmias, such as QT prolongation with D + T (n = 59; Reporting Odds Ratio, ROR = 5.09, 95% Confidence Interval, CI = 3.94–6.58), cardiac failure with V + C (29; 3.76, 2.6–5.42), and tachyarrhythmias, particularly atrial fibrillation with D + T (99; 2.37, 1.94–2.89). Among embolic and thrombotic events, clinically significant SDRs were observed for disseminated intravascular coagulation with D + T (38; 10.22, 7.42–14.06) and pulmonary embolism with V + C (22; 2.79, 1.83–4.24). Conclusions: Our findings underscore the need for comprehensive CV monitoring in patients receiving BRAF/MEKi therapy to prevent or detect cAEs early and reduce treatment-related risks, particularly in high-risk populations.

Background: Olaparib and niraparib are poly (ADP-ribose) polymerase inhibitors (PARPi) used primarily for the treatment of ovarian cancer. While both drugs have demonstrated efficacy in clinical trials, their safety profiles, particularly in real-world clinical settings, remain to be fully elucidated. Objectives: This study aimed to (i) characterize the adverse drug reactions (ADRs) associated with olaparib and niraparib as reported in the EudraVigilance database, (ii) compare the frequency of the ADRs occurring during treatment with the two drugs, and (iii) compare post-marketing safety data with those from clinical trials. Methods: A retrospective analysis was performed using data from the EudraVigilance database (2017–2024), focusing on individual case safety reports (ICSRs) related to olaparib and niraparib. Descriptive statistics and disproportionality analysis were performed to compare the frequency and severity of reported ADRs. Results: Both olaparib and niraparib had common ADRs including nausea, vomiting, anemia, thrombocytopenia, and fatigue. However, olaparib was associated with a higher risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and interstitial lung disease, while niraparib had a higher incidence of gastrointestinal events and thrombocytopenia. Our analysis demonstrates that some specific ADRs, including peripheral neuropathy with niraparib, were reported at higher frequencies compared to clinical trials. The incidence of serious ADRs, including hospitalizations and life-threatening events, was higher with niraparib than with olaparib. Conclusions: This study highlights significant differences in the safety profiles of olaparib and niraparib, with implications for clinical decision-making. Continuous monitoring and personalized management of ADRs are essential to optimize patient outcomes.

AIMS:To assess the risk of anaemia among low-dose aspirin (LDA) exposure in Danish older individuals in a real-world setting. METHODS AND RESULTS:Population based-cohort study conducted using Danish registers. The study population included older individuals (≥65 years) exposed to LDA between 2008 and 2013 for primary or secondary prevention of cardiovascular events. Over a 5-year follow-up, outcomes included anaemia incidence based on haemoglobin values and hematinic deficiency incidence based on antianaemic prescriptions. Among the 313 508 individuals included in the study population, those exposed to LDA (n = 59 869, 19.1%) had an incidence of hematinic deficiency determined by the use of antianaemic treatment of 9.6%, with an incidence rate ratio of 9.11 (95% confidence interval, CI: 8.81-9.41) when compared to non-users of LDA (n = 253 639, 80.9%), who had an incidence of 3.7%. Anaemia determined by haemoglobin value measurements was observed in 5.9% of those exposed to LDA, with an incidence rate ratio of 7.89 (95% CI: 7.58-8.21) when compared to non-users of LDA. Approximately, one in five individuals (n = 2 422, 21.5%) who experienced anaemia also experienced bleeding. Severe anaemia was observed in 1.3% of those exposed to LDA compared to 0.6% of those not exposed. Among the exposed, the reduction in haemoglobin and ferritin levels was associated with the severity of anaemia. CONCLUSION:These findings indicate that in a real-world setting, anaemia with LDA can occur in 6-10 older individuals out of every 100 LDA users during the first 5 years of treatment.

The purpose of the second meeting of the Epilepsy Study Group of the Italian Society of Neurology, held in Sicily, Italy, and titled "Episicily" was on a new holistic approach to people with epilepsy. The most important points that the experts at the conference addressed and considered significant were the modern clinical approach of a physician dedicated to epilepsy that requests multidisciplinary collaboration and a dynamic vision throughout new diagnostic procedures. Then, the new antiseizures medications and their peculiarities, the role of neuroinflammation and finally the bidirectional relationship with sleep disorders.

INTRODUCTION:This review examines clinically relevant drug interactions (DIs) between newer antidepressants and medications used to manage neurological disorders frequently comorbid with depression, including Parkinson's disease, Alzheimer's disease, migraine, multiple sclerosis, and neuropathic pain. AREAS COVERED:Articles were obtained from PubMed®, Web of Science, SCOPUS, and Google Scholar searches performed for each of the newer antidepressants and neurological medications. The pharmacokinetic (PK) and pharmacodynamic (PD) mechanisms underlying these DIs were summarized. Some newer antidepressants, such as fluoxetine, paroxetine, fluvoxamine, duloxetine, and bupropion, are moderate to potent inhibitors of various cytochrome P450 (CYP) isoenzymes and can produce clinically relevant interactions with neurologic drugs metabolized by these pathways. In addition, serotonergic antidepressants can precipitate potentially fatal serotonin syndrome when co-administered with monoamine-oxidase-B inhibitors or triptans; these interactions are noted as warnings or contraindications in product labeling. EXPERT OPINION:Clinicians must remain alert to possible DIs between antidepressants and neurological medications. Understanding PK and PD principles, coupled with proactive measures, such as pharmacogenetic testing, therapeutic drug monitoring, use of drug-interaction databases, and close clinical observation, can help to predict, prevent, and manage adverse interactions. Avoiding unnecessary polypharmacy, together with regular medication reviews and deprescribing, is particularly important for older adults with multiple comorbidities.

Safety signals for potential drug-induced adverse events (AEs) typically emerge from multiple data sources, primarily spontaneous reporting systems, despite known limitations. Increasingly, real-world data from sources such as electronic health records (EHRs) and administrative databases are leveraged for signal detection. Although network analysis has shown promise in mapping relationships between clinical attributes for signal detection in spontaneous reporting system databases, its application in real-world data from EHRs and administrative databases remains limited. This study aimed to evaluate the performance of network analysis in detecting safety signals within Italian administrative databases, using drug-induced acute myocardial infarction (AMI) as a proof of concept. We employed a case–crossover design to explore the association between drug exposure and AMI using the Healthcare Administrative Database of Mantova, Italy, from 2014 to 2018. Patients with their first AMI hospitalization were identified after a 365-day washout period to exclude prior hospitalizations. We constructed a network to analyse the relationships between prescribed drugs and diagnoses, represented as nodes, with undirected edges illustrating their interactions. For each patient with AMI, we identified all diagnoses and drugs recorded or redeemed within 365 days of the first AMI episode and generated various drug–diagnosis, drug–drug, and diagnosis–diagnosis pairs. We calculated the frequency of these pairs, and three types of edge weights quantified the strength of connections. We identified outlier drug–AMI pairs using a predictive score (F) based on frequency (C) and full edge weights (WF), with validation for known AMI associations. We prioritized signals using the F score, C of AMI, and WF, analysed through k-means clustering to identify patterns in the data. From 2014 to 2018, a total of 3918 patients had an AMI, with 4686 AMI diagnoses. Of those, 2866 had prescriptions in the previous year, totalling 498,591 prescriptions. A network analysis identified 2968 unique nodes, revealing 529,935 diagnosis–diagnosis connections, 235,380 drug–diagnosis connections, and 102,831 drug–drug connections. The median number of connections (C) was 404 (Q1–Q3: 194–671) for drug nodes and 380 (Q1–Q3: 216–664) for diagnosis nodes. The median WF was 11.8 (Q1–Q3: 9–14), and the median F score across pairs was 0.1 (Q1–Q3: 0.1–0.3). A total of 249 potential safety signals were detected, with 63.4

BACKGROUND:Major depressive disorder (MDD) exhibits significant heterogeneity in treatment responses, necessitating multiple pharmacological trials to achieve therapeutic success. Pharmacogenetic (PGx) testing has emerged as a promising tool to personalize antidepressant (AD) treatments, though its clinical utility remains controversial. METHODS:This study assessed the efficacy of PGx-guided treatment in improving clinical outcomes among 287 MDD patients within the PANDORA trial, a prospective randomized, participant- and rater-blinded, controlled trial conducted in Italy. A total of 268 adults with moderate-to-severe MDD were randomized into Treated as Usual (TAU) or Treated with Genetic Test Guide (TGTG). Patients were assessed using the Hamilton Depression Rating Scale (HAM-D17), Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory, MINI-ICF-APP for psychosocial functioning, and the UKU Side Effects Rating Scale, at baseline and at 4, 8, and 12 weeks. RESULTS:Both groups demonstrated significant symptom improvement over the 12-week period. No significant differences were observed between the groups in terms of response and remission rates, measured by HAM-D17 and BDI-II, at weeks 8 and 12. Notably, in the BDI-II symptom cluster analysis, significant differences were found only in neurovegetative symptoms, with TGTG patients showing greater improvement at the 4-week and 8-week follow-up visits. Among patients with severe baseline symptoms, those in the TGTG group exhibited greater symptom reduction and higher response rates at week 8. CONCLUSIONS:These findings suggest that while PGx testing did not significantly improve overall treatment efficacy in MDD compared to TAU, it may offer benefits in managing patients with severe symptoms and specific symptom domains.

Background/Objectives: Monoclonal antibodies (mAbs) have revolutionized multiple myeloma (MM) treatment. However, post-marketing data on their neuropsychiatric safety are limited. This study aimed to evaluate neuropsychiatric adverse events (AEs) related to mAbs used for MM through a retrospective pharmacovigilance analysis using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database. Methods: Individual case safety reports (ICSRs) from 2015 to 2023 with at least one neuropsychiatric AE and one of the MM-approved mAbs as the suspected drug (i.e., daratumumab, elotuzumab, isatuximab, belantamab mafodotin, teclistamab, elranatamab, and talquentamab) were analyzed using descriptive and disproportionality approaches. Results: Unknown signals of disproportionate reporting (SDR) included the following: cerebral infarction for daratumumab (n = 45; reporting odds ratio (ROR) = 2.39, 95% confidence interval (CI) = 1.79–3.21; information component (IC) = 1.54, IC025–IC075 = 1.05–1.9), elotuzumab (25; 7.61, 5.13–11.28; 3.03, 2.37–3.51), and isatuximab (10; 2.56, 1.38–4.76; 1.67, 0.59–2.4); mental status changes for daratumumab (40; 2.66, 1.95–3.63; 1.67, 1.14–2.04) and belantamab mafodotin (10; 4.23, 2.28–7.88; 2.3, 1.22–3.03); an altered state of consciousness for daratumumab (32; 1.97, 1.39–2.78; 1.32, 0.73–1.74) and belantamab mafodotin (6; 2.35, 1.05–5.23; 1.6, 0.19–2.52); Guillain-Barre syndrome (GBS) for daratumumab (23; 6.42, 4.26–9.69; 2.81, 2.11–3.3), isatuximab (8; 10.72, 5.35–21.48; 3.57, 2.35–4.37), and elotuzumab (3; 4.74, 1.53–14.7; 2.59, 0.52–3.8); and orthostatic intolerance for daratumumab (10; 12.54, 6.71–23.43; 3.75, 2.67–4.48) and elotuzumab (4; 28.31, 10.58–75.73; 5, 3.24–6.08). Conclusions: Our analysis highlighted several previously unacknowledged SDRs for MM-approved mAbs. Given the complex and not entirely understood etiology of some neuropsychiatric AEs, including GBS, further investigations are necessary.

The prevalence of major and mild cognitive impairment (CI) in type-2 diabetes older patients is 15–25

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a type 2 pattern of inflammation resulting in the production of some cytokines. Dupilumab radically changes the treatment of CRSwNP, but, considering its recent approval, it may be useful to evaluate its safety profile in a real-world setting. This work aimed to prospectively highlight the effectiveness and safety profile of dupilumab in patients with CRSwNP enrolled in the Otorhinolaryngology Unit of the University Hospital of Messina. An observational cohort study was carried out considering all patients treated with dupilumab. A descriptive analysis was conducted reporting all demographic characteristics, endoscopic evaluations, and symptom conditions. A total of 66 patients were treated with dupilumab, but three patients were excluded due to a lack of adherence during the observational period. A statistically significant reduction in the Sino-Nasal Outcome Test 22 (SNOT-22) and nasal polyps score (NPS) was shown at the 6th and 12th months compared to baseline values (SNOT-22, -37 and -50, p < 0.001 for both comparisons; NPS, -3 and -4, p < 0.001 for both comparisons). During the follow-up, eight patients (12.7%) had a reaction at the site of injection, and seven (11.1%) had transient hypereosinophilia. Given the optimal treatment response and the minimal adverse effects observed, clinicians should consider dupilumab a safe and effective treatment. Further studies are necessary to better understand the long-term effects.

Background: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. Methods: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. Results: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to >= 1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). Conclusion: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).