This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Background: Evidence on risk factors for postpartum depression (PPD) are fragmented and inconsistent.Aims: To assess the strength and credibility of evidence on risk factors of PPD, ranking them based on the umbrella review methodology.Method: Databases were searched until 1 December 2020, for systematic reviews and meta-analyses of observational studies. Two reviewers assessed quality, credibility of associations according to umbrella review criteria (URC) and evidence certainty according to Grading of Recommendations-Assessment-Development-Evaluations criteria.Results: Including 185 observational studies (n = 3 272 093) from 11 systematic reviews, the association between premenstrual syndrome and PPD was the strongest (highly suggestive: odds ratio 2.20, 95%CI 1.81–2.68), followed by violent experiences (highly suggestive: odds ratio (OR) = 2.07, 95%CI 1.70–2.50) and unintended pregnancy (highly suggestive: OR=1.53, 95%CI 1.35–1.75). Following URC, the association was suggestive for Caesarean section (OR = 1.29, 95%CI 1.17–1.43), gestational diabetes (OR = 1.60, 95%CI 1.25–2.06) and 5-HTTPRL polymorphism (OR = 0.70, 95%CI 0.57–0.86); and weak for preterm delivery (OR = 2.12, 95%CI 1.43–3.14), anaemia during pregnancy (OR = 1.47, 95%CI 1.17–1.84), vitamin D deficiency (OR = 3.67, 95%CI 1.72–7.85) and postpartum anaemia (OR = 1.75, 95%CI 1.18–2.60). No significant associations were found for medically assisted conception and intra-labour epidural analgesia. No association was rated as ‘convincing evidence’. According to GRADE, the certainty of the evidence was low for Caesarean section, preterm delivery, 5-HTTLPR polymorphism and anaemia during pregnancy, and ‘very low’ for remaining factors.Conclusions: The most robust risk factors of PDD were premenstrual syndrome, violent experiences and unintended pregnancy. These results should be integrated in clinical algorithms to assess the risk of PPD.

The quantification of antipsychotic levels in blood, also known as therapeutic drug monitoring (TDM), is a potentially useful tool of modern personalized therapy that can be applied to augment antipsychotic use and dosing decisions. The application of TDM for antipsychotics can be helpful in numerous challenging clinical scenarios, such as lack of therapeutic response, relapse, or adverse drug reactions (ADRs) related to antipsychotic treatment. The benefits of TDM may be particularly evident in the treatment of highly vulnerable patient subgroups, such as children, adolescents, pregnant women, and the elderly. The main aim of this article is to aid clinicians who routinely prescribe antipsychotics to successfully apply TDM in routine clinical practice in order to help optimize the efficacy and safety of those antipsychotics. Participants were clinicians and researchers, members of the American Society of Clinical Psychopharmacology, and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association of Neuropsychopharmacology and Pharmacopsychiatry). TDM literature on antipsychotics was critically reviewed to provide a condensed clinical decision-making algorithm with therapeutic reference ranges for blood antipsychotic levels, within which patients are most likely to respond and tolerate treatment, although TDM is not equally recommended/supported for all antipsychotics. A preliminary draft was prepared and circulated to the writing group members. Consensus was achieved in all cases, and resulting recommendations focused on following areas: steady-state and sampling time, levels of recommendations, indications, therapeutic reference ranges and laboratory alert levels, practical issues, and interpretation, as well as limitations. The utilization of TDM as a tool for problem solving in antipsychotic treatment offers a unique method to improve safety and efficacy. This consensus statement summarizes essential information on the routine use of TDM for antipsychotics and encourages clinicians to perform TDM with the appropriate indications as part of the clinical decision-making process.

Objectives: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug–drug interactions. Methods: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated. Results: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine. Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

Over the past decade, obesity trends have reached epidemic standards.¹ In this context, the understanding of glucagon-like peptide-1 (GLP-1)–based mechanisms and related anorectic properties of GLP-1 receptor agonists (RAs) have revolutionized the treatment of obesity.² In addition to enhancing glucose-dependent insulin release, GLP-1 RAs may reduce glucagon secretion as well as gastric emptying.² Originally introduced for the treatment of type 2 diabetes, the effect of GLP-1 RAs on weight loss soon caught research attention.³ The weight loss properties of liraglutide and semaglutide quickly went viral on social media, leveraging their promotion as lifestyle drugs not just for patients with diabetes⁴ and leading to a global shortage.⁵ Currently, it is estimated that approximately 10% of patients with type 2 diabetes in the US are prescribed GLP-1 RAs.⁶ Accordingly, regulatory authorities over the world have urged health care professionals to direct available supplies to patients with type 2 diabetes who are inadequately managed with other medications over off-label prescriptions.^7,8 Despite the promising potential of GLP-1 RAs, serious concerns have been raised about their safety.^9,10 On July 3, 2023, a series of reports for suicidal or self-harming thoughts associated with liraglutide or semaglutide triggered an ongoing review by the European Medicines Agency (EMA).¹¹ Previously, in the approval trials, 9 of the 3384 patients treated with liraglutide (0.27%) had reported suicidal ideation compared with 2 of 1941 patients allocated to the placebo group (0.10%).¹² On the other hand, no patients using semaglutide for obesity had developed suicidal ideation,^13,14 and no mental health differences were observed in adolescents, with a lower percentage of participants in the semaglutide group than in the placebo group reporting psychiatric adverse events (7% vs 15%).¹⁵

Introduction: This article comprehensively reviews the clinical utility of the serum clozapine/norclozapine (CLO/NCLO) ratio. Areas covered: Fifty-four published studies used this ratio (21 from a PubMed search from onset to 10/21/18 and 33 identified by the authors). To estimate a combined mean of the CLO/NCLO ratio in published studies, a PubMed search on 10/21/18 identified 422 articles leading to 19 included. The systematic review focused on: 1) the combined analysis, 2) CYP1A2 activity, 3) clinical response, 4) cognition, and 5) renal function. Expert opinion: Our combined analysis provided a weighted mean CLO/NCLO ratio of 1.73 in 2,317 adult patients from 19 studies but the range in the studies varied widely from 1.19 to 3.37. No study provided data on variability of the CLO/NCLO ratios within individual patients. The CLO/NCLO ratio is not a measure of CYP1A2 activity and is not associated with clinical response. The association of the CLO/NCLO ratio with cognitive measures is unclear (4 cross-sectional studies were positive and post-hoc analysis of a randomized clinical trial was negative). Future studies must replicate the finding of a case report that gemfibrozil may invert the CLO/NCLO ratio (making it <1), indicating that gemfibrozil inhibit the renal transporter that excretes NCLO.