Markota, Matej

Abstract Introduction Clozapine-induced constipation may occur in at least 60% of patients, with first-line options typically involving polyethylene glycol or sennosides. However, there may be adherence barriers to an over-the-counter bowel regimen due to the dosage form, lack of insurance coverage, or lack of benefit. One possible solution to address these adherence barriers may include prescribing a secretagogue laxative. However, there is limited literature supporting the use of secretagogue laxatives in clozapine-associated constipation. A case series is presented in which adherence barriers impeded the use of over-the-counter laxatives, and a secretagogue laxative was implemented to manage clozapine-induced constipation. Case Report In 4 cases, lubiprostone or linaclotide was initiated, either as monotherapy or in combination with over-the-counter laxatives. Reasons for secretagogue laxative initiation included: (1) reducing a complex over-the-counter laxative regimen, (2) a lack of insurance coverage of over-the-counter laxatives, (3) dissatisfaction with polyethylene glycol’s palatability, and (4) cognitive impairment leading to decreased adherence to polyethylene glycol. Discussion It is important that clozapine-induced constipation is managed adequately to prevent severe consequences of gastrointestinal hypomotility. In addition to timely initiation and titration of constipation pharmacotherapy, adherence should be assessed. When adherence barriers to the use of over-the-counter laxatives are present, the use of a secretagogue laxative may be an option, recognizing there is limited evidence to guide this decision. Conclusion In these cases, adherence barriers to over-the-counter laxatives were identified. A secretagogue laxative was implemented, well-tolerated, and able to be continued for the duration of follow-up.

Few pharmacologic options exist for patients with clozapine-resistant schizophrenia (CRS) or schizoaffective disorder. Xanomeline/trospium represents a new class of antipsychotic medication that has efficacy as monotherapy for schizophrenia. Despite distinct mechanistic differences from standard antipsychotics, phase III evidence suggest limited benefit of xanomeline/trospium in the augmentation of non-clozapine antipsychotics. Research on the use of xanomeline/trospium in patients with clozapine-resistant illness or with partial response to clozapine is even more limited. Two cases of this combination are described with a discussion on key considerations for the management of CRS. The first case is a 42-year-old patient whose clozapine dose was limited by supratherapeutic clozapine levels in response to minor infections. She was ultimately stabilized on a combination of clozapine and xanomeline/trospium, with yet further improvements from electroconvulsive therapy (ECT). The second case is a 31-year-old patient who elected to discontinue clozapine and ECT due to cognitive side effects, despite improvement in psychosis. The addition of xanomeline/trospium to clozapine caused sialorrhea and did not produce observable clinical benefits and was thus discontinued. These case reports describe clozapine-resistant patients who were trialed on xanomeline/trospium combined with clozapine and still required consideration of ECT for symptom control. Overall, future investigation into xanomeline/trospium effectiveness as an augmentation agent or as monotherapy for CRS is necessary to guide clinical decision-making.

Background: Clozapine is the preferred medication for treatment-resistant schizophrenia with therapeutic drug monitoring (TDM) suggested to mediate its safe and effective use. However, clozapine TDM is not a ubiquitous element of care in clinical practice. Understanding the current state of clinicians' perceptions of and barriers to clozapine TDM is a crucial step in improving its use. Methods: A survey related to the use, perceptions, and barriers of clozapine TDM was distributed across multiple national organizations in the United States, representing several disciplines. Results: Most of the 190 respondents were consultants or attending physicians (42.5%) or pharmacists (52.3%). Nearly 80% of respondents had ordered clozapine level measurements in the year before completing the survey but identified slow turnaround time (TaT) as an important barrier; 73.5% of respondents noted that level measurements were performed at an offsite laboratory. Although 86.8% agreed that clozapine levels should be checked once an initial target dose was reached, less than half would subsequently order clozapine level measurements routinely, unless clinical factors such as nonadherence (96.5% agreement), new interaction (94.5% agreement), or change in smoking status (94.5% agreement) occurred. More pharmacists than prescribers indicated confidence in interpreting and clinically applying clozapine TDM results (84.6% versus 70.1%, P = 0.024), with a similar finding between the groups regarding faster clozapine TDM TaT, resulting in improved patient safety (89.0% versus 68.7% agreement, P = 0.003). In addition, more pharmacists would also conduct clozapine TDM in the setting of an acute inflammatory or infectious process (84.9% versus 61.2%, P = 0.002). Conclusions: These data provide insights into clozapine TDM perception, availability, TaT, and barriers. Further research is required to assess whether a faster TaT and more frequent clozapine TDM positively influence patient outcomes from a safety and effectiveness perspective.

Background: Lithium is a mainstay treatment for bipolar disorder, but its narrow therapeutic index and susceptibility to pharmacokinetic interactions make appropriate monitoring crucial. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are increasingly prescribed for type 2 diabetes and weight management. Scarce evidence exists on the potential interaction between semaglutide and lithium. Methods: We present 3 cases involving patients on stable lithium regimens who were initiated on semaglutide, reviewing potential mechanisms underlying the interaction between them. Findings: In 2 cases, lithium levels increased significantly, leading to toxicity despite stable renal function and no changes in concurrent medications. In the third case, preemptive reductions in lithium dosage mitigated toxicity, although lithium levels remained higher than anticipated. Mechanistic hypotheses that might contribute to semaglutide-associated elevated lithium levels include altered kidney function, dehydration from reduced oral intake, vomiting, or diarrhea, and delayed gastric emptying. Conclusions: To our knowledge, this is one of the first documented case series describing a potential interaction between semaglutide and lithium in the medical literature. These cases underscore the importance of vigilant monitoring when combining lithium with semaglutide, and potentially other GLP-1 RAs. Baseline renal function, hydration status, and lithium levels should be assessed before initiating semaglutide, and lithium levels should be monitored more frequently during therapy. Clinicians prescribing semaglutide to patients on lithium should exercise caution, monitor for signs of toxicity, and provide appropriate patient education. Further research is needed to elucidate the mechanisms of this potential interaction and its clinical significance.

Abstract Purpose/Background Clozapine requires careful monitoring to minimize adverse reactions and optimize response. Because of variable pharmacokinetics and interpatient variability, guidelines recommend therapeutic drug monitoring (TDM), although practical guidance is limited. This study aims to characterize patient factors associated with TDM, rates of TDM use over time, turnaround times of TDM results, and influence of institutional initiatives aimed to improve TDM. Methods/Procedures A retrospective chart review was conducted at a large 2000-bed academic medical center from August 1, 2015, to November 26, 2023. Adult patients who were administered clozapine during medical or psychiatric inpatient hospitalizations were included. Data collected included patient demographics, clozapine TDM ordering, and clozapine TDM turnaround time. Yearly TDM rates were analyzed to evaluate the impact of various institutional clozapine-related initiatives on TDM practices. Results There were 679 encounters involving 334 patients; 62.7 % were men, and 84.4% were White. Younger patients were less likely to have levels drawn (odds ratio 0.98, confidence interval 0.97–0.99), while self-identified Asian patients more likely (odds ratio 7.54, confidence interval 1.60–35.42). TDM rates increased significantly over time for both medical ( P = 0.002) and psychiatric ( P < 0.001) admission types, with turnaround times improving from 66.07 hours in 2016 to 28.65 hours in 2022. Overall, TDM annual rates increased from 46.2% in 2015 to 69.6% in 2023. The time-period before and after an institutional initiative, which improved TDM turnaround time, was associated with improvements of TDM rates (36.2% vs 67.9%, P < 0.001) Conclusions This study highlights an increase in clozapine TDM use during the study period, but use remained suboptimal. Improvement of turnaround time was associated with increased TDM rates.

Abstract Background Clozapine is effective for treatment-resistant schizophrenia and bipolar disorder but is often discontinued due to adverse effects. This study compared early clozapine discontinuation rates and reasons in patients with mood and psychotic disorders. Methods Data from all individuals with mood or psychotic disorders who initiated clozapine for the first time at the inpatient psychiatric unit of Mayo Clinic, Rochester, Minnesota, between 2014 and 2022 were retrospectively analyzed. Early clozapine discontinuation, defined as discontinuation within 90 days of initiation, was the primary outcome. Cox proportional hazards regression was used to assess factors associated with discontinuation. Results Of 83 patients (mood group n = 37, psychosis group n = 46), those in the mood group were older (P = 0.022) and more likely to be nonsmokers (P = 0.034). The overall 90-day clozapine discontinuation rate was 45.7%. Early discontinuation was significantly higher in the mood group than in the psychosis group (hazard ratio = 2.41, 95% confidence interval = 1.26–4.64, P = 0.008). Other factors associated with early discontinuation were female sex (P = 0.033), older age (P = 0.026), and nonsmoking (P = 0.001). In multivariable analysis, smoking status was the only factor significantly inversely associated with early clozapine discontinuation (hazard ratio = 0.47, 95% confidence interval = 0.22–0.99, P = 0.048), while diagnostic group, sex, and age did not show significant associations (all P > 0.05). Discontinuations were primarily due to adverse drug reactions in both groups. Conclusions Nearly half of the patients discontinued clozapine early, with higher rates in the mood group. Studies should further explore potential pharmacodynamic and pharmacokinetic factors associated with discontinuation, including the influence of smoking. Careful monitoring and personalized management of side effects are crucial for optimizing clozapine therapy and improving treatment outcomes.

Abstract Clozapine is an effective antipsychotic medication used for treatment‐resistant schizophrenia. However, it is underutilized due to rigorous hematologic monitoring requirements and many adverse drug reactions. Publications have highlighted the occurrence of inflammatory reactions, some life‐threatening, particularly during the early stages of clozapine treatment. Although guidelines have suggested monitoring for inflammatory processes during clozapine initiation, screening in clinical practice is not universal. This systematic review aimed to investigate the relationship between clozapine and inflammation and assess the importance of monitoring for inflammatory reactions. A comprehensive literature search yielded 6915 unique publication records after removal of duplicates. After a rigorous screening process, 75 publications were included in the review, which focused on three main aspects: (i) the impact of clozapine on inflammatory markers, (ii) monitoring cardiac and other organ function during clozapine‐associated inflammatory processes, and (iii) monitoring non‐specific signs and symptoms of inflammation. Elevated levels of C‐reactive protein (CRP) and several proinflammatory cytokines have been observed in association with clozapine treatment. However, the practicality of measuring specific markers in clinical practice remains uncertain. Current evidence supports monitoring CRP levels during the first 4–8 weeks of treatment, especially to facilitate myocarditis screening. Further research is needed to establish clinically relevant CRP thresholds for intervention. The implementation of monitoring protocols during the early phase of clozapine treatment may mitigate adverse reactions and allow for continued use of clozapine. Future studies should also explore the association between clozapine‐associated inflammation and pneumonia, as well as investigate the impact of inflammation on clozapine metabolism to predict the need for dose adjustment. These endeavors may facilitate the development and implementation of evidence‐based guidelines for the monitoring of clozapine‐associated inflammation.