The occurrence of mental health symptoms in isotretinoin-treated adolescents.

BACKGROUND: Isotretinoin treatment for acne can reduce adverse psychiatric outcomes in adults, but there has been little investigation of the incidence of psychiatric outcomes in treated adolescents. METHODS: This retrospective cohort study using the Rochester Epidemiology Project identified 606 patients aged 12-18 prescribed isotretinoin over a 10-year period between January 1, 2008 and December 31, 2017. Medical records were reviewed to identify psychiatric diagnoses before and during isotretinoin therapy, as well as psychiatric symptoms not captured by formal diagnoses and changes to isotretinoin dosing because of psychiatric diagnoses or symptoms. RESULTS: One hundred seventy-seven (29.2%) had a psychiatric diagnosis prior to isotretinoin initiation, but 98 (16.2%) had a new psychiatric diagnosis or psychiatric symptom while taking isotretinoin. Patients with a psychiatric history were no more likely than those without to receive a new psychiatric diagnosis during treatment (4.5% vs. 3.7%; p = .650), but did experience more psychiatric symptoms, primarily low mood and mood swings (23.7% vs. 7.7%; p < .001). Only 25.5% of the 98 with a new psychiatric diagnosis or psychiatric symptom had a subsequent dose change. A dose change was more likely if patients received a new psychiatric diagnosis (41.7% vs. 20.3%; p = .037) or patients did not have a psychosocial explanation for psychiatric symptoms (34.4% vs. 10.8%; p = .009). CONCLUSIONS: A substantial proportion of adolescent patients prescribed isotretinoin had a prior psychiatric diagnosis. This predicts more psychiatric symptoms during isotretinoin treatment. Adolescents with a psychiatric history who have worsening symptoms and those with new-onset psychiatric symptoms would benefit from close monitoring while taking isotretinoin.

Striving for health equity: Stigmatizing language in inpatient pharmacy notes - A pilot study.

BACKGROUND: As pharmacy evolves, pharmacists have an increasing role in documentation. Publications examining the actions of other health professionals show that negative perception in written notes translates to patients receiving lower quality of care, resulting in worse health outcomes, suggesting that the use of stigmatizing language towards patients has concerning consequences. OBJECTIVES: To identify the prevalence of stigmatizing language in inpatient pharmacy progress. notes based on patient specific characteristics and diagnoses. METHODS: This retrospective pilot study reviewed inpatient pharmacy progress notes of a Midwestern (United States) tertiary academic institution from May to June 2023. Stigmatizing words and phrases associated with specified disease states were separated into the categories of general language, substance use disorders, and mental health. Notes of patients on internal medicine, family medicine, kidney/pancreas transplant, liver transplant, and gastroenterology services were included. RESULTS: Stigmatizing language was found in 22% (n = 43) of notes. The words "abuse" and "dependence" had the highest prevalence. Patients diagnosed with substance use disorders experienced stigmatizing language at a high rate, exaggerated further if their note lacked a documented diagnosis. CONCLUSIONS: This study demonstrated that stigmatizing language is present in pharmacy documentation. Providing context and resources of the proper documentation to reflect equitable healthcare is crucial for patient care.

Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder.

There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder (BD) with oftentimes, an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in BD. We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association in a subset of BD-type I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic depressed cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement from response to emergent mania.

Ethnopsychopharmacology: Clinical and scientific writing pearls.

The concept of ethnopsychopharmacology aims to predict or explain the pharmacologic response to psychiatric medications based on the influence of biologic and nonbiologic factors. Interactions involving these factors are complex and influence patient outcomes in health care. Pharmacists and other clinicians working in patient care environments, research, or medical education should engage in lifelong learning to enhance ethnopsychopharmacologic knowledge gaps, which ultimately may improve and individualize care across diverse populations. Through two cases, this paper provides pearls on how biogeographical ancestry and cytochrome P450 status may influence pharmacotherapy selection, dosing, or response. A third scenario highlights a publication, like many other published works, with deficiencies in how data on ancestry, race, and ethnicity are collected or reported. Current recommendations on the use of inclusive language in scientific writing are reviewed, with attention to specific examples.

Impact of sex on antidepressant discontinuation in groups of similar cytochrome P450 phenotypes.

Introduction: Although there are studies assessing reasons for antidepressant discontinuation, little is known about the impact of sex differences or cytochrome P450 phenotypes. Our objective is to assess discontinuation rates between males and females and whether CYP450 phenotype influences discontinuation. Methods: This is a retrospective review of patients previously enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment database with major depressive disorder. Patients were evaluated for antidepressants trialed between January 1, 2009, and September 30, 2019. Survival analyses with competing risks were used to analyze discontinuation reasons. A Kaplan-Meier estimation method was used to assess the time to discontinuation and discontinuation rates. Analyses were also completed to assess discontinuation between men and women by phenotypic groups. All tests were two-sided, and p-values ≤ .05 were considered statistically significant. Results: There were 620 antidepressant discontinuation events discovered from 1015 antidepressant trials included. Overall, the median time to discontinuation for males was 2.6 years and 1.9 years for females (hazard ratio [HR] 0.97 [95% confidence interval (CI): 0.80, 1.19], p = .77). The risk of discontinuation was not different between males and females in any of the phenotype groups, which was consistent in the multivariable analyses. Concomitant use of medications that inhibited or induced antidepressant metabolism increased the overall risk of discontinuation (HR 1.45, 95% CI [1.06, 1.99], p = .020) in a time-dependent analysis. Discussion: We did not detect a significant difference in risk of antidepressant discontinuation rates between males and females even when accounting for cytochrome P450 phenotype. Future studies should account for whether medications that inhibit or induce antidepressant metabolism may be a crucial factor in antidepressant discontinuation.

A systematic review of clozapine-associated inflammation and related monitoring.

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.

Antidepressant-Associated Treatment Emergent Mania: A Meta-Analysis to Guide Risk Modeling Pharmacogenomic Targets of Potential Clinical Value.

BACKGROUND: The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression. METHODS: Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model. RESULTS: Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters. CONCLUSION: Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.

Trends in Stimulant and Sedative/Hypnotic Dispensing: An Exploratory Study.

OBJECTIVE: To investigate patterns and trends of co-prescriptions of stimulants and sedatives within the last 6 years at a tertiary care center. METHOD: Patients 18 years of age and older who were dispensed at least one stimulant prescription from an institutional pharmacy between 1/1/2015 and 7/1/2021 were included. Prescription data for any co-prescribed sedative/hypnotic were collected. RESULTS: Both the number of stimulant dispenses and the number of patients with stimulant dispenses increased significantly with yearly incidence rate ratios of 1.115 (95% CI [1.110, 1.119]) and 1.090 (95% CI [1.084, 1.096]), respectively. The number of patients with a stimulant dispensed who also had a benzodiazepine or "Z-drug" sedative-hypnotic dispensed at any point in the search timeframe increased significantly with incidence rate ratios of 1.077 and 1.092, respectively. The number of stimulant dispenses, number of patients with stimulant dispenses, and number of patients with a stimulant dispensed who also had both a benzodiazepine and Z-drug dispensed at any point in the search timeframe increased significantly more in Non-White than in White patients. CONCLUSIONS: The results confirm previous findings of increases in dispensing of stimulants over the past 6 years and report increased polypharmacy of stimulants and sedative-hypnotics.

Use of Gabapentin for Alcohol Withdrawal Syndrome in the Hospital Setting: A Randomized Open-Label Controlled Trial.

Background/objectives: Patients hospitalized with alcohol withdrawal syndrome (AWS) are typically treated with CIWA-directed benzodiazepines to prevent complications, such as seizures and delirium tremens. Gabapentin is an evidence-based alternative to benzodiazepines in the outpatient setting, but there is limited data for hospitalized patients with AWS. This study compared fixed-dose gabapentin to CIWA-directed benzodiazepines for AWS in the hospital setting. Methods: This open-label, randomized controlled trial enrolled 88 adults from February 1, 2017 to August 16, 2020 with a risk of complicated alcohol withdrawal as defined by the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) ≥4. Patients were randomized within 16 h of admission to either fixed-dose gabapentin taper or continued CIWA-directed benzodiazepine administration. The primary outcome was the length of stay (LOS). Secondary outcomes included seizure, delirium tremens, ICU transfer, and patient-reported symptoms (alcohol cravings, anxiety, sleepiness). Results: LOS was shorter, but not statistically different in the gabapentin group compared to the benzodiazepine group. Because benzodiazepines were received in both gabapentin and benzodiazepine groups before randomization, the mean amount of benzodiazepines received in each group was also not statistically different, although the amount received by the gabapentin group was less than half of that received by the benzodiazepine group (4.3 vs. 10.6 mg, p = 0.146 by per protocol analysis). There were no statistical differences in secondary measures. Conclusions: Fixed-dose gabapentin taper showed similar outcomes compared to CIWA-directed benzodiazepines for the treatment of hospitalized patients with mild/moderate AWS, but the interpretation of the results is limited due to under-enrollment and the use of benzodiazepines in both groups pre-enrollment.Clinical trial registration: NCT03012815.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

The Modernization of Clozapine: A Recapitulation of the Past in the United States and the View Forward.

PURPOSE: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US). METHODS: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed. FINDINGS: The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available. IMPLICATIONS: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US.

Iatrogenic clozapine intoxication after hospital admission: A case-based rationale for an inpatient pharmacy clozapine monitoring service.

BACKGROUND: Clozapine must be retitrated after 2 consecutive days or more of missed doses owing to the risk of severe hypotension, bradycardia, and cardiac arrest. However, other important adverse events such as somnolence, sialorrhea, or respiratory depression can occur without severe cardiovascular sequalae. These other unintended consequences are not well characterized in the literature. Three cases are reported, highlighting the concerns for continuing clozapine without retitration after periods of not taking the medication. Implications are discussed as well as how pharmacists can collaborate with other disciplines to mitigate safety risks associated with clozapine for hospitalized patients. CASE SUMMARIES: The first case highlights the importance of medication reconciliation and verifying adherence before clozapine continuation in the hospital. Waiting for collateral information and missing one dose are safer than unknowingly resuming clozapine. The second case suggests that it may be safer to consider patients with unexplained worsening psychiatric symptoms as nonadherent and even partially reduced clozapine doses after nonadherence may be unsafe. The final case demonstrates the importance assessing comedications (e.g., warfarin, phenytoin) that have available therapeutic drug monitoring to suggest nonadherence. Each case resulted in significant adverse events requiring transfer to a higher level of care or prolonged hospitalization. PRACTICE IMPLICATIONS: Continuation of psychiatric medications when a patient is admitted to the hospital is important to prevent worsening of symptoms. However, assessment of clozapine adherence and confidence in that assessment is crucial to prevent clozapine intoxication, severe hypotension, and even death. Pharmacists are uniquely positioned to assess clozapine adherence and ensure patient safety. A hospital-based service was created at a 2000-bed academic medical center to improve transitions of care when patients are admitted with clozapine. The process was created in collaboration with the psychiatric consultation service. Through this process, pharmacists also complete appropriate hematologic monitoring and ongoing clinical monitoring for adverse events.

Assessing Naltrexone Prescribing and Barriers to Initiation for Alcohol Use Disorder: A Multidisciplinary, Multisite Survey.

Objective: To survey barriers in prescribing naltrexone for alcohol use disorder. Methods: A 12-question survey related to naltrexone prescribing patterns, perceptions, and knowledge was sent to 770 prescribers in the departments of internal medicine, family medicine, and psychiatry across a health system with sites in Arizona, Florida, and Minnesota. Results: Responses were obtained and included for 146/770 prescribers (19.0% response rate). Most respondents were in the department of internal medicine (n = 94, 64.4%), but the departments of psychiatry (n = 22, 15.1%) and family medicine (n = 30, 20.5%) were also represented. Only 34 (23.3%) respondents indicated they had prescribed naltrexone in the previous 3 months. The most common reasons for not prescribing naltrexone were "unfamiliarity with naltrexone for treatment of alcohol use disorder" and "patients do not have appropriate follow-up or are not in a formal treatment program." Compared with those representing internal/family medicine, psychiatry respondents were more likely to prescribe naltrexone and answer knowledge questions correctly. Conclusion: In this survey among primarily non-addiction-trained prescribers, a disparity was shown for prescribing naltrexone and in knowledge barriers between staff in internal/family medicine and psychiatry. There exist opportunities for education and quality improvement that promote the prescribing of naltrexone for alcohol use disorder by non-addiction specialists.

Delayed Signs and Symptoms of Extended Release Guanfacine Overdose in Two Adolescent Patients: Implications of Monitoring on the Psychiatry Unit.

Guanfacine is a selective alpha-2a adrenoreceptor agonist that with overdose can cause symptoms ranging from mild sedation to coma, respiratory depression, hyporeflexia, hypotonia, bradycardia, and hypotension. Despite a well-defined and predictable toxidrome, variations can be seen based on multiple factors including age, quantity ingested, organ functions, coingestions, time since ingestion, and specific dosage form. Here, we describe two cases of delayed presentation of extended release guanfacine toxicity and highlight the variations encountered in the toxidrome presentation. These cases bring to attention the importance of maintaining a high suspicion for such atypical presentations, keeping in mind the limitations of managing these complications on an inpatient psychiatric unit.

Medications and Patient Factors Associated With Increased Readmission for Alcohol-Related Diagnoses.

OBJECTIVE: To investigate medication factors and patient characteristics associated with readmissions following alcohol-related hospitalizations. PATIENTS AND METHODS: Adult patients admitted from September 1, 2016, through August 31, 2019, who had an alcohol-related hospitalization were identified through electronic health records. Patient characteristics and medications of interest administered during hospitalization or prescribed at discharge were identified. Medications of interest included US Food and Drug Administration-approved medications for alcohol use disorder, benzodiazepines, barbiturates, gabapentin, opioids, and muscle relaxants. The primary outcome was to identify medications and patient factors associated with 30-day alcohol-related readmission. Secondary outcomes included medications and patient characteristics associated with multiple alcohol-related readmissions within a year from the index admission (ie, two or more readmissions) and factors associated with 30-day all-cause readmission. RESULTS: Characteristics of the 932 patients included in this study associated with a 30-day alcohol-related readmission included younger age, severity of alcohol withdrawal, history of psychiatric disorder, marital status, and the number of prior alcohol-related admission in the previous year. Benzodiazepine or barbiturate use during hospitalization or upon discharge was associated with 30-day alcohol-related readmission (P=.006). Gabapentin administration during hospitalization or upon discharge was not associated with 30-day alcohol-related readmission (P=.079). CONCLUSION: The findings reinforce current literature identifying patient-specific factors associated with 30-day readmissions. Gabapentin use was not associated with readmissions; however, there was an association with benzodiazepine/barbiturate use.