Patterns of psychotropic drug use in veterans with epilepsy: Do drug interactions matter?

RATIONALE: Patients with epilepsy are likely to suffer from psychiatric comorbidities, including depression and anxiety. They often require treatment with multiple psychotropic drugs (PDs). While it is clear that CYP-inducing ASMs (EIASMs) can increase the oral clearance of multiple medications (thus lowering systemic exposure), it is less clear that all PK interactions are clinically meaningful (e.g. lower efficacy). As a first step in addressing this issue, this study sought to quantify the potential impact of ASM choice, whether EIASM or non-inducer (NIASM), on surrogate markers of suggestive of clinical use, including resultant antidepressant (AD) or antipsychotic (AP) dose, frequency of combination use of AD & AP, and number of multiple drug switches of PDs. Our hypothesis is that because of PK interactions, EIAED treatment would be associated with higher psychotropic drug doses, more frequent Rx adjustments and poly psychotropic comedication, all in order to optimize therapeutic response. METHODS: Using VA pharmacy and national encounter databases, veterans with epilepsy were identified based on having a seizure diagnosis and being prescribed concomitantly an ASM and a psychotropic drug for at least 365 days between 10/1/2010 and 9/30/2014. Patients for whom psychotropic drugs were prescribed any time between beginning and end prescriptions dates of ASMs were considered. Among those, patients receiving both an EIASM + NEIASM concomitantly were categorized with the EIASM group. Patients were evaluated for AD only, AP only and both (AD & AP). To compute average drug doses per day, averages for each patient were computed and averaged again. Multiple drug switches were defined to be for patients who had been prescribed more than three psychotropic drugs during the observation period. Pearson's Chi-Square test was used to compare relative proportions of AD, AP and AD + AP in both groups. RESULTS: In all, 16,188 patients were identified (57.0% on EIASM, 43.0% on NIASM) with a mean age of 58.7 years (91.2% male). A larger proportion of patients on EIASM received mono treatment with any psychotropic drug, as compared to NIASM (42.0% vs 36.1%). Among all, 59.6% received AD only, 6.5% received AP only, and 33.8% received both concurrently. Of EIASM, 62.5% were on AD, 5.9% on AP, and 31.7% on both AP & AD. For NIASM, 55.9% received AD, 7.4% AP, and 36.7% on AD & AP.Chi-square showed that the distribution of PD was statistically different between EIASM and NIASM groups. Z tests showed that each difference (AD, AP and both) in proportions was statistically significant (p values (4 tests, one Chi-square, 3 Z tests <0.001) between EIASM vs NIASM. Interestingly, mean doses of AD or AP did not appear to differ between ASM groups. CONCLUSIONS: Concurrent psychotropic drug use is quite common in the VA population with epilepsy, and a large number of patients still receive enzyme-inducing ASMs that may complicate other medical therapies. Interestingly, in seeming contradiction to our hypothesis, mean daily doses of either AD or AP did not appear to differ between inducers vs non-inducers. Similarly, use of polytherapy, and/or multiple trials of various psychotropic drugs did not appear increased in the CYP-induced group. In fact, combination therapy of AD + AP was higher in NIASM than EIASM. These data suggest that perhaps these types of PK interactions may not in fact result in meaningful clinical differences. Since the present analyses did not include clinical psychiatric measures, future analyses examining direct clinical outcomes are clearly warranted.

Impact of Clinical Pharmacists on Access to Care in an Epilepsy Clinic.

Background: Epilepsy affects about 1% of the world population and is one of the most burdensome diseases in terms of disability-adjusted life-years. The demand for neurologists and epileptologists is expected to exceed current supply by 2025. One potential strategy to increase access to epilepsy care is to utilize clinical pharmacist practitioners (CPPs) with a broad scope of practice. Methods: Appointments at the William S. Middleton Memorial Veterans Hospital (WSMVH) epilepsy clinic in Madison, Wisconsin, were reviewed to determine the percentage of appointments completed by a CPP or clinical pharmacy resident from October 2019 to May 2021. Additionally, a retrospective chart review was completed on 446 veterans to identify the types of interventions made by a CPP or clinical pharmacy resident at each appointment from October 2017 to June 2021. Results: The CPP or clinical pharmacy resident held approximately 43% of 591 total appointments and spent a mean 27 minutes with each patient. Medication interventions occurred at 27% of 446 appointments in the retrospective chart review. Half (50.4%) of all patients seen by a CPP completed at least 1 mental health screening. Conclusion: The integration of a CPP WSMVH epilepsy clinic allowed for greater and more timely access to care and allowed for the epileptologists to focus their time on new consults, Epilepsy Monitoring Unit admissions, and higher acuity cases.

Levetiracetam-associated irritability and potential role of vitamin B6 use in veterans with epilepsy.

OBJECTIVES: Levetiracetam, a commonly prescribed antiseizure medication (ASM), may cause irritability, depression, and anger. The mechanisms underlying these behavioral effects and individual risk factors remain unknown. Mitigation strategies are limited, including discontinuation, supplementation with vitamin B6, or switching to an alternative ASM. Several retrospective studies and anecdotal reports, primarily in pediatric populations, suggest vitamin B6 supplementation may be helpful in reducing levetiracetam-associated irritability. Although data in adult patients is limited, and no data is available for Veterans. The objective of this project was to describe our preliminarily experience with vitamin B6 supplementation for alleviating levetiracetam-associated irritability in male Veterans with epilepsy. METHODS: Retrospective chart reviews were completed for patients who had an active prescription for levetiracetam from the William S. Middleton Memorial Veterans Hospital from January 1, 2015 to June 1, 2020. A total of 26 charts were screened. Patients were excluded if not using vitamin B6 supplementation or if deceased at end of data collection. Baseline characteristics were compared, including age, sex, comorbidities, and concomitant medications. Charts were then reviewed to identify any clinical description of irritability, including subjective assessment of change in symptoms across multiple visits, and scores from standardized instruments including the patient health questionnaire (PHQ-9), generalized anxiety disorder questionnaire (GAD-7), and/or irritability in adult patients with epilepsy (I-EPI) questionnaire. These symptoms and scores were then compared pre- and post-B6 supplementation. RESULTS: Of 22 patients, data was available for 20 (91%). For patients with data available, 9 (45%) showed improved irritability following supplementation with vitamin B6 and 11 (55%) showed no improvement. CONCLUSIONS: This project suggests that vitamin B6 supplementation may have a role in mitigating levetiracetam-associated irritability in a male Veteran population. These results support future prospective controlled studies to assess further the efficacy of this approach and characteristics associated with successful treatment in veterans.

Using Patient-Centered Clinical Neuroscience to Deliver the Diagnosis of Functional Neurological Disorder (FND): Results from an Innovative Educational Workshop.

OBJECTIVES: Psychiatry training is lacking examples of neuroscience education that translates neuroscience literature into accessible clinically oriented concepts. The authors created a teaching activity using patient-centered neuroscience education that focused on delivering the diagnosis of functional neurological disorder (FND). This study aimed to (i) develop a workshop modeling a clinician-patient interaction, (ii) provide a modern neuroscience perspective of FND, and (iii) evaluate the change in clinicians' perceptions of FND. METHODS: A total of six workshops (each 1 h long and consisting of a video, PowerPoint slides, and pre and post questionnaires) were conducted. Paired t tests were used to measure the change. RESULTS: Forty-seven clinicians participated. After completing the workshop, nearly all endorsed that functional symptoms are "real" (95%) and that treatment is helpful (100%). Participants also reported a greater comfort level with discussing FND diagnosis (46% vs 85%, p < 0.001), an overall increase in understanding the disorder (33% vs 82%, p < 0.001), assessing need for tests (33% vs 66%, p < 0.001), understanding treatment options (26% vs 89%, p < 0.001), and recognition that treatment can help control these symptoms (81% vs 100%, p < 0.01). In addition, learners were more likely to report that patients with FND are truthful (75% vs 95%, p < 0.001) and less likely to be manipulative (48% vs 80%, p < 0.001). CONCLUSIONS: A brief, educational intervention using neuroscience-based content was found to significantly improve clinicians' perception and confidence when delivering the diagnosis of FND.

Alcohol and the law.

Society has had an interest in controlling the production, distribution, and use of alcohol for millennia. The use of alcohol has always had consequences, be they positive or negative, and the role of government in the regulation of alcohol is now universal. This is accomplished at several levels, first through controls on production, importation, distribution, and use of alcoholic beverages, and second, through criminal laws, the aim of which is to address the behavior of users themselves. A number of interventions and policies reduce alcohol-related consequences to society by regulating alcohol pricing, targeting alcohol-impaired driving, and limiting alcohol availability. The legal system defines criminal responsibility in the context of alcohol use, as an enormous percentage of violent crime and motor death is associated with alcohol intoxication. In recent years, recovery-oriented policies have aimed to expand social supports for recovery and to improve access to treatment for substance use disorders within the criminal justice system. The Affordable Care Act, also know as "ObamaCare," made substantial changes to access to substance abuse treatment by mandating that health insurance include services for substance use disorders comparable to coverage for medical and surgical treatments. Rather than a simplified "war on drugs" approach, there appears to be an increasing emphasis on evidence-based policy development that approaches alcohol use disorders with hope for treatment and prevention. This chapter focuses on alcohol and the law in the United States.

High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny.

Decades ago, the "immortal strand hypothesis" was proposed as a means by which stem cells might limit acquiring mutations that could give rise to cancer, while continuing to proliferate for the life of an organism. Originally based on observations in embryonic cells, and later studied in terms of stem cell self-renewal, this hypothesis has remained largely unaccepted because of few additional reports, the rarity of the cells displaying template strand segregation, and alternative interpretations of experiments involving single labels or different types of labels to follow template strands. Using sequential pulses of halogenated thymidine analogs (bromodeoxyuridine [BrdU], chlorodeoxyuridine [CldU], and iododeoxyuridine [IdU]), and analyzing stem cell progeny during induced regeneration in vivo, we observed extraordinarily high frequencies of segregation of older and younger template strands during a period of proliferative expansion of muscle stem cells. Furthermore, template strand co-segregation was strongly associated with asymmetric cell divisions yielding daughters with divergent fates. Daughter cells inheriting the older templates retained the more immature phenotype, whereas daughters inheriting the newer templates acquired a more differentiated phenotype. These data provide compelling evidence of template strand co-segregation based on template age and associated with cell fate determination, suggest that template strand age is monitored during stem cell lineage progression, and raise important caveats for the interpretation of label-retaining cells.

Bradyzoite-specific surface antigen SRS9 plays a role in maintaining Toxoplasma gondii persistence in the brain and in host control of parasite replication in the intestine.

Toxoplasma gondii is a ubiquitous parasite that persists for the life of a healthy mammalian host. A latent, chronic infection can reactivate upon immunosuppression and cause life-threatening diseases, such as encephalitis. A key to the pathogenesis is the parasite's interconversion between the tachyzoite (in acute infection) and bradyzoite (in chronic infection) stages. This developmental switch is marked by differential expression of numerous, closely related surface proteins belonging to the SRS (SAG1-related sequence) superfamily. To probe the functions of bradyzoite-specific SRSs, we created a bioluminescent strain lacking the expression of SRS9, one of the most abundant SRSs of the bradyzoite stage. Imaging of mice intraperitoneally infected with tachyzoites revealed that during an acute infection, wild-type and Deltasrs9 strains replicated at similar rates, disseminated systemically following similar kinetics, and initially yielded similar brain cyst numbers. However, during a chronic infection, Deltasrs9 cyst loads substantially decreased compared to those of the wild type, suggesting that SRS9 plays a role in maintaining parasite persistence in the brain. In oral infection with bradyzoite cysts, the Deltasrs9 strain showed oral infectivity and dissemination patterns indistinguishable from those of the wild type. When chronically infected mice were treated with the immunosuppressant dexamethasone, however, the Deltasrs9 strain reactivated in the intestinal tissue after only 8 to 9 days, versus 2 weeks for the wild-type strain. Thus, SRS9 appears to play an important role in both persistence in the brain and reactivation in the intestine. Possible mechanisms for this are discussed.

Identification and disruption of a rhoptry-localized homologue of sodium hydrogen exchangers in Toxoplasma gondii.

Na+/H+ exchangers (NHEs) are ubiquitous membrane proteins that catalyze the exchange of Na+ for H+ and are critical in pH and cell volume regulation, as well as osmotolerance. In this study, we identify and characterize a novel NHE, TgNHE2, in Toxoplasma gondii. Immunofluorescence studies show that TgNHE2 is localized to the rhoptries, secretory organelles involved in invasion. TgNHE2 is the first intracellular NHE to be characterized in a protozoan parasite and its localization suggests possible roles for the rhoptries in osmotolerance and/or as secretory lysosomes-like granules.