Kelly C. Lee

Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons

Summary This study investigated human-induced pluripotent stem cell (hiPSC) -derived neurons for their ability to secrete neurotransmitters in an activity-dependent manner, the fundamental property required for chemical neurotransmission. Cultured hiPSC neurons showed KCl stimulation of activity-dependent secretion of catecholamines—dopamine (DA), norepinephrine (NE), and epinephrine (Epi)—and the peptide neurotransmitters dynorphin and enkephlain. hiPSC neurons express the biosynthetic enzymes for catecholamines and neuropeptides. Because altered neurotransmission contributes to schizophrenia (SZ), we compared SZ to control cultures of hiPSC neurons and found that SZ cases showed elevated levels of secreted DA, NE, and Epi. Consistent with increased catecholamines, the SZ neuronal cultures showed a higher percentage of tyrosine hydroxylase (TH)-positive neurons, the first enzymatic step for catecholamine biosynthesis. These findings show that hiPSC neurons possess the fundamental property of activity-dependent neurotransmitter secretion and can be advantageously utilized to examine regulation of neurotransmitter release related to brain disorders.

Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings.

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.

Pharmacogenomics: bridging the gap between science and practice.

OBJECTIVE To educate pharmacists about principles and concepts in pharmacogenomics, clinical applications of pharmacogenomic information, and the social, ethical, and legal aspects of pharmacogenomics and to describe a Centers for Disease Control and Prevention (CDC)-supported pharmacogenomics education program for pharmacists and other health professionals. DATA SOURCES Primary literature from PubMed, recommendations from the Food and Drug Administration and Evaluation of Genomic Applications in Practice and Prevention Working Group, prescribing information, websites of government agencies and professional organizations, and relevant textbooks. STUDY SELECTION Not applicable. DATA EXTRACTION Not applicable. DATA SYNTHESIS Principles and concepts of pharmacogenomic nomenclature, polymorphism types, and systematic approach to understanding polymorphisms were reviewed. Drug therapy for select therapeutic areas that highlight the applicability of pharmacogenomics are presented, including abacavir, selective serotonin reuptake inhibitors, tamoxifen, and warfarin. Challenges of translating pharmacogenomics into clinical practice included ethical, social, legal, and economic issues. We have developed a pharmacogenomics education program to disseminate evidence-based pharmacogenomics information and provide a resource for health professionals, including pharmacists. CONCLUSION Pharmacists play a critical role in the education of patients and health professionals in the area of pharmacogenomics.

Pharmacotherapy Considerations in Patients with HIV and Psychiatric Disorders: Focus on Antidepressants and Antipsychotics

OBJECTIVE To review the evidence for the efficacy and safety of pharmacologic agents for the treatment of depressive and psychotic disorders in patients with HIV infection and to provide clinical considerations for the treatment of depression and psychosis in these patients. DATA SOURCES PubMed was searched for articles published between 1966 and August 1, 2012, using the search terms antiretrovirals, HIV, AIDS, depression, psychosis, schizophrenia, antidepressant, antipsychotic, and individual drug names (fluoxetine, sertraline, paroxetine, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, bupropion, haloperidol, perphenazine, fluphenazine, aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone). STUDY SELECTION AND DATA EXTRACTION For the purposes of evaluating efficacy data, we limited our selection to randomized placebo-controlled or active comparator–controlled trials for agents that have been used for depression and psychosis in HIV-infected patients. DATA SYNTHESIS We found 11 studies for depression treatment and 1 study for psychosis treatment that met our inclusion and exclusion criteria. Selective serotonin reuptake inhibitors (SSRIs; especially fluoxetine) and tricyclic antidepressants appear to be effective in treating depressive symptoms in patients with HIV infection without affecting immune status. Testosterone, stimulants, and dehydroepiandrosterone may also be effective in subsyndromal depression; however, studies on these agents in general were limited by small sample size. There are limited data for antipsychotics, with the only controlled study found for haloperidol and chlorpromazine used for AIDS delirium. Drug-drug interactions and potentiation of metabolic syndrome are concerns for the combined use of antidepressants and antipsychotics with antiretrovirals. CONCLUSIONS Larger controlled studies are needed to validate the current findings as well as expand knowledge for non-SSRI antidepressants and second-generation antipsychotics for use in HIV-infected patients.

Clinical Application of Pharmacogenomics

The purpose of this review is to discuss the clinical application of pharmacogenomics for select drug therapies (eg, proton pump inhibitors [PPIs], codeine, and carbamazepine) and to highlight limitations and challenges that preclude implementation of pharmacogenomics into clinical practice. Genetic polymorphisms of cytochrome P450 (CYP) enzymes and the presence of the human leukocyte antigen (HLA)-B*1502 allele influence drug disposition and/or response. A portion of PPI pharmacokinetic and pharmacodynamic variability can be explained by CYP2C19 genotype. However, conflicting evidence exists related to Helicobacter pylori cure rates based on CYP2C19 genotype. For codeine, adverse drug reactions in neonates through breast-feeding from CYP2D6 ultra-rapid metabolizers have been reported. However, there is lack of conclusive evidence regarding the overall influence of CYP2D6 polymorphisms on codeine efficacy and toxicity. Although CYP2C19 and CYP2D6 genotyping tests are available, clinical utility remains low. The presence of the HLA-B*1502 allele is associated with carbamazepine-induced Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN). Pharmacogenomic testing is required prior to initiating carbamazepine in high-risk patients. Lack of sufficient resources, provider knowledge, and ethical, legal, and social issues are several limitations and challenges to implementing pharmacogenomic testing in clinical practice.

HLA-B*5701 testing to predict abacavir hypersensitivity

Abacavir is a nucleoside reverse transcriptase inhibitor used for combination antiretroviral therapy for treating human immunodeficiency virus (HIV) infection. An adverse effect from abacavir is a treatment-limiting hypersensitivity reaction, which can be severe and potentially life-threatening. Abacavir-induced hypersensitivity reaction has been associated with the presence of the major histocompatibility complex class I allele HLA-B*5701. A screening test for the HLA-B*5701 allele can assist clinicians to identify patients who are at risk of developing a hypersensitivity reaction to abacavir.

A Train-the-Trainer Approach to a Shared Pharmacogenomics Curriculum for US Colleges and Schools of Pharmacy

Objective. To assess pharmacy faculty trainers’ perceptions of a Web-based train-the-trainer program for PharmGenEd, a shared pharmacogenomics curriculum for health professional students and licensed clinicians. Methods. Pharmacy faculty trainers (n=58, representing 39 colleges and schools of pharmacy in the United States and 1 school from Canada) participated in a train-the-trainer program consisting of up to 9 pharmacogenomics topics. Posttraining survey instruments assessed faculty trainers’ perceptions toward the training program and the likelihood of their adopting the educational materials as part of their institution’s curriculum. Results. Fifty-five percent of faculty trainers reported no prior formal training in pharmacogenomics. There was a significant increase (p<0.001) in self-reported ability to teach pharmacogenomics to pharmacy students after participants viewed the webinar and obtained educational materials. Nearly two-thirds (64%) indicated at least a “good” likelihood of adopting PharmGenEd materials at their institution during the upcoming academic year. More than two-thirds of respondents indicated interest in using PharmGenEd materials to train licensed health professionals, and 95% indicated that they would recommend the program to other pharmacy faculty members. Conclusion. As a result of participating in the train-the-trainer program in pharmacogenomics, faculty member participants gained confidence in teaching pharmacogenomics to their students, and the majority of participants indicated a high likelihood of adopting the program at their institution. A Web-based train-the-trainer model appears to be a feasible strategy for training pharmacy faculty in pharmacogenomics.

Clinical features of status epilepticus in patients with HIV infection

The authors reviewed the records of 42 patients with HIV infection and status epilepticus (SE). Brain tumor and infection were the most common etiologies. The median duration of SE was 2.0 ± 10 hours. Most patients (37 [88%]) responded to IV benzodiazepine or phenytoin treatment. Nevertheless, 12 (29%) patients died and 15 (36%) developed new neurologic deficits. In patients with HIV infection, aggressive management of seizures may limit the risk of SE.

Clinical Interpretation of Urine Drug Tests: What Clinicians Need to Know About Urine Drug Screens

&NA; Urine drug testing is frequently used in clinical, employment, educational, and legal settings and misinterpretation of test results can result in significant adverse consequences for the individual who is being tested. Advances in drug testing technology combined with a rise in the number of novel misused substances present challenges to clinicians to appropriately interpret urine drug test results. Authors searched PubMed and Google Scholar to identify published literature written in English between 1946 and 2016, using urine drug test, screen, false‐positive, false‐negative, abuse, and individual drugs of abuse as key words. Cited references were also used to identify the relevant literature. In this report, we review technical information related to detection methods of urine drug tests that are commonly used and provide an overview of false‐positive/false‐negative data for commonly misused substances in the following categories: cannabinoids, central nervous system (CNS) depressants, CNS stimulants, hallucinogens, designer drugs, and herbal drugs of abuse. We also present brief discussions of alcohol and tricyclic antidepressants as related to urine drug tests, for completeness. The goal of this review was to provide a useful tool for clinicians when interpreting urine drug test results and making appropriate clinical decisions on the basis of the information presented.

Development of a pharmacist–psychiatrist collaborative medication therapy management clinic

OBJECTIVE To describe a needs assessment, practice description, practice innovation and reimbursement of a psychiatric pharmacist medication therapy management (MTM) clinic with related challenges and opportunities. SETTING An MTM clinic established in collaboration with the Outpatient Psychiatric Services (OPS) at the University of California San Diego (UCSD), under contract with the San Diego County Health and Human Services Agency Adult and Older Adult Mental Health Services (A/OAMHS). PRACTICE DESCRIPTION Two board-certified psychiatric pharmacists provided direct patient care using a collaborative practice protocol 3 days per week. Clinical services included pharmacotherapy management, laboratory monitoring, medication counseling, and psychosocial referrals to other providers. PRACTICE INNOVATION Payment to UCSD OPS for clinical services was based on a contract between the San Diego County A/OAMHS and the clinic. Two pharmacists co-managed mental health patients and billed for medication management based on face-to-face contact time (medication minutes) and documentation time with each patient. MAIN OUTCOME MEASURES Number of patients comanaged, dropout rates, visit duration, and billed minutes. RESULTS From May 2009 to December 2010, two pharmacists comanaged 68 patients, mean (± SD) age 48.6 ± 11.6 years, diagnosed with major depressive, schizophrenic, schizoaffective, and/or bipolar disorder. A total of 56 (82.3%) patients were clinically stable and remained on the pharmacist caseload, but 12 (17.6%) patients were lost to follow-up (10 lost contact, 1 moved, 1 expired). On average, patients had 7.7 patient visits , for 491 total visits (with an average of 26 minutes per visit) that were billed at a rate of