Kelan L. Thomas

Predicting new molecular targets for known drugs

Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug–target combinations exist, it would be useful to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the β1 receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H4 receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug–target associations were confirmed, five of which were potent (<100 nM). The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.

Pharmacogenetics of Selective Serotonin Reuptake Inhibitors and Associated Adverse Drug Reactions

The selective serotonin reuptake inhibitors (SSRIs) have become one of the most widely prescribed classes of drugs. They are relatively safe for the pharmacologic treatment of various psychiatric disorders; however, certain patients cannot tolerate some adverse drug reactions associated with this drug class. In addition, clinicians currently have no way to predict who will respond appropriately to a given SSRI, and the paradigm of trial and error is especially distressing for patients with mental illness. Pharmacogenetic association studies may provide insight into which genetic polymorphisms might be clinically relevant for individualizing pharmacotherapeutic regimens. Thus, we reviewed and summarized the literature regarding the pharmacogenomics of SSRI‐associated adverse drug reactions. This growing body of knowledge may inform subsequent design of pharmacogenetic studies with respect to adverse drug reactions. As we appreciate the many pharmacologic mechanisms related to adverse drug reactions and gain polymorphic functional data, we will have opportunities to refine hypotheses for future pharmacogenetic association analyses.

Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders

Dextromethorphan (DM) is a commonly used antitussive and is currently the only FDA-approved pharmaceutical treatment for pseudobulbar affect. Its safety profile and diverse pharmacologic actions in the central nervous system have stimulated new interest for repurposing it. Numerous preclinical investigations and many open-label or blinded clinical studies have demonstrated its beneficial effects across a variety of neurological and psychiatric disorders. However, the optimal dose and safety of chronic dosing are not fully known. This review summarizes the preclinical and clinical effects of DM and its putative mechanisms of action, focusing on depression, stroke, traumatic brain injury, seizure, pain, methotrexate neurotoxicity, Parkinsons disease and autism. Moreover, we offer suggestions for future research with DM to advance the treatment for these and other neurological and psychiatric disorders.

P-glycoprotein (PGP) Polymorphisms and Sexual Dysfunction in Female Patients With Depression and SSRI-Associated Sexual Side Effects

Sexual dysfunction is common with selective serotonin reuptake inhibitor use for major depressive disorder. Studies have shown associations between genetic variation in the adenosine triphosphate (ATP)-binding cassette, subfamily B, member 1 gene (ABCB1), which encodes the drug efflux transporter P-glycoprotein (PGP), and selective serotonin reuptake inhibitor response. This study measured functionally implicated ABCB1 variants (rs2235015, rs1128503, rs2032582, and rs1045642) and sexual dysfunction using the Changes in Sexual Functioning Questionnaire. This study included outpatients (18–40 years of age) treated for major depressive disorder with a selective serotonin reuptake inhibitor for 6 weeks. Changes in Sexual Functioning Questionnaire outcomes were stratified by ABCB1 genotype and PGP substrate status. The authors recruited 82 individuals (22 men and 57 women). Women receiving a PGP substrate with a rs1128503 TT genotype had a significantly lower Changes in Sexual Functioning Questionnaire total score (37.2 ± 5.4), indicating greater sexual dysfunction, than did those with the CT (42.9 ± 6.3) or CC genotypes (46.6 ± 5.6), F(2) = 6.00, p = .005, p = .02, with multiple testing correction. The results indicate a relationship between genotypes at rs1128503, total sexual dysfunction, and PGP substrates use for women and may explain some of the sexual dysfunction variability seen with selective serotonin reuptake inhibitor treatment. Results need to be confirmed with a larger sample size that includes men.

Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric Disorders

Abstract Recent research suggests that functional connectivity changes may be involved in the pathophysiology of psychiatric disorders. Hyperconnectivity in the default mode network has been associated with psychopathology, but psychedelic serotonin agonists like psilocybin may profoundly disrupt these dysfunctional neural network circuits and provide a novel treatment for psychiatric disorders. We have reviewed the current literature to investigate the efficacy and safety of psilocybin-assisted therapy for the treatment of psychiatric disorders. There were seven clinical trials that investigated psilocybin-assisted therapy as a treatment for psychiatric disorders related to anxiety, depression, and substance use. All trials demonstrated reductions in psychiatric rating scale scores or increased response and remission rates. There were large effect sizes related to improved depression and anxiety symptoms. Psilocybin may also potentially reduce alcohol or tobacco use and increase abstinence rates in addiction, but the benefits of these two trials were less clear due to open-label study designs without statistical analysis. Psilocybin-assisted therapy efficacy and safety appear promising, but more robust clinical trials will be required to support FDA approval and identify the potential role in clinical psychiatry.

The Effects of Dextromethorphan on Driving Performance and the Standardized Field Sobriety Test.

Dextromethorphan (DXM) is abused most commonly among adolescents as a recreational drug to generate a dissociative experience. The objective of the study was to assess driving with and without DXM ingestion. The effects of one‐time maximum daily doses of DXM 120 mg versus a guaifenesin 400 mg dose were compared among 40 healthy subjects using a crossover design. Subjects’ ability to drive was assessed by their performance in a driving simulator (STISIM® Drive driving simulator software) and by conducting a standardized field sobriety test (SFST) administered 1‐h postdrug administration. The one‐time dose of DXM 120 mg did not demonstrate driving impairment on the STISIM® Drive driving simulator or increase SFST failures compared to guaifenesin 400 mg. Doses greater than the currently recommended maximum daily dose of 120 mg are necessary to perturb driving behavior.

Effects of valerian on subjective sedation, field sobriety testing and driving simulator performance

INTRODUCTION The availability of herbal medicines over-the-counter (OTC) has increased the use of natural products for self-treatment. Valerian has been used to effectively treat generalized anxiety disorder and insomnia. Studies suggest that valerenic acid may increase gamma-aminobutyric acid (GABA) modulation in the brain. Benzodiazepines have a similar mechanism of action and have been linked to an increased risk of hospitalizations due to traffic accidents. Despite the risk of somnolence, the safety of driving while under the influence of valerian remains unknown. PURPOSE The purpose of the study was to determine the effects of a one-time valerian 1600mg dose on subjective sedation effects, standardized field sobriety testing (SFST) and driving simulator performance parameters. METHODS The study design was a randomized, placebo-controlled, double-blind, cross-over trial. For each session, participants received either a dose of valerian or placebo. The outcome measures included a simple visual reaction test (SVRT), subjective sleepiness scales, SFST performance scores, and driving simulator performance parameters. RESULTS There were no significant differences in the SVRT or sleepiness scales between placebo and valerian exposures, but the study may have been underpowered. SFST total and individual test failure rates were not significantly different between the two exposures. The driving simulator performance parameters were equivalent between the two exposure conditions. CONCLUSIONS A one-time valerian 1600mg dose, often used to treat insomnia, does not appear to impair driving simulator performance after acute ingestion.

Curriculum in Psychiatry and Neurology for Pharmacy Programs

Objective. To describe pharmacy curricula in psychiatry and neurology and to report on neuropsychiatric pharmacy specialists’ views on optimal curriculum. Methods. Design and administer one electronic survey to accredited pharmacy programs asking them to report information on curricula in psychiatry and neurology for the 2014-2015 academic year. Design and administer a separate electronic survey to board certified pharmacists with an academic affiliation who are members of the College of Psychiatric and Neurologic Pharmacists (CPNP) asking about their teaching activities and their opinion on optimal curricula. Results. Fifty-six percent of pharmacy programs and 65% of CPNP members responded to the surveys. The program survey revealed greater than 80% of topics were taught by full-time faculty. Didactic lecturing, team-based learning, and case studies were the most common teaching methods. Programs dedicated the most didactics (3 to 5+ hours) to epilepsy, depression, schizophrenia, substance use disorders, and pain. Autism, traumatic brain injury, personality, and eating disorders were either not taught or given ≤ 1 hour of didactics in most programs. Inpatient psychiatry had the most APPE placements with a mean of 19.6, range 0-83. APPE electives in psychiatry outnumbered those in neurology 5 to 1. CPNP member survey results showed 2 out of 3 members agreed that curriculum could be improved with additional APPEs in psychiatry and neurology. Conclusion. Didactic hour distribution in psychiatry and neurology could be improved to better align with board certification in psychiatric pharmacy (BCPP) recommendations and disorder prevalence and complexity. Specialists recommend an experiential component in neurology and psychiatry to combat stigma and improve pharmacist knowledge and skills.