Acute pharmacogenetic dystonic reactions in a family with the CYP2D6 *41 allele: a case report

Background Dystonia is a known neurological complication of certain medications; however, the mechanism behind such effects is often undetermined. Similarly, the clinical pharmacogenomic effects associated with various alleles of the cytochrome P450 family of proteins, and their role in acute dystonic reactions, are also presently unknown. Case presentation We describe a woman presenting with acute dystonic reactions to ondansetron, prochlorperazine, and metoclopramide followed by persistent focal dystonia. A similar family history was reported in her siblings and her father to prochlorperazine, drugs all metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme. Pharmacogenomic testing indicated the patient was heterozygous for the intermediate metabolizer *41 allele (CYP2D6 2988G>A, NM_000106.6:c.985+39G>A, rs28371725). Her father was homozygous for this CYP2D6 *41 allele, and consequently, her siblings were obligate carriers. Conclusions The metabolism of ondansetron, metoclopramide, or prochlorperazine in patients with the *41 CYP2D6 allele has not been studied. In this family, clinical evidence implicates the *41 CYP2D6 allele as causing extrapyramidal adverse pharmacologic reactions. Patients with a family history of medication-induced dystonia involving these medications should be considered for pharmacogenomic testing, and patients carrying the *41 CYP2D6 allele should consider reduction or avoidance of CYP2D6-mediated medications to minimize the potential risk of adverse extrapyramidal effects.

Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.

Olfactory Distraction for Management of Nausea in Palliative Care Patients

Nausea is one of the most common and debilitating symptoms Palliative Care patients experience. This can be caused by the life-limiting illness itself, its complications, or its treatments. While there are many options for management, including anti-emetics and motility agents, patients may develop refractory nausea or even intolerance to these treatments. Drug interactions, sedation, extrapyramidal effects, serotonin syndrome, and prolonged QT intervals with risk factors for Torsades de Pointes may all preclude use of these medications. Olfactory distraction using alcohol swabs has supporting literature in the emergency care setting as a means of alleviating nausea in a safe and effective way. We present a case series of 3 patients admitted to a Northwell facility who were referred to the Palliative Care consult service for severe nausea. The patients had nausea of varying etiology and were successfully managed with inhalation of alcohol swabs. This is the first case series that looks into applying this intervention to the Palliative Care population as an easy-to-use, readily-available, and safe method to manage nausea.

The α6 GABAA Receptor Positive Allosteric Modulator DK-I-56-1 Reduces Tic-Related Behaviors in Mouse Models of Tourette Syndrome

Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by multiple, recurrent tics. The pharmacological treatment of TS is currently based on dopaminergic antagonists; however, these drugs are associated with extrapyramidal symptoms and other serious adverse events. Recent evidence suggests that positive allosteric modulators (PAMs) of GABAA receptors containing α6 subunits (α6 GABAARs) oppose the behavioral effects of dopamine. Building on this evidence, in the present study, we tested the efficacy of DK-I-56-1, a highly selective PAM for α6 GABAARs, in mouse models of TS exhibiting tic-related responses. DK-I-56-1 significantly reduced tic-like jerks and prepulse inhibition (PPI) deficits in D1CT-7 transgenic mice, a well-documented mouse model of TS. DK-I-56-1 also prevented the exacerbation of spontaneous eyeblink reflex induced by the potent dopamine D1 receptor agonist SKF 82958, a proxy for tic-like responses. We also showed that both systemic and prefrontal cortical administration of DK-I-56-1 countered the PPI disruption caused by SKF 82958. Although the effects of DK-I-56-1 were akin to those elicited by dopaminergic antagonists, this drug did not elicit extrapyramidal effects, as measured by catalepsy. These results point to α6 GABAAR PAMs as promising TS therapies with a better safety profile than dopaminergic antagonists.

Neuroleptic-induced Parkinsonism in Patient with Obsessive Compulsive Disorder: A Case Report

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by either obsessions (recurrent unwanted thoughts, images or impulses) or compulsions (repetitive behaviors often performed to relieve anxiety or distress). In some cases, it is considered antipsychotic enhancement. However, in high doses, it can exacerbate OCD symptoms and cause extrapyramidal effects such as neuroleptic-induced Parkinsonism.Here, the authors present a clinic case of a single male patient with 50 years old, in which with the age of 42, started with a obsessive-compulsive framework about the developed task at the work place (production of fabric) followed by several verifications of the assembled pieces, which interfered with his work performance. This patient was admitted to the psychiatric hospital due to the deterioration of the symptoms with obsessive ideas of HIV contamination resulting in rigid cleaning rituals. He was medicated with several OCD medications including Clozapine 50 mg.In the following years and complaining of insomnia, the clozapine dose was increased by the patient reaching the dose of 200 mg. In 2016 he started secondary Parkinsonism framework to antipsychotics, characterized by akinesia, facial hypomimia, stiff, coarse tremor and stooped posture. Therapeutic setting was made with a reduction of clozapine at doses of 50 mg occurring fading of extrapyramidal symptoms and decrease the symptoms of OCD.The authors intend with this presented case to highlight the importance of surveillance of patients receiving antipsychotics for OCD to avoid worsening of symptoms and the development of extrapyramidal effects, which deeply contribute to the decrease of quality life of these patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.