The effect of antipsychotic-induced extrapyramidal disorders on patient’s compliance with schizophrenia (a clinical case)

Extrapyramidal disorders are common adverse events in antipsychotic therapy. However, their diagnosis is difficult due to broad differential diagnosis, and often their specific clinical variant is not recognized, and timely intervention is not performed, which leads to severe patient suffering. This affects the quality of life of patients with schizophrenia and leads to their refusal to receive therapy, which aggravates the course of the disease. The article presents a clinical case of a 33-year-old patient at a psychiatric hospital with schizophrenia combined with such rare severe extrapyramidal disorders as antipsychotic-induced tardive dyskinesia and tardive dystonia.The diagnosis was carried out in accordance with the criteria of the International Classification of Diseases, Tenth Revision (ICD-10). The intensity of clinical manifestations was assessed using the Positive and Negative Syndrome Scale (PANSS), the Abnormal Involuntary Movement Scale (AIMS), and the Barnes Akathisia Rating Scale (BARS). Compliance was assessed using the Method for Measuring Medication Adherence in Psychiatry. Detailed differential diagnosis of tardive dyskinesia and tardive dystonia with akathisia and Huntington’s disease was presented. Substantiated treatment strategy and positive clinical dynamics with increased compliance were described.

Impact of drug-induced Parkinsonism and tardive dyskinesia on health-related quality of life in schizophrenia

Background: Both drug-induced Parkinsonism (DIP) and tardive dyskinesia (TD) have been shown to be associated with lower health-related quality of life (HRQOL) in schizophrenia, but few studies have examined their relative impact. Aims: This study aimed to examine and compare the association of DIP and TD with HRQOL in schizophrenia. Methods: In total, 903 patients with schizophrenia were assessed on the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). EuroQoL five-dimensional (EQ-5D-5L) utility scores were derived from PANSS scores via a previously validated algorithm and used as a measure of HRQOL. Results: In total, 160 (17.7%) participants had only DIP, 119 (13.2%) had only TD, and 123 (13.6%) had both DIP and TD. HRQOL was lowest for participants with both DIP and TD, followed by only DIP group, only TD group, and highest in the group with neither condition. HRQOL scores differed significantly between the four groups, F(3, 892) = 13.724, p < 0.001, [Formula: see text] = 0.044). HRQOL of participants having only DIP or both DIP and TD was significantly lower than those having neither condition. There was no significant interaction between the presence of DIP and TD on the association with HRQOL. Conclusions: DIP was the main antipsychotic-induced movement disorder associated with a poorer HRQOL in patients with schizophrenia. Therefore, clinicians should focus on prevention, detection, and effective management of DIP to optimize HRQOL in patients with schizophrenia.

(+)-9-Trifluoroethoxy-α-Dihydrotetrabenazine as a Highly Potent Vesicular Monoamine Transporter 2 Inhibitor for Tardive Dyskinesia

Valbenazine and deutetrabenazine are the only two therapeutic drugs approved for tardive dyskinesia based on blocking the action of vesicular monoamine transporter 2 (VMAT2). But there exist demethylated inactive metabolism at the nine position for both them resulting in low availability, and CYP2D6 plays a major role in this metabolism resulting in the genetic polymorphism issue. 9-trifluoroethoxy-dihydrotetrabenazine (13e) was identified as a promising lead compound for treating tardive dyskinesia. In this study, we separated 13e via chiral chromatography and acquired R,R,R-13e [(+)-13e] and S,S,S-13e [(−)-13e], and we investigated their VMAT2-inhibitory activity and examined the related pharmacodynamics and pharmacokinetics properties using in vitro and in vivo models (+)-13e displayed high affinity for VMAT2 (Ki = 1.48 nM) and strongly inhibited [3H]DA uptake (IC50 = 6.11 nM) in striatal synaptosomes. Conversely, its enantiomer was inactive. In vivo, (+)-13e decreased locomotion in rats in a dose-dependent manner. The treatment had faster, stronger, and longer-lasting effects than valbenazine at an equivalent dose. Mono-oxidation was the main metabolic pathway in the liver microsomes and in dog plasma after oral administration, and glucuronide conjugation of mono-oxidized and/or demethylated products and direct glucuronide conjugation were also major metabolic pathways in dog plasma. O-detrifluoroethylation of (+)-13e did not occur. Furthermore, CYP3A4 was identified as the primary isoenzyme responsible for mono-oxidation and demethylation metabolism, and CYP2C8 was a secondary isoenzyme (+)-13e displayed high permeability across the Caco-2 cell monolayer, and it was not a P-glycoprotein substrate as demonstrated by its high oral absolute bioavailability (75.9%) in dogs. Thus, our study findings highlighted the potential efficacy and safety of (+)-13e in the treatment of tardive dyskinesia. These results should promote its clinical development.

“Evaluating and Managing Tardive Dyskinesia in the Older Adult”

Purpose of Review Tardive dyskinesia is an iatrogenic hyperkinetic movement disorder caused by chronic exposure to antidopaminergic agents. The older adult population is particularly vulnerable to developing TD. It is also more difficult to discern the condition given the confounding medical comorbidities that may present at this age including Parkinson’s and other movement disorders that may mimic TD. Recent Findings This paper reviews the most common risk factors, including both modifiable and non-modifiable risk factors. Additionally, the possible causes and proposed pathways of TD and how to correctly diagnose and evaluate TD are discussed. We then focus on how to prevent and manage TD given the current and evolving body of knowledge and evidence. Our stepwise management approach starts by frequent monitoring, discontinuing the culprit antipsychotic, decreasing the dose otherwise; followed by switching to less potent antipsychotics and prescribing VMAT-2 inhibitors. VMAT-2 inhibitors, initially approved for management of Huntington's disease, have been recently showing favorable results in treating other hyperkinetic movement disorders like Tourette’s disease, quickly becoming the first line in the treatment of tardive dyskinesia. The properties of the three different agents belonging to this class: tetrabenazine, deutetrabenazine, and valbenazine will be examined, including side-effect profiles. Finally, recent investigational agents and treatment modalities, including neuromodulation (TMS and DBS) will be reviewed that can be considered when conventional treatment fails or is not tolerated. Summary Older adults treated with antidopaminergic medications are at greatest risk for development of tardive dyskinesia. It is important to recognize risk factors and accurately diagnose TD early. New FDA-approved treatments and investigational agents are now available to manage the condition, however further research to optimally prevent and manage TD in the older adult population remains necessary.