Safety and efficacy of olanzapine treatment in psychosis: Effect of genetic and epigenetic factors – covariates of treatment response

The primary objective of this study is to evaluate the proportions (frequency) of **gene polymorphisms** in CYP1A2, MDR1, 5HT2A, 5HT2C, HDAC3, and HDAC4 genes in a population of patients with schizophrenia. Understanding the distribution of these genetic variations is clinically relevant as it may influence the response to **olanzapine** treatment, potentially guiding personalized therapeutic strategies for individuals with psychosis.

The secondary objectives include evaluating the effect of various covariates on the efficacy and safety (tolerability) of olanzapine treatment. These covariates encompass gene polymorphisms, CYP1A2 phenotype, cytosine methylation of the 5HT2A receptor gene, levels of olanzapine and desmethylolanzapine in serum, smoking habits, and co-medication. Assessing these factors is crucial for understanding their impact on treatment outcomes and optimizing therapeutic approaches for patients with psychosis.

The clinical trial involves a study population of patients diagnosed with **schizophrenia** or schizoaffective disorders, as classified under ICD-10 codes F20 and F25. The participants are adults aged between 18 and 60 years, encompassing both male and female subjects. The trial does not specifically target a vulnerable population. Participants are either undergoing established treatment with olanzapine or have a planned initiation of such treatment. Women of childbearing potential are included only if they adhere to effective contraceptive measures. The sponsor has not provided information regarding the total number of participants in the study. The selection criteria ensure that participants have expressed informed consent and a willingness to cooperate. Lifestyle factors such as diet, physical activity, or other habits are not specified in the available data.

The clinical trial is designed to assess the **safety** and **efficacy** of **olanzapine** treatment in patients with **psychoses**, specifically focusing on the genetic and epigenetic factors that may influence treatment response. This trial is a low-intervention study, utilizing an authorized investigational medicinal product in accordance with its marketing authorization. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from March 2023 to September 2026, with a maximum treatment period of six months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-60 years), diagnosis of schizophrenia or schizoaffective disorders, and established or planned initiation of olanzapine treatment. Women of childbearing potential must use effective contraceptive measures. Follow-up visits will be scheduled to monitor treatment response, side effects, and any changes in medication. The primary endpoint is the frequency of gene polymorphisms in specific genes, while secondary endpoints include cytosine methylation, metabolic phenotype, response and remission rates, and side effects assessment.

The end-of-study visit will conclude the participant's involvement, which is expected to last up to six months. Conditions that may lead to early termination from the study include withdrawal of consent, significant adverse effects, or non-compliance with study procedures. The trial aims to provide valuable insights into the genetic and epigenetic factors affecting olanzapine treatment in psychosis, contributing to personalized medicine approaches in this field.

The clinical trial involves the administration of **olanzapine**, an experimental medication, to evaluate its safety and efficacy in the treatment of psychosis, specifically in patients with schizophrenia. **Olanzapine** is provided in the form of a film-coated tablet, with the active substance being chemically derived **olanzapine**. The medication is administered orally, with a maximum daily dose of 20 mg and a total maximum dose of 840 mg over the course of the treatment. The treatment period is set for a maximum of 6 months. The study aims to assess the impact of genetic and epigenetic factors on treatment response, focusing on gene polymorphisms in CYP1A2, MDR1, 5HT2A, 5HT2C, HDAC3, and HDAC4.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve a pediatric formulation, and **olanzapine** is not classified as an orphan drug in this study. The pharmaceutical form and administration route are designed to optimize the therapeutic effects while minimizing potential side effects.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint focuses on the frequency of gene polymorphisms in CYP1A2, MDR1, 5HT2A, 5HT2C, HDAC3, and HDAC4 genes within the study population of patients diagnosed with schizophrenia. Secondary endpoints include the evaluation of **cytosine methylation** of 5HT2A, the metabolic phenotype of CYP1A2, and the response rate, which is defined as a 20% reduction in the Positive and Negative Syndrome Scale (PANSS) score on day 14 or a 30% reduction on day 28 compared to baseline. Remission rate is also assessed, defined by the reduction of symptom severity in specific PANSS items to a degree of ≤3, although the original recommended time factor of 6 months will not be included in the evaluation.

Additional secondary endpoints include the time to reach treatment response, the number of drop-outs due to olanzapine treatment cessation and their reasons, and side effects assessment using the UKU scale. The treatment of adverse effects of olanzapine, including medication, doses, treatment duration, and changes in administration, will also be monitored. These efficacy parameters will be measured and collected at specified timepoints, such as day 14 and day 28, using validated scales and laboratory tests. The analysis will focus on determining the impact of genetic and epigenetic factors on the treatment response in patients with schizophrenia.