Effects of clozapine on autophagy in people with treatment-resistant psychosis.

The study is a non-randomised trial conducted in psychiatric hospital and community settings. The intervention will be the prescribed treatment of treatment-resistant psychosis with the pharmaceutical agent clozapine. This study will be utilising an existing workflow and established manner of care, and will not be assigning treatment to individuals. Rather, the study will be recruiting participants as they commence or have commenced their treatment in the routine clinical and community setting. Due to the nature of the psychosis and the established care routine, patients are required to be seen monthly, with routine blood collections necessary for monitoring the health of patients taking clozapine. This study integrates these standard blood measures and clinical assessments that occur during the existing routine care of clozapine patients. The aim of this study is investigate the effects of clozapine on host autophagy to understand potential mechanisms contributing to clozapine's clinical effectiveness, and its side-effect profile (including metabolic, constipation, and inflammatory). The study will include two groups: Group 1: Includes 25 clozapine-naive participants. These participants will be asked to provide blood and stool samples on 4 occasions; at baseline (enrolment), 2 weeks after commencement of clozapine, and 3 and 6 months after commencing clozapine. All patients commencing clozapine are required to be admitted to the in-patient site for pre-work up (2 weeks) commencement of clozapine, then a minimum of 2 weeks for titration and monitoring for clinical effect and side effects. For Group 1, blood (and stool) samples will be collected at baseline, 3 and 6 months. The questionnaires BPRS, PANSS and GAF will be administered at these same time points by the psychiatrist or registrar without requiring time or effort by the participant. Blood samples are routinely taken by medical staff on site. If the participant is agreeable to providing a stool sample this can be self-administered during the admission process. Group 2: Includes 25 chronic clozapine use participants. These participants routinely have their blood tests conducted by a commercial provider at a community site. These participants will be requested, at a single timepoint, for their additional autophagy study blood sample on the day of their routine appointment with their psychiatrist. The questionnaires BPRS, PANSS and GAF will be administered at these same time points by the psychiatrist or registrar without requiring time or effort by the participant. If they agree to provide a stool sample they will be able to provide this on the day of their appointment also, or at home. This group is a cross-sectional group; there will be no follow-up appointments or observations as data will only be collected at the timepoint of enrolment. For both groups, the participants that will be recruited will have a formal diagnosis of schizophrenia or schizoaffective disorder, and will be recruited from the Southern Adelaide Local Health Network Mental Health Service. The normal routine care for all patients commencing clozapine treatment begins with weekly clinical evaluations and blood collection for the first 18 weeks to monitor the health of the patient in response to clozapine. Following these 18 weeks, the patient is then routinely assessed at 4-weekly intervals, including clinical evaluations and blood tests. Metabolic profiling, or evaluations of the interface between the gut microbiome and host physiology, will evaluate clinical differences of how clozapine is altering the host’s systemic metabolism by possible changes to the gut microbiome. Differences will be determined by observing weight and Body Mass Index change obtained from existing clinical data records in SA Health, along with recording the Bristol stool chart in patients treated with clozapine. We will also be integrating the routine Clozapine Management Clinical Guideline provided by SA Health that will provide an opportunity to analyse an existing suite of participant measures that includes c-reactive protein, blood glucose, blood pressure, and clozapine serum levels. This will determine if drug treatment is causing any host metabolic side effects. These measures are collected weekly from the routine blood collection and analysis during the individual's treatment with clozapine, and will be provided for this study from commencement of treatment up until 12 months post-enrolment. Blood and stool samples will be used to measure clozapine serum levels, changes in autophagic flux, microbiome, and inflammatory profiles. These longitudinal changes will be compared against baseline for the group of participants treated with clozapine, and compared against the cross-sectional samples collected from the patients treated with clozapine for more than 12 months. This will help determine the mechanism of action that may be contributing to both short- and long-term clinical and metabolic effects of clozapine.