Effects of Nitraria Retusa Infusion on Clozapine-induced Metabolic Side Effects

A pilot, pre-experimental study will be conducted.

• Study population Patients will be recruited from the outpatient Department of Psychiatry at Farhat Hached Hospital (Sousse, Tunisia). Inclusion criteria are: (1) a diagnosis of treatment-resistant schizophrenia; (2) current treatment with clozapine monotherapy or clozapine combined with other psychotropics that have a minimal documented impact on body weight; (3) demonstration of a response to clozapine, defined as a reduction of at least 20% in the total score on the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS) after 8-12 weeks of treatment at effective therapeutic doses; and (4) presence of obesity (Body Mass Index (BMI) > 30 kg/m²) or central obesity (waist circumference > 94 cm in men and > 80 cm in women), which developed following clozapine introduction. Non-inclusion criteria are: (1) concurrent use of clozapine with other psychotropic agents that have a documented moderate-to-high influence on body weight; (2) current treatment with metformin; and (3) pregnancy or breastfeeding.
• Study procedure Eligible patients with treatment-resistant schizophrenia will be invited to take a daily Nitraria retusa extract infusion at approximately 9 PM for 90 consecutive days, as an adjunct to their usual medications. Patients will be instructed to maintain their usual diet, routine, and lifestyle throughout the study. Clinical and biological evaluations will be conducted prospectively at baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3).
• Plant material and preparation of Nitraria retusa extract Nitraria retusa was collected from saline soils in Kairouan (central Tunisia). The leaves were rinsed with water, air-dried in the shade at room temperature for 15 days, and crushed into a fine powder using a Moulinex grinder (MOULINEX SA, France). Nitraria retusa was supplied to participants in sachets containing 2,000 mg of powder. Participants were instructed to prepare the daily infusion by steeping 2,000 mg of the powder in 100 mL of boiled water for 15 minutes. Qualitative and quantitative analyses of the extract were performed using a validated ultra-high-performance liquid chromatography with diode-array detection method (UHPLC-DAD; SHIMADZU 8045).
• Outcome variables Outcome measures were categorized as primary and secondary.

Primary outcomes included:

• Body weight, measured using a calibrated scale integrated into the bioelectrical impedance analyzer, with participants wearing light clothing.
• Waist circumference, measured at the narrowest point between the lower rib margin and the iliac crest, as an indicator of abdominal adiposity.

Secondary outcomes encompassed:

• Other anthropometric measurements including mid-upper arm circumference measured at the midpoint of the relaxed arm, and mid-thigh circumference measured at the midpoint of the thigh.
• Body composition, assessed via bioelectrical impedance analysis, including body fat, muscle mass, and body water percentages.
• Metabolic panels, including triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose, and glycated hemoglobin (HbA1c).
• Intervention tolerability, monitored via CBC, renal function markers, and hepatic enzymes.
• Ethical considerations Each participant provided written informed consent after receiving a detailed oral explanation of the study objectives and procedure, and after being given the written information sheet. Participants were also informed about their rights to withdraw at any time without any impact on the quality of their clinical care. All data were handled confidentially.

Inclusion criteria

• a diagnosis of treatment-resistant schizophrenia;
• current treatment with clozapine monotherapy or clozapine combined with other psychotropics that have a minimal documented impact on body weight; - demonstration of a response to clozapine, defined as a reduction of at least 20% in the total score on the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS) after 8-12 weeks of treatment at effective therapeutic doses;
• presence of obesity (BMI > 30 kg/m²) or central obesity (waist circumference > 94 cm in men and > 80 cm in women), which developed following clozapine introduction.
• free informed written consent

Exclusion criteria

• concurrent use of clozapine with other psychotropic agents that have a documented moderate-to-high influence on body weight
• current treatment with metformin
• pregnancy or breastfeeding
• non acceptance to take part to the study