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

Efficacy of Nitraria Retusa Infusion in Significantly Reducing Clozapine-induced Metabolic Side Effects in Patients With Treatment-resistant Schizophrenia: A Pre-Experimental Pilot Study

The primary objective of the study is to assess the efficacy and tolerability of a 90-day daily supplementation with a Nitraria retusa dried crushed leaves infusion on the iatrogenic metabolic side effects induced in patients with treatment-resistant schizophrenia following clozapine treatment.

After providing written informed consent, eligible patients with treatment-resistant schizophrenia will be invited to receive 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). Two additional assessments will be planned at day 30 and day 60 to comply with the monthly complete blood count (CBC) surveillance recommended for patients receiving clozapine. Assessments include anthropometric measures, body composition, vital signs, CBC, metabolic panels, and renal and hepatic function. All biological samples were collected after a 12-hour fast.

Study Overview

• Status: Recruiting
• Conditions: Abdominal Obesity; Treatment Resistant Schizophrenia; Obesity & Overweight
• Intervention / Treatment: Dietary supplement: The Nitraria retusa arm

Detailed Description

A pilot, pre-experimental study will be conducted.

1. 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.
2. 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).
3. 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).

4. 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.
5. 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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Bochra Nourhène Saguem, M.D.; Associate Professor; Phone Number: +21655617728; Email: saguem.bochra@gmail.com
• Study Contact Backup: Name: Saad Saguem, Professor; Phone Number: +21653673851; Email: khaled_saguem@yahoo.fr

Study Locations

• Tunisia
  • Sousse, Tunisia, 4000
    • Recruiting
    • Farhat Hached University Hospital
    • Contact: Bochra Nourhène Saguem, M.D.; Associate Professor; Phone Number: +21655617728; Email: saguem.bochra@gmail.com
    • Sub-Investigator: Jaâfar Nakhli, Professor
    • Principal Investigator: Bochra Nourhène Saguem, M.D.; Associate Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment-resistant schizophrenia patients' with clozapine-induced obesity; Inclusion criteria: (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 (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: (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.

Dietary supplement: The Nitraria retusa arm; A daily administration of Nitraria retusa extract infusion at approximately 9 PM for 90 consecutive days, as an adjunct to patients' usual medications, while maintaining usual diet, routine, and lifestyle throughout the study. 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 high-performance liquid chromatography method (UHPLC-DAD, SHIMADZU 8045).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body weight	Body weight, measured using a calibrated scale integrated into the bioelectrical impedance analyzer, with participants wearing light clothing.	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)
Waist circumference	Waist circumference, measured at the narrowest point between the lower rib margin and the iliac crest, as an indicator of abdominal adiposity.	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other anthropometric measurements	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.	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)
Body composition	Body composition, assessed via bioelectrical impedance analysis, including body fat percentage, muscle mass percentage, and body water percentage.	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)
Concentration of Triglycerides	Fasting serum triglyceride (TG) concentration	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)
Concentration of High-Density Lipoprotein Cholesterol	Fasting serum High-Density Lipoprotein Cholesterol (HDL-C) concentration	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)
Concentration of Low-Density Lipoprotein Cholesterol	Fasting serum Low-Density Lipoprotein Cholesterol (LDL-C) concentration	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)
Fasting Blood Glucose Level	Fasting plasma glucose concentration	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)
Glycated Hemoglobin (HbA1c) Level	Percentage of glycated hemoglobin (HbA1c)	baseline (T0) and day 90 (T3)
Incidence of treatment-emergent abnormalities in Complete Blood Count, renal function, and hepatic Enzymes	Number of participants with clinically significant treatment-emergent abnormalities in complete blood count (CBC), renal function markers, or hepatic enzymes during the 90-day intervention period.	baseline (T0), day 10 (T1), day 45 (T2), and day 90 (T3)

Collaborators and Investigators

• Sponsor: Faculty of Medicine, Sousse
• Collaborators: University of Tsukuba
• Investigators: Study Director: Saad Saguem, Professor, Faculty of Medicine, Sousse

Publications and helpful links

General Publications

• Yao J, Zhang Y, Zhao J, Wang XZ, Lin YP, Sun L, Lu QY, Fan GJ. Efficacy of flavonoids-containing supplements on insulin resistance and associated metabolic risk factors in overweight and obese subjects: a systematic review and meta-analysis of 25 randomized controlled trials. Front Endocrinol (Lausanne). 2022 Jul 22;13:917692. doi: 10.3389/fendo.2022.917692. eCollection 2022.
• Laouani A, Nasrallah H, Sassi A, Ferdousi F, Kalai FZ, Hasni Y, Limem K, Isoda H, Saguem S. Exploring the Effects of Short-Term Daily Intake of Nitraria retusa Tea on Lipid Profile: A Pre-Post, Uncontrolled Pilot Study in Both Healthy and Overweight/Obese Adults. Nutrients. 2023 Aug 20;15(16):3649. doi: 10.3390/nu15163649.
• Laouani A, Nasrallah H, Sassi A, Ferdousi F, Kalai FZ, Hasni Y, Isoda H, Saguem S. Antiobesity and Hypolipidemic Potential of Nitraria retusa Extract in Overweight/Obese Women: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. Nutrients. 2024 Jan 21;16(2):317. doi: 10.3390/nu16020317.
• Yuen JWY, Kim DD, Procyshyn RM, Panenka WJ, Honer WG, Barr AM. A Focused Review of the Metabolic Side-Effects of Clozapine. Front Endocrinol (Lausanne). 2021 Feb 25;12:609240. doi: 10.3389/fendo.2021.609240. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: September 3, 2026
• First Submitted That Met QC Criteria: September 9, 2026
• First Posted (Actual): September 14, 2026

Study Record Updates

• Last Update Posted (Actual): September 14, 2026
• Last Update Submitted That Met QC Criteria: September 9, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Obesity; Metabolic syndrome; Clozapine; Flavonoids; Treatment-resistant schizophrenia; Antipsychotic-induced weight gain; Nitraria retusa
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Insulin Resistance; Hyperinsulinism; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Schizophrenia; Schizophrenia, Treatment-Resistant; Overweight; Obesity; Metabolic Syndrome; Obesity, Abdominal
• Other Study ID Numbers: CEFMS 136/2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators plan to share anonymous results of the primary and secondary outcome variables of each study participant in form of Tables.
• IPD Sharing Time Frame: At the end of the trial
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No