Depression, Depressive Disorder, Depressive Symptoms, Overweight or Obesity
Conditions
Brief summary
The patients with depression and obesity will receive add-on metformin with antidepressant therapy, which may result in greater improvement in depressive symptoms and BMI reduction compared to antidepressant monotherapy. NEGR1/RPL31P12 gene polymorphisms may influence the comparative efficacy of antidepressant monotherapy versus combination therapy (antidepressant + metformin) in Pakistani patients. Patients with certain variants may respond better or worse to antidepressants and may have different weight outcomes.
Detailed description
There is a substantial percentage of the Pakistani population who are both overweight/obese and depressed, with estimates from clinical samples averaging 25%. So, the personalized treatment approach for depression and obesity needs to be explored. Obesity and depression commonly coexist and are associated with poorer health outcomes. Metformin, widely used for metabolic disorders and obesity, has shown potential antidepressant effects. However, evidence on its use as an adjunct to antidepressant therapy in patients with depression-obesity comorbidity remains limited, and the influence of genetic variants on treatment response is not well understood. This study aims to evaluate the effectiveness of adjunctive metformin and its association with NEGR1 and RPL31P12 genetic variants in this population.
Interventions
DRUGMetformin
Tab 500-2000 mg/day (500 mg BD to 1000 mg BD)
DRUGAntidepressant
Sertraline 50 mg/day + Metformin 500 mg twice daily or Duloxetine 60 mg/day + Metformin 500 mg twice daily or Bupropion XL 150-300 mg/day + Metformin 500 mg twice daily
Sponsors
Riphah International University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Total 5 groups: 1. Three groups will be negative control, assessed for genetic variants only, and not included in RCT. normal subjects, depression, or obesity (each n=90). 2. Comorbid depression-obesity will be positive control. RCT will be conducted on this group (n=180), and they will be divided into two main groups. Group 1 (n = 90) will receive sertraline, duloxetine, or bupropion monotherapy (groups A, B, and C - 30 patients each). Group 2 (n = 90) will similarly be subdivided into three groups A', B', and C' (30 patients each). They will receive sertraline, duloxetine, or bupropion in combination with metformin. Group 2 combinations: Tab Metformin + Tab sertraline Tab Metformin + Cap. duloxetine Tab Metformin + Tab bupropion
Eligibility
Sex/Gender
ALL
Healthy volunteers
Yes
Inclusion criteria
* Age ≥ 18 years * Both males and females * Recurrent depressive disorder (6A71) according to ICD-11, * Asian cut off: Obese and overweight (BMI \< 23) * BDI score ≥ 13 or PHQ score ≥ 4 * Either medication-naïve or medication-free for at least 2 weeks before enrollment, or the patient did not take antidepressants during the last 7 days before study entry (discontinuation of effective medication to enable study participation is prohibited) * In case of non-psychotropic medication: The patient received stable pharmacological medication for at least 14 days before study entry (any changes in medication dose or frequency of therapy must be answered with no)
Exclusion criteria
Groups I-III: Negative Controls (Normal: no depression and Obesity for SNP comparison only) * Age less than 18 * Dementia/ Mentally impaired who can not fill self report performas for inclusion criteria Group IV: Positive Control (RCT patients) * Patients with comorbid conditions (HTN, CKD) if taking any drug for that condition. * The patient is not an employee of the investigator study site, or a family member of the employees or the investigator, or otherwise dependent on the sponsor, the investigator, or the investigator study site. * The patient did not participate in other interventional trials during the 6 months before and at the time of this trial. The patient does not have a history of non-response to antidepressants included in the study. * The patient has not given birth within the 6 months before study entry and is not breastfeeding * The patient did not receive treatment with ketamine, irreversible MAO inhibitor (e.g. tranylcypromine), electroconvulsive therapy (ECT) or other stimulatory treatments in the index episode. * The patient is not diagnosed with dementia and does not have moderate or severe impairment of general cognitive function according to clinical impression. * The patient does not meet the criteria for alcohol use disorder (DSM-5: 303.90; ICD-10: F10.20) or substance use disorder (DSM-5: 304; ICD-10: F11.20 - F19.20) in DSM-5, and a urine/serum drug screening is negative (except for benzodiazepines and opiates). * The patient does not have: * A known allergy or contraindication against antidepressants included in the study * History of suicidal tendencies * Uncontrolled hepatic disorder, renal or cardiovascular disease * DM * Untreated hypothyroidism * History of myocardial infarction or stroke * Symptomatic peripheral arterial disease * Monogenic familial hypercholesterolemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Severity of the depression | 1 month | The change in the total PHQ-9 score between baseline and 4-weeks follow-up is the primary outcome measure. This measure is a patient-rated inventory of depressive symptoms. All items are scored on scales ranging from 0-3 and the sum of the scores provides the total score for the measure. On this scale, higher scores indicate poorer outcomes. Scores 9-19 and 20-27 are considered moderate and severe depression respectively. |
| Change in BMI | 3 months | Change in Body Mass Index (BMI): BMI will be measured at baseline and study completion and calculated as weight in kilograms divided by height in meters squared (kg/m²). The outcome will be assessed as the change in BMI from baseline. Asian BMI Classification: Underweight: \< 18.5 kg/m² Normal weight: 18.5-22.9 kg/m² Overweight: 23.0-24.9 kg/m² Obesity Class I: 25.0-29.9 kg/m² Obesity Class II: ≥ 30.0 kg/m² BMI reduction \< 1 kg/m²: Minimal change BMI reduction ≥ 1 kg/m²: Clinically meaningful improvement Weight loss ≥ 5% of baseline body weight: Clinically significant weight reduction associated with metabolic health benefits. A decrease in BMI from baseline and/or movement to a lower BMI category will be considered indicative of improvement in obesity-related outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Blood Pressure | 3 months | Change in Blood Pressure: Blood pressure will be measured in mmHg at baseline, 14 days, 28 days, one month and 3 months.. The outcome will be assessed as the change in systolic and diastolic blood pressure from baseline. Normal blood pressure is \<120/80 mmHg, elevated blood pressure is 120-129/\<80 mmHg, and high blood pressure is ≥130/80 mmHg. A reduction in blood pressure values from baseline will indicate improvement in cardiovascular health status. |
| Change in Blood Sugar Levels | 3 months | Change in Blood Sugar: Blood glucose levels will be measured at baseline, 14 days, 28 days, one month and 3 months. The outcome will be assessed as the change in blood glucose from baseline. Normal fasting blood glucose is 70-99 mg/dL, prediabetes is 100-125 mg/dL, and diabetes is ≥126 mg/dL. A reduction in blood glucose levels toward the normal range will indicate improvement in glycemic control, whereas increase will be monitored for safety |
| Change in Renal Function tests | 3 months | Change in Renal Function Tests: Renal function will be monitored by measuring serum creatinine and blood urea levels at baseline and study completion. The outcome will be assessed as the change in these parameters from baseline. Normal serum creatinine is approximately 0.6-1.2 mg/dL, while values \>1.2 mg/dL may indicate impaired renal function. Normal blood urea is approximately 15-40 mg/dL, while values \>40 mg/dL may suggest reduced kidney function or impaired renal clearance. An increase in serum creatinine or blood urea from baseline will be considered indicative of deterioration in renal function, whereas stable values within the normal range will indicate preserved renal function. |
| Change in Liver Function tests | 3 months | Change in Liver Function Tests (LFTs): Liver function will be monitored at baseline and study completion. The outcome will be assessed as the change in liver enzyme levels and bilirubin from baseline. Alanine Aminotransferase (ALT): Normal 7-56 U/L; elevated \>56 U/L may indicate liver injury. Aspartate Aminotransferase (AST): Normal 10-40 U/L; elevated \>40 U/L may indicate hepatic or muscle injury. Alkaline Phosphatase (ALP): Normal 44-147 U/L; elevated \>147 U/L may suggest cholestatic liver disease or biliary obstruction. Total Bilirubin: Normal 0.2-1.2 mg/dL; elevated \>1.2 mg/dL may indicate impaired liver function or biliary obstruction. Albumin: Normal 3.5-5.0 g/dL; decreased \<3.5 g/dL may indicate impaired hepatic synthetic function. |
| C - Reactive Proteins levels | 3 months | Change in C-Reactive Protein (CRP) Levels: CRP levels will be measured at baseline and study completion to assess systemic inflammation. The outcome will be assessed as the change in CRP levels from baseline. Normal: \< 3 mg/L Mildly elevated: 3-10 mg/L Moderately elevated: 10-50 mg/L Markedly elevated: \> 50 mg/L Severely elevated: \> 100 mg/L Decrease in CRP level: Indicates reduction in systemic inflammation. Stable CRP within normal range (\< 3 mg/L): Indicates absence of significant inflammation. Increase in CRP above normal range: Suggests worsening or persistent inflammatory activity. |
| Lipid Profile | 3 months | It will be measured at baseline and study completion to monitor safety of combination therapy. Total Cholesterol (TC): Desirable: \< 200 mg/dL, Borderline high: 200-239 mg/dL, High: ≥ 240 mg/dL Low-Density Lipoprotein Cholesterol (LDL-C): Optimal: \< 100 mg/dL, Near optimal: 100-129 mg/dL, Borderline high: 130-159 mg/dL, High: 160-189 mg/dL, Very high: ≥ 190 mg/dL High-Density Lipoprotein Cholesterol (HDL-C): Low: \< 40 mg/dL (men), \< 50 mg/dL (women), Protective: ≥ 60 mg/dL Triglycerides (TG): Normal: \< 150 mg/dL, Borderline high: 150-199 mg/dL, High: 200-499 mg/dL, Very high: ≥ 500 mg/dL Interpretation: Decrease in TC, LDL-C, and TG levels indicates improvement in lipid metabolism. Increase in HDL-C levels indicates a favorable cardiovascular risk profile. Lipid values remaining within the normal range throughout the study will be considered indicative of metabolic safety of the combination therapy. |
Countries
Pakistan
Contacts
PRINCIPAL_INVESTIGATORAfifa,Siddique, PhD Scholar, MBBS, M.Phil
Islamic International Medical College, Riphah International University
Outcome results
None listed