INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive Disorder

Major Depressive Disorder Clinical Trial

— INSTA-MD  

Official title:

INflammation-based Stratification for Immune-Targeted Augmentation in Major Depressive

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05644301
• Other study ID #: T001222N
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: January 2023
• Est. completion date: September 2026

Study information

• Verified date: December 2022
• Source: Universiteit Antwerpen
• Contact: Jonas Janssens, MD
• Phone: 015304643
• Email: jonas.janssens[@]emmaus.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomised, double-blind, placebo-controlled clinical trial in which patients with major depressive disorder will receive augmentation through minocycline (MCO), celecoxib (CXB) or placebo.

Description:

This project aims to repurpose two established anti-inflammatory compounds as adjuvant therapy for immune-mediated depression, in line with state-of-the-art research of the last 10 years. Immune-mediated depression represents a subtype which accounts for approximately 30% of depressive disorders. Patients with this immunosubtype are more likely to have a higher severity of depression, a lower quality of life and more somatic symptoms. Furthermore it is accompanied by a high incidence of treatment resistance. While their mechanisms of action completely differ from those of existing antidepressant treatment options, immunomodulatory drugs celecoxib and minocycline have proven their merit as add-on treatment in depressive episodes. They have been on the Belgian market for years and come with a known pharmacological and safety profile. Patient stratification at baseline based on inflammatory status will reveal which inflammatory subpopulation benefits most from each of the two investigated anti-inflammatory compounds. Additionally, our distinctive study design allows head-to-head comparison of both add-on therapies and will as such provide the last stepping stones towards clinical implementation of individualised treatment strategies in depression.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 240
• Est. completion date: September 2026
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male or female, 18-65 years inclusive.
• Able and willing to give informed consent and take oral medication.
• Physically healthy.
• Diagnosis of Major Depressive Disorder by DSM-5 criteria, confirmed by the Mini International Neuropsychiatric Interview (MINI).
• The current episode of depression has failed to remit to the current antidepressant treatment at the adequate dose (as defined in the Maudsley Prescribing guidelines). Relapse while taking an antidepressant is also considered a treatment failure.
• Tolerant to the current antidepressant and having no planned changes in their current therapy for the duration of the study.
• Stable on current treatment for a minimum of 4 weeks (6 weeks for fluoxetine) prior to baseline.
• If female and of childbearing age, willing to use adequate contraceptive precautions and willing to take a pregnancy test at baseline.

Exclusion Criteria:

• Primary diagnosis of a bipolar disorder, psychotic spectrum disorder, obsessive-compulsive disorder, eating disorder, post-traumatic stress disorder, or alcohol and/or substance use disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (< 4 weeks before screening, excl. nicotine and caffeine).
• Use of immunosuppressant or immunostimulant drugs within 21 days of screening (e.g., glucocorticoid treatment, methotrexate, etc.).
• History of peptic ulcer disease or gastrointestinal (GI) bleeding.
• Having an acute infection or inflammatory bowel disorder.
• Current severe cardiovascular disease, congestive heart failure (NYHA-class II-IV), ischemic or thrombotic events or unstable coronary artery (incl. coronary artery bypass graft (CABG) surgery),
• Liver impairment (alanine aminotransferase > 2x upper limit, serum albumin < 25 g/l or Child-Pugh Score = 10)
• Renal impairment (creatinine clearance < 30 mL/min).
• Having received >14 days of tetracycline or non-steroidal anti-inflammatory medication within the previous 2 months, or having a history of sensitivity or intolerance to these classes of drugs.
• Chronic severe hypertension (systolic BP > 170 mmHg).
• Serology positive for hepatitis-B surface antigen, hepatitis-C antibodies or HIV antibodies.
• Received electroconvulsive therapy < 2 months prior to screening.
• Blood donation in 30 days prior to screening.
• Pregnancy or breastfeeding.
• Currently enrolled in an intervention study.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Inflammation
• Major Depressive Disorder

Intervention

Drug:
• Celecoxib
Oral capsule, 200 mg, twice daily, for 12 weeks
• Minocyclin
Oral capsule, 100 mg, twice daily, for 12 weeks
• Placebo
Oral capsule, no active substance, twice daily, for 12 weeks

Locations

Country	Name	City	State
Belgium	UZ Brussel	Brussels
Belgium	UPC Duffel	Duffel	Antwerpen
Belgium	Katholiek Universiteit Leuven Campus Kortenberg	Leuven

Sponsors (5)

Lead Sponsor	Collaborator
Universiteit Antwerpen	Amsterdam UMC, location VUmc, KU Leuven, Research Foundation Flanders, Vrije Universiteit Brussel

Country where clinical trial is conducted

Belgium, 

References & Publications (3)

Carvalho LA, Torre JP, Papadopoulos AS, Poon L, Juruena MF, Markopoulou K, Cleare AJ, Pariante CM. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord. 2013 May 15;148(1):136-40. doi: 10.1016/j.jad.2012.10.036. Epub 2012 Nov 27. — View Citation

Foley EM, Parkinson JT, Kappelmann N, Khandaker GM. Clinical phenotypes of depressed patients with evidence of inflammation and somatic symptoms. Compr Psychoneuroendocrinol. 2021 Aug 5;8:100079. doi: 10.1016/j.cpnec.2021.100079. eCollection 2021 Nov. — View Citation

Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med. 2019 Sep;49(12):1958-1970. doi: 10.1017/S0033291719001454. Epub 2019 Jul 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Immune markers	Cytokines: interleukin-6, interleukin-1ß, tumor necrosis factor a, interferon ?, Interleukin-1 receptor, interleukin-7	T0 -> T6 (12 weeks)
Other	Alternate immune markers	Peripheral blood monocytes (PBMCs)	T0 -> T6 (12 weeks)
Other	Tryptophan pathway metabolites	Kynurenine (KYN), Kynurenic Acid (KYNA), Quinolinic Acid (QA), 3-Hydroxykynurenine (3-HK)	T0 -> T6 (12 weeks)
Other	Vascular and (neuro)trophic factors	Vascular endothelial growth factor (VEGF), Brain-derived neurotrophic factor (BDNF)	T0 -> T6 (12 weeks)
Primary	Change in depressive symptom severity (HDRS-17)	Change in severity of depression measured as the change in the 17-point scale of the Hamilton Depression Rating Scale (HDRS-17; score is ranging from 0 to 52, higher scores indicate higher severity of depressive symptoms) between baseline and endpoint	T0 -> T6 (12 weeks)
Primary	Remission rate of depression (HDRS-17)	Rates of remission measured as a score of =7 on the 17-point scale of the Hamilton Depression Rating Scale (HDRS-17; score is ranging from 0 to 52, higher scores indicate higher severity of depressive symptoms and scores 0-7 are considered as being normal) at endpoint	T0 -> T6 (12 weeks)
Secondary	Change in depressive symptom severity (IDS-30SR)	Change in severity of depression measured as the change in the Inventory of Depressive Symptomatology - Self Report (IDS-SR; score is ranging from 0 to 84, higher scores indicate higher severity of depressive symptoms)	T0 -> T6 (12 weeks)
Secondary	Response rate of depressive symptoms (HDRS-17)	Response rates of the depressive symptoms measured on the 17-point scale of the Hamilton Depression Rating Scale (HDRS-17; score is ranging from 0 to 52, higher scores indicate higher severity of depressive symptoms), with response being defined as a 50% reduction in HDRS-17-score from baseline and partial response as a 25% reduction.	T0 -> T6 (12 weeks)
Secondary	Change in night-time sleep (PSQI)	Change in night-time sleep quality and/or quantity measured on the Pittsburgh Sleep Quality Index (PSQI; score is ranging from 0 to 21, higher scores indicate more sleep disturbances)	T0 -> T6 (12 weeks)
Secondary	Change in anxiety (STAI)	Change in anxiety measured on the Stait Trait Anxiety Inventory-Self Report (STAI; score is ranging from 20 tot 80, higher scores indicate higher levels of anxiety intensity)	T0 -> T6 (12 weeks)
Secondary	Change in core assessment of psychomotor change (CORE)	Change in the degree of psychomotor disturbance (which is as an integral component of melancholia) measured on the Core Assessment Of Psychomotor Change (CORE; score is ranging from 0-54, higher scores indicate higher levels of psychomotor disturbances)	T0 -> T6 (12 weeks)
Secondary	Depressive symptom profiles (IDS-SR)	Profile of the depression measured on the Inventory of Depressive Symptomatology - Self Report (IDS-SR; score is ranging from 0 to 84, higher scores indicate higher severity of depressive symptoms)	T0 -> T6 (12 weeks)
Secondary	Therapy compliance (MARS)	Therapy compliance measured on the Medication Adherence Scale (MARS; score is ranging from 0-10, higher scores indicate better medication adherence)	T0 -> T6 (12 weeks)
Secondary	Adverse effects	Side effects measured with a questionnaire based on the list as used in the Antidepressant Side-Effect Checklist (ASEC-21) and the known side effects of Minocycline and Celecoxib	T0 -> T6 (12 weeks)
Secondary	Metabolic blood markers	Cholesterol (mg/dl), High Density Lipoprotein (HDL) (mg/dl), Low Density Lipoprotein (LDL) (mg/dl), fasting glucose (mg/dl), triglycerides (mg/dl)	T0 -> T6 (12 weeks)
Secondary	Other metabolic measures	Waist circumference (cm), height (cm) will be measured to calculate the BMI (kg/m^2)	T0 -> T6 (12 weeks)
Secondary	Other metabolic measures	Weight (kg) will be measured to calculate the BMI (kg/m^2)	T0 -> T6 (12 weeks)