Simvastatin add-on Treatment to Standard Antidepressant Therapy in Patients With Comorbid Obesity and Major Depression (SIMCODE)

Simvastatin add-on to Escitalopram in Patients With Comorbid Obesity and Major Depression: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial

Major depressive disorder (MDD) and obesity are major contributors to impaired health worldwide. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomized controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Therefore, we hypothesize that Simvastatin add-on to standard antidepressant Escitalopram will improve depression to a greater extent than add-on placebo in patients with comorbid obesity and major depression. We will randomize 160 obese MDD patients at 8 recruiting centers to either Simvastatin or placebo as add-on to Escitalopram for 12 weeks. If successful, our trial would have immediate impact on clinical practice given the fact that Simvastatin and Escitalopram are available as inexpensive generic drugs with established safety.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Depressive Disorder, Major
• Intervention / Treatment: Drug: Simvastatin 40mg; Drug: Placebo oral tablet

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christian Otte, MD; Phone Number: 0049 30 450 617615; Email: christian.otte@charite.de
• Study Contact Backup: Name: Woo Ri Chae, MD; Email: woo-ri.chae@charite.de

Study Locations

• Germany
  • Berlin, Germany, 12203
    • Recruiting
    • Charité - Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie
    • Contact: Christian Otte, MD
    • Contact: Stefan Röpke, MD
  • Berlin, Germany, 12203
    • Recruiting
    • Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Psychosomatik
    • Contact: Kim Hinkelmann, MD
    • Contact: Tobias Hofmann, MD
  • Frankfurt, Germany, 60528
    • Recruiting
    • Universitätsklinikum Frankfurt, Klinik für Psychiatrie, Psychosomatik und Psychotherapie
    • Contact: Andreas Reif, MD
    • Contact: David Prvulovic, MD
  • Greifswald, Germany, 17475
    • Recruiting
    • Universitätsmedizin Greifswald, Klinik und Poliklinik für Psychiatrie und Psychotherapie
    • Contact: Hans J Grabe, MD
    • Contact: Deborah Janowitz, MD
  • Hamburg, Germany, 20246
    • Recruiting
    • Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Psychiatrie und Psychotherapie
    • Contact: Gregor Leicht, MD
    • Contact: Daniel Schöttle, MD
  • Hannover, Germany, 30625
    • Not yet recruiting
    • Medizinische Hochschule Hannover, Klinik für Psychiatrie, Sozialpsychiatrie und Psychotherapie
    • Contact: Kai G Kahl, MD
    • Contact: Tillmann Krüger, MD
  • Leipzig, Germany, 04103
    • Recruiting
    • Universitätsklinikum Leipzig, Klinik und Poliklinik für Psychiatrie und Psychotherapie
    • Contact: Maria Strauss, MD
    • Contact: Barbara Ettrich, MD
  • Lübeck, Germany, 23538
    • Not yet recruiting
    • Universitätsklinikum Schleswig-Holstein, Zentrum für Integrative Psychiatrie - Klinik für Psychiatrie und Psychotherapie
    • Contact: Philipp Klein, MD
    • Contact: Klaus Junghanns, MD
  • Stralsund, Germany
    • Recruiting
    • Helios Hanseklinikum Stralsund Klinik und Poliklinik für Psychiatrie, Psychotherapie und Psychosomatik
    • Contact: Deborah Janowitz, MD
    • Contact: Robert Fleischmann, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent is present
• The patient has the capacity to give consent (He/she is able to understand the nature and anticipated effects/side effects of the proposed medical intervention)
• The patient has a major depressive episode according to DSM 5 (Diagnostic and Statistical Manual of Mental Disorders 5th Edition)
• The patient has a score of ≥ 18 in the Montgomery-Asberg Depression Rating Scale (MADRS)
• The patient has a body mass index ≥ 30
• The patient's age is between 18 and 65 years (≥ 18 und ≤ 65)
• The patient has not given childbirth within the 6 months prior to study entry and is not breastfeeding
• In case of non-psychotropic medication: The patient received stable pharmacological medication for at least 14 days prior to study entry (any changes in medication dose or frequency of therapy must be answered with no)
• The patient did not take antidepressants during the last 7 days prior to study entry (discontinuation of effective medication to enable study participation is prohibited)
• The patient did not receive prior treatment with Escitalopram in index episode
• The patient had less than three (<3) trials with antidepressants in index episode
• The patient does not have a history of non-response to Escitalopram
• The patient did not receive treatment with ketamine, irreversible MAO inhibitor (e.g. tranylcypromine), electroconvulsive therapy (ECT) or other stimulatory treatments in index episode
• The patient does not meet any of the following criteria: schizophrenia, schizoaffective disorder, bipolar disorder
• 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 have clinically relevant elevated liver enzymes [GOT or GPT > 3 x upper limit normal (ULN)] and does not have elevated Carbohydrate Deficient Transferrin (CDT) ≥ 2.4 %
• 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 M.I.N.I. for DSM-5 and a urine/serum drug screening is negative (except for benzodiazepines and opiates)
• The patient does not have a history of suicide attempt
• The patient does not have diagnosed epilepsy or increased bleeding diathesis or a history of angle closure glaucoma or other glaucomas
• The patient did not have bariatric surgery prior to study entry
• The patient does not have a known allergy or contraindication against Escitalopram or Simvastatin
• The patient does not meet any of the following criteria: hereditary muscle disease, known history of rhabdomyolysis, elevated creatine kinase (CK) outside of the sex-specific reference intervals, history of muscular symptoms under treatment with statins or fibrates
• The patient does not have elevated TSH level outside of the age- and sex-specific refer-ence intervals.
• The patient does not have insulin-dependent diabetes mellitus
• The patient does not have uncontrolled hepatic disorder, renal or cardiovascular disease
• The patient does not have untreated hypothyroidism
• The patient does not have a history of myocardial infarction or stroke
• The patient does not have symptomatic peripheral arterial disease
• The patient does not have monogenic familial hypercholesterolemia
• The patient does not have clinically significant laboratory abnormalities
• The patient did not participate in other interventional trials during the 6 months before and at the time of this trial
• 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

Exclusion Criteria:

• The patient has current use of statins (for visits 2-6 applies: except for IMP Simvastatin)
• The patient has current use of antidepressants (for visits 2-6 applies: except for standard medication Escitalopram)
• The patient has acute suicidal tendencies (MADRS Item 10 > 4)
• The patient uses potent CYP3A4-inhibitors (e.g. clarithromycin, erythromycin, HIV protease inhibitors - see "Risks, adverse drug reactions, drug interactions, restrictions, contraindications, procedures in case of emergency")
• The patient uses potent CYP3A4 inductors (Carbamazepine, Efavirenz, Nevirapine, Etravirine).
• The patient uses Fibrates, Amiodarone, Amlodipine, Verapamil, Fluconazol, Diltiazem, Fusidic acid, Niacin or Lomitapide or BCRP-Inhibitors (e.g. Elbasvir or Grazoprevir)
• The patient uses Gemfibrozil, Ciclosporin or Danazol
• The patient has known hypersensitivity to other ingredients of Simvastatin and Escitalopram [butylated hydroxyanisole, microcrystalline celluose, citric acid, starch, lactose, magnesium stearate, hypromellose, talc, titanium dioxide, iron oxides, colloidal silicon dioxide, croscarmellose sodium, polyethylene glycol]
• The patient uses medication that is associated with QTc-prolongation [antiarrhythmics class IA and III, antipsychotics (e.g. Haloperidol), phenothiazines, tricyclic antidepressants, antibiotics (e.g. Moxifloxacin), and certain antihistaminergic drugs (e.g. Astemizol, Mizolastine)]
• The patient has clinically significant abnormalities in 12-lead ECG (e.g. QTc-prolongation ≥ 500 ms or increase ≥ 60 ms from baseline visit)
• The patient is pregnant
• The patient with childbearing potential is not willing to use an acceptable form of contraception (defined as Pearl index < 1)
• The patient has current use of psychotropic medication (e.g. antipsychotics, anticonvulsants, lithium or St. John's Wort) except for benzodiazepines, non-benzodiazepines and opiates
• The patient uses nonselective, irreversible monoamine oxidase (MAO) inhibitor (e.g. Tranylcypromine) or selective, reversible inhibitor of monoamine oxidase A (e.g. Moclobemide) or the nonselective, reversible monoamine oxidase inhibitor Linezolid
• The patient is unwilling to consent to saving, processing and propagation of pseudonymized medical data for study reasons
• The patient is legally detained in an official institution

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Simvastatin; Simvastatin and Escitalopram	Drug: Simvastatin 40mg; 12 weeks 40 mg Simvastatin add-on; Other Names: Zocor; C10AA01
Placebo Comparator: Placebo; Placebo and Escitalopram	Drug: Placebo oral tablet; 12 weeks Placebo add-on

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change score in MADRS (Montgomery-Asberg-Depression Rating Scale)	The MADRS is a rating scale to measure depression severity. Each MADRS item is rated on a 0 to 6 scale. Total score range from 0-60, where higher MADRS scores indicate higher levels of depressive symptoms.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MADRS-response	Response is defined as 50% MADRS score reduction at week 12 from baseline.	12 weeks
MADRS-remission	Remission is defined as a MADRS score less than 10 at week 12.	12 weeks
MADRS-MCID	MADRS Minimal Clinically Important Difference represents the smallest improvement that is considered meaningful by the patient. Empirically, the MCID using the MADRS has been identified as a change from baseline between 1.6 - 1.9 at week 12.	12 weeks
Change score in BDI-II (Beck Depression Inventory-II)	The Beck Depression Inventory-II (BDI-II) is a 21-item validated instrument for the self-report of depressive symptoms, with individual item scores summed to yield a total possible BDI score that ranges from 0-63. BDI scores from 0-13 suggest absent to minimal depressive symptoms, from 14-19 mild symptoms, from 20-28 moderate symptoms, and from 29-63 severe symptoms.	12 weeks
BDI-II-MCID	BDI-II Minimal Clinically Important Difference represents the smallest improvement that is considered meaningful by the patient.	12 weeks
Change score in PGIC (Patients' Global Impression of Change Scale)	Participant rated instrument to measure participant's change in overall status on a scale of 0 to 7; range from 1 (very much improved) to 7 (very much worse).	12 weeks
Change score in CGI-S (Clinicians' Global Impression of Severity of Illness)	The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. The CGI-S permits a global evaluation of the participant's condition at a given time.	12 weeks
CGI-I (Clinicians' Global Impression of Improvement )	Clinician rated instrument to measure clinicians' change in overall status on a scale of 0 to 7; range from 1 (very much improved) to 7 (very much worse).	12 weeks
EQ-5D-3L (EuroQol-5 Dimensions-3 Levels Questionnaire)	Generic instrument of quality of life related to health. It contains five dimensions of health (mobility, personal care, daily activities, pain / discomfort and anxiety / depression) and each of them has three levels of seriousness (without problems, some problems or moderate problems and serious problems). The second part of the EQ-5D is a Visual Analogue Scale (VAS) of 20 centimeters, millimeter, ranging from 0 (worse health status imaginable) to 100 (best imaginable health status). In it, the individual must mark the point in the vertical line that best reflects the assessment of their global health status today.	12 weeks
SOFAS (Social and Occupational Functioning Assessment Scale)	The SOFAS is a rating scale used to determine social functioning; range from 0-100. A higher score represents a better outcome.	12 weeks

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: NeuroCure Clinical Research Center, Charite, Berlin; University Medical Center Goettingen
• Investigators: Principal Investigator: Christian Otte, MD, Charite University, Berlin, Germany

Publications and helpful links

General Publications

• Otte C, Chae WR, Nowacki J, Kaczmarczyk M, Piber D, Roepke S, Marschenz S, Lischewski S, Schmidt S, Ettrich B, Grabe HJ, Hegerl U, Hinkelmann K, Hofmann T, Janowitz D, Junghanns K, Kahl KG, Klein JP, Krueger THC, Leicht G, Prvulovic D, Reif A, Schoettle D, Strauss M, Westermair A, Friede T, Gold SM. Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial. BMJ Open. 2020 Dec 1;10(12):e040119. doi: 10.1136/bmjopen-2020-040119.

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2020
• Primary Completion (Anticipated): February 1, 2025
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: March 6, 2020
• First Submitted That Met QC Criteria: March 9, 2020
• First Posted (Actual): March 10, 2020

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 16, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Depressive Disorder; Obesity; Depressive Disorder, Major; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: SIMCODE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No