Clinical trial NCT04301271: Simvastatin add-on Treatment to Standard Antidepressant Therapy in Patients With Comorbid Obesity and Major Depression
Official title: Simvastatin add-on to Escitalopram in Patients With Comorbid Obesity and Major Depression: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Depressive Disorder, Major
Obesity
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: NeuroCure Clinical Research Center, Charite, Berlin
name: University Medical Center Goettingen
First posted: 2020-03-10
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Change score in MADRS (Montgomery-Asberg-Depression Rating Scale)
timeFrame: 12 weeks
Secondary outcomes:
measure: MADRS-response
timeFrame: 12 weeks
measure: MADRS-remission
timeFrame: 12 weeks
measure: MADRS-MCID
timeFrame: 12 weeks
measure: Change score in BDI-II (Beck Depression Inventory-II)
timeFrame: 12 weeks
measure: BDI-II-MCID
timeFrame: 12 weeks
measure: Change score in PGIC (Patients' Global Impression of Change Scale)
timeFrame: 12 weeks
measure: Change score in CGI-S (Clinicians' Global Impression of Severity of Illness)
timeFrame: 12 weeks
measure: CGI-I (Clinicians' Global Impression of Improvement )
timeFrame: 12 weeks
measure: EQ-5D-3L (EuroQol-5 Dimensions-3 Levels Questionnaire)
timeFrame: 12 weeks
measure: SOFAS (Social and Occupational Functioning Assessment Scale)
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Psychosomatik
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt, Klinik für Psychiatrie, Psychosomatik und Psychotherapie
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald, Klinik und Poliklinik für Psychiatrie und Psychotherapie
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Psychiatrie und Psychotherapie
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Psychiatrie, Sozialpsychiatrie und Psychotherapie
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Klinik und Poliklinik für Psychiatrie und Psychotherapie
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Zentrum für Integrative Psychiatrie - Klinik für Psychiatrie und Psychotherapie
city: Stralsund
country: Germany
facility: Helios Hanseklinikum Stralsund Klinik und Poliklinik für Psychiatrie, Psychotherapie und Psychosomatik
Study officials:
affiliation: Charite University, Berlin, Germany
name: Christian Otte, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.