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

Abstract

Introduction: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. 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 randomised 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. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity.

Methods and analysis: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients' self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12.

Ethics and dissemination: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences.

Trial registration numbers: NCT04301271, DRKS00021119, EudraCT 2018-002947-27.

Keywords: clinical trials; depression & mood disorders; mental health.

Conflict of interest statement

Competing interests: CO reports personal fees from Allergan, Ferring, Fortbildungskolleg, Limes Klinikgruppe, Lundbeck, MedOnline, Medical Tribune, Neuraxpharm, SAGE Therapeutics and Stillachhaus outside the submitted work and reports grants from the German Research Foundation (DFG), German Ministry of Education and Research (BMBF), the European Union (Innovative Medicines Initiative) and the Brain & Behavior Foundation (NARSAD). MK participates in the Berlin Institute of Health - Charité Clinician Scientist Program funded by the Charité—Universitätsmedizin Berlin and the Berlin Institute of Health. SM reports grants from Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) during the conduct of the study. HJG reports grants and personal fees from Fresenius Medical Care, personal fees from Neuraxpharm, Servier, Janssen Cilag and grants from German Research Foundation (DFG), German Ministry of Education and Research (BMBF), Damp Foundation, European Union Joint Programme Neurodegenerative Disorders (JPND) and European Social Fund (ESF) outside the submitted work. UH reports personal fees from Janssen and Servier outside the submitted work. TF reports grants and non-financial support from German Ministry of Education and Research (BMBF) during the conduct of the study. KGK reports personal fees and other from Eli Lilly, Servier and Neuraxpharm, and grants, personal fees and other from Ferrer outside the submitted work. JPK reports grants and personal fees from Servier, personal fees from Springer, Hogrefe, Elsevier and Beltz outside the submitted work. THCK reports grants from German Ministry of Education and Research (BMBF) during the conduct of the study and personal fees from Allergan, Lundbeck, Otsuka, Trommsdorf, Novartis and Schwabe outside the submitted work. AR reports grants and personal fees from Medice, personal fees from Shire/Takeda, Janssen, Neuraxpharm, Servier and SAGE outside the submitted work. DS reports honoraria for lectures from or has been an advisor to Janssen, Lundbeck, Otsuka Pharma, Medice and Takeda. TF reports personal fees from Novartis, Bayer, Janssen, SGS, Roche, Boehringer Ingelheim, Daiichi-Sankyo, Galapagos, Penumbra, Parexel, Vifor, BiosenseWebster, CSL Behring, Fresenius Kabi, Coherex Medical and LivaNova outside the submitted work. SMG reports grants from German Ministry of Education and Research (BMBF), German Research Foundation (DFG), Federal Ministry of Health (BMG), Biogen and National Multiple Sclerosis Society (NMSS) during the conduct of the study and personal fees from Almirall S.A., Mylan, Celgene and FomF outside the submitted work. WRC, JN, DoP, SR, SL,SS, BE, KH, DJ, KJ, GL, DaP, MS and AW have nothing to disclose.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study flow chart according to CONSORT. We assume that we need to screen n=1125 patients aged 18–65 with major depression according to Diagnostic and Statistical Manual of Mental Disorders five and obesity (body mass index ≥30) for eligibility at eight recruiting centres to randomise n=160 participants. The sample size and assumed dropout rate (20%) is conservatively based on three earlier pilot RCTs of add-on statin to SSRI treatment in depressed patients. CONSORT, Consolidated Standards of Reporting Trials; SSRI, selective serotonin reuptake inhibitors; RCT, randomised controlled trials.

Figure 2

Scheme of intervention in SIMCODE study. Overview of design and procedures of the SIMCODE study. BDI-II, Beck-Depressions-Inventar II; BMI, body mass index; CGI-I, Clinicians’ Global Impression of Improvement; CGI-S, Clinicians’ Global Impression of Severity of illness; EQ-5D-3L, Generic Quality of Life Questionnaire; MADRS, Montgomery-Åsberg Depression Scale; MINI, Mini International Neuropsychiatric Interview; PGIC, Patient Global Impression of Change; SOFAS, Social and Occupational Functioning Assessment Scale.