Jørgensen et al. Syst Rev (2021) 10:227 https://doi.org/10.1186/s13643-021-01789-0 PROTOCOL Open Access Tricyclic antidepressants versus ‘active placebo’, placebo or no intervention for adults with major depressive disorder: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis Caroline Kamp Jørgensen1* , Sophie Juul1,2,3, Faiza Siddiqui1, Marija Barbateskovic1, Klaus Munkholm4, Michael Pascal Hengartner5, Irving Kirsch6, Christian Gluud1 and Janus Christian Jakobsen1,7 Abstract Background: Major depressive disorder is a common psychiatric disorder causing great burden on patients and societies. Tricyclic antidepressants are frequently used worldwide to treat patients with major depressive disorder. It has repeatedly been shown that tricyclic antidepressants reduce depressive symptoms with a statistically signifcant efect, but the efect is small and of questionable clinical importance. Moreover, the benefcial and harmful efects of all types of tricyclic antidepressants have not previously been systematically assessed. Therefore, we aim to investigate the benefcial and harmful efects of tricyclic antidepressants versus ‘active placebo’, placebo or no intervention for adults with major depressive disorder. Methods: This is a protocol for a systematic review with meta-analysis that will be reported as recommended by Pre- ferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, bias will be assessed with the Cochrane Risk of Bias tool—version 2, our eight-step procedure will be used to assess if the thresholds for clinical signifcance are crossed, Trial Sequential Analysis will be conducted to control random errors and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases and trial registers, such as CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov from their inception to 12 May 2021. Clinical study reports will be applied for from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results from the literature searches, extract data and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing tricyclic antidepressants with ‘active placebo’, placebo or no intervention for adults with major depressive disorder. The following interventions will be assessed: amineptine, amitriptyline, amoxapine, butriptyline, cianopramine, clomipramine, desipramine, demexiptiline, dibenzepin, dosule- pin, dothiepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, melitracen, metapramine, nortriptyline, noxiptiline, opipramol, protriptyline, tianeptine, trimipramine and quinupramine. Primary outcomes will be depressive *Correspondence: [email protected] 1 Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital – Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jørgensen et al. Syst Rev (2021) 10:227 Page 2 of 12 symptoms, serious adverse events and quality of life. Secondary outcomes will be suicide or suicide-attempts and non-serious adverse events. If feasible, we will assess the intervention efects using random-efects and fxed-efect meta-analyses. Discussion: Tricyclic antidepressants are recommended by clinical guidelines and frequently used worldwide in the treatment of major depressive disorder. There is a need for a thorough systematic review to provide the necessary background for weighing the benefts against the harms. This review will ultimately inform best practice in the treat- ment of major depressive disorder. Systematic review registration: PROSPERO CRD42 02122 6161. Keywords: Antidepressants, Tricyclic antidepressants, Major depressive disorder, Benefcial efects, Adverse efects Background [16–18]. Te World Health Organisation Model List of Description of the condition Essential Medicines includes the tricyclic antidepressant Major depressive disorder is a psychiatric condition char- amitriptyline as one of just two essential antidepressants acterised by depressed mood and diminished interest for the treatment of major depressive disorder [19]. or pleasure [1]. Major depressive disorder is associated with cognitive defcits leading to functional and occupa- Why is it important to do this review? tional impairment [2]. Te prevalence of major depres- Several systematic reviews with meta-analysis have sive disorder is estimated to be more than 264 million assessed the benefcial efects of tricyclic antidepressants people globally, making it one of the leading contributors and have concluded that tricyclic antidepressants reduce to functional disability [3]. Additionally, the high preva- depressive symptoms with a statistically signifcant efect lence of major depressive disorder leads to an extensive for patients with major depressive disorder [20–23]. economic burden estimated at more than 210 billion US Some systematic reviews have concluded that tricyclic dollars annually in the US alone, deriving from direct antidepressants, either as a drug class [20] or as an indi- medical costs as well as costs related to occupational vidual drug [21], are indeed the most efective antide- disability and comorbidities [4]. Furthermore, major pressants [20, 21]. However, the efect sizes of tricyclic depressive disorder is associated with an increased risk antidepressants were small and may not be important of suicidal behaviour, with an estimated 15% of patients to the average patient [24]. Furthermore, trials compar- having attempted suicide at least once in their lifetime ing antidepressants with ‘active placebo’ (a placebo that [5–7]. mimics the adverse efects of the experimental interven- tion) indicate that the benefcial efects may in fact be Description of interventions infated due to the unblinding efects of using an inert Tricyclic antidepressants are a group of frst-genera- placebo [25]. tion antidepressants commonly used for treating major Tricyclic antidepressants are associated with a broad depressive disorder, obsessive–compulsive disorder and spectrum of adverse efects, but the serious and non-seri- chronic pain [8, 9]. Te frst tricyclic antidepressant, ous adverse events associated with all types of tricyclic imipramine, was developed in the 1950s by modifying antidepressants have not been systematically assessed in the phenothiazine ring and substituting sulphur with an adults with major depressive disorder. A recent network ethylene bridge [9]. Te majority of tricyclic antidepres- meta-analysis published in Te Lancet in 2018 included sants function as serotonin and norepinephrine reuptake placebo-controlled and head-to-head trials to assess the reuptake inhibitors [10, 11]. By blocking the reuptake of efects of 21 commonly used antidepressants, including monoamine neurotransmitters in the presynaptic neu- two tricyclic antidepressants, amitriptyline and clomi- ron, tricyclic antidepressants theoretically increase the pramine [21]. Te results showed that antidepressants levels of serotonin and norepinephrine in the synaptic compared with placebo seemed to reduce depressive cleft [10, 12]. However, the role of monoamines in major symptoms with a statistically signifcant efect (standard- depression is unclear and the exact mechanism of action ised mean diference (SMD) 0.30, 95% credibility interval of tricyclic antidepressants is uncertain [10, 13–15]. 0.26 to 0.34) [21]. Te results also showed that amitrip- Whilst selective serotonin reuptake inhibitors are gen- tyline was the most efective antidepressant for reducing erally recommended as frst-line treatment for major depressive symptoms (odds ratio (OR) 2.30, 95% cred- depressive disorder, tricyclic antidepressants are amongst ibility interval 1.89 to 2.41), and that clomipramine was recommended treatments for patients whose condition one of the least efective antidepressants for reducing does not improve after treatment with newer medications depressive symptoms in the meta-analysis (OR 1.49, 95% Jørgensen et al. Syst Rev (2021) 10:227 Page 3 of 12 credibility interval 1.21 to 1.85) [21]. However, neither Given the limitations of extant systematic reviews, we serious nor non-serious adverse events were assessed. aim to investigate