Adjunctive simvastatin for treatment-resistant depression: study protocol of a 12-week randomised controlled trial

Husain, Muhammad Ishrat; Chaudhry, Imran B; Khoso, Ameer B; Husain, Muhammad; Rahman, Raza Ur; Hamirani, Munir; Hodsoll, John; Carvalho, André F.; Husain, Nusrat; Young, Allan H.

doi:10.1192/bjo.2018.84

Cited by 18 publications

(17 citation statements)

References 47 publications

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“…Likewise, evidence from most observational studies in non-depressed populations reported that simvastatin had the most beneficial effects (87,90), though another study reported a conflicting finding (76). Again, data from the previously mentioned ongoing trials (146,147), which are both using the highly lipophilic simvastatin, possibly corroborated by further observational studies comparing the effects of individual lipophilic and hydrophilic statins, could provide further useful evidence.…”

Section: Discussionmentioning

confidence: 87%

Statins in Depression: An Evidence-Based Overview of Mechanisms and Clinical Studies

et al. 2021

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Background: Depression is a leading cause of disability, burdened by high levels of non-response to conventional antidepressants. Novel therapeutic strategies targeting non-monoaminergic pathways are sorely needed. The widely available and safe statins have several putative mechanisms of action, especially anti-inflammatory, which make them ideal candidates for repurposing in the treatment of depression. A large number of articles has been published on this topic. The aim of this study is to assess this literature according to evidence-based medicine principles to inform clinical practise and research.Methods: We performed a systematic review of the electronic databases MEDLINE, CENTRAL, Web of Science, CINAHL, and ClinicalTrials.gov, and an unstructured Google Scholar and manual search, until the 9th of April 2021, for all types of clinical studies assessing the effects of statins in depression.Results: Seventy-two studies were retrieved that investigated the effects of statins on the risk of developing depression or on depressive symptoms in both depressed and non-depressed populations. Fifteen studies specifically addressed the effects of statins on inflammatory-related symptoms of anhedonia, psychomotor retardation, anxiety, and sleep disturbances in depression. Most studies suggested a positive effect of statins on the occurrence and severity of depression, with fewer studies showing no effect, while a minority indicated some negative effects.Limitations: We provide a narrative report on all the included studies but did not perform any quantitative analysis, which limits the strength of our conclusions.Conclusions: Robust evidence indicates that statins are unlikely to lead to depressive symptoms in the general population. Promising data suggest a potential role for statins in the treatment of depression. Further clinical studies are needed, especially in specific subgroups of patients identified by pre-treatment assessments of inflammatory and lipid profiles.

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Section: Discussionmentioning

confidence: 87%

Statins in Depression: An Evidence-Based Overview of Mechanisms and Clinical Studies

et al. 2021

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“…Because there is evidence for central inflammation in depressed patients [ 49 ], it is possible that drugs able to modulate brain inflammatory mechanisms directly may be more therapeutically active. Further clinical trials of statins in depressed patients should therefore consider the specific statins profile when selecting the molecule to be used: a currently running randomised controlled trial chose indeed to use simvastatin in addition to antidepressant [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Statins for major depressive disorder: A systematic review and meta-analysis of randomized controlled trials

et al. 2021

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Background The burden of depressive disorder is large and new treatment approaches are required. Repurposing widely available drugs such as statins may be a time- and cost-effective solution. Statins have anti-inflammatory and anti-oxidant properties which have been shown to be relevant to the pathophysiology of depression. This study assesses the efficacy, acceptability, tolerability, and safety of statins in major depressive disorder. Methods Our study is an update and extension of a previous meta-analysis published in 2016 by Salagre et al. We performed a systematic review (PubMed/MEDLINE, Cochrane CENTRAL, ISI Web of Science, CINAHL, and ClinicalTrials.gov until the 1st September 2020) and meta-analysis of randomized controlled trials using any statin against placebo or any other statin in the treatment of major depressive disorder. Our primary efficacy outcome measure was the mean value on any standardized scale for depressive symptoms at 8 weeks of treatment. We also calculated outcomes for efficacy, response, and remission at 2, 4, and 12 weeks, as well as acceptability (dropouts for any cause), tolerability (dropouts due to any adverse event), and safety (any adverse event) outcomes at the studies’ endpoints. Furthermore, we conducted an exploratory network meta-analysis for the primary efficacy outcome to identify potential differences between statins. Results We retrieved five randomized controlled trials meeting our inclusion criteria: four used a statin in addition to an antidepressant and compared it to placebo plus antidepressant, and one compared two statins alone. and one comparing one statin with another. Statins compared to placebo in addition to antidepressants were efficacious at 8 weeks (N = 255, SMD = -0.48, 95% CI = -0.74 to -0. 22) and 12 weeks (N = 134, SMD = -0.47, 95% CI = -0.89 to -0.05, moderate certainty) with no difference for acceptability, tolerability, and safety (low certainty). An exploratory network meta-analysis suggested that the most lipophilic statins, especially simvastatin, could be more efficacious than less lipophilic or hydrophilic molecules. Conclusions This systematic review suggests the efficacy, acceptability, tolerability, and safety of statins in addition to antidepressants in patients with major depressive disorder. Further clinical trials in different settings are required to test this result. Trial rgistration PROSPERO registration: CRD42020170938.

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“…Our findings could have implications for antiinflammatory treatment 6,65 and preventative care [66][67][68][69] in a subgroup of depressed patients with sickness-behaviorrelated symptoms 70 . Research is underway to investigate the effects of anti-TNF-alpha biologic infliximab on measures of anhedonia, motivational behavior, and glutamatergic changes in the basal ganglia 71 and to investigate the effects of simvastatin for treatment-resistant MDD 72 and patients with comorbid obesity and MMD 73 . We recommend that future studies approach depression as a group of separate symptoms rather than as a unified construct.…”

Section: Discussionmentioning

confidence: 99%

Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression

et al. 2020

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Multiple studies show an association between inflammatory markers and major depressive disorder (MDD). People with chronic low-grade inflammation may be at an increased risk of MDD, often in the form of sickness behaviors. We hypothesized that inflammation is predictive of the severity and the course of a subset of MDD symptoms, especially symptoms that overlap with sickness behavior, such as anhedonia, anorexia, low concentration, low energy, loss of libido, psychomotor slowness, irritability, and malaise. We tested the association between basal and lipopolysaccharide (LPS)-induced inflammatory markers with individual MDD symptoms (measured using the Inventory of Depressive Symptomatology Self-Report) over a period of up to 9 years using multivariate-adjusted mixed models in 1147-2872 Netherlands Study of Depression and Anxiety (NESDA) participants. At baseline, participants were on average 42.2 years old, 66.5% were women and 53.9% had a current mood or anxiety disorder. We found that basal and LPSstimulated inflammatory markers were more strongly associated with sickness behavior symptoms at up to 9-year follow-up compared with non-sickness behavior symptoms of depression. However, we also found significant associations with some symptoms that are not typical of sickness behavior (e.g., sympathetic arousal among others). Inflammation was not related to depression as a unified syndrome but rather to the presence and the course of specific MDD symptoms, of which the majority were related to sickness behavior. Anti-inflammatory strategies should be tested in the subgroup of MDD patients who report depressive symptoms related to sickness behavior.

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Adjunctive simvastatin for treatment-resistant depression: study protocol of a 12-week randomised controlled trial

Cited by 18 publications

References 47 publications

Statins in Depression: An Evidence-Based Overview of Mechanisms and Clinical Studies

Statins in Depression: An Evidence-Based Overview of Mechanisms and Clinical Studies

Statins for major depressive disorder: A systematic review and meta-analysis of randomized controlled trials

Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression

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