N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial

Abstract

BackgroundA subgroup of depressed patients with increased inflammatory activity was shown to be more susceptible to develop Treatment Resistant Depression (TRD). Earlier studies with anti-inflammatory drugs have shown benefits in the treatment of major depressive disorder (MDD), but the effects are expected to be higher in patients with increased inflammatory activity. Supplementation of N-acetylcysteine (NAC) to ongoing antidepressant therapy may positively influence outcome of depression treatment in these patients. Therefore, this study aims to investigate the efficacy of NAC supplementation in patients with insufficient response to standard antidepressant treatment, and to explore potential roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD.Methods/designA double-blind randomized placebo-controlled study comparing NAC versus placebo as add-on medication to antidepressant treatment with 12-week treatment and 8-week follow up in patients with TRD and increased inflammatory activity. Apart from clinical efficacy defined as the change in Hamilton Depression Rating Scale (HAMD)-17 score, secondary outcomes include changes in pathophysiological mechanisms related to depression as well as changes in local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). Importantly, sole patients with CRP levels with values between 0.85 and 10 mg/L will be included.DiscussionThis is the first clinical trial taking both TRD and increased inflammatory activity as inclusion criteria. This study will provide reliable evidence for the efficacy of NAC in patients with TRD displaying increased inflammatory activity. And this study also will help explore further the roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD.Trial registrationThe trial protocol has been registered on “ClinicalTrials.gov“with protocol ID “NAC-2015-TJAH” and ClinicalTrials.gov ID “NCT02972398”.

Antidepressant-Like Activity of Myelophil via Attenuation of Microglial-Mediated Neuroinflammation in Mice Undergoing Unpredictable Chronic Mild Stress

“…We used NAC as a positive control because the antidepressant-like effects of NAC have been explored in several studies (Ferreira et al, 2008; Costa-Campos et al, 2013). One study group is planning to evaluate the inflammation-inhibiting NAC effects on depressive disorder in a randomized placebo-controlled trial (Yang et al, 2018).…”

N-Acetylcysteine (NAC): Impacts on Human Health

“…In MDD, inflammatory and oxidative processes seem to be part of the pathophysiology of depression. Inflammation markers, proinflammatory cytokines, acute phase proteins, and adhesion molecules are usually elevated in patients with this disorder, contributing to neuroinflammation that appears to be associated with structural and functional abnormalities in the brain and a lower therapeutic response [ 144 ]. Although NAC is a strong candidate for adjunctive treatment of depression, oral supplementation of 1000 mg/day (2 capsules of 500 mg twice daily) associated with the usual treatment of the disease, when compared to placebo, did not produce positive effects on treatment of individuals with MDD (moderate to severe) at the end of 12 weeks.…”

Role of inflammation in depression relapse

“…Third, higher levels of IL-6 or CRP can predict subsequent development of depressive symptoms (e.g., tiredness, lack of energy, sleep problems, and changes in appetite) [23, 24]. Fourth, increased inflammatory activity leads to greater susceptibility to treatment-resistant depression (TRD) [25]. Fifth, intestinal microbes can influence tryptophan metabolism and cause changes in levels of gamma-aminobutyric acid, dopamine, and serotonin [26, 27].…”

“…Yet, neuroimaging findings and peripheral biomarker measurements in patients with rMDD are relatively scarce. A recent study protocol of a double-blind randomized placebo-controlled trial suggested that increased inflammatory activity indicated a greater susceptibility to TRD [25]. Future studies should thus investigate whether there is any cross-sectional or longitudinal association of peripheral biomarker measurements with neuroimaging in depression relapse.…”