Clinical and biological indicators of tramadol effectiveness as adjunctive pharmacological treatment of major depressive disorder

Abstract

Tramadol is an atypical opioid with a low potential for abuse and dependence. Although studies have pointed to the beneficial effect of adjuvant therapy with tramadol in post-traumatic and obsessive-compulsive stress disorders, no clinical research has been performed so far in patients with major depressive disorder (MDD). Aim: To evaluate the effectiveness of tramadol (daily dose of 150 mg for 14 days) by means of clinical (primary outcome: severity of depressive symptoms, secondary outcome: suicidal ideation) and biological indicators (inflammatory mediators and the hypothalamic-pituitary-adrenal axis reactivity), added to usual treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with severe MDD, compared with placebo adjuvant administration. Method: This is a randomized, double-blind, placebo-controlled clinical trial. The sample will consist of 80 patients with severe MDD diagnosis without psychotic symptoms, of both sexes, aged between 18 and 65 years. Recruitment will occur during hospitalization at the Clinical Hospital Complex, Ribeirão Preto Medical School - University of São Paulo (FMRP/USP). Patients under usual SSRIs treatment will be randomized into two intervention groups: (a) 50 mg of tramadol or (b) placebo (08/08h for 14 days). All the patients will respond to standardized instruments for evaluation of primary and secondary outcomes at the baseline, and at 4, 7, 14, 21, 28 and 84 days after. Blood samples for quantification of plasma concentrations of inflammatory mediators (C-reactive protein, TNF-±, IL-6, IL-10, IL-17A, IL-33 and TGF-²) and saliva samples for the assessment of the HPA axis reactivity (cortisol awakening response) will be collected at the baseline, and at 14, 28 (saliva only) and 84 days later. Statistical analysis: Logistic regression repeated measures MANOVA and MANCOVA tests will be used. Expected results: The adjuvant therapy with tramadol for 14 days will result in significant improvement of: i) the main outcome; ii) the secondary outcome; and iii) the levels of the biological mediators, which will also serve as biological predictors of the primary and secondary outcomes. (AU)