Research Article: Inflammatory mediators and dual depression: Potential biomarkers in plasma of primary and substance-induced major depression in cocaine and alcohol use disorders

Date Published: March 14, 2019

Publisher: Public Library of Science

Author(s): Nuria García-Marchena, Marta Barrera, Joan Ignasi Mestre-Pintó, Pedro Araos, Antonia Serrano, Clara Pérez-Mañá, Esther Papaseit, Francina Fonseca, Juan Jesús Ruiz, Fernando Rodríguez de Fonseca, Magí Farré, Francisco Javier Pavón, Marta Torrens, Daimei Sasayama.


Major depressive disorder (MDD) is the most prevalent comorbid mental disorder among people with substance use disorders. The MDD can be both primary and substance-induced and its accurate diagnosis represents a challenge for clinical practice and treatment response. Recent studies reported alterations in the circulating expression of inflammatory mediators in patients with psychiatric disorders, including those related to substance use. The aim of the study was to explore TNF-α, IL-1β, CXCL12, CCL2, CCL11 (eotaxin-1) and CX3CL1 (fractalkine) as potential biomarkers to identify comorbid MDD and to distinguish primary MDD from substance-induced MDD in patients with substance disorders. Patients diagnosed with cocaine (CUD, n = 64) or alcohol (AUD, n = 65) use disorders with/without MDD were recruited from outpatient treatment programs [CUD/non-MDD (n = 31); CUD/primary MDD (n = 18); CUD/cocaine-induced MDD (N = 15); AUD/non-MDD (n = 27); AUD/primary MDD (n = 16) and AUD/alcohol-induced MDD (n = 22)]. Sixty-two healthy subjects were also recruited as control group. Substance and mental disorders were assessed according to “Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision” (DSM-IV-TR) and a blood sample was collected for determinations in the plasma. The cocaine group showed lower TNF-α (p<0.05) and CCL11 (p<0.05), and higher IL-1β (p<0.01) concentrations than the control group. In contrast, the alcohol group showed higher IL-1β (p<0.01) and lower CXCL12 (p<0.01) concentrations than the control group. Regarding MDD, we only observed alterations in the cocaine group. Thus, CUD/MDD patients showed lower IL-1β (p<0.05), CXCL12 (p<0.05) and CCL11 (p<0.05), and higher CXC3CL1 (p<0.05) concentrations than CUD/non-MDD patients. Moreover, while CUD/primary MDD patients showed higher CCL11 (p<0.01) concentrations than both CUD/non-MDD and CUD/cocaine-induced MDD patients, CUD/cocaine-induced MDD patients showed lower CXCL12 (p<0.05) concentrations than CUD/non-MDD patients. Finally, a logistic regression model in the cocaine group identified CXCL12, CCL11 and sex to distinguish primary MDD from cocaine-induced MDD providing a high discriminatory power. The present data suggest an association between changes in inflammatory mediators and the diagnosis of primary and substance-induced MDD, namely in CUD patients.

Partial Text

Major depressive disorder (MDD) is the most prevalent comorbid mental condition in subjects with substance use disorders (SUD) and closely related to their poor prognosis. As expected, due to their marked clinical severity, these dual diagnosed patients also present considerable psychosocial acuteness and make greater use of health resources, including emergency services and psychiatric admissions [1–3]. The identification of MDD in substance users, however, is often complicated because of its inherent characteristics, that is to say, the acute and chronic effects related to substance consumption/withdrawal can mimic depression. Currently, diagnosis is syndromic and established with clinical criteria using “Diagnostic and Statistical Manual of Mental Disorders 4th Edition Text Revision” (DSM-IV-TR), “DSM 5th Edition” (DSM-5) [4–5] or “International Classification of Diseases and Related Health Problems 10th Edition” (ICD-10) [6], the availability of specific biomarkers to facilitate the diagnosis of MDD in SUD are therefore required [7]. Among others, modulation of inflammatory mediators such as cytokines and chemokines has been recognized as a possible target. A growing body of literature has established that cytokines can play a critical role in the pathogenesis of both MDD [8–9] and SUD [10–13]. Preclinical and clinical studies in MDD and SUD have reported alterations in the immune system and dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) [14–15]. These changes result in a chronic inflammatory response and a disruption of brain integrity and homeostasis as consequence of neuroinflammation [16]. In the brain, glial activation results in the release of cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), inflammatory mediators that influence the central immune system, modulate neural activity, and regulate the HPA axis [14, 17–18]. Chemokines, small chemoattractant proteins, also act as modulators in neuronal transmission and participate in the communication between glia and neurons [8, 19].

The main findings of this observational study are as follows: (a) There were differences in the plasma concentrations of some inflammatory mediators between CUD (TNF-α, IL-1β and CCL11) and AUD (IL-1β and CXCL12) patients when compared with control subjects; (b) CUD patients diagnosed with comorbid MDD showed significant differences in plasma concentrations of IL-1β, CXCL12, CCL11 and CX3CL1. In contrast, there were no differences in the alcohol group; (c) Plasma CCL11 concentrations were found to be higher in CUD patients with primary MDD than those with cocaine-induced MDD.

Patients with dual depression have worse clinical evolution and worse therapeutic response. Namely, the efficacy of antidepressant medication and/or psychological therapies in patients with AUD or CUD and comorbid MDD can be influenced by the type of depression (i.e. primary and substance-induced MDD) (DSM-IV-TR). However, there are no biological substrates that can reveal the difference between both mental conditions for a better clinical management of these patients. The present study represents an attempt at the identification of inflammatory biomarkers for the differentiation between primary and substance-induced disorders. Although our findings indicate that plasma concentrations of chemokine CCL11 could act as a potential biological marker to differentiate between primary and substance-induced MDD in CUD patients, further clinical research is necessary to confirm the role of inflammatory mediators in dual depression.




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