Abstract
The association of cocaine use disorder (CUD) and comorbid major depressive disorder (MDD; CUD/MDD) is characterized by high prevalence and poor treatment outcomes. CUD/MDD may be primary (primary MDD) or cocaine-induced (CUD-induced MDD). Specific biomarkers are needed to improve diagnoses and therapeutic approaches in this dual pathology. Platelet biomarkers [5-HT2A receptor and imidazoline receptor antisera selected (IRAS)/nischarin] were assessed by Western blot in subjects with CUD and primary MDD (n = 16) or CUD-induced MDD (n = 9; antidepressant free, AD−; antidepressant treated, AD+) and controls (n = 10) at basal level and/or after acute tryptophan depletion (ATD). Basal platelet 5-HT2A receptor (monomer) was reduced in comorbid CUD/MDD subjects (all patients: 43%) compared to healthy controls, and this down-regulation was independent of AD medication (decreases in AD−: 47%, and in AD+: 40%). No basal differences were found for IRAS/nischarin contents in AD+ and AD− comorbid CUD/MDD subjects. The comparison of IRAS/nischarin in the different subject groups during/after ATD showed opposite modulations (i.e., increases and decreases) in response to low plasma tryptophan levels with significant differences discriminating between the subgroups of CUD with primary MDD and CUD-induced MDD. These specific alterations suggested that platelet IRAS/nischarin might be useful as a biomarker to discriminate between primary and CUD-induced MDD in this dual pathology.
Highlights
The association of substance use disorders and comorbid major depressive disorder (MDD) is characterized by high prevalence rates (12–80%) [1] and challenging clinical management of patients, implying a great burden for health care systems [2]
The basal content of monomeric 5-HT2A receptor form was markedly reduced in platelets of comorbid cocaine use disorder (CUD)/MDD subjects, when compared with matched controls (100%), and this receptor down-regulation was independent of the presence or absence of antidepressant drugs (AD) medication (Figure 1A, upper panel)
acute tryptophan depletion (ATD) further decreased 5-HT2A receptor density in unmedicated comorbid CUD/MDD subjects (Figure 1B, upper panel), whereas AD medication was associated with an upregulation of 5-HT2A monomeric receptor form
Summary
The association of substance use disorders and comorbid major depressive disorder (MDD) is characterized by high prevalence rates (12–80%) [1] and challenging clinical management of patients, implying a great burden for health care systems [2]. The diagnosis is based on clinical criteria [using DSM-5 [6] or ICD-10 [7]] and there is a need for specific biomarkers to facilitate the differentiation between primary MDD and CUDinduced MDD to improve diagnosis and clinical management. In this sense, there is a growing research about putative biomarkers, mainly involving cytokines, chemokines, several fatty acid derivatives such as endocannabinoids and neurotrophic factors such as brain-derived neurotrophic factor, insulin-like growth factor-1-binding protein 3 [8,9,10]. In a recent post-mortem human brain study, the basal content of I1-IR was marginally increased and downregulated by antidepressant drugs (AD) in the prefrontal cortex of subjects with MDD [15], further suggesting a role of this novel receptor in MDD and in the action mechanisms of AD, including the selective 5-HT re-uptake inhibitors (SSRI) which were the predominant drugs in the medicated depressed patients of the present study
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