Abstract
Major depression disorder (MDD) is the most prevalent psychiatric comorbid condition in cocaine use disorder (CUD). The comorbid MDD might be primary-MDD (CUD-primary-MDD) or cocaine-induced MDD (CUD-induced-MDD), and their accurate diagnoses and treatment is a challenge for improving prognoses. This study aimed to assess the tryptophan/serotonin (Trp/5-HT) system with the acute tryptophan depletion test (ATD), and the kynurenine pathway in subjects with CUD-primary-MDD, CUD-induced-MDD, MDD and healthy controls. The ATD was performed with a randomized, double-blind, crossover, and placebo-controlled design. Markers of enzymatic activity of indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase, kynurenine aminotransferase (KAT) and kynureninase were also established. Following ATD, we observed a decrease in Trp levels in all groups. Comparison between CUD-induced-MDD and MDD revealed significant differences in 5-HT plasma concentrations (512 + 332 ng/mL vs. 107 + 127 ng/mL, p = 0.039) and the Kyn/5-HT ratio (11 + 15 vs. 112 + 136; p = 0.012), whereas there were no differences between CUD-primary-MDD and MDD. Effect size coefficients show a gradient for all targeted markers (d range 0.72–1.67). Results suggest different pathogenesis for CUD-induced-MDD, with lower participation of the tryptophan system, probably more related to other neurotransmitter pathways and accordingly suggesting the need for a different pharmacological treatment approach.
Highlights
Major depression disorder (MDD) is the most prevalent psychiatric comorbid condition in subjects with cocaine use disorder (CUD), and its treatment constitutes a challenge [1]
Some authors have reported no significant differences in Kyn levels between MDD and healthy controls [23], it is generally agreed that higher Kyn levels are found in MDD subjects [24,25,26]
The majority of studies are based on analyses that look for statistically significant differences in concentrations and ratios rather than effect sizes
Summary
Major depression disorder (MDD) is the most prevalent psychiatric comorbid condition in subjects with cocaine use disorder (CUD), and its treatment constitutes a challenge [1]. The acute tryptophan depletion test (ATD) is a standardized method of reducing brain 5-HT through the administration of large neutral amino acids (LNAAs) This limits the transport of endogenous Trp across the blood–brain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. Kyn levels have been observed to correlate with the addition of celecoxib, a cyclooxygenase-2 inhibitor, nonsteroidal anti-inflammatory drug indicated for the treatment of osteoarthritis and rheumatoid arthritis [27,28] in managing MDD [29]. They have been described as predictors of acute responses
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