Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

Abstract

Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance-related processes may be involved in several phenotypes, including the TRD.

Trial registration: ClinicalTrials.gov NCT00021528.

Figure 1

Relative expression mRNA levels of PSMD13 rs3817629. Box-plots showing the median, quartiles and extreme values of relative expression of PSMD13 rs3817629 A allele carriers with respect to GG subjects. The bold lines represent median values, the box boundaries mark the 25th and 75th percentiles of each distribution, respectively. Whiskers, above and below the hinges, mark the largest and smallest observed values. (a) the analysis was performed in all subjects; (b) only in MDD group; (c) only in control group. '*' Indicates significant difference (P-value<0.05) computed by the Mann–Whitney U non-parametric test. MDD, major depressive disorder.

Figure 2

Relative expression mRNA levels of PSMD9 rs1043307. Box-plots showing the median, quartiles and extreme values of relative expression of PSMD9 rs1043307 in (a) MDD patients and controls; (b) in healthy subjects, TRD and non-TRD. The bold lines represent median values, the box boundaries mark the 25th and 75th percentiles of each distribution, respectively. Whiskers, above and below the hinges, mark the largest and smallest observed values, respectively. '**' Indicates significant difference (P-value<0.01), whereas '***' indicates a P-value <0.001, computed by the Kruskal–Wallis and Mann–Whitney U non-parametric tests.