Introduction: Stressful events, particularly early life stress (ELS), are among the variables predicting negative treatment outcomes in Major Depressive Disorder (MDD) and are associated with Treatment-Resistant Depression (TRD). Stress-related genes, such as NR3C1 , FKBP5 , and SGK1 , have been suggested as candidate biomarkers relating stressful events and MDD. Trauma focused psychotherapies have been proposed as beneficial approaches for MDD patients exposed to ELS, however the possible mechanisms underlying the effects of these strategies are still poor known and biomarkers for therapy response are not available yet. Objectives: We aimed at investigating: 1) the association between baseline gene expression levels of NR3C1 , FKBP5 , SGK1 and ELS events, 2) changes in symptoms improvement and gene expression modulations during trauma-focused psychotherapy, and 3) correlations between baseline expression levels and clinical outcomes to identify possible biomarkers as predictors of treatment response and relapse. Methods: Forty-one TRD patients assessed for ELS, including a subgroup undergoing psychotherapy (n = 21), were recruited. Patients received 3 individual sessions of traumafocused psychotherapy per week over 8 weeks. The symptomatological assessments and blood sampling were conducted at the baseline (T0), after 4 (T4), 8 (T8 - end of psychotherapy) and 12 (T12 – follow-up) weeks. After 24 weeks, a clinical interview was conducted by phone. Expression levels were measured through RT-qPCR. We used the Mann- Whitney U test to compare the two groups for continuous measures, the Kendall rank coefficient to evaluate bivariate correlations and an ANOVA analysis to estimate longitudinal changes. Results: Regarding ELS, we found higher peripheral levels of NR3C1 (p = 0.008) and FKBP5 (p = 0.02) in patients exposed to mother neglect. In the group undergoing psychotherapy, the longitudinal analysis revealed significant modifications in the expression levels of NR3C1 (p = 3.5 ×10 −2; F = 3.03), FKBP5 (p = 1.93 ×10 −8; F = 17.2) and SGK1 (p = 2.86 ×10 −3, F = 5.14). We observed significant correlations between gene expression and symptomatological variations. In particular, we found positive correlations between the T0-T8 decrease in FKBP5 expression and T0-T8 cognitive symptoms amelioration (p = 0.012; τ= 0.420) as well as T0-T12 neurovegetative symptoms improvement (p = 0.012; τ= 0.413). There were positive correlations between T0-T8 NR3C1 expression decrease and T0-T8 cognitive (p = 0.005; τ= 0.474) and depressive symptoms amelioration (p = 0.013; τ= 0.390) as well as T0-T12 neurovegetative symptoms decrease (p = 0.01; τ= 0.423). Finally, positive correlations were found between T0-T8 SGK1 expression decrease and T0-T12 neurovegetative and depressive symptoms improvement (p = 0.01, τ= 0.423 and p = 0.016; τ= 0.381, respectively). Moreover, baseline levels of FKBP5 , NR3C1 and SGK1 were higher in patients who relapsed after 24 weeks (p = 0.012, p = 0.046 and p = 0.046, respectively). Conclusion: Our study points to stress-related gene expression signatures of ELS, in particular childhood neglect. It also reveals that trauma-focused psychotherapy induces changes in the expression of stress-related genes and that depressive symptoms amelioration correlates with the modulation of these genes. Moreover, baseline transcriptional levels of these genes could serve as putative predictor of disease relapse.
P.0115 Transcriptional modulation of stress genes in relation to early life stressful events and trauma-focused psychotherapy in patients with treatment-resistant depression
Dattilo, V.;
2021-01-01
Abstract
Introduction: Stressful events, particularly early life stress (ELS), are among the variables predicting negative treatment outcomes in Major Depressive Disorder (MDD) and are associated with Treatment-Resistant Depression (TRD). Stress-related genes, such as NR3C1 , FKBP5 , and SGK1 , have been suggested as candidate biomarkers relating stressful events and MDD. Trauma focused psychotherapies have been proposed as beneficial approaches for MDD patients exposed to ELS, however the possible mechanisms underlying the effects of these strategies are still poor known and biomarkers for therapy response are not available yet. Objectives: We aimed at investigating: 1) the association between baseline gene expression levels of NR3C1 , FKBP5 , SGK1 and ELS events, 2) changes in symptoms improvement and gene expression modulations during trauma-focused psychotherapy, and 3) correlations between baseline expression levels and clinical outcomes to identify possible biomarkers as predictors of treatment response and relapse. Methods: Forty-one TRD patients assessed for ELS, including a subgroup undergoing psychotherapy (n = 21), were recruited. Patients received 3 individual sessions of traumafocused psychotherapy per week over 8 weeks. The symptomatological assessments and blood sampling were conducted at the baseline (T0), after 4 (T4), 8 (T8 - end of psychotherapy) and 12 (T12 – follow-up) weeks. After 24 weeks, a clinical interview was conducted by phone. Expression levels were measured through RT-qPCR. We used the Mann- Whitney U test to compare the two groups for continuous measures, the Kendall rank coefficient to evaluate bivariate correlations and an ANOVA analysis to estimate longitudinal changes. Results: Regarding ELS, we found higher peripheral levels of NR3C1 (p = 0.008) and FKBP5 (p = 0.02) in patients exposed to mother neglect. In the group undergoing psychotherapy, the longitudinal analysis revealed significant modifications in the expression levels of NR3C1 (p = 3.5 ×10 −2; F = 3.03), FKBP5 (p = 1.93 ×10 −8; F = 17.2) and SGK1 (p = 2.86 ×10 −3, F = 5.14). We observed significant correlations between gene expression and symptomatological variations. In particular, we found positive correlations between the T0-T8 decrease in FKBP5 expression and T0-T8 cognitive symptoms amelioration (p = 0.012; τ= 0.420) as well as T0-T12 neurovegetative symptoms improvement (p = 0.012; τ= 0.413). There were positive correlations between T0-T8 NR3C1 expression decrease and T0-T8 cognitive (p = 0.005; τ= 0.474) and depressive symptoms amelioration (p = 0.013; τ= 0.390) as well as T0-T12 neurovegetative symptoms decrease (p = 0.01; τ= 0.423). Finally, positive correlations were found between T0-T8 SGK1 expression decrease and T0-T12 neurovegetative and depressive symptoms improvement (p = 0.01, τ= 0.423 and p = 0.016; τ= 0.381, respectively). Moreover, baseline levels of FKBP5 , NR3C1 and SGK1 were higher in patients who relapsed after 24 weeks (p = 0.012, p = 0.046 and p = 0.046, respectively). Conclusion: Our study points to stress-related gene expression signatures of ELS, in particular childhood neglect. It also reveals that trauma-focused psychotherapy induces changes in the expression of stress-related genes and that depressive symptoms amelioration correlates with the modulation of these genes. Moreover, baseline transcriptional levels of these genes could serve as putative predictor of disease relapse.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
