Influence and interaction of resting state functional magnetic resonance and tryptophan hydroxylase-2 methylation on short-term antidepressant drug response

Abstract

Background Most antidepressants have been developed on the basis of the monoamine deficiency hypothesis of depression, in which neuronal serotonin (5-HT) plays a key role. 5-HT biosynthesis is regulated by the rate-limiting enzyme tryptophan hydroxylase-2 (TPH2). TPH2 methylation is correlated with antidepressant effects. Resting-state functional MRI (rs-fMRI) is applied for detecting abnormal brain functional activity in patients with different antidepressant effects. We will investigate the effect of the interaction between rs-fMRI and TPH2 DNA methylation on the early antidepressant effects. Methods A total of 300 patients with major depressive disorder (MDD) and 100 healthy controls (HCs) were enrolled, of which 60 patients with MDD were subjected to rs-fMRI. Antidepressant responses was assessed by a 50% reduction in 17-item Hamilton Rating Scale for Depression (HAMD-17) scores at baseline and after two weeks of medication. The RESTPlus software in MATLAB was used to analyze the rs-fMRI data. The amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), fractional ALFF (fALFF), and functional connectivity (FC) were used, and the above results were used as regions of interest (ROIs) to extract the average value of brain ROIs regions in the RESTPlus software. Generalized linear model analysis was performed to analyze the association between abnormal activity found in rs-fMRI and the effect of TPH2 DNA methylation on antidepressant responses. Results Two hundred ninety-one patients with MDD and 100 HCs were included in the methylation statistical analysis, of which 57 patients were included in the further rs-fMRI analysis (3 patients were excluded due to excessive head movement). 57 patients were divided into the responder group (n = 36) and the non-responder group (n = 21). Rs-fMRI results showed that the ALFF of the left inferior frontal gyrus (IFG) was significantly different between the two groups. The results showed that TPH2–1–43 methylation interacted with ALFF of left IFG to affect the antidepressant responses (p = 0.041, false discovery rate (FDR) corrected p = 0.149). Conclusions Our study demonstrated that the differences in the ALFF of left IFG between the two groups and its association with TPH2 methylation affect short-term antidepressant drug responses.

Exploring the Influence of DNA Methylation and family factors on OCD and symptoms Severity: Insights into the TPH2 Gene

“…The promoter region of the TPH2 gene contains several scattered CpG sites rather than CpG islands (Chen GL & Miller GM, 2012). Studies have demonstrated that regulatory polymorphisms of TPH2 may differentially in uence the response to environmental factors, presumably due to their differential roles in gene expression regulation (Shen T et al, 2020;Tan T et al, 2022). Similarly, our ndings suggested that the onset and development of OCD may be regulated by DNA methylation at different CpG sites of the TPH2 gene.…”

Serotonergic modulation of normal and abnormal brain dynamics: The genetic influence of the TPH2 G-703T genotype and DNA methylation on wavelet variance in children and adolescents with and without ADHD

“…An ADHD-specific relation between DNA methylation and reaction time variability in a motivational Go/NogoTask has been reported before [ 13 ], supporting the influence of DNA methylation on both, variability and impulsivity. DNA methylation has been linked to personality traits/endophenotypes such as aggression [ 60 ], and the ability to recognize mental states [ 38 ] as well as in the context of affective disorders [ 12 , 61 ] to rs-fMRI-related PFC activity [ 62 ].…”

No association between peripheral serotonin-gene-related DNA methylation and brain serotonin neurotransmission in the healthy and depressed state

“…SLC6A4 methylation percentages were estimated at four CpG sites (Table S2) that were previously linked to clinical phenotypes, including depressive symptoms [ 7 , 16 , 26 , 46 ], early-life adversities [ 7 ], recent environmental stress [ 15 ], antidepressant treatment outcome [ 20 , 21 ] and panic disorder [ 16 ]. TPH2 methylation was estimated at 6 CpG sites (Table S2) based on previous studies showing an association with gene expression ( 13 , 26 , 28 ), early life stress, depressive symptoms, antidepressant treatment outcome [ 23 , 24 , 47 ] and attention deficit hyperactivity disorder [ 48 ].…”

“…More recently, methylation of TPH2 gene has also been suggested as a biomarker for vulnerability to depression and antidepressant treatment outcome [ 23 , 24 ].…”