Repetitive Transcranial Magnetic Stimulation And Urine Metabolomics Study For Major Depressive Disorder

BackgroundsMajor depressive disorder (MDD), as a life-threatening and common mental disorder, affects up to 15% of the total population and is an important cause of disability worldwide. Although there are numerous antidepressants, about 30% of patients experience no or light response. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive brain-stimulation technique, is proofed to be effective on MDD by previous studies. Nowadays, the combination of rTMS and antidepressants is often used to treat MDD. But, previous researches have demonstrated inconsistent findings regarding the efficacy of left rTMS versus right rTMS, bilateral rTMS versus unilateral rTMS in treating MDD. Meanwhile, the timely and accurately diagnosis of MDD is also crucial to increase response rates. Unfortunately, due to the unclear pathogenesis, there is no objective laboratory-based diagnostic method for MDD; the diagnosis only depends on the patients’ displaying and doctors’ judgment. Metabonomics, which identifies and quantifies metabolites in various biofluids such as plasma/serum and urine, is helpful for discovering the disease pathogenesis and identify novel disease-specific biomarkers. Previous studies that used depressive animal models report the relationship between MDD and the metabolic disorder in the central nervous system and peripheral system. Therefore, the use of biofluids from patients with MDD to further perform metabonomics studies will have important clinical implications.Purposes1. We used meta-analysis to comparatively assess the efficacy of left rTMS and right rTMS.2. We used meta-analysis to comparatively assess the efficacy of bilateral rTMS and unilateral rTMS.3. We used gas chromatography-mass spectrometry (GC-MS) based metabonomic method to identify the differential metabolites in urine between MDD subjects and healthy controls (HC), uncover the possible molecular basis of MDD, and identify the potential urinary metabolite biomarkers for MDD.Methods1. Randomized controlled trials (RCTs) about rTMS for the acute treatment of MDD in adults were systematically reviewed in the following databases:PubMed, Cochrane Controlled Trials Register (CCTR), Web of Science and Embase, two Chinese databases (CBMdisc and CNKI) up to March (left rTMS vs. right side rTMS) and October (unilateral rTMS vs. bilateral rTMS) 2013. The search terms used were’depression’,’TMS’and ’transcranial magnetic stimulation’. The primary outcome measures were response and remission rates, the secondary outcome measures was drop-out rates. We used a Mantel-Haenszel random-effects or fixed-effects model, odds ratios (OR) and worst-case scenario analysis.2. GC-MS based metabonomic method was used to detect metabolites in urine from 134 HC and 126 MDD subjects. Then, orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to identify the differential metabolites responsible for distinguishing MDD subjects from HC. Finally, binary logistic regression analysis based on Bayesian Information Criterion (BIC) was used to obtain a most simplified biomarker panel.Results1. Left rTMS vs. right rTMSSeven RCTs were included in the meta-analysis. Seven RCTs reported response rates, the OR=1.15 (95%CI=0.65-2.03. Two RCTs reported drop-out rates, the OR=2.71 (95%CI=0.26-28.06). The clinical characteristics in two groups were similarity. No significant heterogeneity or publication bias existed.2. Bilateral rTMS vs. unilateral rTMSSeven RCTs were included in the meta-analysis. Seven RCTs reported response rates, the OR=1.06 (95%CI=0.58-1.91). Five RCTs reported response rates, the OR=1.05 (95%CI=0.52-2.11). Five RCTs reported response rates, the OR=0.80 (95%CI=0.25-28.50). The clinical characteristics in two groups were similarity. No significant heterogeneity or publication bias existed. Subgroup analysis found that bilateral rTMS was equally effective to both left and right unilateral rTMS.3. GC-MS based metabonomic method was used to detect metabolites in urine from 82HC and 82 first-episode drug-naive depressed subjects. The OPLS-DA model showed that the depressed subjects were distinguishable from HC. The urine samples of MDD subjects exhibited higher levels of sucrose, sorbitol, azelaic acid, fructose, glucose, hydroxylamine, uric acid, and alanine in combination with lower levels of cysteine, phenylalanine,tyrosine, aminoisobutyric acid,2,3-dihydroxybutanoic acid, indoxyl sulfate, N-acetyl-D-glucosamine, a-hydroxyisobutyric acid, hippuric acid, quinolinic acid, pseudouridine,1-methylinosine, 2,4-dihydroxypyrimidine, hypoxanthine, and aminoethanol. Among these metabolites, the combination of sorbitol, azelaic acid, uric acid, quinolinic acid, hippuric acid and tyrosine had good potential clinically diagnose value:the AUC of training set and test set was 0.91 and 0.84, respectively.Conclusion1. The pooled examination displayed that left rTMS and right rTMS were equally effective therapies for MDD. However, considering low-frequency right-sided rTMS produces fewer side effects and is more protective against seizures, its clinical applicability shows greater promise and should be further explored.2. The pooled examination demonstrated that bilateral rTMS displays comparable anti-depressive efficacy and acceptability to unilateral rTMS in treating MDD. These findings suggest that simultaneous rTMS of the right and left dorsolateral prefrontal cortexes in MDD patients does not provide marginal benefits in terms of efficacy or acceptability.3. Through the metabonomics analysis of urine from MDD subjects and HC, we identified a combination panel of differential metabolites of depression in urine. By analyzing their molecular functions, we provided valuable cures for researchers to uncover the pathogenesis of depression. Additionally, we provided potential candidate biomarker metabolites for the development of objective diagnostic methods.