5-HTTLPR and MTHFR 677C>T polymorphisms and response to yoga-based lifestyle intervention in major depressive disorder: A randomized active-controlled trial

Abstract

Background: There is growing evidence suggesting that both genetic and environmental factors modulate treatment outcome in, a highly heterogeneous, major depressive disorder (MDD). 5-HTTLPR variant of the serotonin transporter gene (SLC6A4) and MTHFR 677C>T polymorphisms have been linked to the pathogenesis of MDD, and antidepressant treatment response. The evidence is lacking on the clinical utility of yoga in patients with MDD who have 5-HTTLPR and MTHFR 677C>T polymorphisms and less likely to respond to medications (SSRIs).

Aims: We aimed to examine the impact of YBLI in those who have susceptible 5-HTTLPR and MTHFR 677C>T polymorphisms and are less likely to drug therapy with SSRIs.

Settings and design: In a 12 week randomized active-controlled trial, MDD patients (n = 178) were randomized to receive YBLI or drug therapy.

Methods: Genotyping was conducted using PCR-based methods. The clinical remission was defined as BDI-II score ≤ 9.

Statistical analysis used: An intent-to-treat analysis was performed, and the association of genotype with treatment remission consisted of the logistic regression model. A P value of <0.05 was considered statistically significant.

Results: Multivariate logistic regression models for remission including either 5-HTTLPR or MTHFR 677C>T genotypes showed statistically significant odds of remission in YOGA arm vs. DRUG arm. Neither 5-HTTLPR nor MTHFR 677C>T genotype showed any influence on remission to YBLI (P = 0.73 and P = 0.64, respectively). Further analysis showed childhood adversity interact with 5-HTTLPR and MTHFR 677C>T polymorphisms to decrease treatment response in DRUG treatment arm, but not in YOGA arm.

Conclusions: YBLI provides MDD remission in those who have susceptible 5-HTTLPR and MTHFR 677C>T polymorphisms and are resistant to SSRIs treatment. YBLI may be therapeutic for MDD independent of heterogeneity in its etiopathogenesis.

Keywords: 5-HTTLPR; MTHFR 677C>T; depression; gene-environment; meditation; yoga.

Figure 1

CONSORT flow diagram

Figure 2

5-HTTLPR and MTHFR 677C>T genotype and allele frequencies. (a) 5-HTTLPR genotype distributions by the two treatment arms. (b) 5-HTTLPR allele frequencies by the two treatment arms. (c) MTHFR 677C>T genotype distributions by the two treatment arms. (d) MTHFR 677C>T allele frequencies by the two treatment arms

Figure 3

Treatment efficacy by groups. (a) Rate of major depressive disorder therapy remissions and non-remissions by treatment arms (b) Remission rates in major depressive disorder stratified into mild, moderate, and severe in both YOGA and DRUG groups. (c) The “mean percent reduction in Beck Depression Inventory-II scores from baseline at the 12-week endpoint” in both YOGA and DRUG groups. *Between group difference, P < 0.001; ^†Severe major depressive disorder versus mild and moderate major depressive disorder in YOGA group, all P < 0.001; ^‡Severe major depressive disorder versus moderate major depressive disorder in DRUG group, P < 0.001; ^§Mild major depressive disorder versus moderate major depressive disorder in DRUG group, P = 0.029

Figure 4

Reduction in Beck Depression Inventory-II scores from baseline to 12-week endpoint by genotypes. (a) Association of percent reduction in Beck Depression Inventory-II scores from baseline by 5-HTTLPR genotypes in both treatment arms. (b) Association of percent reduction in Beck Depression Inventory-II scores from baseline by MTHFR 677C>T genotypes in both treatment arms

Figure 5

Remission by genotype. (a and b) MDD remissions by 5-HTTLPR genotype and treatment arm. The treatment by genotype interaction P value is not significant in yoga arm compared to drug arm (yoga P = 0.73; drug P = 0.02 for LL vs. LS vs. SS by treatment). (c and d) MDD remissions by MTHFR 677C>T genotype and treatment arm. The treatment by genotype interaction P value is not significant in both yoga and drug arms (yoga P = 0.64; drug P = 0.45 for CC vs. CT versus TT by treatment). MDD – Major depressive disorder

Figure 6

Results of multivariate logistic regression model for major depressive disorder remission. (a) Odds ratios and 95% confidence intervals for independent variables in the multivariate logistic regression model including 5-HTTLPR genotype. (b) Odds ratios and 95% confidence intervals for independent variables in the multivariate logistic regression model including MTHFR 677C>T genotype. BDI-II – Beck Depression Inventory-II scale