One treatment does not fit all: Indications that spinning therapy benefits only a subgroup of patients with depression characterized by a T memory cell inflation profile

A proportion of patients diagnosed with major depressive disorder (MDD) exhibit signs of premature T cell aging, i.e. memory T cell inflation, characterized by elevated levels of memory CD4⁺ and CD8⁺ T cells. Physical endurance training, including spinning therapy (ST), is known to counteract both T cell aging and depression. The primary aim of this randomized, treatment-as-usual (TAU)-controlled study was to investigate whether signs of T cell aging (determined prior to ST) characterized remitters and responders to the intervention. Patients aged 18-65 years with a diagnosis of MDD (Hamilton Depression Rating Scale (HDRS) ≥ 13) were included and randomized 1:1 to TAU or TAU + ST. The intervention consisted of moderate-intensity cycling sessions (30 min, three times per week), for eight consecutive weeks. A total of 72 patients (n = 35 TAU, n = 37 TAU + ST) with complete baseline immunophenotyping were included in the analyses (49 % females; mean age, 32 years). We found that remitters to TAU + ST displayed significantly higher baseline levels of CD8⁺ memory T cells, particularly T central memory (Tcm) cells and T effector memory cells re-expressing CD45RA (TEMRA) cells, compared to non-remitters. Correction for potential confounders and logistic regression analysis revealed that baseline levels of CD8⁺ Tcm cells showed the strongest predictive value in the TAU + ST group (OR = 7.66, P = 0.03), suggesting that these cells may serve as treatment-specific predictors of remission to adjunctive ST. Post hoc stratification of patients based on the levels of CD8⁺Tcm cells identified a subgroup of n = 20 patients exhibiting several signs of T cell inflation in both the CD8⁺ and CD4⁺ T memory cell populations. This subgroup was older and showed a higher prevalence of cytomegalovirus seropositivity, suggesting a state of post-infectious T cell senescence. In addition, this subgroup was characterized by higher remission rates to TAU + ST compared to TAU alone, particularly in the long run (i.e., 75 % vs. 42 % at week 8, and 75 % vs. 17 % at the end of the follow-up phase at week 24, P = 0.03; note the small group sizes of n = 8 and n = 12 patients, respectively). Although no significant effects of add-on ST on CD8⁺ memory T cells were found, adjunctive ST significantly increased naïve CD4⁺ T cells and decreased effector memory CD4⁺ T cells within the senescent subgroup. Add-on ST was not superior to TAU in the entire group of patients with MDD. Taken together, our findings suggest that patients with MDD with a T memory cell inflation profile may be the one and only who would benefit from TAU + ST as an add-on treatment strategy. These results support the development of personalized psychiatry approaches guided by immunological profiling and challenge the conventional "one-size-fit" treatment model in depression. However, given the small sample size, particularly in the subgroup of interest, the outcomes should be considered preliminary and warrant replication in larger, confirmatory studies.