Mild-Intensity Whole Body Hyperthermia (WBH) for Major Depressive Disorder

Major depressive disorder (MDD) is among the leading causes of overall global disease burden. Much of this burden derives from the fact that currently available pharmacologic modalities suffer from important shortcomings, including limited efficacy, delayed onset of action, and significant side effects that impair quality of life and promote treatment non-adherence and/or discontinuation. These factors provide ample incentive to continue the search for novel antidepressant methodologies that might maximize the benefits of these newer treatment modalities while minimizing their limitations. It is within this context that discoveries regarding the use of whole body hyperthermia (WBH) are of significant potential clinical relevance. The investigators' studies to date suggest that WBH produces a rapid and sustained antidepressant response with an extremely favorable side effect profile in medically-healthy patients with MDD. To follow up on evidence of the antidepressant effect of hyperthermia observed in animal models, the investigators conducted an open trial of WBH in humans. In 16 medically-healthy adults with MDD, the investigators found that a single session of WBH induced a rapid, robust and sustained reduction in depressive symptom scores (Hanusch et al. 2013). Thirteen of the study participants received no other pharmacologic or psychotherapeutic intervention during the study period (pre-treatment and 5 days post-treatment), whereas 3 participants were receiving a stable dose prior to treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant (with no change in dosage during the study period). Interestingly, when looked at separately, WBH appeared to have no effect in these 3 individuals, and, in fact, worsened depressive symptoms in one of them. These findings are consonant with animal data from the investigators' group demonstrating that therapeutic doses of an SSRI (citalopram 20 mg/kg) obviated the antidepressant-like effects of WBH (Hale et al. 2017).

The investigators' group followed-up positive findings from this initial open trial with a randomized, double-blind, sham-controlled study of WBH. Confirming the investigators primary study hypothesis, participants in the active WBH group showed significantly reduced Hamilton Depression Rating Scale (HDRS) scores at one week post-treatment when compared to participants in the sham group. A similar advantage for active WBH at one week post-treatment was apparent based on self-reported Inventory of Depressive Symptomatology Self-Report (IDS-SR) scores which indicated that active WBH separated from sham beginning on day 3 post-treatment. Contrary to the investigators' a priori hypothesis, the antidepressant effect of active WBH remained apparent out to 6 weeks post treatment when compared to sham. Based on HDRS scores, 60% (9 of 15) of the active WBH group met criteria for response and 40% (6 of 15) met criteria for remission during at least one post-intervention assessment, compared with 7% (1 of 14) and 0% respectively for sham. Rates of adverse events were very low in both WBH and sham groups, with no differences between groups, except for increased adverse events at post-intervention week two in the sham group (Janssen et al. 2016).

With regards to the immunosuppressive effects of WBH, much of the investigators' prior work has focused on the role of inflammation in the etiology and treatment of MDD. Given this, in the investigators' initial randomized, sham-controlled, double-blind trial of WBH they examined the impact of WBH on inflammatory cytokines (tumor necrosis factor [TNF], interleukin (IL)-6, IL-1-beta). Based on extensive data from the investigators' group and many others indicating that the cytokines TNF and IL-6 have depressogenic potential and are elevated in MDD, the investigators sought to test the hypothesis that WBH would reduce plasma concentrations of these cytokines and that these reductions would be associated with improved mood. However, when compared to sham, WBH produced a striking acute increase in IL-6 that resolved completely by one-week post-intervention, while having no acute or chronic effect on TNF.

Because IL-6 can come from multiple cell types in the body, and may have more of a pro-inflammatory vs. anti-inflammatory effect depending on whether it comes from immune cells (pro-inflammatory) or other tissues (i.e. adipocytes, muscle fibers, skin cells) (anti-inflammatory), the investigators measured plasma neopterin concentrations prior to, and following, the study interventions and at post-intervention weeks 1 and 4 simultaneous with the measurement of IL-6.

The investigators next explored whether acute changes in IL-6 and/or neopterin were associated with the antidepressant effects of WBH. The investigators found that acute increases in both IL-6 and neopterin in response to WBH were associated with reduced self-reported depressive symptoms one week following the treatment. Smaller but similar associations were observed between this immune signal and reductions in clinician-rated HDRS scores at one-week post-treatment. Increased IL-6 and neopterin in response to WBH were also associated with increased positive emotion from beginning to conclusion of the procedure.

Overall, the objective of this pilot study is to utilize the IL-6 receptor antagonist tocilizumab to prospectively evaluate the role of IL-6 in the antidepressant and immunological effects of WBH. The study will seek to replicate findings thus far that WBH has an antidepressant effect by administering the intervention at a site not involved in studies to date. Moreover, the current proposal may help the investigators better understand the role of IL-6 in the pathogenesis and treatment of depression which might point to novel immune-based interventions for MDD . Finally, the current proposal holds promise for better understanding a novel treatment for MDD, which is among the leading causes of health-related disability in the world.