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• Integrative Body-Mind-Spirit and Qigong interventions were effective in reducing perceived stress depression, sleep disturbance, painful and painless somatic symptoms, and increasing holistic well-being for participants. • Integrative Body-Mind-Spirit and Qigong interventions can reduce the interleukin-6 and interleukin-1β levels for persons with both depressive symptoms and sleep disturbance. • A bidirectional relationship between depression and sleep disturbance was supported by longitudinal measurements in this study. • The influence of depression and sleep disturbance on IL-6 and IL-1β was shown to be significant. Depressed people are prone to sleep disturbance, which may in return perpetuate the depression. Both depression and sleep disturbance influence proinflammatory cytokines interleukin (IL) 6 and 1β. Thus interventions for depression should consider the effect on sleep disturbance, and vice versa. Integrative Body-Mind-Spirit (IBMS) and Qigong interventions have been applied in a wide range of health and mental health conditions, including depression and sleep disturbance. This study aimed to evaluate the effect of these two mind–body therapies for persons with both depressive symptoms and sleep disturbance. A three-arm randomized controlled trial was conducted among 281 participants, who were randomly assigned to either IBMS, Qigong or wait list control group. Participants in IBMS and Qigong groups received eight weekly sessions of intervention. Outcome measures were plasma concentrations of IL-6 and IL-1β, and a questionnaire containing Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, Somatic Symptom Inventory, Perceived Stress Scale and Body-Mind-Spirit Holistic Well-being Scale. Outcomes were assessed at baseline (T0), immediate post-intervention (T1) and at three-months post-intervention (T2). Besides intervention efficacy analysis, path analysis was performed to explore the relations among perceived stress, depression, sleep disturbance, and IL-6 and IL-1β values. The study found both IBMS and Qigong reduced depression, sleep disturbance, painful and painless somatic symptoms, IL-6 and IL-1β levels, and increased holistic well-being. The effect sizes of IBMS and Qigong, mostly in the medium magnitude range, were approximatively equivalent. Path analysis models revealed a predictive role of perceived stress in depression and sleep disturbance, a bidirectional relationship between depression and sleep disturbance, and significant influence of depression and sleep disturbance on IL-6 and IL-1β. Compared with control, the findings support the efficacy of IBMS and Qigong interventions in relieving depression and sleep disturbance, and in reducing IL-6 and IL-1β levels. [ABSTRACT FROM AUTHOR]