Major depressive disorder (MDD) is a disabling psychiatric condition in which physical activity provides clinical benefits. While exercise effectively alleviates depressive symptoms, its biological mechanisms remain unclear.

This systematic review investigated the neurobiological effects of physical exercise on biomarkers in adults with MDD through randomized controlled trials, including studies assessing exercise interventions and reporting data on their biological effects.

A total of 30 studies, including 2194 participants, were included, examining the effects of physical exercise on various biological systems in patients with MDD. Exercise interventions had mixed effects on inflammatory markers, including interleukins, C-reactive protein, and tumor necrosis factor-α, suggesting a potential but inconsistent anti-inflammatory role. Neurotrophic factors, such as brain-derived neurotrophic factor showed promise as biomarkers of treatment response, but their role in clinical improvements remained inconclusive. Findings for the stress-response system, including cortisol and monoaminergic systems, primarily involving serotonin and dopamine, were limited and variable. Exercise demonstrated potential benefits in reducing oxidative stress and enhancing β-endorphin levels, although these effects were not consistently observed.

This systematic review adopted a broader perspective than prior studies, exploring less-studied biological systems and identifying several limitations in the included studies, including small sample sizes, varying methodologies, and a predominant focus on biochemical markers. Future research should prioritize larger, standardized trials and particularly employ omics approaches to better understand the biological mechanisms underlying the effects of exercise in MDD. The findings highlight the complexity of exercise’s biological effects and emphasize the need for further research to clarify its mechanisms.

Difficult-to-treat depression (DTD) is a common clinical challenge for major depressive disorder and bipolar disorders. Electro convulsive therapy (ECT) has proven to be one of the most effective treatments for this condition. Although several studies have investigated individually the clinical factors associated with the DTD response, the role of their interplay in the clinical response to ECT remains unknown. In the present study, we aimed to characterize the network of symptoms in DTD, evaluate the effects of ECT on the interrelationship of depressive symptoms, and identify the network characteristics that could predict the clinical response.

A network analysis of clinical and demographic data from 154 patients with DTD was performed to compare longitudinally the patterns of relationships among depressive symptoms after ECT treatment. Furthermore, we estimated the network structure at baseline associated with a greater clinical improvement (≥80% reduction at Montgomery–Åsberg Depression Rating Scale total score).

ECT modulated the network of depressive symptoms, with increased strength of the global network (p = 0.03, Cohen’s d = −0.98, 95% confidence interval = [−1.07, −0.88]). The strength of the edges between somatic symptoms (appetite and sleep) and cognitive-emotional symptoms (tension, lassitude, and pessimistic thoughts) was also increased. A stronger negative relationship between insomnia and pessimistic thoughts was associated with a greater improvement after ECT. Concentration difficulties and apparent sadness showed the greatest centrality.

In conclusion, ECT treatment may affect not only the severity of the symptoms but also their relationship; this may contribute to the response in DTD.