INSIGHT of Medicine(phase 23,2024)

1.Patterns of stressful life events and polygenic scores for five mental disorders and neuroticism among adults with depression

DOI: 10.1038/s41380-024-02492-x

https://www.nature.com/articles/s41380-024-02492-x

The study explored associations between polygenic scores (PGS) for various mental disorders and exposure to stressful life events (SLEs) in adults with recurrent depression. Among 14,146 participants, higher PGS for ADHD, depression, anxiety, and schizophrenia correlated with childhood SLEs and increased accumulation of SLEs. Notably, ADHD and depression PGSs showed consistent associations across multiple SLE categories, while bipolar disorder PGS displayed reduced odds of certain SLEs. These findings underscore the interplay between genetic vulnerability and stressors, challenging traditional diagnostic distinctions based on life events in depression.

2.Circulating myeloid-derived MMP8 in stress susceptibility and depression

DOI: 10.1038/s41586-023-07015-2

https://www.nature.com/articles/s41586-023-07015-2

The study reveals that matrix metalloproteinase 8 (MMP8) expression increases in serum of individuals with major depressive disorder (MDD) and stress-susceptible mice exposed to chronic social defeat stress (CSDS). Elevated MMP8 levels correlate with alterations in neurophysiology in the nucleus accumbens (NAc) and changes in social behavior. High-dimensional immune cell phenotyping shows stress impacts peripheral monocytes, with increased Mmp8 expression. In stress-susceptible mice, circulating and brain-infiltrating monocytes upregulate Mmp8 post-CSDS. MMP8 directly influences NAc extracellular space. MMP8 depletion mitigates stress-induced social avoidance and NAc alterations. These findings suggest a mechanism where peripheral immune factors, specifically MMP8, affect central nervous system function and behavior under stress, highlighting potential therapeutic targets for stress-related neuropsychiatric disorders.

3.Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial

DOI: 10.1038/s41591-023-02764-z

https://www.nature.com/articles/s41591-023-02764-z

In a randomized controlled trial, personalized neuromodulation targeting disrupted connectivity between the right anterior insula and left dorsolateral prefrontal cortex was investigated for treating treatment-resistant depression. Neuronavigated intermittent theta burst stimulation (cgiTBS) and repetitive transcranial magnetic stimulation (rTMS) were compared over 26 weeks in 255 participants. Both treatments showed persistent decreases in depressive symptoms with no significant difference in effectiveness. Adverse events were rare, with two possibly related to TMS. The study suggests that both cgiTBS and rTMS are equally effective treatments for treatment-resistant depression, highlighting the potential of personalized neuromodulation approaches for managing depression.

4.Melatonin alleviates chronic stress-induced hippocampal microglia pyroptosis and subsequent depression-like behaviors by inhibiting Cathepsin B/NLRP3 signaling pathway in rats

DOI: 10.1038/s41398-024-02887-y

https://www.nature.com/articles/s41398-024-02887-y

Melatonin shows promise in alleviating chronic stress-induced hippocampal damage and depression-like behaviors by inhibiting microglia pyroptosis. In vitro experiments demonstrate that melatonin protects HAPI cells from corticosterone-induced damage by suppressing pyroptosis, potentially targeting Cathepsin B in the NLRP3-mediated pyroptosis pathway. In vivo studies in rats confirm melatonin's ability to inhibit CRS-induced activation of the Cathepsin B/NLRP3 pathway, thereby reducing hippocampal microglia pyroptosis and depression-like behaviors. Furthermore, inhibiting Cathepsin B and NLRP3 also alleviates hippocampal pyroptosis. Overall, these findings elucidate the molecular mechanism by which melatonin mitigates chronic stress-related encephalopathy, offering insights into its therapeutic potential for depression associated with chronic stress.

5.Serotonin effects on human iPSC-derived neural cell functions: from mitochondria to depression

DOI: 10.1038/s41380-024-02538-0

https://www.nature.com/articles/s41380-024-02538-0

Depression has long been linked to serotonin dysregulation, leading to the development of antidepressants targeting serotonin levels. However, recent studies emphasize mitochondrial dysfunction as a significant factor in depression's pathophysiology, suggesting a more complex cause. Investigating the serotonin-mitochondrial connection, a study examined the effects of chronic serotonin treatment on induced-pluripotent stem cell-derived astrocytes and neurons from healthy controls and two case study patients: one with antidepressant non-responding MDD and another with a non-genetic mitochondrial disorder. Results showed that serotonin altered gene expression related to mitochondrial function and dynamics in neurons, while equalizing calcium homeostasis in astrocytes and increasing neuronal excitability. These findings underscore the importance of considering mitochondrial disorders in MDD patients and caution against serotonin-increasing medication without proper evaluation.