Major depressive disorder is one of the most prevalent mental health disorders. Monoamine-based antidepressants were the first drugs developed to treat major depressive disorder. More recently, ketamine and other analogues were introduced as fast-acting antidepressants. Unfortunately, currently available therapeutics are inadequate; lack of efficacy, adverse effects, and risks leave patients with limited treatment options. Efforts are now focused on understanding the etiology of depression and identifying novel targets for pharmacological treatment. In this review, we discuss promising novel pharmacological targets for the treatment of major depressive disorder. Targeting receptors including N-methyl-D-aspartate receptors, peroxisome proliferator-activated receptors, G-protein-coupled receptor 39, metabotropic glutamate receptors, galanin and opioid receptors has potential antidepressant effects. Compounds targeting biological processes: inflammation, the hypothalamic-pituitary-adrenal axis, the cholesterol biosynthesis pathway, and gut microbiota have also shown therapeutic potential. Additionally, natural products including plants, herbs, and fatty acids improved depressive symptoms and behaviors. In this review, a brief history of clinically available antidepressants will be provided, with a primary focus on novel pharmaceutical approaches with promising antidepressant effects in preclinical and clinical studies.

Chronic stress is a major precursor to various neuropsychiatric disorders and is linked with increased inflammation in the brain. However, the bidirectional association between inflammation and chronic stress has yet to be fully understood. Astrocytes are one of the key inflammatory regulators in the brain, and the morphological change in reactive astrocytes serves as an important indicator of inflammation. In this study, we evaluated the sex-specific astrocyte response to chronic stress or systemic inflammation in key brain regions associated with mood disorders. We conducted the unpredictable chronic mild stress (UCMS) paradigm to model chronic stress, or lipopolysaccharide (LPS) injection to model systemic inflammation. To evaluate stress-induced morphological changes in astrocyte complexity, we measured GFAP fluorescent intensity for astrocyte expression, branch bifurcation by quantifying branch points and terminal points, branch arborization by conducting Sholl analysis, and calculated the ramification index. Our analysis indicated that chronic stress-induced morphological changes in astrocytes in all brain regions investigated. The effects of chronic stress were region and sex specific. Notably, females had greater stress or inflammation-induced astrocyte activation in the hypothalamus (HYPO), CA1, CA3, and amygdala (AMY) than males. These findings indicate that chronic stress induces astrocyte activation that may drive sex and region-specific effects in females, potentially contributing to sex-dependent mechanisms of disease.