Mental disorders impose a significant burden across the globe. According to a publication by the Global Burden of Diseases (GBD), Injuries, and Risk Factors Study in 2019, depression and anxiety disorders are positioned within the top 25 (Disease et al., 2018). In 2017, Major depressive disorder (MDD) was responsible for 163,044,100 disability cases, making it the third-highest contributor to years lived with a disability (Vos et al.). The burden was seen to be significant across the lifespans of affected individuals, irrespective of gender, exhibiting an increasing prevalence and global distribution.

The investigation of the underlying processes is a complex task because of the presence of clinical variability, comorbidities, and the impact of psychosocial variables. The inherent complexity of the human brain necessitates the use of various approaches to better understand its functioning. These approaches include the utilization of indirect animal models, the application of theory-driven knowledge, and the development of empirical treatment procedures. Empirical data have demonstrated that monoamines substantially impact several aspects of human physiology and behavior, including mood control, cognitive processes, sleep modulation, and the activation of reward-related brain regions. Since the 1960s, there has been a dominant therapeutic paradigm for depression centered around the neurochemical activities of serotonin, norepinephrine, and dopamine. The aforementioned methodology has led to the formulation of the “Monoamine theory of depression” (Mulinari, 2012). In contrast to the direct modulation of targets within the brain, the primary treatment for depression, inhibitors of monoamines reuptake or modulators of monoamines receptors are given, typically induce gene transcription through neurotransmitters. As a result, a delay is often observed before any significant improvement in clinical symptoms is evident following their administration. Nevertheless, this explanation fails to adequately account for 30 percent of individuals diagnosed with MDD who continue to have persistent symptoms or engage in suicidal conduct despite undergoing repeated therapy interventions (Kalkman, 2019). In recent years, scholars have made significant advancements in understanding the intricate metabolic pathways associated with it. These pathways encompass various interrelated processes such as monoamine regulation, neurotransmitter activity, neuroplasticity, modulation of neural transmission through excitatory and inhibitory mechanisms, fibromyalgia, epigenetic factors, neuropathy, myelination, and the gut-brain axis (Fries et al., 2023). Therefore, the role of neural activity and plasticity holds significant implications in depression.

Astrocytes play a crucial role in regulating synaptic transmission and plasticity and affect synaptic excitability and conduction velocity. They are involved in synchronizing the activity of nearby neurons and the modulation of neuronal communication across distinct brain areas. Astrocytes in the prefrontal cortex can modulate behavior resembling anhedonia (Banasr et al., 2023); also, stress can induce structural and functional modifications in astrocytes (Murphy-Royal et al., 2019; Dolotov et al., 2022). A large body of evidence from preclinical and post-mortem studies suggests that astrocytes are altered in morphology and function, number, or density in animal models of depression and patients with MDD (Wang et al., 2017). In addition, other investigations have reported the direct impact of fluoxetine and venlafaxine on astrocytes (Allaman et al., 2011; Song et al., 2021; Sun et al., 2017). Antidepressants influence the intracellular signaling pathways and gene expression of astrocytes, leading to changes in the expression of receptors and release of trophic factors, and ultimately impacting the physiology, morphology, and abundance of astrocytes (Czéh and Di Benedetto, 2013). There is speculation about the viability of astrocytes as a viable target for the therapy of depression.

This review focuses on the role of astrocytes in the pathophysiological mechanisms underlying depression. In the following discussion, we shall initially examine the dynamic characteristics of astrocytes under both homeostatic and pathological conditions. We will then proceed to explore the correlative and causative data that elucidate the association between astrocyte states and depression in human patients as well as in animal models. This article provides a comprehensive overview of the potential processes by which astrocytes perceive stress and modulate the state of depression. This section provides a comprehensive overview of astrocyte therapies, particularly emphasizing the therapeutic benefits of ketamine, a novel antidepressant. The elucidation of astrocyte-associated processes in MDD can provide valuable insights into developing novel treatment approaches for managing this prevalent condition.