Major depressive disorder (MDD) is the main psychiatric condition affecting people worldwide. Despite the large knowledge that allows its diagnosis, there are remaining issues that hamper their efficient treatment in many patients. The inefficient treatment of depression discloses a lack of knowledge regarding the cellular and molecular mechanisms that underlie this condition. Although animal models have contributed to a better comprehension of this disease, the use of human cells as platforms to study cellular and molecular aspects of depression represents a valuable tool to identify key aspects of their functioning on depression. Regarding this issue, human induced pluripotent stem cells (iPSCs) are a valuable platform to model depression, understand the way neurons and other cells behave in this condition, and test several promising therapeutic agents on them (1). This novel research field represents a promising way through which many underlying mechanisms of depression could be unraveled. The aim of this mini-review is to analyze the most recent and pioneering works exploring the functioning of neurons and other overseen non-neuronal cells such as oligodendrocytes, astrocytes, neuronal precursors, and fibroblasts, derived from iPSCs of patients with this disorder.

Major depressive disorder (MDD) is defined as the persistence of a depressed mood, loss of interest or pleasure in previously pleasurable activities (anhedonia), recurrent thoughts of death, and the onset of physical and cognitive symptoms (1). Since there is not a single symptom that is pathognomonic of depression by itself, its definition refers to a disorder integrated as a syndrome that causes functional impairment; some symptoms are anhedonia, reduced sex drive, diurnal variation of symptoms, guilt, fatigue, loss or gain of appetite or weight, and insomnia. For a diagnosis of depression, symptoms must be present throughout the day, last for two weeks or more, and not be explained by another medical condition (2). Depression not only causes a deterioration in mental health but also has been associated with an increased risk of developing other conditions, which, in addition, have higher mortality rates than the general population, reaching up to 60–80% (3, 4).

Animal models have long been utilized as a fundamental component of psychiatric research, with the objective of replicating the intricate nature of these diseases. However, the complexity of the human nervous system and behavior differ significantly from those of other mammals, and the polygenic nature of psychiatric diseases poses significant limitations to the efficacy of these models (8). Research on psychiatric diseases is hampered by the inability to obtain human brain biopsies or culture primary neurons from humans. In addition, the study of postmortem brains presents some difficulties and does not provide precise information about the onset of the disease (9). Given the ongoing challenges in modeling human diseases via current laboratory assays or animal models, obtaining patient-specific iPSCs from their somatic cells has emerged as a promising alternative. This approach could provide a more profound understanding of the pathogenesis of psychiatric diseases through disease modeling and the design of more efficacious therapeutic interventions. Furthermore, it could also facilitate the acceleration of drug discovery and improve the efficacy of drug testing (10–12). The practical implications of this technology are opening new possibilities in personalized medicine, revolutionizing the field of medicine and drug development.

iPSCs represent a valuable tool for advancing our understanding of neuropsychiatric diseases. Initially, reprogramming human somatic cells into iPSCs was achieved through the integration of retroviral vectors, which delivered the reprogramming genes Oct3/4, Sox2, Klf4, and c-Myc (10, 13). These methodologies have permitted cellular reprogramming to yield neurons derived from different types of patients including those with depression, thereby providing a valuable instrument for the assessment of the development and progression of this psychiatric disorder (14).

Neurons derived from the iPSCs of MDD patients have provided valuable information regarding the underlying mechanisms that promote depression. Recent studies have demonstrated that neurons derived from MDD patients display alterations in their electrophysiological properties in addition to impairments in their bioenergetic and mitochondrial functions (15, 16). Triebelhorn et al. demonstrated that neurons derived from the fibroblasts of MDD patients exhibited a smaller cell size than those derived from healthy subjects. Additionally, these neurons demonstrated lower membrane capacitance, resting membrane potential, and sodium current. Moreover, one of the main characteristics of these neurons is that they exhibit spontaneous activity. These electrophysiological alterations may be attributed to mitochondrial dysfunction in neuronal precursors resulting from a diminished function of the mitochondrial oxidative phosphorylation system (15).

Notably, forebrain neurons derived from MDD patients that do not respond to antidepressant treatments exhibit greater excitability and responsiveness to serotonin (5-HT) than do those derived from responsive patients and healthy controls. This is evidenced by an increase in calcium signaling following 5-HT stimulation. This information is consistent with the observation that neurons derived from nonresponsive MDD patients have increased protein levels of the HTR_2A and HTR₇ receptors. Furthermore, blockade of these receptors has been shown to inhibit neuronal hyperexcitability (17). It remains to be determined whether these alterations are homeostatic processes that counteract the cellular and molecular mechanisms that promote depression or whether impairments in forebrain neurons contribute to the development of this psychiatric disorder (18). Notably, neurons derived from MDD patients with impaired mitochondria also demonstrate heightened activity (15), indicating that the elevated neuronal activity observed in nonresponsive patients may be partially attributable to mitochondrial damage.

Further studies focused on serotonergic neurons demonstrated that this neuronal type derived from nonresponder MDD patients displays longer neurites, which suggests altered plastic processes that could contribute to the symptomatology of depression (19). In accordance with this evidence, another research group reported that cortical neurons derived from nonresponsive MDD patients presented a reduction in synaptic connectivity and an impairment in the number and types of dendritic spines. Additionally, these cortical neurons displayed novel differentially expressed genes, including NPPB, LRRC15, MICB, CHMP4C, and ITGA2, which suggests their potential use as biomarkers for MDD patients who are nonresponsive to antidepressants (20).

GABAergic neurons derived from MDD patients also display plasticity impairments, as evidenced by their hyperexcitability and impairment of calcium signaling. Additionally, these neurons also exhibit a distinct morphology compared with those derived from healthy controls, with a greater number of neurite ramifications. This suggests alterations in structural plasticity. Further experiments confirmed the downregulation of HTR₂ in these neurons. Pharmacological treatment with the HTR₂ agonist Trazodone was found to restore the altered activity and neurite branching of GABAergic neurons (18).

Collectively, these reports demonstrate that distinct morphological patterns, electrophysiological properties, and differential gene and protein expression can be observed in various types of neurons derived from patients diagnosed with MDD ( Table 1 ; Figure 1 ). These findings highlight the significant utility of cell reprogramming and the use of iPSCs in elucidating the pathophysiology underlying MDD. Although relevant, the results from two-dimensional cultures require complementation with other study models to understand complex psychiatric conditions such as depression and obtain robust results that could allow more accurate interpretations of the mechanisms underlying the development of depression and resistance to antidepressive treatments.

To address this issue, three-dimensional cultures of cells from the nervous system, such as brain organoids, have the advantage of displaying spatial organization. Brain organoids self-organize into cell clusters similar to multiple structures of the human brain, which allows the study of the complex interactions between multiple cell types, such as neurons and glial cells, in multiple neurological and psychiatric diseases (8, 21–25).

A study using iPSCs from genetically isolated families with a high prevalence of mood and psychotic disorders, including MDD, successfully generated neural cells and 3D brain organoids (26). These organoids revealed significant rare genetic variants, particularly enriched in this population. Key findings included mutations in genes like CACNA1C (calcium signaling), SLC6A4 (serotonin transport), and BDNF (synaptic plasticity). For example, organoids with CACNA1C mutations showed disrupted calcium signaling, essential for neurotransmitter release, while SLC6A4 alterations were linked to abnormal serotonin signaling, a critical pathway in depression.

These findings suggest that iPSC-derived organoids could be pivotal in uncovering the molecular mechanisms underlying treatment-resistant depression. Disruptions in signaling pathways, including mTOR and ERK, and altered serotonin and dopamine signaling indicate that these genetic variants significantly affect neuronal communication. This understanding could lead to more personalized treatment strategies, with therapies designed to target specific molecular dysfunctions identified in a patient’s genetic profile. By focusing on these pathways, new therapeutic approaches for MDD, especially for those resistant to conventional treatments, could be developed, advancing towards more precise and individualized mental health care (26).

Notably, organoids of the ventral forebrain derived from the iPSCs of MDD patients also contain GABAergic neurons. Remarkably, in this 3D model, neurons display impaired calcium signaling as in 2D cultures, thus demonstrating consistent results between both types of cell culture. These results highlight the importance of 3D cultures as a plausible experimental approach that, when combined with 2D cultures, can provide robust results to strengthen and encourage the use of iPSCs as a study model for MDD (18). However, as the development of brain organoid research accelerates, it introduces significant ethical concerns, such as the possibility that these organoids could develop some level of consciousness or sentient-like qualities, and the variability and unpredictability inherent in brain organoid research, which compromises the quality and integrity of results derived from 3D cultures. These drawbacks underscore the pressing need for comprehensive ethical guidelines, which are essential to ensure that scientific advancements in this field are matched by thorough ethical considerations to protect human dignity and rights, and highly reproducible protocols for brain organoid production and application (27–30).

iPSCs are also suitable platforms for obtaining specific neuronal types and evaluating their effects at the cellular level or the efficacy of potential pharmacological treatments for depression. The use of iPSCs has allowed researchers to analyze the antidepressant effects of ketamine on dopaminergic neurons. Interestingly, ketamine induced structural plasticity in dopaminergic neurons, as their dendrite length, number, and soma area increased in response to ketamine. Further pharmacological experiments on these neurons demonstrated that this effect was mediated mainly by mTORC1 and was dependent on the activation of the receptors AMPA-R, D3R, and TrkB (22). These results provide novel insights into the poorly understood mechanisms that underlie the antidepressive effects of ketamine on dopaminergic neurons.

On the other hand, iPSCs also allow the study of neurodevelopmental processes by generating brain organoids that recapitulate multiple stages of neurodevelopment (31). These properties make it possible to analyze the potential adverse effects of the use of antidepressants during pregnancy, as studied by Zhong and colleagues, who reported that paroxetine alters the expression of synaptic markers and neurite outgrowth in brain organoids, thus suggesting an impairment of structural plasticity in neurodevelopmental stages (21).

The complex interaction between neuronal and nonneuronal cells makes a challenging task the identification and comprehension of the underlying mechanisms that cause depression. Therefore, investigating the role of human nonneuronal cells in depression is mandatory to design more effective strategies for its treatment.

Glial cells play important roles in the proper functioning of the central nervous system (CNS). They include oligodendrocytes, astrocytes, microglia, ependymal cells, Schwann cells and radial cells (32). These cells participate in the maintenance of brain homeostasis, providing support for neurons, and in several immunological processes in both the CNS and the peripheral nervous system (32). The proper functioning of the CNS requires a complex network of interactions between glial cells and neurons. Glial cells communicate through different pathways, such as intracellular calcium signals and the diffusion of chemical messengers (33), and they participate in various repair processes in the CNS (34). Glial cells are important for the metabolic relationship between glia and neurons, as they provide energy substrates to neurons (35) and for the maintenance of the blood–brain barrier, which regulates the chemical composition necessary for neuronal circuit function, synaptic transmission, and neurogenesis in the adult brain (36).

Although MDD is among the most prevalent psychiatric disorders, there is still a paucity of data regarding the molecular mechanisms underlying its onset and progression. Animal and retrospective studies have made substantial contributions to a better comprehension of this psychiatric condition. Nevertheless, there is a pressing need to develop novel platforms to elucidate the manner in which human neurons and nonneuronal cells behave in MDD, and to further comprehend its pathophysiology. The study of human neurons, glial cells, and other nonneuronal cells derived from the iPSCs of MDD patients has demonstrated their potential to elucidate the cellular and molecular aspects of MDD, which could lead to a detailed understanding of this disorder. Consequently, iPSCs utilization in future studies will increase the quantity and quality of information regarding depression and represents a promising avenue for improving the design of treatments and therapies for this disorder.