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About a third of patients with major depressive disorder (MDD) do not show an adequate response to at least two first-line antidepressant treatments, developing a treatment-resistant depression (TRD). Both a partial understanding of MDD pathophysiology and the limitations of available pharmacological treatments constitute the current major barriers to clinical and research progress on this topic. However, recent advances in genome editing techniques as well as pluripotent stem cells (iPSC) technology are offering unprecedented opportunities in both human disease modelling and drug discovery. In particular, hiPSC technology progress has been enabling to set up disease-relevant patient-specific in vitro disease modeling for various mental disorders. The resulting models have the potential to significantly improve pathophysiologic understanding of both MDD and TRD, and then overcome some limitations inherent to animal and post-mortem models. Moreover, the psychiatric field has started to investigate the rapid antidepressant effects of ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist. Although ketamine appears to have the potential to transform the treatment of depression, including TRD, its specific mechanisms of action are only partially known. Such knowledge would be necessary to develop a model to understand the mechanisms behind rapid-acting antidepressants, which may enable the discovery of novel compound for the treatments of MDD and TRD. The aim of this chapter is threefold: after having briefly described prevalence and characteristics of MDD and TRD, it will discuss (1) the current understanding of ketamine’s mechanisms of action, as derived from preclinical animal studies, (2) the state of the art of human iPSC technology, and finally (3) the implementation of a TRD model based on iPSC human technology.