Progress in neuro-psychopharmacology & biological psychiatryOct 17, 2025

Neuron Imbalances in Hard-to-Treat Depression: Insights from Patient Cells

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 19, 2025

Abstract

Major depressive disorder (MDD) affects many people and is a leading cause of health issues worldwide. Some patients don’t respond to common treatments, leading to what is known as treatment-resistant depression (TRD). Understanding why this happens is challenging, especially with current research models. In this study, we used special cells from patients with TRD to create different types of neurons in the lab. We found that the neurons from TRD patients showed unique problems and an imbalance between excitatory and inhibitory signals, which is thought to contribute to depression. When we treated these neurons with a common antidepressant, they didn’t change as expected, highlighting their resistance to treatment. This approach using patient-derived neurons could help us better understand TRD and develop more personalized treatment options.

Simplified

Major depressive disorder (MDD) is a common condition and a leading cause of global health burden. Despite the availability of pharmacological treatments, many patients do not respond to at least two antidepressant therapies, leading to treatment-resistant depression (TRD). The underlying molecular mechanisms of TRD remain unclear, partly due to the limitations of current preclinical models. Induced pluripotent stem cells (iPSCs) represent a novel approach to study MDD and TRD, allowing for examining patient-derived neurons at both molecular and cellular levels. Previous studies using iPSCs from MDD and TRD patients have focused on single-cell populations. We now propose to employ the iPSCs technology to derive multiple neuronal subtypes, including GABAergic and glutamatergic neurons, as an in vitro model for replicating the neurobiological complexity of MDD. iPSCs-derived neurons from two female TRD patients and a healthy control were used. We found that the two TRD cultures showed patient-specific abnormalities in the number and/or morphology of neuronal subpopulations, but converged on an excitatory/inhibitory imbalance, which is hypothesized to underlie MDD and TRD. Neuron morphology was analyzed after fluoxetine treatment, showing that TRD neurons were resistant to the morphological changes observed in control neurons, consistent with fluoxetine failing to relieve depressive symptoms in these patients. Thus, this multi-cell-type iPSC model may offer a platform for exploring cellular mechanisms in TRD patients and could help in developing personalized treatment strategies.

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Neuron Imbalances in Hard-to-Treat Depression: Insights from Patient Cells

Abstract

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