Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In this study from a large cohort of well-characterized MDD patients, the authors have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. Serotonergic neurotransmission in patient forebrain neurons in vitro were studied and the authors observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. This data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.
Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons
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