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Mol Psychiatry. 2019 Jun;24(6):795-807. doi: 10.1038/s41380-019-0363-y. Epub 2019 Jan 30.

Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons.

Author information

1
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA.
2
University of Utah School of Medicine, Salt Lake City, UT, USA.
3
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
4
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
5
Lieber Institute for Brain Development, 855N Wolfe St, Ste 300, Baltimore, MD, USA.
6
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA. gage@salk.edu.

Abstract

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 our study fromĀ a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and 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. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.

PMID:
30700803
DOI:
10.1038/s41380-019-0363-y

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