Major Depressive Disorder: Neurons from SSRI Non-Responders Have Longer Neuron Projections Than Responders; Gene Analysis Reveals That SSRI Non-Responders Also Have Low Levels of Protocadherin Genes (PCDHA6 & PCDHA8) Involved in Forming Neuronal Circuits

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medication for major depressive disorder (MDD), yet scientists still do not understand why the treatment does not work in nearly thirty percent of patients with MDD. Now, Salk Institute researchers have discovered differences in growth patterns of neurons of SSRI-resistant patients. The work, published in Molecular Psychiatry on March 22, 2019, has implications for depression as well as other psychiatric conditions such as bipolar disorder and schizophrenia that likely also involve abnormalities of the serotonin system in the brain. "With each new study, we move closer to a fuller understanding of the complex neural circuitry underlying neuropsychiatric diseases, including major depression," says Salk Professor Fred “Rusty” Gage (, PhD, President of the Salk Institute, Professor-Laboratory of Genetics, and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, and the study's senior author. “This paper, along with another we recently published (January 30, 2019 in Molecular Psychiatry), not only provides insights into this common treatment, but also suggests that other drugs, such as serotonergic antagonists, could be additional options for some patients." The title of the new article is “Altered Serotonergic Circuitry in SSRI-Resistant Major Depressive Disorder Patient-Derived Neurons” ( The earlier paper is titled “Serotonin-Induced Hyperactivity in SSRI-Resistant Major Depressive Disorder Patient-Derived Neurons” (
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