title: Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles.
abstract: Examining transcriptional regulation by antidepressants in key neural circuits implicated in depression and understanding the relation to transcriptional mechanisms of susceptibility and natural resilience may help in the search for new therapeutic agents. Given the heterogeneity of treatment response in human populations, examining both treatment response and nonresponse is critical.
  
  
  
  We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine, and a rapidly acting, non-monoamine-based antidepressant, ketamine, in mice subjected to chronic social defeat stress, a validated depression model, and used RNA sequencing to analyze transcriptional profiles associated with susceptibility, resilience, and antidepressant response and nonresponse in the prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala.
  
  
  
  We identified similar numbers of responders and nonresponders after ketamine or imipramine treatment. Ketamine induced more expression changes in the hippocampus; imipramine induced more expression changes in the nucleus accumbens and amygdala. Transcriptional profiles in treatment responders were most similar in the PFC. Nonresponse reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptibility-associated transcriptional changes and induced resilience-associated transcription in the PFC.
  
  
  
  We generated a uniquely large resource of gene expression data in four interconnected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by antidepressant drugs and in both reversing susceptibility- and inducing resilience-associated molecular adaptations. In addition, we found region-specific effects of each drug, suggesting both common and unique effects of imipramine versus ketamine.
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Rosemary C
authors: RC
authors: Bagot
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Hannah M
authors: HM
authors: Cates
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Immanuel
authors: I
authors: Purushothaman
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Vincent
authors: V
authors: Vialou
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Elizabeth A
authors: EA
authors: Heller
authors: Janssen Research & Development, LLC, Titusville, New Jersey.
authors: Lynn
authors: L
authors: Yieh
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Benoit
authors: B
authors: LaBonté
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Catherine J
authors: CJ
authors: Peña
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Li
authors: L
authors: Shen
authors: Janssen Research & Development, LLC, La Jolla, California.
authors: Gayle M
authors: GM
authors: Wittenberg
authors: Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: eric.nestler@mssm.edu.
authors: Eric J
authors: EJ
authors: Nestler
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000008:administration & dosage*; D007649:Ketamine / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D055500:Resilience, Psychological; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D007649:Ketamine; D007099:Imipramine
keywords: Depression; Imipramine; Ketamine; RNA-seq; Resilience; Susceptibility