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Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles

  • Author Footnotes
    1 RCB and HMC contributed equally to this work.
    Rosemary C. Bagot
    Footnotes
    1 RCB and HMC contributed equally to this work.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    1 RCB and HMC contributed equally to this work.
    Hannah M. Cates
    Footnotes
    1 RCB and HMC contributed equally to this work.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
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  • Immanuel Purushothaman
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    2 Current affiliation (VV) is Paris Seine, INSERM U1130, CNRS 8246, UPMC, Paris, France. Current affiliation (HAH) is Department of Pharmacology (HAH), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
    Vincent Vialou
    Footnotes
    2 Current affiliation (VV) is Paris Seine, INSERM U1130, CNRS 8246, UPMC, Paris, France. Current affiliation (HAH) is Department of Pharmacology (HAH), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
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  • Elizabeth A. Heller
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
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  • Lynn Yieh
    Affiliations
    Janssen Research & Development, LLC, Titusville, New Jersey
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  • Benoit LaBonté
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
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  • Catherine J. Peña
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
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  • Li Shen
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
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  • Gayle M. Wittenberg
    Affiliations
    Janssen Research & Development, LLC, La Jolla, California
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  • Eric J. Nestler
    Correspondence
    Address correspondence to: Eric J Nestler, M.D., Ph.D., Icahn School of Medicine at Mount Sinai, Fishberg Department of Neuroscience and Friedman Brain Institute, One Gustave Levy Place, Box 1065, New York, NY 10029-6574.
    Affiliations
    Fishberg Department of Neuroscience and Friedman Brain Institute , Icahn School of Medicine at Mount Sinai, New York, New York
    Search for articles by this author
  • Author Footnotes
    1 RCB and HMC contributed equally to this work.
    2 Current affiliation (VV) is Paris Seine, INSERM U1130, CNRS 8246, UPMC, Paris, France. Current affiliation (HAH) is Department of Pharmacology (HAH), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

      Abstract

      Background

      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.

      Methods

      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.

      Results

      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.

      Conclusions

      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.

      Keywords

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      References

        • Greenberg P.E.
        • Fournier A.A.
        • Sisitsky T.
        • Pike C.T.
        • Kessler R.C.
        The economic burden of adults with major depressive disorder in the United States (2005 and 2010).
        J Clin Psychiatry. 2015; 76: 155-162
        • Block S.G.
        • Nemeroff C.B.
        Emerging antidepressants to treat major depressive disorder.
        Asian J Psychiatr. 2014; 12: 7-16
        • Krishnan V.
        • Nestler E.J.
        The molecular neurobiology of depression.
        Nature. 2008; 455: 894-902
        • Duric V.
        • Duman R.S.
        Depression and treatment response: Dynamic interplay of signaling pathways and altered neural processes.
        Cell Mol Life Sci. 2013; 70: 39-53
        • Murrough J.W.
        • Iosifescu D.V.
        • Chang L.C.
        • Al Jurdi R.K.
        • Green C.E.
        • Perez A.M.
        • et al.
        Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial.
        Am J Psychiatry. 2013; 170: 1134-1142
        • Zarate Jr, C.A.
        • Singh J.B.
        • Carlson P.J.
        • Brutsche N.E.
        • Ameli R.
        • Luckenbaugh D.A.
        • et al.
        A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
        Arch Gen Psychiatry. 2006; 63: 856-864
        • Li N.
        • Lee B.
        • Liu R.J.
        • Banasr M.
        • Dwyer J.M.
        • Iwata M.
        • et al.
        mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
        Science. 2010; 329: 959-964
        • Autry A.E.
        • Adachi M.
        • Nosyreva E.
        • Na E.S.
        • Los M.F.
        • Cheng P.F.
        • et al.
        NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
        Nature. 2011; 475: 91-95
        • Monteggia L.M.
        • Zarate Jr, C.
        Antidepressant actions of ketamine: From molecular mechanisms to clinical practice.
        Curr Opin Neurobiol. 2015; 30: 139-143
        • Pandya M.
        • Altinay M.
        • Malone Jr, D.A.
        • Anand A.
        Where in the brain is depression?.
        Curr Psychiatry Rep. 2012; 14: 634-642
        • Ressler K.J.
        • Mayberg H.S.
        Targeting abnormal neural circuits in mood and anxiety disorders: From the laboratory to the clinic.
        Nat Neurosci. 2007; 10: 1116-1124
        • Bagot R.C.
        • Parise E.M.
        • Pena C.J.
        • Zhang H.X.
        • Maze I.
        • Chaudhury D.
        • et al.
        Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression.
        Nat Commun. 2015; 6: 7062
        • Christoffel D.J.
        • Golden S.A.
        • Walsh J.J.
        • Guise K.G.
        • Heshmati M.
        • Friedman A.K.
        • et al.
        Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress.
        Nat Neurosci. 2015; 18: 962-964
        • Goto Y.
        • Grace A.A.
        Limbic and cortical information processing in the nucleus accumbens.
        Trends Neurosci. 2008; 31: 552-558
        • Covington III, H.E.
        • Lobo M.K.
        • Maze I.
        • Vialou V.
        • Hyman J.M.
        • Zaman S.
        • et al.
        Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex.
        J Neurosci. 2010; 30: 16082-16090
        • Vialou V.
        • Bagot R.C.
        • Cahill M.E.
        • Ferguson D.
        • Robison A.J.
        • Dietz D.M.
        • et al.
        Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: Role of DeltaFosB.
        J Neurosci. 2014; 34: 3878-3887
        • Kennedy S.H.
        • Evans K.R.
        • Kruger S.
        • Mayberg H.S.
        • Meyer J.H.
        • McCann S.
        • et al.
        Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression.
        Am J Psychiatry. 2001; 158: 899-905
        • Mayberg H.S.
        • Brannan S.K.
        • Tekell J.L.
        • Silva J.A.
        • Mahurin R.K.
        • McGinnis S.
        • et al.
        Regional metabolic effects of fluoxetine in major depression: Serial changes and relationship to clinical response.
        Biol Psychiatry. 2000; 48: 830-843
        • Jaworska N.
        • Yang X.R.
        • Knott V.
        • MacQueen G.
        A review of fMRI studies during visual emotive processing in major depressive disorder.
        World J Biol Psychiatry. 2015; 16: 448-471
        • Sequeira A.
        • Mamdani F.
        • Ernst C.
        • Vawter M.P.
        • Bunney W.E.
        • Lebel V.
        • et al.
        Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression.
        PloS One. 2009; 4: e6585
        • Guilloux J.P.
        • Douillard-Guilloux G.
        • Kota R.
        • Wang X.
        • Gardier A.M.
        • Martinowich K.
        • et al.
        Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression.
        Mol Psychiatry. 2012; 17: 1130-1142
        • Chang L.C.
        • Jamain S.
        • Lin C.W.
        • Rujescu D.
        • Tseng G.C.
        • Sibille E.
        A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies.
        PloS One. 2014; 9: e90980
        • Ding Y.
        • Chang L.C.
        • Wang X.
        • Guilloux J.P.
        • Parrish J.
        • Oh H.
        • et al.
        Molecular and genetic characterization of depression: Overlap with other psychiatric disorders and aging. Mol.
        Neuropsychiatry. 2015; 1: 1-12
        • Nasca C.
        • Zelli D.
        • Bigio B.
        • Piccinin S.
        • Scaccianoce S.
        • Nistico R.
        • et al.
        Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity.
        Proc Natl Acad Sci U S A. 2015; 112: 14960-14965
        • McEwen B.S.
        • Nasca C.
        • Gray J.D.
        Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex.
        Neuropsychopharmacology. 2016; 41: 3-23
        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Krishnan V.
        • Han M.H.
        • Graham D.L.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Tsankova N.M.
        • Berton O.
        • Renthal W.
        • Kumar A.
        • Neve R.L.
        • Nestler E.J.
        Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action.
        Nat Neurosci. 2006; 9: 519-525
        • Donahue R.J.
        • Muschamp J.W.
        • Russo S.J.
        • Nestler E.J.
        • Carlezon Jr, W.A.
        Effects of striatal DeltaFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice.
        Biol Psychiatry. 2014; 76: 550-558
        • Law C.W.
        • Chen Y.
        • Shi W.
        • Smyth G.K.
        voom: Precision weights unlock linear model analysis tools for RNA-seq read counts.
        Genome Biol. 2014; 15: R29
        • Friedman A.K.
        • Walsh J.J.
        • Juarez B.
        • Ku S.M.
        • Chaudhury D.
        • Wang J.
        • et al.
        Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience.
        Science. 2014; 344: 313-319
        • Wilkinson M.B.
        • Xiao G.
        • Kumar A.
        • LaPlant Q.
        • Renthal W.
        • Sikder D.
        • et al.
        Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models.
        J Neurosci. 2009; 29: 7820-7832
        • Dias C.
        • Feng J.
        • Sun H.
        • Shao N.Y.
        • Mazei-Robison M.S.
        • Damez-Werno D.
        • et al.
        beta-Catenin mediates stress resilience through Dicer1/microRNA regulation.
        Nature. 2014; 516: 51-55
        • Duclot F.
        • Kabbaj M.
        Individual differences in novelty seeking predict subsequent vulnerability to social defeat through a differential epigenetic regulation of brain-derived neurotrophic factor expression.
        J Neurosci. 2013; 33: 11048-11060
        • Mayberg H.S.
        • Lozano A.M.
        • Voon V.
        • McNeely H.E.
        • Seminowicz D.
        • Hamani C.
        • et al.
        Deep brain stimulation for treatment-resistant depression.
        Neuron. 2005; 45: 651-660
        • Brody A.L.
        • Saxena S.
        • Silverman D.H.
        • Alborzian S.
        • Fairbanks L.A.
        • Phelps M.E.
        • et al.
        Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine.
        Psychiatry Res. 91. 1999: 127-139
        • Brody A.L.
        • Saxena S.
        • Stoessel P.
        • Gillies L.A.
        • Fairbanks L.A.
        • Alborzian S.
        • et al.
        Regional brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: Preliminary findings.
        Arch Gen Psychiatry. 2001; 58: 631-640
        • Haertzen C.A.
        • Hooks Jr, N.T.
        Dictionary of drug associations to heroin, benzedrine, alcohol, barbiturates and marijuana.
        J Clin Psychol. 1973; 29: 115-164
        • Duric V.
        • Banasr M.
        • Licznerski P.
        • Schmidt H.D.
        • Stockmeier C.A.
        • Simen A.A.
        • et al.
        A negative regulator of MAP kinase causes depressive behavior.
        Nat Med. 2010; 16: 1328-1332
        • Turner C.A.
        • Watson S.J.
        • Akil H.
        The fibroblast growth factor family: Neuromodulation of affective behavior.
        Neuron. 2012; 76: 160-174
        • Elsayed M.
        • Banasr M.
        • Duric V.
        • Fournier N.M.
        • Licznerski P.
        • Duman R.S.
        Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression.
        Biol Psychiatry. 2012; 72: 258-265
        • Villafuerte S.M.
        • Vallabhaneni K.
        • Sliwerska E.
        • McMahon F.J.
        • Young E.A.
        • Burmeister M.
        SSRI response in depression may be influenced by SNPs in HTR1B and HTR1A.
        Psychiatr Genet. 2009; 19: 281-291
        • Zhuang X.
        • Gross C.
        • Santarelli L.
        • Compan V.
        • Trillat A.C.
        • Hen R.
        Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.
        Neuropsychopharmacology. 1999; 21: 52S-60S
        • Jun T.Y.
        • Pae C.U.
        • Chae J.H.
        • Bahk W.M.
        • Kim K.S.
        Polymorphism of CTLA-4 gene for major depression in the Korean population.
        Psychiatry Clin Neurosci. 2001; 55: 533-537
        • Liu J.
        • Li J.
        • Li T.
        • Wang T.
        • Li Y.
        • Zeng Z.
        • et al.
        CTLA-4 confers a risk of recurrent schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population.
        Brain Behav Immun. 2011; 25: 429-433

      Linked Article

      • Comparative Transcriptomic Analysis of the Effects of Antidepressant Drugs in Stress-Susceptible Mice
        Biological PsychiatryVol. 81Issue 4
        • Preview
          As major depressive and bipolar disorders continue to be leading causes of disability worldwide (1), there is an urgent need for more effective treatments and better understanding of the mechanisms of actions of classical and novel classes of antidepressants. For the past 60 years, the treatment of depression has relied on pharmacological targeting of monoaminergic neurotransmission. This approach, however, has yielded limited efficacy, with over 50% of patients failing to achieve full remission (2), while weeks to months often pass before symptoms subside in those who do respond—which poses a marked risk for suicidal patients in particular.
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