Neuropsychopharmacology Reviews | Published:

Sex differences in antidepressant efficacy

Neuropsychopharmacologyvolume 44pages140154 (2019) | Download Citation



Sex differences have been observed across many psychiatric diseases, especially mood disorders. For major depression, the most prevalent psychiatric disorder, females show a roughly two-fold greater risk as compared to males. Depression is sexually dimorphic with males and females exhibiting differences in clinical presentation, course, and response to antidepressant treatment. In this review, we first discuss sex differences observed in depressed patients, as well as animal models that reveal potential underlying mechanisms. We then discuss antidepressant treatments including their proposed mechanism of action and sex differences observed in treatment response. We include possible mechanisms underlying these sex differences with particular focus on synaptic transmission.

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  1. 1.

    Brody DJ, Pratt LA, Hughes JP. Prevalence of depression among adults aged 20 and over: United States, 2013–2016. NCHS data brief; 2018.

  2. 2.

    Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Joyce PR, et al. Prevalence of suicide ideation and suicide attempts in nine countries. Psychol Med. 1999;29:9–17.

  3. 3.

    Marcus SM, Young EA, Kerber KB, Kornstein S, Farabaugh AH, Mitchell J, et al. Gender differences in depression: findings from the STAR*D study. J Affect Disord. 2005;87:141–50.

  4. 4.

    Bigos KL, Pollock BG, Stankevich BA, Bies RR. Sex differences in the pharmacokinetics and pharmacodynamics of antidepressants: an updated review. Gend Med. 2009;6:522–43.

  5. 5.

    Dalla C, Pitychoutis PM, Kokras N, Papadopoulou-daifoti Z. Sex differences in animal models of depression and antidepressant response. Neuroscience 2009;226–33.

  6. 6.

    Fiedler JL, Herrera L, Handa RJ, Program HG. Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones. Horm Metab Res. 2012;607–18.

  7. 7.

    Jiawan VCR, Melgert BN. Sex differences in the pharmacokinetics of antidepressants: influence of female sex hormones and oral contraceptives. Clin Pharmacokinet. 2014;509–19.

  8. 8.

    Palanza P. Animal models of anxiety and depression: how are females different? Neurosci Biobehav Rev. 2001;25:219–33.

  9. 9.

    Bale TL, Epperson CN. Sex differences and stress across the lifespan. Nat Neurosci. 2015;18:1413–20.

  10. 10.

    Piccinni A, Pisa U, Carlini M, Pisa U, Marazziti D, Baroni S, et al. Pharmacokinetics and pharmacodynamics of psychotropic drugs: effect of sex. CNS Spectrums. 2013.

  11. 11.

    Altemus M, Sarvaiya N, Neill Epperson C. Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol. 2014;35:320–30.

  12. 12.

    Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993.

  13. 13.

    Gater R, Tansella M, Korten A, Tiemens BG, Mavreas VG, Olatawura MO. Sex differences in the prevalence and detection of depressive and anxiety disorders in general health care settings: report from the World Health Organization Collaborative Study on Psychological Problems in General Health Care. Arch Gen Psychiatry. 1998;55:405–13.

  14. 14.

    Anderson JC, Williams S, McGee R, Silva PA. DSM-III disorders in preadolescent children—prevalence in a large sample from the general-population. Arch Gen Psychiatry. 1987;44:69–76.

  15. 15.

    Angold A, Costello EJ, Worthman CM. Puberty and depression: the roles of age, pubertal status and pubertal timing. Psychol Med. 1998.

  16. 16.

    Wade TJ, Cairney J, Pevalin DJ. Emergence of gender differences in depression during adolescence: national panel results from three countries. J Am Acad Child Adolesc Psychiatry. 2002;41:190–8.

  17. 17.

    Hankin BL, Abramson LY, Moffitt TE, Silva PA, Mcgee R, Angell KE. Development of depression from preadolescence to /bung adulthood: emerging gender differences in a 10-year longitudinal study. J Abnorm Psycholoe. 1998;107:128–1.

  18. 18.

    Zimmerman M, Ellison W, Young D, Chelminski I, Dalrymple K. How many different ways do patients meet the diagnostic criteria for major depressive disorder? Compr Psychiatry. 2015.

  19. 19.

    Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am. 2003;26:457–94.

  20. 20.

    Marcus SM, Kerber KB, Rush AJ, Wisniewski SR, Nierenberg A, Balasubramani GK, et al. Sex differences in depression symptoms in treatment-seeking adults: confirmatory analyses from the Sequenced Treatment Alternatives to Relieve Depression study. Compr Psychiatry. 2008;49:238–46.

  21. 21.

    Ting SA, Sullivan AF, Boudreaux ED, Miller I, Camargo CA. Trends in US emergency department visits for attempted suicide and self-inflicted injury, 1993-2008. Gen Hosp Psychiatry. 2012;34:557–65.

  22. 22.

    Doshi A, Boudreaux ED, Wang N, Pelletier AJ, Camargo CA. National study of US emergency department visits for attempted suicide and self-inflicted injury, 1997–2001. Ann Emerg Med. 2005.

  23. 23.

    Shors TJ, Millon EM, Chang HYM, Olson RL, Alderman BL. Do sex differences in rumination explain sex differences in depression? J Neurosci Res. 2017;95:711–8.

  24. 24.

    Nolen-Hoeksema S, Larson J, Grayson C. Explaining the gender difference in depressive symptoms. J Pers Soc Psychol. 1999.

  25. 25.

    Ernst C, Angst J. The Zurich Study. XII. Sex differences in depression. Evidence from longitudinal epidemiological data. Eur Arch Psychiatry Clin Neurosci. 1992;241:222–30.

  26. 26.

    Hankin BL. Development of sex differences in depressive and co-occurring anxious symptoms during adolescence: descriptive trajectories and potential explanations in a multiwave prospective study. J Clin Child Adolesc Psychol. 2009;38:460–72.

  27. 27.

    Kendler KS, Thornton LM, Prescott CA. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Am J Psychiatry. 2001;158:587–93.

  28. 28.

    Young MA, Scheftner WA, Fawcett J, Klerman GL. Gender differences in the clinical features of unipolar major depressive disorder. J Nerv Ment Dis. 1990;178:200–3.

  29. 29.

    Silverstein B. Gender difference in the prevalence of clinical depression: the role played by depression associated with somatic symptoms. Am J Psychiatry 1999;1563.

  30. 30.

    Angst J, Gamma A, Sellaro R, Zhang H, Merikangas K. Toward validation of atypical depression in the community: results of the Zurich cohort study. J Affect Disord. 2002.

  31. 31.

    Blanco C, Vesga-López O, Stewart JW, Liu S-M, Grant BF, Hasin DS. Epidemiology of major depression with atypical features: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). J Clin Psychiatry. 2012;73:224–32.

  32. 32.

    Petersen AC, Sarigiani PA, Kennedy RE. Adolescent depression: why more girls? J Youth Adolesc. 1991;20:247–71.

  33. 33.

    Abramson LY, Metalsky GI, Alloy LB. Hopelessness depression: a theory-based subtype of depression. Psychol Rev. 1989.

  34. 34.

    Hankin BL. Cognitive vulnerability-stress model of depression during adolescence: investigating depressive symptom specificity in a multi-wave prospective study. J Abnorm Child Psychol. 2008;36:999–1014.

  35. 35.

    Kessler RC. The effects of stressful life events on depression. Annu Rev Psychol. 1997;48:191–214.

  36. 36.

    Weaver ICG, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004.

  37. 37.

    Hartlage SA, Brandenburg DL, Kravitz HM. Premenstrual exacerbation of depressive disorders in a community-based sample in the United States. Psychosom Med. 2004.

  38. 38.

    Haley CL, Sung SC, Rush AJ, Trivedi MH, Wisniewski SR, Luther JF, et al. The clinical relevance of self-reported premenstrual worsening of depressive symptoms in the management of depressed outpatients: a STAR*D report. J Women’s Heal. 2013;22:219–29.

  39. 39.

    Freeman EW, Sammel MD, Boorman DW, Zhang R. ongitudinal pattern of depressive symptoms around natural menopause. JAMA Psychiatry 2014;71:36–43.

  40. 40.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Arlington, VA: American Psychiatric Publishing; 2013.

  41. 41.

    Wisner KL, Sit DKY, McShea MC, Rizzo DM, Zoretich RA, Hughes CL, et al. Onset Timing, Thoughts of Self-harm, and Diagnoses in Postpartum Women With Screen-Positive Depression Findings. JAMA Psychiatry 2013;70:490–8.

  42. 42.

    Barron ML, Flick LH, Cook CA, Homan SM, Campbell C. Associations between psychiatric disorders and menstrual cycle characteristics. Arch Psychiatr Nurs. 2008;22:254–65.

  43. 43.

    Bleil ME, Bromberger JT, Latham MD, Adler NE, Pasch LA, Gregorich SE, et al. Disruptions in ovarian function are related to depression and cardiometabolic risk during premenopause. Menopause. 2013;20:631–9.

  44. 44.

    Gottesman II, Gould TD. The endophenotype concept in psychiatry: Etymology and strategic intentions. Am J Psychiatry. 2003;160:636–45.

  45. 45.

    Gould TD, Gottesman II. Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav. 2006;5:113–9.

  46. 46.

    Anisman H, Merali Z. Understanding stress: characteristics and caveats. Alcohol Res Health. 1999;23:241–9.

  47. 47.

    Paykel ES. Stress and affective disorders in humans. Semin Clin Neuropsychiatry. 2001;6:4–11.

  48. 48.

    Bale TL. Stress sensitivity and the development of affective disorders. Horm Behav. 2006;50:529–33.

  49. 49.

    Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress. 2017;6:78–93.

  50. 50.

    Konkle ATM, Baker SL, Kentner AC, Barbagallo LS, Merali Z, Bielajew C. Evaluation of the effects of chronic mild stressors on hedonic and physiological responses: sex and strain compared. Brain Res. 2003;992:227–38.

  51. 51.

    Baker SL, Kentner AC, Konkle ATM, Santa-Maria Barbagallo L, Bielajew C. Behavioral and physiological effects of chronic mild stress in female rats. Physiol Behav. 2006;87:314–22.

  52. 52.

    Atchley DPD, Weaver KL, Eckel LA. Taste responses to dilute sucrose solutions are modulated by stage of the estrous cycle and fenfluramine treatment in female rats. Physiol Behav. 2005;86:265–71.

  53. 53.

    Overmier JB, Seligman ME. Effects of inescapable shock upon subsequent escape and avoidable responding. J Comp Physiol Psychol. 1967;63:28–33.

  54. 54.

    Maier SF, Watkins LR. Stressor controllability and learned helplessness: The roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev. 2005;29:829–41.

  55. 55.

    Steenbergen HL, Heinsbroek RPW, Van HestA, Van de PollNE. Sex-dependent effects of inescapable shock administration on shuttlebox-escape performance and elevated plus-maze behavior. Physiol Behav. 1990;48:571–6.

  56. 56.

    Steenbergen HL, Farabollini F, Heinsbroek RPW. Sex-dependent effects of aversive stimulation on holeboard and elevated plus-maze behavior. Behav Brain Res. 1991;43:159–65.

  57. 57.

    Mazure CM. Life stressors as risk factors in depression. Clin Psychol Sci Pract. 1998;5:291–313.

  58. 58.

    Hankin BL, Mermelstein R, Roesch L. Sex differences in adolescent depression: stress exposure and reactivity models. Child Dev. 2007;78:279–95.

  59. 59.

    Taylor SE, Klein LC, Lewis BP, Gruenewald TL, Gurung RAR, Updegraff JA. Biobehavioral responses to stress in females: tend-and-befriend, not fight-or-flight. Psychol Rev. 2000;107:411–29.

  60. 60.

    Hollis F, Kabbaj M. Social defeat as an animal model for depression. ILAR J. 2014;55:221–32.

  61. 61.

    Martinez M, Calvo-Torrent A, Pico-Alfonso MA. Social defeat and subordination as models of social stress in laboratory rodents: a review. Aggress Behav. 1998;24:241–56.

  62. 62.

    Takahashi A, Chung JR, Zhang S, Zhang H, Grossman Y, Aleyasin H, et al. Establishment of a repeated social defeat stress model in female mice. Sci Rep. 2017;7.

  63. 63.

    Haney M, Miczek KA. Ultrasounds during agonistic interactions between female rats (Rattus norvegicus). J Comp Psychol. 1993;107:373–9.

  64. 64.

    Kudryavtseva NN. Experience of defeat decreases the behavioural reactivity to conspecifics in the partition test. Behav Process. 1994;32:297–304.

  65. 65.

    Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain. Pharmacol Biochem Behav. 1991;38:315–20.

  66. 66.

    Poll NE, Van de, Jonge FDe, Van OyenHG, Van PeltJ. Aggressive behaviour in rats: effects of winning or losing on subsequent aggressive interactions. Behav Process. 1982;7:143–55.

  67. 67.

    Haney M, Maccari S, Le MoalM, Simon H, Piazza P. Social stress increases the acquisition of cocaine self-administration in male and female rats. Brain Res. 1995;698:46–52.

  68. 68.

    Meerlo P, Hoofdakker RHVanDen, Koolhaas JM, Daan S. Stress-induced changes in circadian rhythms of body temperature and activity in rats are not caused by pacemaker changes. J Biol Rhythms. 1997;12:80–92.

  69. 69.

    Meerlo P, Overkamp GJF, Daan S, Van Den HoofdakkerRH, Koolhaas JM. Changes in behaviour and body weight following a single or double social defeat in rats. Stress. 1996;1:21–32.

  70. 70.

    Ruis MAW, Brake JHATe, Buwalda B, Boer SFDe, Meerlo P, Korte SM, et al. Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat. Psychoneuroendocrinology. 1999;24:285–300.

  71. 71.

    Berton O, Aguerre S, Sarrieau A, Mormede P, Chaouloff F. Differential effects of social stress on central serotonergic activity and emotional reactivity in Lewis and spontaneously hypertensive rats. Neuroscience. 1998;82:147–59.

  72. 72.

    Hollis F, Duclot F, Gunjan A, Kabbaj M. Individual differences in the effect of social defeat on anhedonia and histone acetylation in the rat hippocampus. Horm Behav. 2011;59:331–7.

  73. 73.

    Hollis F, Wang H, Dietz D, Gunjan A, Kabbaj M. The effects of repeated social defeat on long-term depressive-like behavior and short-term histone modifications in the hippocampus in male Sprague-Dawley rats. Psychopharmacology (Berlin). 2010;211:69–77.

  74. 74.

    Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.

  75. 75.

    Heinrich LM, Gullone E. The clinical significance of loneliness: a literature review. Clin Psychol Rev. 2006;26:695–718.

  76. 76.

    Rich AR, Scovel M. Causes of depression in college students: a cross-lagged panel correlational analysis. Psychol Rep. 1987;60:27–30.

  77. 77.

    Green BH, Copeland JRM, Dewey ME, Sharma V, Saunders PA, Davidson IA, et al. Risk factors for depression in elderly people: a prospective study. Acta Psychiatr Scand. 1992;86:213–7.

  78. 78.

    Barrot M, Wallace DL, Bolanos CA, Graham DL, Perrotti LI, Neve RL, et al. Regulation of anxiety and initiation of sexual behavior by CREB in the nucleus accumbens. Proc Natl Acad Sci. 2005;102:8357–62.

  79. 79.

    Wallace DL, Han MH, Graham DL, Green TA, Vialou V, Ĩiguez SD, et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci. 2009;12:200–9.

  80. 80.

    Ahmed SH, Stinus L, Le MoalM, Cador M. Social deprivation enhances the vulnerability of male Wistar rats to stressor- and amphetamine-induced behavioral sensitization. Psychopharmacology (Berlin). 1995;117:116–24.

  81. 81.

    Deroche V, Piazza PV, Le MoalM, Simon H. Social isolation-induced enhancement of the psychomotor effects of morphine depends on corticosterone secretion. Brain Res. 1994;640:136–9.

  82. 82.

    Sarkar A, Kabbaj M. Sex differences in effects of ketamine on behavior, spine density, and synaptic proteins in socially isolated rats. Biol Psychiatry. 2016;80:448–56.

  83. 83.

    Carrier N, Kabbaj M. Testosterone and imipramine have antidepressant effects in socially isolated male but not female rats. Horm Behav. 2012;61:678–85.

  84. 84.

    Haller J, Fuchs E, Halász J, Makara GB. Defeat is a major stressor in males while social instability is stressful mainly in females: towards the development of a social stress model in female rats. Brain Res Bull. 1999;50:33–39.

  85. 85.

    Schmidt MV, Scharf SH, Sterlemann V, Ganea K, Liebl C, Holsboer F, et al. High susceptibility to chronic social stress is associated with a depression-like phenotype. Psychoneuroendocrinology. 2010;35:635–43.

  86. 86.

    Schmidt MV, Sterlemann V, Ganea K, Liebl C, Alam S, Harbich D, et al. Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence. Psychoneuroendocrinology. 2007;32:417–29.

  87. 87.

    Saavedra-Rodríguez L, Feig LA. Chronic social instability induces anxiety and defective social interactions across generations. Biol Psychiatry. 2013;73:44–53.

  88. 88.

    Schmidt MV, Scharf SH, Liebl C, Harbich D, Mayer B, Holsboer F, et al. A novel chronic social stress paradigm in female mice. Horm Behav. 2010a;57:415–20.

  89. 89.

    Syed Sa, Nemeroff CB. Early life stress, mood, and anxiety disorders. Chronic Stress. 2017;1:247054701769446.

  90. 90.

    Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology. 1996;137:1212–8.

  91. 91.

    Marais L, Rensburg SJ, van, Zyl JM, van, Stein DJ, Daniels WMU. Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus. Neurosci Res. 2008;61:106–12.

  92. 92.

    Millstein RA, Holmes A. Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. Neurosci Biobehav Rev. 2007;31:3–17.

  93. 93.

    O’Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EMM, et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009;65:263–7.

  94. 94.

    Pryce CR, Feldon J. Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev. 2003;27:57–71.

  95. 95.

    Franklin TB, Russig H, Weiss IC, Grff J, Linder N, Michalon A, et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry. 2010;68:408–15.

  96. 96.

    Leussis MP, Freund N, Brenhouse HC, Thompson BS, Andersen SL. Depressive-like behavior in adolescents after maternal separation: sex differences, controllability, and GABA. Dev Neurosci. 2012;34:210–7.

  97. 97.

    Viveros MP, Llorente R, López-Gallardo M, Suarez J, Bermúdez-Silva F, la Fuente M De, et al. Sex-dependent alterations in response to maternal deprivation in rats. Psychoneuroendocrinology 2009;34:S217–26.

  98. 98.

    El KhouryA, Gruber SHM, Mørk A, Mathé AA. Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2006;30:535–40.

  99. 99.

    Lambás-Señas L, Mnie-Filali O, Certin V, Faure C, Lemoine L, Zimmer L, et al. Functional correlates for 5-HT1A receptors in maternally deprived rats displaying anxiety and depression-like behaviors. Prog Neuro-Psychopharmacol Biol Psychiatry. 2009;33:262–8.

  100. 100.

    Lee JH, Kim HJ, Kim JG, Ryu V, Kim BT, Kang DW, et al. Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation. Neurosci Res. 2007;58:32–39.

  101. 101.

    Aisa B, Tordera R, Lasheras B, Del RíoJ, Ramírez MJ. Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats. Psychoneuroendocrinology. 2007;32:256–66.

  102. 102.

    Rüedi-Bettschen D, Pedersen EM, Feldon J, Pryce CR. Early deprivation under specific conditions leads to reduced interest in reward in adulthood in Wistar rats. Behav Brain Res. 2005;156:297–310.

  103. 103.

    Mourlon V, Baudin A, Blanc O, Lauber A, Giros B, Naudon L, et al. Maternal deprivation induces depressive-like behaviours only in female rats. Behav Brain Res. 2010;213:278–87.

  104. 104.

    Hendriksen H, Mechiel Korte S, Olivier B, Oosting RS. The olfactory bulbectomy model in mice and rat: one story or two tails? Eur J Pharmacol. 2015;753:105–13.

  105. 105.

    Morales-Medina JC, Dumont Y, Bonaventure P, Quirion R. Chronic administration of the Y2 receptor antagonist, JNJ-31020028, induced anti-depressant like-behaviors in olfactory bulbectomized rat. Neuropeptides. 2012;46:329–34.

  106. 106.

    Morales-Medina JC, Iannitti T, Freeman A, Caldwell HK. The olfactory bulbectomized rat as a model of depression: the hippocampal pathway. Behav Brain Res. 2017;317:562–75.

  107. 107.

    Morales-Medina JC, Juarez I, Venancio-García E, Cabrera SN, Menard C, Yu W, et al. Impaired structural hippocampal plasticity is associated with emotional and memory deficits in the olfactory bulbectomized rat. Neuroscience. 2013;236:233–43.

  108. 108.

    Rinwa P, Kumar A. Quercetin suppress microglial neuroinflammatory response and induce antidepressent-like effect in olfactory bulbectomized rats. Neuroscience. 2013;255:86–98.

  109. 109.

    Kelly JP, Wrynn AS, Leonard BE. The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther. 1997;74:299–316.

  110. 110.

    Song C, Leonard BE. The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev. 2005;29:627–47.

  111. 111.

    Belcheva I, Ivanova M, Tashev R, Belcheva S. Differential involvement of hippocampal vasoactive intestinal peptide in nociception of rats with a model of depression. Peptides 2009;30:1497–1501.

  112. 112.

    Wang W, Qi WJ, Xu Y, Wang JY, Luo F. The differential effects of depression on evoked and spontaneous pain behaviors in olfactory bulbectomized rats. Neurosci Lett 2010;472:143–7.

  113. 113.

    Stock HS, Ford K, Wilson MA. Gender and gonadal hormone effects in the olfactory bulbectomy animal model of depression. Pharmacol Biochem Behav. 2000;67:183–91.

  114. 114.

    Cryan JF, Mombereau C. In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry. 2004;9:326–57.

  115. 115.

    Overstreet DH, Friedman E, Mathé AA, Yadid G. The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev. 2005;29:739–59.

  116. 116.

    Kokras N, Antoniou K, Dalla C, Bekris S, Xagoraris M. Sex-related differential response to clomipramine treatment in a rat model of depression. J. Psychopharmacol. 2009;23:945–56.

  117. 117.

    Disner SG, Beevers CG, Haigh EAP, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011;12:467–77.

  118. 118.

    Johnson DP, Whisman MA. Gender differences in rumination: a meta-analysis. Pers Individ Dif. 2013;55:367–74.

  119. 119.

    Harding EJ, Paul ES, Mendl M. Animal behaviour: cognitive bias and affective state. Nature. 2004;427:312–312.

  120. 120.

    Bondi CO, Rodriguez G, Gould GG, Frazer A, Morilak DA. Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology. 2008;33:320–31.

  121. 121.

    Barker TH, Bobrovskaya L, Howarth GS, Whittaker AL. Female rats display fewer optimistic responses in a judgment bias test in the absence of a physiological stress response. Physiol Behav. 2017;173:124–31.

  122. 122.

    Brown GR, Cullum P, Martin S, Healy SD. Sex differences in performance on a cognitive bias task in Norway rats. Behav Process. 2016;133:52–55.

  123. 123.

    Beyer S. Gender differences in self-perception and negative recall biases. Sex Roles. 1998;38:103–33.

  124. 124.

    Lopez-Munoz F, Alamo C. Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm Des. 2009;15:1563–86.

  125. 125.

    Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007;151:737–48.

  126. 126.

    Thanacoody HKR, Thomas SHL. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev. 2005;24:205–14.

  127. 127.

    Grunebaum MF, Ellis SP, Li S, Oquendo MA, Mann JJ. Antidepressants and suicide risk in the United States, 1985-99. J Clin Psychiatry. 2004;65:1456–62.

  128. 128.

    White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by antidepressant type. J Med Toxicol. 2008;4:238–50.

  129. 129.

    Khan A, Brodhead AE, Schwartz KA, Kolts RL, Brown WA. Sex differences in antidepressant response in recent antidepressant clinical trials. J Clin Psychopharmacol. 2005;25:318–24.

  130. 130.

    Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157:1445–52.

  131. 131.

    Moore TJ, Mattison DR. Adult utilization of psychiatric drugs and differences by sex, age, and race. JAMA Intern Med. 2017;177:274–5.

  132. 132.

    Thompson SM, Kallarackal AJ, Kvarta MD, Dyke AM Van, Legates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci 2005;1–16.

  133. 133.

    Gartlehner G, Hansen R, Morgan L, Thaler K, Lux L, Noord M Van, et al. (2011). Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. AHRQ Publ No 12-EHC012-EF 1–954 AHRQ Publication No. 12-EHC012-EF.

  134. 134.

    Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush aJ. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. 2009;60:1439–45.

  135. 135.

    Berman R, Cappiello A, Anand A. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry. 2000;3223:351–4.

  136. 136.

    Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522–6.

  137. 137.

    Zarate CA, Singh JB, Carlson P, Brutsche N, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.

  138. 138.

    Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng P, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–95.

  139. 139.

    Li N, Lee B, Liu R-J, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.

  140. 140.

    Voleti B, Navarria A, Liu R, Banasr M, Li N, Terwilliger R. et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry. 2013;74:742–9.

  141. 141.

    Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6.

  142. 142.

    Atack JR, Maubach KA, Wafford KA, Connor DO, Rodrigues AD, Evans DC, et al. In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol- selective inverse agonist. Pharmacology. 2009;331:470–84.

  143. 143.

    Fischell J, Dyke AMVan, Kvarta MD, LeGates TA, Thompson SM. Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of alpha5-containing GABAA receptors. Neuropsychopharmacology. 2015;40:1–11.

  144. 144.

    Zanos P, Nelson ME, Highland JN, Krimmel SR. A negative allosteric modulator for 5 subunit- containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro. 2017;4:1–11.

  145. 145.

    Kellner CH, Knapp RG, Petrides G, Rummans TA, Husain MM, Rasmussen K, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the consortium for research in electroconvulsive therapy (CORE). Arch Gen Psychiatry. 2006;63:1337–44.

  146. 146.

    Sackeim HA, Haskett RF, Mulsant BH, Thase ME, Mann JJ, Pettinati HM, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285:1299–307.

  147. 147.

    George MS, Lisanby SH, Sackeim HA. Transcranial magnetic stimulation: applications in neuropsychiatry. Arch Gen Psychiatry. 1999;56:300–11.

  148. 148.

    Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. Int J Neuropsychopharmacol. 2002;5:73–103.

  149. 149.

    George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010;67:507–16.

  150. 150.

    Mayberg HS. Targeted electrode-based modulation of neural circuits for depression. J Clin Invest. 2009;119:717–25.

  151. 151.

    Malone Da, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65:267–75.

  152. 152.

    Manohar H, Subramanian K, Menon V, Kattimani S. Does gender influence electroconvulsive therapy sessions required across psychiatric diagnoses? A 5-year experience from a single center. J Neurosci Rural Pract. 2017;8:427.

  153. 153.

    Alino JJ, Jimenez JL, Flores SC, Alcocer MI. Efficacy of transcranial magnetic stimulation (TMS) in depression: naturalistic study. Actas Esp Psiquiatr. 2010;38:87–93.

  154. 154.

    Huang CC, Wei IH, Chou YH, Su TP. Effect of age, gender, menopausal status, and ovarian hormonal level on rTMS in treatment-resistant depression. Psychoneuroendocrinology. 2008;33:821–31.

  155. 155.

    Raskin A. Age-sex differences in response to antidepressant drugs. J Nerv Ment Dis. 1974;159:120–30.

  156. 156.

    Frank E, Carpenter LL, Kupfer DJ. Sex differences in recurrent depression: are there any that are significant? Am J Psychiatry. 1988;145:41–45.

  157. 157.

    Haykal RF, Akiskal HS. The long-term outcome of dysthymia in private practice: clinical features, temperament, and the art of management. J Clin Psychiatry. 1999;60:508–18.

  158. 158.

    Berlanga C, Flores-Ramos M. Different gender response to serotonergic and noradrenergic antidepressants. A comparative study of the efficacy of citalopram and reboxetine. J Affect Disord. 2006;95:119–23.

  159. 159.

    Kim JM, Kim SW, Stewart R, Kim SY, Yoon JS, Jung SW, et al. Predictors of 12-week remission in a nationwide cohort of people with depressive disorders: the CRESCEND study. Hum Psychopharmacol. 2011;26:41–50.

  160. 160.

    Thase ME, Entsuah R, Cantillon M, Kornstein SG. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Women’s Heal. 2005;14:609–16.

  161. 161.

    Keers R, Aitchison KJ. Gender differences in antidepressant drug response. 2010;22:485–500.

  162. 162.

    Pande AC, Birkett M, Fechner-Bates S, Haskett RF, Greden JF. Fluoxetine versus phenelzine in atypical depression. Biol Psychiatry. 1996;40:1017–20.

  163. 163.

    Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba MP, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158:1617–22.

  164. 164.

    Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121–30.

  165. 165.

    Carrier N, Kabbaj M. Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology. 2013;70:27–34.

  166. 166.

    Franceschelli A, Sens J, Herchick S, Thelen C, Pitychoutis PM. Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and “depressed” mice exposed to chronic mild stress. Neuroscience. 2015;290:49–60.

  167. 167.

    Saland SK, Schoepfer KJ, Kabbaj M. Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner. Sci Rep. 2016;6:1–16.

  168. 168.

    Kokras N, Antoniou K, Mikail HG, Kafetzopoulos V, Papadopoulou-daifoti Z, Dalla C. Neuropharmacology Forced swim test: what about females? Neuropharmacology. 2015;99:408–21.

  169. 169.

    Stoffel EC, Craft RM. Ovarian hormone withdrawal-induced “depression” in female rats. Physiol Behav. 2004;83:505–13.

  170. 170.

    Koss Wa, Einat H, Schloesser RJ, Manji HK, Rubinow DR. Estrogen effects on the forced swim test differ in two outbred rat strains. Physiol Behav. 2012;106:81–86.

  171. 171.

    Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med. 2001;7:541–7.

  172. 172.

    Rajkowska G. Histopathology of the prefrontal cortex in major depression: what does it tell us about dysfunctional monoaminergic circuits? Prog Brain Res. 2000;126:397–412.

  173. 173.

    Zhu MY, Klimek V, Dilley GE, Haycock JW, Stockmeier C, Overholser JC, et al. Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry. 1999;46:1275–86.

  174. 174.

    Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol. 2001;11:240–9.

  175. 175.

    Russo S, Nestler E. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25.

  176. 176.

    McEwen BS, Weiss JM, Schwartz LS. Selective retention of corticosterone by limbic structures in rat brain. Nature. 1968;220:911–2.

  177. 177.

    Myers B, McKlveen JM, Herman JP. Neural regulation of the stress response: the many faces of feedback. Cell Mol Neurobiol. 2012;32:683–94.

  178. 178.

    Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;19:5034–43.

  179. 179.

    Soetanto A, Wilson RS, Talbot K, Un A, Schneider JA, Sobiesk M, et al. Association of anxiety and depression with microtubule-associated protein 2- and synaptopodin-immunolabeled dendrite and spine densities in hippocampal CA3 of older humans. Arch Gen Psychiatry. 2010;67:448–57.

  180. 180.

    Bora E, Fornito A, Pantelis C, Yücel M. Gray matter abnormalities in Major Depressive Disorder: a meta-analysis of voxel based morphometry studies. J Affect Disord. 2012;138:9–18.

  181. 181.

    Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157:115–8.

  182. 182.

    Kelley SP, Mittleman G. Effects of hippocampal damage on reward threshold and response rate during self-stimulation of the ventral tegmental area in the rat. Behav Brain Res. 1999;99:133–41.

  183. 183.

    Boulenguez P. Modulation of dopamine release in the nucleus accumbens by 5HTlB agonists: Involvement of the hippocampo-accumbens pathway. Neuropharmacology. 1996;35:1521–9.

  184. 184.

    Floresco SB, Todd CL, Grace AA. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci. 2001;21:4915–22.

  185. 185.

    O’Donnell P, Grace AA. Synaptic interactions among excitatory afferents to nucleus accumbens neurons: hippocampal gating of prefrontal cortical input. J Neurosci. 1995;15:3622–39.

  186. 186.

    Goto Y, O’Donnell P. Synchronous activity in the hippocampus and nucleus accumbens in vivo. J Neurosci. 2001;21:RC131.

  187. 187.

    Whitehead G, Jo J, Hogg EL, Piers T, Kim D-H, Seaton G, et al. Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus. Brain. 2013;136:3753–65.

  188. 188.

    Kvarta MD, Bradbrook KE, Dantrassy HM, Bailey AM, Thompson SM. Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. J Neurophysiol. 2015;114:1713–24.

  189. 189.

    Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74.

  190. 190.

    Conrad CD, LeDoux JE, Magariños AM, McEwen BS. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav Neurosci. 1999;113:902–13.

  191. 191.

    Galea La, McEwen B, Tanapat P, Deak T, Spencer R, Dhabhar F. Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress. Neuroscience. 1997;81:689–97.

  192. 192.

    Magariños AM, McEwen BS. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Comparison of stressors. Neuroscience. 1995;69:83–88.

  193. 193.

    Magariños AM, McEwen BS, Flügge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16:3534–40.

  194. 194.

    Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588:341–5.

  195. 195.

    McLaughlin KJ, Baran SE, Wright RL, Conrad CD. Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: possible involvement of CA1 neurons. Neuroscience. 2005;135:1045–54.

  196. 196.

    Gould E, McEwen BSS, Tanapat P, Galea LAM A, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997;17:2492–8.

  197. 197.

    Malberg JE, Duman RS. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology. 2003;28:1562–71.

  198. 198.

    Pham K, Nacher J, Hof PR, McEwen BS. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci. 2003;17:879–86.

  199. 199.

    Kuroda Y, McEwen BS. Effect of chronic restraint stress and tianeptine on growth factors, growth-associated protein-43 and microtubule-associated protein 2 mRNA expression in the rat hippocampus. Brain Res Mol Brain Res. 1998;59:35–39.

  200. 200.

    Norrholm SD, Ouimet CC. Altered dendritic spine density in animal models of depression and in response to antidepressant treatment. Synapse. 2001;42:151–63.

  201. 201.

    Duman RS, Nakagawa S, Malberg JE. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology. 2001;25:836–44.

  202. 202.

    Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104–10.

  203. 203.

    Cai X, Kallarackal AJ, Kvarta MD, Goluskin S, Gaylor K, Bailey AM, et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci. 2013;16:464–72.

  204. 204.

    Holderbach R, Clark K, Moreau J-L, Bischofberger J, Normann C. Enhanced long-term synaptic depression in an animal model of depression. Biol Psychiatry. 2007;62:92–100.

  205. 205.

    LeGates Ta, Altimus CM, Wang H, Lee H-K, Yang S, Zhao H, et al. Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature. 2012;491:594–8.

  206. 206.

    Iyo AH, Feyissa AM, Chandran A, Austin MC, Regunathan S, Karolewicz B. Chronic corticosterone administration down-regulates metabotropic glutamate receptor 5 protein expression in the rat hippocampus. Neuroscience. 2010;169:1567–74.

  207. 207.

    Li C, Brake WG, Romeo RD, Dunlop JC, Gordon M, Buzescu R, et al. Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice. Proc Natl Acad Sci. 2004;101:2185–90.

  208. 208.

    Woolley CS, Weiland NG, McEwen BS, Schwartzkroin PA. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density. J Neurosci. 1997;17:1848–59.

  209. 209.

    González-Burgos I, Alejandre-Gómez M, Cervantes M. Spine-type densities of hippocampal CA1 neurons vary in proestrus and estrus rats. Neurosci Lett. 2005;379:52–54.

  210. 210.

    Gould E, Woolley CS, Frankfurt M, McEwen BS. Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J Neurosci. 1990;10:1286–91.

  211. 211.

    Yankova M, Hart Sa, Woolley CS. Estrogen increases synaptic connectivity between single presynaptic inputs and multiple postsynaptic CA1 pyramidal cells: a serial electron-microscopic study. Proc Natl Acad Sci USA. 2001;98:3525–30.

  212. 212.

    Tyler WJ. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem. 2002;9:224–37.

  213. 213.

    Fernandez SM, Lewis MC, Pechenino AS, Harburger LL, Orr PT, Gresack JE, et al. Estradiol-induced enhancement of object memory consolidation involves hippocampal extracellular signal-regulated kinase activation and membrane-bound estrogen receptors. J Neurosci. 2008;28:8660–7.

  214. 214.

    Naumenko VS, Kondaurova EM, Bazovkina DV, Tsybko AS, Tikhonova MA, Kulikov AV, et al. Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains. Neuroscience. 2012;214:59–67.

  215. 215.

    Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM. BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res. 1996;710:11–20.

  216. 216.

    Yokomaku D, Numakawa T, Numakawa Y, Suzuki S, Matsumoto T, Adachi N, et al. Estrogen enhances depolarization-induced glutamate release through activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase in cultured hippocampal neurons. Mol Endocrinol. 2003;17:831–44.

  217. 217.

    Barth C, Villringer A, Sacher J. Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front Neurosci. 2015;9:1–20.

  218. 218.

    Borrow AP, Cameron NM. Estrogenic mediation of serotonergic and neurotrophic systems: implications for female mood disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;54:13–25.

  219. 219.

    Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8:365–71.

  220. 220.

    Berridge KC, Kringelbach ML. Neuroscience of affect: brain mechanisms of pleasure and displeasure. Curr Opin Neurobiol. 2013;23:294–303.

  221. 221.

    Licznerski P, Duman RS. Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression. Neuroscience 2013;251:33–50.

  222. 222.

    Fales CL, Barch DM, Rundle MM, Mintun MA, Mathews J, Snyder AZ, et al. Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression. J Affect Disord. 2009;112:206–11.

  223. 223.

    Kennedy SH, Evans KR, Krüger S, Mayberg HS, Meyer JH, 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.

  224. 224.

    Smith DF, Jakobsen S. Molecular neurobiology of depression: PET findings on the elusive correlation with symptom severity. Front Psychiatry. 2013;4.

  225. 225.

    Brown SM, Henning S, Wellman CL. Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex. Cereb Cortex. 2005;15:1714–22.

  226. 226.

    Cook SC, Wellman CL. Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol. 2004;60:236–48.

  227. 227.

    Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4.

  228. 228.

    Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, et al. Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol. 2008;507:1141–50.

  229. 229.

    Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron. 2012;73:962–77.

  230. 230.

    Garrett JE, Wellman CL. Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence. Neuroscience. 2009a;162:195–207.

  231. 231.

    Hao J, Rapp PR, Janssen WGM, Lou W, Lasley BL, Hof PR, et al. Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. Proc Natl Acad Sci USA. 2007;104:11465–70.

  232. 232.

    Luine V, Attalla S, Mohan G, Costa A, Frankfurt M. Dietary phytoestrogens enhance spatial memory and spine density in the hippocampus and prefrontal cortex of ovariectomized rats. Brain Res. 2006;1126:183–7.

  233. 233.

    Garrett JE, Wellman CL. Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence. Neuroscience. 2009b;162:195–207.

  234. 234.

    Shansky RM, Hamo C, Hof PR, Lou W, McEwen BS, Morrison JH. Estrogen promotes stress sensitivity in a prefrontal cortex-amygdala pathway. Cereb Cortex. 2010;20:2560–7.

  235. 235.

    Eiland L, Ramroop J, Hill MN, Manley J, McEwen BS. Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats. Psychoneuroendocrinology. 2013;37:39–47.

  236. 236.

    Emslie GJ, Ryan ND, Wagner KD. Major depressive disorder in children and adolescents: clinical trial design and antidepressant efficacy. J Clin Psychiatry. 2005;66(Suppl 7):14–20.

  237. 237.

    Wei J, Yuen EY, Liu W, Li X, Zhong P, Karatsoreos IN, et al. Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition. Mol Psychiatry. 2014;19:588–98.

  238. 238.

    Amin Z, Epperson CN, Constable RT, Canli T. Effects of estrogen variation on neural correlates of emotional response inhibition. Neuroimage. 2006;32:457–64.

  239. 239.

    Konrad C, Engelien A, Schöning S, Zwitserlood P, Jansen A, Pletziger E, et al. The functional anatomy of semantic retrieval is influenced by gender, menstrual cycle, and sex hormones. J Neural Transm. 2008;115:1327–37.

  240. 240.

    Zeidan MA, Igoe SA, Linnman C, Vitalo A, Levine JB, Klibanski A, et al. Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biol Psychiatry. 2011;70:920–7.

  241. 241.

    Joffe H, Hall JE, Gruber S, Sarmiento IA, Cohen LS, Yurgelun-Todd D, et al. Estrogen therapy selectively enhances prefrontal cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently postmenopausal women. Menopause. 2006;13:411.

  242. 242.

    Craig MC, Fletcher PC, Daly EM, Rymer J, Cutter WJ, Brammer M, et al. Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women. Psychoneuroendocrinology. 2007;32:1116–27.

  243. 243.

    Burton CL, Chatterjee D, Chatterjee-Chakraborty M, Lovic V, Grella SL, Steiner M, et al. Prenatal restraint stress and motherless rearing disrupts expression of plasticity markers and stress-induced corticosterone release in adult female Sprague-Dawley rats. Brain Res. 2007;1158:28–38.

  244. 244.

    Castrén E. Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol. 2004;4:58–64.

  245. 245.

    Dwivedi Y, Rizavi HS, Zhang H, Mondal AC, Roberts RC, Conley RR, et al. Neurotrophin receptor activation and expression in human postmortem brain: effect of suicide. Biol Psychiatry. 2009;65:319–28.

  246. 246.

    Prickaerts J, Moechars D, Cryns K, Lenaerts I, Craenendonck H, van, Goris I, et al. Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania. J Neurosci. 2006;26:9022–9.

  247. 247.

    Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci. 2003;23:349–57.

  248. 248.

    Cavus I, Duman RS. Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats. Biol Psychiatry. 2003;54:59–69.

  249. 249.

    Pizzagalli Da, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R, et al. Reduced caudate and nucleus accumbens response to rewards in unmedicated subjects with major depressive disorder. Am J Psychiatry. 2009;166:702–10.

  250. 250.

    Wacker J, Dillon DG, Pizzagalli DA. The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: Integration of resting EEG, fMRI, and volumetric techniques. Neuroimage. 2009;46:327–37.

  251. 251.

    Martínez-Téllez RI, Hernández-Torres E, Gamboa C, Flores G. Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring. Synapse. 2009;63:794–804.

  252. 252.

    Monroy E, Hernández-Torres E, Flores G. Maternal separation disrupts dendritic morphology of neurons in prefrontal cortex, hippocampus, and nucleus accumbens in male rat offspring. J Chem Neuroanat. 2010;40:93–101.

  253. 253.

    Morales-Medina JC, Sanchez F, Flores G, Dumont Y, Quirion R. Morphological reorganization after repeated corticosterone administration in the hippocampus, nucleus accumbens and amygdala in the rat. J Chem Neuroanat. 2009;38:266–72.

  254. 254.

    Bessa JM, Morais M, Marques F, Pinto L, Palha JA, OFX Almeida, et al. Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. Transl Psychiatry. 2013;3:e266–7.

  255. 255.

    Qiao H, Li MX, Xu C, Bin ChenH, An SC, Ma XM. Dendritic spines in depression: what we learned from animal models. Neural Plast. 2016;2016:20–24.

  256. 256.

    Abdallah CG, Jackowski A, Salas R, Gupta S, Sato JR, Mao X, et al. The nucleus accumbens and ketamine treatment in major depressive disorder. Neuropsychopharmacology. 2017;42:1739–46.

  257. 257.

    Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212–22.

  258. 258.

    Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature. 2012;487:183–9.

  259. 259.

    Campioni MR, Xu M, McGehee DS. Stress-induced changes in nucleus accumbens glutamate synaptic plasticity. J Neurophysiol. 2009;101:3192–8.

  260. 260.

    Wissman AM, May RM, Woolley CS. Ultrastructural analysis of sex differences in nucleus accumbens synaptic connectivity. Brain Struct Funct. 2012;217:181–90.

  261. 261.

    Forlano PM, Woolley CS. Quantitative analysis of pre-and postsynaptic sex differences in the nucleus accumbens. J Comp Neurol. 2010;518:1330–48.

  262. 262.

    Wissman AM, McCollum AF, Huang G-Z, Nikrodhanond AA, Woolley CS. Sex differences and effects of cocaine on excitatory synapses in the nucleus accumbens. Neuropharmacology. 2011;61:217–27.

  263. 263.

    Bassareo V, Chiara G, Di. Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum. J Neurosci. 1997;17:851–61.

  264. 264.

    Di ChiaraG, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci. 1988;85:5274–8.

  265. 265.

    Fiorino DF, Phillips AG. Facilitation of sexual behavior and enhanced dopamine efflux in the nucleus accumbens of male rats after D-amphetamine-induced behavioral sensitization. J Neurosci. 1999;19:456–63.

  266. 266.

    Davis BA, Clinton SM, Akil H, Becker JB. The effects of novelty-seeking phenotypes and sex differences on acquisition of cocaine self-administration in selectively bred high-responder and low-responder rats. Pharmacol Biochem Behav. 2008;90:331–8.

  267. 267.

    Lynch WJ, Arizzi MN, Carroll ME. Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats. Psychopharmacology (Berlin). 2000;152:132–9.

  268. 268.

    Xiao L, Becker JB. Quantitative microdialysis determination of extracellular striatal dopamine concentration in male and female rats: effects of estrous cycle and gonadectomy. Neurosci Lett. 1994;180:155–8.

  269. 269.

    Becker JB. Direct effect of 17 beta-estradiol on striatum: sex differences in dopamine release. Synapse. 1990;5:157–64.

  270. 270.

    Becker JB. Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during microdialysis. Neurosci Lett. 1990;118:169–71.

  271. 271.

    Andersen SL, Rutstein M, Benzo JM, Hostetter JC, Teicher MH. Sex differences in dopamine receptor overproduction and elimination. Neuroreport 1997;8:1495–8.

  272. 272.

    Hruska RE, Pitman KT. Distribution and Localization of Estrogen-Sensitive Dopamine Receptors in the Rat Brain. J Neurochem 1982;39:1418–23.

  273. 273.

    Bazzett TJ, Becker JB. Sex differences in the rapid and acute effects of estrogen on striatal D2 dopamine receptor binding. Brain Res. 1994;637:163–72.

  274. 274.

    Lewis-Hall FC, Wilson MG, Tepner RG, Koke SC. Fluoxetine vs. tricyclic antidepressants in women with major depressive disorder. J Women’s Health. 1997;6:337–43.

  275. 275.

    Montejo-Gonzalez AL, Liorca G, Izquierdo JA, Ledesma A, Bousono M, Calcedo A, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23:176–94.

  276. 276.

    Hansen DG, Vach W, Rosholm JU, Søndergaard J, Gram LF, Kragstrup J. Early discontinuation of antidepressants in general practice: association with patient and prescriber characteristics. Fam Pract. 2004;21:623–9.

  277. 277.

    Krivoy A, Balicer RD, Feldman B, Hoshen M, Zalsman G, Weizman A, et al. The impact of age and gender on adherence to antidepressants: a 4-year population-based cohort study. Psychopharmacology. 2015;3385–90.

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We thank Adam Van Dyke for his helpful input. This work was supported by R01MH086828 (S.M.T.) and a NARSAD Young Investigator Award (T.A.L.). S.M.T. and M.D.K. are listed as a co-inventors on a patent application for the use of negative allosteric modulators of GABA-A receptors containing alpha5 subunits as fast-acting antidepressants. They have assigned their patent rights to the University of Maryland Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. S.M.T. and M.D.K. are co-founders of a company, Asulon Therapeutics Inc., developing alpha5-selective GABA-NAMs as fast-acting antidepressants.

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  1. Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    • Tara A. LeGates
    •  & Scott M. Thompson
  2. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    • Mark D. Kvarta
    •  & Scott M. Thompson


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The authors declare no competing interests.

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Correspondence to Tara A. LeGates.

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