Abstract
Increasing evidence points to an association between major depressive disorders (MDDs) and diverse types of GABAergic deficits. In this review, we summarize clinical and preclinical evidence supporting a central and causal role of GABAergic deficits in the etiology of depressive disorders. Studies of depressed patients indicate that MDDs are accompanied by reduced brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and by alterations in the subunit composition of the principal receptors (GABAA receptors) mediating GABAergic inhibition. In addition, there is abundant evidence that suggests that GABA has a prominent role in the brain control of stress, the most important vulnerability factor in mood disorders. Furthermore, preclinical evidence suggests that currently used antidepressant drugs (ADs) designed to alter monoaminergic transmission and nonpharmacological therapies may ultimately act to counteract GABAergic deficits. In particular, GABAergic transmission has an important role in the control of hippocampal neurogenesis and neural maturation, which are now established as cellular substrates of most if not all antidepressant therapies. Finally, comparatively modest deficits in GABAergic transmission in GABAA receptor-deficient mice are sufficient to cause behavioral, cognitive, neuroanatomical and neuroendocrine phenotypes, as well as AD response characteristics expected of an animal model of MDD. The GABAergic hypothesis of MDD suggests that alterations in GABAergic transmission represent fundamentally important aspects of the etiological sequelae of MDDs that are reversed by monoaminergic AD action.
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References
Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289: 3095â3105.
Kendler KS . Major depression and generalised anxiety disorder. Same genes (partly) different environmentsârevisited. Br J Psychiatry Suppl 1996; 30: 68â75.
Kaufman J, Charney D . Comorbidity of mood and anxiety disorders. Depress Anxiety 2000; 12 (Suppl 1): 69â76.
Fava M, Kendler KS . Major depressive disorder. Neuron 2000; 28: 335â341.
Vos T, Mathers CD . The burden of mental disorders: a comparison of methods between the Australian burden of disease studies and the Global Burden of Disease study. Bull World Health Organ 2000; 78: 427â438.
Eley TC, Bolton D, OâConnor TG, Perrin S, Smith P, Plomin R . A twin study of anxiety-related behaviours in pre-school children. J Child Psychol Psychiatry 2003; 44: 945â960.
Murphy JM, Horton NJ, Laird NM, Monson RR, Sobol AM, Leighton AH . Anxiety and depression: a 40-year perspective on relationships regarding prevalence, distribution, and comorbidity. Acta Psychiatr Scand 2004; 109: 355â375.
Kessler RC, Chiu WT, Demler O, Walters EE . Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 617â627.
Gamez W, Watson D, Doebbeling BN . Abnormal personality and the mood and anxiety disorders: implications for structural models of anxiety and depression. J Anxiety Disord 2007; 21: 526â539.
Schildkraut J . The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965; 122: 509â522.
Bunney Jr WE, Davis JM . Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry 1965; 13: 483â494.
Coppen A . The biochemistry of affective disorders. Br J Psychiatry 1967; 113: 1237â1264.
Matussek N . Die Catecholamin- und serotoninhypothese der depression. In: Hippius, H & Seebach, H (eds). Das Depressive Syndrom. Urban & Schwarzenberg, München: Berlin, Wien, 1969.
Nutt DJ . The neuropharmacology of serotonin and noradrenaline in depression. Int Clin Psychopharmacol 2002; 17 (Suppl 1): S1â12.
Hirschfeld RM . History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry 2000; 61 (Suppl 6): 4â6.
Heninger GR, Delgado PL, Charney DS . The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 1996; 29: 2â11.
Kendler KS, Karkowski LM, Prescott CA . Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 1999; 156: 837â841.
Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko NB, Orr SP et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 2002; 5: 1242â1247.
Gold PW, Chrousos GP . Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 2002; 7: 254â275.
Holsboer F . Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 2001; 62: 77â91.
Hatzinger M . Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA) system: review of recent research strategies in depression. World J Biol Psychiatry 2000; 1: 105â111.
Binder EB, Nemeroff CB . The CRF system, stress, depression and anxietyâinsights from human genetic studies. Mol Psychiatry 2010; 15: 574â588.
Warner-Schmidt JL, Duman RS . Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 2006; 16: 239â249.
Dranovsky A, Hen R . Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 2006; 59: 1136â1143.
Manji HK, Drevets WC, Charney DS . The cellular neurobiology of depression. Nat Med 2001; 7: 541â547.
Duman RS, Monteggia LM . A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006; 59: 1116â1127.
Pittenger C, Duman RS . Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 2008; 33: 88â109.
Krishnan V, Nestler EJ . The molecular neurobiology of depression. Nature 2008; 455: 894â902.
Mombereau C, Kaupmann K, Froestl W, Sansig G, van der Putten H, Cryan JF . Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior. Neuropsychopharmacology 2004; 29: 1050â1062.
Mombereau C, Kaupmann K, Gassmann M, Bettler B, van der Putten H, Cryan JF . Altered anxiety- and depression-related behaviour in mice lacking GABAB(2) receptor subunits. Neuroreport 2005; 16: 307â310.
Olsen RW, Sieghart W . International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev 2008; 60: 243â260.
Farrant M, Nusser Z . Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 2005; 6: 215â229.
Rudolph U, Mohler H . GABA-based therapeutic approaches: GABA(A) receptor subtype functions. Curr Opin Pharmacol 2006; 6: 18â23.
Whiting PJ . GABA(A) receptors: a viable target for novel anxiolytics? Curr Opin Pharmacol 2006; 6: 24â29.
Rudolph U, Crestani F, Benke D, Brünig I, Benson J, Fritschy JM et al. Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 1999; 401: 796â800.
McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci 2000; 3: 587â592.
Tan KR, Brown M, Labouebe G, Yvon C, Creton C, Fritschy JM et al. Neural bases for addictive properties of benzodiazepines. Nature 2010; 463: 769â774.
Crestani F, Martin JR, Mohler H, Rudolph U . Resolving differences in GABA(A) receptor mutant mouse studies. Nat Neurosci 2000; 3: 1059.
Knabl J, Witschi R, Hosl K, Reinold H, Zeilhofer UB, Ahmadi S et al. Reversal of pathological pain through specific spinal GABA(A) receptor subtypes. Nature 2008; 451: 330â334.
Low K, Crestani F, Keist R, Benke D, Brunig I, Benson JA et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 2000; 290: 131â134.
Crestani F, Low K, Keist R, Mandelli M, Mohler H, Rudolph U . Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol 2001; 59: 442â445.
Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L et al. Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci USA 2002; 99: 8980â8985.
Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABA(A) receptor. J Neurosci 2002; 22: 5572â5580.
van Rijnsoever C, Tauber M, Choulli MK, Keist R, Rudolph U, Mohler H et al. Requirement of alpha5-GABA(A) receptors for the development of tolerance to the sedative action of diazepam in mice. J Neurosci 2004; 24: 6785â6790.
Prut L, Prenosil G, Willadt S, Vogt K, Fritschy JM, Crestani F . A reduction in hippocampal GABA(A) receptor alpha5 subunits disrupts the memory for location of objects in mice. Genes Brain Behav 2010; 9: 478â488.
Fritschy J-M, Mohler H . GABA(A) receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol 1995; 359: 154â194.
Drevets WC, Price JL, Furey ML . Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213: 93â118.
Rigucci S, Serafini G, Pompili M, Kotzalidis GD, Tatarelli R . Anatomical and functional correlates in major depressive disorder: the contribution of neuroimaging studies. World J Biol Psychiatry 2010; 11: 165â180.
Shen Q, Lal R, Luellen BA, Earnheart JC, Andrews AM, Luscher B . Gamma-aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry 2010; 68: 512â520.
Wallner M, Hanchar HJ, Olsen RW . Low-dose alcohol actions on alpha4beta3delta GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513. Proc Natl Acad Sci USA 2006; 103: 8540â8545.
Hanchar HJ, Dodson PD, Olsen RW, Otis TS, Wallner M . Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity. Nat Neurosci 2005; 8: 339â345.
Korpi ER, Grunder G, Luddens H . Drug interactions at GABA(A) receptors. Prog Neurobiol 2002; 67: 113â159.
Petty F, Schiesser MA . Plasma GABA in affective illness. A preliminary investigation. J Affect Disord 1981; 3: 339â343.
Petty F, Sherman AD . Plasma GABA levels in psychiatric illness. J Affect Disord 1984; 6: 131â138.
Gerner RH, Hare TA . GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. Am J Psychiatry 1981; 138: 1098â1101.
Honig A, Bartlett JR, Bouras N, Bridges PK . Amino acid levels in depression: a preliminary investigation. J Psychiatr Res 1988; 22: 159â164.
Francis PT, Poynton A, Lowe SL, Najlerahim A, Bridges PK, Bartlett JR et al. Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem. Brain Res 1989; 494: 315â324.
Petty F . Plasma concentrations of gamma-aminobutyric acid (GABA) and mood disorders: a blood test for manic depressive disease? Clin Chem 1994; 40: 296â302.
Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA et al. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999; 56: 1043â1047.
Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004; 61: 705â713.
Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC . Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2007; 64: 193â200.
Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, Matthews PM et al. Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol 2008; 11: 255â260.
Rajkowska G, OâDwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ . GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 2007; 32: 471â482.
Price RB, Shungu DC, Mao X, Nestadt P, Kelly C, Collins KA et al. Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder. Biol Psychiatry 2009; 65: 792â800.
Petty F, Kramer GL, Fulton M, Moeller FG, Rush AJ . Low plasma GABA is a trait-like marker for bipolar illness. Neuropsychopharmacology 1993; 9: 125â132.
Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ . Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder. Arch Gen Psychiatry 1998; 55: 715â720.
Davidson RJ . Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry 2002; 51: 68â80.
Davidson RJ . Affective style, psychopathology, and resilience: brain mechanisms and plasticity. Am Psychol 2000; 55: 1196â1214.
Nutt DJ, Glue P, Lawson CW, Wilson SJ . Flumazenil provocation of panic attacks. Arch Gen Psychiat 1990; 47: 917â925.
Tokunaga M, Ida I, Higuchi T, Mikuni M . Alterations of benzodiazepine receptor binding potential in anxiety and somatoform disorders measured by 123I-iomazenil SPECT. Radiat Med 1997; 15: 163â169.
Bremner JD, Innis RB, White T, Fujita M, Silbersweig D, Goddard AW et al. SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry 2000; 47: 96â106.
Tiihonen J, Kuikka J, Rasanen P, Lepola U, Koponen H, Liuska A et al. Cerebral benzodiazepine receptor binding and distribution in generalized anxiety disorder: a fractal analysis. Mol Psychiat 1997; 2: 463â471.
Bremner JD, Innis RB, Southwick SM, Staib L, Zoghbi S, Charney DS . Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 2000; 157: 1120â1126.
Kugaya A, Sanacora G, Verhoeff NP, Fujita M, Mason GF, Seneca NM et al. Cerebral benzodiazepine receptors in depressed patients measured with [123I]iomazenil SPECT. Biol Psychiatry 2003; 54: 792â799.
Kosel M, Rudolph U, Wielepp P, Luginbuhl M, Schmitt W, Fisch HU et al. Diminished GABA(A) receptor-binding capacity and a DNA base substitution in a patient with treatment-resistant depression and anxiety. Neuropsychopharmacology 2004; 29: 347â350.
Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 2004; 24: 1478â1485.
Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 2009; 4: e6585.
Sequeira A, Klempan T, Canetti L, Ffrench-Mullen J, Benkelfat C, Rouleau GA et al. Patterns of gene expression in the limbic system of suicides with and without major depression. Mol Psychiatry 2007; 12: 640â655.
Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 2005; 102: 15653â15658.
Klempan TA, Sequeira A, Canetti L, Lalovic A, Ernst C, Ffrench-Mullen J et al. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry 2009; 14: 175â189.
Aston C, Jiang L, Sokolov BP . Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. Mol Psychiatry 2005; 10: 309â322.
Poulter MO, Du L, Zhurov V, Palkovits M, Faludi G, Merali Z et al. Altered organization of GABA(A) receptor mRNA expression in the depressed suicide brain. Front Mol Neurosci 2010; 3: 3.
Poulter MO, Du L, Weaver IC, Palkovits M, Faludi G, Merali Z et al. GABA(A) receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biol Psychiatry 2008; 64: 645â652.
Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 2004; 22: 409â418.
Luscher B, Keller CA . Regulation of GABA(A) receptor trafficking and channel activity in functional plasticity of inhibitory synapses. Pharmacol Ther 2004; 102: 195â221.
Jacob TC, Moss SJ, Jurd R . GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci 2008; 9: 331â343.
Kalscheuer VM, Musante L, Fang C, Hoffmann K, Fuchs C, Carta E et al. A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. Hum Mutat 2009; 30: 61â68.
Papadopoulos T, Korte M, Eulenburg V, Kubota H, Retiounskaia M, Harvey RJ et al. Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice. EMBO J 2007; 26: 3888â3899.
Blundell J, Tabuchi K, Bolliger MF, Blaiss CA, Brose N, Liu X et al. Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2. Genes Brain Behav 2008; 8: 114â126.
Wellcome Trust Case Control Consortium. Genome-wide association study of 14â000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661â678.
Craddock N, Jones L, Jones IR, Kirov G, Green EK, Grozeva D et al. Strong genetic evidence for a selective influence of GABA(A) receptors on a component of the bipolar disorder phenotype. Mol Psychiatry 2010; 15: 146â153.
Papadimitriou GN, Dikeos DG, Karadima G, Avramopoulos D, Daskalopoulou EG, Stefanis CN . GABA(A) receptor beta3 and alpha5 subunit gene cluster on chromosome 15q11-q13 and bipolar disorder: a genetic association study. Am J Med Genet 2001; 105: 317â320.
Massat I, Souery D, Del-Favero J, Oruc L, Noethen MM, Blackwood D et al. Excess of allele1 for alpha3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study. Mol Psychiatry 2002; 7: 201â207.
Chen J, Tsang SY, Zhao CY, Pun FW, Yu Z, Mei L et al. GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations. Biochem Soc Trans 2009; 37: 1415â1418.
Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW et al. Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders. PLoS ONE 2009; 4: e6977.
Oruc L, Verheyen GR, Furac I, Ivezic S, Jakovljevic M, Raeymaekers P et al. Positive association between the GABRA5 gene and unipolar recurrent major depression. Neuropsychobiology 1997; 36: 62â64.
Horiuchi Y, Nakayama J, Ishiguro H, Ohtsuki T, Detera-Wadleigh SD, Toyota T et al. Possible association between a haplotype of the GABA(A) receptor alpha 1 subunit gene (GABRA1) and mood disorders. Biol Psychiatry 2004; 55: 40â45.
Yamada K, Watanabe A, Iwayama-Shigeno Y, Yoshikawa T . Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorders. Neurosci Lett 2003; 349: 9â12.
Serretti A, Macciardi F, Cusin C, Lattuada E, Lilli R, Di Bella D et al. GABA(A) alpha-1 subunit gene not associated with depressive symptomatology in mood disorders. Psychiatr Genet 1998; 8: 251â254.
Yoshikawa T, Watanabe A, Ishitsuka Y, Nakaya A, Nakatani N . Identification of multiple genetic loci linked to the propensity for âbehavioral despairâ in mice. Genome Res 2002; 12: 357â366.
Feng Y, Kapornai K, Kiss E, Tamas Z, Mayer L, Baji I et al. Association of the GABRD gene and childhood-onset mood disorders. Genes Brain Behav 2010; 9: 668â672.
McEwen BS . Early life influences on life-long patterns of behavior and health. Ment Retard Dev Disabil Res Rev 2003; 9: 149â154.
Gross C, Hen R . The developmental origins of anxiety. Nat Rev Neurosci 2004; 5: 545â552.
Nemeroff CB . Neurobiological consequences of childhood trauma. J Clin Psychiatry 2004; 65 (Suppl 1): 18â28.
de Kloet ER, Sibug RM, Helmerhorst FM, Schmidt MV . Stress, genes and the mechanism of programming the brain for later life. Neurosci Biobehav Rev 2005; 29: 271â281.
McGowan PO, Szyf M . The epigenetics of social adversity in early life: implications for mental health outcomes. Neurobiol Dis 2010; 39: 66â72.
Lupien SJ, McEwen BS, Gunnar MR, Heim C . Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 2009; 10: 434â445.
Caldji C, Francis D, Sharma S, Plotsky PM, Meaney MJ . The effects of early rearing environment on the development of GABA(A) and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Neuropsychopharmacology 2000; 22: 219â229.
Caldji C, Diorio J, Meaney MJ . Variations in maternal care alter GABA(A) receptor subunit expression in brain regions associated with fear. Neuropsychopharmacology 2003; 28: 1950â1959.
Earnheart JC, Schweizer C, Crestani F, Iwasato T, Itohara S, Mohler H et al. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J Neurosci 2007; 27: 3845â3854.
Skilbeck KJ, Johnston GA, Hinton T . Stress and GABA receptors. J Neurochem 2010; 112: 1115â1130.
Willner P . Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 2005; 52: 90â110.
Surget A, Wang Y, Leman S, Ibarguen-Vargas Y, Edgar N, Griebel G et al. Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal. Neuropsychopharmacology 2008; 34: 1363â1380.
Drugan RC, Morrow AL, Weizman R, Weizman A, Deutsch SI, Crawley JN et al. Stress-induced behavioral depression in the rat is associated with a decrease in GABA receptor-mediated chloride ion flux and brain benzodiazepine receptor occupancy. Brain Res 1989; 487: 45â51.
Orchinik M, Weiland NG, McEwen BS . Chronic exposure to stress levels of corticosterone alters GABAA receptor subunit mRNA levels in rat hippocampus. Brain Res Mol Brain Res 1995; 34: 29â37.
Orchinik M, Carroll SS, Li YH, McEwen BS, Weiland NG . Heterogeneity of hippocampal GABA(A) receptors: regulation by corticosterone. J Neurosci 2001; 21: 330â339.
Maguire J, Mody I . Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress. J Neurosci 2007; 27: 2155â2162.
Serra M, Pisu MG, Mostallino MC, Sanna E, Biggio G . Changes in neuroactive steroid content during social isolation stress modulate GABA(A) receptor plasticity and function. Brain Res Rev 2008; 57: 520â530.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Press: Washington, DC, 2000.
Brown ES, Varghese FP, McEwen BS . Association of depression with medical illness: does cortisol play a role? Biol Psychiatry 2004; 55: 1â9.
Tichomirowa MA, Keck ME, Schneider HJ, Paez-Pereda M, Renner U, Holsboer F et al. Endocrine disturbances in depression. J Endocrinol Invest 2005; 28: 89â99.
Hennings JM, Owashi T, Binder EB, Horstmann S, Menke A, Kloiber S et al. Clinical characteristics and treatment outcome in a representative sample of depressed inpatients â findings from the Munich Antidepressant Response Signature (MARS) project. J Psychiatr Res 2009; 43: 215â229.
Radley JJ, Gosselink KL, Sawchenko PE . A discrete GABAergic relay mediates medial prefrontal cortical inhibition of the neuroendocrine stress response. J Neurosci 2009; 29: 7330â7340.
Hu W, Zhang M, Czeh B, Flugge G, Zhang W . Stress impairs GABAergic network function in the hippocampus by activating nongenomic glucocorticoid receptors and affecting the integrity of the parvalbumin-expressing neuronal network. Neuropsychopharmacology 2010; 35: 1693â1707.
Maggio N, Segal M . Differential corticosteroid modulation of inhibitory synaptic currents in the dorsal and ventral hippocampus. J Neurosci 2009; 29: 2857â2866.
Schloesser RJ, Manji HK, Martinowich K . Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response. Neuroreport 2009; 20: 553â557.
Hewitt SA, Wamsteeker JI, Kurz EU, Bains JS . Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis. Nat Neurosci 2009; 12: 438â443.
Shen H, Sabaliauskas N, Sherpa A, Fenton A, Stelzer A, Aoki C et al. A critical role for alpha4betadelta GABA(A) receptors in shaping learning deficits at puberty in mice. Science 2010; 327: 1515â1518.
Stell BM, Brickley SG, Tang CY, Farrant M, Mody I . Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci USA 2003; 100: 14439â14444.
Bianchi MT, Haas KF, Macdonald RL . Alpha1 and alpha6 subunits specify distinct desensitization, deactivation and neurosteroid modulation of GABA(A) receptors containing the delta subunit. Neuropharmacology 2002; 43: 492â502.
Sapolsky RM, Krey LC, McEwen BS . Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. Proc Natl Acad Sci USA 1984; 81: 6174â6177.
Diorio D, Viau V, Meaney MJ . The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 1993; 13: 3839â3847.
Herman JP, Cullinan WE, Morano MI, Akil H, Watson SJ . Contribution of the ventral subiculum to inhibitory regulation of the hypothalamo-pituitary-adrenocortical axis. J Neuroendocrinol 1995; 7: 475â482.
Akana SF, Chu A, Soriano L, Dallman MF . Corticosterone exerts site-specific and state-dependent effects in prefrontal cortex and amygdala on regulation of adrenocorticotropic hormone, insulin and fat depots. J Neuroendocrinol 2001; 13: 625â637.
Cullinan WE, Herman JP, Watson SJ . Ventral subicular interaction with the hypothalamic paraventricular nucleus: evidence for a relay in the bed nucleus of the stria terminalis. J Comp Neurol 1993; 332: 1â20.
Li HY, Sawchenko PE . Hypothalamic effector neurons and extended circuitries activated in âneurogenicâ stress: a comparison of footshock effects exerted acutely, chronically, and in animals with controlled glucocorticoid levels. J Comp Neurol 1998; 393: 244â266.
Duman RS, Malberg J, Nakagawa S . Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther 2001; 299: 401â407.
Calfa G, Bussolino D, Molina VA . Involvement of the lateral septum and the ventral hippocampus in the emotional sequelae induced by social defeat: role of glucocorticoid receptors. Behav Brain Res 2007; 181: 23â34.
Arnsten AF . Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 2009; 10: 410â422.
Gould E, Tanapat P . Stress and hippocampal neurogenesis. Biol Psychiatry 1999; 46: 1472â1479.
Malberg JE, Duman RS . Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 2003; 28: 1562â1571.
Murray F, Smith DW, Hutson PH . Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice. Eur J Pharmacol 2008; 583: 115â127.
Varoqueaux F, Poulain P . Projections of the mediolateral part of the lateral septum to the hypothalamus, revealed by Fos expression and axonal tracing in rats. Anat Embryol (Berl) 1999; 199: 249â263.
Pezawas L, Meyer-Lindenber A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 2005; 8: 828â834.
Liberzon I, King AP, Britton JC, Phan KL, Abelson JL, Taylor SF . Paralimbic and medial prefrontal cortical involvement in neuroendocrine responses to traumatic stimuli. Am J Psychiatry 2007; 164: 1250â1258.
Frodl TS, Koutsouleris N, Bottlender R, Born C, Jager M, Scupin I et al. Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry 2008; 65: 1156â1165.
Tan H, Zhong P, Yan Z . Corticotropin-releasing factor and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons. J Neurosci 2004; 24: 5000â5008.
Herman JP, Cullinan WE . Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 1997; 20: 78â84.
Spencer SJ, Buller KM, Day TA . Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: possible role of the bed nucleus of the stria terminalis. J Comp Neurol 2005; 481: 363â376.
Choi DC, Furay AR, Evanson NK, Ostrander MM, Ulrich-Lai YM, Herman JP . Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic-pituitary-adrenal axis activity: implications for the integration of limbic inputs. J Neurosci 2007; 27: 2025â2034.
Kovacs KJ, Miklos IH, Bali B . GABAergic mechanisms constraining the activity of the hypothalamo-pituitary-adrenocortical axis. Ann N Y Acad Sci 2004; 1018: 466â476.
Verkuyl JM, Hemby SE, Joels M . Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus. Eur J Neurosci 2004; 20: 1665â1673.
Holsboer F, Barden N . Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 1996; 17: 187â205.
Purdy RH, Morrow AL, Moore Jr PH, Paul SM . Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA 1991; 88: 4553â4557.
Girdler SS, Klatzkin R . Neurosteroids in the context of stress: implications for depressive disorders. Pharmacol Ther 2007; 116: 125â139.
Smith SS, Shen H, Gong QH, Zhou X . Neurosteroid regulation of GABA(A) receptors: focus on the alpha4 and delta subunits. Pharmacol Ther 2007; 116: 58â76.
Shen H, Smith SS . Plasticity of the alpha4betadelta GABA(A) receptor. Biochem Soc Trans 2009; 37: 1378â1384.
Romeo E, Strohle A, Spalletta G, di Michele F, Hermann B, Holsboer F et al. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry 1998; 155: 910â913.
Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E et al. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA 1998; 95: 3239â3244.
Strohle A, Romeo E, Hermann B, Pasini A, Spalletta G, di Michele F et al. Concentrations of 3 alpha-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol Psychiatry 1999; 45: 274â277.
Strohle A, Pasini A, Romeo E, Hermann B, Spalletta G, di Michele F et al. Fluoxetine decreases concentrations of 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) in major depression. J Psychiatr Res 2000; 34: 183â186.
Compagnone NA, Mellon SH . Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol 2000; 21: 1â56.
Pinna G, Agis-Balboa RC, Pibiri F, Nelson M, Guidotti A, Costa E . Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice. Neurochem Res 2008; 33: 1990â2007.
Luscher B, Häuselmann R, Leitgeb S, Rülicke T, Fritschy J-M . Neuronal subtype-specific expression directed by the GABAA receptor delta subunit gene promoter in transgenic mice and in cultured cells. Mol Brain Res 1997; 51: 197â211.
Park JB, Skalska S, Son S, Stern JE . Dual GABA(A) receptor-mediated inhibition in rat presympathetic paraventricular nucleus neurons. J Physiol 2007; 582: 539â551.
Owens MJ, Ritchie JC, Nemeroff CB . 5 Alpha-pregnane-3 alpha, 21-diol-20-one (THDOC) attenuates mild stress-induced increases in plasma corticosterone via a non-glucocorticoid mechanism: comparison with alprazolam. Brain Res 1992; 573: 353â355.
Patchev VK, Hassan AH, Holsboer DF, Almeida OF . The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus. Neuropsychopharmacology 1996; 15: 533â540.
Sundstrom-Poromaa I, Smith DH, Gong QH, Sabado TN, Li X, Light A et al. Hormonally regulated alpha(4)beta(2)delta GABA(A) receptors are a target for alcohol. Nat Neurosci 2002; 5: 721â722.
Griffiths J, Lovick T . Withdrawal from progesterone increases expression of alpha4, beta1, and delta GABA(A) receptor subunits in neurons in the periaqueductal gray matter in female Wistar rats. J Comp Neurol 2005; 486: 89â97.
Sanna E, Mostallino MC, Murru L, Carta M, Talani G, Zucca S et al. Changes in expression and function of extrasynaptic GABA(A) receptors in the rat hppocampus during pregnancy and after delivery. J Neurosci 2009; 29: 1755â1765.
Shen H, Gong QH, Aoki C, Yuan M, Ruderman Y, Dattilo M et al. Reversal of neurosteroid effects at alpha4beta2delta GABA(A) receptors triggers anxiety at puberty. Nat Neurosci 2007; 10: 469â477.
Maguire JL, Stell BM, Rafizadeh M, Mody I . Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 2005; 8: 797â804.
Maguire J, Mody I . GABA(A)R plasticity during pregnancy: relevance to postpartum depression. Neuron 2008; 59: 207â213.
Maguire J, Ferando I, Simonsen C, Mody I . Excitability changes related to GABAA receptor plasticity during pregnancy. J Neurosci 2009; 29: 9592â9601.
Sundstrom-Poromaa I, Smith S, Gulinello M . GABA receptors, progesterone and premenstrual dysphoric disorder. Arch Women Ment Health 2003; 6: 23â41.
Herd MB, Belelli D, Lambert JJ . Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors. Pharmacol Ther 2007; 116: 20â34.
Johnson DA . The use of benzodiazepines in depression. Br J Clin Pharmacol 1985; 19 (Suppl 1): 31Sâ35S.
Remick RA, Keller FD, Buchanan RA, Gibson RE, Fleming JA . A comparison of the efficacy and safety of alprazolam and desipramine in depressed outpatients. Can J Psychiatry 1988; 33: 590â594.
Petty F . GABA and mood disorders: a brief review and hypothesis. J Affect Disord 1995; 34: 275â281.
Jonas JM, Hearron Jr AE . Alprazolam and suicidal ideation: a meta-analysis of controlled trials in the treatment of depression. J Clin Psychopharmacol 1996; 16: 208â211.
Fawcett J, Edwards JH, Kravitz HM, Jeffriess H . Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients. J Clin Psychopharmacol 1987; 7: 295â310.
Laakman G, Faltermaier-Temizel M, Bossert-Zaudig S, Baghai T, Lorkowski G . Treatment of depressive outpatients with lorazepam, alprazolam, amytriptyline and placebo. Psychopharmacology 1995; 120: 109â115.
Coryell W, Moranville JT . Alprazolam for psychotic depression. Biol Psychiatry 1989; 25: 367â369.
Birkenhager TK, Moleman P, Nolen WA . Benzodiazepines for depression? A review of the literature. Int Clin Psychopharmacol 1995; 10: 181â195.
Petty F, Trivedi MH, Fulton M, Rush AJ . Benzodiazepines as antidepressants: does GABA play a role in depression? Biol Psychiatry 1995; 38: 578â591.
Wolf B, Griffiths RR . Physical dependence on benzodiazepines: differences within the class. Drug Alcohol Depend 1991; 29: 153â156.
Laakmann G, Faltermaier-Temizel M, Bossert-Zaudig S, Baghai T . Are benzodiazepines antidepressants? Psychopharmacology 1996; 124: 291â292.
Valenstein M, Taylor KK, Austin K, Kales HC, McCarthy JF, Blow FC . Benzodiazepine use among depressed patients treated in mental health settings. Am J Psychiatry 2004; 161: 654â661.
Dunlop BW, Davis PG . Combination treatment with benzodiazepines and SSRIs for comorbid anxiety and depression: a review. Prim Care Companion J Clin Psychiatry 2008; 10: 222â228.
Soares CN, Joffe H, Rubens R, Caron J, Roth T, Cohen L . Eszopiclone in patients with insomnia during perimenopause and early postmenopause: a randomized controlled trial. Obstet Gynecol 2006; 108: 1402â1410.
Joffe H, Petrillo L, Viguera A, Koukopoulos A, Silver-Heilman K, Farrell A et al. Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial. Am J Obstet Gynecol 2010; 202: 171. e1â171. e11.
Krystal A, Fava M, Rubens R, Wessel T, Caron J, Wilson P et al. Evaluation of eszopiclone discontinuation after cotherapy with fluoxetine for insomnia with coexisting depression. J Clin Sleep Med 2007; 3: 48â55.
Donati RJ, Dwivedi Y, Roberts RC, Conley RR, Pandey GN, Rasenick MM . Postmortem brain tissue of depressed suicides reveals increased Gs alpha localization in lipid raft domains where it is less likely to activate adenylyl cyclase. J Neurosci 2008; 28: 3042â3050.
Zhang L, Rasenick MM . Chronic treatment with escitalopram but not R-citalopram translocates Galpha(s) from lipid raft domains and potentiates adenylyl cyclase: a 5-hydroxytryptamine transporter-independent action of this antidepressant compound. J Pharmacol Exp Ther 2010; 332: 977â984.
Andrade R, Nicoll RA . Pharmacologically distinct actions of serotonin on single pyramidal neurones of the rat hippocampus recorded in vitro. J Physiol 1987; 394: 99â124.
Ropert N, Guy N . Serotonin facilitates GABAergic transmission in the CA1 region of rat hippocampus in vitro. J Physiol 1991; 441: 121â136.
McMahon LL, Kauer JA . Hippocampal interneurons are excited via serotonin-gated ion channels. J Neurophysiol 1997; 78: 2493â2502.
Shen RY, Andrade R . 5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. J Pharmacol Exp Ther 1998; 285: 805â812.
Lee K, Dixon AK, Pinnock RD . Serotonin depolarizes hippocampal interneurones in the rat stratum oriens by interaction with 5HT2 receptors. Neurosci Lett 1999; 270: 56â58.
Egeland M, Warner-Schmidt J, Greengard P, Svenningsson P . Neurogenic effects of fluoxetine are attenuated in p11 (S100A10) knockout mice. Biol Psychiatry 2010; 67: 1048â1056.
Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 2006; 311: 77â80.
Warner-Schmidt JL, Chen EY, Zhang X, Marshall JJ, Morozov A, Svenningsson P et al. A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry 2010; 68: 528â535.
Tozuka Y, Fukuda S, Namba T, Seki T, Hisatsune T . GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 2005; 47: 803â815.
Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H . GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 2006; 439: 589â593.
Sanacora G, Mason GF, Rothman DL, Krystal JH . Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 2002; 159: 663â665.
Bhagwagar Z, Wylezinska M, Taylor M, Jezzard P, Matthews PM, Cowen PJ . Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am J Psychiatry 2004; 161: 368â370.
Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, OâLeary OF et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 2008; 320: 385â388.
Kawaguchi Y, Shindou T . Noradrenergic excitation and inhibition of GABAergic cell types in rat frontal cortex. J Neurosci 1998; 18: 6963â6976.
Bennett BD, Huguenard JR, Prince DA . Adrenergic modulation of GABAA receptor-mediated inhibition in rat sensorimotor cortex. J Neurophysiol 1998; 79: 937â946.
Lei S, Deng PY, Porter JE, Shin HS . Adrenergic facilitation of GABAergic transmission in rat entorhinal cortex. J Neurophysiol 2007; 98: 2868â2877.
Hillman KL, Lei S, Doze VA, Porter JE . Alpha-1A adrenergic receptor activation increases inhibitory tone in CA1 hippocampus. Epilepsy Res 2009; 84: 97â109.
Kaneko K, Tamamaki N, Owada H, Kakizaki T, Kume N, Totsuka M et al. Noradrenergic excitation of a subpopulation of GABAergic cells in the basolateral amygdala via both activation of nonselective cationic conductance and suppression of resting K(+) conductance: a study using glutamate decarboxylase 67-green fluorescent protein knock-in mice. Neuroscience 2008; 157: 781â797.
Herman JP, Renda A, Bodie B . Norepinephrine-gamma-aminobutyric acid (GABA) interaction in limbic stress circuits: effects of reboxetine on GABAergic neurons. Biol Psychiatry 2003; 53: 166â174.
Karolewicz B, Maciag D, OâDwyer G, Stockmeier CA, Feyissa AM, Rajkowska G . Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol 2010; 13: 411â420.
Garcia-Colunga J, Vazquez-Gomez E, Miledi R . Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors. Pharmacogenomics J 2004; 4: 388â393.
Garcia-Colunga J, Awad JN, Miledi R . Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac). Proc Natl Acad Sci USA 1997; 94: 2041â2044.
Breitinger HG, Geetha N, Hess GP . Inhibition of the serotonin 5-HT3 receptor by nicotine, cocaine, and fluoxetine investigated by rapid chemical kinetic techniques. Biochemistry 2001; 40: 8419â8429.
Fan P . Inhibition of a 5-HT3 receptor-mediated current by the selective serotonin uptake inhibitor, fluoxetine. Neurosci Lett 1994; 173: 210â212.
Fan P . Effects of antidepressants on the inward current mediated by 5-HT3 receptors in rat nodose ganglion neurones. Br J Pharmacol 1994; 112: 741â744.
Maertens C, Wei L, Voets T, Droogmans G, Nilius B . Block by fluoxetine of volume-regulated anion channels. Br J Pharmacol 1999; 126: 508â514.
Tytgat J, Maertens C, Daenens P . Effect of fluoxetine on a neuronal, voltage-dependent potassium channel (Kv1.1). Br J Pharmacol 1997; 122: 1417â1424.
Deak F, Lasztoczi B, Pacher P, Petheo GL, Valeria K, Spat A . Inhibition of voltage-gated calcium channels by fluoxetine in rat hippocampal pyramidal cells. Neuropharmacology 2000; 39: 1029â1036.
Sung MJ, Ahn HS, Hahn SJ, Choi BH . Open channel block of Kv3.1 currents by fluoxetine. J Pharmacol Sci 2008; 106: 38â45.
Kim HJ, Choi JS, Lee YM, Shim EY, Hong SH, Kim MJ et al. Fluoxetine inhibits ATP-induced [Ca(2+)](i) increase in PC12 cells by inhibiting both extracellular Ca(2+) influx and Ca(2+) release from intracellular stores. Neuropharmacology 2005; 49: 265â274.
Choi BH, Choi JS, Ahn HS, Kim MJ, Rhie DJ, Yoon SH et al. Fluoxetine blocks cloned neuronal A-type K+ channels Kv1.4. Neuroreport 2003; 14: 2451â2455.
Choi JS, Hahn SJ, Rhie DJ, Yoon SH, Jo YH, Kim MS . Mechanism of fluoxetine block of cloned voltage-activated potassium channel Kv1.3. J Pharmacol Exp Ther 1999; 291: 1â6.
Robinson RT, Drafts BC, Fisher JL . Fluoxetine increases GABA(A) receptor activity through a novel modulatory site. J Pharmacol Exp Ther 2003; 304: 978â984.
Ye ZY, Zhou KQ, Xu TL, Zhou JN . Fluoxetine potentiates GABAergic IPSCs in rat hippocampal neurons. Neurosci Lett 2008; 442: 24â29.
Leander JD . Fluoxetine a selective serotonin-uptake inhibitor, enhances the anticonvulsant effects of phenytoin, carbamazepine, and ameltolide (LY201116). Epilepsia 1992; 33: 573â576.
Uzunov DP, Cooper TB, Costa E, Guidotti A . Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc Natl Acad Sci USA 1996; 93: 12599â12604.
Serra M, Pisu MG, Muggironi M, Parodo V, Papi G, Sari R et al. Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain. Psychopharmacology 2001; 158: 48â54.
Uzunova V, Wrynn AS, Kinnunen A, Ceci M, Kohler C, Uzunov DP . Chronic antidepressants reverse cerebrocortical allopregnanolone decline in the olfactory-bulbectomized rat. Eur J Pharmacol 2004; 486: 31â34.
Pinna G, Costa E, Guidotti A . Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology 2006; 186: 362â372.
Freeman EW, Purdy RH, Coutifaris C, Rickels K, Paul SM . Anxiolytic metabolites of progesterone: correlation with mood and performance measures following oral progesterone administration to healthy female volunteers. Neuroendocrinology 1993; 58: 478â484.
Khisti RT, Chopde CT, Jain SP . Antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice forced swim test. Pharmacol Biochem Behav 2000; 67: 137â143.
Griffin LD, Mellon SH . Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci USA 1999; 96: 13512â13517.
Nin MS, Salles FB, Azeredo LA, Frazon AP, Gomez R, Barros HM . Antidepressant effect and changes of GABA(A) receptor gamma2 subunit mRNA after hippocampal administration of allopregnanolone in rats. J Psychopharmacol 2008; 22: 477â485.
Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi ZP et al. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci USA 1999; 96: 12905â12910.
Vicini S, Losi G, Homanics GE . GABA(A) receptor delta subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons. Neuropharmacology 2002; 43: 646â650.
Wohlfarth KM, Bianchi MT, Macdonald RL . Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the delta subunit. J Neurosci 2002; 22: 1541â1549.
Belelli D, Casula A, Ling A, Lambert JJ . The influence of subunit composition on the interaction of neurosteroids with GABA(A) receptors. Neuropharmacology 2002; 43: 651â661.
Belelli D, Herd MB, Mitchell EA, Peden DR, Vardy AW, Gentet L et al. Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance. Neuroscience 2006; 138: 821â829.
Matsumoto K, Puia G, Dong E, Pinna G . GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders. Stress (Amsterdam, Netherlands) 2007; 10: 3â12.
Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F et al. Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. J Neurochem 2000; 75: 732â740.
Mellon SH . Neurosteroid regulation of central nervous system development. Pharmacol Ther 2007; 116: 107â124.
Pinna G, Costa E, Guidotti A . SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake. Curr Opin Pharmacol 2009; 9: 24â30.
Schule C, di Michele F, Baghai T, Romeo E, Bernardi G, Zwanzger P et al. Influence of sleep deprivation on neuroactive steroids in major depression. Neuropsychopharmacology 2003; 28: 577â581.
Giedke H . The usefulness of therapeutic sleep deprivation in depression. J Affect Disord 2004; 78: 85â86, author reply 87.
Padberg F, di Michele F, Zwanzger P, Romeo E, Bernardi G, Schule C et al. Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression. Neuropsychopharmacology 2002; 27: 874â878.
Baghai TC, di Michele F, Schule C, Eser D, Zwanzger P, Pasini A et al. Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression. Neuropsychopharmacology 2005; 30: 1181â1186.
Sanacora G, Fenton LR, Fasula MK, Rothman DL, Levin Y, Krystal JH et al. Cortical gamma-aminobutyric acid concentrations in depressed patients receiving cognitive behavioral therapy. Biol Psychiatry 2006; 59: 284â286.
Sanacora G, Mason GF, Rothman DL, Hyder F, Ciarcia JJ, Ostroff RB et al. Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 2003; 160: 577â579.
Mervaala E, Kononen M, Fohr J, Husso-Saastamoinen M, Valkonen-Korhonen M, Kuikka JT et al. SPECT and neuropsychological performance in severe depression treated with ECT. J Affect Disord 2001; 66: 47â58.
Aston-Jones G, Zhu Y, Card JP . Numerous GABAergic afferents to locus ceruleus in the pericerulear dendritic zone: possible interneuronal pool. J Neurosci 2004; 24: 2313â2321.
Judge SJ, Ingram CD, Gartside SE . GABA receptor modulation of 5-HT neuronal firing: characterization and effect of moderate in vivo variations in glucocorticoid levels. Neurochem Int 2004; 45: 1057â1065.
Holmes A, Murphy DL, Crawley JN . Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry 2003; 54: 953â959.
Holmes A, Yang RJ, Lesch KP, Crawley JN, Murphy DL . Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology 2003; 28: 2077â2088.
Lira A, Zhou M, Castanon N, Ansorge MS, Gordon JA, Francis JH et al. Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol Psychiatry 2003; 54: 960â971.
Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA . Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004; 306: 879â881.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS . Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104â9110.
Nakagawa S, Kim JE, Lee R, Malberg JE, Chen J, Steffen C et al. Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J Neurosci 2002; 22: 3673â3682.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805â809.
Wang JW, David DJ, Monckton JE, Battaglia F, Hen R . Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci 2008; 28: 1374â1384.
Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K . High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 2007; 317: 819â823.
Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, Griebel G et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry 2008; 64: 293â301.
Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza PV et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry 2009; 14: 959â967.
Bergami M, Rimondini R, Santi S, Blum R, Gotz M, Canossa M . Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proc Natl Acad Sci USA 2008; 105: 15570â15575.
Taliaz D, Stall N, Dar DE, Zangen A . Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry 2010; 15: 80â92.
David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 2009; 62: 479â493.
Gould E, McEwen BS, Tanapat P, Galea LA, 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: 2492â2498.
Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E . Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA 1998; 95: 3168â3171.
Tanapat P, Galea LA, Gould E . Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus. Int J Dev Neurosci 1998; 16: 235â239.
Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY et al. Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry 2004; 56: 640â650.
Frodl T, Meisenzahl EM, Zill P, Baghai T, Rujescu D, Leinsinger G et al. Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression. Arch Gen Psychiatry 2004; 61: 177â183.
Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS . Hippocampal volume reduction in major depression. Am J Psychiatry 2000; 157: 115â118.
Czeh B, Lucassen PJ . What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur Arch Psychiatry Clin Neurosci 2007; 257: 250â260.
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: 5034â5043.
Sheline YI, Gado MH, Kraemer HC . Untreated depression and hippocampal volume loss. Am J Psychiatry 2003; 160: 1516â1518.
MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA 2003; 100: 1387â1392.
Mirescu C, Gould E . Stress and adult neurogenesis. Hippocampus 2006; 16: 233â238.
Jha S, Rajendran R, Davda J, Vaidya VA . Selective serotonin depletion does not regulate hippocampal neurogenesis in the adult rat brain: differential effects of p-chlorophenylalanine and 5,7-dihydroxytryptamine. Brain Res 2006; 1075: 48â59.
Ueda S, Sakakibara S, Yoshimoto K . Effect of long-lasting serotonin depletion on environmental enrichment-induced neurogenesis in adult rat hippocampus and spatial learning. Neuroscience 2005; 135: 395â402.
Kulkarni VA, Jha S, Vaidya VA . Depletion of norepinephrine decreases the proliferation, but does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus. Eur J Neurosci 2002; 16: 2008â2012.
Liu X, Wang Q, Haydar TF, Bordey A . Nonsynaptic GABA signaling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors. Nat Neurosci 2005; 8: 1179â1187.
Carleton A, Petreanu LT, Lansford R, Alvarez-Buylla A, Lledo PM . Becoming a new neuron in the adult olfactory bulb. Nat Neurosci 2003; 6: 507â518.
LoTurco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR . GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 1995; 15: 1287â1298.
Lledo PM, Alonso M, Grubb MS . Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 2006; 7: 179â193.
Ge S, Pradhan DA, Ming Gl, Song H . GABA sets the tempo for activity-dependent adult neurogenesis. Trends Neurosci 2007; 30: 1â8.
Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R . GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev 2007; 87: 1215â1284.
Wang DD, Kriegstein AR . Defining the role of GABA in cortical development. J Physiol 2009; 587: 1873â1879.
Sernagor E, Chabrol F, Bony G, Cancedda L . GABAergic control of neurite outgrowth and remodeling during development and adult neurogenesis: general rules and differences in diverse systems. Front Cell Neurosci 2010; 4: 11.
Wu X, Castren E . Co-treatment with diazepam prevents the effects of fluoxetine on the proliferation and survival of hippocampal dentate granule cells. Biol Psychiatry 2009; 34: 367â381.
Schmidt-Hieber C, Jonas P, Bischofberger J . Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 2004; 429: 184â187.
Maric D, Liu QY, Maric I, Chaudry S, Chang YH, Smith SV et al. GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl- channels. J Neurosci 2001; 21: 2343â2360.
Borodinsky LN, OâLeary D, Neale JH, Vicini S, Coso OA, Fiszman ML . GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABA(A) receptor activation, calcium influx and CaMKII and erk1/2 pathways. J Neurochem 2003; 84: 1411â1420.
Fiszman ML, Schousboe A . Role of calcium and kinases on the neurotrophic effect induced by gamma-aminobutyric acid. J Neurosci Res 2004; 76: 435â441.
Gascon E, Dayer AG, Sauvain MO, Potter G, Jenny B, De Roo M et al. GABA regulates dendritic growth by stabilizing lamellipodia in newly generated interneurons of the olfactory bulb. J Neurosci 2006; 26: 12956â12966.
Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH . NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 2006; 442: 929â933.
Shaywitz AJ, Greenberg ME . CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 1999; 68: 821â861.
Fujioka T, Fujioka A, Duman RS . Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus. J Neurosci 2004; 24: 319â328.
Gur TL, Conti AC, Holden J, Bechtholt AJ, Hill TE, Lucki I et al. cAMP response element-binding protein deficiency allows for increased neurogenesis and a rapid onset of antidepressant response. J Neurosci 2007; 27: 7860â7868.
Jagasia R, Steib K, Englberger E, Herold S, Faus-Kessler T, Saxe M et al. GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci 2009; 29: 7966â7977.
Carlezon Jr WA, Duman RS, Nestler EJ . The many faces of CREB. Trends Neurosci 2005; 28: 436â445.
Chen AC, Shirayama Y, Shin KH, Neve RL, Duman RS . Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect. Biol Psychiatry 2001; 49: 753â762.
Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S et al. cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 2000; 20: 4030â4036.
Dowlatshahi D, MacQueen GM, Wang JF, Young LT . Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet 1998; 352: 1754â1755.
Duman RS . Depression: a case of neuronal life and death? Biol Psychiatry 2004; 56: 140â145.
Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME . Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 1998; 20: 709â726.
Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A . Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 1998; 20: 727â740.
Obrietan K, Gao XB, Van Den Pol AN . Excitatory actions of GABA increase BDNF expression via a MAPK-CREB-dependent mechanismâa positive feedback circuit in developing neurons. J Neurophysiol 2002; 88: 1005â1015.
Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM . Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 2002; 109: 143â148.
Sen S, Duman R, Sanacora G . Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 2008; 64: 527â532.
Bonnin CM, Martinez-Aran A, Torrent C, Pacchiarotti I, Rosa AR, Franco C et al. Clinical and neurocognitive predictors of functional outcome in bipolar euthymic patients: a long-term, follow-up study. J Affect Disord 2010; 121: 156â160.
Cunhaa ABM, Frey BN, Andreazza AC, Goia JD, Rosa AR, Gonçalves CA et al. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett 2006; 398: 215â219.
Gronli J, Bramham C, Murison R, Kanhema T, Fiske E, Bjorvatn B et al. Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharmacol Biochem Behav 2006; 85: 842â849.
Nibuya M, Morinobu S, Duman RS . Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995; 15: 7539â7547.
Nibuya M, Nestler EJ, Duman RS . Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16: 2365â2372.
Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT . Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001; 50: 260â265.
Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM . Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997; 56: 131â137.
Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS . Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002; 22: 3251â3261.
Koponen E, Rantamaki T, Voikar V, Saarelainen T, MacDonald E, Castren E . Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines. Cell Mol Neurobiol 2005; 25: 973â980.
Hoshaw BA, Malberg JE, Lucki I . Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res 2005; 1037: 204â208.
Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci USA 2004; 101: 10827â10832.
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: 349â357.
Chan JP, Cordeira J, Calderon GA, Iyer LK, Rios M . Depletion of central BDNF in mice impedes terminal differentiation of new granule neurons in the adult hippocampus. Mol Cell Neurosci 2008; 39: 372â383.
Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS . Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 2000; 3: 323â329.
Baldelli P, Novara M, Carabelli V, Hernandez-Guijo JM, Carbone E . BDNF up-regulates evoked GABAergic transmission in developing hippocampus by potentiating presynaptic N- and P/Q-type Ca2+ channels signalling. Eur J Neurosci 2002; 16: 2297â2310.
Shulga A, Thomas-Crusells J, Sigl T, Blaesse A, Mestres P, Meyer M et al. Posttraumatic GABA(A)-mediated [Ca2+]i increase is essential for the induction of brain-derived neurotrophic factor-dependent survival of mature central neurons. J Neurosci 2008; 28: 6996â7005.
Aguado F, Carmona MA, Pozas E, Aguilo A, Martinez-Guijarro FJ, Alcantara S et al. BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2. Development 2003; 130: 1267â1280.
Fiumelli H, Woodin MA . Role of activity-dependent regulation of neuronal chloride homeostasis in development. Curr Opin Neurobiol 2007; 17: 81â86.
Tanaka T, Saito H, Matsuki N . Inhibition of GABA(A) synaptic responses by brain-derived neurotrophic factor (BDNF) in rat hippocampus. J Neurosci 1997; 17: 2959â2966.
Brunig I, Penschuck S, Berninger B, Benson J, Fritschy JM . BDNF reduces miniature inhibitory postsynaptic currents by rapid downregulation of GABA(A) receptor surface expression. Eur J Neurosci 2001; 13: 1320â1328.
Henneberger C, Juttner R, Rothe T, Grantyn R . Postsynaptic action of BDNF on GABAergic synaptic transmission in the superficial layers of the mouse superior colliculus. J Neurophysiol 2002; 88: 595â603.
Wardle RA, Poo MM . Brain-derived neurotrophic factor modulation of GABAergic synapses by postsynaptic regulation of chloride transport. J Neurosci 2003; 23: 8722â8732.
Jovanovic JN, Thomas P, Kittler JT, Smart TG, Moss SJ . Brain-derived neurotrophic factor modulates fast synaptic inhibition by regulating GABA(A) receptor phosphorylation, activity, and cell-surface stability. J Neurosci 2004; 24: 522â530.
Berninger B, Marty S, Zafra F, da Penha Berzaghi M, Thoenen H, Lindholm D . GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro. Development 1995; 121: 2327â2335.
Castren E, Rantamaki T . The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 2010; 70: 289â297.
Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S et al. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 2006; 59: 673â680.
Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Kim YH et al. Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry 2007; 62: 423â428.
Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR et al. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 2009; 14: 681â695.
Nutt DJ, Sahl SM . Searching for perfect sleep: the continuing evolution of GABA(A) receptor modulators as hypnotics. J Psychopharmacol OnlineFirst 2009; 24: 1601â1612.
Methippara M, Bashir T, Suntsova N, Szymusiak R, McGinty D . Hippocampal adult neurogenesis is enhanced by chronic eszopiclone treatment in rats. J Sleep Res 2010; 19: 384â393.
Su XW, Li XY, Banasr M, Duman RS . Eszopiclone and fluoxetine enhance the survival of newborn neurons in the adult rat hippocampus. Int J Neuropsychopharmacol 2009; 12: 1421â1428.
Fava M, McCall WV, Krystal A, Wessel T, Rubens R, Caron J et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry 2006; 59: 1052â1060.
Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP et al. Decreased GABA(A)-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci 1999; 2: 833â839.
Chapman DP, Whitfield CL, Felitti VJ, Dube SR, Edwards VJ, Anda RF . Adverse childhood experiences and the risk of depressive disorders in adulthood. J Affect Disord 2004; 82: 217â225.
Anda RF, Felitti VJ, Bremner JD, Walker JD, Whitfield C, Perry BD et al. The enduring effects of abuse and related adverse experiences in childhood. A convergence of evidence from neurobiology and epidemiology. Eur Arch Psychiatry Clin Neurosci 2006; 256: 174â186.
Austin MP, Mitchell P, Wilhelm K, Parker G, Hickie I, Brodaty H et al. Cognitive function in depression: a distinct pattern of frontal impairment in melancholia? Psychol Med 1999; 29: 73â85.
Schatzberg AF, Posener JA, DeBattista C, Kalehzan BM, Rothschild AJ, Shear PK . Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness. Am J Psychiatry 2000; 157: 1095â1100.
Rogers MA, Bellgrove MA, Chiu E, Mileshkin C, Bradshaw JL . Response selection deficits in melancholic but not nonmelancholic unipolar major depression. J Clin Exp Neuropsychol 2004; 26: 169â179.
Sheline YI . Hippocampal atrophy in major depression: a result of depression-induced neurotoxicity? Mol Psychiatry 1996; 1: 298â299.
Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010; 303: 47â53.
Young EA, Altemus M, Lopez JF, Kocsis JH, Schatzberg AF, DeBattista C et al. HPA axis activation in major depression and response to fluoxetine: a pilot study. Psychoneuroendocrinology 2004; 29: 1198â1204.
Swartz CM, Guadagno G . Melancholia with onset during treatment with SSRIs. Ann Clin Psychiatry 1998; 10: 177â179.
Perry PJ . Pharmacotherapy for major depression with melancholic features: relative efficacy of tricyclic versus selective serotonin reuptake inhibitor antidepressants. J Affect Disord 1996; 39: 1â6.
Clerc GE, Ruimy P, Verdeau-Palles J . A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. The Venlafaxine French Inpatient Study Group. Int Clin Psychopharmacol 1994; 9: 139â143.
Roose SP, Glassman AH, Attia E, Woodring S . Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 1994; 151: 1735â1739.
Parker G, Mitchell P, Wilhelm K, Menkes D, Snowdon J, Schweitzer I et al. Are the newer antidepressant drugs as effective as established physical treatments? Results from an Australasian clinical panel review. Aust N Z J Psychiatry 1999; 33: 874â881.
Parker G, Roy K, Wilhelm K, Mitchell P . Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study. J Clin Psychiatry 2001; 62: 117â125.
Kasckow JW, Baker D, Geracioti Jr TD . Corticotropin-releasing hormone in depression and post-traumatic stress disorder. Peptides 2001; 22: 845â851.
Contreras F, Menchon JM, Urretavizcaya M, Navarro MA, Vallejo J, Parker G . Hormonal differences between psychotic and non-psychotic melancholic depression. J Affect Disord 2007; 100: 65â73.
Heuser IJ, Schweiger U, Gotthardt U, Schmider J, Lammers CH, Dettling M et al. Pituitary-adrenal-system regulation and psychopathology during amitriptyline treatment in elderly depressed patients and normal comparison subjects. Am J Psychiatry 1996; 153: 93â99.
Young TL, Cepko CL . A role for ligand-gated ion channels in rod photoreceptor development. Neuron 2004; 41: 867â879.
MacLeod AK, Byrne A . Anxiety, depression, and the anticipation of future positive and negative experiences. J Abnorm Psychol 1996; 105: 286â289.
Chan SW, Harmer CJ, Goodwin GM, Norbury R . Risk for depression is associated with neural biases in emotional categorisation. Neuropsychologia 2008; 46: 2896â2903.
Dearing KF, Gotlib IH . Interpretation of ambiguous information in girls at risk for depression. J Abnorm Child Psychol 2009; 37: 79â91.
Tsetsenis T, Ma X-H, Iacono LL, Beck SG, Gross CT . Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nat Neurosci 2007; 10: 896â902.
Elliott R, Rees G, Dolan RJ . Ventromedial prefrontal cortex mediates guessing. Neuropsychologia 1999; 37: 403â411.
Chaudhry AM, Parkinson JA, Hinton EC, Owen AM, Roberts AC . Preference judgements involve a network of structures within frontal, cingulate and insula cortices. Eur J Neurosci 2009; 29: 1047â1055.
Duman RS, Malberg J, Nakagawa S, DâSa C . Neuronal plasticity and survival in mood disorders. Biol Psychiatry 2000; 48: 732â739.
Cherubini E, Gaiarsa JL, Ben-Ari Y . GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 1991; 14: 515â519.
Caldji C, Diorio J, Anisman H, Meaney MJ . Maternal behavior regulates benzodiazepine/GABA(A) receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice. Neuropsychopharmacology 2004; 29: 1344â1352.
Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ . World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry 2002; 3: 5â43.
Bortone D, Polleux F . KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner. Neuron 2009; 62: 63â71.
Fagiolini M, Fritschy JM, Low K, Mohler H, Rudolph U, Hensch TK . Specific GABA(A) circuits for visual cortical plasticity. Science 2004; 303: 1681â1683.
Chattopadhyaya B, Di Cristo G, Wu CZ, Knott G, Kuhlman S, Fu Y et al. GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron 2007; 54: 889â903.
Concas A, Mostallino MC, Porcu P, Follesa P, Barbaccia ML, Trabucchi M et al. Role of brain allopregnanolone in the plasticity of γ-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery. Proc Natl Acad Sci USA 1998; 95: 13284â13289.
Follesa P, Floris S, Tuligi G, Mostallino MC, Concas A, Biggio G . Molecular and functional adaptation of the GABA(A) receptor complex during pregnancy and after delivery in the rat brain. Eur J Neurosci 1998; 10: 2905â2912.
Backstrom T, Andersson A, Andree L, Birzniece V, Bixo M, Bjorn I et al. Pathogenesis in menstrual cycle-linked CNS disorders. Ann N Y Acad Sci 2003; 1007: 42â53.
Brussaard AB, Koksma JJ . Conditional regulation of neurosteroid sensitivity of GABAA receptors. Ann N Y Acad Sci 2003; 1007: 29â36.
Vithlani M, Moss SJ . The role of GABA(A) receptor phosphorylation in the construction of inhibitory synapses and the efficacy of neuronal inhibition. Biochem Soc Trans 2009; 37: 1355â1358.
Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312â324.
Charych EI, Liu F, Moss SJ, Brandon NJ . GABA(A) receptors and their associated proteins: implications in the etiology and treatment of schizophrenia and related disorders. Neuropharmacology 2009; 57: 481â495.
Feder A, Nestler EJ, Charney DS . Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 2009; 10: 446â457.
Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry 2010 (e-pub ahead of print).
Hamidi M, Drevets WC, Price JL . Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry 2004; 55: 563â569.
Acknowledgements
We thank Byron Jones, Pam Mitchell and Casey Kilpatrick for critical reading of the manuscript. Research in the Luscher laboratory is supported by grants MH62391, MH60989 and RC1MH089111 from the National Institutes of Mental Health (NIMH), and a grant from the Pennsylvania Department of Health using Tobacco Settlement Funds. The contents of this review are solely the responsibility of the authors and do not necessarily represent the views of the NIMH or the NIH. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions.
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Luscher, B., Shen, Q. & Sahir, N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 16, 383â406 (2011). https://doi.org/10.1038/mp.2010.120
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DOI: https://doi.org/10.1038/mp.2010.120
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