Novel therapeutic strategies in major depression: Focus on RNAi and ketamine

Current Pharmaceutical Design

Volumn 20, Issue 23, 2014, Pages 3848-3860

  Bortolozzi, Analía ^a   Celada, Pau ^a   Artigas, Francesc ^a  

^a INST D INVESTIGACIONS B   (Spain)

Author keywords

5 hydroxytryptamine (serotonin) receptors; Antidepressant drugs; Cg25; Cingulate gyrus; DBS; Deep brain stimulation; Ketamine; Medial prefrontal cortex; NMDA receptors; Serotonin transporter; SERT

Indexed keywords

GLUTAMIC ACID; KETAMINE; NEUROTRANSMITTER; SEROTONIN NORADRENALIN REUPTAKE INHIBITOR; SMALL INTERFERING RNA; ANTIDEPRESSANT AGENT; MICRORNA; SEROTONIN 1A RECEPTOR; SEROTONIN TRANSPORTER;

ANTERIOR CINGULATE; ANTIDEPRESSANT ACTIVITY; ARTICLE; BRAIN DEPTH STIMULATION; BRAIN REGION; DISEASE SEVERITY; DRUG MECHANISM; GENE EXPRESSION; HUMAN; MAJOR DEPRESSION; MONOAMINERGIC SYSTEM; MOOD; NONHUMAN; PRIORITY JOURNAL; QUALITY OF LIFE; REMISSION; RNA INTERFERENCE; SUICIDE; TREATMENT RESISTANT DEPRESSION; TREATMENT RESPONSE; ANIMAL; CLINICAL TRIAL (TOPIC); DEPRESSIVE DISORDER, MAJOR; DISEASE MODEL; GENETICS; METABOLISM;

ANIMALS; ANTIDEPRESSIVE AGENTS; CLINICAL TRIALS AS TOPIC; DEEP BRAIN STIMULATION; DEPRESSIVE DISORDER, MAJOR; DISEASE MODELS, ANIMAL; HUMANS; KETAMINE; MICRORNAS; RECEPTOR, SEROTONIN, 5-HT1A; RNA INTERFERENCE; RNA, SMALL INTERFERING; SEROTONIN PLASMA MEMBRANE TRANSPORT PROTEINS;

EID: 84910081374     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/13816128113196660137     Document Type: Article

References (174)

1. Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global burden of disease study. Lancet 1997; 349: 1498-504
2. Andlin-Sobocki P, Rehnberg P, Jonsson B. Cost of affective disorders in Europe. Value in Health 2005; 8: A210
3. Kessler RC, Demler O, Frank RG, et al. Prevalence and treatment of mental disorders, 1990 to 2003. New England J Medicine 2005; 352: 2515-23
4. Gustavsson A, Svensson M, Jacobi F, et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011; 21: 718-79
5. Murray CJL, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2197-223
6. Danish University Antidepressant Group. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology (Berl) 1986; 90: 131-8
7. Danish University Antidepressant Group. Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Disord 1990; 18: 289-99
8. Tollefson GD, Holman SL. How Long to Onset of Antidepressant Action-A Metaanalysis of Patients Treated with Fluoxetine Or Placebo. International Clinical Psychopharmacology 1994; 9: 245-50
9. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. British J Psychiatry 2001; 178: 234-41
10. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354: 1243-52
11. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. New Eng J Med 2006; 354: 1231-42
12. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longerterm outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905-17
13. Carvalho AF, Machado JR, Cavalcante JL. Augmentation strategies for treatment-resistant depression. Curr Opinion Psychiatry 2009; 22: 7-12
14. Kellner CH, Knapp RG, Petrides G, 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). Archives General Psychiatry 2006; 63: 1337-44
15. Bostwick JM, Pankratz VS. Affective disorders and suicide risk: A reexamination. American J Psychiatry 2000; 157: 1925-32
16. Blier P, Demontigny C. Current Advances and Trends in the Treatment of Depression. Trends Pharmacol Sci 1994; 15: 220-6
17. D’Sa C, Duman RS. Antidepressants and neuroplasticity. Bipolar Disorders 2002; 4: 183-94
18. Nestler EJ, Barrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron 2002; 34: 13-25
19. Dranovsky A, Hen R. Hippocampal neurogenesis: Regulation by stress and antidepressants. Biological Psychiatry 2006; 59: 1136-43
20. Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behavioural Pharmacol 2007; 18: 391-418
21. Vidal R, Pilar-Cuellar F, dos Anjos S, et al. New Strategies in the Development of Antidepressants: Towards the Modulation of Neuroplasticity Pathways. Curr Pharm Des 2011; 17: 521-33
22. Smeraldi E, Zanardi R, Benedetti F, et al. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Molecular Psychiatry 1998; 3: 508-11
23. Zanardi R, Benedetti F, Di Bella D, et al. Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacology 2000; 20: 105-7
24. Serretti A, Kato M, De Ronchi D, et al. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 2007; 12: 247-57
25. Stockmeier CA, Shapiro LA, Dilley GE, et al. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci 1998; 18: 7394-401
26. Lemonde S, Turecki G, Bakish D, et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003; 23: 8788-99
27. Neff CD, Abkevich V, Packer JC, et al. Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression. Mol Psychiatry 2009; 14: 621-30
28. Binder EB, Salyakina D, Lichtner P, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36: 1319-25
29. Bel N, Artigas F. Reduction of serotonergic function in rat brain by tryptophan depletion: effects in control and fluvoxamine-treated rats. J Neurochem 1996; 67: 669-76
30. Delgado PL, Charney DS, Price LH, et al. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressantinduced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 47: 411-8
31. Bejjani BP, Damier P, Arnulf I, et al. Transient acute depression induced by high-frequency deep-brain stimulation. New Eng J Med 1999; 340: 1476-80
32. Blomstedt P, Hariz MI, Lees A, et al. Acute severe depression induced by intraoperative stimulation of the substantia nigra: A case report. Parkinsonism Related Disorders 2008; 14: 253-6
33. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45: 651-60
34. Holtzheimer PE, Kelley ME, Gross RE, et al. Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Unipolar and Bipolar Depression. Archives General Psychiatry 2012; 69: 150-8
35. Puigdemont D, Perez-Egea R, Portella MJ, et al. Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression. International J Neuropsychopharmacol 2012; 15: 121-33
36. Lozano AM, Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 2013; 77: 406-24
37. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an Nmethyl-D-aspartate antagonist in treatment-resistant major depression. Archives General Psychiatry 2006; 63: 856-64
38. Artigas F, Perez V, Alvarez E. Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry 1994; 51: 248-51
39. Artigas F, Romero L, de Montigny C, et al. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 1996; 19: 378-83
40. Perez V, Gilaberte I, Faries D, et al. Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 1997; 349: 1594-7
41. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001; 158: 131-4
42. Marek GJ, Martin-Ruiz R, Abo A, et al. The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 2005; 30: 2205-15
43. Beaulieu C. Numerical Data on Neocortical Neurons in Adult-Rat, with Special Reference to the Gaba Population. Brain Research 1993; 609: 284-92
44. Fremeau RT, Voglmaier S, Seal RP, et al. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosciences 2004; 27: 98-103
45. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990; 13: 266-71
46. Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev 1992; 72: 165-229
47. Rogan SC, Roth BL. Remote control of neuronal signaling. Pharmacol Rev 2011; 63: 291-315
48. Swanson CJ, Bures M, Johnson MP, et al. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 2005; 4: 131-44
49. Niswender CM, Conn PJ. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 2010; 50: 295-322
50. Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 2007; 8: 413-26
51. Paoletti P, Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opinion Pharmacol 2007; 7: 39-47
52. Cavara NA, Hollmann M. Shuffling the deck anew: How NR3 tweaks NMDA receptor function. Mol Neurobiol 2008; 38: 16-26
53. Javitt DC, Zukin SR. Recent Advances in the Phencyclidine Model of Schizophrenia. Am J Psychiatry 1991; 148: 1301-8
54. Krystal JH, D’Souza DC, Mathalon D, et al. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 2003; 169: 215-33
55. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 2000; 47: 351-4
56. Skolnick P, Popik P, Trullas R. Glutamate-based antidepressants: 20 years on. Trends Pharmacological Sci 2009; 30: 563-9
57. Ibrahim L, Diazgranados N, Franco-Chaves J, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, doubleblind, placebo-controlled study. Neuropsychopharmacology 2012; 37: 1526-33
58. Ibrahim L, Diazgranados N, Luckenbaugh DA, et al. Rapid decrease in depressive symptoms with an N-methyl-D-aspartate antagonist in ECT-resistant major depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2011; 35: 1155-9
59. Murrough JW, Perez AM, Mathew SJ, et al. A Case of Sustained Remission Following an Acute Course of Ketamine in Treatment-Resistant Depression. J Clinical Psychiatry 2011; 72: 414-5
60. Mathew SJ, Shah A, Lapidus K, et al. Ketamine for Treatment-Resistant Unipolar Depression Current Evidence. Cns Drugs 2012; 26: 189-204
61. Murrough JW. Ketamine as a Novel Antidepressant: From Synapse to Behavior. Clinical Pharmacology & Therapeutics 2012; 91: 303-9
62. Larkin GL, Beautrais AL. A preliminary naturalistic study of lowdose ketamine for depression and suicide ideation in the emergency department. International J Neuropsychopharmacology 2011; 14: 1127-31
63. Abdallah CG, Fasula M, Kelmendi B, et al. ECT Attenuates the Rapid Antidepressant Effect of Ketamine. Biological Psychiatry 2012; 71: 294S
64. Loo CK, Katalinic N, Garfield JBB, et al. Neuropsychological and mood effects of ketamine in electroconvulsive therapy: A randomised controlled trial. J Affective Disorders 2012; 142: 233-40
65. aan het Rot M, Collins KA, Murrough JW, et al. Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression. Biological Psychiatry 2010; 67: 139-45
66. Breier A, Malhotra AK, Pinals DA, et al. Association of ketamineinduced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 1997; 154: 805-11
67. Vollenweider FX, Leenders KL, Oye I, et al. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)-and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol 1997; 7: 25-38
68. Vollenweider FX, Kometer M. OPINION The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience 2010; 11: 642-51
69. Rowland LM, Bustillo JR, Mullins PG, et al. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: A 4-T proton MRS study. American J Psychiatry 2005; 162: 394-6
70. Scheidegger M, Walter M, Lehmann M, et al. Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action. Plos One 2012; 7:
71. Sheline YI, Price JL, Yan ZZ, et al. Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proceedings of the National Academy of Sciences of the United States of America 2010; 107: 11020-5
72. Salvadore G, Cornwell BR, Sambataro F, et al. Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine. Neuropsychopharmacology 2010; 35: 1415-22
73. Engin E, Treit D, Dickson CT. Anxiolytic-and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models. Neuroscience 2009; 161: 359-69
74. Li NX, Lee B, Liu RJ, et al. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science 2010; 329: 959-64
75. Autry AE, Adachi M, Nosyreva E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475: 91-U109
76. Adams BW, Moghaddam B. Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex. Biological Psychiatry 2001; 50: 750-7
77. Amargos-Bosch M, Lopez-Gil X, Artigas F, et al. Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine. International J Neuropsychopharmacology 2006; 9: 565-73
78. Lopez-Gil X, Babot Z, Amargos-Bosch M, et al. Clozapine and haloperidol differently suppress the MK-801-Increased Glutamatergic and Serotonergic transmission in the medial prefrontal cortex of the rat. Neuropsychopharmacology 2007; 32: 2087-97
79. Duman RS, Aghajanian GK. Synaptic Dysfunction in Depression: Potential Therapeutic Targets. Science 2012; 338: 68-72
80. Kargieman L, Santana N, Mengod G, et al. Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. Proc Natl Acad Sci USA 2007; 104: 14843-8
81. Santana N, Troyano-Rodriguez E, Mengod G, et al. Activation of Thalamocortical Networks by the N-methyl-D-aspartate Receptor Antagonist Phencyclidine: Reversal by Clozapine. Biological Psychiatry 2011; 69: 918-27
82. Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex Interneurons and pyramidal neurons. J Neuroscience 2007; 27: 11496-500
83. Vaisinen J, Ihalainen J, Tanila H, et al. Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia. Cellular and Molecular Neurobiology 2004; 24: 769-80
84. Duncan GE, Moy SS, Knapp DJ, et al. Metabolic mapping of the rat brain after subanesthetic doses of ketamine: potential relevance to schizophrenia. Brain Research 1998; 787: 181-90
85. Imre G, Fokkema DS, Den Boer JA, et al. Dose-response characteristics of ketamine effect on locomotion, cognitive function and central neuronal activity. Brain Res Bull 2006; 69: 338-45
86. Forero DA, vand, V, Callaerts P, et al. miRNA genes and the brain: implications for psychiatric disorders. Hum Mutat 2010; 31: 1195-204
87. Guo AY, Sun J, Jia P, et al. A novel microRNA and transcription factor mediated regulatory network in schizophrenia. BMC Syst Biol 2010; 4: 10
88. Im HI, Kenny PJ. MicroRNAs in neuronal function and dysfunction. Trends Neurosci 2012; 35: 325-34
89. Ambros V. microRNAs: tiny regulators with great potential. Cell 2001; 107: 823-6
90. John B, Enright AJ, Aravin A, et al. Human MicroRNA targets. Plos Biology 2004; 2: 1862-79
91. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15-20
92. Xie X, Lu J, Kulbokas EJ, et al. Systematic discovery of regulatory motifs in human promoters and 3’ UTRs by comparison of several mammals. Nature 2005; 434: 338-45
93. Miska EA, Alvarez-Saavedra E, Townsend M, et al. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol 2004; 5: R68
94. Kapsimali M, Kloosterman WP, de Bruijn E, et al. MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol 2007; 8: R173
95. Landgraf P, Rusu M, Sheridan R, et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 2007; 129: 1401-14
96. Smirnova L, Grafe A, Seiler A, et al. Regulation of miRNA expression during neural cell specification. Eur J Neurosci 2005; 21: 1469-77
97. He X, Zhang Q, Liu Y, et al. Cloning and identification of novel microRNAs from rat hippocampus. Acta Biochim Biophys Sin (Shanghai) 2007; 39: 708-14
98. Kim J, Inoue K, Ishii J, et al. A MicroRNA feedback circuit in midbrain dopamine neurons. Science 2007; 317: 1220-4
99. Kye MJ, Liu T, Levy SF, et al. Somatodendritic microRNAs identified by laser capture and multiplex RT-PCR. RNA 2007; 13: 1224-34
100. [100] Ashraf SI, Kunes S. A trace of silence: memory and microRNA at the synapse. Curr Opin Neurobiol 2006; 16: 535-9
101. [101] Schratt G. microRNAs at the synapse. Nat Rev Neurosci 2009; 10: 842-9
102. [102] Choi PS, Zakhary L, Choi WY, et al. Members of the miRNA-200 family regulate olfactory neurogenesis. Neuron 2008; 57: 41-55
103. [103] Krichevsky AM, Sonntag KC, Isacson O, et al. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 2006; 24: 857-64
104. [104] Makeyev EV, Zhang J, Carrasco MA, et al. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 2007; 27: 435-48
105. [105] Vo N, Klein ME, Varlamova O, et al. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci USA 2005; 102: 16426-31
106. [106] Baudry A, Mouillet-Richard S, Schneider B, et al. miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science 2010; 329: 1537-41
107. [107] Davidson BL, Paulson HL. Molecular medicine for the brain: silencing of disease genes with RNA interference. Lancet Neurol 2004; 3: 145-9
108. [108] Behlke MA. Progress towards in vivo use of siRNAs. Mol Ther 2006; 13: 644-70
109. [109] de Fougerolles A, Vornlocher HP, Maraganore J, et al. Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 2007; 6: 443-53
110. [110] Boudreau RL, Rodriguez-Lebron E, Davidson BL. RNAi medicine for the brain: progresses and challenges. Hum Mol Genet 2011; 20: R21-R27
111. [111] Davidson BL, McCray PB, Jr. Current prospects for RNA interference-based therapies. Nat Rev Genet 2011; 12: 329-40
112. [112] Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391: 806-11
113. [113] Hamilton AJ, Baulcombe DC. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 1999; 286: 950-2
114. [114] Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001; 411: 494-8
115. [115] Meister G, Tuschl T. Mechanisms of gene silencing by doublestranded RNA. Nature 2004; 431: 343-9
116. [116] Tiemann K, Rossi JJ. RNAi-based therapeutics-current status, challenges and prospects. EMBO Mol Med 2009; 1: 142-51
117. [117] Zamore PD. RNA interference: big applause for silencing in Stockholm. Cell 2006; 127: 1083-6
118. [118] Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281-97
119. [119] Tang G. siRNA and miRNA: an insight into RISCs. Trends Biochem Sci 2005; 30: 106-14
120. [120] Filipowicz W, Jaskiewicz L, Kolb FA, et al. Post-transcriptional gene silencing by siRNAs and miRNAs. Curr Opin Struct Biol 2005; 15: 331-41
121. [121] Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296: 550-3
122. [122] Paddison PJ, Caudy AA, Hannon GJ. Stable suppression of gene expression by RNAi in mammalian cells. Proc Natl Acad Sci USA 2002; 99: 1443-8
123. [123] Boudreau RL, Davidson BL. Generation of hairpin-based RNAi vectors for biological and therapeutic application. Methods Enzymol 2012; 507: 275-96
124. [124] Chung KH, Hart CC, Al Bassam S, et al. Polycistronic RNA polymerase II expression vectors for RNA interference based on BIC/miR-155. Nucleic Acids Res 2006; 34: e53
125. [125] Silva JM, Li MZ, Chang K, et al. Second-generation shRNA libraries covering the mouse and human genomes. Nat Genet 2005; 37: 1281-8
126. [126] Stegmeier F, Hu G, Rickles RJ, et al. A lentiviral microRNA-based system for single-copy polymerase II-regulated RNA interference in mammalian cells. Proc Natl Acad Sci USA 2005; 102: 13212-7
127. [127] Xia H, Mao Q, Eliason SL, et al. RNAi suppresses polyglutamineinduced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 2004; 10: 816-20
128. [128] Lewis J, Melrose H, Bumcrot D, et al. In vivo silencing of alphasynuclein using naked siRNA. Mol Neurodegener 2008; 3: 19
129. [129] McBride JL, Pitzer MR, Boudreau RL, et al. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol Ther 2011; 19: 2152-62
130. [130] Godinho BM, Ogier JR, Darcy R, et al. Self-assembling Modified beta-Cyclodextrin Nanoparticles as Neuronal siRNA Delivery Vectors: Focus on Huntington’s Disease. Mol Pharm 2013; 10: 640-9
131. [131] Hoyer D, Dev K.K. RNA interference as a therapeutic strategy for treating CNS disorders. Drug Discovery Today 2006; 3: 451-6
132. [132] Dessy A, Gorman JM. The emerging therapeutic role of RNA interference in disorders of the central nervous system. Clin Pharmacol Ther 2011; 89: 450-4
133. [133] Lesch KP. When the serotonin transporter gene meets adversity: the contribution of animal models to understanding epigenetic mechanisms in affective disorders and resilience. Curr Top Behav Neurosci 2011; 7: 251-80
134. [134] Russo SJ, Murrough JW, Han MH, et al. Neurobiology of resilience. Nat Neurosci 2012; 15: 1475-84
135. [135] Sun H, Kennedy PJ, Nestler EJ. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 2013; 38: 124-37
136. [136] Vialou V, Feng J, Robison AJ, et al. Epigenetic mechanisms of depression and antidepressant action. Annu Rev Pharmacol Toxicol 2013; 53: 59-87
137. [137] Andreasen NC. Schizophrenia: the fundamental questions. Brain Res Brain Res Rev 2000; 31: 106-12
138. [138] Lewis DA, Lieberman JA. Catching up on schizophrenia: natural history and neurobiology. Neuron 2000; 28: 325-34
139. [139] Nelson PT, Wang WX, Rajeev BW. MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol 2008; 18: 130-8
140. [140] Uchida S, Nishida A, Hara K, et al. Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor. Eur J Neurosci 2008; 27: 2250-61
141. [141] Jensen KP, Covault J, Conner TS, et al. A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors. Mol Psychiatry 2009; 14: 381-9
142. [142] Saus E, Soria V, Escaramis G, et al. Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia. Hum Mol Genet 2010; 19: 4017-25
143. [143] Xu Y, Liu H, Li F, et al. A polymorphism in the microRNA-30e precursor associated with major depressive disorder risk and P300 waveform. J Affect Disord 2010; 127: 332-6
144. [144] Beveridge NJ, Tooney PA, Carroll AP, et al. Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Hum Mol Genet 2008; 17: 1156-68
145. [145] Beveridge NJ, Gardiner E, Carroll AP, et al. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 2010; 15: 1176-89
146. [146] Santarelli DM, Beveridge NJ, Tooney PA, et al. Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia. Biol Psychiatry 2011; 69: 180-7
147. [147] Shishkina GT, Kalinina TS, Dygalo NN. Attenuation of alpha2Aadrenergic receptor expression in neonatal rat brain by RNA interference or antisense oligonucleotide reduced anxiety in adulthood. Neuroscience 2004; 129: 521-8
148. [148] Thakker DR, Natt F, Husken D, et al. Neurochemical and behavioral consequences of widespread gene knockdown in the adult mouse brain by using nonviral RNA interference. Proc Natl Acad Sci USA 2004; 101: 17270-5
149. [149] Thakker DR, Natt F, Husken D, et al. siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain. Mol Psychiatry 2005; 10: 782-9, 714
150. [150] Salahpour A, Medvedev IO, Beaulieu JM, et al. Local knockdown of genes in the brain using small interfering RNA: a phenotypic comparison with knockout animals. Biol Psychiatry 2007; 61: 65-9
151. [151] Jean A, Conductier G, Manrique C, et al. Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens. Proc Natl Acad Sci USA 2007; 104: 16335-40
152. [152] Fendt M, Schmid S, Thakker DR, et al. mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity. Mol Psychiatry 2008; 13: 970-9
153. [153] Bortolozzi A, Castane A, Semakova J, et al. Selective siRNAmediated suppression of 5-HT1A autoreceptors evokes strong antidepressant-like effects. Mol Psychiatry 2012; 17: 612-23
154. [154] Noori-Daloii MR, Mojarrad M, Rashidi-nezhad A, et al. Use of siRNA in knocking down of dopamine receptors, a possible therapeutic option in neuropsychiatric disorders. Molecular Biology Reports 2012; 39: 2003-10
155. [155] Ferres-Coy A, Santana N, Castane A, et al. Acute 5-HT(1)A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions. Psychopharmacology (Berl) 2013; 225: 61-74
156. [156] Ferres-Coy A, Pilar-Cuellar F, Vidal R, et al. RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis. Transl Psychiatry 2013; 3: e211
157. [157] Torres GE, Gainetdinov RR, Caron MG. Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 2003; 4: 13-25
158. [158] Millan MJ. Dual-and triple-acting agents for treating core and comorbid symptoms of major depression: novel concepts, new drugs. Neurotherapeutics 2009; 6: 53-77
159. [159] Wong ML, Licinio J. Research and treatment approaches to depression. Nat Rev Neurosci 2001; 2: 343-51
160. [160] Fabre V, Boutrel B, Hanoun N, et al. Homeostatic regulation of serotonergic function by the serotonin transporter as revealed by nonviral gene transfer. J Neurosci 2000; 20: 5065-75
161. [161] Gourley SL, Taylor JR. Recapitulation and reversal of a persistent depression-like syndrome in rodents. Curr Protoc Neurosci 2009; Chapter 9: Unit
162. [162] David DJ, Samuels BA, Rainer Q, et al. Neurogenesis-dependent and-independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 2009; 62: 479-93
163. [163] Artigas F. Serotonin receptors involved in antidepressant effects. Pharmacol Ther 2013; 137: 119-31
164. [164] Fakra E, Hyde LW, Gorka A, et al. Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety. Arch Gen Psychiatry 2009; 66: 33-40
165. [165] Sullivan GM, Ogden RT, Oquendo MA, et al. Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression. Biol Psychiatry 2009; 66: 223-30
166. [166] Artigas F, Celada P, Laruelle M, et al. How does pindolol improve antidepressant action? Trends Pharmacological Sciences 2001; 22: 224-8
167. [167] Haddjeri N, Blier P, de Montigny C. Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. J Neurosci 1998; 18: 10150-6
168. [168] Scorza MC, Llado-Pelfort L, Oller S, et al. Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment. Br J Pharmacol 2012; 167: 1021-34
169. [169] Kumar P, Wu H, McBride JL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature 2007; 448: 39-43
170. [170] Burgess A, Huang Y, Querbes W, et al. Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. J Control Release 2012; 163: 125-9
171. [171] Stiles DK, Zhang Z, Ge P, et al. Widespread suppression of huntingtin with convection-enhanced delivery of siRNA. Exp Neurol 2012; 233: 463-71
172. [172] Bortolozzi A, Artigas F, Alvarado G, Vila M, Montefeltro A, inventors; nLife Therapeutics S.L., assignee. Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types. Eur Patent EP2380595 (A1). 1-10-2011.
173. [173] Adell A, Casanovas JM, Artigas F. Comparative study in the rat of the actions of different types of stress on the release of 5-HT in raphe nuclei and forebrain areas. Neuropharmacology 1997; 36: 735-41
174. [174] Kurreck J. RNA interference: from basic research to therapeutic applications. Angew Chem Int Ed Engl 2009; 48: 1378-98