Glutamate-based anxiolytic ligands in clinical trials

Expert Opinion on Investigational Drugs

Volumn 22, Issue 8, 2013, Pages 1007-1022

  Wierońska, Joanna M ^a   Pilc, Andrzej ^a,b  

^a INSTITUTE OF PHARMACOLOGY   (Poland)

^b JAGIELLONIAN UNIVERSITY   (Poland)

Author keywords

Anxiety disorders; d cycloserine; Fenobam; Glutamate; LY354740; Memantine; MGlu receptors; NMDA receptors; Tiagabine; Topiramate

Indexed keywords

ACAMPROSATE; BENZODIAZEPINE DERIVATIVE; CYCLOSERINE; EGLUMETAD; FENOBAM; GLUTAMIC ACID; LAMOTRIGINE; MEMANTINE; METABOTROPIC RECEPTOR; RILUZOLE; TALAGLUMETAD; TIAGABINE; TOPIRAMATE;

AMYOTROPHIC LATERAL SCLEROSIS; ANXIETY; BIPOLAR DISORDER; CONTROLLED CLINICAL TRIAL (TOPIC); DEPRESSION; DRUG DOSE TITRATION; DRUG EFFECT; DRUG MEGADOSE; DRUG POTENTIATION; EPILEPSY; EXCITATION; GABAERGIC SYSTEM; HUMAN; MIGRAINE; NEUROTRANSMISSION; OBSESSIVE COMPULSIVE DISORDER; PANIC; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHASE 4 CLINICAL TRIAL (TOPIC); POSTTRAUMATIC STRESS DISORDER; REVIEW; SOCIAL PHOBIA; SYNAPSE; TRANQUILIZING ACTIVITY;

ANIMALS; ANTI-ANXIETY AGENTS; ANXIETY; EXCITATORY AMINO ACID AGENTS; GLUTAMIC ACID; HUMANS; ION CHANNELS; LIGANDS; SYNAPSES;

EID: 84880244362     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2013.803066     Document Type: Review

References (118)

1. Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur J Neurol 2005;12(Suppl 1):1-27
2. Wittchen HU, Jacobi F, Rehm J, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011;21:655-79
3. Millan MJ. The neurobiology and control of anxious states. Prog Neurobiol 2003;70:83-244
4. Davidson JRT, Foa EB, Huppert JD, et al. Fluoxetine, comprehensive cognitive behavioral therapy, and placebo in generalized social phobia. Arch Gen Psychiatry 2004;61:1005-13
5. Haefely W, Kulcsar A, Mohler H, et al. Possible involvement of GABA in the central actions of benzodiazepines. Adv Biochem Psychopharmacol 1975;14:131-51
6. Wieronska JM, Stachowicz K, Nowak G, et al. The loss of glutamate-GABA harmony in anxiety disorders. Anxiety Disorders, Prof. Vladimir Kalinin (Ed.) In Tech. 2011; p. 135-58
7. Stevens JC, Pollack MH. Benzodiazepines in clinical practice: Consideration of their long-term use and alternative agents. J Clin Psychiatry 2005;66:21-7
8. Bandelow B, Sher L, Bunevicius R, et al. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Practice 2013;17:76-6
9. 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
10. Linden AM, Schoepp DD. Metabotropic glutamate receptor target for neuropsychiatric disorder. Drug Discov Today 2006;3:507-17
11. Moghaddam B. Stress activation of glutamate neurotransmission in the prefrontal cortex: Implications for dopamine-associated psychiatric disorders. Biol Psychiatry 2002;51:775-87
12. Fontella FU, Vendite DA, Tabajara AS, et al. Repeated restraint stress alters hippocampal glutamate uptake and release in the rat. Neurochem Res 2004;29:1703-9
13. Yang CH, Huang CC, Hsu KS. Behavioral stress enhances hippocampal CA1 long-term depression through the blockade of the glutamate uptake. J Neurosci 2005;25:4288-93
14. Chakrabarty K, Bhattacharyya S, Christopher R, et al. Glutamatergic dysfunction in OCD. Neuropsychopharmacology 2005;30:1735-40
15. Pittenger C, Krystal JH, Coric V. Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder. NeuroRx 2006;3:69-81
16. Grachev ID, Apkarian AV. Anxiety in healthy humans is associated with orbital frontal chemistry. Mol Psychiatry 2000;5:482-8
17. Mathew SJ, Price RB, Mao XL, et al. Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder. Biol Psychiatry 2008;63:891-8
18. Tokarski K, Bobula B, Wabno J, et al. Repeated administration of imipramine attenuates glutamatergic transmission in rat frontal cortex. Neuroscience 2008;153:789-95
19. Nowak G, Trullas R, Layer RT, et al. Adaptive changes in the N-methyl-Daspartate receptor complex after chronic treatment with imipramine and 1- aminocyclopropanecarboxylic acid. J Pharmacol Exp Ther 1993;265:1380-6
20. Parsons CG, Danysz W, Quack G. Glutamate in CNS disorders as a target for drug development: An update. Drug News Perspect 1998;11:523-69
21. Pin JP, Duvoisin R. The metabotropic glutamate receptors: Structure and functions. Neuropharmacology 1995;34:1-26
22. Cortese BM, Phan KL. The role of glutamate in anxiety and related disorders. CNS Spectr 2005;10:820-30
23. Riaza Bermudo-Soriano C, Perez-Rodriguez MM, Vaquero-Lorenzo C, et al. New perspectives in glutamate and anxiety. Pharmacol Biochem Behav 2012;100:752-74
24. Chojnacka-Wojcik E, Klodzinska A, Pilc A. Glutamate receptor ligands as anxiolytics. Curr Opin Investig Drugs 2001;2:1112-19
25. Harvey BH, Shahid M. Metabotropic and ionotropic glutamate receptors as neurobiological targets in anxiety and stress-related disorders: Focus on pharmacology and preclinical translational models. Pharmacol Biochem Behav 2012;100:775-800
26. Wieronska JM, Pilc A. Metabotropic glutamate receptors in the tripartite synapse as a target for new psychotropic drugs. Neurochem Int 2009;55:85-97
27. Araque A, Parpura V, Sanzgiri RP, et al. Tripartite synapses: Glia, the unacknowledged partner. Trends Neurosci 1999;22:208-15
28. Fellin T, Pascual O, Haydon PG. Astrocytes coordinate synaptic networks: Balanced excitation and inhibition. Physiology 2006;21:208-15
29. Machado-Vieira R, Salvadore G, Ibrahim LA, et al. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 2009;15:1595-611
30. Attucci S, Carla V, Mannaioni G, et al. Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges. Br J Pharmacol 2001;132:799-806
31. Awad H, Hubert GW, Smith Y, et al. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 2000;20:7871-9
32. Doherty AJ, Palmer MJ, Bortolotto ZA, et al. A novel, competitive mGlu(5) receptor antagonist (LY344545) blocks DHPG-induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices. Br J Pharmacol 2000;131:239-44
33. Pisani A, Gubellini P, Bonsi P, et al. Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 2001;106:579-87
34. Szewczyk B, Palucha-Poniewiera A, Poleszak E, et al. Investigational NMDA receptor modulators for depression. Expert Opin Investig Drugs 2012;21:91-102
35. Palucha A, Pilc A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther 2007;115:116-47
36. Cartmell J, Schoepp DD. Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 2000;75:889-907
37. Schoepp DD. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 2001;299:12-20
38. Helton DR, Tizzano JP, Monn JA, et al. Anxiolytic and side-effect profile of LY354740: A potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. J Pharmacol Exp Ther 1998;284:651-60
39. Monn JA, Valli MJ, Massey SM, et al. Design, synthesis, and pharmacological characterization of (+)-2- aminobicyclo [3.1.0]hexane-2,6- dicarboxylic acid (LY354740): A potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. J Med Chem 1997;40:528-37
40. Klodzinska A, Chojnackawojcik E, Palucha A, et al. Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models. Neuropharmacology 1999;38:1831-9
41. Rorick-Kehn LM, Johnson BG, Burkey JL, et al. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: In vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6- dicarboxylic acid (LY404039). J Pharmacol Exp Ther 2007;321:308-17
42. Wieronska JM, Stachowicz K, Branski P, et al. On the mechanism of anti-hyperthermic effects of LY379268 and LY487379, group II mGlu receptors activators, in the stress-induced hyperthermia in singly housed mice. Neuropharmacology 2012;62:322-31
43. Johnson MP, Baez M, Jagdmann GE Jr, et al. Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: Synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy) phenyl)-N-(2,2,2- trifluoroethylsulfonyl) pyrid-3-ylmethylamine. J Med Chem 2003;46:3189-92
44. Johnson MP, Barda D, Britton TC, et al. Metabotropic glutamate 2 receptor potentiators: Receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(S). Psychopharmacology 2005;179:271-83
45. Grillon C, Cordova J, Levine LR, et al. Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear- potentiated startle paradigm in humans. Psychopharmacology 2003;168:446-54
46. Bergink V, Westenberg HG. Metabotropic glutamate II receptor agonists in panic disorder: A double blind clinical trial with LY354740. Int Clin Psychopharmacol 2005;20:291-3
47. Rorick-Kehn LM, Perkins EJ, Knitowski KM, et al. Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: In vivo pharmacology of LY544344. J Pharmacol Exp Ther 2006;316:905-13
48. Perkins EJ, Abraham T. Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15A1)-targeted prodrug (1S, 2S,5R,6S)-2-[(2' S)-(2-Amino)propionyl]aminobicyclo[3.1.0.] hexen-2,6- dicarboxylic acid (LY544344) in rats and dogs: Assessment of first-pass bioactivation and dose linearity. Drug Metabol Dispos 2007;35:1903-9
49. Kellner M, Muhtz C, Stark K, et al. Effects of a metabotropic glutamate(2/3) receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: Preliminary results. Psychopharmacology 2005;179:310-15
50. Dunayevich E, Erickson J, Levine L, et al. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology 2008;33:1603-10
51. Cryan JF, Kelly PH, Chaperon F, et al. Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N,N'-dicyclopentyl-2- methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-like activity without side effects associated with baclofen or benzodiazepines. J Pharmacol Exp Ther 2004;310:952-63
52. Partyka A, Klodzinska A, Szewczyk B, et al. Effects of GABA(B) receptor ligands in rodent tests of anxiety-like behavior. Pharmacol Rep 2007;59:757-62
53. Frankowska M, Filip M, Przegalinski E. Effects of GABA(B) receptor ligands in animal tests of depression and anxiety. Pharmacol Rep 2007;59:645-55
54. Crane D. Tiagabine for the treatment of anxiety. Depress Anxiety 2003;18:51-2
55. Dunlop BW, Papp L, Garlow SJ, et al. Tiagabine for social anxiety disorder. Hum Psychopharmacol Clin Exp 2007;22:241-4
56. Schwartz TL, Nasra GS, Ashton AK, et al. An open-label study to evaluate switching from an SSRI or SNRI to tiagabine to alleviate antidepressant-induced sexual dysfunction in generalized anxiety disorder. Ann Clin Psychiatry 2007;19:25-30
57. Pollack MH, Roy-Byrne PP, Van Ameringen M, et al. The selective GABA Reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: Results of a placebo-controlled study. J Clin Psychiatry 2005;66:1401-8
58. Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder: A randomized, open-label, clinical trial with paroxetine as a positive control. J Clin Psychiatry 2003;64:1245-9
59. Connor K, Davidson J, Weisler R, et al. Tiagabine for posttraumatic stress disorder: Effects of open-label and double-blind discontinuation treatment. Eur Neuropsychopharmacol 2004;14:S304-5
60. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: Diversity, development and disease. Curr Opin Neurobiol 2001;11:327-35
61. Parsons CG, Danysz W, Hesselink M, et al. Modulation of NMDA receptors by glycine-introduction to some basic aspects and recent developments. Amino Acids 1998;14:207-16
62. Sani G, Serra G, Kotzalidis GD, et al. The role of memantine in the treatment of psychiatric disorders other than the dementias a review of current preclinical and clinical evidence. CNS Drugs 2012;26:663-90
63. Aboujaoude E, Barry JJ, Gamel N. Memantine augmentation in treatment-resistant obsessive-compulsive disorder an open-label trial. J Clin Psychopharmacol 2009;29:51-5
64. Stewart SE, Jenike EA, Hezel DM, et al. A single-blinded case-control study of memantine in severe obsessive-compulsive disorder. J Clin Psychopharmacoly 2010;30:34-9
65. Feusner JD, Kerwin L, Saxena S, et al. differential efficacy of memantine for obsessive-compulsive disorder vs. generalized anxiety disorder: An open-label trial. Psychopharmacol Bull 2009;42:81-93
66. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856-64
67. Diazgranados N, Ibrahim L, Brutsche NE, et al. A Randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010;67:793-802
68. Bloch MH, Wasylink S, Landeros-Weisenberger A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry 2012;72:964-70
69. Chessell IP, Procter AW, Francis PT, et al. D-cycloserine, a putative cognitive enhancer, facilitates activation of the Nmethyl-D-aspartate receptor ionophore complex in alzheimer. Brain Res 1991;565:345-8
70. Tart CD, Handelsman PR, DeBoer LB, et al. Augmentation of exposure therapy with post-session administration of d-cycloserine. J Psychiatr Res 2013;47:168-74
71. Wilhelm S, Buhlmann U, Tolin DF, et al. Augmentation of behavior therapy with D-cycloserine for obsessive-compulsive disorder. Am J Psychiatry 2008;165:335-41
72. Storch EA, Murphy TK, Goodman WK, et al. A preliminary study of D-cycloserine augmentation of cognitive-behavioral therapy in pediatric obsessive-compulsive disorder. Biol Psychiatry 2010;68:1073-6
73. Kushner MG, Kim SW, Donahue C, et al. D-cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biol Psychiatry 2007;62:835-8
74. Guastella AJ, Richardson R, Lovibond PF, et al. A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol Psychiatry 2008;63:544-9
75. Hofmann SG, Meuret AE, Smits JAJ, et al. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry 2006;63:298-304
76. Heresco-Levy U, Vass A, Bloch B, et al. Pilot controlled trial of D-serine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol 2009;12:1275-82
77. Heresco-Levy U, Kremer I, Javitt DC, et al. Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol 2002;5:301-7
78. Litz BT, Salters-Pedneault K, Steenkamp MM, et al. A randomized placebo-controlled trial of D-cycloserine and exposure therapy for posttraumatic stress disorder. J Psychiatry Res 2012;46:1184-90
79. de Kleine RA, Hendriks GJ, Kusters WJC, et al. A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder. Biol Psychiatry 2012;71:962-8
80. Choi DC, Rothbaum BO, Gerardi M, et al. Pharmacological enhancement of behavioral therapy: Focus on posttraumatic stress disorder. 2010;2010:279-99
81. Otto MW, Tolin DF, Simon NM, et al. Efficacy of D-cycloserine for enhancing response to cognitive-behavior therapy for panic disorder. Biol Psychiatry 2010;67:365-70
82. Spooren WPJM, Vassout A, Neijt HC, et al. Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6- (Phenylethynyl)pyridine in rodents. J Pharmacol Exp Ther 2000;295:1267-75
83. Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E, et al. Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 2001;132:1423-30
84. Pecknold JC, McClure DJ, Appeltauer L, et al. Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol 1982;2:129-33
85. Porter RH, Jaeschke G, Spooren W, et al. Fenobam: A clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 2005;315:711-21
86. Schwartz TL, Siddiqui UA, Raza S, et al. Acamprosate calcium as augmentation therapy for anxiety disorders annals of pharmacotherapy. 2010;44:1930-2
87. Vacher H, Mohapatra DP, Trimmer JS. Localization and targeting of voltage-dependent ion channels in mammalian central neurons. Phys Rev 2008;88:1407-47
88. Westenbroek RE, Merrick DK, Catterall WA. Differential. subcellular-localization of the Ri and Rii Na+ channel subtypes in central neurons. Neuron 1989;3:695-704
89. Amiel JM, Mathew SJ. Glutamate and anxiety disorders. Curr Psychiatry Rep 2007;9:278-83
90. Mula M, Pini S, Cassano GB. The role of anticonvulsant drugs in anxiety disorders - a critical review of the evidence. J Clin Psychopharmacol 2007;27:263-72
91. Lason W, Dudra-Jastrzebska M, Rejdak K, et al. Basic mechanisms of antiepileptic drugs and their pharmacokinetic/pharmacodynamic interactions: An update. Pharmacol Rep 2011;63:271-92
92. Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003;23:240-9
93. Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder - a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry 2005;62:1022-30
94. Rickels K, Mangano R, Khan A. A double-blind, placebo-controlled study of a flexible dose of venlafaxine ER in adult outpatients with generalized social anxiety disorder. J Clin Psychopharmacol 2004;24:488-96
95. Montgomery SA, Tobias K, Zornberg GL, et al. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: A 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry 2006;67:771-82
96. Tucker P, Trautman RP, Wyatt DB, et al. Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: A randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2007;68:201-6
97. Berlant JL. Topiramate in posttraumatic stress disorder: Preliminary clinical observations. J Clin Psychiatry 2001;62:60-3
98. Van Ameringen M, Mancini C, Pipe B, et al. An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry 2004;65:1674-8
99. Lochner C, Seedat S, Niehaus DJH, et al. Topiramate in the treatment of trichotillomania: An open-label pilot study. Int Clin Psychopharmacol 2006;21:255-9
100. Hertzberg MA, Butterfield MI, Feldman ME, et al. A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biol Psychiatry 1999;45:1226-9
101. Carbone M, Duty S, Rattray M. Riluzole elevates GLT-1 activity and levels in striatal astrocytes. Neurochem Int 2012;60:31-8
102. Mathew SJ, Amiel JM, Coplan JD, et al. Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry 2005;162:2379-81
103. Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: An open-label trial. Biol Psychiatry 2005;58:424-8
104. Mcbean GJ. Cerebral cystine uptake: A tale of two transporters. Trends Pharm Sci 2002;23:299-302
105. Madayag A, Lobner D, Kau KS, et al. Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J Neurosci 2007;27:13968-76
106. Berk M, Munib A, Dean O, et al. Qualitative methods in early-phase drug trials: Broadening the scope of data and methods from an RCT of N-acetylcysteine in schizophrenia. J Clin Psychiatry 2011;72:909-13
107. Berk M, Dean O, Cotton SM, et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: An open label trial. J Affect Disord 2011;135:389-94
108. Lafleur DL, Pittenger C, Kelmendi B, et al. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology 2006;184:254-6
109. Rodriguez CI, Corcoran C, Simpson HB. Diagnosis and treatment of a patient with both psychotic and obsessive-compulsive symptoms. Am J Psychiatry 2010;167:754-61
110. Nations KR, Smits JAJ, Tolin DF, et al. Evaluation of the glycine transporter inhibitor org 25935 as augmentation to cognitive-behavioral therapy for panic disorder: A multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2012;73:647-53
111. Wu PL, Tang HS, Lane HY, et al. Sarcosine therapy for obsessive compulsive disorder a prospective, open-label study. J Clin Psychopharmacol 2011;31:369-74
112. Wieronska JM, Smialowska M, Branski P, et al. In the amygdala anxiolytic action of mGlu5 receptors antagonist MPEP involves neuropeptide Y but not GABAA signaling. Neuropsychopharmacology 2004;29:514-21
113. Fenske JN, Schwenk TL. Obsessive-compulsive disorder: Diagnosis and management. Am Fam Physician 2009;80:239-45
114. Michelson D, Levine LR, Dellva MA, et al. Clinical studies with mGlu2/3 receptor agonists: LY354740 compared with placebo in patients with generalized anxiety disorder. Neuropharmacology 2005;49(S1): 84-257
115. Dunayevich E, Erickson J, Levine L, et al. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacol 2008;33(7):1603-10
116. Schwartz TL, Siddiqui UA, Raza S. Memantine as an augmentation therapy for anxiety disorders. Case Rep Psychiatry 2012;2012:749-96
117. Kasper S, Herman B, Nivoli G. Van, et al. Efficacy of pregabalin and venlafaxine-XR in generalized anxiety disorder: Results of a double-blind, placebo-controlled 8-week trial. Int Clin Psychopharmacol 2009;24(2):87-96
118. Mello MF, Yeh MS, Barbosa Neto J, et al. A randomized, double-blind, placebo-controlled trial to assess the efficacy of topiramate in the treatment of post-traumatic stress disorder. BMC Psychiatry 2009;9:28