Emerging drugs for schizophrenia: An update

Expert Opinion on Emerging Drugs

Volumn 19, Issue 4, 2014, Pages 511-531

  Köster, Luisa Sophie ^a,b   Carbon, Maren ^b   Correll, Christoph U ^b,c,d,e  

^a TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^b ZUCKER HILLSIDE HOSPITAL   (United States)

^c DONALD AND BARBARA ZUCKER SCHOOL OF MEDICINE AT HOFSTRA NORTHWELL   (United States)

^d FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH   (United States)

^e ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

Author keywords

Agonist; Antagonist; Dopamine; Mechanisms of action; Medications; Non dopaminergic; Psychosis; Schizophrenia

Indexed keywords

2 [4 [1 METHYL 4 (4 PYRIDINYL) 3 PYRAZOLYL]PHENOXYMETHYL]QUINOLINE; 4 [(5 PHENYL 1,3,4 THIADIAZOL 2 YL)OXY] 1 AZONIATRICYCLO[3.3.1.1 3,7]DECANE 3,4 DICARBOXY 3 HYDROXYBUTANOATE; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; ARIPIPRAZOLE LAUROXIL; ATYPICAL ANTIPSYCHOTIC AGENT; BITOPERTIN; BLONANSERIN; BREXPIPRAZOLE; CANNABINOID RECEPTOR; CANNABINOID RECEPTOR ANTAGONIST; CARIPRAZINE; DOPAMINE 1 RECEPTOR; DOPAMINE RECEPTOR; ENCENICLINE; GLUTAMATE RECEPTOR; MINOCYCLINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NEUROPROTECTIVE AGENT; NICOTINIC AGENT; OMS 824; PHOSPHODIESTERASE INHIBITOR; PIMAVANSERIN; RBP 7000; RISPERIDONE; SEROTONIN RECEPTOR; SEROTONIN RECEPTOR AFFECTING AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALBENAZINE; ZICRONAPINE; DOPAMINE RECEPTOR BLOCKING AGENT; NEUROLEPTIC AGENT;

CHOLINERGIC TRANSMISSION; CLINICAL RESEARCH; CLINICAL TRIAL (TOPIC); DRUG TARGETING; HUMAN; MODULATION; NEGATIVE SYNDROME; NEUROTRANSMISSION; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; SCHIZOPHRENIA; SCREENING; ANIMAL; DRUG DESIGN; MOLECULARLY TARGETED THERAPY; PATHOPHYSIOLOGY; PSYCHOLOGY;

ANIMALS; ANTIPSYCHOTIC AGENTS; CLINICAL TRIALS, PHASE II AS TOPIC; CLINICAL TRIALS, PHASE III AS TOPIC; DOPAMINE ANTAGONISTS; DRUG DESIGN; HUMANS; MOLECULAR TARGETED THERAPY; SCHIZOPHRENIA; SCHIZOPHRENIC PSYCHOLOGY;

EID: 84912071305     PISSN: 14728214     EISSN: 17447623     Source Type: Journal    
DOI: 10.1517/14728214.2014.958148     Document Type: Review

References (138)

1. Rossler W, Salize HJ, van Os J, et al. Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol 2005;15(4):399-409
2. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013;382(9904):1575-86
3. Salomon JA, Vos T, Hogan DR, et al. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet 2012;380(9859):2129-43
4. Kane JM, Correll CU. Past and present progress in the pharmacologic treatment of schizophrenia. J Clin Psychiatry 2010;71(9):1115-24
5. Insel TR. Rethinking schizophrenia. Nature 2010;468(7321):187-93
6. Abi-Dargham A. Do we still believe in the dopamine hypothesis? New data bring new evidence. Int J Neuropsychopharmacol 2004;7(Suppl 1):S1-5
7. Merritt K, McGuire P, Egerton A. Relationship between glutamate dysfunction and symptoms and cognitive function in psychosis. Front Psychiatry 2013;4:151
8. Keefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol 2012(213):11-37
9. Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry 2005;66(9):1122-9
10. Miyamoto S, Miyake N, Jarskog LF, et al. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 2012;17(12):1206-27
11. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004;161(3):414-25
12. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373(9657):31-41
13. Kishimoto T, Agarwal V, Kishi T, et al. Relapse prevention in schizophrenia: a systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol Psychiatry 2013;18(1):53-66
14. Zhang JP, Gallego JA, Robinson DG, et al. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2013;16(6):1205-18
15. Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med 2011;17(2):97-107
16. De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 2012;8(2):114-26
17. Bowie CR, Leung WW, Reichenberg A, et al. Predicting schizophrenia patients' real-world behavior with specific neuropsychological and functional capacity measures. Biol Psychiatry 2008;63(5):505-11
18. Kane JM. Clinical efficacy of clozapine in treatment-refractory schizophrenia: an overview. Br J Psychiatry Suppl 1992;160(17):41-5
19. Adams DH, Kinon BJ, Baygani S, et al. A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. BMC Psychiatry 2013;13(1):143
20. Adams DH, Zhang L, Millen BA, et al. Pomaglumetad Methionil (LY2140023 monohydrate) and aripiprazole in patients with schizophrenia: a phase 3, multicenter, double-blind comparison. Schizophr Res Treatment 2014;2014:758212. [Epub ahead of print]
21. Cipriani A, Boso M, Barbui C. Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database Syst Rev 2009(3):Cd006324
22. Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull 2009;35(2):443-57
23. Schwarz C, Volz A, Li C, et al. Valproate for schizophrenia. Cochrane Database Syst Rev 2008(3):Cd004028
24. Leucht S, Helfer B, Dold M, et al. Carbamazepine for schizophrenia. Cochrane Database Syst Rev 2014;5:Cd001258
25. Leucht S, Kissling W, McGrath J, et al. Carbamazepine for schizophrenia. Cochrane Database Syst Rev 2007(3):Cd001258
26. Goff DC, Keefe R, Citrome L, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol 2007;27(6):582-9
27. Dold M, Li C, Tardy M, et al. Benzodiazepines for schizophrenia. Cochrane Database Syst Rev 2012;11:Cd006391
28. Shek E, Bardhan S, Cheine MV, et al. Beta-blocker supplementation of standard drug treatment for schizophrenia. Schizophr Bull 2010;36(6):1079-80
29. Nitta M, Kishimoto T, Muller N, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull 2013;39(6):1230-41
30. Sommer IE, van Westrhenen R, Begemann MJ, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull 2014;40(1):181-91
31. Hecht EM, Landy DC. Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis. Schizophr Res 2012;134(2-3):202-6
32. Rummel C, Kissling W, Leucht S. Antidepressants for the negative symptoms of schizophrenia. Cochrane Database Syst Rev 2006(3):Cd005581
33. Sepehry AA, Potvin S, Elie R, et al. Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis. J Clin Psychiatry 2007;68(4):604-10
34. Singh SP, Singh V, Kar N, et al. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry 2010;197(3):174-9
35. Ribeiz SR, Bassitt DP, Arrais JA, et al. Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs 2010;24(4):303-17
36. Fusar-Poli P, Berger G. Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. J Clin Psychopharmacol 2012;32(2):179-85
37. Saavedra-Velez C, Yusim A, Anbarasan D, et al. Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. J Clin Psychiatry 2009;70(1):104-12
38. Stauffer VL, Millen BA, Andersen S, et al. Pomaglumetad methionil: no significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo. Schizophr Res 2013;150(2-3):434-41
39. Goff DC. Bitopertin: The Good News and Bad News. JAMA Psychiatry 2014;71(6):621-2
40. Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs 2011;25(10):859-85
41. Correll CU. What are we looking for in new antipsychotics? J Clin Psychiatry 2011;72(Suppl 1):9-13
42. Karam CS, Ballon JS, Bivens NM, et al. Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci 2010;31(8):381-90
43. Lieberman JA, Bymaster FP, Meltzer HY, et al. Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 2008;60(3):358-403
44. Miyamoto S, Jarskog LF, Fleischhacker WW. Alternative pharmacologic targets for the treatment of schizophrenia: results from phase I and II trials. Curr Opin Psychiatry 2013;26(2):158-65
45. Roesch-Ely D, Pfueller U, Mundt C, et al. [Treatment of cognitive deficits in schizophrenia. Part 2: pharmacological strategies]. Nervenarzt 2010;81(5):564-76
46. Correll CU, Kishimoto T, Nielsen J, et al. Quantifying clinical relevance in the treatment of schizophrenia. Clin Ther 2011;33(12):B16-39
47. Correll CU, Canas F, Larmo I, et al. Individualizing antipsychotic treatment selection in schizophrenia: characteristics of empirically derived patient subgroups. Eur Psychiatry 2011;26(1 Suppl 1):3-16
48. Correll CU. From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry 2010;25(Suppl 2):S12-21
49. Fuxe K, Borroto-Escuela DO, Tarakanov AO, et al. Dopamine D2 heteroreceptor complexes and their receptor-receptor interactions in ventral striatum: novel targets for antipsychotic drugs. Prog Brain Res 2014;211:113-39
50. Gregory KJ, Noetzel MJ, Niswender CM. Pharmacology of metabotropic glutamate receptor allosteric modulators: structural basis and therapeutic potential for CNS disorders. Prog Mol Biol Transl Sci 2013;115:61-121
51. Johnstone EK, Pfleger KD. Receptor-Heteromer Investigation Technology and its application using BRET. Front Endocrinol (Lausanne) 2012;3:101
52. Niswender CM, Conn PJ. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 2010;50:295-322
53. Inoue A, Nakata Y. Strategy for modulation of central dopamine transmission based on the partial agonist concept in schizophrenia therapy. Jpn J Pharmacol 2001;86(4):376-80
54. Kegeles LS, Abi-Dargham A, Frankle WG, et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 2010;67(3):231-9
55. Sesack SR, Carr DB. Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav 2002;77(4-5):513-17
56. Kirkpatrick B, Fenton WS, Carpenter WT Jr, et al. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006;32(2):214-19
57. Rummel-Kluge C, Komossa K, Schwarz S, et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull 2012;38(1):167-77
58. Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs 2014;28(5):421-53
59. Wood MD, Wren PB. Serotonin-dopamine interactions: implications for the design of novel therapeutic agents for psychiatric disorders. Prog Brain Res 2008;172:213-30
60. Meltzer HY, Elkis H, Vanover K, et al. Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day. Schizophr Res 2012;141(2-3):144-52
61. Sumiyoshi T, Park S, Jayathilake K, et al. Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res 2007;95(1-3):158-68
62. Jensen NH, Cremers TI, Sotty F. Therapeutic potential of 5-HT2C receptor ligands. Scientific World Journal 2010;10:1870-85
63. Shen JH, Zhao Y, Rosenzweig-Lipson S, et al. A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia. J Psychiatr Res 2014;53:14-22
64. Terry AV Jr, Buccafusco JJ, Wilson C. Cognitive dysfunction in neuropsychiatric disorders: selected serotonin receptor subtypes as therapeutic targets. Behav Brain Res 2008;195(1):30-8
65. Codony X, Vela JM, Ramirez MJ. 5-HT (6) receptor and cognition. Curr Opin Pharmacol 2011;11(1):94-100
66. Adler CM, Malhotra AK, Elman I, et al. Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 1999;156(10):1646-9
67. Malhotra AK, Pinals DA, Adler CM, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 1997;17(3):141-50
68. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 2001;158(9):1367-77
69. Kleckner NW, Dingledine R. Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 1988;241(4867):835-7
70. Kehler J, Nielsen J. PDE10A inhibitors: novel therapeutic drugs for schizophrenia. Curr Pharm Des 2011;17(2):137-50
71. Smith SM, Uslaner JM, Cox CD, et al. The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. Neuropharmacology 2013;64:215-23
72. Bugra H, Rapp C, Studerus E, et al. [Can cannabis use increase the risk for schizophrenic psychoses?]. Fortschr Neurol Psychiatr 2012;80(11):635-43
73. Zamberletti E, Rubino T, Parolaro D. The endocannabinoid system and schizophrenia: integration of evidence. Curr Pharm Des 2012;18(32):4980-90
74. Gupta S, Cahill JD, Ranganathan M, et al. The endocannabinoid system and schizophrenia: links to the underlying pathophysiology and to novel treatment approaches. J Clin Psychiatry 2014;75(3):285-7
75. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2012;2:e94
76. Jones CK, Byun N, Bubser M. Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology 2012;37(1):16-42
77. Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry 2008;165(8):1033-9
78. Levkovitz Y, Levi U, Braw Y, et al. Minocycline, a second-generation tetracycline, as a neuroprotective agent in an animal model of schizophrenia. Brain Res 2007;1154:154-62
79. Fond G, Hamdani N, Kapczinski F, et al. Effectiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disorders: a systematic qualitative review. Acta Psychiatr Scand 2014;129(3):163-79
80. Maher AR, Maglione M, Bagley S, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. Jama 2011;306(12):1359-69
81. George MS, Molnar CE, Grenesko EL, et al. A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia. Schizophr Res 2007;93(1-3):42-50
82. Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol 2013;9(2):193-206
83. Otsuka Web Page. Press Release: investigational Compound Brexiprazole met primary and secondary Study Endpoints in Phase III Clinical Trial in Major Depressive Disorder MDD. 2014. Available from: http://www.otsuka. com/en/hd-release/release/pdf.php? news=880
84. Lundbeck Web Page. Press Release: otsuka and Lundbeck submit New Drug Application for brexpiprazole for the treatment of schizophrenia and as adjunctive therapy for the treatment of major depression. 2014. Available from: http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=859357
85. Clinical Psychiatry News Web Page. Novel antipsychotic shows early promise. 2013. Available from: http://www.revivapharma.com/docs/Reviva-RP5063-Clinical-Psychiatry-News-11July2013.pdf
86. Lundbeck Web Page. Press Release: zicronapine shows significant positive data in clinical phase II in the treatment of patients with schizophrenia-planning for continued clinical work. 2009. Available from: http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=608605
87. Lundbeck Web Page. Press Release: the clinical phase III programme commenced on zicronapine. 2011. Available from: http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=608573
88. Li P, Zhang Q, Robichaud AJ, et al. Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders. J Med Chem 2014;57(6):2670-82
89. Intra-Cellular Therapies Web Page. Press Release: intra Celluar Therapies Announces Multiple Presentaions on ITI-007 at the 4th Bienial Schizophrenia International Research Society (SIRS) Conference. 2014. Available from: http://www.intracellulartherapies.com/press-room/press-releases/10-press-releases/63-april-7-2014.html
90. Vanover KE, Davis RE, Ereshefsky L, et al. Poster presentation: postive results with ITI-007 for the treatment of schizophrenia: Randomized, Double-Blind, Placebo-Active-Controlled Phase 2 Study. Presented at the 4th Schizophrenia International Research Society Conference. Florence, Italy 5-9 April, 2014. p. M 245
91. ClinicalTrials.gov. Effects of Eltroprazine on Cognitive Impairment associated with Schizophrenia (CIAS) in Adults (NCT01266174). 2012. Available from: http://clinicaltrials.gov/show/NCT01266174
92. Amarantus Web Page. Press Release: amarantus announces positive phase 2a data for eltoprazine in adult adhd. 2014. Available from: http://ir.stockpr. com/amarantus/company-news/detail/1104/amarantus-announces-positive-phase-2a-data-for-eltoprazine-in-adult-adhd
93. Fox SH. Pimavanserin as treatment for Parkinson's disease psychosis. Lancet 2014;383(9916):494-6
94. Business Wire Web Page. Cyrenaic Pharmaceuticals Reports Improvement of Negative Symptoms and Cognition in Schizophrenia Patientes Treated with CYR-101. 2010. Available from: http://www.businesswire.com/news/home/20101130005939/en/Cyrenaic-Pharmaceuticals-Reports-Improvement-Negative-Symptoms-Cognition-. U43-ui9wXfY
95. Morozova MA, Lepilkina TA, Rupchev GE, et al. Add-on clinical effects of selective antagonist of 5HT6 receptors AVN-211 (CD-008-0173) in patients with schizophrenia stabilized on antipsychotic treatment: pilot study. CNS Spectr 2012;19(4):316-23
96. Avineuro Web Page. Press Release. 2013. Available from: http://www.avineuro.com/avineuro-pharmaceuticals-inc-announces-beginning-of-phase-2b-clinical-studies-of-avn-211-potent-small-molecule-for-treatment-of-schizophrenia/
97. Addex Web Page. Press Release: addex reports Top-line Data from a Successful Phase 2a Clinical Study with ADX71149 in Schizophrenia Patients. 2012. Available from: http://www.addextherapeutics.com/investors/press-releases/news-details/article/addex-reports-top-line-data-from-a-successful-phase-2a-clinical-study-with-adx71149-in-schizophrenia
98. Hashimoto K, Malchow B, Falkai P, et al. Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 2013;263(5):367-77
99. Noetzel MJ, Jones CK, Conn PJ. Emerging approaches for treatment of schizophrenia: modulation of glutamatergic signaling. Discov Med 2012;14(78):335-43
100. Harvey RJ, Yee BK. Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov 2013;12(11):866-85
101. Umbricht D, Alberati D, Martin-Facklam M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study. JAMA Psychiatry 2014;71(6):637-46
102. Roche Web Page. Press Release: roche provides update on the first two of six phase III studies of bitopertin in schizophrenia. 2014. Available from: http://www.roche.com/media/media-releases/med-cor-2014-01-21.htm
103. Arango C, Nasrallah HA, Lawrie S, et al. Efficacy and safety of adjunctive bitopertin (5 and 10mg) versus pacebo in subjects with persistant predominant negative symptoms of schizophrenia treated with antipsychotics-Results form the Phase III DayLyte study. Schizophrenia Research 2014;158(1):e1
104. Blaettler T, Bugarski-Kirola D, Fleischhacker WW, et al. Efficacy and safety of adjunctive bitopertin (10 and 20mg) versus placebo in subjects with persistent predominant negative symptoms of schizophrenia treated with antipsychotics-Results form the Phase III FlashLyte Study. Schizophrenia Research 2014;158(1):e2-e3
105. Bugarski-Kirola D, Fleischhacker WW, Blaettler T, et al. Poster Presentation: Efficacy and safety od adjunctive bitopertin (10 and 20mg) versus placebo in subjects with sub-optimally controlled symptoms of schizophrenia treated with antipsychotics-Results form the Phase III TwiLyte study. Presented at the International College of Neuropsychopharmacology (CINP) World Congress, June 22-26, 2014, Vancouver, Canada
106. Roche. Roche Half-Yearly Report 2014 Business Review. 2014. Available from: http://www.roche.com/hy14e.pdf
107. Bugarski-Kirola D, Wang A, Abi-Saab D, et al. A phase II/III trial of bitopertin monotherapy compared with placebo in patients with an acute exacerbation of schizophrenia-Results from the CandleLyte study. Eur Neuropsychopharmacol 2014;24(7):1024-36
108. Bartolome-Nebreda JM, Delgado F, Martin-Martin ML, et al. Discovery of a Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitor for the Potential Treatment of Schizophrenia. J Med Chem 2014;57(10):4196-212
109. ClinicalTrials.gov. An Outpatient Study Of Effiacy, Safety, and Tolerability of PF-02545920 In The Adjunctive Treatment of Sub-Optimally Controlled Symptoms of Schizophrenia (NCT01939548). 2014. Available from: http://clinicaltrials.gov/ct2/show/NCT01939548? term=NCT01939548&rank=1
110. Omeros Web Page. Press Release: Omeros reports Additional Positive Data from its OMS824 Phase 2a Schizophrenia Clinical trial. 2014. Available from: http://investor. omeros.com/phoenix.zhtml? c=219263&p=irol-newsArticle- Print&ID=1906687&highlight=
111. GW Pharmaceuticals Web Page. Press Release: GW Pharmaceuticals Provides Update on Cannabinoid Pipeline. 2014. Available from: http://www. gwpharm.com/GW Pharmaceuticals Provides Update on Cannabinoid Pipeline.aspx
112. Reuters Web Page. GW Pharmaceuticals Provides Update on Cannabinoid Pipeline. 2014. Available from: http://www.reuters.com/article/2014/03/17/idUSnGNXN9cR3+f2+GNW20140317
113. Biospace Web Page. XTL Biopharmaceuticals Ltd. (XTLB) completes the Acquisition of MinoGuard. 2011. Available from: http://www. biospace.com/News/xtl-biopharmaceuticals-ltd-completes-the/242304/source=MoreNews
114. ClinicalTrials.gov. Study Information is available by using the Clinicaltrials.gov Identifier: NCT01730768, NCT0082553, NCT01163227. Available from: Error! Hyperlink reference not valid.
115. ClinicalTrials.gov. Study Information is available by using the Clinicaltrials.gov Identifier: NCT01095562, NCT01678755. Available from: Error! Hyperlink reference not valid.
116. Preskorn SH, Gawryl M, Dgetluck N, et al. Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract 2014;20(1):12-24
117. Lombardo IMG, et al. EnVivo Pharmaceutical Poster Presentation: EVP-6124, an alpha 7 nicotinic partial agonist, produces positive effects on cognition, and clinical function in patients with chronic schizophrenia on stable antipsychotic therapy. Presented at 2013 53rd NCDEU. May 28-31, 2013, Westin Diplomat, Hollywood Florida. p. 73
118. Envivo Pharmaceuticals Web Page. Press Release: enVivo Pharmaceuticals Presents Positive Comprehensive Phase 2b Study Results in Schizophrenia at American College of Neuropsychopharmacology Annual Meeting. 2011. Available from: http://www.forumpharma.com/content/news-events/comprehensive-phase2b-study-results
119. Chue P, Lalonde JK. Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options. Neuropsychiatr Dis Treat 2014;10:777-89
120. Johnson and Johnson Web Page. Press Release: Janssen Investigational Treatment for Schizophrenia Shows Positive Efficacy, Delays Relapse. 2014. Available from: http://www.jnj.com/news/all/Janssen-Investigational-Treatment-for-Schizophrenia-Shows-Positive-Efficacy-Delays-Relapse
121. Laffont CM, Gomeni R, Zheng B, et al. Population pharmacokinetics and prediction of dopamine D2 receptor occupancy after multiple doses of RBP-7000, a new sustained-release formulation of risperidone, in schizophrenia patients on stable oral risperidone treatment. Clin Pharmacokinet 2014;53(6):533-43
122. ClinicalTrials.gov. Randomized, Double-blind, Placebo-Controlled, Multi-center Trial of Efficiacy, Safety and Tolerability of RBP-7000 in Schizophrenia Patients (NCT02109562). 2014. Available from: http://clinicaltrials.gov/ct2/show/results/NCT02109562
123. Rovi Pharmaceuticals Web Page. Annual Report 2011. 2011. Available from: http://www.rovi.es/ficheros/auditorias/ingles/65i.pdf page 17
124. ClinicalTrials.gov. Pharmacokinetics and Tolerability Study of Risperidone ISM® in Schizophrenia (NCT02086786). 2014. Available from: http://clinicaltrials.gov/ct2/show/NCT02086786?term=risperidone+ISM&rank=2
125. Alkermes Web Page. Press Release: alkermes Presents Phase 3 Data From Successful Pivotal Study of Aripiprazole Lauroxil for Treatment of Schizophrenia at ASCP Annual Meeting. 2014. Available from: http://investor. alkermes.com/phoenix.zhtml? c=92211&p=irol-newsArticle&ID=1940691&highlight=
126. Lundbeck Web Page. Press Release: FDA accepts for review Otsuka Pharmaceutical and Lundbeck's supplemental New Drug Application to expand Abilify Maintena® (aripiprazole) labelling. 2014. Available from: http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=844047
127. Nitto Web Page. Press Release 2012: phase 2 studies on the worlds first transdermal patch formulation for schizophrenia treatment. 2012. Available from: http://www.ds-pharma.com/ir/library/presentation/pdf/eir20140508.pdf
128. ClinicalTrials.gov. Proof-of-Concept-Study of Pipamperone Added to Stable Treatment With Risperidone or Paliperidone in Chronic Schizophrenia (NCT01450514). 2012. Available from: http://clinicaltrials.gov/show/NCT01450514
129. Alkermes Web Page. Press Release: alkermes Announces Initionation of Phase 2 Clinical Study of ALKS 3831, Designed to Be a Broad Spectrum Oral Antipsychotic the the Treatment of Schizophrenia. 2013. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=92211&p=irol-newsArticle&ID=1838550&highlight
130. ClinicalTrials.gov. A Study of ALKS 3831 in Subjects With Schizophrenia and Alcohol Use Disorder (NCT02161718). 2014. Available from: http://www.clinicaltrials.gov/ct2/show/NCT02161718?term=3831&rank=1
131. Neurocrine Biosciences Inc. Web Page. NBI-98854-Vesicular Monoamine Transporter 2 Inhibitor (VMAT2). Available from: http://www.neurocrine. com/index.cfm?navId=83
132. De Berardis D, Marini S, Iasevoli F, et al. The role of intranasal oxytocin in the treatment of patients with schizophrenia: a systematic review. CNS Neurol Disord Drug Targets 2013;12(2):252-64
133. Gibson CM, Penn DL, Smedley KL, et al. A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia. Schizophr Res 2014;156(2-3):261-5
134. Fond G, Macgregor A, Attal J, et al. Treating patients with schizophrenia deficit with erythropoietin? Psychiatry Clin Neurosci 2012;66(5):375-82
135. Correll CU, Kishimoto T, Kane JM. Randomized controlled trials in schizophrenia: opportunities, limitations, and trial design alternatives. Dialogues Clin Neurosci 2011;13(2):155-72
136. Marder SR, Alphs L, Anghelescu IG, et al. Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia. Schizophr Res 2013;150(2-3):328-33
137. Millan MJ, Agid Y, Brune M, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 2012;11(2):141-68
138. NAMHC Concept Clearance Web Page. New Experimental Medicine Studies: fast-Fail Trials (FAST). 2012. Available from: http://www.nimh. nih.gov/funding/grant-writing-and-application-process/concept-clearances/2012/new-experimental-medicine-studies-fast-fail-trials-fast.shtml