Therapeutic improvements expected in the near future for schizophrenia and schizoaffective disorder: An appraisal of phase III clinical trials of schizophrenia-targeted therapies as found in US and EU clinical trial registries

Expert Opinion on Pharmacotherapy

Volumn 17, Issue 7, 2016, Pages 921-936

  Garay, Ricardo P ^a,b   Citrome, Leslie ^c   Samalin, Ludovic ^d   Liu, Chen Chung ^e   Thomsen, Morten S ^f   Correll, Christoph U ^g,h   Hameg, Ahcène ^b   Llorca, Pierre Michel ^d  

^a Universite Paris Sud   (France)

^b Pharmacology and Therapeutics   (France)

^c NEW YORK MEDICAL COLLEGE   (United States)

^d UNIVERSITY HOSPITAL OF CLERMONT FERRAND   (France)

^e NATIONAL TAIWAN UNIVERSITY HOSPITAL   (Taiwan)

^f UNIVERSITY OF COPENHAGEN   (Denmark)

^g ZUCKER HILLSIDE HOSPITAL   (United States)

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

Author keywords

brexpiprazole; cariprazine; clinical trials; encenicline; phase III; Schizophrenia; valbenazine

Indexed keywords

ACETYLSALICYLIC ACID; BENZOIC ACID; BREXPIPRAZOLE; CARIPRAZINE; CLONIDINE; DRONABINOL; ENCENICLINE; EXENDIN 4; FAMOTIDINE; LUMATEPERONE; MEMANTINE; NEUROLEPTIC AGENT; ONDANSETRON; OXYTOCIN; PSYCHOTROPIC AGENT; RALOXIFENE; SIMVASTATIN; TOLCAPONE; VALBENAZINE;

DRUG APPROVAL; DRUG INDUSTRY; EUROPE; HUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PSYCHOPHARMACOTHERAPY; REVIEW; SCHIZOAFFECTIVE PSYCHOSIS; SCHIZOPHRENIA; UNITED STATES; UNIVERSITY HOSPITAL; COGNITION DISORDERS; EUROPEAN UNION; PSYCHOLOGY; PSYCHOTIC DISORDERS; REGISTER;

ANTIPSYCHOTIC AGENTS; CLINICAL TRIALS, PHASE III AS TOPIC; COGNITION DISORDERS; EUROPEAN UNION; HUMANS; PSYCHOTIC DISORDERS; REGISTRIES; SCHIZOPHRENIA; SCHIZOPHRENIC PSYCHOLOGY; UNITED STATES;

EID: 84958741397     PISSN: 14656566     EISSN: 17447666     Source Type: Journal    
DOI: 10.1517/14656566.2016.1149164     Document Type: Review

References (142)

1. Tandon R, Gaebel W, Barch DM, et al. Definition and description of schizophrenia in the DSM-5. Schizophr Res. 2013; 150: 3-10.
2. Leucht S, Burkard T, Henderson J, et al. Physical illness and schizophrenia: a review of the literature. Acta Psychiatr Scand. 2007; 116: 317-333.
3. Millier A, Schmidt U, Angermeyer MC, et al. Humanistic burden in schizophrenia: a literature review. J Psychiatric Res. 2014; 54: 85-93.
4. Jaäskelaïnen E, Juola P, Hirvonen N, et al. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013; 39: 1296-1306.
5. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380: 2163-2196.
6. 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: 2129-2143.
7. Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatr. 2007; 64: 1123-1131.
8. Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol. 2015; 29: 97-115.
9. APA. American Psychiatric Association: practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161: 1-56.
10. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013; 382: 951-962.
11. Leucht S, Tardy M, Komossa K, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 2012; 379: 2063-2071.
12. Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013; 27: 879-911.
13. Dixon L, Perkins D, Calmes C. Guideline Watch (September 2009): practice Guideline for the Treatment of Patients With Schizophrenia; [cited 2015 Sep 16[. Available from: http://psychiatryonline.org/content.aspx?bookid=28§ionid=1682213-5010052009
14. Citrome L. Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains. J Clin Psychiatry. 2014; 75 (Suppl 1): 21-26.
15. EMA. European Medicines Agency. Guideline on clinical investigation of medicinal products, including depot preparations in the treatment of schizophrenia. Committee for Medicinal Products for Human Use (CHMP) 2012; Human Regulatory. Scientific guidelines. Clinical efficacy and safety. Nervous system; Available from: http://www.ema.europa.eu
16. Buchanan RW, Keefe RSE, Umbricht D, et al. The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr Bull. 2011; 37: 1209-1217.
17. Isaac M, Pani L, Wied CG-D, et al. European licensing of maintenance treatment in schizophrenia. Lancet. 2012; 380: 562-563.
18. Köster L-S, Carbon M, Correll CU. Emerging drugs for schizophrenia: an update. Expert Opin Emerg Drugs. 2014; 19: 511-531.
19. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13: 261-276.
20. Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014; 350: 589-604.
21. Correll CU, Skuban A, Ouyang J, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015; 172: 870-880.
22. Kane JM, Skuban A, Ouyang J, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015; 164: 127-135.
23. Maeda K, Lerdrup L, Sugino H, et al. Brexpiprazole II: antipsychoticLike and procognitive effects of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014; 350: 605-614.
24. Citrome L. Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic-what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Intl Clin Practice. 2015; 69: 978-997.
25. Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013; 9: 193-206.
26. Durgam S, Starace A, Li D, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014; 152: 450-457.
27. Laszlovszky I, Lu K, Debelle M, et al. EPA-0870-efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia: results of two phase III trials. Eur Psychiatr. 2014; 29 (Supplement 1): 1.
28. Kane JM, Zukin S, Wang Y, et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an international, phase III clinical trial. J Clin Psychopharmacol. 2015; 35: 367-373.
29. Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013; 30: 114-126.
30. Gyertyán I, Kiss B, Sághy K, et al. Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychoticLike and procognitive effects in rodents. Neurochem Int. 2011; 59: 925-935.
31. Debelle M, Nemeth G, Szalai E, et al. Cariprazine as monotherapy for the treatment of schizophrenia patients with predominant negative symptoms: a double-blind, active controlled trial. 28th ECNP Congress; 2015 Aug 29-Sep 1; Amsterdam. Abstract P.3.d.053.
32. Nasrallah HA, Cutler AJ, Wang Y, et al. P.3.d.025 safety and tolerability of cariprazine in long-term treatment of schizophrenia: integrated summary of safety data. Eur Neuropsychopharmacol. 2014; 24: S536.
33. Actavis. Richter and Actavis announce positive phase III results for cariprazine in the prevention of relapse in patients with schizophrenia; [cited 2015 Sep 17[. Available from: http://www.actavis.com/news/news/thomson-reuters/richter-and-actavis-announce-positive-phase-iii-re2015
34. FDA. FDA approves new drug to treat schizophrenia and bipolar disorder 2015 [cited 2015 Sep 29[. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm463103.htm
35. Snyder GL, Vanover KE, Zhu H, et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacol. 2015; 232: 605-621.
36. Davis RE, Vanover KE, Zhou Y, et al. ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. Psychopharmacol. 2015; 232: 2863-2872.
37. Lieberman JA, Davis RE, Correll CU, et al. ITI-007 for the treatment of schizophrenia: a 4-week randomized, double-blind, controlled trial. Biol Psychiatr. 2015. doi: 10.1016/j.biopsych.2015.08.026.
38. Melville NA. Novel drug promising for schizophrenia. 15th International Congress on Schizophrenia Research (ICOSR); 2015 [cited 2015 Sep 15[. Available from: http://www.medscape.com/viewarticle/842591
39. ICT. Intra-Cellular Therapies announces positive topLine results from the first phase 3 trial of ITI-007 in patients with schizophrenia and confirms the unique pharmacology of ITI-007 in a separate Positron Emission Tomography study 2015 [cited 2015 Sep 29[. Available from: http://ir.intracellulartherapies.com/releasedetail.cfmreleaseid=931821
40. Keefe RSE, Meltzer HA, Dgetluck N, et al. Randomized, double-blind, placebo-controlled study of encenicline, an α7 nicotinic acetylcholine receptor agonist, as a treatment for cognitive impairment in schizophrenia. Neuropsychopharmacol. 2015 [cited 2015 Jul 15[. doi: 10.1038/npp.2015.176.
41. Prickaerts J, Van Goethem NP, Chesworth R, et al. EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors. Neuropharmacol. 2012; 62: 1099-1110.
42. Barbier AJ, Hilhorst M, Vliet AV, et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective α7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies. Clin Ther. 2015; 37: 311-324.
43. Forum. Forum Pharmaceuticals Inc. updates encenicline phase 3 clinical trial programs in Alzheimers disease and cognitive impairment in Schizophrenia 2015 [cited 2015 Sep 22[. Available from: http://www.forumpharma.com/content/news-events/PressRelease/71
44. Müller T. Valbenazine granted breakthrough drug status for treating tardive dyskinesia. Expert Opin Investig Drugs. 2015; 24: 737-742.
45. Ben Amar M. Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol. 2006; 105: 1-25.
46. Albertson T, Chenoweth J, Ford J, et al. Is it prime time for alpha2-adrenocepter agonists in the treatment of withdrawal syndromes? J Med Toxicol. 2014; 10: 369-381.
47. De Lucena D, Fernandes BS, Berk M, et al. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. J Clin Psychiatry. 2009; 70: 1416-1423.
48. Rezaei F, Mohammad-karimi M, Seddighi S, et al. Memantine add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2013; 33: 336-342.
49. Krivoy A, Weizman A, Laor L, et al. Addition of memantine to antipsychotic treatment in schizophrenia inpatients with residual symptoms: a preliminary study. Eur Neuropsychopharmacol. 2008; 18: 117-121.
50. Lee JG, Lee SW, Lee BJ, et al. Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: a placebo-controlled pilot study. Psychiatr Invest. 2012; 9: 166-173.
51. Lieberman JA, Papadakis K, Csernansky J, et al. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacol. 2009; 34: 1322-1329.
52. Bitsios P, Roussos P. Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia. Pharmacogenomics. 2011; 12: 559-566.
53. Weiser M, Burstein S, Fodoreanu L, et al. Positive symptoms respond to add-on aspirin in schizophrenia patients with high sera CRP levels: a post-hoc analysis of an RCT. Schizophrenia Res. 2014; 153 (Suppl. 1): S79.
54. Ishøy PL, Knop FK, Broberg BV, et al. Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist-protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study: the TAO study protocol. BMJ Open. 2014; 4:e004158.
55. Meskanen K, Ekelund H, Laitinen J, et al. A randomized clinical trial of histamine 2 receptor antagonism in treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013; 33: 472-478.
56. Kishi T, Mukai T, Matsuda Y, et al. Selective serotonin 3 receptor antagonist treatment for schizophrenia: meta-analysis and systematic review. Neuromol Med. 2014; 16: 61-69.
57. Heringa SM, Begemann MJH, Goverde AJ, et al. Sex hormones and oxytocin augmentation strategies in schizophrenia: a quantitative review. Schizophr Res. 2015; 168: 603-613.
58. Perez-Rodriguez M, Mahon K, Russo M, et al. Oxytocin and social cognition in affective and psychotic disorders. Eur Neuropsychopharmacol. 2015; 25: 265-282.
59. Oya K, Matsuda Y, Matsunaga S, et al. Efficacy and safety of oxytocin augmentation therapy for schizophrenia: an updated systematic review and meta-analysis of randomized, placebo-controlled trials. Eur Arch Psychiatr Clin Neurosci. 2015. [Epub ahead of print]
60. Weickert TW, Weinberg D, Lenroot R, et al. Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol Psychiatry. 2015; 20: 685-694.
61. Usall J, Huerta-Ramos E, Iniesta R, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011; 72: 1552-1557.
62. Chaudhry IB, Husain N, Drake R, et al. Add-on clinical effects of simvastatin and ondansetron in patients with schizophrenia stabilized on antipsychotic treatment: pilot study. Ther Adv Psychopharmacol. 2014; 4: 110-116.
63. Lane H, Lin C, Green MF, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of d-amino acid oxidase inhibitor. JAMA Psychiatr. 2013; 70: 1267-1275.
64. Bak M, Fransen A, Janssen J, et al. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE. 2014; 9: e94112.
65. Rummel-Kluge C, Komossa K, Schwarz S, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010; 123: 225-233.
66. Howland R. Brexpiprazole: another multipurpose antipsychotic drug? J Psychosoc Nurs Ment Health Serv. 2015; 53: 23-25.
67. Garay RP, Samalin L, Hameg A, et al. Investigational drugs for anxiety in patients with schizophrenia. Expert Opin Investig Drugs. 2015; 24: 507-517.
68. Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders? Expert Rev Neurother. 2015; 15: 1219-1229.
69. Citrome L, Ota A, Nagamizu K, et al. The effect of brexpiprazole (OPC-34712) versus aripiprazole in adult patients with acute schizophrenia: an exploratory study. Biol Psychiatr. 2015; 77 (Suppl. 1): 203S.
70. Hobart M, Ouyang J, Forbes A, et al. Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia: a randomized, double-blind, placebo-controlled study. American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; 2015 Jun 22-25; Miami, US.
71. Malla A, Ota A, Perry P, et al. The effect of brexpiprazole (OPC-34712) in adult outpatients with early-episode schizophrenia: an exploratory study. American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; 2015 Jun 22-25; Miami, US
72. Otsuka. U.S. FDA approves Otsuka and Lunbecks REXULTI® (brexpiprazole) as adjunctive treatment for adults with major depressive disorder and as a treatment for adults with schizophrenia; 2015 [cited 2015 Oct 8[. Available from: http://www.otsuka.com/en/hd-release/release/pdf.php?news=1177
73. Seneca N, Finnema S, Laszlovszky I, et al. Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography. Psychopharmacol. 2011; 218: 579-587.
74. Thomsen MS, Hansen HH, Timmerman DB, et al. Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des. 2010; 16: 323-343.
75. Pedersen CS, Sørensen DB, Parachikova AI, et al. PCP-induced deficits in murine nest building activity: employment of an ethological rodent behavior to mimic negativeLike symptoms of schizophrenia. Behav Brain Res. 2014; 273: 63-72.
76. Van Goethem NP, Prickaerts J, Welty D, et al. Continuous infusion of the α7 nicotinic acetylcholine receptor agonist EVP-6124 produces no signs of tolerance at memory-enhancing doses in rats: a pharmacokinetic and behavioral study. Behav Pharmacol. 2015; 26: 403-406.
77. Forum. Encenicline. Agonist of alpha 7 receptor response; 2015 [cited 2015 Sep 15[. Available from: http://www.forumpharma.com/innovation-pipeline/alpha-7-agonists/
78. Castro NG, Albuquerque EX. BriefLifetime, fast-inactivating ion channels account for the α-bungarotoxin-sensitive nicotinic response in hippocampal neurons. Neurosci Lett. 1993; 164: 137-140.
79. Thomsen MS, El-Sayed M, Mikkelsen JD. Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats. PLoS ONE. 2011; 6: e27014.
80. Hilt D, Lombardo I, Gawryl M, et al. Poster #T94. Optimizing treatment and signal detection with EVP-6124 in a CIAS phase 2b study. Schizophr Res. 2014; 153 (Supplement 1): S322.
81. Schafer MKH, Weihe E, Eiden LE. Localization and expression of VMAT2 across mammalian species: a translational guide for its visualization and targeting in health and disease. Adv Pharmacol. 2013; 68: 319-334.
82. Correll CU, Schenk EM. Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatr. 2008; 21: 151-156.
83. Kenney C, Hunter C, Jankovic J. Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Movement Disorders. 2007; 22: 193-197.
84. NB. Neurocrine biosciences (NBIX) announces significant data from NBI-98854 Kinect 3 in Lardive Dyskinesia; [cited 2015 Oct 23[. Available from: http://www.streetinsider.com/Corporate+News/Neurocrine+Biosciences+%28NBIX%29+Announces+Significant+Data+from+NBI-98854+Kinect+3+in+Lardive+Dyskinesia/10956697.html, 2015
85. Neurocrine. The KINECT 3 study for Treatment of Tardive Dyskinesia has completed enrollment 2015 [cited 2015 Sep 30[. Available from: http://www.neurocrine.com/pipeline/nbi-98854-vmat2-inhibitor/tardive-dyskinesia/clinical-trials/
86. Volkow ND. Substance use disorders in schizophrenia-clinical implications of comorbidity. Schizophr Bull. 2009; 35: 469-472.
87. Levin FR, Mariani JJ, Brooks DJ, et al. Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2011; 116: 142-150.
88. Xia P, Chen HS, Zhang D, et al. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci. 2010; 30: 11246-11250.
89. McKeage K. Memantine: a review of its use in moderate to severe Alzheimers disease. CNS Drugs. 2009; 23: 881-897.
90. Schneider LS, Dagerman KS, Higgins JT, et al. Lack of evidence for the efficacy of memantine in mild alzheimer disease. Arch Neurol. 2011; 68: 991-998.
91. Aracava Y, Pereira EFR, Maelicke A, et al. Memantine blocks α7∗ nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther. 2005; 312: 1195-1205.
92. Banerjee P, Samoriski G, Gupta S. Comments on "memantine blocks α7∗ nicotinic acetylcholine receptors more potently than N-methyl-d-aspartate receptors in rat hippocampal neurons". J Pharmacol Exp Ther. 2005; 313: 928-929.
93. Williams HJ, Owen MJ, ODonovan MC. Is COMT a susceptibility gene for schizophrenia? Schizophr Bull. 2007; 33: 635-641.
94. Lachman HM, Papolos DF, Saito T, et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996; 6: 243-250.
95. Girgis RR, Kumar SS, Brown AS. The cytokine model of schizophrenia: emerging therapeutic strategies. Biol Psychiatr. 2014; 75: 292-299.
96. Doorduin J, De Vries EFJ, Willemsen ATM, et al. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nuclear Med. 2009; 50: 1801-1807.
97. Van Berckel BN, Bossong MG, Boellaard R, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatr. 2008; 64: 820-822.
98. Nitta M, Kishimoto T, Müller N, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013; 39: 1230-1241.
99. Bradley DP, Kulstad R, Schoeller DA. Exenatide and weight loss. Nutrition. 2010; 26: 243-249.
100. Kishi T, Iwata N. Efficacy and tolerability of histamine-2 receptor antagonist adjunction of antipsychotic treatment in schizophrenia: a meta-analysis of randomized placebo-controlled trials. Pharmacopsychiatr. 2015; 48: 30-36.
101. Andrade C. Famotidine augmentation in schizophrenia: hope or hype? J Clin Psychiatr. 2013; 74: e855-e858.
102. Ye JH, Ponnudurai R, Schaefer R. Ondansetron: a selective 5-HT(3) receptor antagonist and its applications in CNS-related disorders. CNS Drug Rev. 2001; 7: 199-213.
103. Bakermans-Kranenburg MJ, Van Ijzendoorn MH. Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Translational Psychiatr. 2013; 3: e258.
104. Lewis-Wambi J, Jordan VC. 8.09-raloxifene. In: Triggle JBTJ., editor. Comprehensive medicinal chemistry II. Oxford: Elsevier; 2007. p. 103-121.
105. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci. 1998; 19: 26-37.
106. Matoori S, Leroux J-C. Recent advances in the treatment of hyperammonemia. Adv Drug Deliv Rev. 2015; 90: 55-68.
107. Kalin M, Kaplan S, Gould F, et al. Social cognition, social competence, negative symptoms and social outcomes: inter-relationships in people with schizophrenia. J Psychiatr Res. 2015; 68: 254-260.
108. Buckley PF, Stahl SM. Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or Cul-de-sac? Acta Psychiatr Scand. 2007; 115: 93-100.
109. Lindenmayer J-P, Khan A. Galantamine augmentation of long-acting injectable risperidone for cognitive impairments in chronic schizophrenia. Schizophr Res. 2011; 125: 267-277.
110. Rummel C, Kissling W, Leucht S. Antidepressants as add-on treatment to antipsychotics for people with schizophrenia and pronounced negative symptoms: a systematic review of randomized trials. Schizophr Res. 2005; 80: 85-97.
111. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010; 36: 71-93.
112. Buchanan RW, Javitt DC, Murder SR, et al. The cognitive and negative symptoms in schizophrenia trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007; 164: 1593-1602.
113. Goff DC. Bitopertin: the good news and bad news. JAMA Psychiatr. 2014; 71: 621-622.
114. Iwata Y, Nakajima S, Suzuki T, et al. Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. Mol Psychiatry. 2015; 20: 1151-1160.
115. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med. 2007; 13: 1102-1107.
116. 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: 434-441.
117. Downing AM, Kinon BJ, Millen BA, et al. A double-blind, placebo-controlled comparator study of LY2140023 monohydrate in patients with schizophrenia. BMC Psychiatr. 2014; 14: 351.
118. Citrome L. The ABCs of dopamine receptor partial agonists-aripiprazole, brexpiprazole, and cariprazine: the 15-minute challenge to sort these agents out. Int J Clin Pract. 2015; 69: 1211-1220.
119. Kiss B, Horváth A, Némethy Z, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010; 333: 328-340.
120. Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013; 67: 407-411.
121. Actavis. VRAYLAR (cariprazine) capsules, for oral use. Prescribing information; [cited 2015 Oct 14[. Available from: http://pi.actavis.com/data
122. Durgam S, Earley W, Li R, et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: a double-blind, placebo-controlled trial. Poster presentation. 28th Congress of the European College of Neuropsychopharmacology 2015; 2015 Aug 29-Sep 1; Amsterdam, Netherlands.
123. Leucht S, Kane JM, Etschel E, et al. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacol. 2006; 31: 2318-2325.
124. Leucht S, Kane JM, Kissling W, et al. What does the PANSS mean? Schizophr Res. 2005; 79: 231-238.
125. Citrome L. Lurasidone for the acute treatment of adults with schizophrenia: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed? Clin Schizophr Related Psychoses. 2012; 6: 76-85.
126. Marder SR, Kirkpatrick B. Defining and measuring negative symptoms of schizophrenia in clinical trials. Eur Neuropsychopharmacol. 2014; 24: 737-743.
127. Garcia-Portilla M, Garcia-Alvarez L, Saiz P, et al. Psychometric evaluation of the negative syndrome of schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2015; 265: 559-566.
128. Keefe RSE, Haig GM, Marder SR, et al. Report on ISCTM consensus meeting on clinical assessment of response to treatment of cognitive impairment in schizophrenia. Schizophr Bull. 2015 [cited 2015 Sep 11[. doi: 10.1093/schbul/sbv111.
129. Carter CS, Barch DM, Buchanan RW, et al. Identifying cognitive mechanisms targeted for treatment development in schizophrenia: an overview of the first meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative. Biol Psychiatr. 2008; 64: 4-10.
130. Moore H, Geyer MA, Carter CS, et al. Harnessing cognitive neuroscience to develop new treatments for improving cognition in schizophrenia: CNTRICS selected cognitive paradigms for animal models. Neurosci Biobehav Rev. 2013; 37: 2087-2091.
131. Green MF, Harris JG, Nuechterlein KH. The MATRICS consensus cognitive battery: what we know 6 years later. Am J Psychiatr. 2014; 171: 1151-1154.
132. Elliott CS, Fiszdon JM. Comparison of self-report and performance-based measures of everyday functioning in individuals with schizophrenia: implications for measure selection. Cognitive Neuropsychiatr. 2014; 19: 485-494.
133. Trampush JW, Lencz T, DeRosse P, et al. Relationship of cognition to clinical response in first-episode schizophrenia spectrum disorders. Schizophrenia Bull. 2015; 41: 1237-1247.
134. Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008; 455: 232-236.
135. The International Schizophrenia C. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008; 455: 237-241.
136. Arnedo J, Svrakic DM, Val C, et al. Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies. Am J Psychiatr. 2015; 172: 139-153.
137. Harrison PJ. Recent genetic findings in schizophrenia and their therapeutic relevance. J Psychopharmacol (Oxford, England). 2015; 29: 85-96.
138. Liang SG, Greenwood TA. The impact of clinical heterogeneity in schizophrenia on genomic analyses. Schizophr Res. 2015; 161: 490-495.
139. Schubert Christian R, Xi HS, Wendland Jens R, et al. Translating human genetics into novel treatment targets for schizophrenia. Neuron. 2014; 84: 537-541.
140. Cella M, Reeder C, Wykes T. Lessons learnt? The importance of metacognition and its implications for cognitive remediation in schizophrenia. Front Psychol. 2015; 6: 1259.
141. Chan JYC, Hirai HW, Tsoi KKF. Can computer-assisted cognitive remediation improve employment and productivity outcomes of patients with severe mental illness? A meta-analysis of prospective controlled trials. J Psychiatr Res. 2015; 68: 293-300.
142. Kurzban S, Davis L, Brekke J. Vocational, social, and cognitive rehabilitation for individuals diagnosed with schizophrenia: a review of recent research and trends. Curr Psychiatr Rep. 2010; 12: 345-355.