1,146
Views
23
CrossRef citations to date
0
Altmetric
Review

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

, , , , , , & show all
Pages 921-936 | Received 25 Oct 2015, Accepted 27 Jan 2016, Published online: 19 Feb 2016

References

  • Tandon R, Gaebel W, Barch DM, et al. Definition and description of schizophrenia in the DSM-5. Schizophr Res. 2013;150:3–10.
  • Leucht S, Burkard T, Henderson J, et al. Physical illness and schizophrenia: a review of the literature. Acta Psychiatr Scand. 2007;116:317–333.
  • Millier A, Schmidt U, Angermeyer MC, et al. Humanistic burden in schizophrenia: a literature review. J Psychiatric Res. 2014;54:85–93.
  • Jääskeläinen E, Juola P, Hirvonen N, et al. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013;39:1296–1306.
  • 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.
  • 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.
  • 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.
  • Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol. 2015;29:97–115.
  • APA. American Psychiatric Association: practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161:1–56.
  • 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.
  • 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.
  • 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.
  • 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&sectionid=1682213-5010052009
  • 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.
  • 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
  • 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.
  • Isaac M, Pani L, Wied CG-D, et al. European licensing of maintenance treatment in schizophrenia. Lancet. 2012;380:562–563.
  • Köster L-S, Carbon M, Correll CU. Emerging drugs for schizophrenia: an update. Expert Opin Emerg Drugs. 2014;19:511–531.
  • Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261–276.
  • 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.
  • 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.
  • 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.
  • Maeda K, Lerdrup L, Sugino H, et al. Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350:605–614.
  • 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.
  • Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013;9:193–206.
  • 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.
  • 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.
  • 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.
  • Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013;30:114–126.
  • 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 antipsychotic-like and procognitive effects in rodents. Neurochem Int. 2011;59:925–935.
  • Debelle M, Németh 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • ICT. Intra-Cellular Therapies announces positive top-line 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.cfm?releaseid=931821
  • 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.
  • 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.
  • 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.
  • Forum. Forum Pharmaceuticals Inc. updates encenicline phase 3 clinical trial programs in Alzheimer’s disease and cognitive impairment in Schizophrenia; 2015 [cited 2015 Sep 22]. Available from: http://www.forumpharma.com/content/news-events/PressRelease/71
  • Müller T. Valbenazine granted breakthrough drug status for treating tardive dyskinesia. Expert Opin Investig Drugs. 2015;24:737–742.
  • Ben Amar M. Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol. 2006;105:1–25.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Bitsios P, Roussos P. Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia. Pharmacogenomics. 2011;12:559–566.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Perez-Rodriguez M, Mahon K, Russo M, et al. Oxytocin and social cognition in affective and psychotic disorders. Eur Neuropsychopharmacol. 2015;25:265–282.
  • 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]
  • 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.
  • 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.
  • 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.
  • 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.
  • Bak M, Fransen A, Janssen J, et al. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE. 2014;9:e94112.
  • 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.
  • Howland R. Brexpiprazole: another multipurpose antipsychotic drug? J Psychosoc Nurs Ment Health Serv. 2015;53:23–25.
  • Garay RP, Samalin L, Hameg A, et al. Investigational drugs for anxiety in patients with schizophrenia. Expert Opin Investig Drugs. 2015;24:507–517.
  • 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.
  • 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.
  • 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.
  • 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
  • Otsuka. U.S. FDA approves Otsuka and Lunbeck’s 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
  • 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.
  • 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.
  • Pedersen CS, Sørensen DB, Parachikova AI, et al. PCP-induced deficits in murine nest building activity: employment of an ethological rodent behavior to mimic negative-like symptoms of schizophrenia. Behav Brain Res. 2014;273:63–72.
  • 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.
  • Forum. Encenicline. Agonist of alpha 7 receptor response; 2015 [cited 2015 Sep 15]. Available from: http://www.forumpharma.com/innovation-pipeline/alpha-7-agonists/
  • Castro NG, Albuquerque EX. Brief-lifetime, fast-inactivating ion channels account for the α-bungarotoxin-sensitive nicotinic response in hippocampal neurons. Neurosci Lett. 1993;164:137–140.
  • 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.
  • 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.
  • 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.
  • Correll CU, Schenk EM. Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatr. 2008;21:151–156.
  • Kenney C, Hunter C, Jankovic J. Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Movement Disorders. 2007;22:193–197.
  • 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.html2015
  • 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/
  • Volkow ND. Substance use disorders in schizophrenia—clinical implications of comorbidity. Schizophr Bull. 2009;35:469–472.
  • 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.
  • 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.
  • McKeage K. Memantine: a review of its use in moderate to severe Alzheimer’s disease. CNS Drugs. 2009;23:881–897.
  • 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.
  • 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.
  • 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.
  • Williams HJ, Owen MJ, O’Donovan MC. Is COMT a susceptibility gene for schizophrenia? Schizophr Bull. 2007;33:635–641.
  • 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.
  • Girgis RR, Kumar SS, Brown AS. The cytokine model of schizophrenia: emerging therapeutic strategies. Biol Psychiatr. 2014;75:292–299.
  • Doorduin J, De Vries EFJ, Willemsen ATM, et al. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nuclear Med. 2009;50:1801–1807.
  • 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.
  • 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.
  • Bradley DP, Kulstad R, Schoeller DA. Exenatide and weight loss. Nutrition. 2010;26:243–249.
  • 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.
  • Andrade C. Famotidine augmentation in schizophrenia: hope or hype? J Clin Psychiatr. 2013;74:e855–e858.
  • 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.
  • 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.
  • Lewis-Wambi J, Jordan VC. 8.09 - raloxifene. In: Triggle JBTJ, editor. Comprehensive medicinal chemistry II. Oxford: Elsevier; 2007. p. 103–121.
  • 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.
  • Matoori S, Leroux J-C. Recent advances in the treatment of hyperammonemia. Adv Drug Deliv Rev. 2015;90:55–68.
  • 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.
  • Buckley PF, Stahl SM. Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or Cul-de-sac? Acta Psychiatr Scand. 2007;115:93–100.
  • Lindenmayer J-P, Khan A. Galantamine augmentation of long-acting injectable risperidone for cognitive impairments in chronic schizophrenia. Schizophr Res. 2011;125:267–277.
  • 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.
  • Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36:71–93.
  • 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.
  • Goff DC. Bitopertin: the good news and bad news. JAMA Psychiatr. 2014;71:621–622.
  • 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.
  • 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.
  • 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.
  • 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.
  • Citrome L. The ABC’s 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.
  • 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.
  • 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.
  • Actavis. VRAYLAR (cariprazine) capsules, for oral use. Prescribing information; [cited 2015 Oct 14]. Available from: http://pi.actavis.com/data_stream.asp?product_group=2028&p=pi&language=E2015
  • 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.
  • Leucht S, Kane JM, Etschel E, et al. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacol. 2006;31:2318–2325.
  • Leucht S, Kane JM, Kissling W, et al. What does the PANSS mean? Schizophr Res. 2005;79:231–238.
  • 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.
  • Marder SR, Kirkpatrick B. Defining and measuring negative symptoms of schizophrenia in clinical trials. Eur Neuropsychopharmacol. 2014;24:737–743.
  • 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.
  • 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.
  • 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.
  • 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.
  • Green MF, Harris JG, Nuechterlein KH. The MATRICS consensus cognitive battery: what we know 6 years later. Am J Psychiatr. 2014;171:1151–1154.
  • 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.
  • 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.
  • Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–236.
  • The International Schizophrenia C. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455:237–241.
  • 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.
  • Harrison PJ. Recent genetic findings in schizophrenia and their therapeutic relevance. J Psychopharmacol (Oxford, England). 2015;29:85–96.
  • Liang SG, Greenwood TA. The impact of clinical heterogeneity in schizophrenia on genomic analyses. Schizophr Res. 2015;161:490–495.
  • Schubert Christian R, Xi HS, Wendland Jens R, et al. Translating human genetics into novel treatment targets for schizophrenia. Neuron. 2014;84:537–541.
  • 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.
  • 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.
  • 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.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.