Pharmacological treatment of schizophrenia: A critical review of the pharmacology and clinical effects of current and future therapeutic agents

Molecular Psychiatry

Volumn 17, Issue 12, 2012, Pages 1206-1227

  Miyamoto, S ^a   Miyake, N ^a   Jarskog, L F ^b,c   Fleischhacker, W W ^d   Lieberman, J A ^e  

^a ST MARIANNA UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^b UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^c North Carolina Psychiatric Research Center   (United States)

^d INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^e Columbia University ^*  (United States)

Author keywords

add on treatment; antipsychotics; cognition; mechanism of action; negative symptoms; schizophrenia

Indexed keywords

5 (2,3 DIHYDROBENZOFURAN 7 YL) 2,3,4,5 TETRAHYDRO 3 METHYL 8 NITRO 1H 3 BENZAZEPIN 7 OL; 6 QUINOXALINECARBOXYLIC ACID PIPERIDIDE; AMISULPRIDE; ARIPIPRAZOLE; BITOPERTIN; CARIPRAZINE; CLOZAPINE; ECOPIPAM; FARAMPATOR; GINKGO BILOBA EXTRACT; HALOPERIDOL; MESORIDAZINE; N (3,5 DICHLORO 2 METHOXYPHENYL) 4 METHOXY 3 (1 PIPERAZINYL)BENZENESULFONAMIDE; OLANZAPINE; PALIPERIDONE; PIMAVANSERIN; PIMOZIDE; PLACEBO; POMAGLUMETAD METHIONIL; PREGNENOLONE; QUETIAPINE; RECOMBINANT ERYTHROPOIETIN; RISPERIDONE; SARCOSINE; SECRETIN; SERTINDOLE; THIORIDAZINE; UNINDEXED DRUG; ZIPRASIDONE; ZOTEPINE;

COGNITION; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENTIATION; DRUG RECEPTOR BINDING; DRUG SAFETY; HEART ARRHYTHMIA; HUMAN; HYPERPROLACTINEMIA; NEUROPROTECTION; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROLACTIN BLOOD LEVEL; QT PROLONGATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SCHIZOPHRENIA; SIDE EFFECT; WEIGHT GAIN;

ANIMALS; ANTIPSYCHOTIC AGENTS; DRUG DISCOVERY; HUMANS; MODELS, NEUROLOGICAL; MOLECULAR TARGETED THERAPY; SCHIZOPHRENIA; SYNAPTIC TRANSMISSION;

EID: 84870057403     PISSN: 13594184     EISSN: 14765578     Source Type: Journal    
DOI: 10.1038/mp.2012.47     Document Type: Review

References (359)

1. Insel TR. Rethinking schizophrenia. Nature 2010; 468: 187-193.
2. Lieberman JA. Is schizophrenia a neurodegenerative disorder? A clinical and pathophysiological perspective. Biol Psychiatry 1999; 46: 729-739.
3. Kim DH, Maneen MJ, Stahl SM. Building a better antipsychotic: receptor targets for the treatment of multiple symptom dimensions of schizophrenia. Neurotherapeutics 2009; 6: 78-85.
4. Miyamoto S, Merrill DB, Lieberman JA, Fleischhacker WW, Marder SR. Antipsychotic drugs. In: Tasman A, Kay J, Lieberman JA, et al. (eds). Psychiatry, 3rd edn John Wiley & Sons: Chichester, 2008, pp 2161-2201.
5. Jarskog LF, Miyamoto S, Lieberman JA. Schizophrenia: new pathological insights and therapies. Annu Rev Med 2007; 58: 49-61.
6. Biedermann F, Fleischhacker WW. Emerging drugs for schizophrenia. Expert Opin Emerg Drugs 2011; 16: 271-282.
7. Conn PJ, Tamminga C, Schoepp DD, Lindsley C. Schizophrenia: moving beyond monoamine antagonists. Mol Interv 2008; 8: 99-107.
8. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373: 31-41.
9. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153: 321-330.
10. Miyamoto S, Duncan GE, Goff DC, Lieberman JA. Therapeutics of schizophrenia. In: Davis KL, Charney D, Coyle JT, et al. (eds). Neuropsychopharmacology: The Fifth Generation of Progress. Lippincott Williams & Wilkins: Philadelphia, 2002, pp 775-807.
11. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10: 79-104.
12. Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry 2007; 12: 904-922.
13. Barch DM. Pharmacological strategies for enhancing cognition in schizophrenia. Curr Top Behav Neurosci 2010; 4: 43-96.
14. Buchanan RW, Freedman R, Javitt DC, Abi-Dargham A, Lieberman JA. Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull 2007; 33: 1120-1130.
15. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474-1486.
16. Seeman P. Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 1992; 7: 261-284.
17. Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 2005; 122: 261-273.
18. Masri B, Salahpour A, Didriksen M, Ghisi V, Beaulieu JM, Gainetdinov RR et al. Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci USA 2008; 105: 13656-13661.
19. Remington G, Kapur S. D2 and 5-HT2 receptor effects of antipsychotics: bridging basic and clinical findings using PET. J Clin Psychiatry 1999; 60(suppl 10): 15-19.
20. Sharif Z, Miyamoto S, Lieberman JA. Pharmacotherapy of schizophrenia. In: Sibley D, Hanin I, Kuhar M, et al. (eds). The Handbook of Contemporary Neuropharmacology. John Wiley & Sons: Hoboken, 2007, pp 369-409.
21. Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992; 49: 538-544.
22. Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P. A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 2000; 57: 553-559.
23. Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and Serotonin2 pKi values. J Pharmacol Exp Ther 1989; 251: 238-246.
24. Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001; 158: 360-369.
25. Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002; 47: 27-38.
26. Seeman P. An update of fast-off dopamine D2 atypical antipsychotics. Am J Psychiatry 2005; 162: 1984-1985.
27. Kim DH, Stahl SM. Antipsychotic drug development. Curr Top Behav Neurosci 2010; 4: 123-139.
28. Cutler A, Ball S, Stahl SM. Dosing atypical antipsychotics. CNS Spectr 2008; 13: 1-16.
29. Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B et al. Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 2006; 31: 1991-2001.
30. Xiberas X, Martinot JL, Mallet L, Artiges E, Loc'h C, Maziere B et al. Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 2001; 179: 503-508.
31. Bigliani V, Mulligan RS, Acton PD, Ohlsen RI, Pike VW, Ell PJ et al. Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study. Psychopharmacology (Berl) 2000; 150: 132-140.
32. Bressan RA, Erlandsson K, Jones HM, Mulligan RS, Ell PJ, Pilowsky LS. Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J Clin Psychopharmacol 2003; 23: 5-14.
33. Bressan RA, Erlandsson K, Jones HM, Mulligan R, Flanagan RJ, Ell PJ et al. Is regionally selective D2/D3 dopamine occupancy sufficient for atypical antipsychotic effect? An in vivo quantitative [123I]epidepride SPET study of amisulpride-treated patients. Am J Psychiatry 2003; 160: 1413-1420.
34. Stone JM, Davis JM, Leucht S, Pilowsky LS. Cortical dopamine D2/D3 receptors are a common site of action for antipsychotic drugs-an original patient data meta-analysis of the SPECT and PET in vivo receptor imaging literature. Schizophr Bull 2009; 35: 789-797.
35. Lieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs 2004; 18: 251-267.
36. Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 2006; 20: 389-409.
37. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 2003; 28: 1400-1411.
38. Janssen PA, Niemegeers CJ, Awouters F, Schellekens KH, Megens AA, Meert TF. Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 1988; 244: 685-693.
39. Deeks ED, Keating GM. Blonanserin: a review of its use in the management of schizophrenia. CNS Drugs 2010; 24: 65-84.
40. Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT 2 and D 2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999; 156: 286-293.
41. Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 2001; 50: 873-883.
42. Carlsson A. Focusing on dopaminergic stabilizers and 5-HT2A receptor antagonists. Curr Opin CPNS Invest Drugs 2000; 2: 22-24.
43. de Paulis T. M-100907 (Aventis). Curr Opin Investig Drugs 2001; 2: 123-132.
44. Schotte A, Janssen PFM, Gommeren W, Luyten WHML, Van Gompel P, Lesage AS et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 1996; 124: 57-73.
45. Millan MJ. Improving the treatment of schizophrenia: focus on serotonin (5-HT)(1A) receptors. J Pharmacol Exp Ther 2000; 295: 853-861.
46. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991; 148: 1301-1308.
47. Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 1996; 3: 241-253.
48. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199-214.
49. Duncan GE, Zorn S, Lieberman JA. Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Mol Psychiatry 1999; 4: 418-428.
50. Millan MJ. N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology (Berl) 2005; 179: 30-53.
51. Duncan GE, Miyamoto S, Leipzig JN, Lieberman JA. Comparison of the effects of clozapine, risperidone, and olanzapine on ketamine-induced alterations in regional brain metabolism. J Pharmacol Exp Ther 2000; 293: 8-14.
52. Duncan GE, Miyamoto S, Lieberman JA. Chronic administration of haloperidol and olanzapine attenuates ketamine-induced brain metabolic activation. J Pharmacol Exp Ther 2003; 305: 999-1005.
53. Javitt DC, Duncan L, Balla A, Sershen H. Inhibition of system A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action. Mol Psychiatry 2005; 10: 275-287.
54. Erlandsson K, Bressan RA, Mulligan RS, Gunn RN, Cunningham VJ, Owens J et al. Kinetic modelling of [123I]CNS 1261-a potential SPET tracer for the NMDA receptor. Nucl Med Biol 2003; 30: 441-454.
55. Bressan RA, Erlandsson K, Stone JM, Mulligan RS, Krystal JH, Ell PJ et al. Impact of schizophrenia and chronic antipsychotic treatment on [123I]CNS-1261 binding to N-methyl-D-aspartate receptors in vivo. Biol Psychiatry 2005; 58: 41-46.
56. Gray JA, Roth BL. Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr Bull 2007; 33: 1100-1119.
57. Davies MA, Compton-Toth BA, Hufeisen SJ, Meltzer HY, Roth BL. The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine's actions? Psychopharmacology (Berl) 2005; 178: 451-460.
58. Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 2001; 50: 884-897.
59. Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J, Phillips LJ et al. Neuroanatomical abnormalities before and after onset of psychosis: a crosssectional and longitudinal MRI comparison. Lancet 2003; 361: 281-288.
60. Cahn W, Hulshoff Pol HE, Lems EB, van Haren NE, Schnack HG, van der Linden JA et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 2002; 59: 1002-1010.
61. Ho BC, Andreasen NC, Nopoulos P, Arndt S, Magnotta V, Flaum M. Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 2003; 60: 585-594.
62. Harrison PJ. The neuropathological effects of antipsychotic drugs. Schizophr Res 1999; 40: 87-99.
63. Konradi C, Heckers S. Antipsychotic drugs and neuroplasticity: insights into the treatment and neurobiology of schizophrenia. Biol Psychiatry 2001; 50: 729-742.
64. Dean CE. Antipsychotic-associated neuronal changes in the brain: toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia? Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 174-189.
65. Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE et al. Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 2008; 60: 358-403.
66. Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005; 62: 361-370.
67. van Haren NE, Hulshoff Pol HE, Schnack HG, Cahn W, Mandl RC, Collins DL et al. Focal gray matter changes in schizophrenia across the course of the illness: a 5-year follow-up study. Neuropsychopharmacology 2007; 32: 2057-2066.
68. Haren NV, Cahn W, Hulshoff Pol HE, Kahn RS. The course of brain abnormalities in schizophrenia: can we slow the progression? J Psychopharmacol 2012 (in press).
69. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 2011; 68: 128-137.
70. Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology 2005; 30: 1649-1661.
71. Konopaske GT, Dorph-Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology 2007; 32: 1216-1223.
72. Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR et al. Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 2008; 63: 759-765.
73. Marder SR, Van Putten T, Schatzberg AF, Nemeroff CB. Antipsychotic medications. The American Psychiatric Press Textbook of Psychopharmacology. American Psychiatric Press: Washington, DC, 1995, pp 247-261.
74. Miyamoto S, Lieberman JA, Fleischhacker WW, Aoba A, Marder SR. Antipsychotic drugs. In: Tasman A, Kay J, Lieberman JA (eds). Psychiatry, 2nd edn, Vol. 2. John Wiley & Sons: Chichester, 2003, pp 1928-1964.
75. Kane JM. The current status of neuroleptic therapy. J Clin Psychiatry 1989; 50: 322-328.
76. Fleischhacker WW. New drugs for the treatment of schizophrenic patients. Acta Psychiatr Scand (Suppl) 1995; 388: 24-30.
77. Hill SK, Bishop JR, Palumbo D, Sweeney JA. Effect of second-generation antipsychotics on cognition: current issues and future challenges. Expert Rev Neurother 2010; 10: 43-57.
78. Schulz C, McGorry P, Buckley PF, Waddington JL. Traditional antipsychotic medications: contemporary clinical use. Schizophrenia and Mood Disorders: The New Drug Therapies in Clinical Practice. Butterworth-Heinemann: Woburn, MA, 2000, pp 14-20.
79. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-796.
80. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209-1223.
81. Keltner NL, Johnson V. Biological perspectives. Aripiprazole: a third generation of antipsychotics begins? Perspect Psychiatr Care 2002; 38: 157-159.
82. Miyake N, Miyamoto S, Jarskog LF. New serotonin/dopamine antagonists for the treatment of schizophrenia: are we making real progress? Clin Schizophr Relat Psychoses in press.
83. Ishibashi T, Horisawa T, Tokuda K, Ishiyama T, Ogasa M, Tagashira R et al. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther 2010; 334: 171-181.
84. Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP et al. Randomized controlled trial of the effect on Quality of Life of second-vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079-1087.
85. Fleischhacker WW, Keet IP, Kahn RS. The European First Episode Schizophrenia Trial (EUFEST): rationale and design of the trial. Schizophr Res 2005; 78: 147-156.
86. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371: 1085-1097.
87. Miyamoto S, Fleischhacker WW, Lieberman JA. Pharmacologic treatment of schizophrenia. In: Murray R, Lieberman JA (eds). Comprehensive Care of Schizophrenia (2nd edn). Oxford University Press: New York (in press).
88. Buchanan RW, Gold JM. Negative symptoms: diagnosis, treatment and prognosis. Int Clin Psychopharmacol 1996; 11(Suppl 2): 3-11.
89. Murphy BP, Chung YC, Park TW, McGorry PD. Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res 2006; 88: 5-25.
90. Hafner H, Riecher-Rossler A, Maurer K, Fatkenheuer B, Loffler W. First onset and early symptomatology of schizophrenia. A chapter of epidemiological and neurobiological research into age and sex differences. Eur Arch Psychiatry Clin Neurosci 1992; 242: 109-118.
91. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual 'atypical' antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 2002; 159: 180-190.
92. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163: 600-610.
93. Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006; 163: 611-622.
94. Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol 2005; 8: 457-472.
95. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the 'right stuff'? Schizophr Bull 2000; 26: 119-136.
96. Thornton AE, Van Snellenberg JX, Sepehry AA, Honer W. The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: a quantitative review. J Psychopharmacol 2006; 20: 335-346.
97. Carpenter WT, Gold JM. Another view of therapy for cognition in schizophrenia. Biol Psychiatry 2002; 51: 969-971.
98. Harvey PD, Keefe RS. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 2001; 158: 176-184.
99. Goldberg TE, Keefe RS, Goldman RS, Robinson DG, Harvey PD. Circumstances under which practice does not make perfect: a review of the practice effect literature in schizophrenia and its relevance to clinical treatment studies. Neuropsychopharmacology 2010; 35: 1053-1062.
100. Mishara AL, Goldberg TE. A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol Psychiatry 2004; 55: 1013-1022.
101. Green MF, Marder SR, Glynn SM, McGurk SR, Wirshing WC, Wirshing DA et al. The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone. Biol Psychiatry 2002; 51: 972-978.
102. Keefe RS, Seidman LJ, Christensen BK, Hamer RM, Sharma T, Sitskoorn MM et al. Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry 2004; 161: 985-995.
103. Keefe RS, Seidman LJ, Christensen BK, Hamer RM, Sharma T, Sitskoorn MM et al. Long-term neurocognitive effects of olanzapine or low-dose haloperidol in first-episode psychosis. Biol Psychiatry 2006; 59: 97-105.
104. Keefe RS, Young CA, Rock SL, Purdon SE, Gold JM, Breier A. One-year doubleblind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia. Schizophr Res 2006; 81: 1-15.
105. Davidson M, Galderisi S, Weiser M, Werbeloff N, Fleischhacker WW, Keefe RS et al. Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST). Am J Psychiatry 2009; 166: 675-682.
106. Heinrichs RW. Cognitive improvement in response to antipsychotic drugs: neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64: 631-632.
107. Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64: 633-647.
108. Burton S. Symptom domains of schizophrenia: the role of atypical antipsychotic agents. J Psychopharmacol 2006; 20: 6-19.
109. Siris SG. Depression in schizophrenia: perspective in the era of 'Atypical' antipsychotic agents. Am J Psychiatry 2000; 157: 1379-1389.
110. Lieberman JA. Pathophysiologic mechanisms in the pathogenesis and clinical course of schizophrenia. J Clin Psych 1999; 60(suppl 12): 9-12.
111. Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biol Psychiatry 2001; 50: 898-911.
112. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158: 518-526.
113. McIlwain ME, Harrison J, Wheeler AJ, Russell BR. Pharmacotherapy for treatmentresistant schizophrenia. Neuropsychiatr Dis Treat 2011; 7: 135-149.
114. Lewis SW, Davies L, Jones PB, Barnes TR, Murray RM, Kerwin R et al. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment. Health Technol Assess 2006; 10: iii-ixi, 1.
115. Lewis SW, Barnes TR, Davies L, Murray RM, Dunn G, Hayhurst KP et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32: 715-723.
116. Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003; 60: 82-91.
117. Hor K, Taylor M. Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol 2010; 24: 81-90.
118. Crocq MA, Naber D, Lader MH, Thibaut F, Drici M, Everitt B et al. Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone. Eur Neuropsychopharmacol 2010; 20: 829-838.
119. Volavka J, Citrome L. Heterogeneity of violence in schizophrenia and implications for long-term treatment. Int J Clin Pract 2008; 62: 1237-1245.
120. Krakowski MI, Czobor P, Citrome L, Bark N, Cooper TB. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 2006; 63: 622-629.
121. Citrome L, Volavka J, Czobor P, Sheitman B, Lindenmayer JP, McEvoy J et al. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatr Serv 2001; 52: 1510-1514.
122. Volavka J, Czobor P, Derks EM, Bitter I, Libiger J, Kahn RS et al. Efficacy of antipsychotic drugs against hostility in the European First-Episode Schizophrenia Trial (EUFEST). J Clin Psychiatry 2011; 72: 955-961.
123. Swanson JW, Swartz MS, Van Dorn RA, Volavka J, Monahan J, Stroup TS et al. Comparison of antipsychotic medication effects on reducing violence in people with schizophrenia. Br J Psychiatry 2008; 193: 37-43.
124. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990; 264: 2511-2518.
125. Green AI, Noordsy DL, Brunette MF, O'Keefe C. Substance abuse and schizophrenia: pharmacotherapeutic intervention. J Subst Abuse Treat 2008; 34: 61-71.
126. Tandon R, Belmaker RH, Gattaz WF, Lopez-Ibor Jr JJ, Okasha A, Singh B et al. World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res 2008; 100: 20-38.
127. Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics: differential risk and clinical implications. CNS Drugs 2007; 21: 911-936.
128. Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and metaanalysis. Schizophr Res 2010; 123: 225-233.
129. Yap YG, Camm J. Risk of torsades de pointes with non-cardiac drugs. Doctors need to be aware that many drugs can cause qt prolongation. BMJ 2000; 320: 1158-1159.
130. Glassman AH, Bigger Jr JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158: 1774-1782.
131. Gill SS, Bronskill SE, Normand SL, Anderson GM, Sykora K, Lam K et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med 2007; 146: 775-786.
132. Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 2007; 176: 627-632.
133. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360: 225-235.
134. Waddington JL. Pre-and postsynaptic D 1 to D 5 dopamine receptor mechanisms in relation to antipsychotic activity. In: Barnes TRE (ed). Antipsychotic Drugs and Their Side Effects. Academic Press: London, 1993, pp 65-85.
135. Karlsson P, Smith L, Farde L, Harnryd C, Sedvall G, Wiesel FA. Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients. Psychopharmacology (Berl) 1995; 121: 309-316.
136. Den Boer JA, van Megen HJ, Fleischhacker WW, Louwerens JW, Slaap BR, Westenberg HG et al. Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia. Psychopharmacology (Berl) 1995; 121: 317-322.
137. Karle J, Clemmesen L, Hansen L, Andersen M, Andersen J, Fensbo C et al. NNC 01-0687, a selective dopamine D1 receptor antagonist, in the treatment of schizophrenia. Psychopharmacology (Berl) 1995; 121: 328-329.
138. Goldman-Rakic PS, Muly Iii EC, Williams GV. D1 receptors in prefrontal cells and circuits. Brain Res Rev 2000; 31: 295-301.
139. Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995; 376: 572-575.
140. Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS. Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl) 1994; 116: 143-151.
141. Schneider JS, Sun ZQ, Roeltgen DP. Effects of dihydrexidine, a full dopamine D-1 receptor agonist, on delayed response performance in chronic low dose MPTPtreated monkeys. Brain Res 1994; 663: 140-144.
142. Cai JX, Arnsten AF. Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 1997; 283: 183-189.
143. Bubenikova-Valesova V, Svoboda J, Horacek J, Vales K. The effect of a full agonist/antagonist of the D1 receptor on locomotor activity, sensorimotor gating and cognitive function in dizocilpine-treated rats. Int J Neuropsychopharmacol 2009; 12: 873-883.
144. George MS, Molnar CE, Grenesko EL, Anderson B, Mu Q, Johnson K et al. A single 20mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia. Schizophr Res 2007; 93: 42-50.
145. Mu Q, Johnson K, Morgan PS, Grenesko EL, Molnar CE, Anderson B et al. A single 20mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia. Schizophr Res 2007; 94: 332-341.
146. Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl) 2004; 174: 3-16.
147. Benkert O, Muller-Siecheneder F, Wetzel H. Dopamine agonists in schizophrenia: a review. Eur Neuropsychopharmacol 1995; 5(Suppl): 43-53.
148. Newman-Tancredi A, Cussac D, Depoortere R. Neuropharmacological profile of bifeprunox: merits and limitations in comparison with other third-generation antipsychotics. Curr Opin Investig Drugs 2007; 8: 539-554.
149. Grunder G. Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression. Curr Opin Investig Drugs 2010; 11: 823-832.
150. Kiss B, Horvath A, Nemethy Z, Schmidt E, Laszlovszky I, Bugovics G 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.
151. Tadori Y, Kitagawa H, Forbes RA, McQuade RD, Stark A, Kikuchi T. Differences in agonist/antagonist properties at human dopamine D(2) receptors between aripiprazole, bifeprunox and SDZ 208-912. Eur J Pharmacol 2007; 574: 103-111.
152. Emsley R. Drugs in development for the treatment of schizophrenia. Expert Opin Investig Drugs 2009; 18: 1103-1118.
153. Cosi C, Carilla-Durand E, Assie MB, Ormiere AM, Maraval M, Leduc N et al. Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release. Eur J Pharmacol 2006; 535: 135-144.
154. Depoortere R, Boulay D, Perrault G, Bergis O, Decobert M, Francon D et al. SSR181507, a dopamine D2 receptor antagonist and 5-HT1A receptor agonist. II: behavioral profile predictive of an atypical antipsychotic activity. Neuropsychopharmacology 2003; 28: 1889-1902.
155. Thase ME, Fava M, Hobart M, Skuban A, Zhang P, McQuade RD et al. Efficacy and safety of adjunctive OPC-34712 in major depressive disorder: a phase II, randomized, placebo-controlled study. Presented at the 164th Annual Meeting of the American Psychiatric Association: Honolulu, Hawaii, 2011.
156. Schwartz JC, Diaz J, Pilon C, Sokoloff P. Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions. Brain Res Brain Res Rev 2000; 31: 277-287.
157. Remington G, Kapur S. SB-277011 GlaxoSmithKline. Curr Opin Investig Drugs 2001; 2: 946-949.
158. Millan MJ, Brocco M. Cognitive impairment in schizophrenia: a review of developmental and genetic models, and pro-cognitive profile of the optimised D(3) 4 D(2) antagonist, S33138. Therapie 2008; 63: 187-229.
159. Watson DJ, Marsden CA, Millan MJ, Fone KC. Blockade of dopamine D3 but not D2 receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment. Int J Neuropsychopharmacol 2012; 15: 471-484.
160. Lahti AC, Weiler M, Carlsson A, Tamminga CA. Effects of the D3 and autoreceptor-preferring dopamine antagonist (+)-UH232 in schizophrenia. J Neural Transm 1998; 105: 719-734.
161. Redden L, Rendenbach-Mueller B, Abi-Saab WM, Katz DA, Goenjian A, Robieson WZ et al. A double-blind, randomized, placebo-controlled study of the dopamine D3 receptor antagonist ABT-925 in patients with acute schizophrenia. J Clin Psychopharmacol 2011; 31: 221-225.
162. Kramer MS, Last B, Getson A, Reines SA. The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. Arch Gen Psychiatry 1997; 54: 567-572.
163. Truffinet P, Tamminga CA, Fabre LF, Meltzer HY, Riviere ME, Papillon-Downey C. Placebo-controlled study of the D4/5-HT2A antagonist fananserin in the treatment of schizophrenia. Am J Psychiatry 1999; 156: 419-425.
164. Corrigan MH, Gallen CC, Bonura ML, Merchant KM. Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial. Biol Psychiatry 2004; 55: 445-451.
165. Wadenberg ML, Ahlenius S. Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy. J Neural Transm Gen Sect 1991; 83: 43-53.
166. Burnet PW, Eastwood SL, Harrison PJ. 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 1996; 15: 442-455.
167. Simpson MD, Lubman DI, Slater P, Deakin JF. Autoradiography with [3H]8-OHDPAT reveals increases in 5-HT(1A) receptors in ventral prefrontal cortex in schizophrenia. Biol Psychiatry 1996; 39: 919-928.
168. Sumiyoshi T, Matsui M, Nohara S, Yamashita I, Kurachi M, Sumiyoshi C et al. Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry 2001; 158: 1722-1725.
169. Sumiyoshi T, Park S, Jayathilake K, Roy A, Ertugrul A, Meltzer HY. Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res 2007; 95: 158-168.
170. Jones CA, McCreary AC. Serotonergic approaches in the development of novel antipsychotics. Neuropharmacology 2008; 55: 1056-1065.
171. O'Neill MF, Heron-Maxwell CL, Shaw G. 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB. Pharmacol Biochem Behav 1999; 63: 237-243.
172. Lieberman JA, Mailman RB, Duncan G, Sikich L, Chakos M, Nichols DE et al. Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatry 1998; 44: 1099-1117.
173. Gelders YG. Thymosthenic agents, a novel approach in the treatment of schizophrenia. Br J Psychiatry 1989; 5(Suppl): 33-36.
174. Reynetjens A, Gelders ML, Hoppenbrouwers JA, Bussche GV. Thymosthenic effects of ritanserin (R 55667), a centrally acting serotonin-S2 receptor blocker. Drug Dev Res 1986; 8: 205-211.
175. Duinkerke SJ, Botter PA, Jansen AA, van Dongen PA, van Haaften AJ, Boom AJ et al. Ritanserin, a selective 5-HT2/1C antagonist, and negative symptoms in schizophrenia. A placebo-controlled double-blind trial [see comments]. Br J Psychiatry 1993; 163: 451-455.
176. Akhondzadeh S, Malek-Hosseini M, Ghoreishi A, Raznahan M, Rezazadeh SA. Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1879-1883.
177. Meltzer HY, Arvanitis L, Bauer D, Rein W. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 2004; 161: 975-984.
178. Weiner DM, Burstein ES, Nash N, Croston GE, Currier EA, Vanover KE et al. 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 2001; 299: 268-276.
179. Agid O, Kapur S, Remington G. Emerging drugs for schizophrenia. Expert Opin Emerg Drugs 2008; 13: 479-495.
180. Abbas A, Roth BL. Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert Opin Pharmacother 2008; 9: 3251-3259.
181. Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 2007; 113: 296-320.
182. Jensen NH, Cremers TI, Sotty F. Therapeutic potential of 5-HT2C receptor ligands. ScientificWorldJournal 2010; 10: 1870-1885.
183. Marquis KL, Sabb AL, Logue SF, Brennan JA, Piesla MJ, Comery TA et al. WAY-163909. [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4] diazepino[ 6,7,1hi[indole]: a novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 2007; 320: 486-496.
184. Siuciak JA, Chapin DS, McCarthy SA, Guanowsky V, Brown J, Chiang P et al. CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity. Neuropharmacology 2007; 52: 279-290.
185. Shen HQJ, Zhao Y, Rosenzweig-Lipson S, Popp D, Williams BWJ, Giller E et al. A 6-week randomized, double-blind, placebo-controlled, comparator referenced, multicenter trial of vabicaserin in subjects with acute exacerbation of schizophrenia. Poster Resented at ACNP 50th Anniversary Meeting: Waikoloa Beach, Hawaii, USA, December 4-8, 2011.
186. Ramirez MJ, Cenarruzabeitia E, Lasheras B, Del Rio J. Involvement of GABA systems in acetylcholine release induced by 5-HT3 receptor blockade in slices from rat entorhinal cortex. Brain Res 1996; 712: 274-280.
187. Costall B, Naylor RJ. 5-HT3 receptors. Curr Drug Targets CNS Neurol Disord 2004; 3: 27-37.
188. Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A et al. Improved p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry 2005; 162: 386-388.
189. Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ. Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study. Schizophr Res 2006; 88: 102-110.
190. Akhondzadeh S, Mohammadi N, Noroozian M, Karamghadiri N, Ghoreishi A, Jamshidi AH et al. Added ondansetron for stable schizophrenia: a double blind, placebo controlled trial. Schizophr Res 2009; 107: 206-212.
191. Levkovitz Y, Arnest G, Mendlovic S, Treves I, Fennig S. The effect of Ondansetron on memory in schizophrenic patients. Brain Res Bull 2005; 65: 291-295.
192. Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999; 38: 1083-1152.
193. Roth BL, Hanizavareh SM, Blum AE. Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl) 2004; 174: 17-24.
194. Lamirault L, Guillou C, Thal C, Simon H. Combined treatment with galanthaminium bromide, a new cholinesterase inhibitor, and RS 67333, a partial agonist of 5-HT4 receptors, enhances place and object recognition in young adult and old rats. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 185-195.
195. Moser PC, Bergis OE, Jegham S, Lochead A, Duconseille E, Terranova JP et al. SL65.0155, a novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties. J Pharmacol Exp Ther 2002; 302: 731-741.
196. Stone JM, Pilowsky LS. Novel targets for drugs in schizophrenia. CNS Neurol Disord Drug Targets 2007; 6: 265-272.
197. Fone KC. An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function. Neuropharmacology 2008; 55: 1015-1022.
198. King MV, Marsden CA, Fone KC. A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory. Trends Pharmacol Sci 2008; 29: 482-492.
199. Terry Jr AV, Buccafusco JJ, Wilson C. Cognitive dysfunction in neuropsychiatric disorders: selected serotonin receptor subtypes as therapeutic targets. Behav Brain Res 2008; 195: 30-38.
200. Marcos B, Chuang TT, Gil-Bea FJ, Ramirez MJ. Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat. Br J Pharmacol 2008; 155: 434-440.
201. Hirst WD, Stean TO, Rogers DC, Sunter D, Pugh P, Moss SF et al. SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. Eur J Pharmacol 2006; 553: 109-119.
202. Rosse G, Schaffhauser H. 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. Curr Top Med Chem 2010; 10: 207-221.
203. Li Z, Huang M, Prus AJ, Dai J, Meltzer HY. 5-HT6 receptor antagonist SB-399885 potentiates haloperidol and risperidone-induced dopamine efflux in the medial prefrontal cortex or hippocampus. Brain Res 2007; 1134: 70-78.
204. Meneses A. 5-HT system and cognition. Neurosci Biobehav Rev 1999; 23: 1111-1125.
205. Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL. Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo. Psychopharmacology (Berl) 2009; 205: 119-128.
206. Pouzet B, Didriksen M, Arnt J. Effects of the 5-HT(7) receptor antagonist SB-258741. in animal models for schizophrenia. Pharmacol Biochem Behav 2002; 71: 655-665.
207. Leeson PD, Iversen LL. The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J Med Chem 1994; 37: 4053-4067.
208. Tsai GE, Lin PY. Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des 2010; 16: 522-537.
209. Hashimoto A, Oka T. Free D-aspartate and D-serine in the mammalian brain and periphery. Prog Neurobiol 1997; 52: 325-353.
210. Lane HY, Lin CH, Huang YJ, Liao CH, Chang YC, Tsai GE. A randomized, doubleblind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. Int J Neuropsychopharmacol 2010; 13: 451-460.
211. Tsai GE, Yang P, Chang YC, Chong MY. D-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2006; 59: 230-234.
212. Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP 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.
213. Betz H, Gomeza J, Armsen W, Scholze P, Eulenburg V. Glycine transporters: essential regulators of synaptic transmission. Biochem Soc Trans 2006; 34: 55-58.
214. Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2004; 55: 452-456.
215. Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry 2005; 62: 1196-1204.
216. Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 2006; 60: 645-649.
217. Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH et al. Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, doubleblind study. Biol Psychiatry 2008; 63: 9-12.
218. Umbricht D, Yoo K, Youssef E, Dorflinger E, Martin-Facklam M, Bausch A et al. Investigational glycine transporter type 1 (GlyT1) inhibitor RG1678: results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia. Presented at the ACNP 49th Annual Meeting, Miami Beach, Florida 2010.
219. Szegedi A, Jansen TW, Karson C, Schipper J, Schoemaker HJ. Adjunctive treatment with the selective glycine uptake inhibitor Org 25935 in persistent negative symptoms of schizophrenia: results from the GIANT trial. Poster Resented at ACNP 50th Anniversary Meeting: Waikoloa Beach, Hawaii, USA, December 4-8, 2011.
220. Rowley M, Bristow LJ, Hutson PH. Current and novel approaches to the drug treatment of schizophrenia. J Med Chem 2001; 44: 477-501.
221. Chavez-Noriega LE, Schaffhauser H, Campbell UC. Metabotropic glutamate receptors: potential drug targets for the treatment of schizophrenia. Curr Drug Target CNS Neurol Disord 2002; 1: 261-281.
222. Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotrophic glutamate receptor agonist in rats. Science 1998; 281: 1349-1352.
223. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV 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.
224. Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S et al. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 2011; 31: 349-355.
225. Kinon B, Adams DH, Baygani S, Millen B, Velona I, Kollack-Walker S. A long-term, phase 2, safety study of LY2140023 monohydrate versus atypical antipsychotic standard of care in schizophrenia 13th International Congress on Schizophrenia Research: Colorado Springs, 2011.
226. Gravius A, Pietraszek M, Dekundy A, Danysz W. Metabotropic glutamate receptors as therapeutic targets for cognitive disorders. Curr Top Med Chem 2010; 10: 187-206.
227. Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G et al. ADX47273 [S-(4-fluorophenyl)-{ 3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin- 1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. J Pharmacol Exp Ther 2008; 327: 827-839.
228. Kinney GG, O'Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK et al. A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J Pharmacol Exp Ther 2005; 313: 199-206.
229. Hampson RE, Rogers G, Lynch G, Deadwyler SA. Facilitative effects of the ampakine CX516 on short-term memory in rats: correlations with hippocampal neuronal activity. J Neurosci 1998; 18: 2748-2763.
230. Hampson RE, Rogers G, Lynch G, Deadwyler SA. Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayednonmatch-to- sample performance. J Neurosci 1998; 18: 2740-2747.
231. Marenco S, Egan MF, Goldberg TE, Knable MB, McClure RK, Winterer G et al. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res 2002; 57: 221-226.
232. Goff DC, Lamberti JS, Leon AC, Green MF, Miller AL, Patel J et al. A placebocontrolled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 2008; 33: 465-472.
233. Ward SE, Bax BD, Harries M. Challenges for and current status of research into positive modulators of AMPA receptors. Br J Pharmacol 2010; 160: 181-190.
234. Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011; 36: 78-86.
235. Janaky R, Ogita K, Pasqualotto BA, Bains JS, Oja SS, Yoneda Y et al. Glutathione and signal transduction in the mammalian CNS. J Neurochem 1999; 73: 889-902.
236. Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 2000; 12: 3721-3728.
237. Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O et al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 2008; 33: 2187-2199.
238. Goldman-Rakic PS, Lidow MS, Gallager DW. Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex. J Neurosci 1990; 10: 2125-2138.
239. Friedman JI, Adler DN, Davis KL. The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease. Biol Psychiatry 1999; 46: 1243-1252.
240. Arnsten AF, Goldman-Rakic PS. Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 1985; 230: 1273-1276.
241. Arnsten AF, Cai JX, Goldman-Rakic PS. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 1988; 8: 4287-4298.
242. Marrs W, Kuperman J, Avedian T, Roth RH, Jentsch JD. Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats. Neuropsychopharmacology 2005; 30: 1500-1510.
243. Fields RB, Van Kammen DP, Peters JL, Rosen J, Van Kammen WB, Nugent A et al. Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res 1988; 1: 417-423.
244. Friedman JI, Adler DN, Temporini HD, Kemether E, Harvey PD, White L et al. Guanfacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology 2001; 25: 402-409.
245. Gobert A, Rivet JM, Audinot V, Newman-Tancredi A, Cistarelli L, Millan MJ. Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto-and heteroreceptor-mediated control of release. Neuroscience 1998; 84: 413-429.
246. Millan MJ, Gobert A, Newman-Tancredi A, Lejeune F, Cussac D, Rivet JM et al. S18327 (1-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperid-1-yl]ethyl]3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1)-and alpha(2)-adrenergic receptors: I. Receptorial, neurochemical, and electrophysiological profile. J Pharmacol Exp Ther 2000; 292: 38-53.
247. Marcus MM, Wiker C, Franberg O, Konradsson-Geuken A, Langlois X, Jardemark K et al. Adjunctive alpha2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission. Int J Neuropsychopharmacol 2010; 13: 891-903.
248. Litman RE, Su TP, Potter WZ, Hong WW, Pickar D. Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine. Br J Psychiatry 1996; 168: 571-579.
249. Wadenberg ML, Wiker C, Svensson TH. Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive alpha2 adrenoceptor blockade: experimental evidence. Int J Neuropsychopharmacol 2007; 10: 191-202.
250. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK et al. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001; 50: 825-844.
251. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917-6922.
252. Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS et al. Executive subprocesses in working memory: relationship to catechol-Omethyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 2003; 60: 889-896.
253. Liljequist R, Haapalinna A, Ahlander M, Li YH, Mannisto PT. Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behav Brain Res 1997; 82: 195-202.
254. Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 2007; 32: 1011-1020.
255. Holden C. Neuroscience. Deconstructing schizophrenia. Science 2003; 299: 333-335.
256. Watkins P. COMT inhibitors and liver toxicity. Neurology 2000; 55: S51-S52.
257. Borges N. Tolcapone-related liver dysfunction: implications for use in Parkinson's disease therapy. Drug Saf 2003; 26: 743-747.
258. Martin LF, Kem WR, Freedman R. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology (Berl) 2004; 174: 54-64.
259. EnVivo Pharmaceuticals. EnVivo reports positive results of its EVP-6124 clinical bio-marker study in schizophrenia patients. Available from URL: http://www.envivopharma.com/news-item.php?id19 Press release, 12 January 2009.
260. Hauser TA, Kucinski A, Jordan KG, Gatto GJ, Wersinger SR, Hesse RA et al. TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochem Pharmacol 2009; 78: 803-812.
261. Mazurov A, Hauser T, Miller CH. Selective alpha7 nicotinic acetylcholine receptor ligands. Curr Med Chem 2006; 13: 1567-1584.
262. Rezvani AH, Kholdebarin E, Brucato FH, Callahan PM, Lowe DA, Levin ED. Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 269-275.
263. Acker BA, Jacobsen EJ, Rogers BN, Wishka DG, Reitz SC, Piotrowski DW et al. Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5- carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity. Bioorg Med Chem Lett 2008; 18: 3611-3615.
264. Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 2008; 165: 1040-1047.
265. Tregellas JR, Olincy A, Johnson L, Tanabe J, Shatti S, Martin LF et al. Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia. Neuropsychopharmacology 2010; 35: 938-942.
266. Tregellas JR, Tanabe J, Rojas DC, Shatti S, Olincy A, Johnson L et al. Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biol Psychiatry 2011; 69: 7-11.
267. Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T et al. A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry 2010; 9: 27.
268. Hosford D, Dunbar G, Lieberman JA, Segreti A. The alpha7 neuronal nicotinic receptor (NNR) agonist TC-5619 had beneficial effects and was generally well tolerated in a phase 2 trial in cognitive dysfunction in schizophrenia (CDS). 13th international congress on schizophrenia research Colorado Springs, Colorado, USA 2011.
269. Arneric SP, Holladay M, Williams M. Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. Biochem Pharmacol 2007; 74: 1092-1101.
270. Biedermann F, Fleischhacker WW. Antipsychotics in the early stage of development. Curr Opin Psychiatry 2009; 22: 326-330.
271. Smith RC, Lindenmayer JP, Davis JM, Cornwell J, Noth K, Gupta S et al. Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder. Schizophr Res 2009; 110: 149-155.
272. Shim JC, Jung DU, Jung SS, Seo YS, Cho DM, Lee JH et al. Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia: a randomized double-blind placebo-controlled trial. Neuropsychopharmacology 2012; 37: 660-668.
273. Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar disorder. Am J Psychiatry 2007; 164: 1269-1270.
274. Freedman R. Exacerbation of schizophrenia by varenicline. Am J Psychiatry 2007; 164: 1269.
275. Bymaster FP. Possible role of muscarinic receptor agonists as therapeutic agents for psychosis. In: Breier A, Tran PV, Herrera JM, et al. (eds). Current Issues in the Psychopharmacology of Schizophrenia. Lippincott Williams & Wilkins Healthcare: Philadelphia, 2001, pp 333-348.
276. Bymaster FP, Felder C, Ahmed S, McKinzie D. Muscarinic receptors as a target for drugs treating schizophrenia. Curr Drug Target CNS Neurol Disord 2002; 1: 163-181.
277. Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dube S, Mallinckrodt C et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry 2008; 165: 1033-1039.
278. Buchanan RW, Conley RR, Dickinson D, Ball MP, Feldman S, Gold JM et al. Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J Psychiatry 2008; 165: 82-89.
279. Lee SW, Lee JG, Lee BJ, Kim YH. A 12-week, double-blind, placebo-controlled trial of galantamine adjunctive treatment to conventional antipsychotics for the cognitive impairments in chronic schizophrenia. Int Clin Psychopharmacol 2007; 22: 63-68.
280. Noren U, Bjorner A, Sonesson O, Eriksson L. Galantamine added to antipsychotic treatment in chronic schizophrenia: cognitive improvement? Schizophr Res 2006; 85: 302-304.
281. Schubert MH, Young KA, Hicks PB. Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biol Psychiatry 2006; 60: 530-533.
282. Sacco KA, Creeden C, Reutenauer EL, George TP. Effects of galantamine on cognitive deficits in smokers and non-smokers with schizophrenia. Schizophr Res 2008; 103: 326-327.
283. Lindenmayer JP, Khan A. Galantamine augmentation of long-acting injectable risperidone for cognitive impairments in chronic schizophrenia. Schizophr Res 2011; 125: 267-277.
284. Dyer MA, Freudenreich O, Culhane MA, Pachas GN, Deckersbach T, Murphy E et al. High-dose galantamine augmentation inferior to placebo on attention, inhibitory control and working memory performance in nonsmokers with schizophrenia. Schizophr Res 2008; 102: 88-95.
285. Conley RR, Boggs DL, Kelly DL, McMahon RP, Dickinson D, Feldman S et al. The effects of galantamine on psychopathology in chronic stable schizophrenia. Clin Neuropharmacol 2009; 32: 69-74.
286. Lazewska D, Kiec-Kononowicz K. Recent advances in histamine H3 receptor antagonists/inverse agonists. Expert Opin Ther Pat 2010; 20: 1147-1169.
287. Esbenshade TA, Browman KE, Bitner RS, Strakhova M, Cowart MD, Brioni JD. The histamine H3 receptor: an attractive target for the treatment of cognitive disorders. Br J Pharmacol 2008; 154: 1166-1181.
288. Ligneau X, Landais L, Perrin D, Piriou J, Uguen M, Denis E et al. Brain histamine and schizophrenia: potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649. Biochem Pharmacol 2007; 73: 1215-1224.
289. Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 2007; 370: 319-328.
290. Emrich HM, Leweke FM, Schneider U. Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacol Biochem Behav 1997; 56: 803-807.
291. Cota D, Sandoval DA, Olivieri M, Prodi E, D'Alessio DA, Woods SC et al. Food intake-independent effects of CB1 antagonism on glucose and lipid metabolism. Obesity (Silver Spring) 2009; 17: 1641-1645.
292. Kelly DL, Gorelick DA, Conley RR, Boggs DL, Linthicum J, Liu F et al. Effects of the cannabinoid-1 receptor antagonist rimonabant on psychiatric symptoms in overweight people with schizophrenia: a randomized, double-blind, pilot study. J Clin Psychopharmacol 2011; 31: 86-91.
293. Boggs DL, Kelly DL, McMahon RP, Gold JM, Gorelick DA, Linthicum J et al. Rimonabant for neurocognition in schizophrenia: a 16-week double blind randomized placebo controlled trial. Schizophr Res 2012; 134: 207-210.
294. Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 2006; 39: 421-429.
295. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312-324.
296. Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA et al. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry 2008; 165: 1585-1593.
297. Buchanan RW, Keefe RS, Lieberman JA, Barch DM, Csernansky JG, Goff DC et al. A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol Psychiatry 2011; 69: 442-449.
298. Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res 2007; 90: 179-185.
299. Muller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M et al. Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res 2010; 121: 118-124.
300. Fujita Y, Ishima T, Kunitachi S, Hagiwara H, Zhang L, Iyo M et al. Phencyclidineinduced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 336-339.
301. Levkovitz Y, Levi U, Braw Y, Cohen H. Minocycline, a second-generation tetracycline, as a neuroprotective agent in an animal model of schizophrenia. Brain Res 2007; 1154: 154-162.
302. Zhang L, Shirayama Y, Iyo M, Hashimoto K. Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology 2007; 32: 2004-2010.
303. Zhang L, Kitaichi K, Fujimoto Y, Nakayama H, Shimizu E, Iyo M et al. Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1381-1393.
304. Plane JM, Shen Y, Pleasure DE, Deng W. Prospects for minocycline neuroprotection. Arch Neurol 2010; 67: 1442-1448.
305. Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 2010; 71: 138-149.
306. Gueudet C, Santucci V, Soubrie P, Le Fur G. Blockade of neurokinin3 receptors antagonizes drug-induced population response and depolarization block of midbrain dopamine neurons in guinea pigs. Synapse 1999; 33: 71-79.
307. Kamali F. Osanetant Sanofi-Synthelabo. Curr Opin Investig Drugs 2001; 2: 950-956.
308. Evangelista S. Talnetant GlaxoSmithKline. Curr Opin Investig Drugs 2005; 6: 717-721.
309. Spooren W, Riemer C, Meltzer H. Opinion: NK3 receptor antagonists: the next generation of antipsychotics? Nat Rev Drug Discov 2005; 4: 967-975.
310. Dawson LA, Smith PW. Therapeutic utility of NK3 receptor antagonists for the treatment of schizophrenia. Curr Pharm Des 2010; 16: 344-357.
311. Kulkarni J. Oestrogen-a new treatment approach for schizophrenia? Med J Aust 2009; 190: S37-S38.
312. Hallonquist JD, Seeman MV, Lang M, Rector NA. Variation in symptom severity over the menstrual cycle of schizophrenics. Biol Psychiatry 1993; 33: 207-209.
313. Hafner H, Behrens S, De Vry J, Gattaz WF. An animal model for the effects of estradiol on dopamine-mediated behavior: implications for sex differences in schizophrenia. Psychiatr Res 1991; 38: 125-134.
314. Fleischhacker WW. New developments in the pharmacotherapy of schizophrenia. J Neural Transm 2003; 64(Suppl): 105-117.
315. Kulkarni J, de Castella A, Fitzgerald PB, Gurvich CT, Bailey M, Bartholomeusz C et al. Estrogen in severe mental illness: a potential new treatment approach. Arch Gen Psychiatry 2008; 65: 955-960.
316. Kulkarni J, Riedel A, de Castella AR, Fitzgerald PB, Rolfe TJ, Taffe J et al. Estrogen-a potential treatment for schizophrenia. Schizophr Res 2001; 48: 137-144.
317. Rupprecht R, Holsboer F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 1999; 22: 410-416.
318. Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009; 30: 65-91.
319. Marx CE, Stevens RD, Shampine LJ, Uzunova V, Trost WT, Butterfield MI et al. Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. Neuropsychopharmacology 2006; 31: 1249-1263.
320. Marx CE, Keefe RS, Buchanan RW, Hamer RM, Kilts JD, Bradford DW et al. Proofof-concept trial with the neurosteroid pregnenolone targeting cognitive and
321. Strous RD, Maayan R, Lapidus R, Stryjer R, Lustig M, Kotler M et al. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 2003; 60: 133-141.
322. Strous RD, Stryjer R, Maayan R, Gal G, Viglin D, Katz E et al. Analysis of clinical symptomatology, extrapyramidal symptoms and neurocognitive dysfunction following dehydroepiandrosterone (DHEA) administration in olanzapine treated schizophrenia patients: a randomized, double-blind placebo controlled trial. Psychoneuroendocrinology 2007; 32: 96-105.
323. Nachshoni T, Ebert T, Abramovitch Y, Assael-Amir M, Kotler M, Maayan R et al. Improvement of extrapyramidal symptoms following dehydroepiandrosterone (DHEA) administration in antipsychotic treated schizophrenia patients: a randomized, double-blind placebo controlled trial. Schizophr Res 2005; 79: 251-256.
324. Ritsner MS, Gibel A, Ratner Y, Tsinovoy G, Strous RD. Improvement of sustained attention and visual and movement skills, but not clinical symptoms, after dehydroepiandrosterone augmentation in schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychopharmacol 2006; 26: 495-499.
325. Peet M, Stokes C. Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs 2005; 65: 1051-1059.
326. Jicha GA, Markesbery WR. Omega-3 fatty acids: potential role in the management of early Alzheimer's disease. Clin Interv Aging 2010; 5: 45-61.
327. Farooqui AA, Ong WY, Horrocks LA, Chen P, Farooqui T. Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res Rev 2007; 56: 443-471.
328. Fenton WS, Hibbeln J, Knable M. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol Psychiatry 2000; 47: 8-21.
329. Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 2006; 67: 1954-1967.
330. Joy CB, Mumby-Croft R, Joy LA. Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Database Syst Rev 2006; 3: CD001257.
331. Amminger GP, Schafer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 2010; 67: 146-154.
332. Uvnas-Moberg K. Oxytocin may mediate the benefits of positive social interaction and emotions. Psychoneuroendocrinology 1998; 23: 819-835.
333. Carter CS. Neuroendocrine perspectives on social attachment and love. Psychoneuroendocrinology 1998; 23: 779-818.
334. Feifel D, Reza T. Oxytocin modulates psychotomimetic-induced deficits in sensorimotor gating. Psychopharmacology (Berl) 1999; 141: 93-98.
335. Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI. Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin. Neuropsychopharmacology 2005; 30: 1883-1894.
336. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature 2005; 435: 673-676.
337. Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC. Oxytocin improves 'mind-reading' in humans. Biol Psychiatry 2007; 61: 731-733.
338. Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010; 67: 692-694.
339. Feifel D, Macdonald K, Nguyen A, Cobb P, Warlan H, Galangue B et al. Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients. Biol Psychiatry 2010; 68: 678-680.
340. Pedersen CA, Gibson CM, Rau SW, Salimi K, Smedley KL, Casey RL et al. Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia. Schizophr Res 2011; 132: 50-53.
341. Kehler J, Kilburn JP. Patented PDE10A inhibitors: novel compounds since 2007. Expert Opin Ther Pat 2009; 19: 1715-1725.
342. Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL et al. Immunohistochemical localization of PDE10A in the rat brain. Brain Res 2003; 985: 113-126.
343. Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R et al. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther 2009; 331: 574-590.
344. Myers K, Goulet M, Rusche J, Boismenu R, Davis M. Inhibition of fear potentiated startle in rats following peripheral administration of secretin. Psychopharmacology (Berl) 2004; 172: 94-99.
345. Myers KM, Goulet M, Rusche J, Boismenu R, Davis M. Partial reversal of phencyclidine-induced impairment of prepulse inhibition by secretin. Biol Psychiatry 2005; 58: 67-73.
346. Sheitman BB, Knable MB, Jarskog LF, Chakos M, Boyce LH, Early J et al. Secretin for refractory schizophrenia. Schizophr Res 2004; 66: 177-181.
347. Bolbecker AR, Hetrick WP, Johannesen JK, O'Donnell BF, Steinmetz JE, Shekhar AS. Secretin effects on cerebellar-dependent motor learning in schizophrenia. Am J Psychiatry 2009; 166: 460-466.
348. Ehrenreich H, Degner D, Meller J, Brines M, Behe M, Hasselblatt M et al. Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Mol Psychiatry 2004; 9: 42-54.
349. Siren AL, Fasshauer T, Bartels C, Ehrenreich H. Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics 2009; 6: 108-127.
350. Ehrenreich H, Hinze-Selch D, Stawicki S, Aust C, Knolle-Veentjer S, Wilms S et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 2007; 12: 206-220.
351. Wustenberg T, Begemann M, Bartels C, Gefeller O, Stawicki S, Hinze-Selch D et al. Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol Psychiatry 2011; 16: 26-36, 21.
352. Singh V, Singh SP, Chan K. Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. Int J Neuropsychopharmacol 2010; 13: 257-271.
353. Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 2004; 3: 353-359.
354. Stahl SM. Multifunctional drugs: a novel concept for psychopharmacology. CNS Spectr 2009; 14: 71-73.
355. Wong EH, Tarazi FI, Shahid M. The effectiveness of multi-target agents in schizophrenia and mood disorders: relevance of receptor signature to clinical action. Pharmacol Ther 2010; 126: 173-185.
356. Carter CS, Barch DM. Cognitive neuroscience-based approaches to measuring and improving treatment effects on cognition in schizophrenia: the CNTRICS initiative. Schizophr Bull 2007; 33: 1131-1137.
357. Carpenter WT, Koenig JI. The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 2008; 33: 2061-2079.
358. Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 2007; 12: 707-747.
359. McGorry PD, Nelson B, Amminger GP, Bechdolf A, Francey SM, Berger G et al. Intervention in individuals at ultra-high risk for psychosis: a review and future directions. J Clin Psychiatry 2009; 70: 1206-1212.