The pipeline and future of drug development in schizophrenia

Molecular Psychiatry

Volumn 12, Issue 10, 2007, Pages 904-922

  Gray, J A ^a   Roth, B L ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

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

Author keywords

Antipsychotics; Cognition; Drug discovery; Negative symptoms; Preclinical models; Target validation

Indexed keywords

1 (3 CHLORO 4 CYCLOHEXYLPHENYL) 3 (HEXAHYDRO 1 AZEPINYL)PROPENE; 1 [4 [4 (6 IMIDAZO[2,1 B]THIAZOLYL)PHENOXY]BUTYL] 4 (2 METHOXYPHENYL)PIPERAZINE; 2 [4 [2 (4 PHENYL 1 PIPERAZINYL)ETHYL]CYCLOHEXYLAMINO]PYRIMIDINE; 2 [4 [4 (5 FLUORO 1H INDOL 3 YL) 1,2,3,6 TETRAHYDRO 1 PYRIDINYL]BUTYL]PHTHALIMIDE; 2 [4 METHOXY 3 (2 PHENYLETHOXY)PHENYL] N,N DIPROPYLETHYLAMINE; 2 AMINO N [4 [4 (1,2 BENZISOTHIAZOL 3 YL) 1 PIPERAZINYL]BUTYL]BENZAMIDE; 2 DIPROPYLAMINO 5,6 DIMETHOXYINDAN; 2 PHENYL 4 [4 (2 PYRIMIDINYL) 1 PIPERAZINYLMETHYL]IMIDAZOLE; 4 (4 FLUOROPHENYL) 1,2,3,6 TETRAHYDRO 1 [4 (1,2,4 TRIAZOL 1 YL)BUTYL]PYRIDINE; 5 [4 [5 (4 FLUOROPHENYL) 3 PYRIDINYLMETHYL] 1 PIPERAZINYL] 1,4 BENZODIOXAN; 7 CHLORO 2 [[1 (2 METHOXYPHENYL) 4 PIPERIDYL]METHYLAMINOMETHYL] 1,4 BENZODIOXAN; ABAPERIDONE; ABS 201; ACP 104; ALX 5407; APLINDORE FUMARATE; ARIPIPRAZOLE; ASENAPINE; AVE 5997EF; BEXAROTENE; BGC 20 761; BIFEPRUNOX; BL 1020; BLONANSERIN; BP 4.879A; BSF 78438; CDD 0304; CLOZAPINE; CRD 101; DEXTRO SERINE; E 6276; EMONAPRIDE; EPLIVANSERIN; FARAMPATOR; GMC 283; HMR 2934; IDAZOXAN; ILOPERIDONE; LE 300; LURASIDONE; MEM 3454; MS 377; N (2 CHLORO 6 METHYLERGOLIN 8ALPHA YL)PIVALAMIDE; N [4 [2 (6 CYANO 1,2,3,4 TETRAHYDRO 2 ISOQUINOLINYL)ETHYL]CYCLOHEXYL] 4 QUINOLINECARBOXAMIDE; NEUROLEPTIC AGENT; OCAPERIDONE; OLANZAPINE; ORG 23366; ORG 24461; OSANETANT; P 1704; PALIPERIDONE; PD 157533; PD 157695; PD 165167; PD 172760; PNU 177864; PNU 282987; QUETIAPINE; R 1678; RISPERIDONE; RMG 40083; SDZ MAR 327; SERTINDOLE; SPI 376; SSR 103800; SSR 125047; SSR 181507; SSR 504734; TC 1698; TC 5280; TGOF 02N; U 99363E; UNCLASSIFIED DRUG; UNINDEXED DRUG; Y 931; YKP 1358; ZD 3638; ZIPRASIDONE;

CLINICAL TRIAL; COGNITION; DRUG TARGETING; GENETIC ANALYSIS; HUMAN; PIPELINE; PRIORITY JOURNAL; REVIEW; SCHIZOPHRENIA; SCIENTIST; TREATMENT INDICATION;

ANIMALS; ANTIPSYCHOTIC AGENTS; DRUG DESIGN; HUMANS; MODELS, BIOLOGICAL; SCHIZOPHRENIA;

EID: 34748864737     PISSN: 13594184     EISSN: 14765578     Source Type: Journal    
DOI: 10.1038/sj.mp.4002062     Document Type: Review

References (168)

1. Labhardt F. Largactil therapy in schizophrenia and other psychotic conditions. Schweiz Arch Neurol Psychiatr 1954; 73: 309-338.
2. 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.
3. Kane J, Honigfeld G, Singer J, Meltzer HY. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-796.
4. 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.
5. Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159: 1018-1028.
6. Lindstrom LH. The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand 1988; 77: 524-529.
7. 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.
8. Fleischhacker WW. New drugs for the treatment of schizophrenic patients. Acta Psychiatr Scand Suppl 1995; 388: 24-30.
9. Swartz MS, Perkins DO, Stroup TS, Davis SM, Capuano G, Rosenheck RA et al. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry 2007; 164: 428-436.
10. 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.
11. Keefe RS, Silva SG, Perkins DO, Lieberman JA. The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull 1999; 25: 201-222.
12. Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res 1999; 35: 51-68.
13. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686-1696.
14. Newcomer JW, Haupt DW, Fucetola R, Melson AK, Schweiger JA, Cooper BP et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry 2002; 59: 337-345.
15. Kozikowski AP, Roth B, Tropsha A. Why academic drug discovery makes sense. Science 2006; 313: 1235-1236.
16. Roth BL. Contributions of molecular biology to antipsychotic drug discovery: promises fulfilled or unfulfilled? Dialogues Clin Neurosci 2006; 8: 303-309.
17. Kane J, Canas F, Kramer M, Ford L, Gassmann-Mayer C, Lim P et al. Treatment of schizophrenia with paliperidone extendedrelease tablets: a 6-week placebo-controlled trial. Schizophr Res 2007; 90: 147-161.
18. Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol 2006; 28: 185-206.
19. O'Connor KA, Roth BL. Finding new tricks for old drugs: an efficient route for public-sector drug discovery. Nat Rev Drug Discov 2005; 4: 1005-1014.
20. Hyman SE, Fenton WS. Medicine. What are the right targets for psychopharmacology? Science 2003; 299: 350-351.
21. Agid Y, Buzsaki G, Diamond DM, Frackowiak R, Giedd J, Girault JA et al. How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov 2007; 6: 189-201.
22. Norman RM, Malla AK, McLean T, Voruganti LP, Cortese L, McIntosh E et al. The relationship of symptoms and level of functioning in schizophrenia to general wellbeing and the Quality of Life Scale. Acta Psychiatr Scand 2000; 102: 303-309.
23. Katschnig H. Schizophrenia and quality of life. Acta Psychiatr Scand Suppl 2000; 102: 33-37.
24. Kirkpatrick B, Fenton WS, Carpenter Jr WT, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006; 32: 214-219.
25. Keefe RS, Bilder RM, Harvey PD, Davis SM, Palmer BW, Gold JM et al. Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology 2006; 31: 2033-2046.
26. Bowie CR, Harvey PD. Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatr Clin North Am 2005; 28: 613-633, 626.
27. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153: 321-330.
28. Purdon SE, Jones BD, Stip E, Labelle A, Addington D, David SR et al. Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Arch Gen Psychiatry 2000; 57: 249-258.
29. Harvey PD, Keefe RS. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 2001; 158: 176-184.
30. Marder SR, Fenton W. Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res 2004; 72: 5-9.
31. 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.
32. Davies MA, Sheffler DJ, Roth BL. Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology. CNS Drug Rev 2004; 10: 317-336.
33. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481-483.
34. Seeman P, Chau-Wong M, Tedesco J, Wong K. Dopamine receptors in human and calf brains, using [3H]apomorphine and an antipsychotic drug. Proc Natl Acad Sci USA 1976; 73: 4354-4358.
35. Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C et al. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry 1993; 33: 227-235.
36. 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.
37. Meltzer HY. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 1989; 99(Suppl): S18-S27.
38. 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.
39. Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF et al. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 2002; 27: 248-259.
40. 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.
41. Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE et al. Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J Pharmacol Exp Ther 2005; 315: 1278-1287.
42. 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.
43. Weiner DM, Meltzer HY, Veinbergs I, Donohue EM, Spalding TA, Smith TT et al. The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology (Berl) 2004; 177: 207-216.
44. Sams-Dodd F. Target-based drug discovery: is something wrong? Drug Discov Today 2005; 10: 139-147.
45. Gray JA, Roth BL. Developing selectively nonselective drugs for treating CNS disorders. Drug Discov Today 2006; 3: 413-419.
46. 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.
47. Castner SA, Williams GV, Goldman-Rakic PS. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 2000; 287: 2020-2022.
48. 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.
49. 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.
50. 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.
51. 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.
52. Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995; 376: 572-575.
53. Castner SA, Goldman-Rakic PS. Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation. J Neurosci 2004; 24: 1446-1450.
54. Joyce JN, Millan MJ. Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today 2005; 10: 917-925.
55. Gurevich EV, Bordelon Y, Shapiro RM, Arnold SE, Gur RE, Joyce JN. Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch Gen Psychiatry 1997; 54: 225-232.
56. Witkin J, Gasior M, Acri J, Beekman M, Thurkauf A, Yuan J et al. Atypical antipsychotic-like effects of the dopamine D3 receptor agonist, (+)-PD 128,907. Eur J Pharmacol 1998; 347: R1-R3.
57. Vonderfecht SL, Stone ML, Eversole RR, Yancey MF, Schuette MR, Duncan BA et al. Myopathy related to administration of a cationic amphiphilic drug and the use of multidose drug distribution analysis to predict its occurrence. Toxicol Pathol 2004; 32: 318-325.
58. Hackling AE, Stark H. Dopamine D3 receptor ligands with antagonist properties. Chembiochem 2002; 3: 946-961.
59. Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY et al. Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 2000; 294: 1154-1165.
60. Laszy J, Laszlovszky I, Gyertyan I. Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl) 2005; 179: 567-575.
61. Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 1991; 350: 610-614.
62. Tarazi FI, Zhang K, Baldessarini RJ. Dopamine D4 receptors: beyond schizophrenia. J Recept Signal Transduct Res 2004; 24: 131-147.
63. 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.
64. 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.
65. 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.
66. Kotecha SA, Oak JN, Jackson MF, Perez Y, Orser BA, Van Tol HH et al. A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron 2002; 35: 1111-1122.
67. Rubinstein M, Cepeda C, Hurst RS, Flores-Hernandez J, Ariano MA, Falzone TL et al. Dopamine D4 receptor-deficient mice display cortical hyperexcitability. J Neurosci 2001; 21: 3756-3763.
68. Jentsch JD, Taylor JR, Redmond Jr DE, Elsworth JD, Youngren KD, Roth RH. Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys. Psychopharmacology (Berl) 1999; 142: 78-84.
69. Tunbridge EM, Harrison PJ, Weinberger DR. Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 2006; 60: 141-151.
70. Kopin IJ. Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev 1985; 37: 333-364.
71. Karoum F, Chrapusta SJ, Egan MF. 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem 1994; 63: 972-979.
72. Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 1998; 95: 9991-9996.
73. 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.
74. Gasparini M, Fabrizio E, Bonifati V, Meco G. Cognitive improvement during Tolcapone treatment in Parkinson's disease. J Neural Transm 1997; 104: 887-894.
75. Watkins P. COMT inhibitors and liver toxicity. Neurology 2000; 55: S51-S52; discussion S53-S56.
76. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004; 75: 807-821.
77. Woodward ND, Jayathilake K, Meltzer HY. COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr Res 2007; 90: 86-96.
78. Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 1989; 251: 238-246.
79. Altar CA, Wasley AM, Neale RF, Stone GA. Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain. Brain Res Bull 1986; 16: 517-525.
80. de Paulis T. M-100907 (Aventis). Curr Opin Investig Drugs 2001; 2: 123-132.
81. 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.
82. Nocjar C, Roth BL, Pehek EA. Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. Neuroscience 2002; 111: 163-176.
83. Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 2007; 113: 296-320.
84. Meltzer HY. Pre-clinical pharmacology of atypical antipsychotic drugs: a selective review. Br J Psychiatry Suppl 1996; 168: 23-31.
85. Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol 2002; 441: 137-140.
86. Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O'Laughlin IA, Meltzer HY. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 2001; 76: 1521-1531.
87. Millan MJ, Dekeyne A, Gobert A. Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology 1998; 37: 953-955.
88. 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.
89. De Luca V, Mueller DJ, de Bartolomeis A, Kennedy JL. Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol 2007 [E-pub ahead of print].
90. Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P et al. H1-histamine receptor affinity predicts shortterm weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 2003; 28: 519-526.
91. Sargent PA, Sharpley AL, Williams C, Goodall EM, Cowen PJ. 5-HT2C receptor activation decreases appetite and body weight in obese subjects. Psychopharmacology (Berl) 1997; 133: 309-312.
92. Roth BL. Drugs and valvular heart disease. N Engl J Med 2007; 356: 6-9.
93. 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.
94. Reynolds GP, Mason SL, Meldrum A, De Keczer S, Parnes H, Eglen RM et al. 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases. Br J Pharmacol 1995; 114: 993-998.
95. Cho S, Hu Y. Activation of 5-HT4 receptors inhibits secretion of beta-amyloid peptides and increases neuronal survival. Exp Neurol 2007; 203: 274-278.
96. Roth BL, Craigo SC, Choudhary MS, Uluer A, Monsma Jr FJ, Shen Y et al. Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther 1994; 268: 1403-1410.
97. Mitchell ES, Neumaier JF. 5-HT6 receptors: a novel target for cognitive enhancement. Pharmacol Ther 2005; 108: 320-333.
98. Bourson A, Boess FG, Bos M, Sleight AJ. Involvement of 5-HT6 receptors in nigro-striatal function in rodents. Br J Pharmacol 1998; 125: 1562-1566.
99. Rogers DC, Robinson CA, Quilter AJ, Hunter C, Routledge C, Hagan JJ. Cognitive enhancement effects of the selective 5-HT6 antagonist SB-271046. Br J Pharmacol Suppl 1999; 127: 22.
100. Coull JT. Pharmacological manipulations of the alpha 2-noradrenergic system. Effects on cognition. Drugs Aging 1994; 5: 116-126.
101. 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.
102. 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.
103. 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.
104. 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.
105. 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.
106. Sarter M, Bruno JP. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev 1997; 23: 28-46.
107. Friedman JI. Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists. Psychopharmacology (Berl) 2004; 174: 45-53.
108. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006 (Issue 1. Art. No.: CD005593. doi:10.1002/14651858. CD005593).
109. Friedman JI, Temporini H, Davis KL. Pharmacologic strategies for augmenting cognitive performance in schizophrenia. Biol Psychiatry 1999; 45: 1-16.
110. Ferreri F, Agbokou C, Gauthier S. Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy. J Psychiatry Neurosci 2006; 31: 369-376.
111. Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B. Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry 2007; 12: 232-246.
112. Bymaster FP, Felder C, Ahmed S, McKinzie D. Muscarinic receptors as a target for drugs treating schizophrenia. Curr Drug Targets CNS Neurol Disord 2002; 1: 163-181.
113. Sur C, Mallorga PJ, Wittmann M, Jacobson MA, Pascarella D, Williams JB et al. N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci USA 2003; 100: 13674-13679.
114. Watson J, Brough S, Coldwell MC, Gager T, Ho M, Hunter AJ et al. Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Br J Pharmacol 1998; 125: 1413-1420.
115. Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS Drug Rev 2003; 9: 159-186.
116. Lazareno S, Popham A, Birdsall NJ. Progress toward a high-affinity allosteric enhancer at muscarinic M1 receptors. J Mol Neurosci 2003; 20: 363-367.
117. Kumari V, Postma P. Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev 2005; 29: 1021-1034.
118. Simosky JK, Stevens KE, Freedman R. Nicotinic agonists and psychosis. Curr Drug Targets CNS Neurol Disord 2002; 1: 149-162.
119. Simosky JK, Stevens KE, Kem WR, Freedman R. Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice. Biol Psychiatry 2001; 50: 493-500.
120. Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 2006; 63: 630-638.
121. Levin ED, McClernon FJ, Rezvani AH. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 2006; 184: 523-539.
122. Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004; 9: 979, 984-997.
123. Javitt DC. Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry 2006; 19: 151-157.
124. Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 2000; 157: 826-828.
125. Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 1999; 156: 1822-1825.
126. Goff DC, Tsai G, Manoach DS, Flood J, Darby DG, Coyle JT. D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry 1996; 153: 1628-1630.
127. Brown A, Carlyle I, Clark J, Hamilton W, Gibson S, McGarry G et al. Discovery and SAR of org 24598-a selective glycine uptake inhibitor. Bioorg Med Chem Lett 2001; 11: 2007-2009.
128. Aubrey KR, Vandenberg RJ. N[3-(4′-fluorophenyl)-3-(4′- phenylphenoxy)propyl]sarcosine (NFPS) is a selective persistent inhibitor of glycine transport. Br J Pharmacol 2001; 134: 1429-1436.
129. 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.
130. 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.
131. Moghaddam B. Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl) 2004; 174: 39-44.
132. Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC et al. Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice. J Pharmacol Exp Ther 2006; 318: 173-185.
133. Govek SP, Bonnefous C, Hutchinson JH, Kamenecka T, McQuiston J, Pracitto R et al. Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 (mGluR2): efficacy in an animal model for schizophrenia. Bioorg Med Chem Lett 2005; 15: 4068-4072.
134. Marino MJ, Conn PJ. Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol 2006; 6: 98-102.
135. Black MD. Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data. Psychopharmacology (Berl) 2005; 179: 154-163.
136. Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC et al. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 2001; 21: 484-487.
137. 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.
138. Vanover KE. Effects of AMPA receptor antagonists on dopaminemediated behaviors in mice. Psychopharmacology (Berl) 1998; 136: 123-131.
139. Mathe JM, Fagerquist MV, Svensson TH. Antipsychotic-like effect of the AMPA receptor antagonist LY326325 as indicated by suppression of conditioned avoidance response in the rat. J Neural Transm 1999; 106: 1003-1009.
140. Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17: 2921-2927.
141. Henquet C, Murray R, Linszen D, van Os J. The environment and schizophrenia: the role of cannabis use. Schizophr Bull 2005; 31: 608-612.
142. Vinod KY, Hungund BL. Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders. Expert Opin Ther Targets 2006; 10: 203-210.
143. Poncelet M, Barnouin MC, Breliere JC, Le Fur G, Soubrie P. Blockade of cannabinoid (CB1) receptors by 141716 selectively antagonizes drug-induced reinstatement of exploratory behaviour in gerbils. Psychopharmacology (Berl) 1999; 144: 144-150.
144. Alonso R, Voutsinos B, Fournier M, Labie C, Steinberg R, Souilhac J et al. Blockade of cannabinoid receptors by SR141716 selectively increases Fos expression in rat mesocorticolimbic areas via reduced dopamine D2 function. Neuroscience 1999; 91: 607-620.
145. Husum H, Vasquez PA, Mathe AA. Changed concentrations of tachykinins and neuropeptide Y in brain of a rat model of depression: lithium treatment normalizes tachykinins. Neuropsychopharmacology 2001; 24: 183-191.
146. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998; 281: 1640-1645.
147. Tooney PA, Crawter VC, Chahl LA. Increased tachykinin NK(1) receptor immunoreactivity in the prefrontal cortex in schizophrenia. Biol Psychiatry 2001; 49: 523-527.
148. Keller M, Montgomery S, Ball W, Morrison M, Snavely D, Liu G et al. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 2006; 59: 216-223.
149. Meltzer H, Prus A. NK3 receptor antagonists for the treatment of schizophrenia. Drug Discov Today 2006; 3: 555-560.
150. Caceda R, Kinkead B, Nemeroff CB. Neurotensin: role in psychiatric and neurological diseases. Peptides 2006; 27: 2385-2404.
151. Feifel D, Reza TL, Wustrow DJ, Davis MD. Novel antipsychotic-like effects on prepulse inhibition of startle produced by a neurotensin agonist. J Pharmacol Exp Ther 1999; 288: 710-713.
152. Riedel M, Strassnig M, Schwarz MJ, Muller N. COX-2 inhibitors as adjunctive therapy in schizophrenia: rationale for use and evidence to date. CNS Drugs 2005; 19: 805-819.
153. Muller N, Ulmschneider M, Scheppach C, Schwarz MJ, Ackenheil M, Moller HJ et al. COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations and clinical effects of celecoxib add-on therapy. Eur Arch Psychiatry Clin Neurosci 2004; 254: 14-22.
154. Menniti FS, Chappie TA, Humphrey JM, Schmidt CJ. Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. Curr Opin Investig Drugs 2007; 8: 54-59.
155. Sheitman BB, Knable MB, Jarskog LF, Chakos M, Boyce LH, Early J et al. Secretin for refractory schizophrenia. Schizophr Res 2004; 66: 177-181.
156. Maurice T, Phan VL, Urani A, Kamei H, Noda Y, Nabeshima T. Neuroactive neurosteroids as endogenous effectors for the sigma1 (sigma1) receptor: pharmacological evidence and therapeutic opportunities. Jpn J Pharmacol 1999; 81: 125-155.
157. Noda Y, Kamei H, Kamei Y, Nagai T, Nishida M, Nabeshima T. Neurosteroids ameliorate conditioned fear stress: an association with sigma receptors. Neuropsychopharmacology 2000; 23: 276-284.
158. 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.
159. Spedding M, Jay T, Costa e Silva J, Perret L. A pathophysiological paradigm for the therapy of psychiatric disease. Nat Rev Drug Discov 2005; 4: 467-476.
160. Kelsoe JR. Genomics and the Human Genome Project: implications for psychiatry. Int Rev Psychiatry 2004; 16: 294-300.
161. Carlsson M, Carlsson A. Schizophrenia: a subcortical neurotransmitter imbalance syndrome? Schizophr Bull 1990; 16: 425-432.
162. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40-68; image 45.
163. Sawa A, Snyder SH. Schizophrenia: neural mechanisms for novel therapies. Mol Med 2003; 9: 3-9.
164. Insel TR, Scolnick EM. Cure therapeutics and strategic prevention: raising the bar for mental health research. Mol Psychiatry 2006; 11: 11-17.
165. Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron 2006; 52: 139-153.
166. Hyman SE, Nestler EJ. Initiation and adaptation: a paradigm for understanding psychotropic drug action. Am J Psychiatry 1996; 153: 151-162.
167. Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry 2005; 10: 434-449.
168. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. From the cover: antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci USA 2007; 104: 3456-3459.