A multi-target drug treatment in schizophrenia and schizoaffective disorder using adjunctive agents with non-D 2 mechanisms of action

Polypharmacy in Psychiatry Practice Volume I: Multiple Medication Use Strategies

Volumn , Issue , 2013, Pages 157-210

  Ritsner, Michael S ^a  

^a TECHNION ISRAEL INSTITUTE OF TECHNOLOGY   (Israel)

Author keywords

Antidepressants; Antiepileptic drugs; Augmentation; Benzodiazepines; Hormones; Lithium; Mood stabilizers; Schizoaffective disorder; Schizophrenia; Supplements

Indexed keywords

EID: 84896700589     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-94-007-5805-6_8     Document Type: Chapter

References (310)

1. Moncrieff J (2009) A critique of the dopamine hypothesis of schizophrenia and psychosis. Harv Rev Psychiatry 17:214-225
2. Miyamoto S, Miyake N, Jarskog LF, et al (2012) Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry (15 May 2012) doi:10.1038/mp.2012.47
3. Kim DH, Maneen MJ, Stahl SM (2009) Building a better antipsychotic: receptor targets for the treatment of multiple symptom dimensions of schizophrenia. Neurotherapeutics6(1):78-85
4. Stahl SM (2009) Multifunctional drugs: a novel concept for psychopharmacology. CNS Spectr 14:2
5. Reid JL (2007) Fall and rise of polypharmacy? Hypertension 49:266-267. doi:10.1161/01.HYP.0000254485.43156.02
6. Volpe M, Chin D, Paneni F (2010) The challenge of polypharmacy in cardiovascular medicine. Fundam Clin Pharmacol 24(1):9-17
7. Wald NJ, Law MR (2003) A strategy to reduce cardiovascular disease by more than 80%. BMJ 326:1419-1424
8. Myers MG, Asmar R, Leenen FH, Safar M (2000) Fixed low-dose combination therapy in hypertension-a dose response study of perindopril and indapamide. J Hypertens18:317-325
9. Law MR, Wald NJ, Morris JL, Jordan RE (2003) Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 326:1427-1435
10. Mahmud A, Feely J (2007) Low-dose quadruple antihypertensive combination: more efficacious than individual agents-a preliminary report. Hypertension 49:272-275
11. Goodwin G, Fleischhacker W, Arango C et al (2009) Advantages and disadvantages of combination treatment with antipsychotics ECNP Consensus Meeting, March 2008, Nice. Eur Neuropsychopharmacol 19(7):520-532
12. Gardos G (2005) Antipsychotic polypharmacy or monotherapy? Neuropsychopharmacol Hung 7(2):72-77
13. Bartzokis G, Altshuler L (2005) Reduced intracortical myelination in schizophrenia. Am J Psychiatry 162(6):1229-1230
14. Bartzokis G (2011) Neuroglialpharmacology: white matter pathophysiologies and psychiatric treatments. Front Biosci 17:2695-2733
15. Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327-347
16. Beaulieu JM (2012) A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health. J Psychiatry Neurosci 37(1):7-16
17. Bartzokis G (2012) Neuroglialpharmacology: myelination as a shared mechanism of action of psychotropic treatments. Neuropharmacology 62(7):2136-2152
18. Pickar D, Vinik J, Bartko JJ (2008) Pharmacotherapy of schizophrenic patients: preponderance of off-label drug use. PLoS One 3(9):e3150
19. Nielsen J, le Quach P, Emborg C, Foldager L, Correll CU (2010) 10-year trends in the treatment and outcomes of patients with first-episode schizophrenia. Acta Psychiatr Scand 122(5):356-366
20. Yoshio T, Inada T, Uno J et al (2012) Prescription profiles for pharmacological treatment of Japanese inpatients with schizophrenia: comparison between 2007 and 2009. Hum Psychopharmacol 27(1):70-75
21. Stahl SM (2002) Essential psychopharmacology of antipsychotics and mood stabilizers. Cambridge University Press, New York
22. Stahl SM (2008) Psychosis and Schizophrenia. In: Grandy MM (ed) Stahl’s essential psychopharmacology, 3rd edn. Cambridge University Press, New Delhi, p 293
23. Rosenberg JM, Salzman C (2007) Update: new uses for lithium and anticonvulsants. CNS Spectr 12(11):831-841
24. Zink M, Englisch S, Meyer-Lindenberg A (2010) Polypharmacy in schizophrenia. Curr Opin Psychiatry 23(2):103-111
25. Ritsner MS (ed) (2010) Brain protection in schizophrenia, mood and cognitive disorders. Springer, New York, p 663
26. Ritsner MS (ed) (2011) Handbook of schizophrenia spectrum disorders. Vol. I, II, III. Springer Science+Business Media B.V.
27. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160(4):636-645
28. Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 35(3):528-548
29. Ritsner MS (2010) Is a neuroprotective therapy suitable for schizophrenia patients? In: Ritsner MS (ed) Brain protection in schizophrenia, mood and cognitive disorders. Springer Science+Business Media B.V., pp 343-395
30. Silver H, Barash I, Aharon N et al (2000) Fluvoxamine augmentation of antipsychotics improves negative symptoms in psychotic chronic schizophrenic patients: a placebo-controlled study. Int Clin Psychopharmacol 15:257-261
31. Sepehry AA, Potvin S, Elie R et al (2007) Selective serotonin reuptake inhibitor (SSRI) addon therapy for the negative symptoms of schizophrenia: a meta-analysis. J Clin Psychiatry 68:604-610
32. Singh SP, Singh V, Kar N et al (2010) Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry 197:174-179
33. Tiihonen J, Wahlbeck K, Kiviniemi V (2009) The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res 109:10-14
34. Tsai GE, Lin PY (2010) Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des16(5):522-537
35. Singh SP, Singh V (2011) Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs 25(10):859-885. doi:10.2165/11586650-000000000-00000
36. Ritsner MS (2011) The clinical and therapeutic potentials of dehydroepiandrosterone and pregnenolone in schizophrenia. Neuroscience 191:91-100
37. Sommer IE, de Witte L, Begemann M, Kahn RS (2012) Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? a meta-analysis. J Clin Psychiatry73(4):414-419
38. Johns C, Thompson J (1995) Adjunctive treatments in schizophrenia: pharmacotherapies and electroconvulsive therapy. Schizophr Bull 21(4):607-619
39. Fusar-Poli P, Berger G (2012) Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. J Clin Psychopharmacol32(2):179-185
40. Ritsner MS (ed) (2009) The handbook of neuropsychiatric biomarkers, endophenotypes, and genes. Vol I-IV. Springer, New York
41. Herz MI, Liberman RP, Lieberman JA et al (1997) Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry 154(suppl 4):1-63
42. National Institute for Clinical Excellence (NICE) (2003) The treatment and management of schizophrenia in primary and secondary care (Core Interventions)
43. Paton C, Barnes TR, Cavanagh MR et al (2008) High-dose and combination antipsychotic prescribing in acute adult wards in the UK: The challenges posed by p.r.n. prescribing. Br J Psychiatry 192:435-439. doi:10.1192/bjp.bp. 107.042895
44. Freedman R (2003) Drug therapy: schizophrenia. N Engl J Med 349:1738-1749
45. Deakin JFW, Slater P, Simpson MD, Gilchrist AC, Skan WJ, Royston AJ et al (1989) Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia. J Neurochem 52:1781-1786
46. Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349-1352
47. Yamamoto K, Hornykiewicz O (2004) Proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28(5):913-922
48. Remington G (2008) Alterations of dopamine and serotonin transmission in schizophrenia. Prog Brain Res 172:117-140
49. Lieberman JA (1999) Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry 46:729-739
50. Harrison PJ (2000) Postmortem studies in schizophrenia. Dialogues Clin Neurosci 2(4):349-357
51. Shenton ME, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizophrenia. Schizophr Res 49(1-2):1-52
52. Hunsberger J, Austin DR, Henter ID, Chen G (2009) Dialogues. Clin Neurosci 11(3):333-348
53. Cascade EF, Kalali AH, Buckley PF (2008) Current management of schizophrenia: antipsychotic monotherapy versus combination therapy. Psychiatry (Edgmont) 5(5):28-30
54. Dussias P, Kalali AH, Citrome L (2010) Polypharmacy of schizophrenia. Psychiatry (Edgmont) 7(8):17-19
55. Langle G, Steinert T, Weiser P, et al. (2012) Effects of polypharmacy on outcome in patients with schizophrenia in routine psychiatric treatment. Acta Psychiatr Scand 2012 Feb 9. doi:10.1111/j.1600-0447.2012.01835.x. [Epub ahead of print] PubMed PMID: 22321029
56. Shinfuku M, Uchida H, Tsutsumi C, et al. (2011) How psychotropic polypharmacy in schizophrenia begins: a longitudinal perspective. Pharmacopsychiatry. 2011 Dec 15. [Epub ahead of print] PubMed PMID: 22174025
57. Himelhoch S, Slade E, Kreyenbuhl J et al (2012) Antidepressant prescribing patterns among VA patients with schizophrenia. Schizophr Res 136:32-35
58. Haw C, Stubbs J (2005) A survey of the off-label use of mood stabilizers in a large psychiatric hospital. J Psychopharmacol 19(4):402-407
59. Sim K, Yong KH, Chan YH et al (2011) Adjunctive mood stabilizer treatment for hospitalized schizophrenia patients: Asia psychotropic prescription study (2001-2008). Int J Neuropsychopharmacol 14:1157-1164. doi:1157
60. Xiang YT, Dickerson F, Kreyenbuhl J, et al (2012) Adjunctive mood stabilizer and benzodiazepine use in older Asian patients with schizophrenia, 2001-2009. Pharmacopsychiatry 45(6):217-222. doi:10.1055/s-0031-1301292
61. Haw C, Stubbs J (2007) Benzodiazepines-a necessary evil? A survey of prescribing at a specialist UK psychiatric hospital. J Psychopharmacol 21(6):645-649
62. Chakos M, Patel JK, Rosenheck R et al (2011) Concomitant psychotropic medication use during treatment of schizophrenia patients: longitudinal results from the CATIE study. Clin Schizophr Relat Psychoses 5(3):124-134
63. Mallinger JB, Lamberti SJ (2007) Racial differences in the use of adjunctive psychotropic medications for patients with schizophrenia. J Ment Health Policy Econ 10(1):15-22
64. Wood K, Harris MJ, Morreale A, Rizos AL (1988) Drug induced psychosis and depression in the elderly. Psychiatr Clin North Am 11:167-193
65. Van Putten T, May PRA (1978) “Akinetic depression” in schizophrenia. Arch Gen Psychiatry 35:1101-1107
66. Bandelow B, Muller P, Gaebel W et al (1990) Depressive syndromes in schizophrenic patients after discharge from the hospital. Eur Arch Psychiatry Clin Neurosci 240:113-120
67. Paulsen JS, Romero R, Chan A et al (1996) Impairment of the semantic network in schizophrenia. Psychiatry Res 63:109-121
68. Zisook S, McAdams LA, Kuck J et al (1999) Depressive symptoms in schizophrenia. Am J Psychiatry 156:1736-1743
69. Zisook S, Nyer M, Kasckow J et al (2006) Depressive symptom patterns in patients with chronic schizophrenia and subsyndromal depression. Schizophr Res 86(1-3):226-233
70. Lako IM, Taxis K, Bruggeman R, et al. (2012) The course of depressive symptoms and prescribing patterns of antidepressants in schizophrenia in a one-year follow-up study. Eur Psychiatry 27(4):240-244
71. Lenox RH, Frazer A (2002) Mechanism of action of antidepressants and mood stablizers. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds) Neuropsychopharmacology: The fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, pp 1139-1163
72. Chertkow Y, Weinreb O, Youdim MB, Silver H (2009) Molecular mechanisms underlying synergistic effects of SSRI-antipsychotic augmentation in treatment of negative symptoms in schizophrenia. J Neural Transm 116(11):1529-1541
73. Silver H, Susser E, Danovich L et al (2011) SSRI augmentation of antipsychotic alters expression of GABA(A) receptor and related genes in PMC of schizophrenia patients. Int J Neuropsychopharmacol 14(5):573-584
74. Mulholland C, Lynch G, King DJ, Cooper SJ (2003) A double-blind, placebo-controlled trial of sertraline for depressive symptoms in patients with stable, chronic schizophrenia. J Psychopharmacol 17:107-112
75. Iancu I, Tschernihovsky E, Bodner E et al (2010) Escitalopram in the treatment of negative symptoms in patients with chronic schizophrenia: a randomized double-blind placebo-controlled trial. Psychiatry Res 179:19-23
76. Cho SJ, Yook K, Kim B et al (2011) Mirtazapine augmentation enhances cognitive and negative symptoms in schizophrenia patients treated with risperidone: a randomized controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 35:208-211
77. Barnes TRE (2011) Schizophrenia Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 25:567-620
78. Dawes SE, Palmer BW, Meeks T, Golshan S, Kasckow J, Mohamed S, Zisook S (2012) Does antidepressant treatment improve cognition in older people with schizophrenia or schizoaffective disorder and comorbid subsyndromal depression? Neuropsychobiology65(3):168-172
79. Silver H, Nassar A (1992) Fluvoxamine improves negative symptoms in treated chronic schizophrenia. An add on double blind placebo controlled study. Biol Psychiatry 31:698-704
80. Silver H, Aharon N, Kaplan A (2003) Add-on fluvoxamine improves primary negative symptoms: evidence for specificity from response analysis of individual symptoms. Schizophr Bull29(3):541-546
81. Niitsu T, Shirayama Y, Fujisaki M, Hashimoto K, Iyo M (2010) Fluvoxamine improved cognitive impairments in a patient with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 34(7):1345-1346
82. Yasui-Furukori N, Kondo T, Mihara K et al (2004) Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia. Psychopharmacology (Berl) 171(2):223-227
83. D’Arrigo C, Migliardi G, Santoro V et al (2005) Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia. Pharmacol Res 52(6):497-501
84. Silver H (2004) Selective serotonin re-uptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia. Expert Opin Pharmacother 5(10):2053-2058
85. Salokangas RK, Saarijarvi S, Taiminen T et al (1996) Citalopram as an adjuvant in chronic schizophrenia: a double-blind placebo-controlled study. Acta Psychiatr Scand 94(3):175-180
86. Kasckow JW, Mohamed S, Thallasinos A et al (2001) Citalopram augmentation of antipsychotic treatment in older schizophrenia patients. Int J Geriatr Psychiatry 16(12):1163-1167
87. Friedman JI, Ocampo R, Elbaz Z et al (2005) The effect of citalopram adjunctive treatment added to atypical antipsychotic medications for cognitive performance in patients with schizophrenia. J Clin Psychopharmacol 25(3):237-242
88. Zisook S, Kasckow JW, Lanouette NM et al (2010) Augmentation with citalopram for suicidal ideation in middle-aged and older outpatients with schizophrenia and schizoaffective disorder who have subthreshold depressive symptoms: a randomized controlled trial. J Clin Psychiatry 71(7):915-922
89. Vartiainen H, Tiihonen J, Putkonen A et al (1995) Citalopram, a selective serotonin reuptake inhibitor, in the treatment of aggression in schizophrenia. Acta Psychiatr Scand 91(5): 348-351
90. Delle Chiaie R, Salviati M, Fiorentini S, Biondi M (2007) Add-on mirtazapine enhances effects on cognition in schizophrenic patients under stabilized treatment with clozapine. Exp Clin Psychopharmacol 15(6):563-568
91. Joffe G, Terevnikov V, Joffe M et al (2009) Add-on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: a double-blind, randomized, placebo-controlled trial. Schizophr Res 108(1-3):245-251
92. Berk M, Gama CS, Sundram S et al (2009) Mirtazapine add-on therapy in the treatment of schizophrenia with atypical antipsychotics: a double-blind, randomised, placebo-controlled clinical trial. Hum Psychopharmacol 24:233-238
93. Abbasi SH, Behpournia H, Ghoreshi A et al (2010) The effect of mirtazapine add on therapy to risperidone in the treatment of schizophrenia: a double-blind randomized placebo-controlled trial. Schizophr Res 116:101-106
94. Terevnikov V, Stenberg JH, Joffe M et al (2010) More evidence on additive antipsychotic effect of adjunctive mirtazapine in schizophrenia: an extension phase of a randomized controlled trial. Hum Psychopharmacol 25(6):431-438
95. Terevnikov V, Stenberg JH, Tiihonen J, et al. (2011) Add-on mirtazapine improves depressive symptoms in schizophrenia: a double-blind randomized placebo-controlled study with an open-label extension phase. Hum Psychopharmacol 26(3):188-193
96. Stenberg JH, Terevnikov V, Joffe M et al (2010) Effects of add-on mirtazapine on neurocognition in schizophrenia: a double-blind, randomized, placebo-controlled study. Int J Neuropsychopharmacol 13(4):433-441
97. Stenberg JH, Terevnikov V, Joffe M et al (2011) More evidence on proneurocognitive effects of add-on mirtazapine in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry35(4): 1080-1086
98. Phan SV, Kreys TJ (2011) Adjunct mirtazapine for negative symptoms of schizophrenia. Pharmacotherapy 31(10):1017-1030
99. Decina P, Mukherjee S, Bocola V et al (1994) Adjunctive trazodone in the treatment of negative symptoms of schizophrenia. Hosp Community Psychiatry 45(12):1220-1223
100. Hayashi T, Yokota N, Takahashi T et al (1997) Benefit s of trazodone and mianserin for patients with late-life chronic schizophrenia and tardive dyskinesia: an add-on, double-blind, placebo-controlled study. Int Clin Psychopharmacol 12(4):199-205
101. Englisch S, Inta D, Eer A, Zink M (2010) Bupropion for depression in schizophrenia. Clin Neuropharmacol 33(5):257-259
102. Harvey KV, Balon R (1995) Augmentation with buspirone: a review. Ann Clin Psychiatry 7(3):143-147
103. Sumiyoshi T, Park S, Jayathilake K et al (2007) Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res 95(1-3):158-168
104. Piskulic D, Olver JS, Maruff P, Norman TR (2009) Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5-HT(1A) receptor agonist. Hum Psychopharmacol 24(6):437-446
105. Ghaleiha A, Noorbala AA, Farnaghi F et al (2010) A double-blind, randomized, and placebo-controlled trial of buspirone added to risperidone in patients with chronic schizophrenia. J Clin Psychopharmacol 30(6):678-682
106. Watanabe N (2011) Fluoxetine, trazodone and ritanserin are more effective than placebo when used as add-on therapies for negative symptoms of schizophrenia. Evid Based Ment Health 14(1):21
107. Tiihonen J, Suokas JT, Suvisaari JM, Haukka J, Korhonen P (2012) Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry 69(5):476-483
108. Barnes TRE, Paton C (2011) Do antidepressants improve negative symptoms in schizophrenia? BMJ 342:d3371. doi:10.1136/bmj.d3371
109. Williams RS, Harwood AJ (2000) Lithium therapy and signal transduction. Trends Pharmacol Sci 21:61-64
110. Manji HK, Lenox RH (2000) Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry 48:518-530
111. Lenox RH, Hahn CG (2000) Overview of the mechanism of action of lithium in the brain: fifty-year update. J Clin Psychiatry 61(Suppl 9):5-15
112. Rowe MK, Chuang DM (2004) Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med 6(21):1-18
113. Quiroz JA, Machado-Vieira R, Zarate CA Jr, Manji HK (2010) Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology 62(1):50-60
114. Schulz SC, Thompson PA, Jacobs M et al (1999) Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients. J Clin Psychiatry 60(6):366-372
115. Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, Roukas DK (2005) Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review. Eur Psychiatry 20(5-6):409-415
116. Leucht S, Kissling W, McGrath J (2007) Lithium for schizophrenia. Cochrane Database Syst Rev (3):CD003834
117. Grunze HC (2010) Anticonvulsants in bipolar disorder. J Ment Health 19(2):127-141
118. Deckers CLP, Czuczwar SJ, Hekster YA et al (2000) Selection of antiepileptic drug polytherapy based on mechanism of action: The evidence reviewed. Epilepsia 41:1364-1374
119. Czuczwar SJ, Patsalos PN (2001) The new generation of GABA enhancers. CNS Drugs15:339-350
120. Anand A, Charney DS, Oren DA et al (2000) Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: Support for hyperglutamatergic effects of N-methyl-daspartate receptor antagonists. Arch Gen Psychiatry 57:270-276
121. Dursun SM, Deakin JF (2001) Augmenting antipsychotic treatment with lamotrigine or topi-ramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J Psychopharmacol 15:297-301
122. Williams HJ, Zamzow CR, Robertson H, Dursun SM (2006) Effects of clozapine plus lamotrigine on phencyclidine-induced hyperactivity. Prog Neuropsychopharmacol Biol Psychiatry 30:239-243
123. Deutsch SI, Rosse RB, Billingslea EN et al (2002) Topiramate antagonizes MK-801 in an animal model of schizophrenia. Eur J Pharmacol 449:121-125
124. Konradsson A, Marcus MM, Sitzia R et al (2007) Adjuvant treatment with the anticonvulsant drug topiramate in schizophrenia. Eur Neuropsychopharmacol 17:S33-S34
125. Deutsch SI, Schwartz BL, Rosse RB et al (2003) Adjuvant topiramate administration: a pharmacologic strategy for addressing NMDA receptor hypofunction in schizophrenia. Clin Neuropharmacol 26:199-206
126. Frau R, Orru M, Fa M et al (2007) Effects of topiramate on the prepulse inhibition of the acoustic startle in rats. Neuropsychopharmacology 32:320-331
127. Czapinski P, Blaszczyk B, Czuczwar SJ (2005) Mechanisms of action of antiepileptic drugs. Curr Top Med Chem 5:3-14
128. Johannessen Landmark C (2008) Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs 22(1):27-47
129. Simhandl C, Meszaros K (1992) The use of carbamazepine in the treatment of schizophrenic and schizoaffective psychosis: a review. J Psychiatry Neurosci 17:1-14
130. Nakamura A, Mihara K, Nagai G et al (2009) Pharmacokinetic and pharmacodynamic interactions between carbamazepine and aripiprazole in patients with schizophrenia. Ther Drug Monit 31(5):575-578
131. Leucht S, Kissling W, McGrath J, White P (2007) Carbamazepine for schizophrenia. Cochrane Database Syst Rev (3):CD001258
132. Schwarz C, Volz A, Li C, et al. (2008) Valproate for schizophrenia. Cochrane Database Syst Rev (3):CD004028
133. Casey DE, Daniel DG, Wassef AA et al (2003) Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology 28(1):182-192
134. Casey DE, Daniel DG, Tamminga C et al (2009) Divalproex ER combined with olanzapine or risperidone for treatment of acute exacerbations of schizophrenia. Neuropsychopharmacology 34:1330-1338
135. Citrome L (2004) Antipsychotic polypharmacy versus augmentation with anticonvulsants: The U.S. perspective(presentation). Paris: Collegium InternationaleNeuro-Psychopharmacologicum (CINP), June 2004 [abstract in Int J Neuropsychopharmacol 2004; 7(suppl 1):S69]
136. Tiihonen J, Hallikainen T, Ryynanen OP et al (2003) Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled trial. Biol Psychiatry 54(11):1241-1248
137. Goff DC, Keefe R, Citrome L et al (2007) Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol 27:582-589
138. Zoccali R, Muscatello MR, Bruno A et al (2007) The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res 93(1-3):109-116
139. Glick ID, Bosch J, Casey DE (2009) A double-blind randomized trial of mood stabilizer augmentation using lamotrigine and valproate for patients with schizophrenia who are stabilized and partially responsive. J Clin Psychopharmacol 29(3):267-271
140. Premkumar TS, Pick J (2006) Lamotrigine for schizophrenia. Cochrane Database Syst Rev (4):CD005962
141. Drapalski AL, Rosse RB, Peebles RR et al (2001) Topiramate improves deficit symptoms in a patient with schizophrenia when added to a stable regimen of antipsychotic medication. Clin Neuropharmacol 24:290-294
142. Hosak L, Libiger J (2002) Antiepileptic drugs in schizophrenia: a review. Eur Psychiatry 17:371-378
143. Afshar H, Roohafza H, Mousavi G et al (2009) Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol 23: 157-162
144. Arnone D (2005) Review of the use of topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 4:5
145. Hahn MK, Remington G, Bois D, Cohn T (2010) Topiramate augmentation in clozapine-treated patients with schizophrenia: clinical and metabolic effects. J Clin Psychopharmacol 30(6):706-710
146. Huband N, Ferriter M, Nathan R, Jones H (2010) Antiepileptics for aggression and associated impulsivity. Cochrane Database Syst Rev (2):CD003499
147. Lingjaerde O (1991) Benzodiazepines in the treatment of Schizophrenia: an update survey. Acta Psychiatr Scanol 84:453-459
148. Wolkowitz OM, Pickar D (1991) Benzodiazepines in the treatment of schizophrenia: a review and re-appraisal. Am J Psychiatry 148:714-726
149. Bobruff A, Gardos G, Tarsy Detal (1981) Clonazepam and phenobarbital in tardive dyskinesia. Am J Psychiatry 138:189-193
150. Nutt DJ, Malizia AL (2001) New insights into the role of the GABAA-benzodiazepine receptor in psychiatric disorder. Br J Psychiatry 179:390-396
151. Gaillard R, Ouanas A, Spadone C et al (2006) Benzodiazepines and schizophrenia, a review of the literature. Encephale 32(6 Pt 1):1003-1010
152. Jimerson DC, Van Kammen DP, Post RM (1982) Diazepam in schizophrenia: a preliminary double-blind trial. Am J Psychiatry 139:489-491
153. Nestoros JN, Nair NP, Pulman JR(1983) High doses of diazepam improve neuroleptic resistant chronic schizophrenic patients. Psychopharmacology 81:42-47
154. Wolkowitz OM, Turetsky N, Rues VI, Hargreaves W (1992) Benzodiazepine augmentation of neuroleptics in treatment-resistant schizophrenia. Psychopharmacol Bull 28:291-295
155. Carpenter WT Jr, Buchanan RW, Kirkpatrick B, Breier AF (1999) Diazepam treatment of early signs of exacerbation in schizophrenia. Am J Psychiatry 156:299-303
156. Lingjaerde O (1991) Benzodiazepines in the treatment of schizophrenia: an updated survey. Acta Psychiatr Scand 84(5):453-459
157. Tor PC, Ng TP, Yong KH et al (2011) Adjunctive benzodiazepine treatment of hospitalized schizophrenia patients in Asia from 2001 to 2008. Int J Neuropsychopharmacol 14(6):735-745
158. Volz A, Khorsand V, Gillies D, Leucht S (2007) Benzodiazepines for schizophrenia. Cochrane Database Syst Rev (1):CD006391
159. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148(10):1301-1308
160. Heresco-Levy U, Javitt DC, Ebstein R et al (2005) D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment refractory schizophrenia. Biol Psychiatry 57:577-585
161. Moghaddam B, Javitt D (2012) From revolution to evolution: The glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37(1):4-15
162. Lin CH, Lane HY, Tsai GE (2012) Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol Biochem Behav 100(4):665-677
163. Javitt DC, Zylberman I, Zukin SR et al (1994) Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 151(8):1234-1236
164. Javitt DC, Silipo G, Cienfuegos A et al (2001) Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol 4:385-391
165. Heresco-Levy U, Ermilov M, Lichtenberg P et al (2004) High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry 55:165-171
166. Tsai GE, Yang P, Chang YC, Chong MY (2006) D-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 59:230-234
167. Goff DC, Cather C, Gottlieb JD et al (2008) Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study. Schizophr Res 106(2-3): 320-327
168. Goff DC (2012) D-Cycloserine: an evolving role in learning and neuroplasticity in schizophrenia. Schizophr Bull 2012 Feb 23. [Epub ahead of print] PubMed PMID
169. Wolosker H, Dumin E, Balan L, Foltyn VN (2008) D-amino acids in the brain: D-serine in neurotransmission and neurodegeneration. FEBS J 275(14):3514-3526
170. Nishikawa T (2011) Analysis of free D-serine in mammals and its biological relevance. J Chromatogr B Analyt Technol Biomed Life Sci 879(29):3169-3183
171. Heresco-Levy U, Javitt DC, Ebstein R et al (2005) D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry57(6):577-585
172. Kantrowitz JT, Malhotra AK, Cornblatt B et al (2010) High dose D-serine in the treatment of schizophrenia. Schizophr Res 121(1-3):125-130
173. Lane HY, Lin CH, Huang YJ et al (2010) A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. Int J Neuropsychopharmacol 13(4):451-460
174. Tsai G, Lane HY, Yang P et al (2004) Glycine transporter 1 inhibitor N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 55:452-456
175. Lane HY, Huang CL, Wu PL et al (2006) Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry60(6):645-649
176. Tiihonen J, Wahlbeck K (2006) Glutamatergic drugs for schizophrenia. Cochrane Database Syst Rev (2): CD003730. doi:10.1002/14651858.CD003730.pub2
177. de Bartolomeis A, Sarappa C, Magara S, Iasevoli F (2012) Targeting glutamate system for novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia. Eur J Pharmacol 682(1-3):1-11
178. Baulieu EE (1997) Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res 52:1-32
179. Labrie F, Luu-The V, Belanger A et al (2005) Is dehydroepiandrosterone a hormone? J Endocrinol 187:169-196
180. Maninger N, Wolkowitz OM, Reus VI et al (2009) Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 30:65-91
181. George MS, Guidotti A, Rubinow D et al (1994) CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psychiatry 35:775-780
182. Semeniuk T, Jhangri GS, Le Melledo JM (2001) Neuroactive steroid levels in patients with generalized anxiety disorder. J Neuropsychiatry Clin Neurosci 13:396-398
183. Heydari B, Le Melledo JM (2002) Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med 32:929-933
184. Ritsner M, Maayan R, Gibel A, Weizman A (2007) Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol 17:358-365
185. Tourney G, Erb JL (1979) Temporal variations in androgens and stress hormones in control and schizophrenic subjects. Biol Psychiatry 14:395-404
186. Oades RD, Schepker R (1994) Serum gonadal steroid hormones in young schizophrenic patients. Psychoneuroendocrinology 19:373-385
187. Strous RD, Maayan R, Lapidus R et al (2004) Increased circulatory dehydroepiandrosterone and dehydroepiandrosterone-sulphate in first-episode schizophrenia: relationship to gender, aggression and symptomatology. Schizophr Res 71:427-434
188. Goyal RO, Sagar R, Ammini AC et al (2004) Negative correlation between negative symptoms of schizophrenia and testosterone levels. Ann N Y Acad Sci 1032:291-294
189. di Michele F, Caltagirone C, Bonaviri G, Romeo E, Spalletta G (2005) Plasma dehydroepiandrosterone levels are strongly increased in schizophrenia. J Psychiatr Res 39:267-273
190. Ritsner M, Maayan R, Gibel A et al (2004) Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur Neuropsychopharmacol 14:267-273
191. Ritsner M, Gibel A, Ram E et al (2006) Alterations in DHEA metabolism in schizophrenia: Two-month case-control study. Eur Neuropsychopharmacol 16:137-146
192. Gallagher P, Watson S, Smith MS et al (2007) Plasma cortisol-dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder. Schizophr Res 90:258-265
193. Yilmaz N, Herken H, Cicek HK et al (2007) Increased levels of nitric oxide, cortisol and adrenomedullin in patients with chronic schizophrenia. Med Princ Pract 16:137-141
194. Ritsner MS (2008) Dehydroepiandrosterone administration in treating medical and neuropsychiatric disorders: High hopes, disappointing results, and topics for future research. In: Ritsner MS, Weizman A (eds) Neuroactive steroids in brain functions, and mental health. New perspectives for research and treatment. Springer Science + Business Media B.V., pp 337-368
195. Oberbeck R, Benschop RJ, Jacobs R et al (1998) Endocrine mechanisms of stress-induced DHEA-secretion. J Endocrinol Invest 21:148-153
196. Rasmusson AM, Vasek J, Lipschitz DS et al (2004) An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacology 29:1546-1557
197. Porcu P, Rogers LS, Morrow AL, Grant KA (2006) Plasma pregnenolone levels in cynomol-gus monkeys following pharmacological challenges of the hypothalamic-pituitary-adrenal axis. Pharmacol Biochem Behav 84:618-627
198. Bradlow HL, Murphy J, Byrne JJ (1999) Immunological properties of dehydroepiandrosterone, its conjugates, and metabolites. Ann N Y Acad Sci 876:91-101
199. Majewska MD (1992) Neurosteroids: endogenous bimodal modulators of the GABAa receptor. Mechanisms of action and physiological significance. Prog Neurobiol 38:379-395
200. Debonnel G, Bergeron R, de Montigny C (1996) Potentiation by dehydroepiandrosterone of the neuronal response to N-methyl-D-aspartate in the CA3 region of the rat dorsal hippocampus: an effect mediated via sigma receptors. J Endocrinol 150(suppl):33-42
201. Rupprecht R (2003) Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 28:139-168
202. Le Melledo JM, Baker GB (2002) Neuroactive steroids and anxiety disorders. J Psychiatry Neurosci 27:161-165
203. Majewska MD, Demigoren S, Spivak CE, London ED (1990) The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor. Brain Res 526:143-146
204. Widstrom RL, Dillon JS (2004) Adrenal androgens in human physiology. Semin Reprod Med 22:289-298, Editor in Chief, Bruce R. Carr, M.D.; Guest Editors, William E. Rainey, Ph.D. and Bruce R. Carr, M.D
205. Schumacher M, Liere P, Akwa Y et al (2008) All psychotic roads lead to increased dopamine D2 High receptors: a perspective. Clin Schizophr Relat Psychoses 1:351-355
206. Obut TA, Ovsyukova MV, Cherkasova OP (2006) Prolonged decrease in stress reactivity caused by dehydroepiandrosterone sulfate. Bull Exp Biol Med 141:571-573
207. Luppi C, Fioravanti M, Bertolini B et al (2009) Growth factors decrease in subjects with mild to moderate Alzheimer’s disease (AD): potential correction with dehydroepiandrosterone-sulphate (DHEAS). Arch Gerontol Geriatr 49(Suppl 1):173-184
208. Flood J, Morley JE, Roberts E (1995) Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures. Proc Nat Acad Sci USA 92:10806-10810
209. Valenti G, Ferrucci L, Lauretani F et al (2009) Dehydroepiandrosterone sulfate and cognitive function in the elderly: The InCHIANTI Study. J Endocrinol Invest 32:766-772
210. Reddy DS, Kaur G, Kulkarni SK (1998) Sigma (o1) receptor mediated antidepressant-like effects of neurosteroids in the Porsolt forced swim test. Neuroreport 9:3069-3073
211. Belelli D, Lambert JJ (2005) Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 6:565-575
212. Baulieu EE, Robel P (1996) Dehydroepiandrosterone and dehydroepiandrosterone sulfate as neuroactive neurosteroids. J Endocrinol 150(Suppl):221-239
213. Friess E, Schiffelholz T, Steckler T, Steiger A (2000) Dehydroepiandrosterone-a neurosteroid. Eur J Clin Invest 30(Suppl 3):46-50
214. Nafziger AN, Bowlin SJ, Jenkins PL, Pearson TA (1998) Longitudinal changes in dehydroepiandrosterone concentrations in men and women. J Lab Clin Med 131:316-323
215. Orentreich N, Brind JL, Vogelman JH et al (2002) Long-term longitudinal measurements of plasma dehydro-epiandrosterone sulfate in normal men. J Clin Endocrinol Metab 75:1002-1004
216. Melcangi RC, Panzica G, Garcia-Segura LM (2011) Neuroactive steroids: focus on human brain. Neuroscience 191:1-5
217. Marx CE, Keefe RS, Buchanan RW et al (2009) Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology 34(8):1885-1903
218. Ritsner MS, Gibel A, Shleifer T et al (2010) Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial. J Clin Psychiatry 71:1351-1362
219. Strous RD, Maayan R, Lapidus R et al (2003) Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 60:133-141
220. Strous RD, Stryjer R, Maayan R et al (2007) 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 32:96-105
221. Strous RD, Gibel A, Maayan R, Weizman A, Ritsner MS (2008) Hormonal response to dehydroepiandrosterone administration in schizophrenia: findings from a randomized, doubleblind, placebo-controlled, crossover study. J Clin Psychopharmacol 28:456-459
222. Nachshoni T, Ebert T, Abramovitch Y et al (2005) Improvement of extrapyramidal symptoms following dehydroepiandrosterone (DHEA) administration in antipsychotic treated schizophrenia patients: a randomized, double-blind placebo controlled trial. Schizophr Res 79:251-256
223. Ritsner MS, Gibel A, Ratner Y et al (2006) 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 26:495-499
224. Ritsner MS, Strous RD (2010) Neurocognitive deficits in schizophrenia are associated with alterations in blood levels of neurosteroids: a multiple regression analysis of findings from a double-blind, randomized, placebo-controlled, crossover trial with DHEA. J Psychiatr Res44:75-80
225. Ritsner MS (2010) Pregnenolone, dehydroepiandrosterone, and schizophrenia: alterations and clinical trials. CNS Neurosci Ther 16(1):32-44
226. Mortimer AM (2007) Relationship between estrogen and schizophrenia. Expert Rev Neurother 7(1):45-55
227. Kulkarni J, de Castella A, Fitzgerald PB (2008) Estrogen in severe mental illness: a potential new treatment approach. Arch Gen Psychiatry 65:955-960
228. Kulkarni J, Hayes E, Gavrilidis E (2012) Hormones and schizophrenia. Curr Opin Psychiatry 25(2):89-95
229. Bryant DN, Dorsa DM (2010) Roles of estrogen receptors alpha and beta in sexually dimorphic neuroprotection against glutamate toxicity. Neuroscience 170:1261-1269
230. Arevalo MA, Santos-Galindo M, Bellini MJ et al (2010) Actions of estrogens on glial cells: implications for neuroprotection. Biochim Biophys Acta 1800:1106-1112
231. Arevalo MA, Santos-Galindo M, Lagunas N et al (2011) Selective estrogen receptor modulators as brain therapeutic agents. J Mol Endocrinol 46:R1-R9
232. Liu M, Kelley MH, Herson PS, Hurn PD (2010) Neuroprotection of sex steroids. Minerva Endocrinol 35:127-143
233. Riecher-Rossler A, Kulkarni J (2011) Estrogens and gonadal function in schizophrenia and related psychoses. Curr Top Behav Neurosci 8:155-171
234. Taylor GT, Maloney S, Dearborn J, Weiss J (2009) Hormones in the mentally disturbed brain: steroids and peptides in the development and treatment of psychopathology. Cent Nerv Syst Agents Med Chem 9:331-360
235. Hughes ZA, Liu F, Marquis K et al (2009) Estrogen receptor neurobiology and its potential for translation into broad spectrum therapeutics for CNS disorders. Curr Mol Pharmacol 2:215-236
236. Kulkarni J, Riedel A, de Castella AR, Fitzgerald PB, Rolfe TJ, Taffe J, Burger H (2002) A clinical trial of adjunctive oestrogen treatment in women with schizophrenia. Arch Womens Ment Health 5(3):99-104
237. Akhondzadeh S, Nejatisafa AA, Amini H et al (2003) Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 27(6):1007-1012
238. Chua WL, Santiago AD, Kulkarni J, et al (2005) Estrogen for schizophrenia. Cochrane Database Syst Rev (4):CD004719
239. Kulkarni J, de Castella A, Headey B et al (2011) Estrogens and men with schizophrenia: is there a case for adjunctive therapy? Schizophr Res 125(2-3):278-283
240. Heringa M (2003) Review on raloxifene: profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther 41(8):331-345
241. Kulkarni J, Gurvich C, Lee SJ et al (2010) Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia. Psychoneuroendocrinology 35(8):1142-1147
242. Usall J, Huerta-Ramos E, Iniesta R et al (2011) Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 72(11):1552-1557
243. Ko YH, Lew YM, Jung SW, Joe SH, Lee CH, Jung HG, Lee MS (2008) Short-term testosterone augmentation in male schizophrenics: a randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol 28(4):375-383
244. Wagner E, Luo T, Drager UC (2002) Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental stages and functional systems. Cereb Cortex 12:1244-1253
245. Balmer JE, Blomhoff R (2002) Gene expression regulation by retinoic acid. J Lipid Res43:1773-1808
246. Goodman AB (1998) Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci USA 95:7240-7244
247. Palha JA, Goodman AB (2006) Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia. Brain Res Rev 51:61-71
248. Luthi-Carter R, Strand A, Peters NL et al (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9:1259-1271
249. Wan C, Shi Y, Zhao X, T. Tang et al (2009) Positive association between ALDH1A2 and schizophrenia in the Chinese population. Prog Neuro-Psychopharmacol Biol Psychiatry3(8): 1491-1495
250. Bailey SJ, McCaffery PJ (2009) Retinoic acid signalling in neuropsychiatric disease: possible markers and treatment agents. In: Ritsner MS (ed) The Handbook of neuropsychiatric biomarkers, endophenotypes and genes, vol III. Springer, Netherlands, pp 171-189
251. Samad TA, Krezel W, Chambon P, Borrelli E (1997) Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family. Proc Natl Acad Sci USA 94(26):14349-14354
252. Krezel W, Ghyselinck N, Samad TA et al (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279(5352):863-867
253. Citver AS, Shields AM, Ciaccia LM et al (2002) Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: III. Retinoids. J Clin Pharm Ther 27(3): 161-168
254. Sharma RP (2005) Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics. Schizophr Res 72:79-90
255. Boehm MF, Zhang L, Badea BA et al (1994) Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 37:2930-2941
256. Lerner V, Miodownik C, Gibel A, Kovalyonok E, Shleifer T, Goodman AB, Ritsner MS(2008) Bexarotene as add-on to antipsychotic treatment in schizophrenia patients: a pilot open-label trial. Clin Neuropharmacol 31:25-33
257. Muller N, Schwarz M (2006) Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res 10(2):131-148
258. Muller C, Hennebert O, Morfin R (2006) The native anti-glucocorticoid paradigm. The J Steroid Biochem Mol Biol 100:95-105
259. Richard MD, Brahm NC (2012) Schizophrenia and the immune system: pathophysiology, prevention, and treatment. Am J Health Syst Pharm 69(9):757-766
260. Muller N (2010) COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr Opin Investig Drugs 11(1):31-42
261. Muller N, Riedel M, Scheppach C et al (2002) Beneficial antipsychotic effects of celecoxib addon therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 159:1029-1034
262. Muller NE, Riedel M, Dehning S et al (2004) Is the therapeutic effect of celecoxib in schizophrenia depending from duration of disease? Neuropsychopharmacology 29(Suppl 1):S176
263. Rapaport MH, Delrahim KK, Bresee CJ et al (2005) Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry 57(12):1594-1596
264. Akhondzadeh S, Tabatabaee M, Amini H et al (2007) Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res90(1-3):179-185
265. Muller N, Krause D, Dehning S et al (2010) 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 121(1-3):118-124
266. Laan W, Grobbee DE, Selten JP et al (2010) Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 71:520-527
267. Patel SS, Attard A, Jacobsen P, Shergill S (2010) Acetylcholinesterase inhibitors (AChEI’s) for the treatment of visual hallucinations in schizophrenia: a review of the literature. BMC Psychiatry 10:69
268. Birks J, Harvey RJ (2006) Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev (1):CD001190
269. Singh J, Kour K, Jayaram MB (2012) Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database Syst Rev 2012 Jan 18;1:CD007967
270. Ago Y, Koda K, Takuma K, Matsuda T (2011) Pharmacological aspects of the acetylcholinesterase inhibitor galantamine. J Pharmacol Sci 116(1):6-17
271. Keefe RS, Malhotra AK, Meltzer HY et al (2008) Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology33(6):1217-1228
272. Lee SW, Lee JG, Lee BJ, Kim YH (2007) 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 22(2):63-68
273. Lindenmayer JP, Khan A (2011) Galantamine augmentation of long-acting injectable risperidone for cognitive impairments in chronic schizophrenia. Schizophr Res 125(2-3):267-277
274. Ribeiz SR, Bassitt DP, Arrais JA et al (2010) Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs 24(4):303-317
275. Lara DR, Souza DO (2000) Schizophrenia: a purinergic hypothesis. Med Hypotheses 54(2):157-166
276. Buie LW, Oertel MD, Cala SO (2006) Allopurinol as adjuvant therapy in poorly responsive or treatment refractory schizophrenia. Ann Pharmacother 40(12):2200-2204
277. Dickerson FB, Stallings CR, Origoni AE et al (2009) A double-blind trial of adjunctive allopurinol for schizophrenia. Schizophr Res 109(1-3):66-69
278. Weiser M, Gershon AA, Rubinstein K, et al. (2012) A randomized controlled trial of allopurinol vs. placebo added on to antipsychotics in patients with schizophrenia or schizoaffective disorder. Schizophr Res 2012 Apr 4. [Epub ahead of print] PubMed PMID: 22483162
279. Goldberg TE, Bigelow LB, Weinberger DR et al (1991) Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia. Am J Psychiatry148:78-84
280. Barch DM, Carter CS (2005) Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers. Schizophr Res 77:43-58
281. Pietrzak RH, Snyder PJ, Maruff P (2010) Use of an acute challenge with d-amphetamine to model cognitive improvement in chronic schizophrenia. Hum Psychopharmacol 25:353-358
282. Minzenberg MJ, Carter CS (2008) Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 33(7):1477-1502
283. Kumar R (2008) Approved and investigational uses of modafinil: an evidence-based review. Drugs 68(13):1803-1839
284. Saavedra-Velez C, Yusim A, Anbarasan D, Lindenmayer JP (2009) Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. J Clin Psychiatry 70(1):104-112
285. Rosenthal MH, Bryant SL (2004) Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia. Clin Neuropharmacol 27:38-43
286. Farrow TF, Hunter MD, Haque R, Spence SA (2006) Modafinil and unconstrained motor activity in schizophrenia: double-blind crossover placebo-controlled trial. Br J Psychiatry189:461-462
287. Pierre JM, Peloian JH, Wirshing DA et al (2007) A randomized, double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia. J Clin Psychiatry 68(5):705-710
288. Freudenreich O, Henderson DC, Macklin EA et al (2009) Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. J Clin Psychiatry70(12): 1674-1680
289. Sevy S, Rosenthal MH, Alvir J et al (2005) Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. J Clin Psychiatry 66(7):839-843
290. Kane JM, D’Souza DC, Patkar AA et al (2010) Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study. J Clin Psychiatry 71(11):1475-1481
291. Bobo WV, Woodward ND, Sim MY et al (2011) The effect of adjunctive armodafinil on cognitive performance and psychopathology in antipsychotic-treated patients with schizo-phrenia/schizoaffective disorder: a randomized, double-blind, placebo-controlled trial. Schizophr Res 130(1-3):106-113
292. Scoriels L, Barnett JH, Soma PK et al (2012) Effects of modafinil on cognitive functions in first episode psychosis. Psychopharmacology (Berl) 220(2):249-258
293. Scoriels L, Barnett JH, Murray GK et al (2011) Effects of modafinil on emotional processing in first episode psychosis. Biol Psychiatry 69(5):457-464
294. Cheine M, Ahone J, Wahlbeck K (2003) Beta-blocker supplementation of standard drug treatment for schizophrenia (Cochrane Review). Cochrane Database Syst Rev (3):CD000234
295. Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M (2001)Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study. Int Clin Psychopharmacol 16(2):111-115
296. Pur BK, Richardson AJ, Horrobin DF et al (2000) Eicosapentaenoic acid treatment in schizophrenia associated with symptom remission, normalization of blood fatty acids, reduced neuronal membrane phospholipid turnover and structural brain changes. Int J Clin Pract54:57-63
297. Peet M, Horrobin DF (2002) EE Multi Centre Study Group. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 36:7-18
298. Joy CB, Mumby-Croft R, Joy LA (2006) Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Database Syst Rev (3):CD001257
299. Juneja LR (1999) Suntheanine and its relaxation effect in humans. Trends Food Sci Tech 10:199-204
300. Kimura K, Ozeki M, Juneja LR, Ohira H (2007) L-Theanine reduces psychological and physiological stress responses. Biol Psychol 74(1):39-45
301. Ritsner MS, Miodownik C, Ratner Y et al (2011) L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study. J Clin Psychiatry 72(1):34-42
302. Miodownik C, Maayan R, Ratner Y, Lerner V, Pintov L, Mar M, Weizman A, Ritsner MS(2011) Serum levels of brain-derived neurotrophic factor and cortisol to sulfate of dehydroe-piandrosterone molar ratio associated with clinical response to L-theanine as augmentation of antipsychotic therapy in schizophrenia and schizoaffective disorder patients. Clin Neuropharmacol 34(4):155-160
303. Cantoni GL (1953) S-adenosylmethionine: a new intermediate formed enzymatically from L-methionine and adenosine-triphosphate. J Biol Chem 204:403-416
304. Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338:1550-1554
305. Strous RD, Ritsner MS, Adler S et al (2009) Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. Eur Neuropsychopharmacol 19(1):14-22
306. Monti JM (2010) Serotonin 5-HT(2A) receptor antagonists in the treatment of insomnia: present status and future prospects. Drugs Today (Barc) 46(3):183-193
307. Werkman TR, McCreary AC, Kruse CG, Wadman WJ (2011) NK3 receptors mediate an increase in firing rate of midbrain dopamine neurons of the rat and the guinea pig. Synapse65(8):814-826. doi:10.1002/syn.20908
308. Kirilly E, Gonda X, Bagdy G (2012) CB(1) receptor antagonists: new discoveries leading to new perspectives. Acta Physiol (Oxf) 205(1):41-60
309. Lopez-Munoz F, Alamo C (2011) Neurobiological background for the development of new drugs in schizophrenia. Clin Neuropharmacol 34(3):111-126
310. Correll CU. Adjunctive therapy for schizophrenia: current and emerging directions. From Medscape Education Psychiatry & Mental Health. Available at http://www.medscape.org/viewarticle/738924. Accessed February 25, 2012