Pharmacological approaches to treating negative symptoms: A review of clinical trials

Schizophrenia Research

Volumn 150, Issue 2-3, 2013, Pages 346-352

  Arango, Celso ^a   Garibaldi, George ^b   Marder, Stephen R ^c,d  

^a UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

^b F HOFFMANN LA ROCHE LTD   (Switzerland)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d Education   (United States)

Author keywords

Negative symptoms; Pharmacology; Schizophrenia

Indexed keywords

3 (2,4 DIMETHOXYBENZYLIDENE)ANABASEINE; AMISULPRIDE; ANTIDEPRESSANT AGENT; ARMODAFINIL; ASENAPINE; ATYPICAL ANTIPSYCHOTIC AGENT; CHOLINERGIC RECEPTOR STIMULATING AGENT; CHOLINESTERASE INHIBITOR; CLOZAPINE; DONEPEZIL; DOPAMINE RECEPTOR STIMULATING AGENT; FLUOXETINE; FLUPHENAZINE; GLUTAMATE RECEPTOR AGONIST; GLYCINE RECEPTOR AGONIST; HALOPERIDOL; LISDEXAMFETAMINE; MINOCYCLINE; MODAFINIL; NEUROLEPTIC AGENT; NICOTINIC AGENT; OLANZAPINE; PLACEBO; QUETIAPINE; RISPERIDONE; RITANSERIN; SELEGILINE; TC 5619; TRAZODONE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ADD ON THERAPY; ADJUVANT THERAPY; CLINICAL EFFECTIVENESS; CLINICAL EVALUATION; CLINICAL TRIAL (TOPIC); DISEASE EXACERBATION; DISEASE SEVERITY; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG EFFECT; DRUG EFFICACY; DRUG MEGADOSE; HUMAN; LOW DRUG DOSE; NEGATIVE SYNDROME; NONHUMAN; POSITIVE SYNDROME; PRIORITY JOURNAL; REVIEW; TREATMENT DURATION; TREATMENT OUTCOME;

NEGATIVE SYMPTOMS; PHARMACOLOGY; SCHIZOPHRENIA;

ANTIDEPRESSIVE AGENTS; ANTIPSYCHOTIC AGENTS; CLINICAL TRIALS AS TOPIC; HUMANS; SCHIZOPHRENIA;

EID: 84886297495     PISSN: 09209964     EISSN: 15732509     Source Type: Journal    
DOI: 10.1016/j.schres.2013.07.026     Document Type: Review

References (87)

1. Akhondzadeh S., Gerami M., Noroozian M., Karamghadiri N., Ghoreishi A., Abbasi S.H., Rezazadeh S.A. A 12-week, double-blind, placebo-controlled trial of donepezil adjunctive treatment to risperidone in chronic and stable schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2008, 32:1810-1815.
2. Amiri A., Noorbala A.A., Nejatisafa A.A., Ghoreishi A., Derakhshan M.K., Khodaie-Ardakani M.R., Hajiazim M., Raznahan M., Akhondzadeh S. Efficacy of selegiline add on therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Hum. psychopharmacol. 2008, 23:79-86.
3. Arango C., Buchanan R.W., Kirkpatrick B., Carpenter W.T. The deficit syndrome in schizophrenia: implications for the treatment of negative symptoms. Eur. Psychiatry 2004, 19:21-26.
4. Arbabi M., Bagheri M., Rezaei F., Ahmadi-Abhari S.A., Tabrizi M., Khalighi-Sigaroudi F., Akhondzadeh S. A placebo-controlled study of the modafinil added to risperidone in chronic schizophrenia. Psychopharmacology 2012, 220:591-598.
5. Artaloytia J.F., Arango C., Lahti A., Sanz J., Pascual A., Cubero P., Prieto D., Palomo T. Negative signs and symptoms secondary to antipsychotics: a double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy volunteers. Am. J. Psychiatry 2006, 163:488-493.
6. Axelrod B.N., Goldman R.S., Alphs L.D. Validation of the 16-item Negative Symptom Assessment. J. Psychiatr. Res. 1993, 27:253-258.
7. Bennett A.C., Vila T.M. The role of ondansetron in the treatment of schizophrenia. Ann. Pharmacother. 2010, 44:1301-1306.
8. Berk M., Copolov D., Dean O., Lu K., Jeavons S., Schapkaitz I., Anderson-Hunt M., Judd F., Katz F., Katz P., Ording-Jespersen S., Little J., Conus P., Cuenod M., Do K.Q., Bush A.I. N-acetyl cysteine as a glutathione precursor for schizophrenia-a double-blind, randomized, placebo-controlled trial. Biol. Psychiatry 2008, 64:361-368.
9. Bobes J., Arango C., Garcia-Garcia M., Rejas J. Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS study. J. Clin. Psychiatry 2010, 71:280-286.
10. Bodkin J.A., Cohen B.M., Salomon M.S., Cannon S.E., Zornberg G.L., Cole J.O. Treatment of negative symptoms in schizophrenia and schizoaffective disorder by selegiline augmentation of antipsychotic medication. A pilot study examining the role of dopamine. J. Nerv. Ment. Dis. 1996, 184:295-301.
11. Bodkin J.A., Siris S.G., Bermanzohn P.C., Hennen J., Cole J.O. Double-blind, placebo-controlled, multicenter trial of selegiline augmentation of antipsychotic medication to treat negative symptoms in outpatients with schizophrenia. Am. J. Psychiatry 2005, 162:388-390.
12. Breier A., Buchanan R.W., Kirkpatrick B., Davis O.R., Irish D., Summerfelt A., Carpenter W.T. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am. J. Psychiatry 1994, 151:20-26.
13. Buchanan R.W., Javitt D.C., Marder S.R., Schooler N.R., Gold J.M., McMahon R.P., Heresco-Levy U., Carpenter W.T. 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.
14. Buchanan R.W., Panagides J., Zhao J., Phiri P., den Hollander W., Ha X., Kouassi A., Alphs L., Schooler N., Szegedi A., Cazorla P. Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia. J. Clin. Psychopharmacol. 2012, 32:36-45.
15. Carpenter W.T., Davis J.M. Another view of the history of antipsychotic drug discovery and development. Mol. Psychiatry 2012, 17:1168-1173.
16. Cascella N.G., Macciardi F., Cavallini C., Smeraldi E. d-cycloserine adjuvant therapy to conventional neuroleptic treatment in schizophrenia: an open-label study. J. Neural transm. 1994, 95:105-111. (General section).
17. Chaudhry I.B., Hallak J., Husain N., Minhas F., Stirling J., Richardson P., Dursun S., Dunn G., Deakin B. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J. Psychopharmacol. 2012, 26:1185-1193.
18. Conley R.R., Boggs D.L., Kelly D.L., McMahon R.P., Dickinson D., Feldman S., Ball M.P., Buchanan R.W. The effects of galantamine on psychopathology in chronic stable schizophrenia. Clin. Neuropharmacol. 2009, 32:69-74.
19. Coyle J.T. NMDA receptor and schizophrenia: a brief history. Schizophr. Bull. 2012, 38:920-926.
20. Danion J.M., Rein W., Fleurot O. Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group. Am. J. Psychiatry 1999, 156:610-616.
21. Domino E.F., Mirzoyan D., Tsukada H. N-methyl-D-aspartate antagonists as drug models of schizophrenia: a surprising link to tobacco smoking. Prog. Neuropsychopharmacol. Biol. Psychiatry 2004, 28:801-811.
22. Duncan E.J., Szilagyi S., Schwartz M.P., Bugarski-Kirola D., Kunzova A., Negi S., Stephanides M., Efferen T.R., Angrist B., Peselow E., Corwin J., Gonzenbach S., Rotrosen J.P. Effects of D-cycloserine on negative symptoms in schizophrenia. Schizophr. Res. 2004, 71:239-248.
23. Essali A., Al-Haj Haasan N., Li C., Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst. Rev. 2009, 1-219. (CD000059).
24. Evins A.E., Fitzgerald S.M., Wine L., Rosselli R., Goff D.C. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am. J. Psychiatry 2000, 157:826-828.
25. Freedman R., Olincy A., Buchanan R.W., Harris J.G., Gold J.M., Johnson L., Allensworth D., Guzman-Bonilla A., Clement B., Ball M.P., Kutnick J., Pender V., Martin L.F., Stevens K.E., Wagner B.D., Zerbe G.O., Soti F., Kem W.R. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am. J. Psychiatry 2008, 165:1040-1047.
26. Freudenreich O., Henderson D.C., Macklin E.A., Evins A.E., Fan X., Cather C., Walsh J.P., Goff D.C. Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. J. Clin. Psychiatry 2009, 70:1674-1680.
27. Goff D.C., Tsai G., Manoach D.S., Coyle J.T. Dose-finding trial of D-cycloserine added to neuroleptics for negative symptoms in schizophrenia. Am. J. Psychiatry 1995, 152:1213-1215.
28. Goff D.C., Tsai G., Manoach D.S., Flood J., Darby D.G., Coyle J.T. D-cycloserine added to clozapine for patients with schizophrenia. Am. J. Psychiatry 1996, 153:1628-1630.
29. Goff D.C., Tsai G., Levitt J., Amico E., Manoach D., Schoenfeld D.A., Hayden D.L., McCarley R., Coyle J.T. A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch. Gen. Psychiatry 1999, 56:21-27.
30. Goff D.C., Freudenreich O., Evins A.E. Augmentation strategies in the treatment of schizophrenia. CNS Spectr. 2001, 6(904):907-911.
31. Goff D.C., Herz L., Posever T., Shih V., Tsai G., Henderson D.C., Freudenreich O., Evins A.E., Yovel I., Zhang H., Schoenfeld D. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology 2005, 179:144-150.
32. Goff D.C., Cather C., Gottlieb J.D., Evins A.E., Walsh J., Raeke L., Otto M.W., Schoenfeld D., Green M.F. Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study. Schizophr. Res. 2008, 106:320-327.
33. Heresco-Levy U., Silipo G., Javitt D.C. Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia. Psychopharmacol. Bull. 1996, 32:731-740.
34. Heresco-Levy U., Ermilov M., Lichtenberg P., Bar G., Javitt D.C. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol. Psychiatry 2004, 55:165-171.
35. Hopkins C.R. Is there a path forward for mGlu(2) positive allosteric modulators for the treatment of schizophrenia?. ACS Chem. Neurosci. 2013, 4:211-213.
36. Hyman S.E., Fenton W.S. Medicine. What are the right targets for psychopharmacology?. Science 2003, 299:350-351.
37. Javitt D.C. Twenty-five years of glutamate in schizophrenia: are we there yet?. Schizophr. Bull. 2012, 38:911-913.
38. Javitt D.C., Zylberman I., Zukin S.R., Heresco-Levy U., Lindenmayer J.P. Amelioration of negative symptoms in schizophrenia by glycine. Am. J. Psychiatry 1994, 151:1234-1236.
39. Jungerman T., Rabinowitz D., Klein E. Deprenyl augmentation for treating negative symptoms of schizophrenia: a double-blind, controlled study. J. Clin. Psychopharmacol. 1999, 19:522-525.
40. 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.
41. Kane J.M., Marder S.R., Schooler N.R., Wirshing W.C., Umbricht D., Baker R.W., Wirshing D.A., Safferman A., Ganguli R., McMeniman M., Borenstein M. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison. Arch. Gen. Psychiatry 2001, 58:965-972.
42. Kane J.M., Cohen M., Zhao J., Alphs L., Panagides J. Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. J. Clin. Psychopharmacol. 2010, 30:106-115.
43. Kane J.M., D'Souza D.C., Patkar A.A., Youakim J.M., Tiller J.M., Yang R., Keefe R.S. Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study. The Journal of clinical psychiatry 2010, 71:1475-1481.
44. Kane J.M., Yang R., Youakim J.M. Adjunctive armodafinil for negative symptoms in adults with schizophrenia: a double-blind, placebo-controlled study. Schizophr. Res. 2012, 135:116-122.
45. Kantrowitz J.T., Malhotra A.K., Cornblatt B., Silipo G., Balla A., Suckow R.F., D'Souza C., Saksa J., Woods S.W., Javitt D.C. High dose D-serine in the treatment of schizophrenia. Schizophr. Res. 2010, 121:125-130.
46. Kay S.R., Fiszbein A., Opler L.A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 1987, 13:261-276.
47. Khodaie-Ardakani M.R., Seddighi S., Modabbernia A., Rezaei F., Salehi B., Ashrafi M., Shams-Alizadeh N., Mohammad-Karimi M., Esfandiari G.R., Hajiaghaee R., Akhondzadeh S. Granisetron as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study. J. Psychiatr. Res. 2013, 47:472-478.
48. Kinon B.J., Zhang L., Millen B.A., Osuntokun O.O., Williams J.E., Kollack-Walker S., Jackson K., Kryzhanovskaya L., Jarkova N., Group H.S. 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.
49. Kirkpatrick B., Fenton W.S., Carpenter W.T., Marder S.R. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr. Bull. 2006, 32:214-219.
50. Lane H.Y., Lin C.H., Huang Y.J., Liao C.H., Chang Y.C., Tsai G.E. A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. Int. J. Neuropsychopharmacol. 2010, 13:451-460.
51. Lasser R.A., Dirks B., Nasrallah H., Kirsch C., Gao J., Pucci M.L., Knesevich M.A., Lindenmayer J.P. Adjunctive lisdexamfetamine dimesylate therapy in adult outpatients with predominant negative symptoms of schizophrenia: open-label and randomized-withdrawal phases. Neuropsychopharmacology 2013.
52. Lecrubier Y., Quintin P., Bouhassira M., Perrin E., Lancrenon S. The treatment of negative symptoms and deficit states of chronic schizophrenia: olanzapine compared to amisulpride and placebo in a 6-month double-blind controlled clinical trial. Acta Psychiatr. Scand. 2006, 114:319-327.
53. Lee M.R., Wehring H.J., McMahon R.P., Linthicum J., Cascella N., Liu F., Bellack A., Buchanan R.W., Strauss G.P., Contoreggi C., Kelly D.L. Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: results from a randomized double blind placebo controlled pilot study. Schizophr. Res. 2013, 145:110-115.
54. Levkovitz Y., Mendlovich S., Riwkes S., Braw Y., Levkovitch-Verbin H., Gal G., Fennig S., Treves I., Kron S. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. The Journal of clinical psychiatry 2010, 71:138-149.
55. Lieberman J.A., Dunbar G., Segreti A.C., Girgis R.R., Seoane F., Beaver J.S., Duan N., Hosford D.A. A Randomized exploratory trial of an alpha-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia. Neuropsychopharmacology 2013, 38:968-975.
56. Loo H., Poirier-Littre M.F., Theron M., Rein W., Fleurot O. Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br. J. Psychiatry 1997, 170:18-22.
57. Marder S.R., Davis J.M., Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J. Clin. Psychiatry 1997, 58:538-546.
58. Marder S.R., Daniel D.G., Alphs L., Awad A.G., Keefe R.S. Methodological issues in negative symptom trials. Schizophr. Bull. 2011, 37:250-254.
59. Marx C.E., Keefe R.S., Buchanan R.W., Hamer R.M., Kilts J.D., Bradford D.W., Strauss J.L., Naylor J.C., Payne V.M., Lieberman J.A., Savitz A.J., Leimone L.A., Dunn L., Porcu P., Morrow A.L., Shampine L.J. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology 2009, 34:1885-1903.
60. Mazeh D., Zemishlani H., Barak Y., Mirecki I., Paleacu D. Donepezil for negative signs in elderly patients with schizophrenia: an add-on, double-blind, crossover, placebo-controlled study. Int. Psychogeriatr. 2006, 18:429-436.
61. Moghaddam B., Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 2012, 37:4-15.
62. Moller H.J. Amisulpride: a review of its efficacy in schizophrenia. Acta Psychiatr. Scand. Suppl. 2000, 400:17-22.
63. Moller H.J. Amisulpride: efficacy in the management of chronic patients with predominant negative symptoms of schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 2001, 251:217-224.
64. Noroozian M., Ghasemi S., Hosseini S.M., Modabbernia A., Khodaie-Ardakani M.R., Mirshafiee O., Farokhnia M., Tajdini M., Rezaei F., Salehi B., Ashrafi M., Yekehtaz H., Tabrizi M., Akhondzadeh S. A placebo-controlled study of tropisetron added to risperidone for the treatment of negative symptoms in chronic and stable schizophrenia. Psychopharmacology 2013, 228:595-602.
65. Patil S.T., Zhang L., Martenyi F., Lowe S.L., Jackson K.A., Andreev B.V., Avedisova A.S., Bardenstein L.M., Gurovich I.Y., Morozova M.A., Mosolov S.N., Neznanov N.G., Reznik A.M., Smulevich A.B., Tochilov V.A., Johnson B.G., Monn J.A., Schoepp D.D. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat. Med. 2007, 13:1102-1107.
66. Potkin S.G., Jin Y., Bunney B.G., Costa J., Gulasekaram B. Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am. J. Psychiatry 1999, 156:145-147.
67. Potkin S.G., Cohen M., Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J. Clin. Psychiatry 2007, 68:1492-1500.
68. Rabinowitz J., Levine S.Z., Garibaldi G., Bugarski-Kirola D., Berardo C.G., Kapur S. Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: analysis of CATIE data. Schizophr. Res. 2012, 137:147-150.
69. Ritsner M.S., Gibel A., Ratner Y., Tsinovoy G., Strous R.D. 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.
70. Ritsner M.S., Gibel A., Shleifer T., Boguslavsky I., Zayed A., Maayan R., Weizman A., Lerner V. Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial. The Journal of clinical psychiatry 2010, 71:1351-1362.
71. Roffman J.L., Lamberti J.S., Achtyes E., Macklin E.A., Galendez G.C., Raeke L.H., Silverstein N.J., Smoller J.W., Hill M., Goff D.C. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA psychiatry 2013, 1-9.
72. Rosenheck R., Dunn L., Peszke M., Cramer J., Xu W., Thomas J., Charney D. Impact of clozapine on negative symptoms and on the deficit syndrome in refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. Am. J. Psychiatry 1999, 156:88-93.
73. Rosse R.B., Fay-McCarthy M., Kendrick K., Davis R.E., Deutsch S.I. D-cycloserine adjuvant therapy to molindone in the treatment of schizophrenia. Clin. Neuropharmacol. 1996, 19:444-450.
74. Sevy S., Rosenthal M.H., Alvir J., Meyer S., Visweswaraiah H., Gunduz-Bruce H., Schooler N.R. Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. The Journal of clinical psychiatry 2005, 66:839-843.
75. Shiina A., Shirayama Y., Niitsu T., Hashimoto T., Yoshida T., Hasegawa T., Haraguchi T., Kanahara N., Shiraishi T., Fujisaki M., Fukami G., Nakazato M., Iyo M., Hashimoto K. A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann. Gen. psychiatry 2010, 9:27.
76. Singh S.P., Singh V., Kar N., Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br. J. Psychiatry 2010, 197:174-179.
77. Singh J., Kour K., Jayaram M.B. Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database Syst. Rev. 2012, 1. (CD007967).
78. Speller J.C., Barnes T.R., Curson D.A., Pantelis C., Alberts J.L. One-year, low-dose neuroleptic study of in-patients with chronic schizophrenia characterised by persistent negative symptoms. Amisulpride v. haloperidol. Br. J. Psychiatry 1997, 171:564-568.
79. Strous R.D., Maayan R., Lapidus R., Stryjer R., Lustig M., Kotler M., Weizman A. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch. Gen. Psychiatry 2003, 60:133-141.
80. Strous R.D., Stryjer R., Maayan R., Gal G., Viglin D., Katz E., Eisner D., Weizman A. 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.
81. Tsai G., Yang P., Chung L.C., Lange N., Coyle J.T. D-serine added to antipsychotics for the treatment of schizophrenia. Biol. Psychiatry 1998, 44:1081-1089.
82. Tsai G.E., Yang P., Chung L.C., Tsai I.C., Tsai C.W., Coyle J.T. D-serine added to clozapine for the treatment of schizophrenia. Am. J. Psychiatry 1999, 156:1822-1825.
83. Tsai G.E., Yang P., Chang Y.C., Chong M.Y. D-alanine added to antipsychotics for the treatment of schizophrenia. Biol. Psychiatry 2006, 59:230-234.
84. Umbricht D., Lentz E., Lalonde J., Santarelli L.A. Post-hoc analysis of the negative symptom factor score in a proof-of-concept study with the glycine reuptake inhibitor (GRI), bitopertin, in schizophrenia. Eur. Neuropsychopharmacol. 2012, 22:311.
85. Weiser M., Heresco-Levy U., Davidson M., Javitt D.C., Werbeloff N., Gershon A.A., Abramovich Y., Amital D., Doron A., Konas S., Levkovitz Y., Liba D., Teitelbaum A., Mashiach M., Zimmerman Y. A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia. The Journal of clinical psychiatry 2012, 73:e728-e734.
86. Wise R.A., Spindler J., deWit H., Gerberg G.J. Neuroleptic-induced "anhedonia" in rats: pimozide blocks reward quality of food. Science 1978, 201:262-264.
87. Zhang X.Y., Zhou D.F., Zhang P.Y., Wu G.Y., Su J.M., Cao L.Y. A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia. The Journal of clinical psychiatry 2001, 62:878-883.