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Pharmacotherapy of cognitive deficits in schizophrenia

Published online by Cambridge University Press:  08 November 2013

Lewis A. Opler ,
Alice Medalia ,
Mark G. Opler  and
Stephen M. Stahl
Lewis A. Opler*
Affiliation:
Department of Psychiatry, Columbia University Medical Center, New York, New York, USA Department of Psychiatry, New York University School of Medicine, New York, New York, USA
Alice Medalia
Affiliation:
Department of Psychiatry, Columbia University Medical Center, New York, New York, USA
Mark G. Opler
Affiliation:
Department of Psychiatry, New York University School of Medicine, New York, New York, USA
Stephen M. Stahl
Affiliation:
Department of Psychiatry, University of California, San Diego, La Jolla, California, USA
*
*Address for correspondence: Lewis A. Opler, MD, Columbia University, Department of Psychiatry, 765 Gramatan Avenue, Mount Vernon, NY 10552, USA. (Email laop1@juno.com)
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Abstract

While second-generation antipsychotics treat negative as well as positive symptoms, recovery for persons with schizophrenia remains elusive, in part because there are no FDA-approved medications that treat the cognitive deficits of schizophrenia (CDS). Recent work has identified agents that, when added to antipsychotics, improve cognition in schizophrenia. This work and hypothesized mechanisms of action will be reviewed.

Keywords

Clinical trialscognitive deficitsMATRICSpharmacotherapyschizophrenia
Type
Review Articles
Information
CNS Spectrums , Volume 19 , Issue 2 , April 2014 , pp. 142 - 156
Copyright
Copyright © Cambridge University Press 2013 

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References

REFERENCES

1. Medalia, A, Revheim, N. Dealing with Cognitive Dysfunction Associated with Psychiatric Disabilities: A Handbook for Families and Friends of Individuals with Psychiatric Disorders. Albany, NY: New York State Office of Mental Health; 2002.Google Scholar
2. Green, MF, Kern, RS, Heaton, RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004; 72(1): 41–51.Google Scholar
3. Green, MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996; 153(3): 321–330.Google ScholarPubMed
4. 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(1): 5–9.CrossRefGoogle ScholarPubMed
5. Tamminga, CA. The neurobiology of cognition in schizophrenia. J Clin Psychiatry. 2006; 67(9): 9–13.Google Scholar
6. Marder, SR. The NIMH-MATRICS project for developing cognition-enhancing agents for schizophrenia. Dialogues Clin Neurosci. 2006; 8(1): 109–113.Google Scholar
7. Arnsten, AF, Cai, JX, Murphy, BL, Goldman-Rakia, PS. Dopamine D1 receptor mechanism in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl). 1994; 116(2): 143–151.Google Scholar
8. Goldman-Rakic, PS, Muly, EC, Williams, GV. D1 receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000; 31(2–3): 295–301.Google Scholar
9. Barch, DM, Carter, CS. Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers. Schizophr Res. 2005; 77(1): 43–58.Google Scholar
10. George, MS, Molnar, CE, Grenesko, EL, etal. A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia. Schizophr Res. 2007; 93(1–3): 42–50.Google Scholar
11. Sumiyoshi, T, Park, S, Jayathilake, K, etal. Effect of buspirone, a serotonin1A agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res. 2007; 95(1–3): 158–168.CrossRefGoogle ScholarPubMed
12. Sumiyoshi, T, Matsui, M, Nohara, S, etal. Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry. 2001; 158(10): 1722–1725.Google Scholar
13. Sumiyoshi, T, Matsui, M, Yamashita, I, etal. The effect of tandospirone, a serotonin(1A) agonist, on memory function in schizophrenia. Biol Psychiatry. 2001; 49(10): 861–868.CrossRefGoogle ScholarPubMed
14. Meltzer, HY, Li, Z, Kaneda, Y, Ichikawa, J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(7): 1159–1172.CrossRefGoogle ScholarPubMed
15. Akhondzadeh, S, Mohammadi, N, Noroozian, M, etal. Added ondansetron for stable schizophrenia: a double blind, placebo controlled trial. Schizophr Res. 2009; 107(2–3): 206–212.Google Scholar
16. Morozova, MA, Beniashvili, AG, Lepilkina, TA, Rupchev, GE. Double-blind placebo-controlled randomized efficacy and safety trial of add-on treatment of dimebon plus risperidone in schizophrenic patients during transition from acute psychotic episode to remission. Psychiatr Danub. 2012; 24(2): 159–166.Google Scholar
17. Morozova, MA, Lepilkina, TA, Rupchev, G, etal. Add-on effects of selective antagonist of 5-HT6 receptors AVN-211 (CD-008-0173) in patients with schizophrenia stabilized on antipsychotic treatment: pilot study. CNS Spectr. 2013; June 17 (Epub ahead of print).Google Scholar
18. Efficacy study exploring the effect of Lu AE58054 as augmentation therapy in patients with schizophrenia. ClinicalTrials.gov. Identifier: NCT00810667.Google Scholar
19. Barr, RS, Culhave, MA, Jubelt, LE, etal. The effects of transdermal nicotine on cognition in nonsmokers with schizophrenia and nonpsychiatric controls. Neuropsychopharmacology. 2008; 33(3): 480–490.Google Scholar
20. Zhang, XY, Liu, L, Hong, X, etal. Short-term tropisetron treatment and cognitive and p50 auditory gating deficits in schizophrenia. Am J Psychiatry. 2012; 169(9): 974–981.Google Scholar
21. Macor, JE, Gurley, D, Lanthorn, T, etal. The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha-7 nicotinic receptor partial agonist. Bioorg Med Chem Lett. 2001; 11(3): 319–321.Google Scholar
22. Hufford, M, Gawryl, M, Dgetluck, N, etal. Methodological issues affecting signal detection in a clinical trial for cognitive impairment in schizophrenia. Poster Abstracts, ISCTM 8th Annual Scientific Meeting; 21–23 February, 2012; Washington D.C.Google Scholar
23. Radek, RJ, Kohlhaas, KL, Rueter, LE, Mohler, EG. Treating the cognitive deficits of schizophrenia with alpha4beta2 neuronal nicotinic receptor agonists. Curr Pharm Des. 2010; 16(3): 309–322.Google Scholar
24. A phase 2 study to evaluate ABT-126 for the treatment of cognitive deficits in schizophrenia. ClinicalTrials.gov. Identifier: NCT01678755.Google Scholar
25. Lieberman, JA, Dunbar, G, Segreti, AC, etal. A randomized exploratory trial of an alpha-7 nicotinic receptor agonist (tc-5619) for cognitive enhancement in schizophrenia. Neuropsychopharmacology. 2013; 38(6): 968–975.Google Scholar
26. Shekhar, A, Potter, WZ, Lightfoot, J, etal. Selective muscarinic receptor agonist xanomeline as a novel treatment approach to schizophrenia. Am J Psychiatry. 2008; 165(8): 1033–1039.Google Scholar
27. Scarr, E. Muscarinic M1 receptor agonists: can they improve cognitive performance? Int J Neuropsychopharmacol. 2013; 16(4): 717–720.CrossRefGoogle ScholarPubMed
28. Lee, BJ, Lee, JG, Kim, YH. A 12-week, double-blind, placebo-controlled trial of donepezil as an adjunct to haloperidol for treating cognitive impairments in patients with chronic schizophrenia. J Psychopharmacol. 2007; 21(4): 421–427.Google Scholar
29. Freudenreich, O, Herz, L, Deckersbach, T, etal. Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacology. 2005; 181(2): 358–363.Google Scholar
30. Kohler, CG, Martin, EA, Kujawski, E, etal. No effect of donepezil on neurocognition and social cognition in young persons with stable schizophrenia. Cognit Neuropsychiatry. 2007; 12(5): 412–442.Google Scholar
31. Sharma, T, Reed, C, Aasen, I, Kumari, V. Cognitive effects of adjunctive 24-weeks rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation. Schizophr Res. 2006; 85(1–3): 73–83.CrossRefGoogle ScholarPubMed
32. Chouinard, S, Stip, E, Poulin, J, etal. Rivastigmine treatment as an add-on to antipsychotics in patients with schizophrenia and cognitive deficits. Curr Med Res Opin. 2007; 23(3): 575–583.CrossRefGoogle ScholarPubMed
33. Schubert, MH, Young, KA, Hicks, PB. Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biol Psychiatry. 2006; 60(6): 530–533.Google Scholar
34. Lee, SW, Lee, JG, Lee, BJ, Kim, YH. A 12-week, double-blind, placebo-controlled trial of galantamine adjunctive treatment to conventional antipsychotics for the cognitive impairments in chronic schizophrenia. Int Clin Psychopharmacol. 2007; 22(2): 63–68.Google Scholar
35. Woodruff-Pak, DS, Vogel, RW, Wenk, GL. Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci U S A. 2001; 98(4): 2089–2094.CrossRefGoogle ScholarPubMed
36. Luby, ED, Gottlieb, JS, Cohen, BD, Rosenbaum, G, Domino, EF. Model psychoses and schizophrenia. Am J Psychiatry. 1962; 119(1): 61–67.Google Scholar
37. Domino, EF, Luby, ED. Phencyclidine/schizophrenia: one view toward the past, the other to the future. Schizophr Bull. 2012; 38(5): 914–919.Google Scholar
38. Javitt, DC, Jotkowitz, A, Sircar, R, Zukin, SR. Non-competitive regulation of phencyclidine/sigma-receptors by the N-methyl-D-aspartate receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid. Neurosci Lett. 1987; 78(2): 193–198.Google Scholar
39. Javitt, DC, Zukin, SR. Interaction of [3H]MK-801 with multiple states of the N-methyl-D-aspartate receptor complex of rat brain. Proc Natl Acad Sci U S A. 1989; 86(2): 740–744.Google Scholar
40. Javitt, DC, Zukin, SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991; 148(10): 1301–1308.Google ScholarPubMed
41. Berk, M, Copolov, D, Dean, O, etal. N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008; 64(5): 361–368.CrossRefGoogle ScholarPubMed
42. Lavoie, S, Murray, MM, Deppen, P, etal. Glutathione precursor, n-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology. 2008; 33(9): 2187–2199.Google Scholar
43. Goff, DC, Cather, C, Gottlieb, JD, etal. Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study. Schizophr Res. 2008; 106(2–3): 320–327.Google Scholar
44. Mezler, M, Geneste, H, Gault, L, Marek, GJ. LY2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia. Curr Opin Investig Drugs. 2010; 11(7): 833–845.Google Scholar
45. Malinow, R, Malenka, RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002; 25: 103–126.Google Scholar
46. Meador-Woodruff, JH, Healy, DJ. Glutamate receptor expression in schizophrenic brain. Brain Res Rev. 2000; 31(2–3): 288–294.CrossRefGoogle ScholarPubMed
47. Goff, DC, Leahy, L, Berman, I, etal. A placebo-controlled pilot study of the ampakine, CX516, added to clozapine in schizophrenia. J Clin Psychopharmacol. 2001; 21(5): 484–487.Google Scholar
48. Goff, DC, Lamberti, S, Leon, AC, etal. A placebo-controlled add-on trial of the ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology. 2008; 33(3): 465–472.Google Scholar
49. A study of the effect of RO4917838 on biomarker measures of cognitive dysfunction in patients with schizophrenia. ClinicalTrials.gov. Identifier: NCT01116830.Google Scholar
50. Kantrowitz, JT, Malhotra, AK, Cornblatt, B, etal. High dose D-serine in the treatment of schizophrenia. Schizophr Res. 2010; 121(1–3): 125–130.CrossRefGoogle ScholarPubMed
51. Menzies, L, Ooi, C, Kamath, S, etal. Effects of gamma-aminobutyric acid-modulating drugs on working memory and brain function in patients with schizophrenia. Arch Gen Psychiatry. 2007; 64(2): 156–167.Google Scholar
52. Lewis, DA, Cho, RY, Carter, CS, etal. Subunit-selective modulation of GABA type A neurotransmission and cognition in schizophrenia. Am J Psychiatry. 2008; 165(12): 1585–1593.Google Scholar
53. Buchanan, RW, Keefe, RS, Lieberman, JA, etal. A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol Psychiatry. 2011; 69(5): 442–449.Google Scholar
54. Keefe, RS, Bilder, RM, Davis, SM, etal. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry. 2007; 64(6): 633–647.Google Scholar
55. Keefe, RS, Sweeney, JA, Hongbin, G, etal. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized double-blind 52-week comparison. Am J Psychiatry. 2007; 164(7): 1061–1071.Google Scholar
56. Goldberg, TE, Goldman, RS, Burdick, KF, etal. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry. 2007; 64(10): 1115–1122.Google Scholar
57. Ritsner, MS, Gibel, A, Ratner, Y, Tsinovoy, G, Strous, RD. Improvement of sustained attention and visual and movement skills, but not clinical symptoms, after dehydroepiandrosterone augmentation in schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychopharmacol. 2006; 26(5): 495–499.Google Scholar
58. Ritsner, MS, Gibel, A, Shleifer, T, etal. 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. 2010; 71(10): 1351–1362.Google Scholar
59. Levkovitz, Y, Medlovich, S, Riskes, S, etal. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010; 71(2): 138–149.Google Scholar
60. Cho, SJ, Yook, K, Kim, B, etal. Mirtazapine augmentation enhances cognitive and reduces negative symptoms in schizophrenia patients treated with risperidone: a randomized controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(1): 208–211.Google Scholar
61. Stenberg, J-H, Terevnikov, V, Joffe, M, etal. Predictors and mediators of add-on mirtazapine-induced cognitive enhancement in schizophrenia—a path model investigation. Neuropharmacology. 2013; 64: 248–253.Google Scholar
62. Scoriels, L, Jones, PB, Sahakian, BJ. Modafanil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain. Neuropharmacology. 2013; 64: 168–184.Google Scholar
63. Prasad, KM, Eack, SM, Keshavan, JS, etal. Antiherpes virus-specific treatment and cognition in schizophrenia: a test-of-concept randomized double-blind placebo-controlled trial. Schizophr Bull. 2013; 39(4): 857–866.Google Scholar
64. Goff, DC, Hill, M, Barch, B. The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav. 2011; 99(2): 245–253.CrossRefGoogle ScholarPubMed
65. Fioravanti, M, Bianchi, V, Cinti, ME. Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence. BMC Psychiatry. 2012; 12: 64.Google Scholar
66. Medalia, A, Opler, MG, Opler, LA. Integrating psychopharmacology and cognitive remediation to treat cognitive dysfunction in the psychotic disorders. In: de Oliveira IR, Schwartz T, Stahl SM, eds. Integrating Psychotherapy and Psychopharmacology: A Handbook for Clinicians, New York, NY: Routledge Books; In press.Google Scholar
67. Medalia, A, Opler, LA, Saperstein, A. Integrating psychopharmacology and cognitive remediation to treat cognitive dysfunction in the psychotic disorders. CNS Spectr. 2013, July 23; 1–6 (Epub ahead of print).Google Scholar