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Better pharmacotherapy for schizophrenia: What does the future hold?

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Abstract

Despite the expansion of available antipsychotic drugs over the past 50 years, functional outcomes for individuals with schizophrenia have not markedly improved. These agents are efficacious for psychosis but do not adequately address other core domains of schizophrenia psychopathology, namely negative symptoms and cognitive impairment, which have a greater impact on functional outcomes, including vocational or academic performance and interpersonal relationships. In addition, treatment-refractory psychosis still precludes functional improvement in many patients. Schizophrenia is a clinical syndrome consisting of these domains, which likely have some disparities in their respective pathophysiologies. This suggests that drug development should look to other molecular targets besides the D2 receptor, which characterizes the mechanism of available medications for schizophrenia. In this report, we review novel pharmacologic approaches that aim to specifically address each individual domain of schizophrenia. The goal of this future pharmacotherapy strategy is to advance outcomes beyond psychosis remission and toward functional recovery.

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References and Recommended Reading

  1. Hegarty JD, Baldessarini RJ, Tohen M, et al.: One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry 1994, 151:1409–1416.

    PubMed  CAS  Google Scholar 

  2. Green MF: What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996, 153:321–330.

    PubMed  CAS  Google Scholar 

  3. Stahl SM, Buckley PF: Negative symptoms of schizophrenia: a problem that will not go away. Acta Psychiatr Scand 2007, 115:4–11.

    Article  PubMed  CAS  Google Scholar 

  4. Carpenter WT: Clinical constructs and therapeutic discovery. Schizophr Res 2004, 72:69–73.

    Article  PubMed  Google Scholar 

  5. Davidson L, Schmutte T, Dinzeo T, et al.: Remission and recovery in schizophrenia: practitioner and patient perspectives. Schizophr Bull 2008, 34:5–8.

    Article  PubMed  Google Scholar 

  6. Bellack AS: Scientific and consumer models of recovery in schizophrenia: concordance, contrasts, and implications. Schizophr Bull 2006, 32:432–442.

    Article  PubMed  Google Scholar 

  7. Brekke JS, Maanse H, Long J, Green MF: How neurocognitive and social cognition influence functional change during community-based psychosocial rehabilitation for individuals with schizophrenia. Schizophr Bull 2007, 33:1247–1256.

    Article  PubMed  Google Scholar 

  8. McGurk SR, Mueser KT, Feldman K, et al.: Cognitive training for supported employment: 2–3 year outcomes of a randomized controlled trial. Am J Psychiatry 2007, 164:437–441.

    Article  PubMed  Google Scholar 

  9. Peer JE, Spaulding WD: Heterogeneity in recovery of psychosocial functioning during psychiatric rehabilitation: an exploratory study using latent growth mixture modeling. Schizophr Res 2007, 93:186–193.

    Article  PubMed  Google Scholar 

  10. McEvoy JP, Lieberman JA, Stroup TS, et al.: Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006, 163:600–610.

    Article  PubMed  Google Scholar 

  11. Sur C, Mallorga PJ, Wittmann M, et al.: N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A 2003, 100:13674–13679.

    Article  PubMed  CAS  Google Scholar 

  12. Shim SS, Hammonds MD, Kee BS: Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site. Eur Arch Psychiatry Clin Neurosci 2008, 258:16–27.

    Article  PubMed  Google Scholar 

  13. Javitt DC, Duncan L, Balla A, Sershen H: Inhibition of system A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action. Mol Psychiatry 2005, 10:276–286.

    Article  CAS  Google Scholar 

  14. Evins AE, Fitzgerald SM, Wine L, et al.: Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 2000, 157:826–828.

    Article  PubMed  CAS  Google Scholar 

  15. Goff DC, Tsai G, Manoach DS, et al.: D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry 1996, 153:1628–1630.

    PubMed  CAS  Google Scholar 

  16. Shaw P, Sporn A, Gogtay N, et al.: Childhood-onset schizophrenia: a double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry 2006, 63:721–730.

    Article  PubMed  CAS  Google Scholar 

  17. Lameh J, Burstein ES, Taylor E, et al.: Pharmacology of N-desmethylclozapine. Pharmacol Ther 2007, 115:223–231.

    Article  PubMed  CAS  Google Scholar 

  18. Natesan S, Reckless GE, Barlow KB, et al.: Evaluation of N-desmethylclozapine as a potential antipsychotic-preclinical studies. Neuropsychopharmacology 2007, 32:1540–1549.

    Article  PubMed  CAS  Google Scholar 

  19. Buchanan RW: Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull 2007, 33:1013–1022.

    Article  PubMed  Google Scholar 

  20. Kirkpatrick B, Fenton WS, Carpenter WT, Marder SR: The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006, 32:214–219.

    Article  PubMed  Google Scholar 

  21. Berk M, Ichim C, Brook S: Efficacy of mirtazapine add-on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind, randomized, placebo-controlled study. Int Clin Psychopharmacol 2001, 16:87–92.

    Article  PubMed  CAS  Google Scholar 

  22. Jockers-Scherubl MC, Bauer A, Godemann F, et al.: Negative symptoms of schizophrenia are improved by the addition of paroxetine to neuroleptics: a double-blind, placebo-controlled study. Int Clin Psychopharmacol 2005, 20:27–31.

    Article  PubMed  CAS  Google Scholar 

  23. Silver H, Aharon N, Kaplan A: Add-on fluvoxamine improves primary negative symptoms: evidence for specificity from response analysis of individual symptoms. Schizophr Bull 2003, 29:541–546.

    PubMed  Google Scholar 

  24. Bodkin JA, Siris SG, Bermanzohn PC, et al.: 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.

    Article  PubMed  Google Scholar 

  25. Amiri A, Noorbala AA, Nejatisafa AA, et al.: 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.

    Article  PubMed  CAS  Google Scholar 

  26. Heresco-Levy U, Javitt DC, Ermilov M, et al.: Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 1999, 56:29–36.

    Article  PubMed  CAS  Google Scholar 

  27. Heresco-Levy U, Javitt DC: Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res 2004, 66:89–96.

    Article  PubMed  Google Scholar 

  28. Buchanan RW, Javitt DC, Marder SR, et al.: The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry 2007, 164:1593–1602.

    Article  PubMed  Google Scholar 

  29. Patil ST, Zhang L, Martenyi F, et al.: Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 2007, 13:1102–1107.

    Article  PubMed  CAS  Google Scholar 

  30. Nuechterlein KH, Barch DM, Gold JM, et al.: Identification of separable cognitive factors in schizophrenia. Schizophr Res 2004, 72:29–39.

    Article  PubMed  Google Scholar 

  31. Marder SR, Fenton W: Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res 2004, 72:5–9.

    Article  PubMed  Google Scholar 

  32. Green MF: Stimulating the development of drug treatments to improve cognition in schizophrenia. Annu Rev Clin Psychol 2007, 3:159–180.

    Article  PubMed  Google Scholar 

  33. Gray JA, Roth BL: Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr Bull 2007, 33:1100–1119.

    Article  PubMed  Google Scholar 

  34. Buchanan RW, Freedman R, Javitt DC, et al.: Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull 2007, 33:1120–1130.

    Article  PubMed  Google Scholar 

  35. Olincy A, Harris JG, Johnson LL, et al.: Proof-of-concept trial of an alpha-7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 2006, 63:630–638.

    Article  PubMed  CAS  Google Scholar 

  36. Keefe RS, Malhotra AK, Meltzer HY, et al.: 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. Neuropsychopharmacology 2008, 33:1217–1228.

    Article  PubMed  CAS  Google Scholar 

  37. 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, 85:73–83.

    Article  PubMed  Google Scholar 

  38. Buchanan RW, Conley RR, Dickinson D, et al.: Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J Psychiatry 2008, 165:82–89.

    Article  PubMed  Google Scholar 

  39. Raedler TJ, Bymaster FP, Tandon R, et al.: Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry 2007, 12:232–246.

    PubMed  CAS  Google Scholar 

  40. Li Z, Huang M, Ichikawa J, et al.: N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors. Neuropsychopharmacology 2005, 30: 1986–1995.

    Article  PubMed  CAS  Google Scholar 

  41. George MS, Molnar CE, Grenesko EL, et al.: 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, 93:42–50.

    Article  PubMed  Google Scholar 

  42. Mu Q, Johnson K, Morgan PS, et al.: A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia. Schizophr Res 2007, 94:332–341.

    Article  PubMed  Google Scholar 

  43. Goff DC, Leahy L, Berman I, et al.: A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 2001, 21:484–487.

    Article  PubMed  CAS  Google Scholar 

  44. Goff DC, Lamberti JS, Leon AC, et al.: A placebo-controlled add-on trial of the ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 2008, 33:465–472.

    Article  PubMed  CAS  Google Scholar 

  45. Tsai G, Yang P, Chung LC, et al.: D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 1998, 44:1081–1089.

    Article  PubMed  CAS  Google Scholar 

  46. Friedman JI, Temporini H, Davis KL: Pharmacologic strategies for augmenting cognitive performance in schizophrenia. Biol Psychiatry 1999, 45:1–16.

    Article  PubMed  CAS  Google Scholar 

  47. Fields RB, Van Kammen DP, Peters JL, et al.: Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res 1988, 1:417–423.

    Article  PubMed  CAS  Google Scholar 

  48. Friedman JI, Adler DN, Temporini H, et al.: Guanfacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology 2001, 25:402–409.

    Article  PubMed  CAS  Google Scholar 

  49. Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005, 6:312–324.

    Article  PubMed  CAS  Google Scholar 

  50. Lewis DA, Moghaddam B: Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 2006, 63:1372–1376.

    Article  PubMed  Google Scholar 

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Correspondence to Stephen R. Marder.

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Webber, M.A., Marder, S.R. Better pharmacotherapy for schizophrenia: What does the future hold?. Curr Psychiatry Rep 10, 352–358 (2008). https://doi.org/10.1007/s11920-008-0056-8

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