Skip to main content Accessibility help
  • Print publication year: 2012
  • Online publication date: July 2012

Chapter 12 - The importance of treating cognition in schizophrenia and other severe mental illnesses: background, strategies, and findings to date


CNS drug development is rapidly evolving to meet the unique and changing demands of the fields of psychiatry and neurology. Phase I studies are traditionally focused on determining the safety, tolerability, and pharmacokinetics of a new molecular entity in young healthy volunteers: first in a single ascending dose (SAD) study and then in a multiple ascending dose (MAD) study. The use of an adaptive design to examine data and modify the study in real time may also promote time- and cost-efficient identification of novel molecular entities (NMEs) that have the characteristics necessary to be successful in confirm stages of drug development research. This chapter discusses how use of biomarkers as surrogate endpoints can be incorporated into early clinical trials to determine if a drug modulates the appropriate targets, which enhances the likelihood of demonstrating efficacy in the confirm phase of clinical testing.


Bowie, C. R., Twamley, E. W., Anderson, H., et al. (2007). Self-assessment of functional status in schizophrenia. J Psychiatr Res, 41, 1012–18.
Bowie, C. R., Leung, W. W., Reichenberg, A., et al. (2008). Predicting schizophrenia patients' real world behavior with specific neuropsychological and functional capacity measures. Biol Psychiat, 63, 505–11.
Buchanan, R. W., Davis, M., Goff, D., et al. (2005). A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophrenia Bull, 31, 5–19.
Buchanan, R. W., Keefe, R. S. E., Umbricht, D., et al. (2010). The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: What do we know 5 years later? Schizophrenia Bull, [epub ahead of print].
Burdick, K. E., Goldberg, T. E., Cornblatt, B. A., et al. (2011). The MATRICS Consensus Cognitive Battery in Patients with Bipolar I Disorder. Neuropsychopharmacology, 36, 1587–92.
Dunning, D. and Story, A. L. (1991). Depression, realism, and the overconfidence effect: are the sadder wiser when predicting future actions and events?J Person Soc Psychol, 61, 521–32.
Fisher, M., Holland, C., Merzenich, M. M., and Vinogradov, S. (2009). Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia. Am J Psychiat, 166, 805–11.
Fisher, M., Holland, C., Subramaniam, K., and Vinogradov, S. (2010). Neuroplasticity-based cognitive training in schizophrenia: An interim report on the effects 6 months later. Schizophrenia Bull, 36, 869–79.
Green, M. F., Kern, R. S., Braff, D. L., and Mintz, J. (2000). Neurocognitive deficits and functional outcome in schizophrenia: Are we measuring the “right stuff”?Schizophrenia Bull, 26, 119–36.
Green, M. F., Nuechterlein, K. H., and Kern, R. S. (2008). Functional co-primary measures for clinical trials in schizophrenia: results from the MATRICS Psychometric and Standardization Study. Am J Psychiat, 165, 221–8.
Green, M. F., Schooler, N. R., Kern, R. D., et al. (2011). Evaluation of functionally-meaningful measures for clinical trials of cognition enhancement in schizophrenia. Am J Psychiat, 168, 400–7.
Harvey, P. D. (2009). Pharmacological cognitive enhancement in schizophrenia. Neuropsychol Rev, 19, 324–35.
Harvey, P. D. and McClure, M. M. (2006). Pharmacological approaches to the management of cognitive dysfunction in schizophrenia. Drugs, 66, 1465–73.
Harvey, P. D., Velligan, D. I., and Bellack, A. S. (2007). Performance-based measures of functional skills: usefulness in clinical treatment studies. Schizophrenia Bull, 33, 1138–48.
Harvey, P. D., Keefe, R. S. E., Patterson, T. L., Heaton, R. K., and Bowie, C. R. (2009). Abbreviated neuropsychological assessments in schizophrenia: Association with different outcomes measures. J Clin Exp Neuropsychol, 31, 462–71.
Harvey, P. D., Ogasa, M., Cucchiaro, J., Loebel, A., and Keefe, R. S. E. (2011a). Performance and interview-based assessments of cognitive change in a randomized, double-blind comparison of lurasidone vs. ziprasidone. Schizophr Res, 127, 188–94.
Harvey, P. D., Raykov, T., Twamley, E. M., et al. (2011b). In press. Validating the measurement of real-world functional outcome: Phase I results of the VALERO study. Am J Psychiat.
Heaton, R. K. and Pendleton, M. G. (1981). Use of neuropsychological tests to predict patients' everyday functioning. J Con Consult Psychol, 49, 807–21.
Huxley, N. and Baldessarini, R. J. (2007). Disability and its treatment in bipolar disorder patients. Bipolar Disorder, 9, 183–96.
Keefe, R. S., Goldberg, T. E., Harvey, P. D., et al. (2004). The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res, 68, 283–97.
Keefe, R. S. E., Bilder, R. M., Harvey, P. D., et al. (2006a). Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology, 31, 2033–46.
Keefe, R. S. E., Poe, M., Walker, T. M., Kang, J. W., and Harvey, P. D. (2006b). The schizophrenia cognition rating scale: An interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity. Am J Psychiat, 163, 426–32.
Keefe, R. S. E., Bilder, R. M., Davis, S. M., et al. (2007). Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiat, 64, 633–47.
Keefe, R. S. E., Vinogradov, S., Medalia, A., et al. (2010). Report from the Working Group Conference on multi-site trial design for cognitive remediation in schizophrenia. Schizophrenia Bull, doi: 10.1093/schbul/sub010.
Keefe, R. S. E., Fox, K. H., Harvey, P. D., et al. (2011). Characteristics of the MATRICS Consensus Cognitive Battery in a 29-site antipsychotic schizophrenia clinical trial. Schizophr Res, 125, 161–8.
Kern, R. S., Nuechterlein, K. H., Green, M. F., et al. (2008). The MATRICS Consensus Cognitive Battery: Part 2. Co-norming and standardization. Am J Psychiat, 165, 214–20.
Laughren, T. (2001). A regulatory perspective on psychiatric syndromes in Alzheimer's disease. Am J Geriatr Psychiat, 9, 340–5.
Leifker, F. R., Patterson, T. L., Bowie, C. R., Mausbach, B. T., and Harvey, P. D. (2010). Psychometric properties of performance-based measurements of functional capacity: test-retest reliability, practice effects, and potential sensitivity to change. Schizophr Res, 119, 246–52.
Leifker, F. R., Patterson, T. L., Heaton, R. K., and Harvey, P. D. (2011). Validating measures of real-world outcome: the results of the VALERO Expert Survey and RAND Panel. Schizophrenia Bull, 37, 334–43.
Leung, W. W., Bowie, C. R., and Harvey, P. D. (2008). Functional implications of neuropsychological normality and symptom remission in older outpatients diagnosed with schizophrenia: a cross-sectional study. J Int Neuropsychol Soc, 14, 479–88.
Lindenmayer, J. P., McGurk, S. R., Mueser, K. T., et al. (2008). A randomized controlled trial of cognitive remediation among inpatients with persistent mental illness. Psychiatric Serv, 59, 241–7.
McClure, M. M., Bowie, C. R., Patterson, T. L., et al. (2007). Correlations of functional capacity and neuropsychological performance in older patients with schizophrenia: evidence for specificity of relationships?Schizophr Res, 89, 330–8.
McGurk, S. R., Mueser, K. T., and Pascaris, A. (2005). Cognitive training and supported employment for persons with severe mental illness: one-year results from a randomized controlled trial. Schizophrenia Bull, 31, 898–909.
McGurk, S. R., Mueser, K. T., Feldman, K., Wolfe, R., and Pascaris, A. (2007a). Cognitive training for supported employment: 2–3 year outcomes of a randomized controlled trial. Am J Psychiat, 164, 437–41.
McGurk, S. R., Twamley, E. W., Sitzer, D. I., McHugo, G. J., and Mueser, K. T. (2007b). A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiat, 164, 1791–802.
McKibbin, C., Patterson, T. L., and Jeste, D. V. (2004). Assessing disability in older patients with schizophrenia: results from the WHODAS-II. J Nerv Ment Dis, 192, 405–13.
Medalia, A., Revheim, N., and Herlands, T. (2009). Cognitive Remediation for Psychological Disorders, Therapist Guide. New York: Oxford University Press.
Neuchterlein, K. H., Green, M. F., Kern, R. S., et al. (2008). The MATRICS Consensus Cognitive Battery: Part 1. Test selection, reliability, and validity. Am J Psychiat, 165, 203–13.
Patterson, T. L., Semple, S. J., Shaw, W. S., Grant, I., and Jeste, D. V. (1996). Researching the caregiver: family members who care for older psychotic patients. Psychiatr Ann, 26, 772–84.
Patterson, T. L., Goldman, S., McKibbin, C. L., Hughs, T., and Jeste, D. V. (2001a). UCSD performance-based skills assessment: development of a new measure of everyday functioning for severely mentally ill adults. Schizophrenia Bull, 27, 235–45.
Patterson, T. L., Moscona, S., McKibbin, C. L., Davidson, K., and Jeste, D. V. (2001b). Social skills performance assessment among older patients with schizophrenia. Schizophr Res, 48, 351–60.
Sabbag, S., Twamley, E. W., Vella, L., Heaton, R. K., Patterson, T. L., and Harvey, P. D. (2011). Assessing everyday functioning in schizophrenia: Not all informants seem equally informative. Schizophr Res, 131, 250–5.
Silverstein, S. M., Jaeger, J., Donovan-Lepore, A. M., et al. (2010). A comparative study of the MATRICS and IntegNeuro cognitive assessment batteries. J Clin Exp Neuropsychol, 32 (9), 937–52.
Wingo, A., Harvey, P. D., and Baldessarini, R. J. (2009). Neurocognitive impairment in bipolar disorder patients: functional implications. Bipolar Disord, 11, 113–25.
Wykes, T., Huddy, V., Cellard, C., McGurk, S. R., and Czobor, P. (2011). A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiat, 168 (5), 472–85.