Skip to main content

Cognitive impairment in schizophrenia: the great unmet need

  • Ralph Aquila (a1) (a2) and Leslie Citrome (a3)

Cognitive impairment in schizophrenia is present in almost all persons with the disorder and can be a substantial obstacle to efforts in the recovery process. In clinical research, cognition is assessed through neuropsychological testing as well as by different types of structured instruments focusing on function. Although nonpharmacological interventions such as cognitive remediation have been therapeutic, particularly in combination with vocational rehabilitation and supported employment, these modalities are not always easy to access. Pharmacological interventions are in development and have principally focused on the dopamine, glutamate, and acetylcholine neurotransmitter systems, aiming to target the dorsolateral prefrontal cortex and its interactions with other brain regions.

Corresponding author
*Address for correspondence: Ralph Aquila, Sidney R. Baer Jr. Center, 347 West 37th Street, New York, NY 10018. (Email:
Hide All

This activity is supported by an unrestricted educational grant from FORUM Pharmaceuticals, LLC.

Hide All
1.Aquila, R, Malamud, TJ, Sweet, T, Kelleher, JD. The store front, Fountain House, and the rehabilitation alliance. MedGenMed. 2006; 8(3): 67.
2.Keefe, RS, Eesley, CE, Poe, MP. Defining a cognitive function decrement in schizophrenia. Biol Psychiatry. 2005; 57(6): 688691.
3.Nuechterlein, KH, Green, MF, Kern, RS, et al. The MATRICS Consensus Cognitive Battery. Part 1: test selection, reliability and validity. Am J Psychiatry. 2008; 165(2): 203213.
4.Lindenmayer, JP, McGurk, SR, Mueser, KT, et al. A randomized controlled trial of cognitive remediation among inpatients with persistent mental illness. Psychiatr Serv. 2008; 59(3): 241247.
5.Chan, JY, Hirai, HW, Tsoi, KK. Can computer-assisted cognitive remediation improve employment and productivity outcomes of patients with severe mental illness? A meta-analysis of prospective controlled trials. J Psychiatr Res. 2015; 68: 293300.
6.Kaneko, Y, Keshavan, M. Cognitive remediation in schizophrenia. Clin Psychopharmacol Neurosci. 2012; 10(3): 125135.
7.McGurk, SR, Mueser, KT, Xie, H, et al. Cognitive enhancement treatment for people with mental illness who do not respond to supported employment: a randomized controlled trial. Am J Psychiatry. 2015; 172(9): 852861.
8.Kurzban, S, Davis, L, Brekke, JS. Vocational, social, and cognitive rehabilitation for individuals diagnosed with schizophrenia: a review of recent research and trends. Curr Psychiatry Rep. 2010; 12(4): 345355.
9.Folstein, MF, Folstein, SE, McHugh, PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3): 189198.
10.Nasreddine, ZS, Phillips, NA, Bédirian, V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005; 53(4): 695699.
11.Morosini, PL, Magliano, L, Brambilla, L, Ugolini, S, Pioli, R. Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000; 101(4): 323329.
12.Nafees, B, van Hanswijck de Jonge, P, et al. Reliability and validity of the Personal and Social Performance scale in patients with schizophrenia. Schizophr Res. 2012; 140(1–3): 7176.
13.Patterson, TL, Goldman, S, McKibbin, CL, Hughs, T, Jeste, DV. UCSD Performance-Based Skills Assessment: development of a new measure of everyday functioning for severely mentally ill adults. Schizophr Bull. 2001; 27(2): 235245.
14.Keefe, RS, Haig, GM, Marder, SR, et al. Report on ISCTM Consensus Meeting on Clinical Assessment of Response to Treatment of Cognitive Impairment in Schizophrenia. Schizophr Bull. In press. DOI: 10.1093/schbul/sbv111.
15.Rosenheck, R, Leslie, D, Keefe, R, et al. Barriers to employment for people with schizophrenia. Am J Psychiatry. 2006; 163(3): 411417.
16.Schonebaum, AD, Boyd, JK, Dudek, KJ. A comparison of competitive employment outcomes for the clubhouse and PACT models. Psychiatr Serv. 2006; 57(10): 14161420.
17.Norman, C. The Fountain House movement, an alternative rehabilitation model for people with mental health problems, members’ descriptions of what works. Scand J Caring Sci. 2006; 20(2): 184192.
18.Howes, OD, Kapur, S. The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull. 2009; 35(3): 549562.
19.Howes, O, McCutcheon, R, Stone, J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol. 2015; 29(2): 97115.
20.Jones, CK, Byun, N, Bubser, M. Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology. 2012; 37(1): 1642.
21.Barch, DM, Ceaser, A. Cognition in schizophrenia: core psychological and neural mechanisms. Trends Cogn Sci. 2012; 16(1): 2734.
22.Nielsen, RE, Levander, S, Kjaersdam Telléus, G, Jensen, SO, Østergaard Christensen, T, Leucht, S. Second-generation antipsychotic effect on cognition in patients with schizophrenia—a meta-analysis of randomized clinical trials. Acta Psychiatr Scand. 2015; 131(3): 185196.
23.Kantrowitz, JT, Javitt, DC. Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models. Clin Schizophr Relat Psychoses. 2010; 4(3): 189200.
24.Tsapakis, EM, Travis, MJ. Glutamate and psychiatric disorders. Adv Psychiatr Treat. 2002; 8(3): 189197.
25.Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron. 2003; 40(5): 881884.
26.Kantrowitz, JT, Javitt, DC. Glutamate: new hope for schizophrenia treatment. Curr Psychiatry. 2011; 10(4): 6974.
27.Citrome, L. Neurochemical models of schizophrenia: transcending dopamine. Curr Psychiatry. 2011; 10(9): S10S14.
28.Stahl, MS. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd ed. New York: Cambridge University Press; 2008.
29.Kantrowitz, JT, Javitt, DC. N-Methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull. 2010; 83(3–4): 108121.
30.Citrome, L. Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains. J Clin Psychiatry. 2014; 75(Suppl 1): 2126.
31.Iwata, Y, Nakajima, S, Suzuki, T, et al. Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. Mol Psychiatry. In press. DOI: 10.1038/mp.2015.68.
32.Birks, J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;(1): CD005593.
33.Singh, J, Kour, K, Jayaram, MB. Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database Syst Rev. 2012; 1: CD007967.
34.Young, JW, Geyer, MA. Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia. Biochem Pharmacol. 2013; 86(8): 11221132.
35.Levin, ED, McClernon, FJ, Rezvani, AH. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl). 2006; 184(3–4): 523539.
36.Huang, M, Felix, AR, Flood, DG, et al. The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens. Psychopharmacology (Berl). 2014; 231(23): 45414551.
37.Prickaerts, J, van Goethem, NP, Chesworth, R, et al. EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors. Neuropharmacology. 2012; 62(2): 10991110.
38.Keefe, RS, Meltzer, HA, Dgetluck, N, et al. Randomized, double-blind, placebo-controlled study of encenicline, an α7 nicotinic acetylcholine receptor agonist, as a treatment for cognitive impairment in schizophrenia. Neuropsychopharmacology. In press. DOI: 10.1038/npp.2015.176.
39.Deardorff, WJ, Shobassy, A, Grossberg, GT. Safety and clinical effects of EVP-6124 in subjects with Alzheimer’s disease currently or previously receiving an acetylcholinesterase inhibitor medication. Expert Rev Neurother. 2015; 15(1): 717.
40. Forum Pharmaceuticals. FORUM Pharmaceuticals Inc. Updates Encenicline Phase 3 Clinical Trial Programs in Alzheimer’s Disease and Cognitive Impairment in Schizophrenia. Press Release. 14 September 2015. Available at: Accessed 15 September 2015.
41.Carruthers, SP, Gurvich, CT, Rossell, SL. The muscarinic system, cognition and schizophrenia. Neurosci Biobehav Rev. 2015; 55: 393402.
42.Köster, LS, Carbon, M, Correll, CU. Emerging drugs for schizophrenia: an update. Expert Opin Emerg Drugs. 2014; 19(4): 511531.
43.Green, MF, Nuechterlein, KH, Gold, JM, et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry. 2004; 56(5): 301307.
44.Buchanan, RW, Freedman, R, Javitt, DC, Abi-Dargham, A, Lieberman, JA. Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull. 2007; 33(5): 11201130.
45.Goff, DC, Hill, M, Barch, D. The treatment of cognitive impairment in schizophrenia. Pharmacol Biochem Behav. 2011; 99(2): 245253.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed