The Longitudinal Course of Cognitive Impairment in Schizophrenia: An Examination of Data From Premorbid Through Posttreatment Phases of Illness

Richard S. E. Keefe, PhD

Cognitive impairment is a core feature of schizophrenia that appears to begin prior to the onset of psychosis and persists throughout the life span of someone with the illness. However, the specific longitudinal course of cognitive impairment in schizophrenia is not fully understood. The aim of this review is to examine some of the more recent studies that address components of the course of cognitive impairment in schizophrenia and to address current gaps in the literature.

A Sample of Cross-Sectional Cognitive Deficits in Schizophrenia Patients

The first reviewed data are from the cognitive test battery derived from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project. The MATRICS Consensus Cognitive Battery (MCCB) was designed to evaluate the effects of treatment on cognitive impairment in patients with schizophrenia. An examination of the cross-sectional baseline differences between schizophrenia patients and healthy adults using this battery suggests that it is reliable and sensitive to impairments in 7 different domains of cognitive functioning.1 Patients with schizophrenia performed 1 to 2 standard deviations below the general population on all domains based on normative data collected from healthy controls, and close to 2.5 standard deviations on a composite measure.2 These results are consistent with other studies indicating a similar range of impairment.2,3

The profile of cognitive impairment in first-episode patients demonstrated a similar severity of cognitive impairment with a global deficit of 1.5 standard deviations relative to healthy controls at the first psychotic episode.4 Memory was the most impaired specific domain, with additional deficits in motor and executive function. The data from this and other similar studies make clear that the level of cognitive impairment at the first episode is severe.

Examination of Premorbid and Longitudinal Symptoms in Patients Who Later Develop Schizophrenia

Cognitive impairment appears to be present, on average, in those who will eventually develop schizophrenia.5 Draftees into the Israeli army who were later diagnosed with schizophrenia performed 0.5 standard deviations worse than the draftees who did not develop psychiatric illness.6 Examination of school records suggests that children who later develop schizophrenia start out 1 grade level behind their peers and, by the time they finish high school, are even further behind.7

Premorbid academic performance was used to compare schizophrenia patients to their healthy peers in a retrospective longitudinal study.8 Standardized test scores were lower than average at grades 4 and 8, but not significantly different. However, a small but statistically significant drop in scores occurred between grades 8 and 11, a timeframe corresponding to the onset of puberty, in those who subsequently developed schizophrenia. While these cognitive changes are statistically significant, they are based on group changes and are likely not observable in any single individual based on current testing methodology and educational evaluation.

Subtle declines have also been reported across the time period preceding the overt onset of psychotic symptoms, with further impairment at the initial episode of illness. A community study from New Zealand assessed most of the approximately 1,000 residents (91%) from birth, with a series of assessments initiated at 3 years of age that extended out 30 years.9 Results indicated 2 interrelated developmental processes evident from childhood to early adolescence (ages 7–13 years). Static cognitive impairments were found on measures assessing verbal and visual knowledge acquisition, reasoning, and conceptualization in the children who developed schizophrenia as adults. In addition to the static deficits, these children exhibited developmental lags in processing speed, attention, visual-spatial problem solving ability, and working memory.

The Course of Cognitive Impairment Posttreatment: What Is the Evidence From Recent Large Trials?

Although there was initial promise of improved cognitive function for second- generation antipsychotics, recent studies indicate no differences among antipsychotics,10,11 with the initial improvement likely attributable to practice effects, inappropriate medication dosing, and poor study design.12 The impact on cognitive function of haloperidol and several second-generation antipsychotics was assessed in patients with schizophrenia after the first episode of psychosis.13 The study design provided more generalizability because of the broad eligibility criteria. Composite cognitive scores improved modestly across the 6-month period in the treatment groups (AV 1), and there were no significant treatment differences between antipsychotics. The authors concluded that there were minimal to no differences in cognitive improvement across the 5 antipsychotics.

AV 1. Change in the Cognitive Composite Score From Baseline to 6 Months in First-Episode Psychosis (00:47)


In summary, patients who develop schizophrenia demonstrate cognitive impairment beginning as early as the first grade, with deterioration seen across school. After the initiation of psychosis, patients with schizophrenia demonstrate substantial cognitive deficits ranging from 1.5 to 2.5 standard deviations below healthy controls. Finally, while antipsychotic treatment improves symptoms, there appear to be no differences in the degree of cognitive improvement between first- and second-generation agents.14

  1. Nuechterlein KH, Green MF, Kern RS, et al. Am J Psychiatry. 2008;165(2):203–213. doi:10.1176/appi.ajp.2007.07010042 PubMed
  2. August SM, Kiwanuka JN, McMahon RP, et al. Schizophr Res. 2012;134(1):76–82. doi:10.1016/j.schres.2011.10.015 PubMed
  3. Umbricht D, Keefe RS, Murray S, et al. Neuropsychopharmacology. 2014;39(7):1568–1577. doi:10.1038/npp.2014.17 PubMed
  4. Bilder RM, Goldman RS, Robinson D, et al. Am J Psychiatry. 2000;157(4):549–559. doi:10.1176/appi.ajp.157.4.549 PubMed
  5. Seidman LJ, Giuliano AJ, Meyer EC, et al. Arch Gen Psychiatry. 2010;67(6):578–588. doi:10.1001/archgenpsychiatry.2010.66 PubMed
  6. Davidson M, Reichenberg A, Rabinowitz J, et al. Am J Psychiatry. 1999;156(9):1328–1335. PubMed
  7. Bilder RM, Reiter G, Bates J, et al. J Clin Exp Neuropsychol. 2006;28(2):270–282. doi:10.1080/13803390500360554 PubMed
  8. Fuller R, Nopoulos P, Arndt S, et al. Am J Psychiatry. 2002;159(7):1183–1189. doi:10.1176/appi.ajp.159.7.1183 PubMed
  9. Reichenberg A, Caspi A, Harrington H, et al. Am J Psychiatry. 2010;167(2):160–169. doi:10.1176/appi.ajp.2009.09040574 PubMed
  10. Keefe RSE, Silva SG, Perkins DO, et al. Schizophr Bull. 1999;25(2):201–222. doi:10.1093/oxfordjournals.schbul.a033374 PubMed
  11. Woodward ND, Purdon SE, Meltzer HY, et al. Schizophr Res. 2007;89(1–3):211–224. doi:10.1016/j.schres.2006.08.021 PubMed
  12. Harvey PD, Keefe RS. Am J Psychiatry. 2001;158(2):176–184. doi:10.1176/appi.ajp.158.2.176 PubMed
  13. Davidson M, Galderisi S, Weiser M, et al. Am J Psychiatry. 2009;166(6):675–682. doi:10.1176/appi.ajp.2008.08060806 PubMed
  14. Keefe RS, Bilder RM, Davis SM, et al. Arch Gen Psychiatry. 2007;64(6):633–647. doi:10.1001/archpsyc.64.6.633 PubMed
John W. Newcomer, MD

Richard S. E. Keefe, PhD

Duke University Medical Center, Durham, North Carolina

This Brief Report is derived from the roundtable meeting “Understanding the lifetime course of schizophrenia: a longitudinal perspective on neurobiology to promote better outcomes and recovery,” which was held October 15, 2013. The author acknowledges Healthcare Global Village for editorial assistance in developing the manuscripts.

The meeting, manuscript preparation, and dissemination of this brief report were supported by Otsuka America Pharmaceutical, Inc., and Lundbeck. All faculty received a fee for service from Otsuka America Pharmaceutical, Inc., and Lundbeck for participation in the meeting and preparation of the manuscripts.

Faculty Disclosure

Dr Keefe received a fee for service from Otsuka America Pharmaceutical, Inc., and Lundbeck for participation in the meeting and preparation of this manuscript. Currently or in the past 12 months, he has received investigator-initiated research funding support from the Department of Veteran’s Affair, Feinstein Institute for Medical Research, National Institute of Mental Health, Research Foundation for Mental Hygiene, Inc, and the Singapore National Medical Research Council; has received honoraria, served as a consultant, or served as an advisory board member for Abbvie, Akebia, Amgen, Asubio, AviNeuro/ChemRar, BiolineRx, Biomarin, Boehringer-Ingelheim, EnVivo, GW Pharmaceuticals, Lundbeck, Merck, Mitsubishi, Novartis, Otsuka America Pharmaceutical, Inc., Roche, Shire, Takeda, and Targacept; receives royalties from the BACS testing battery, the MATRICS Battery (BACS Symbol Coding), and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) and is also a shareholder in NeuroCog Trials, Inc, and Sengenix.


The opinions expressed herein are those of the authors and do not necessarily reflect the opinions of the publisher, the American Society of Clinical Psychopharmacology, Healthcare Global Village, or the commercial supporters.

doi: 10.4088/JCP.13065br2

​​​​​​​​​​​​​​​​​​​​​​​ The Journal of Clinical Psychiatry The Primary Care Companion for CNS Disorders The CME Institute Neurology Knowledge Terms of Use Privacy Policy