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The Early Longitudinal Course of Cognitive Deficits in Schizophrenia

Keith H. Nuechterlein, PhD; Joseph Ventura, PhD; Kenneth L. Subotnik, PhD; and George Bartzokis, MD

Cognitive impairment is a core feature of schizophrenia. However, the longitudinal course and pattern of this impairment, and its relationship to functional outcome, are not fully understood. Among the likely factors in the persistence of cognitive deficits in schizophrenia are brain tissue changes over time, which in turn appear to be related to antipsychotic medication adherence.

What Evidence Indicates That Early Cognitive Deficits Are a Core Feature of Schizophrenia?

Cognitive deficits are viewed as a core feature of schizophrenia primarily because they clearly exist before the onset of psychosis and can predict illness onset among those at high risk of developing the illness. Additionally, these deficits often persist during symptomatic remissions in patients and are relatively stable across time both in patients and in individuals at risk for schizophrenia.

A good example of this comes from a study evaluating the change in cognitive abilities across the course of illness. Patients with a first hospitalization for schizophrenia were compared with healthy controls using a battery of neuropsychological tests.1 Results indicated large deficits for schizophrenia patients compared with controls on virtually all neuropsychol​ogical tests, with these deficits remaining stable across the first 5 years.

Are Initial Levels of Cognitive Deficit Related Longitudinally to Functional Outcome?

Despite clear evidence that cognitive impairment can predict functional outcome in chronic schizophrenia, results of studies examining this relationship in the early phase of psychosis have been mixed.2 A predictive relationship in this early period is critical because it would suggest that early intervention that improved cognitive functioning might prevent the development of chronic disability.

Recent data, however, strongly suggest early cognitive impairment does predict functional outcome. Results of a study of first-episode schizophrenia patients indicated that neurocognitive factors predicted 52% of the variance in work outcome 9 months after outpatient clinical stabilization (AV 1).3 These results clearly indicated that neurocognitive factors are critical to functional outcome after an onset of schizophrenia and thereby suggest that interventions targeting early cognitive deficits may be crucial to the prevention of chronic disability.

AV 1. Neurocognitive Predictors of Work Outcome in Recent-Onset Schizophrenia (00:48)

AV1
What Are the Separable Cognitive Domains in Schizophrenia and Are They All Relatively Stable?

In order to develop new treatments for the core cognitive deficits in schizophrenia, the key separable cognitive domains needed to be identified in schizophrenia. The National Institute of Mental Health (NIMH) created the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative to develop an expert consensus on the best way to evaluate changes in the core cognitive domains in clinical trials. This expert panel concluded that the consensus assessment battery should include 7 cognitive domains4 and then determined empirically that 10 cognitive tests should be selected for the MATRICS Consensus Cognitive Battery (MCCB).5 The 7 cognitive domains are (1) processing speed, (2) attention/vigilance, (3) working memory, (4) verbal learning, (5) visual learning, (6) reasoning and problem solving, and (7) social cognition.5

Are Changes in Intracortical Myelination in the Early Course of Schizophrenia Related to Antipsychotic Medication Adherence?

Data suggest that it is vital to keep schizophrenia patients consistently on their antipsychotic medications after an initial psychotic episode. Recently, a method of examining intracortical myelin volume was developed. Two important studies using this technology examined schizophrenia patients treated with either an oral agent (risperidone)6,7 or a long-acting injectable (fluphenazine decanoate6 or risperidone7) and compared them with healthy controls.6,7 Results indicated that second-generation antipsychotic medication was associated with greater intracortical myelin volume than first-generation antipsychotic medication.6 Furthermore, a group of patients receiving the long-acting formulation of a second-generation antipsychotic medication had significantly better medication adherence and increased initial intracortical myelin volume over time compared with a group receiving oral medication.7

CONCLUSIONS

There are several important conclusions from the studies reviewed. First, cognitive deficits clearly precede the onset of psychosis and are relatively stable across the first 5 years after a first episode of psychosis.

Second, these initial cognitive deficits are related longitudinally to functional outcome. A recent study of recent-onset schizophrenia determined that over half of the variance in work outcome after 9 months was explained by 3 cognitive factors after a clinical stabilization period, strongly suggesting that early cognitive deficits are critical to functional outcome and should be targeted early to prevent chronic disability.

Third, the recently developed MCCB measures 7 key domains of cognitive functioning in schizophrenia. All 7 of these domains in the MCCB demonstrated moderate to good stability across a 1-year period.8

Finally, the data suggest that it is critical to keep schizophrenia patients consistently on their antipsychotic medications after an initial psychotic episode. A novel method of examining intracortical myelin volume indicated that longacting injectable second-generation antipsychotic medication may prevent intracortical myelin decline through better adherence and pharmacokinetics. This consistency of antipsychotic medication may also have advantages for cognitive functioning.

References
  1. Hoff AL, Sakuma M, Weineke M, et al. Am J Psychiatry. 1999;156(9):1336–1341.PubMed
  2. Allott K, Liu P, Proffitt TM, et al. Schizophr Res. 2011;125(2–3):221–235. doi:10.1016/j.schres.2010.11.001 PubMed
  3. Nuechterlein KH, Subotnik KL, Green MF, et al. Schizophr Bull. 2011;37(suppl 2):S33–S40. doi:10.1093/schbul/sbr084 PubMed
  4. Green MF, Nuechterlein KH, Gold JM, et al. Biol Psychiatry. 2004;56(5):301–307. doi:10.1016/j.biopsych.2004.06.023 PubMed
  5. Nuechterlein KH, Green MF, Kern RS, et al. Am J Psychiatry. 2008;165(2):203–213. doi:10.1176/appi.ajp.2007.07010042 PubMed
  6. Bartzokis G, Lu PH, Stewart SB, et al. Schizophr Res. 2009;113(2–3):322–331. doi:10.1016/j.schres.2009.06.014 PubMed
  7. Bartzokis G, Lu PH, Raven EP, et al. Schizophr Res. 2012;140(1–3):122–128. doi:10.1016/j.schres.2012.06.036 PubMed
  8. Nuechterlein KH, Ventura J, Subotnik KL, et al. Cognitive remediation in the initial phase of schizophrenia. Paper presented at the Cognitive Remediation in Psychiatry Conference. New York, NY; June 8, 2012.
Keith H. Nuechterlein, PhD

Keith H. Nuechterlein, PhD; Joseph Ventura, PhD; Kenneth L. Subotnik, PhD; and George Bartzokis, MD

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Geffen School of Medicine and Department of Psychology, University of California, Los Angeles

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 Nuechterlein received a fee for service from Otsuka America Pharmaceutical, Inc., and Lundbeck for participation in the meeting and preparation of this manuscript. In the last year, Dr Nuechterlein has received consulting fees from Otsuka America Pharmaceutical, Inc., and Genentech. He has received research grants from PositScience, Inc., Genentech, and Janssen Scientific Affairs and has been on the speakers/advisory boards for Genentech, Janssen, and Otsuka America Pharmaceutical, Inc. Dr Ventura has been a consultant for Genentech, has received grant/research support from PositScience, Inc, and has been on the speakers/advisory board for Boehringer-Ingleheim. Dr Subotnik has been a consultant for Otsuka America Pharmaceutical, Inc., and has received grant/research support from Janssen Scientific Affairs, LLC. Dr Bartzokis has been a consultant for Otsuka America Pharmaceutical, Inc., and has received grant/research support from Janssen.


Acknowledgment

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.13065br3

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