Is Cognitive Impairment in Schizophrenia Multidimensional?

Symptom Dimensions in Schizophrenia

Since the earliest conceptions of schizophrenia, dating back to the 19th century, there has been a focus on the heterogeneity of the illness. Both Kraepelin and Bleuler agreed that schizophrenia had many different variants or subtypes and that the condition may be the result of more than one illness process. Kraepelin's focus was on the subtypes of schizophrenia, describing classical subtypes that are still contained in the DSM today. Blueler focused on the fact that patients with schizophrenia present with an array of different symptoms, even if there is core pathology reflected by the fundamental symptoms (affect, autism, associations, ambivalence).

Since that time, the diversity of schizophrenia has been investigated through studies of symptomatic structure, often using factor analysis. Symptoms in schizophrenia generally tend to assort themselves into three different dimensions, including psychosis (“reality distortion”), negative symptoms, and disorganization. This dimensional structure is found in both treated and untreated patients, and the structure of changes during treatment are related to the dimensions of symptoms seen in untreated patients. Thus, these dimensions have considerable validity and temporal stability.

Dimensions of Cognitive Impairment in Schizophrenia

Interest in dimensions of cognitive impairment in schizophrenia was originally spurred by ideas that the impairments seen in the illness resemble those seen in illnesses with generally focal brain dysfunction. For instance, the behavioral disorganization and emotional changes seen in schizophrenia led to the idea that deficits in frontal lobe functioning were the driver of the cognitive impairments. Further, the consistent findings of impairments in working memory have also been consistent with that idea, since working memory functions appear localized to the frontal lobe in imaging studies.¹ Major disturbances in episodic memory led to the suggestion that dysfunctions in hippocampal and medial temporal lobe structures were the origin of cognitive changes seen in the illness.² Slowed speed of processing and reductions in reaction time are consistent with the idea of changes in basal ganglia functioning. In fact, over 15 years ago an issue of Schizophrenia Bulletin (Volume 16, 1990), guest edited by Monte Buchsbaum, was entitled “Frontal Lobes, Temporal Lobes, and Basal Ganglia: Three sites for schizophrenia?”³

There has been considerable discussion about whether the presence of deficits in tasks sensitive to regional brain dysfunction can actually substantiate the presence of focal brain lesions. Most contemporary thinking about the functions of cortical and subcortical structures has focused on network relationships, wherein several regions function in concert and where disruptions in any one of these linked regions can lead to deficits in tests previously shown to be sensitive to focal lesions.

A primary clinical example of such relationships is that of frontostriatal dementing conditions, such as Huntington's disease. In this genetically transmitted illness, deterioration in the head of the caudate nucleus leads to a series of changes in cognition, behavior, and emotional functioning. One of the primary cognitive consequences of Huntington's disease is disruption in executive functioning, as indexed by tests such as the Wisconsin Card Sorting test (WCST). This test, shown to be sensitive to anterior cortical lesions and the be associated with substantial performance deficits in people with schizophrenia, elicits substantial changes in frontal lobe regional cerebral blood flow when performed. However, in Huntington's disease the brain changes are not in the anterior frontal lobes and these performance deficits, on a test often cited as evidence of frontal lobe dysfunction in schizophrenia, are not caused directly by frontal lobe lesions. Lesions throughout the brain can produce deficits on the WCST,⁴ suggesting that cortical network failures are probably leading to performance deficits on tests of “focal” neuropsychological abilities.

The Possibility of Global Cognitive Deficits

It has been known for 50 years that people with schizophrenia often perform very poorly on most cognitive tests. This poor performance has generally been shown not to be due to poor motivation, as some cognitive tests are performed at levels consistent with premorbid functioning. It has been argued that there are “overriding deficits,” which produce reduced scores on other measures. This possibility is also consistent with the generally overlapping nature of the ability areas measured across cognitive tests. For instance, many neuropsychological tests require attention, concentration, working memory, and speeded processing for efficient performance even if they are really aimed at verbal learning and memory.

Several recent factor analytic studies have produced somewhat inconsistent results. Some of these studies have produced factor structures consistent with multiple cognitive dimensions, with separate dimensions for attention, processing speed, episodic memory, and verbal skills, while others have found a single dimension reflecting overall severity as the best fitting model. When analyses have been aimed at identification of the most informative or most important predictor of functioning, both working memory and processing speed have been implicated. This is an important finding, because test-based measures of working memory and processing speed are easily available, easy to administer, and have excellent normative standards.

Given the fact that cognitive impairments in schizophrenia likely originate from dysfunctions in cortical and subcortical networks rather than in discrete brain regions, it seems likely that the “true” answer to the dimensionality question is somewhere between a single global deficit and a multidimensional factor structure reflecting the contributions of multiple dysfunctional regions. Clinical neuropsychological tests themselves may be too overlapping in their domain coverage and thus not sensitive to specific regional deficits in any case. It may be that much less extensive assessment is required in order to see how impaired an individual patient with schizophrenia actually is.

Clinical Implications

There are several important implications for clinicians for the potential unidimensionality of cognitive impairment in schizophrenia. The most import one is efficiency of assessment. If all of the cognitive impairment in schizophrenia can be explained by performance on one or two tests, then the assessment demands for schizophrenia are markedly reduced and cognitive impairment can be estimated very easily. In the recent baseline publication of the CATIE baseline cognitive performance, the test that explained the greatest part of the total score was WAIS-III digit symbol.⁵ This test takes 120 seconds to administer, has limited practice effects, and has extensive normative standards available. As a result, over 60 percent of the variance in total scores for cognitive impairment in schizophrenia can be understood in less than three minutes. This test has also been shown very recently to be the single most impaired neuropsychological measure in patients with schizophrenia.⁶

News from Mental Health America.

Bridging the Gap Between Ordinary Practice and Recommended Care

by David Shern, PhD, President and CEO, Mental Health America

As with all sub-specialties in medicine, the delivery of mental healthcare is plagued by a significant gap between ordinary practice and recommended care. The widely cited RAND study indicates that only about half of the time do individuals receive care that comports with evidence-based guidelines. Reducing this gap between “what we know” and “what we do” is vital to our nation's health.

Various strategies have been used to help close the gap. Comparative effectiveness research (CER) is one technique that can be used as a support for healthcare decision-making. CER involves systematic reviews of clinical studies to compare efficacy of treatment approaches for specified health conditions. Such research typically focuses on pharmaceuticals (e.g., AHRQ's Effective Healthcare Program), but is expanding to healthcare interventions broadly. The benefit: Wider access to information can help patients and clinicians weigh benefits and risks for all treatment options.. CER can also identify areas for further research investment and frame dialogue about how such research informs coverage and reimbursement decisions. The risk: Comparative effectiveness research can be used as a blunt policy instrument for cost control. CER is only as good as the measures and populations that are included in the research being compared and synthesized. Its applicability to a specific individual or a particular circumstance may be importantly limited. Within a cost containment framework, however, similar average outcomes on a limited number of targets can provide a rationale for limiting treatment choices. Differences between people in their response to treatment and multifaceted outcomes that often accompany the management of chronic illnesses can confound this method.

Restrictions on patient and clinician choice of therapies in state Medicaid programs and in Medicare Part D drug plans demonstrate the potential for inappropriate application of CER to coverage decisions, particularly for high-cost chronic health conditions. These approaches fail to recognize and support individualized care decisions and imply “population-based” solutions to complex individual health conditions.

A recent Congressional hearing demonstrated growing consensus among legislators, policy makers, and some advocates regarding the importance of CER as a clinical and policy tool. The hearings also highlighted differing opinions about how cost should be estimated and incorporated in comparative value determinations as well as the appropriate role of government, industry, and payers in conducting and using such research. The voice of primary consumers was noticeably missing from these deliberations, which highlights a serious need to better balance the perspectives represented in designing and synthesizing clinical evidence. Patient perspectives on valuing outcomes, improving dissemination methods, and representing the unique nature of each clinical situation are essential. Full participation of patients and families in every aspect of CER is critically important and consistent with the historical tenets of evidence-based medicine that balance research, clinical expertise with patient perspectives, and preferences.

Mental Health America convenes the National Working Group on Evidence-Based Healthcare, which promotes awareness and engagement in EBM-related initiatives. A paper on patient/consumer inclusion is forthcoming. Visit www.evidencebasedhealthcare.org for more information.