Should cognitive impairment be included in the diagnostic criteria for schizophrenia?
Authors: RICHARD S.E. KEEFE
Journal: World Psychiatry (2008)

Neurocognitive impairment in schizophrenia is clinically relevant and profound. Patients with schizophrenia perform 11/2 to 2 standard deviations below healthy controls on various neurocognitive tests. The severity of this impairment is greatest in the domains of memory, attention, working memory, problem solving, processing speed, and social cognition 1. These deficits are present prior to the initiation of antipsychotic treatment 2 and are not caused by psychotic symptoms in patients who are able to complete cognitive testing, which includes the overwhelming majority 3. Many of the various cognitive deficits in schizophrenia have been shown to be associated with functional outcomes such as difficulty with community functioning, difficulty with instrumental and problem-solving skills, reduced success in psychosocial rehabilitation programs 4, and the inability to maintain successful employment 5. Cognitive deficits are better able to explain important functional outcomes such as work performance and independent living 6 than positive or negative symptoms. The importance of cognitive deficits in schizophrenia goes beyond their severity and relation to functional outcomes. Cognitive deficits are present in some patients with schizophrenia prior to the onset of psychosis and are correlated with measurable brain dysfunction more than any other aspect of the illness. Perhaps most importantly, cognition is increasingly considered as a primary target for treatment 7–10. Despite the relevance of cognitive impairment to biology, function, and treatment in schizophrenia, it is not included in the DSM-IV-TR or ICD-10 criteria. It is noteworthy, however, that the first sentence of the description of schizophrenia in DSM-IV-TR includes four references to cognitive disturbances: "the characteristic symptoms of schizophrenia involve a range of cognitive and emotional dysfunctions that include perception, inferential thinking, language and communication, behavioral monitoring, affect, fluency and productivity of thought and speech, hedonic capacity, volition and drive, and attention" 11. Thus, it is clear that cognition was important to the schizophrenia experts who authored DSM-IV-TR, but a method for including this fundamental aspect of the illness in the diagnostic criteria for schizophrenia has not been determined. This article raises the question of whether cognitive impairment should be included in the diagnostic criteria for schizophrenia, and forwards a proposal for consideration that severe cognitive impairment should be part of the criteria for schizophrenia in DSM-V and ICD-11 12. In addition, a research agenda for determining the validity and usefulness of including cognitive impairment as part of the criteria for schizophrenia will be discussed. The following criterion is proposed for consideration in the diagnostic criteria for DSM-V and ICD-11 schizophrenia: "A level of cognitive functioning suggesting a consistent severe impairment and/or a significant decline from premorbid levels considering the patient's educational, familial, and socioeconomic background". If these diagnostic systems focus less on specific criteria in favor of a completely dimensional approach 13, the above recommendation could be easily revised to include cognitive impairment as one of the key dimensions. This proposal will be considered in the context of several issues, including the evidence for diagnostic differences in cognition, the clinical importance of recognizing cognitive impairment in schizophrenia, and the assessment challenges that would be produced by such a change in the criteria. The ability of a diagnostic refinement to improve the distinction between two entities and thus create an increased non-overlap between them is considered to be a crucial determinant for inclusion 14. Thus, the first question to be considered is whether adding the above definition of cognitive impairment to the criteria for schizophrenia will help define a "point of rarity" with other diagnostic entities, particularly affective disorders. The cognitive experts in the Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project concluded that "schizophrenia and schizoaffective disorder share a similar pattern of cognitive impairments, which is distinct from patterns in major depression, bipolar disorder, and Alzheimer's dementia" 10. The group came to this conclusion based upon previous work suggesting that patients with schizophrenia demonstrate a pattern of deficits that is more profound than those in major depression and bipolar disorder, is more stable over the course of illness, and is less related to other symptoms and clinical state. Patients with schizophrenia have more profound impairment on all of the cognitive tests that were measured in each diagnostic group. The deficits of schizophrenia have also been shown to be more severe than those in affective disorders in other comparisons 10,15. A meta-analysis comparing the performances of patients with schizophrenia and bipolar disorder concluded that the cognitive performance of patients with schizophrenia is about 0.5 SD more impaired, even when patient groups are matched on the severity of their clinical symptoms. Deficits in patients with schizophrenia were found to be especially profound on tests of verbal fluency, working memory, executive control, visual memory, mental speed, and verbal memory 15. Studies of patients with first episode schizophrenia and affective disorder appear to support the meta-analyses completed on more chronic patients. In an epidemiological study of all first admission psychotic disorders in Suffolk County, New York, patients who received a diagnosis of schizophrenia at 24 months follow-up (n=148) were found to have significantly greater cognitive deficits compared to those first episode psychotic patients who were diagnosed with bipolar disorder (n=87) and depression (n=56) 24 months later. Again, the differences between schizophrenia and affective psychoses were particularly profound with regard to memory, executive functions, and mental speed tasks 16. These results support the predictive validity of the new cognitive criterion, and suggest that cognitive information at first episode may aid in the decision of whether an individual's later diagnosis will be in the affective or schizophrenia spectrum. Although patients with affective psychoses also have cognitive impairment, in these patients cognitive deficits are more strongly associated with clinical symptoms and state-related factors than they are in patients with schizophrenia 17,18. In a study of patients with schizophrenia or bipolar disorder who were assessed when psychotic at baseline and then 8 months later when remitted, only the bipolar patients improved in their cognitive performance 19; the patients with schizophrenia showed the same level of cognitive impairment at follow-up. Similar data have been reported in first episode samples. First episode patients with affective psychoses perform similarly to those with first episode schizophrenia, but patients with non-psychotic affective disorders perform significantly better than both psychotic groups 20. Thus, although the cognitive deficits of affective disorders may be profound in some cases, these deficits are related to clinical symptoms. In contrast, cognitive impairment in patients with schizophrenia has been repeatedly demonstrated to be uncorrelated with psychotic symptoms 3,21–23. This absence of correlation is partially due to the distinct longitudinal differences between psychotic symptoms and cognition: the symptoms of schizophrenia vary over time in almost all patients, leading to low stability coefficients over time 24, while the stability of cognitive deficits in all domains is very high, with test-retest coefficients ranging between 0.70 and 0.85 even in patients tested one year apart following their initial treatment for psychosis 24. Thus, although there are cognitive deficits in affective disorders, they fluctuate in parallel with other symptom changes. In schizophrenia, however, they appear to be the most stable aspect of the disorder. If cognitive impairment is to be considered a part of the diagnosis of schizophrenia, it will be important to demonstrate that its prevalence among patients with schizophrenia is higher than in other diagnostic groups. Little comparative work has been done to address this issue. However, almost all patients with schizophrenia may demonstrate some measure of cognitive impairment. In comparing patients with schizophrenia and healthy controls on the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) (25), the distribution of a large number of patients with schizophrenia (n=575) is shifted about 2 SDs below the 540 healthy controls from the standardization sample 25,26. Although there is significant overlap between these two distributions, there are very few healthy controls at the lower ends of this distribution and very few schizophrenia patients at the upper ends. Traditional neuropsychological criteria for cognitive impairment would identify those individuals who performed better than one SD below the healthy control mean as "unimpaired" 27–29. By these criteria, about 20% of the patients in this study would be considered to have cognitive functions in the normal range. However, it is possible that many of the individuals at the upper end of this schizophrenia distribution have demonstrated cognitive decline compared to what their cognitive functions would have been if they had never developed the illness. Although this conjecture can never be proven, it is strongly supported by the differences between patients with schizophrenia and controls regarding the relationship of current cognitive functions to antecedent factors such as parental education and reading scores. In healthy controls, current cognitive ability is clearly predicted by antecedent factors such as maternal education and reading score 30. The healthy controls whose mothers had greater education had higher cognitive functions. Due to the natural variability of cognitive performance among healthy controls, about half of the individuals performed above expectations while half performed below expectations. However, almost all of the patients with schizophrenia in this sample performed below the expectations established by maternal education. Thus, it is likely that the overwhelming majority of patients with schizophrenia have some measure of cognitive deficit compared to what their level of cognitive function would have been if they had never developed the illness. These types of analyses will need to be completed on other diagnostic groups to compare the prevalence of cognitive impairment relative to expectations between patients with schizophrenia and other diagnoses. Although most patients with schizophrenia show some cognitive decline based upon what would have been predicted by antecedent factors, patients with schizophrenia, on average, start out at a lower baseline prior to the onset of the illness. Children who will eventually develop schizophrenia demonstrate cognitive impairment compared to healthy controls and children who later develop affective disorders (31,32). However, individuals who will eventually develop schizophrenia also demonstrate decline on scholastic measures between early childhood and late adolescence (32). The presence of cognitive deficits or cognitive decline during adolescence has been found to predict the conversion to schizophrenia in a variety of samples 32–39. Thus, patients with schizophrenia appear to begin life with cognitive performance that is slightly worse than their peers. As childhood progresses, cognitive performance tends to worsen in these children. By the time psychosis develops in late adolescence or early adulthood, they perform substantially worse than their healthy peers. Although patients with affective disorders also demonstrate cognitive impairment in adulthood, it appears as though these individuals do not show as much impairment prior to the adult onset of their disorders 31. The literature reviewed above supports the notion that the severity and longitudinal course of cognitive impairment in schizophrenia differ substantially from that found in patients with affective disorders. Yet it remains undetermined whether including a criterion of cognitive impairment or cognitive decline from healthy premorbid levels in the diagnosis of schizophrenia will help define a "point of rarity" with affective psychoses. If the recommended change in the diagnostic criteria for DSM and ICD is implemented, the point of rarity with other psychoses may increase. It is possible that some patients diagnosed with schizophrenia who have little or no cognitive impairment have treatment responses and courses of illness that are more consistent with a diagnosis of affective disorder. If this is the case, it will benefit clinicians to change their expectations based upon this revised diagnosis. Similarly, some patients diagnosed with affective disorders and severe cognitive impairment may follow a longitudinal course and treatment response that is more characteristic of typical patients with schizophrenia. It will be important for research studies and analyses of existing data bases to address the question of whether these diagnostic changes are validated by differences in course and treatment outcome. In addition, these studies can address whether patients whose diagnosis changes based upon the new criteria are more likely to have genetic and other biological indicators consistent with the new diagnosis. Even if the inclusion of a definition of "cognitive impairment" in the criteria for schizophrenia does not increase the point of rarity between schizophrenia and other psychotic disorders, it should be considered whether such a change would be able to "provide useful information not contained in the definition of the disorder that helps in decisions about management and treatment" 14. Psychiatrists rarely consider cognitive function in their evaluation of patients with schizophrenia. Including cognitive impairment in the criteria for schizophrenia may increase psychiatrists' attention toward a core component of the disorder that is the largest determinant of long-term functioning 7. Since cognitive impairment is also rarely considered as an important treatment target, its inclusion in the diagnosis may help to educate clinicians about the importance of cognition in their treatment options. Furthermore, representatives from the US Food and Drug Administration have indicated that the recognition of cognitive impairment in the diagnostic nomenclature would be an important step in approving a drug for a cognitive improvement indication for patients with schizophrenia 10. A large number of pharmaceutical companies and government agencies are involved in intense work to develop compounds that may improve cognition with schizophrenia. If successful, these compounds have the potential to alter the treatment of schizophrenia. However, if clinicians are not trained to recognize cognitive improvement, a potential great benefit to patients would be missed. Inclusion of cognitive impairment in the diagnostic criteria for schizophrenia may force educational systems to teach clinicians how to recognize cognitive impairment and improvement and direct treatments accordingly. The implementation of this change in diagnostic criteria will present two challenges for clinicians to collect relevant data: using reliable assessment methods for the determination of current cognitive deficits, and the collection of historical information to establish the context for the current cognitive abilities. Although formal cognitive testing is sensitive to the cognitive impairments found in schizophrenia, the resources required to complete full neuropsychological evaluations are often prohibitive. However, resource requirements have not kept cognitive impairment out of the diagnostic criteria for other disorders of cognition, such as Alzheimer's dementia and attention-deficit/hyperactivity disorder (ADHD), which do not require formal cognitive testing. Brief assessment may help reduce the burden of collecting cognitive performance data, but psychiatrists frequently are pressed to find enough time even to complete standard clinical evaluations. If cognitive paradigms were developed that were able definitively to separate diagnostic entities, a case could be made that this testing is essential to patient diagnosis and treatment planning. Unfortunately, however, as discussed above, we are not yet at this stage. Thus, the methods for establishing the presence of cognitive impairment in schizophrenia for diagnostic purposes will need to be established. A few possible methods are outlined below. Almost all of the variance in cognitive composite scores can be accounted for by a small number of tests 3, and short batteries may be as effective in assessing general cognitive deficits as lengthy ones 36,37. Thus, clinicians may be able to develop the capacity to assess cognitive impairment in schizophrenia without overwhelming time requirements. However, education and training in the use of standardized cognitive tests for clinicians will be essential to assure that the assessment procedures are completed in a manner that maintains test standardization. This aspect of training is usually included in the curriculum of clinical psychologists and neuropsychologists, but is rarely a component of education for physicians, social workers and nurses. A program for training in cognitive testing and supervision of data collection will be essential steps to increase the capacity for clinicians to assess the cognitive impairments of schizophrenia, and some psychological tests require supervision by a licensed psychologist. It will take time to work cognitive assessment training into the traditional education of psychiatrists and other non-psychologists. This training does not need to be limited to formal neuropsychological tests, and may be better aimed toward the assessment of patients' ability on practical cognitive tasks, which may have stronger direct correlations with outcome 40. Although the unavailability of trained testers may prohibit testing in many clinical environments, recent methodological advances have included the assessment of cognition in patients with schizophrenia with interview-based measures. Similar to ADHD assessment methods, which do not involve formal testing, these measures involve a series of questions directed toward the patient with schizophrenia and his or her relatives or caregivers. These questions address whether people with schizophrenia have cognitive deficits that impair fundamental aspects of their daily lives. For instance, some of the questions ask whether patients have difficulty remembering names, concentrating well enough to read a newspaper or book, being able to follow group conversations, and handling changes in daily routines 41,42. Interview-based assessments of cognition have historically been unreliable and have demonstrated low correlations with cognitive performance. However, these measures have generally relied upon the reports from patients and their treating clinicians, which have been unreliable and potentially invalid 43–46. A methodology that assesses cognition with interviews of patients and caregivers, such as relatives or caseworkers, appears to have improved reliability and validity. For example, the Schizophrenia Cognition Rating Scale (SCoRS) has been found to have excellent reliability, and substantial correlations with cognitive performance and functional outcomes 41,47. One of the potential weaknesses of this methodology, however, is that reports from patients have been found to have reduced reliability if patients are the only source of information. This weakness is particularly problematic in the assessment of patients with schizophrenia, since many patients do not have an available informant who can provide information about the patient's cognitive deficits and how these deficits affect the patient's daily behavior. For example, in a study that validated the MATRICS Consensus Cognitive Battery (MCCB), the test-retest reliability coefficient (ICC) for the SCoRS collected over the course of one month was high when ratings were based upon a patient and informant as a source of information (ICC=0.82) 47. However, when patients were the only source of information, the reliability was low (ICC=0.60). A more extensive series of questions, as found in the CGI-CoGS 42, appears to improve the reliability of patient reports up to ICC=0.80, but patients describe these longer interviews, which require up to 45 minutes per interview, as burdensome 47. A shorter, less burdensome instrument that would not require an informant and could be completed on almost all patients would be ideal, although is not currently available. Future studies should focus on this methodology, and must also determine whether interview-based assessments and brief assessments of cognition can contribute to the diagnostic separation between schizophrenia and affective psychoses. The criterion for cognitive impairment will frequently depend upon an evaluation of a patient's longitudinal course of cognitive functioning in the context of his or her personal background, requiring clinicians to gather substantial amounts of historical information. A statement that a patient's background must be assessed was included to avoid over-diagnosing schizophrenia in individuals whose environments deprive them of the opportunity to develop cognitive skills. People with very low levels of education and socioeconomic disadvantage may perform very poorly on cognitive tests independent of a psychiatric diagnosis. Thus, the evaluation of a patient's cognitive impairment must place the cognitive data in the context of his or her background and educational history 26. On the other end of the spectrum, some patients who had demonstrated high levels of cognitive skills early in their lives may have cognitive performance that is in the "normal range" despite significant decline from high premorbid levels 30. How will diagnosticians determine how historical and demographic factors interact with a patient's illness to result in his or her current cognitive levels? It will be important for diagnosticians to understand the average course of cognitive performance in someone with schizophrenia. During childhood and adolescence, patients who will eventually develop schizophrenia perform about 0.5 SDs below their peers who will not develop schizophrenia 31,32,34. Although there have not been sufficient data to make a definitive estimate, immediately prior to the onset of psychosis patients who are about to develop schizophrenia demonstrate cognitive performance that is about one SD below healthy controls 33,39. Diagnosticians must determine whether there has been a decline in cognitive functions from expected cognitive levels based upon antecedent factors such as parental education, early school performance, and reading level. They will also need to collect as complete a history as possible on the cognitive performance of each patient, including how the patient's current cognitive performance compares to early school performance and any academic, intelligence or cognitive testing that was performed during premorbid and prodromal periods. Further, a patient's level of cognitive performance should be compared to other members of the patient's family and sociocultural background, if available. In many cases, testing will benefit this assessment. In other cases, the amount of cognitive impairment in a patient will be clearly obvious and in direct contrast to early cognitive competence. Longitudinal cognitive information is also important to distinguish the more transient cognitive impairment of affective disorders from the more stable cognitive impairment in schizophrenia 10,17,18. In contrast to affective disorders, the cognitive deficits in schizophrenia are expected to be present throughout non-acute periods of illness. Although this longitudinal assessment may help to differentiate schizophrenia and affective psychoses, it may also result in delays in definitive diagnoses in cases where cognitive impairment is only known to be present in the context of symptom exacerbation. Although this historical and longitudinal data collection may initially appear to add burden, if indeed the level and course of cognitive deficit is crucial not only to diagnosis but to prognosis and treatment planning, it is likely that this "front-loading" of clinical care may eventually reduce clinical burden in the form of improved treatment response and long-term functioning. In sum, this paper has recommended for consideration that a criterion for consistent severe cognitive impairment should be added to the DSM and ICD diagnostic criteria for schizophrenia. There are several challenges that must be met before this suggestion will be accepted. Research is needed to determine: if such a criterion will increase the point of rarity between schizophrenia and other diagnostic entities; if clinicians are ableto evaluate cognition reliably with brief formal assessment instruments or interview-based methods; and if the inclusion of such a criterion will improve the value of the diagnosis of schizophrenia for prognosis, treatment outcomes, and the identification of its biological and genetic determinants. This paper elaborates on a previously published article 12, which was generated from a meeting on "Deconstructing Psychosis" at the Headquarters of the American Psychiatric Association in Alexandria, Virginia, on February 16–17, 2006. In that meeting, the author presented many of the ideas discussed in this paper, and they were commented on formally by Wayne Fenton and informally by other panel participants. Although Wayne Fenton agreed to co-author the previously published paper, he was not able to make comments on that manuscript before his tragic death on September 2, 2006. The author discloses that he has received research funding from Eli Lilly and Pfizer through Duke University. He also owns a company that trains and certifies cognitive testers for clinical trials, and he consults and has received funding from various pharmaceutical companies, universities and government agencies to carry out this work. He receives royalties through Duke University for cognitive measures developed in his laboratory, including the Brief Assessment of Cognition in Schizophrenia (BACS), and the BACS symbol coding subtest of the MATRICS Consensus Cognitive Battery (MCCB), some of which are discussed in this paper. Currently, there is no fee charged for the use of the Schizophrenia Cognition Rating Scale (SCoRS), copyrighted by Duke University, discussed in this paper; however, in the future a fee may be charged. The author has devoted much of his career to research on cognitive impairment in schizophrenia. Thus, if the suggestions of this article are carried out, he stands potentially to benefit academically and financially. Courtney Kennel and Cathy Lefebvre provided editorial assistance for this manuscript.