Cognition and the differential diagnosis of schizophrenia

I agree with Richard Keefe in terms of all of the evidence he presents. I firmly believe that cognitive impairments are a cardinal symptom of the schizophrenic illness, similar to Bleuler’s conception of fundamental symptoms. I also agree that more work may be required before cognitive impairments may be added to the diagnostic criteria for schizophrenia. Keefe does an excellent job in discussing the issues associated with assessment. However, we are also trying to talk about improvement of diagnostic criteria, with a goal of identifying more homogenous groups that clearly are separable (i.e., having a clear point of rarity) from other groups. One of the implications of acceptance of a Bleulerian monothetic taxonomy is that the assumption is: “all patients with schizophrenia have cognitive impairments and patients with cognitive impairments therefore have schizophrenia”. This may not be a supportable statement with the evidence currently available in the field. In this commentary, I will focus strictly on the implications for classification accuracy of adding cognitive impairments to the diagnostic criteria. Do the current diagnostic criteria already capture a group with a 100% prevalence of cognitive impairments and, if so, what would be added by including cognition as a diagnostic criterion? As clearly shown by Keefe, the current diagnostic criteria already capture a group of patients who all have the cognitive impairments described. It is not clear if additional diagnostic information or precision would be gained by requiring the assessment of a feature of the illness that is already present in all cases. In fact, this requirement has the potential of decreasing the reliability (and hence limiting the potential validity) of the diagnostic process. Requiring assessment of cognitive impairment would clearly raise awareness and have a positive impact, but might reduce diagnostic reliability from its current level. The trade-off between these two outcomes is a matter for further consideration. How much would diagnostic sensitivity and specificity increase if cognitive impairments were added? This is also a particularly important question. Validity and specificity of diagnoses include at least two important attributes: the utility of the elements of the diagnostic criteria for identifying features of illness that separate from healthy people and the utility of the elements of the diagnostic criteria for separation from other illnesses. The substantial separation from healthy controls in terms of cognitive impairments is shown quite clearly by Keefe. If the group means on a variable of interest are separated from each other by 2 SD, that implies that the lower functioning distribution and the higher functioning distribution will overlap at a level of 17%, which is quite an acceptable level of misclassification. This problem is addressed in detail by Zakzanis et al 1: they use a criterion that a deviation from normal performance associated with a similar sample overlap should provide suitable evidence of a true “syndromal” difference. By these criteria, the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) data cited by Keefe provide clear evidence that neuropsychological performance is a suitable syndrome indicator when patients are compared to healthy control samples. The smaller differences in neuropsychological performance between different patient samples are a much more challenging issue. To examine this directly, we will consider the data from the Suffolk County Mental Health project 2reviewed by Keefe. In that dataset, subjects with schizophrenia demonstrated a general deficit score (measuring global impairments in cognitive functioning) that averaged 1.4 (SD=0.9), while bipolar patients had an average general deficit score of 0.8 (SD=0.8). This means that the effect size for the overall difference in cognitive impairments between the group means was 0.66 [(1.4-0.8)/(0.9)]. This difference is hugely statistically significant: p<0.0001. At the same time, this means that about 33% of the cases with bipolar disorder are scoring within 2 SD of the schizophrenia mean and vice versa, leading to substantial overlap in samples and likelihood of misclassification of cases on the basis of neuropsychological performance alone. It is entirely true that patients with mood disorder generally show more impairment when experiencing symptoms than when euthymic. However, there are several issues that make this situation more complicated. First, in order to perform a true differential diagnosis of schizophrenia versus mood disorder, the mood disordered patient would have to be assessed while euthymic. This may reduce the validity of assessment, because euthymic periods may be more rare in people with bipolar disorder than previously thought. Follow-up studies have suggested that people with bipolar disorder spend as much as 50% of the time between identified episodes experiencing symptoms 3-5. Therefore, although asymptomatic periods are associated with reduced neuropsychological impairment, these periods may be uncommon, and the modal mood state of someone with bipolar disorder may be not euthymic. Second, recent data have shown that disability in bipolar disorder is much more prevalent and severe than clinical lore would suggest. For instance, functional recovery rates (defined only as return to premorbid functioning) in first episode cases with bipolar disorder who experienced a period of symptomatic remission are only about 40% over a three year follow-up 6, compared to less than 20% in similar patients with schizophrenia 7. This would suggest that disability is present in most cases with bipolar disorder as well as in cases with schizophrenia. For instance, the rate of marriage in people with bipolar disorder is only about 25% 8; independent living is impaired in 20-60% of cases across studies 9; unemployment rates are reported to be in the vicinity of 60% 10. These figures are slightly better than those seen in schizophrenia 11, but reflect clear functional disability. However, there have been no studies that directly measured the correlation between cognitive impairments and functional deficits. In conclusion, cognitive impairments are present in essentially all patients with schizophrenia when diagnosed with the current criteria. These impairments clearly separate from those of healthy people, but there is considerable overlap in distributions with people with other conditions, particularly bipolar disorder. Bipolar disorder is also marked by the same aspects of disability and cognitive impairment as seen in schizophrenia, but the level of sophistication and detail in assessment that has been applied to people with schizophrenia is lacking in the study of bipolar disorder. The only argument that I can see against including cognitive impairment as an element of the diagnostic criteria for schizophrenia is that it is already captured by the current criteria. Adding cognitive impairment might reduce the reliability of assessment by adding false negatives, but this still might be acceptable if the overall result is an increased awareness of cognitive deficits. It is also likely that cognitive impairment is as viable a diagnostic criterion for bipolar disorder as it is for schizophrenia, but the state of the research on bipolar disorder is much less well developed. Further research on the functional relevance of cognitive impairment across psychiatric conditions is clearly needed.