Dr. Tsuang Replies

To the Editor: Drs. Duggal and Nizamie make several interesting points in their response to our article outlining an alternative approach to the diagnosis of schizophrenia. For one, they describe evidence of a neurophysiological abnormality in the bereitschaftspotential in both schizophrenic patients and their nonpsychotic first-degree relatives that may be relevant to our conception of schizotaxia. The finding is especially interesting because bereitschaftspotential is a neurobiological marker of planning, which is a neuropsychological function that is impaired in schizotaxia (1). Moreover, bereitschaftspotential abnormalities correlated significantly with negative symptoms (which are also associated with schizotaxia) in schizophrenic patients.

Drs. Duggal and Nizamie use these findings to raise the issue of whether this type of abnormality might reflect a neurobiological component of schizotaxia. More generally, their findings underscore questions about how to define and validate the syndrome. It is clear that research over several decades shows a wide range of clinical, social, neurobiological, and neuropsychological deficits in the first-degree relatives of patients with schizophrenia. Nevertheless, while these features may resemble those that occur in schizophrenia, and may even differ significantly from those of normal comparison subjects, they are not all necessarily good candidates for use as diagnostic criteria (2). This is true, for example, if performance variability on a particular measure precludes useful estimates of sensitivity or specificity. In fact, Drs. Duggal and Nizamie make a similar point when they describe how negative symptoms may occur in unrelated clinical conditions. This highlights the need for field trials to determine the utility of including particular symptoms as diagnostic criteria in schizotaxic syndrome.

In addition to the need to define a syndrome that demonstrates acceptable levels of sensitivity and specificity, the validation of schizotaxia must adhere to other guidelines. Among these, the diagnostic criteria need to be reliable and heritable. The use of negative symptoms and neuropsychological deficits in our preliminary formulation of schizotaxia reflects their robust occurrence in family studies (2–4). Moreover, if the symptoms of schizotaxia reflect an underlying vulnerability to schizophrenia, it is important to show that they are stable.

Thus far, several neuropsychological deficits in the relatives of patients, such as those in long-term verbal memory, have remained stable after a 4-year follow-up period (5). Evidence for the reliability, heritability, and stability of schizotaxia adds to its validity. Further evidence for the validity of the syndrome comes from a preliminary study (6) showing that subjects who meet the criteria for schizotaxia perform worse on several independent clinical measures (e.g., the Global Assessment of Functioning Scale and the Social Adjustment Scale) than subjects who do not. While encouraging, these results show that the definition and validation of schizotaxia is at a formative stage. One way to proceed at this point would be to use neurobiological abnormalities, such as those seen in bereitschaftspotential, to establish the external validity of the proposed syndrome and then evaluate their suitability for incorporation into the syndrome itself. In this way, the definition of the condition will hopefully evolve along with its conceptual and pragmatic utility.