Dr. Meador-Woodruff Replies

To the Editor: In their letter addressing our publication on glutamate receptor expression in the thalamus in schizophrenia, Drs. Gurling and Chen raise the issue that plagues the vast majority of postmortem studies in schizophrenia, that of antipsychotic treatment as a potential confounding variable. We suggested in our report that the abnormalities of NR subunit expression that we found in patients with schizophrenia might not be due to long-term antipsychotic treatment, on the basis of an earlier report that antipsychotic treatment did not affect the expression of these molecules in the thalamus (Ulas, 1993).

We recently reviewed the literature on the effects of antipsychotic treatment on the expression of receptors associated with multiple neurotransmitter systems (1). Three interesting observations emerged from this review: neurotransmitter receptors are not regulated by antipsychotics in the same manner throughout the brain but, rather, are altered in a fashion specific to each brain region and circuit; typical and atypical antipsychotics have differential effects on the expression of a number of neurotransmitter receptors in a given region of the brain, and there is considerable variability in published reports, in part attributable to different study methods, drug doses, administration schedules, and discrepancies in the definitions of the brain regions studied. In the specific case of NR subunits that Drs. Gurling and Chen raise, the literature is contradictory, but most studies suggest that in many regions of the brain these molecules are in fact increased in number by antipsychotic treatment (Ulas, 1993) and not decreased, as suggested by Drs. Gurling and Chen.

There are literally hundreds of published reports on the effects of antipsychotics on neurotransmitter receptor expression. Given the emerging evidence for brain region–specific regulation of glutamate (and other) receptors by antipsychotics, we cited the only article of which we are aware that specifically studied the thalamus (Ulas, 1993). In the investigation by the letter authors’ group (Chen et al., 1998), the thalamus was not specifically studied; rather, the subject was a gross subcortical dissection, which included a number of structures, likely including the striatum and pallidum in addition to the thalamus. Given that this large body of literature points to differential effects of typical antipsychotics on the expression of NR subunits in various brain areas, this earlier report from Drs. Gurling and Chen’s group is relatively uninterpretable vis-à-vis any thalamus-specific effects.

The effect of antipsychotic treatment is a critical issue in the interpretation of postmortem studies in schizophrenia. We feel that given the regional variability of antipsychotic effects in the brain, it is difficult to generalize results from one brain region to another. Of course, our original findings could nonetheless be related to antipsychotic exposure, but the only report of which we are aware that directly addresses this question in the thalamus suggests otherwise (Ulas, 1993). We agree with Drs. Gurling and Chen that the recent completion of the sequencing of the human genome is an exciting development, and as the expression of even more genes is studied in brains from mentally ill subjects, issues such as this will remain an important problem in the interpretation of the voluminous data that are sure to be forthcoming.