On Biology, Phenomenology, and Pharmacology in Schizophrenia

To the Editor: Such an extravagantly comprehensive synthesis perhaps is permitted from Dr. Kapur, given his significant contribution to schizophrenia research. He appears to favor a simple linear relation between excess dopamine and abnormal salience, with antipsychotics “damping down” aberrant salience. This model of schizophrenia based on a quantitative change in dopamine function struggles to accommodate receptor imaging studies of antipsychotic drug action. Profound dopamine blockade produces little clinical benefit in up to 30% of schizophrenia patients. The most effective antipsychotic, clozapine, has only relatively modest dopamine D₂ antagonism. At issue is not whether but how dopamine function in schizophrenia is abnormal. These findings seem more consistent with a more complex qualitative change in dopamine function. The efficacy of antipsychotics may depend on their dopaminergic antagonism but may be relatively independent of its magnitude.

The difficulties in accounting for the psychological mechanisms of psychosis are similar to those just presented in relation to the neurochemistry of schizophrenia. Actually, since the mechanism of normal belief formation remains unknown, it might appear premature, even presumptuous, to propose a mechanism for abnormal beliefs. Dr. Kapur adhered to a viewpoint common in modern cognitive psychology that supposes that psychotic beliefs reflect a quantitative change from normal belief mechanisms. Such an approach has led to the specific cognitive therapy of psychosis. But as with dopamine antagonism, cognitive therapy is not as effective as it should be if this view of psychosis is correct. The alternative is that psychosis involves a qualitatively distinct belief mechanism. While this does not immediately suggest novel therapeutic approaches, it has been previously suggested to account for the symptoms of schizophrenia (1).

What matters is not whether ideas are true but whether they are useful. The last decade has witnessed the introduction of a veritable cornucopia of new treatments. Such times probably needed a theoretical account that predicted the success of these treatments. In this respect, Dr. Kapur’s thesis seems a good few years out of date. The inadequacy of current treatments and the persistence of resistant symptoms of schizophrenia suggest a need to reevaluate our current understanding of psychosis.