The formerly leading dopamine hypothesis was based largely on the response of psychotic symptoms to phenothiazine and related medications, which implicates the dopaminergic system of the temporal lobe (see review by Carlsson). The evidence for this has been circumstantial but is supported by observations that antipsychotic drugs reduce the electrical activity of mesolimbic dopaminergic neurons in experimental models. Furthermore, there have been several demonstrations of increased concentrations of dopamine or its metabolite, homovanillic acid, in schizophrenic brains obtained at autopsy. The finding that dopamine receptors are organized in 2 systems, one limbic and the other cortical, has led to an expanded but speculative hypothesis that an excess of dopaminergic activity in the mesolimbic system gives rise to the positive symptoms of schizophrenia—that is, psychosis—whereas a diminished activity in the mesocortical system accounts for the negative symptoms. The involvement of the mesolimbic system, which plays a role in attention, has prompted further speculation that the thought disorder of schizophrenia is attributable to a breakdown of the normal “filtering” of stimuli reaching cognition. As mentioned earlier, it has been found that a variant in the gene for COMT that enhances metabolism of dopamine is overrepresented in schizophrenia, further incriminating a disorder of dopaminergic neurotransmission in the pathophysiology of this disease (Egan et al).
As pointed out in the review by Freedman, however, the dopamine hypothesis has weaknesses, the most prominent of which is the relative ineffectiveness of dopamine-blocking drugs in alleviating many aspects of the disease. The complexity of dopamine systems and their interaction with other neurotransmitter circuits make a simplistic mechanism unlikely. Modifications of the dopamine hypothesis of psychosis have included deficiency of GABA or of NMDA receptors, both of which the balance in dopamine (and glutamate) systems.
More recently, a hypothesis based on changes in the serotoninergic system has been again proposed. As with the dopaminergic model, attention was drawn to mechanisms relating to a new class of antipsychotics (clozapine, risperidone), which have major effects on the serotonin system and were found to ameliorate the psychosis. Several groups have reported alterations in serotonin receptors in the brains of schizophrenic patients (see later). A further connection is based on the finding by Williams and colleagues of an allelic variation in the gene on chromosome 13 encoding for a serotonin receptor (5-HT2A) that confers a susceptibility to schizophrenia. The variation in this gene is insufficient to explain the presence of the disease in any one individual, if for no other reason than that many patients who are homozygous for the suspect allele do not develop schizophrenia. Perhaps a nearby region relating to the receptor may be at fault through linkage disequilibrium (see commentary by Harrison and Geddes). A third currently favored biochemical hypothesis derives from the psychosis syndrome produced by chronic ingestion of phencyclidine (PCP), an N-methyl-d-aspartate (NMDA) antagonist. This implicates the glutaminergic system, but it must be pointed out that the dopaminergic and glutaminergic systems converge on certain cortical neurons and that glutaminergic release is modulated in several places in the brain by dopamine. These various neurochemical hypotheses are summarized by Lieberman and First.
A great variety of physiologic and endocrine differences between schizophrenic and healthy subjects have been claimed. None has proved to be significant. Because psychoses may complicate corticosteroid administration and certain endocrine disorders (Cushing syndrome, thyrotoxicosis, see later), there have been many attempts to uncover such abnormalities in the schizophrenic patient. All have failed.