From the animal literature, we know that chronic neuroleptic treatment attenuates the heightened dopamine activity seen with acute treatment, a phenomenon usually described as 'tolerance'. However, a review of longitudinal studies in schizophrenic patients, examining the response of the major dopamine metabolite homovanillic acid (HVA) to chronic neuroleptic treatment, suggests two patterns of metabolic response. The first pattern is sometimes characterized by an acute increase in HVA, but followed more generally by a gradual decrease of the HVA level to within or below the range of the pretreatment value. The second pattern is best characterized by continued heightened production of HVA during chronic treatment. Further, the first pattern is usually associated with a good clinical outcome, while the second pattern with a poor outcome. Concomitantly, there is also evidence to suggest an abnormality in serotonergic functioning in schizophrenic patients. Thus, the reported therapeutic effects of various serotonergic agonists and antagonists, the antidopaminergic side effects of high potency serotonergic antidepressants, and the efficacy of clozapine indicate a significant serotonergic involvement both in the pathophysiology of schizophrenia as well as the modulation of dopaminergic activity. We hypothesize that the inability of a subsample of schizophrenic patients to reduce their dopamine activity with chronic neuroleptic treatment (i.e., nontolerance) indicates the dysfunctioning of an internal regulatory system providing long loop feedback inhibition that may include nondopaminergic neurotransmitter systems such as serotonin. The tolerance/nontolerance paradigm may identify a biochemically homogeneous subgroup of patients who have abnormalities in serotonergic activity. We will identify a subgroup of patients who demonstrate 'nontolerance' to treatment with steady state plasma levels of haloperidol for four weeks by measuring CSF and plasma HVA. We will compare these patients with those that show the expected 'tolerance' pattern, on differences in clinical response, and several peripheral and central measures of serotonergic activity. We will compare platelet 5-HT2 receptors, platelet 5-HT content, and the endocrine (prolactin), metabolic (plasma HVA), and behavioral response to fenfluramine.
