The purposes of this study are threefold: (1) to assess the relevance of dopamine hyperactivity to psychotic symptomatology in neuroleptic non-responders, (2) to test the hypothesis that neuroleptic nonresponse in schizophrenia specifically results from an inability to decrease DA presynaptic activity; and (3) to evaluate the efficacy of reducing DA presynaptic activity as an adjunct treatment in neuroleptic non-responders. The study is based on preclinical and clinical observations which suggest that the therapeutic efficacy of anti-psychotic drugs are contingent upon time dependent changes in dopaminergic pre-synaptic activity and that these changes may be absent in some neuroleptic non-responders. There is particular need for efficacious treatment of neuroleptic non-responders. As many as one third of schizophrenics have a poor response to neuroleptics. This group of chronically hospitalized and deteriorated patients presents a major dilemma in the care of schizophrenics. We will test the above hypothesis by studying the effects in neuroleptic non-responders of three drugs that decrease presynaptic dopamine release as adjuvants to neuroleptic treatment. Subjects will be 80 schizophrenic patients who have been on a stable dose of haloperidol for least 6 weeks, and who meet rigorous criteria of past neuroleptic non-response. Subjects will be continued on the same individually determined haloperidol dose through the protocol. The study will entad a one week baseline evaluation period followed by a 4 week double blind treatment period for which subjects will be randomly assigned to receive either placebo, reserpine, gamma-hydroxybutyrate, or alpha-methyltyrosine. Following this core component of the study, patients who respond to the augmentation treatment win continue on study drug alone for an additional month. The total protocol duration of the core study will be 5 weeks. Efficacy will be evaluated based on standard rating instruments of psychopathology, with emphasis on core psychotic, positive symptoms. Effects on pre-synaptic activity will be assessed by change in plasma HVA levels. Antipsychotic efficacy of adjunct treatments in association with a decrease in HVA will be interpreted as supporting the hypothesis. Conversely, lack of improvement across all three drug groups in association with a decrease in HVA will suggest that DA system hyperactivity is not a significant component in the pathophysiology of schizophrenia in this subgroup. The study is proposed for three years.
| Wolkin, A; Duncan, E; Sanfilipo, M et al. (1994) Persistent psychosis after reduction in pre- and post-synaptic dopaminergic function. J Neural Transm Gen Sect 95:49-61 |
