Schizophrenics fully remitted on neuroleptics for 3-5 years--to stop or continue drugs? [Adjuvant treatment of schizophrenic illness with carbamazepine]. Prophylactic effect of neuroleptics in symptom-free schizophrenics. Clozapine versus perphenazine: the value of the biochemical mode of action of neuroleptics in predicting their therapeutic activity. Initial improvement as a criterion for drug choice in acute schizophrenia.
A double-blind comparison between benzodiazepines and neuroleptics was carried out for 1 1/2 years on 30 schizophrenics who had hitherto continuously received neuroleptics and remained apparently in full remission for at least 3-5 years. The benzodiazepine-group had a significantly higher relapse rate than the neuroleptic-group, meaning that we cannot stop neuroleptics for these patients yet. Three possible reasons for this are (1) demand of the natural course of the illness, (2) the fact that the patients agreed to stay in therapy for so long may signify a need for therapy, (3) some of the relapses on stopping neuroleptics may be 'withdrawal psychosis' after prolonged neuroleptic therapy. If withdrawal of neuroleptics is really needed, however, it may be considered for a subgroup of female patients whose illness started after the age of 40. Very few controlled clinical trials have been assessing the interaction of antipsychotics and antiepileptics. However, schizophrenic patients frequently receive a combination therapy consisting of haloperidol and carbamazepine. The data for this treatment strategy are contradictory and may depend on the initial plasma concentration of the antipsychotic. There is convincing evidence that after addition of carbamazepine the plasma concentration of neuroleptics drops due to hepatic enzyme induction. In this study, we treated 18 schizophrenic patients either with haloperidol alone or in combination with carbamazepine. The use of carbamazepine was associated with a dramatic fall in haloperidol plasma levels and a worse clinical outcome compared to the monotherapy group. These results, together with a review of the literature, lead us to the conclusion that there are no obvious advantages of carbamazepine co-medication in schizophrenia compared to an optimized neuroleptic monotherapy. Prophylactic effects of psychotropic drugs on 55 schizophrenics in remission were evaluated for 3 years in a double-blind controlled study employing a cross-over design. Patients were randomly assigned to the following drugs orally administered twice a day: placebo; diazepam 15 mg; imipramine 50 mg; chlorpromazine 75 mg; and haloperidol 3 mg. The number of days of remission for each patient was recorded. Since only two patients received all five drug treatments, the data were analyzed using the number of days allocated to the "first assigned drugs" only and the cross-over aspect of the experimental design was disregarded. All patients treated with either the placebo, diazepam or imipramine relapsed within a year. On the other hand, four patients treated with chlorpromazine, or with haloperidol, were in remission for more than 1 year. Fifty percent of the patients relapsed within 16 days with placebo; 88 days with diazepam; 30 days with imipramine; 165 days with chlorpromazine; and 74 days with haloperidol. Within a year, only chlorpromazine significantly prolonged the remission state as compared to placebo and imipramine. At the end of the 3-year trial, both chlorpromazine and haloperidol significantly prolonged the remission state as compared to the other three drugs. These data suggest that neuroleptic treatment for a longer period is vitally important to prevent relapse even in schizophrenics in remission and that such a trial seems an efficient method for investigating the prophylactic effects of neuroleptics. The chemical structure of a neuroleptic does not relaibly predict the exact profile of its therapeutic action. We considered the question whether the biochemical action of a neuroleptic, and specifically the ratio between DA-receptor block and NA-receptor block, might have a higher predictive value in this respect. In this context we carried out a double-blind study of the therapeutic value of clozapine and perphenazine in acute psychoses of varying symptomatology anc aetiology. There are strong indications that clozapine has only a slight inhibitory effect on transmission in central DA-ergic neurons, but markedly inhibits transmission in central NA-ergic neurons, and that the reverse applies to perphenazine. In view of these data we expected perphenazine to be a stronger antipsychotic and a weaker sedative than clozapine, and vice versa. The plausibility of this hypothesis was demonstrated. Partly also on the basis of earlier research, we concluded that the biochemical action of a neuroleptic is a more faithful predictor of its therapeutic action profile than the chemical structure. Several investigators have found that the initial improvement of acute schizophrenia after some days of neuroleptic treatment is correlated in a statistically significant way to the outcome after four weeks. In all these studies the question arises as to whether the correlation between early response and subsequent outcome is due to a specific response to a certain neuroleptic, or whether patients who respond early simply have a better prognosis. In order to isolate the specific drug effect from prognostic influences we performed a controlled double-blind study in 50 newly admitted schizophrenic inpatients. All patients were treated over three days with 15 mg haloperidol i.v., following which they were classified as 'early responders (ER)' (markedly improved or improved) or as 'early nonresponders (EN)' and then randomly assigned to group 1 (3 x 5 mg haloperidol p.o./d) or to group 2 (3 x 100 mg perazin p.o./d). If there was a specific drug effect on the correlation between early response and subsequent outcome a therapeutic superiority of perazin in EN and no superiority in ER was expected. Independently of the treatment condition the mean BPRS score had decreased from 61.2 (Sx = 12.1) to 38.1 (Sx = 13.9) at the end of the study. ER and EN were evenly distributed in the haloperidol and perazin group. The analysis of variance revealed no significant interactions of the factors 'treatment condition' x 'duration' x 'early response' (p = 0.27) and 'treatment condition' x 'early response' (p = 0.88) on the outcome (BPRS, CGI). This means that the initial hypothesis of this study has to be rejected.(ABSTRACT TRUNCATED AT 250 WORDS)
Limited data from small studies using neuroleptic reduction or specific neuroleptic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration in order to fully investigate this area.