Prophylactic effects of neuroleptics in symptom-free schizophrenics: Roles of dopaminergic and noradrenergic blockers

doi:10.1016/0006-3223(85)90174-X

Biological Psychiatry

Volume 20, Issue 11, November 1985, Pages 1161-1166

https://doi.org/10.1016/0006-3223(85)90174-X Get rights and content

Abstract

A clinical trial was undertaken to determine the role of dopaminergic and noradrenergic blockers in the maintenance treatment of remitted schizophrenics. One hundred and six remitted schizophrenic outpatients were treated with one of nine treatments, viz., thioridazine 25 mg or 75 mg, pimozide 2 mg or 6 mg, and their respective combinations, for 1 year in a double-blind controlled study employing a randomized design. The data from a previous study were utilized as a retrospective placebo group. Pimozide prolonged the number of symptom-free days in a dose-dependent manner and did so more markedly than thioridazine. Combined administration of pimozide and thioridazine prolonged the number of symptom-free days to a greater extent than their single administration. However, an inverted U-shaped dose-response curve was obtained with the combined administration of these agents. These data suggest that both the dopaminergic and noradrenergic blocking action of neuroleptics are important in preventing relapse in remitted schizophrenics.

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Cited by (31)

Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials
2021, The Lancet Psychiatry
Citation Excerpt :
22 references were included in the meta-analysis, reporting on 24 individual trials and 3282 individuals. Altogether, 18 randomised controlled trials were double-blind (n=2838),21–44 while six were open-label or single-blind (n=444; table 1).31–42 Altogether, 1777 individuals were in the standard dose group, 726 in the low dose group, and 779 in the very low dose group.
Dose reduction of antipsychotic maintenance treatment in individuals with schizophrenia could be desirable to minimise adverse effects, but evidence for this strategy is unclear. We aimed to compare risks and benefits of reduced versus standard doses of antipsychotics.
We searched Embase, Medline, PsycINFO, and the Cochrane Library from database inception until June 17, 2020, for randomised trials in adults with schizophrenia or schizoaffective disorder lasting at least 24 weeks, including individuals clinically stable at baseline, and comparing at least two doses of the same antipsychotic, excluding trials in first-episode psychosis or treatment-resistant schizophrenia. We compared low-dose (within 50–99% of the lower limit of the standard dose) and very-low dose (less than 50% of the lower limit) with standard dose, defined as doses higher than the lower limit of the treatment dose recommended by the International Consensus Study. Data from published reports on number of participants, treatment, sex, age, number of events, and changes in psychopathology scores were extracted independently by at least two authors. Investigators or sponsors were contacted by email to obtain missing information regarding outcomes. Co-primary outcomes were relapse and all-cause discontinuation. Study-level data were meta-analysed using random-effects models, calculating risk ratios (RRs) for dichotomous data, and Hedges' g for continuous data. The protocol was registered with OSF registries.
7853 references were identified in the database search and one additional reference from a manual review of relevant studies. 5744 abstracts were assessed for eligibility, and 101 references were assessed for full-text review. Of these, 79 were excluded for a variety of reasons, resulting in 22 studies being included in the meta-analysis, reporting on 24 trials and 3282 individuals. Study participants had a median age of 38 years (IQR 36–40) with 2166 (65·9%) males and 1116 (34·0%) females. Compared with standard dose, low dose increased the risk of relapse by 44% (16 trials, 1920 participants; RR 1·44, 95% CI 1·10–1·87; p=0·0076; I²=46%) and the risk of all-cause discontinuation by 12% (16 trials, 1932 participants; RR 1·12, 1·03–1·22; p=0·0085; I²=0%). Very low dose increased the risk of relapse by 72% (13 trials, 2058 participants; RR 1·72, 95% CI 1·29–2·29; p=0·0002; I²=70%) and all-cause discontinuation by 31% (11 trials, 1866 participants; RR 1·31, 1·11–1·54; p=0·0011; I²=63%). Compared with low dose, very low dose did not significantly increase the risk of relapse (five trials, 686 participants; RR 1·31, 95% CI 0·96–1·79; p=0·092; I²=51%) or all-cause discontinuation (five trials 686 participants; RR 1·11, 95% CI 0·95–1·30; p=0·18; I²=43%). Subgroup analyses comparing double-blind versus open-label studies, first-generation versus second-generation antipsychotics, and oral versus long-acting injectable antipsychotics were consistent with the overall results. Most studies were classified as having some concerns in the risk of bias assessment, which was mainly caused by absence of publicly available study registrations.
During maintenance treatment in multi-episode schizophrenia, antipsychotic doses should probably not be reduced below the standard dose range recommended for acute stabilisation, because reducing the dose further is associated with an increased risk of both relapse and all-cause discontinuation.
None
Pharmacokinetic considerations in antipsychotic augmentation strategies: How to combine risperidone with low-potency antipsychotics
2017, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Combining low-potency antipsychotics with first or second generation antipsychotics is lacks the risk of dependence, withdrawal and recurrence of anxiety following cessation of the treatment (Sim et al., 2015). Moreover, possible pharmacodynamic interactions including amplified dopaminergic and noradrenergic blockade may prevent psychotic relapses (Nishikawa et al., 1985). Widely prescribed low-potency antipsychotics include chlorprothixene, levomepromazine, melperone, pipamperone and prothipendyl.
To investigate in vivo the effect of low-potency antipsychotics on metabolism of risperidone (RIS).
A therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-OH-RIS of 1584 patients was analyzed. Five groups were compared; a risperidone group (n = 842) and four co- medication groups; a group co-medicated with chlorprothixene (n = 67), a group with levomepromazine (n = 32), a group with melperone (n = 46), a group with pipamperone (n = 63) and a group with prothipendyl (n = 24). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and active moiety (RIS + 9-OH-RIS; AM) as well as the metabolic ratios (9-OH-RIS/RIS; MR) were computed.
Differences in plasma concentrations were detected for AM and RIS. Pairwise comparisons revealed significant findings; RIS plasma concentrations were higher in co-medication groups than in monotherapy group. Chlorprothixene- and prothipendyl- medicated patients demonstrated no other differences. In the levomepromazine and melperone group plasma and C/D concentrations of AM and RIS were higher, while MRs were lower. For pipamperone, differences included higher C/D values of RIS and lower MRs.
Alterations of risperidone metabolism suggest pharmacokinetic interactions for levomepromazine and melperone. In the pipamperone-group, lower MRs as well as higher plasma and C/D levels of RIS suggest potential interactions.
When is antipsychotic polypharmacy supported by research evidence? Implications for QI
2008, Joint Commission Journal on Quality and Patient Safety
Citation Excerpt :
Three of the trials studied samples with mixed diagnoses,65–67 whereas three studied schizophrenia or schizoaffective disorder.68–70 Of the four trials reporting clinical outcomes, three reported no improvement,65,66,69 while the fourth study reported mixed results.70 Multiple antipsychotics were more beneficial than monotherapy at lower dosages but no better than monotherapy at higher dosages.70
Concurrent use of multiple standing antipsychotics (antipsychotic polypharmacy) is increasingly common among both inpatients and outpatients. Although this has often been cited as a potential quality-of-care problem, reviews of research evidence on antipsychotic polypharmacy have not distinguished between appropriate versus inappropriate use.
A MEDLINE search from 1966 to December 2007 was completed to identify studies comparing changes in symptoms, functioning, and/or side effects between patients treated with multiple antipsychotics and patients treated with a single antipsychotic. The studies were reviewed in two groups on the basis of whether prescribing was concordant with guideline recommendations for multiple-antipsychotic use.
A review of the literature, including three randomized controlled trials, found no support for the use of antipsychotic polypharmacy in patients without an established history of treatment resistance to multiple trials of monotherapy. In patients with a history of treatment resistance to multiple monotherapy trials, limited data support antipsychotic polypharmacy, but positive outcomes were primarily found in studies of clozapine augmented with a second-generation antipsychotic.
Research evidence is consistent with the goal of avoiding antipsychotic polypharmacy in patients who lack guideline-recommended indications for its use. The Joint Commission is implementing a core measure set for Hospital-Based Inpatient Psychiatric Services. Two of the measures address antipsychotic polypharmacy. The first measure assesses the overall rate. The second measure determines whether clinically appropriate justification has been documented supporting the use of more than one antipsychotic medication.
Dose-response relationships for the antipsychotic effects and parkinsonian side-effects of typical neuroleptic drugs: Practical and theoretical implications
1997, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1.
  1. From a review of published literature it is concluded that the minimum dose of a neuroleptic drug (NLD) required to alleviate psychosis is very similar to that producing minimal parkinsonian side effects (PSE). This conclusion is reached both from group comparisons and individual comparisons of dose/response relations (DRR) for the two effects.
- 2.
  2. A lower dose of NLD is usually sufficient to prevent relapse in well stabilized patients than is needed to check an active psychotic state.
- 3.
  3. Anticholinergic agents used to reduce side effects of typical NLD can retard the therapeutic process during neuroleptic treatment of acute psychosis. Although it is not fully established that this is a central interaction, it is consistent with the idea that minimal side effects are a necessary condition for therapeutic effectiveness with typical antipsychotic drugs.
- 4.
  4. In relapse-free maintenance of psychosis-prone patients, tolerance occurs to PSE. Thus few patients need experience prolonged side effects during maintenance treatment with neuroleptics.
- 5.
  5. The evidence reviewed is discussed with respect to a previous hypothesis of the supposedly “indirect” action of typical neuroleptic drugs in therapy for psychosis.
The evidence is consistent with the idea of a close causal relation between minimal PSE of these drugs, and their therapeutic effectiveness in the acute stage of treatment.
Low-dose neuroleptic therapy and relapse in schizophrenia: Meta-analysis of randomized controlled trials
1996, European Psychiatry
We assessed the relative efficacy and effectiveness of low-versus standard-dose neuroleptic therapy in reducing relapse rate in schizophrenic patients. Six long-term randomized controlled trials were retrieved through a MEDLINE search. A dose regimen between 50 and 100 mg equivalent of chlorpromazine, compared to a conventional one between 200 and 500 mg, was found to increase the likelihood of relapse in chronic schizophrenic patients. Differences, however, were statistically significant at 12 but not at 24 months of treatment.
Treatment of schizophrenia: A clinical and preclinical evaluation of neuroleptic drugs
1993, Pharmacology and Therapeutics
Forty years after the first clinical report on the effectiveness of chlorpromazine in psychiatric patients, neuroleptic drugs are still the most widely used drugs in the treatment of schizophrenia. Indeed, there are no other drugs which have proven to be as effective in the treatment of this severe psychiatric disorder. Yet, there are still many unresolved problems relating to neuroleptic drugs. The present review gives a comprehensive overview of our knowledge (and our lack of knowledge) with respect to the clinical and preclinical effects of neuroleptic drugs and tries to integrate this knowledge in order to identify the neuronal mechanisms underlying the therapeutic and side effects of neuroleptic drugs.

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Prophylactic effects of neuroleptics in symptom-free schizophrenics: Roles of dopaminergic and noradrenergic blockers

Abstract

Eur J Pharmacol

Compr Psychiatry

Psychoneuroendocrinology

Schizophrenics fully remitted on neuroleptics for 3–5 years—To stop or continue drugs?

Br J Psychiatry

Phenothiazines in prevention of psychiatric hospitalization. IV. Delay or prevention of hospitalization—A reevaluation

Arch Gen Psychiatry

Outpatient maintenance of chronic schizophrenic patients with long-acting fluphenazine: Double-blind placebo trial

Br Med J

Low-dose neuroleptic treatment of outpatient schizophrenics

Arch Gen Psychiatry