Treatment Of Clozapine-induced Hypersalivation Research Articles

Analysis of clinical studies on clozapine from 2012-2022

Clozapine has been considered the “gold standard” in the treatment of schizophrenia for many years. Clozapine has a superior effect, particularly in the treatment of negative symptoms and suicidal behaviour. However, due to its numerous adverse reactions, clozapine is mainly used for treatment-resistant schizophrenia. The aim of this paper is to analyze the results of clinical studies on clozapine from 2012-2022. PubMed was used as the database. Sixty-four studies were included and categorised by topic. The pharmacokinetic properties of clozapine tablets and a clozapine suspension solution did not differ markedly. Clozapine was superior to olanzapine and risperidone in reducing aggression and depression. A long-term study showed that metabolic parameters changed comparably with olanzapine and clozapine after 8 years. Risperidone and ziprasidone can be used as an alternative to clozapine. Scopolamine, atropine drops, and metoclopramide are effective in the treatment of clozapine-induced hypersalivation. Eight drugs, including liraglutide, exenatide, metformin, and orlistat, are potentially effective in the treatment of clozapine-induced weight gain. Ziprasidone, haloperidol, and aripiprazole showed a positive effect on symptoms when added to clozapine. No investigated drug was superior to clozapine for the treatment of schizophrenia. Ziprasidone and risperidone can also be used well for the treatment of schizophrenia. In the treatment of clozapine-induced hypersalivation and weight gain, some drugs proved to be effective.

A retrospective case notes review of the effectiveness and tolerability of metoclopramide in the treatment of clozapine-induced hypersalivation (CIH)

ObjectiveThe objective of the study is to explore the long-term effectiveness and tolerability of metoclopramide in the treatment of CIH.MethodThis study is a retrospective, observational cohort study of patients prescribed metoclopramide for CIH at the South London & Maudsley (SLaM) NHS Foundation Trust.ResultsOf the 96 patients identified, 14 patients were eligible for inclusion in our study. Five patients continued treatment with a mean duration of 27 months (SD = 17.8), and one patient continued until transfer with a duration of 3 months. Eight patients discontinued treatment after a mean duration of 8 months.ConclusionMetoclopramide may be an effective and tolerated drug in CIH, but more data is required to establish its place in the pharmacotherapy of this condition.

A natural study of the efficacy of replacement medications for the treatment of clozapine-induced hypersalivation.

Clozapine-induced hypersalivation is a stigmatizing and debilitating side effect of clozapine treatment that may threaten adherence to treatment [Taylor et al. 2009]. Hyoscine hydrobromide is the most popular treatment for hypersalivation, but has a poor evidence base [Syed et al. 2008]. During autumn 2013, a shortage of hyoscine tablets in the UK (due to production problems) required patients who had been prescribed hyoscine to change to a replacement medication. This provided an opportunity to assess the subjective relative efficacy of hyoscine hydrobromide compared with alternative medications in the treatment of clozapine-induced hypersalivation. We undertook a service evaluation and surveyed patients prescribed clozapine at Ashworth Hospital (Mersey Care NHS Trust) who had been prescribed hyoscine hydrobromide for hypersalivation. Participants were prescribed alternative medication for clozapine-induced hypersalivation by September 2013 and we conducted our survey in November 2013. Of the 42 consenting participants, 15 were prescribed pirenzepine, 13 were prescribed atropine, and 6 were prescribed a small number other replacement medications (procyclidine, orphenedrine, hyoscine patches) which, owing to small sample sizes, were excluded from our analysis. Eight patients previously prescribed hyoscine were prescribed no replacement medication. In each case, we asked patients to rate on a 7 point scale (1 = much worse, 4 = no change, 7 = much better) their current experience of nocturnal salivation, daytime salivation and a number of other side effects (vision problems, dizziness) compared with when previously prescribed hyoscine. Mean ratings of subjective relative efficacy in comparison with hyoscine for each of the three medication groups (pirenzepine, atropine, no replacement) are shown in Table 1. Subjective ratings showed that nocturnal salivation improved for both the pirenzepine group and the atropine group, but all patients in the no replacement group reported unchanged scores in night salivation. A one-way analysis of variance (ANOVA) showed this to be statistically significant [F(2,35) = 34.36, p < 0.001], with post hoc Tukey tests suggesting that ratings in the pirenzepine and atropine groups were both higher than in the no replacement group. Similarly, ANOVA confirmed that changes in daytime salivation for the pirenzepine group and the atropine group were significantly different to the no replacement group which again reported no change [F(2,35) = 23.4, p < 0.001]. This is unlikely to be a general reporting bias in the pirenzepine and atropine groups because the three groups did not differ in their ratings of changes in vision problems [F(2,35) = 0.99, p = 0.38] and dizziness [F(2,35) = 0.0, p = 1.0]. Table 1. Mean rated changes in side effects according to replacement medication groups. Participants who ceased taking hyoscine and with no replacement medication reported no change in hypersalivation. By comparison, participants who replaced hyoscine with pirenzepine or atropine consistently reported an improvement in salivation (day and night). It should be noted that our service evaluation survey did not implement any randomization to groups and that the data are in the form of retrospective report, both of which limit the interpretation of the outcome. Nevertheless, whilst hyoscine hydrobromide is the treatment of choice for clozapine-induced hypersalivation, a Cochrane Review has indicated that the evidence base is weak [Syed et al. 2008]. There is a broad range of treatment alternatives but these appear equally unsupported in the literature. Thus, clinicians are forced to make pragmatic prescribing judgements in the absence of reliable evidence. Our small-scale survey suggests that hyoscine may not be an effective treatment for hypersalivation and there is a clear need for more convincing evidence of the efficacy of treatments to confidently inform clinical practice. Indeed, a feasibility study funded by the UK National Institute for Health Research (NIHR) to investigate glycopyrrolate and hyoscine in the treatment of clozapine-induced hypersalivation is currently being conducted by our clinical team.

Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation

Objectives. Previous publications demonstrated substitute benzamides as effective agents in treatment of clozapine-induced sialorrhea (CIS). The aim of this study was to compare efficacy of amisulpride and moclobemide (both from the substitute benzamide group) in controlling, or at least minimizing, CIS. Methods. The study was designed as a 6-week, two-center, fixed-dose, comparison study of 400 mg/day of amisulpride versus 300 mg/day of moclobemide as an adjunctive treatment in 53 schizophrenia and schizoaffective disorder patients (diagnosed according to DSM-IV) suffering from CIS. The patients were treated with each medication during 2 weeks, followed by a washout period of 2 weeks. Primary outcome measures included the reduction in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Secondary outcomes included the Positive and Negative Syndrome Scale (PANSS), Manic State Assessment Scale, and Extrapyramidal Symptom Rating Scale (ESRS). Results. Both amisulpride and moclobemide were very effective in reducing CIS. Almost 74% of patients treated with amisulpride and 83% of patients treated with moclobemide showed some level of improvement on NHRS. Only in one patient treated with amisulpride, CIS worsened. Conclusions. Both medications were safe and effective as treatment of CIS. Although moclobemide exceeded amisulpride in antisalivation activity, treatment of CIS with amisulpride leads to improvement in psychotic symptoms.

Treatment of Clozapine-Induced Hypersalivation With Ipratropium Bromide

Clozapine-induced hypersalivation (CIH) occurs in up to 57% of treated patients and can be the source of considerable subjective distress. Previous open-label studies suggest that sublingual ipratropium bromide may be effective in treating CIH. We conducted a randomized, double-blind, placebo-controlled crossover trial to evaluate the efficacy of ipratropium in 20 individuals with CIH between September 2006 and August 2007. This study was 5 to 6 weeks in duration, based on the participants' clozapine blood-monitoring schedule, and it consisted of two 2-week crossover phases separated by a 1- or 2-week washout period. Primary outcome measures included the reduction in the Toronto Nocturnal Hypersalivation Scale (TNHS) and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. Secondary outcomes included visual analog scales assessing hypersalivation severity (VAS-S) and distress (VAS-D). No significant reduction in CIH was found on the TNHS (P = .379), CGI-S (P = .266), or CGI-I (P = .599). Moreover, no difference was noted between study groups on the VAS-S (P = .969) and VAS-D (P = .527). There was no difference in the number of CIH responders at the conclusion of the 2-week placebo (40%, n = 8) and ipratropium (45%, n = 9) study phases (45%, n = 9) according to the TNHS. Randomization order did not have a significant effect on TNHS, CGI-S, or CGI-I scores. Tolerability was comparable between groups, with dry mouth occurring in 1 placebo group subject and 2 ipratropium group subjects. Despite the reports of some preliminary studies that ipratropium is an efficacious treatment for CIH, ipratropium failed to demonstrate significant clinical effect in comparison to placebo. Further research should explore the efficacy of other locally acting anticholinergic agents or other classes of medications. clinicaltrials.gov Identifier: NCT00381589.

Moclobemide Treatment of Clozapine-Induced Hypersalivation

Clozapine-induced hypersalivation (CIHS) affects a mean of approximately 30% patients and is a troublesome adverse effect that leads to massive compliance problems in patients with schizophrenia. For the management of this distressing adverse effect, different pharmacological agents have been recommended, yet none of them have been proven to be effective. The aim of our study was to investigate moclobemide, a reversible monoamine oxidase inhibitor-A, as an additional possibility for controlling or at least minimizing CIHS. We enrolled 14 patients with schizophrenia who experienced CIHS. Moclobemide (150-300 mg/d) was added to their conventional regular treatment during 14 days. Hypersalivation was assessed at the start of the treatment and at its end point by the 5-point Nocturnal Hypersalivation Rating Scale. Two thirds of the subjects who experienced CIHS have demonstrated a beneficial effect after the addition of moclobemide, whereas one third of them have been nonresponders. None of the patients had any adverse effects. We assume that moclobemide can be another additional and safe medication for the treatment of CIHS; however, more data, based on controlled studies, are needed.

Clozapine-Induced Hypersalivation: A Review of Treatment Strategies

Clozapine-induced hypersalivation (CIH) is a significant side effect affecting about one-third of patients treated with clozapine. CIH can be stigmatizing, can affect quality of life, and can result in discontinuation of clozapine treatment. The purpose of this review is to provide an understanding of CIH, specifically, its pathophysiology, measurement, and the evidence for CIH treatment alternatives. We searched MEDLINE from 1980 to June 2006 for all reported pharmacologic treatment studies related to CIH. We identified additional references by a manual search of the bibliographies of retrieved articles. Several studies reported improvement of CIH with both selective and nonselective anticholinergic medications. However, with the exception of local anticholinergic agents such as ipratropium bromide and atropine eye drops, potential systemic adverse effects limit the effectiveness of this class of medications. Open-label studies of clonidine, an alpha2 antagonist, suggest that it may be beneficial in managing CIH. Other pharmacologic treatments, such as amisulpride and botulinum toxin, may be useful in refractory CIH cases. Although few randomized controlled trials were found in the literature, this review highlights potential treatment alternatives for this common and disabling cause of hypersalivation. Prompt and effective treatment of CIH may assist with treatment tolerability, adherence, and outcomes in patients with treatment-refractory schizophrenia. Information on funding and support and author affiliations appears at the end of the article.

Clonidine Treatment of Clozapine-Induced Hypersalivation

Clonidine Treatment of Clozapine-Induced Hypersalivation