A retrospective case notes review of the effectiveness and ... - BMC Psychiatry

The exact pathophysiology of CIH is unclear, and several possible mechanisms have been suggested. Clozapine is an agonist at the muscarinic (M₄) receptor; and an antagonist at the adrenergic receptors (alpha₁ and alpha₂), dopamine receptors (D₁-D₅), histamine receptor (H₁), muscarinic receptors (M₁-M₃ and M₅), and serotonin receptors (5-HT₂ and 5-HT₄). The alpha₂ antagonistic and M₄-muscarinic agonist effects of clozapine can stimulate salivation, however, its anticholinergic effects can reduce the secretion of saliva [14]. Medications with various pharmacological actions have been proposed to manage CIH, such as centrally acting alpha₂-adrenoceptor agonists (e.g. clonidine, lofexidine), anticholinergics (e.g. hyoscine hydrobromide, atropine 1% drops, pirenzepine), and substitute benzamide derivatives (e.g. amisulpride, sulpiride, metoclopramide) [15,16,17,18]. There is no licensed medication for CIH and treatment recommendations are limited by the insufficient available evidence and the risk of bias in the published studies [19].

The mechanism of metoclopramide in reducing hypersalivation is not clearly defined. Substituted benzamide derivatives do not have adrenergic antagonistic, anticholinergic, or adrenomimetic properties [4]. Previous trials with this group of drugs with high selective binding to the dopamine D₂/D₃ receptors have shown efficacy in treating CIH [20]. Metoclopramide is a 5-HT₄ receptor agonist, a mixed 5-HT₃ receptor antagonist and a dopamine D₂ receptor antagonist. The antiemetic effect of metoclopramide is presumed to be caused by its D₂ receptor antagonism in the chemoreceptor trigger zone in the central nervous system, and dry mouth is one of its side effects. The antisalivary effect is presumed to be attributable to the entire substitute benzamide group [21].

The results of this study showed that 6 out of 14 patients (43%) continued treatment with metoclopramide for CIH with a mean duration of 27 months. On the other hand, a total of 8 patients (57%) in this study discontinued metoclopramide with a mean duration of 8 months. It is not known how the continuation rate in our study compares because there are no long-term studies in CIH. In a systematic review of 19 studies in treatment strategies for CIH, the duration of treatment ranged from 10 days to 6 weeks [10].

Tolerability of metoclopramide

A total of 5 patients (35.7%) in this study reported adverse effects during their treatment with metoclopramide. Four patients experienced tremors between 2–9 months after the initiation of metoclopramide, and one patient discontinued due to this side effect. However, it must be noted that these patients had previously reported EPSE(s) prior to starting metoclopramide. Furthermore, all the patients who reported adverse neurological effects were all prescribed concomitant medications that could cause or exacerbate tremors such as sodium valproate, lithium and other antipsychotics. Nonetheless, metoclopramide is recognised to cause both short and long-term neurological adverse effects, hence the guidance by EMEA in limiting the use to 5 days.

There are currently no guidelines available that recommend a treatment algorithm for CIH including duration of treatment of medications. The most sensible first step in the management of CIH would be to review the dose of clozapine and consider a dose reduction to minimise side effect burden, although this may affect patients' mental state and the decision should be made by clinicians on an individual basis. The second step would be to consider a trial of medication to manage CIH, such as hyoscine hydrobromide, pirenzepine, and metoclopramide. However, the evidence for the medications used for CIH largely comes from case reports, case series, and several randomised controlled trials. Thus, a direct comparison of the effectiveness between the medications used for CIH cannot be determined due to the lack of good quality evidence [22]. It is notable from our small cohort, many patients continue to suffer from CIH without benefit from various treatments. The mean duration of clozapine treatment at metoclopramide initiation was 6.5 years and all patients had been tried on at least one medication prior to metoclopramide. duration.

Despite the potential neurological adverse effect of metoclopramide, it is an agent that warrants further investigation, not least because, many of the agents used in CIH can cause constipation, a potentially fatal complication of clozapine use. Where possible, agents that cause constipation should best be avoided with clozapine. Metoclopramide is an agonist at 5HT₄ whereas clozapine is a potent antagonist at this receptor site. The activity of clozapine at this receptor site contributes to the burden of constipation. It is therefore a potential benefit for using one agent to mitigate both CIH and constipation.

Our study is a retrospective case notes review which has some limitations: small sample size, lack of measurements of serum clozapine levels and a lack of accurate and objective measurement of the effectiveness and tolerability of metoclopramide as no hypersalivation rating scales were used. While, real-world persistence has been suggested to be a proxy for treatment effectiveness and adherence, it is plausible that some continued treatment despite limited efficacy. The response to treatment was mainly determined by observation of drooling and patient experience as recorded in the medical notes. Moreover, the response to metoclopramide may be influenced by the dose of clozapine. We did not track the changes in clozapine dose during the study period. Finally, the lack of systematic reporting of adverse events means our results need to be interpreted cautiously.