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Unless you work in a busy clozapine clinic, you wouldn’t ever prescribe clozapine 450 times. Even if you do work in such a clinic, you might want to compare your observations with those from Western Australia. They asked, what percentage of patients stop clozapine? And what percentage later resume after waiting how long?
Hi! Jim Phelps here for the Psychopharmacology Institute. In this Quick Take, we’ll look at a self-report, if you will, of psychiatrists looking at their own patient records for insights into the experience of clozapine treatment. It’s a great idea, especially when your sample size can be as large as 450 regarding a rather specialized treatment like clozapine. As you know, this medication can be challenging to prescribe, initiate, and stick with. There’s the blood testing every week to start and the logistics of getting those results to the right place at the right time. But once underway, patients have to contend with problems like constipation, sialorrhea, and weight gain.
In their introduction, the authors of this retrospective chart review remind us that clozapine is associated with multiple benefits in schizophrenia—reduced mortality, hospitalization, suicide, aggression, and psychosocial decline. But lots of patients stop it. “Are there ways to predict, to anticipate that discontinuation?”, the authors asked. To answer that, they used their termination report, a checklist that clinicians in these clinics had to complete if clozapine was discontinued for any reason. These data were entered directly into patients’ electronic medical records.
Reasons for therapy interruption could be grouped into 3 main categories: Nonadherence, meaning some form of patient’s personal choice; adverse effects; and inadequate efficacy. Excluding 2 patients who never actually started clozapine and 8 who died, the authors examined records for 448 patients.
Here’s what they found. Thirty percent of their patients never stopped clozapine in an average of 8 years of follow up. Among the 70% who did stop, which of the authors’ 3 reasons do you think was the most common? Well, it depends on whether the patient later chose to resume treatment or not. Of the 70% who did stop clozapine, about half never restarted. In that group, the never returners, for two-thirds of them, discontinuation was due to nonadherence. But among the resumers, the initial discontinuation was due to nonadherence in only about half. So, two-thirds vs half. By contrast, side effects accounted for one-third of the discontinuations among those who resumed vs 20% of the never-returned group.
Overall, this makes sense. The restarters group basically recognized the need for treatment either initially or eventually. Eighty percent of them resumed within the first year after stopping. They were somewhat more likely to have stopped due to a side effect, not just nonadherence, so this suggests that aggressively managing side effects could reduce discontinuation rates somewhat.
One more interesting finding. Discontinuation due to inadequate efficacy was only 6% and that was among the restarters. In the never-returned group, only 1 of 140 patients stopped because of inadequate efficacy. In other words, discontinuing clozapine because it didn’t work well enough was remarkably rare.
In summary, clozapine is hard to start, and it’s also hard to keep going. In this study, 70% of patients stopped. Half of those later resumed. So, it’s tricky, isn’t it? Efficacy is not the problem; lack of insight and side effects are. For more on this, there’s literature on clozapine in diagnosis other than schizophrenia, which was not examined here.
Abstract
Objective: The proportion of patients who recommence clozapine after cessation, the time taken to resume clozapine post-cessation, and distinguishing demographic and clinical characteristics of this group have been poorly researched. We evaluated these in the current study.
Method: We retrospectively extracted selected demographic and clinical variables and clozapine treatment interruption and recommencement data up to December 2018 of a cohort of 458 patients who first commenced clozapine between 2006 and 2016. The study was conducted at three Australian health services.
Results: Of the 310 (69%) patients who had at least one interruption of clozapine treatment, 170 (54.8%) did not resume clozapine, and 140 (45.2%) recommenced it after the first interruption. More than half of those who recommenced did so within a month and 80% by 12 months. Cox regression analysis revealed that age was significantly associated with recommencement, with a 2% decrease in the likelihood of restarting after an interruption for each year later that clozapine was initially commenced (HR = 0.98 95%CI: 0.97, 0.997, p = 0.02). Those who ceased clozapine due to adverse effects were less likely to restart than those who ceased due to noncompliance (HR = 0.63 95%CI: 0.41, 0.97, p = 0.03). More time on clozapine prior to interruption increased the likelihood of restarting it, with each additional month on clozapine increasing this likelihood by 1% (HR = 1.01 95%CI: 1.01, 1.02, p < 0.001).
Conclusion: If the distinguishing demographic and clinical characteristics of the group identified in this study are corroborated through further research, this could further validate the need to identify treatment resistance and commence clozapine early in people with schizophrenia and provide appropriate interventions to those more at risk of permanent discontinuation of clozapine.
Keywords: clozapine; clozapine recommencement; therapy interruption; treatment-resistant schizophrenia
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Reference
John, A. P., Burrows, S., Stanley, S., Acabo, C., Shymko, G., Jaworska, A., & Velayudhan, A. (2022). Demographic and clinical characteristics of patients who recommence clozapine following therapy interruptions. Acta Psychiatrica Scandinavica,145(3), 293-300.
