Clozapine Is Severely Underused in Parkinson's Disease Patients

Abstract

Clozapine is a unique drug for people with Parkinson's disease (PD). It was the first drug shown to be an effective antipsychotic that did not worsen motor function.1, 2 It was the first drug shown in a double-blind, placebo-controlled trial (DBPCT) to treat any psychiatric symptom in PD. It has strong antitremor properties as well as antidyskinetic effects. However, I will show that it is markedly underused because of the lack of US Food and Drug Administration (FDA) approval for its use in PD, concerns about safety, and the logistics required for blood count monitoring. The next sections discuss how these concerns have been exagerated. Clozapine is thought to be underused in schizophrenia as well for different reasons, namely, noncompliance and the metabolic syndrome.3, 4 Clozapine was approved by the European Medical Agency for the treatment of psychotic symptoms in people with PD (PDP) in France and Italy in 2002 and is also approved in England. It has not been approved in the United States. Clozapine has never been submitted for FDA approval for PDP because of clozapine's status as a generic drug, making approval financially unattractive. In open-label studies, starting in 19885 it has been reported to be extremely effective in treating PDP without worsening motor function.6-8 One multicentered DBPCT in the United States1 funded by the FDA's Orphan Drug Division and another in France,2 using identical designs, produced similar results with exceptional efficacy at a mean dose of 25 mg/day in the United States and 36 mg/day in France without a worsening of motor function. There was clinically and statistically significant improvement in resting tremor in the US study, an outcome not addressed in the French study. Clozapine was approved by the FDA in the United States for treating refractory schizophrenia after a large DBPCT.9 It has been shown in head-to-head trials against other antipsychotics in schizophrenia to be superior.10 In treating PDP, only 1 drug aside from clozapine, pimavanserin, has even a single DBPCT showing efficacy and tolerance.11 Although clozapine has not been compared with pimavanserin in a trial, the 2 clozapine trials involved patients with considerably lower Mini-Mental State Examination scores than the pimavanserin trials and worse scores on psychosis at baseline, yet had faster and stronger responses. Both clozapine trials showed a response within 1 week in comparison with pimavanserin, which showed benefits starting between 2 and 4 weeks.12 Open-label studies of clozapine reported significant antipsychotic responses after a single dose in some cases (personal observation). Open-label long-term data6, 12, 13 suggest that it is continued longer than other antipsychotics14 in treating PDP. Furthermore, no other neuroleptic has proven efficacy in PDP. All 4 DBPCT trials of olanzapine found poor tolerance due to worsened parkinsonism,15-17 requiring discontinuation of 2 of the studies,15, 16 and no efficacy in any.15-17 One of these studies15 compared clozapine with olanzapine but was aborted because of intolerance to olanzapine. Risperidone and aripiprazole worsen parkinsonism18, 19 as well, and quetiapine has failed to show benefit in DBPCT,20-22 although open-label studies23 and clinical experience24 support its use. Clozapine has excellent antitremor effects in PD25 confirmed in double-blind trials. In 1 double-blind study, it had similar efficacy to benztropine.26 In a retrospective report8 in which clozapine results at 4 major movement disorders centers were combined, tremor improved in the majority of patients. The Unified Parkinson's Disease Rating Scale tremor score in patients in the US DBPCT study1 improved by 1 point, a statistically and clinically significant benefit in a study that did not require tremor as an inclusion criterion. Tremor was not studied in the French DBPCT. It has been particularly useful in tremor unresponsive to levodopa.26 It has been found to be effective for treating levodopa-induced dyskinesias in open trials.6, 27, 28 The claim that the drug is underused is based on several reports. A study published in 201829 using data from 2006 found that 29 patients with PD were treated for psychotic symptoms in Olmsted County, MN, of whom 22 were treated with quetiapine, 3 on olanzapine, and 2 on risperidone. None received clozapine, although both double-blind, placebo-controlled trials of clozapine and numerous open-label trials had been published before 2004.1, 2 In 8 years, a large, university-based movement disorders clinic treated 38 patients with clozapine.30 The number of patients seen or followed was not published, but as of June 22, 2022, the same clinic was treating 43 of 5080 distinct patients with PD with clozapine (M. Okun, personal communication). A report analyzing more than 3300 patients with PD aged 40 years and older and treated for psychosis with antipsychotic drugs in the database of Optum30 from 2001 to 2019 found that “clozapine was too rare to include in our statistical analyses.” Layton et al31 evaluated patients in a large data set who met clearly defined inclusion criteria for PDP and identified 982 taking antipsychotics, of whom less than 1% were treated with clozapine. Using a different database covering 2016 to 2019, the same researchers32 identified 2892 PDP treated with pimavanserin and compared them with 19,083 matched comparators treated with atypicals, of whom 37 were on clozapine. A study using the Medicare minimum data set for the years 2007 to 2010 of patients with PD with depression identified 31,099 patients with PD also treated with atypical antipsychotics, 62 of whom were treated with clozapine compared with 8848 with quetiapine and 3825 with risperidone.33 In contrast, in my personal clinic, 65 of 648 distinct patients with PD seen over 8 months from 2020 to 2021 were treated with clozapine,34 mostly for psychotic symptoms, but some for tremor. The psychotic symptoms were primarily related to treatment for PD, but rare patients were on clozapine for primary psychiatric conditions such as schizophrenia or bipolar disease. Some prescribers may think that drug initiation and monitoring is a time-consuming, complicated task. Using the Risk Evaluation and Mitigation Strategy program to register and then monitor patients is easy and takes about 2 minutes to register and a minute for follow-ups. The inconvenience to the patient and family of the weekly monitoring is far outweighed by the improvements in paranoid delusions and frightening hallucinations. If the benefits do not occur, the drug and its monitoring are discontinued. A review of the safety of atypical antipsychotics in treating PD psychosis reported that clozapine was safer to use than any drug but pimavanserin.35 The possibility of granulocytopenia requires weekly blood monitoring for 6 months, then biweekly evaluations for 6 months, followed by monthly evaluations. This risk is believed to not be dose related, although the doses used in PDP are usually between 6.25 and 50 mg/day and between 300 and 800 mg/day in schizophrenia. The data showing this lack of a dose–response relationship, however, is based only on schizophrenic-level drug treatments.36 However, no data have been made available to me for evaluating this relationship despite requests. In my experience, even the extremely low doses used in PD put patients at risk, and the current blood-monitoring system is required for safety.37 The “metabolic syndrome,” a disorder of weight gain, type II diabetes, hypertension, and hyperlipidemia is common in people taking the usual doses of clozapine for primary psychiatric disturbances. There are no data on its occurrence in the usual PD doses, but personal experience has shown it to be rare or nonexistent, and it is not described in retrospective, long-term PD studies. Sedation is a common adverse effect of clozapine, which often limits dose tolerability.1, 2, 27, 28 On the other hand, sedation is often salutary in that PD psychotic symptoms tend to be worse at night, interrupting sleep for the patient and the caregivers. Sleeping through the night may be associated with a better and faster antipsychotic effect (personal observation). Drooling may increase, but is uncommon,1, 2, 6 as well as orthostatic hypotension. The first DBPCT clozapine trial1 reported a mortality rate of 10% within 3 months of completing the 4-week trial and 3 weeks in the French trial. No deaths occurred during the 4-week trials, and serious adverse events were more common in the placebo group during the double-blind phase of the French2 while the serious side effects were equal in the two groups in the American trial. No death was attributed to clozapine. Several studies have shown an increased mortality rate associated with psychotic symptoms in PD38 and have also shown a significant increase in mortality with the use of risperidone, quetiapine, and olanzapine, all second-generation neuroleptics, and conflicting results with pimavanserin.38, 39 The numbers of patients with PD treated with clozapine has been too small to be analyzed even in large databases. In addition, there are caveats in comparing mortality in second-generation neuroleptic treated versus untreated because of the limited ability to control for confounds. Clozapine, albeit an inexpensive drug, about $210/mo for the drug, requires about $100 for each complete blood count and a small amount for secretarial handling of the results plus the possible cost of home blood drawers, varying from area to area but estimated at about $500/visit. This means that 4 weeks of clozapine will cost approximately $2600/mo compared with more than $4400 for pimavanserin. After 6 months, the clozapine monitoring costs are halved and then halved again at 12 months. In my clinic, undoubtedly a nonrandom sample, 10% of all patients with PD are treated with clozapine compared with most studies showing use in fewer than 1% of patients with PD who are psychotic, tantamount to nonuse. Safety has not been adequately assessed in patients with PD because of its low use. Duration of use with clozapine compared with other antipsychotics suggest that the quality of life is likely improved significantly. It is significantly more costly to use than other generic atypicals, but even with home drawers of blood is less than half the cost of pimavanserin for the first 6 months, and lower thereafter. Comparing the cost and risks of deep brain stimulation and highly focused ultrasound versus clozapine for the treatment of rest tremor, clozapine should certainly be considered first. Other uses for the drug, such as for dyskinesias, have less supportive data. Ethical Compliance Statement: This article used only published data; no institutional review board approval was required as no data were accrued. The author confirms that the approval of an institutional review board/patient consent was not required for this work. Informed consent was not obtained as there were no subjects as there was no study. The author confirms that he has read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: There was no funding provided for this article other than the author's salary from Kent Physicians Group of Care New England. No specific funding was received for this work. The author declares that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The author has received royalties from Medlink, Karger Press, and Cambridge University Press. The author has received consulting fees from EpiQ unrelated to this article or its contents.

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