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        Prescribing trends and safety of clozapine in an older persons mental health population
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        Prescribing trends and safety of clozapine in an older persons mental health population
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Abstract

Objectives:

To provide additional data concerning the safety, effectiveness and local prescribing trends of clozapine in elderly patients.

Design:

Retrospective observational case-series analysis.

Setting:

Data were collected from the medical files of 167 patients prescribed clozapine.

Participants:

All patients prescribed clozapine in the last 15 years by the psychogeriatric service in Christchurch, New Zealand. The subjects were mostly aged over 65; however, patients under 65 are also accepted into the service on a case by case basis if they have an age-related health condition.

Results:

Twenty-five (15.0%) patients had their clozapine stopped due to a significant adverse reaction, including eleven who developed significant neutropenia. Seventy-four (44.3%) of the patients had no recorded side effects at all. Sixty-five (38.9%) of our elderly patients died while taking clozapine, though none of these deaths was felt to be related to clozapine use. Several patients safely initiated clozapine in either their own home or a nursing home without requiring hospital admission. Only two patients ceased clozapine due to ineffectiveness, and one hundred, forty-two (86.1%) of the patients had positive comments in their medical record regarding the benefits of clozapine for their particular case.

Conclusions:

We found clozapine could be used safely and effectively in our patient group, for a wider range of indications and at lower doses than younger patients. Data collection regarding cause of death in elderly patients who were ever prescribed clozapine was problematic, and more research into this area is required.

Introduction

There is a relatively large body of research surrounding usage and safety of clozapine in adult populations with schizophrenia, including a large meta-analysis suggesting clozapine is both the most effective of all available antipsychotic medications and is well-tolerated by patients (Leucht et al., 2013). Existing research demonstrates that patients prescribed clozapine are at higher risk of hematological problems, oversedation, hypersalivation, constipation, seizures, and electrocardiograph (ECG) abnormalities, than those taking other antipsychotics (Asenjo Lobos et al., 2010; Essali et al., 2009). Yet, all-cause mortality rates may be lower, perhaps, because clozapine has been shown to reduce the risk of psychotic relapse and, consequently, improve outcomes in other domains such as lowering the risk of suicide (Hennen and Baldessarini 2005; Kiviniemi et al., 2013; Walker et al., 1997).

Unfortunately, there is comparatively little research on clozapine usage amongst geriatric populations, with most studies of antipsychotic medication specifically excluding this patient group. The first research into clozapine in the elderly was published in the early 1990s, with several small case series (n between 3 and 20) published demonstrating potential utility of clozapine in this patient group but recommending further research, especially with regard to adverse effects and dosing regimens (Frankenburg and Kalunian, 1994; Pitner et al., 1995; Salzman et al., 1995; Sajatovic et al., 1996; Shulman et al., 1997).

A Cochrane review of antipsychotic medication for elderly patients with schizophrenia found little robust data to assist clinicians in selecting appropriate antipsychotics (Marriott et al., 2006). Some studies suggest clozapine carries an increased risk of medical complications when used in a geriatric population, particularly agranulocytosis, myocarditis, seizures, weight gain, and metabolic effects (Gareri et al., 2008; Herst and Powell, 1997). Attempts have been made to quantify the risk of clozapine-induced neutropenia in the elderly. A case series of 13 psychogeriatric patients found 4 (30.7%) who developed serious neutropenia (Snowdon and Halliday, 2011). A literature review encompassing 133 elderly patients on clozapine without neurological comorbidity found only 7 (5.3%) who developed serious neutropenia (Barak et al., 1999), while a case series of 28 elderly patients found a risk of serious neutropenia of 12.5% (Guenette et al., 2013). Other research has been more encouraging, with a small retrospective analysis of 43 elderly patients on clozapine finding that none required discontinuation of the drug due to side effects or complications (Pridan et al., 2015). Comparatively, younger adults on clozapine have been found to experience serious white blood cell problems necessitating cessation of the drug in around 1–2% of patients (Alvir et al., 1993).

Clinicians working with elderly psychiatric patients in Australia and New Zealand are anecdotally (to the author’s knowledge) reluctant to prescribe clozapine due to perceived increased risks and a relative paucity of data regarding its safety in older adults. A postal survey of 155 old age psychiatrists in England found 67% of respondents felt clozapine had a useful place in the treatment of elderly patients (Paranthaman and Baldwin, 2006). However, the majority of respondents expressed concern about a lack of published data regarding safety and side effects of clozapine, and familiarity/confidence of clinicians in prescribing clozapine in the elderly was an important determinant of its use. Clinicians also may avoid initiating clozapine due to the “compliance costs” of time consuming patient registration and monitoring. A recent study of antipsychotic prescribing pathways (Gören et al., 2013) found significant clozapine underutilization, thought to be related to such “costs.”

Clozapine may also be used for a broader range of indications in elderly patients than in a general adult population. It may be used not only for schizophrenia and related disorders, but also for other disorders such as neuropsychiatric complications of Parkinson’s Disease and behavioral and psychological symptoms associated with dementia (BPSD). Further research into the indications for use and safety of clozapine in an elderly population is required to help guide clinicians with treatment decisions.

This study aimed to provide additional data concerning the safety, effectiveness and local prescribing trends of clozapine in elderly patients through a retrospective observational case series analysis of all those prescribed clozapine by the older person’s mental health service in Christchurch. This is the largest such study the authors are aware of and, therefore, has potential to provide significant clinical value.

Methods

Canterbury District Health Board’s (CDHB) Older Person’s Mental Health Service (OPMH) provides psychogeriatric care for the region with a mixture of inpatient, day hospital, and outpatient services. OPMH treats mainly patients over the age of 65; however, patients under 65 are also accepted into the service on a case-by-case basis if they have an age-related health condition (for example, frontotemporal dementia). Ageing patients with chronic psychiatric conditions who are already seeing a mental health team in the general adult service stay under their general adult team unless they develop an age-related health condition (for example, advancing frailty or cerebrovascular accident [CVA]). The authors estimate approximately 50% of people over 65 in our area receiving clozapine are prescribed it from OPMH.

All patients under OPMH care who had been prescribed clozapine from 1999–2015 were identified from our existing database. The full medical record (paper and electronic files) for each patient was obtained, and the information audited by a single researcher (AL). The medical files were reviewed on-site within the CDHB, and the information collected was stored on a secure, internal CDHB computer. Ethical approval was obtained from the Health Research Council.

Multiple data were extracted from each patient’s medical records including demographic information, age at commencing clozapine, maximum clozapine dose, and duration of clozapine treatment. The documented indication for clozapine was recorded, along with whether the patient was under the Mental Health Act (MHA) at the time of starting clozapine. Medical complications such as neutropenia or postural hypotension were recorded if they were mentioned in the treating psychiatrist’s notes as being likely related to clozapine. If the patient died, the recorded cause of death (if available) was identified with the treating team’s opinion about whether clozapine was thought to be implicated in the patient’s death. If clozapine had been discontinued, the reason was sought. The number of admissions to hospital and lengths of stay for the 12 months prior to starting clozapine and 12 months after starting clozapine were calculated as one potential measure of effectiveness, along with HoNOS (Health of the Nation Outcome Scale) scores recorded during the same time periods. Additionally, any qualitative comments about the effectiveness of clozapine were recorded.

Results

One hundred, sixty-seven patients were identified as having been on clozapine prescribed by OPMH between January 1999 and December 2015. Of these, 85 were male and 82 female. One hundred, sixty-three patients were identified as New Zealand European, three identified as New Zealand Maori, and one identified as Indian. The mean age at commencing clozapine was 74.6 years, ranging from 51–95 years, with a median age of commencement of 75 years.

The most common indication for clozapine was a Parkinson’s spectrum disorder with psychosis (including both Parkinson’s disease and Lewy body dementia) for 84 patients (50.2%), followed by schizophrenia (n = 20, 12.0%). Other indications included schizoaffective disorder (n = 14, 8.4%), psychotic depression (n = 10, 6%), dementia (not including Lewy body) with non-psychotic BPSD (n = 10, 6%), late onset schizophrenia (n = 8, 4.8%), bipolar affective disorder (n = 8, 4.8%), dementia (not including Lewy body) with psychotic BPSD (n = 6, 3.6%), and delusional disorder (n = 3, 1.8%). This left four patients with other indications, which included undifferentiated chronic psychotic illness (n = 2), organic psychosis (n = 1), and severe post-CVA delirium (n = 1).

The mean maximum daily dose of clozapine was 90.6 mg, and ranged from 6.25 mg (given to two male patients aged 71 and 81 with Parkinson’s disease psychosis) to 375 mg (prescribed to a 77-year-old woman with severe treatment-resistant manic psychosis as part of a bipolar affective disorder type I). Those patients with a Parkinson’s spectrum disorder had the lowest average maximum daily dose (43.2 mg), and those with schizoaffective disorder had the highest average maximum daily dose (223.2 mg), closely followed by those with bipolar affective disorder (195.3 mg).

There were seven patients where data regarding clozapine initiation and outcomes was unavailable due to them either dying over ten years ago, meaning their paper medical records were destroyed, or moving away from the Canterbury district soon after commencing clozapine. This left 160 patients with accessible information about clozapine initiation and outcomes. At the time of collecting the data, patients had spent a mean of 1,415 days (3.9 years) taking clozapine, with 26 patients still alive and taking clozapine at the time of examining their medical records. There were 23 patients who had taken clozapine for less than 90 days, and 41 patients who took clozapine for 5 years or more. Given the study method, the time post-initiation was different for every patient so these lengths of time only give an indication of what might be possible in terms of treatment duration and, therefore, should be interpreted with caution.

Of the 160 patients about whom complete data could be collected, 34 patients (21.3%) were under the Mental Health Act (MHA) at the time of starting clozapine. Most patients started clozapine as an inpatient on a psychiatric ward (n = 125, 78.1%). Fourteen patients (8.8%) commenced clozapine while on a medical ward, fourteen (8.8%) while in a rest home placement (including one patient temporarily placed for respite care), and seven (4.4%) patients started clozapine at home with close follow-up by their treating psychiatrist. This close follow-up typically entailed home visits by a psychiatric district nurse every two days for blood pressure, pulse, and temperature monitoring, and at least a weekly outpatient review by the psychiatrist, though these arrangements were flexible depending on the clinical needs of the patient.

Seventy-four patients (46.3%) had no recorded adverse effects with clozapine. As this was a retrospective study, adverse effects not documented in the patient’s file could not be taken into account so caution is needed to interpret this result. It was found that 44 (27.5%) patients experienced oversedation, 22 (13.8%) experienced hypotension, 17 (10.6%) experienced constipation, and 14 (8.8%) experienced sialorrhea. None of those with constipation developed a major complication of this (for example, megacolon, intestinal obstruction, bowel perforation). There were seven (4.4%) patients who reported developing urinary incontinence, three (1.9%) with dermatitis, two (1.3%) with worsened confusion/delirium, one case of worsened obsessive-compulsive disorder symptoms, one case of syncope, one case of interstitial pneumonitis, one case of cardiomyopathy, and one case of a new-onset tic. There was also one case of possible mild neuroleptic malignant syndrome, but the treating clinicians in this case were not convinced of the diagnosis and successfully re-challenged this patient with clozapine with no ill effect. We attempted to gather information about metabolic effects of clozapine (i.e. weight gain, impaired glucose tolerance, and hyperlipidemia), but in most cases this was either never recorded or poorly recorded in the notes, so these data were not able to be collected.

In New Zealand, the clozapine blood monitoring program involves weekly cell counts for the first 18 weeks of treatment and monthly cell counts thereafter. If the white blood cell (WBC) count drops below 3000/L or the absolute neutrophil count (ANC) drops below 1500/L in the first 18 weeks, clozapine is ceased immediately. Levels between 3000–3500/L for WBC and 1500–2000/L for ANC require more frequent (twice weekly) monitoring but not cessation of clozapine. After the first 18 weeks, clozapine is ceased if the WBC drops below 2500/L or the ANC drops below 1000/L. More frequent monitoring is required for a WBC between 2500–3000/L or an ANC between 1000–1500/L (Douglas Pharmaceuticals Ltd, 2010). In our study population, 11 (6.9%) patients experienced low WBC or ANC requiring cessation of clozapine. One of these went on to be diagnosed with chronic myeloid leukemia leading the clinicians to wonder if leukemia could have caused the neutropenia rather than clozapine. Excluding this latter patient, all other patients with severe neutropenia had their white cell counts normalize once clozapine was ceased. One patient required treatment with GCSF (granulocyte colony stimulating factor) and transfer to the bone marrow unit.

Clozapine had been discontinued in 134 patients. The most common reason for discontinuation was death (n = 65), followed by it being no longer needed (n = 36). The latter group of patients were all entering a palliative phase of their illness, and as would be usual practice, clozapine was withdrawn if psychiatric symptoms were no longer a key problem. Many of these patients died within a few days or weeks of their clozapine being withdrawn, but as they no longer needed specialist psychogeriatric input they were discharged from follow-up. No further information was readily available about the likely cause of their death, as they often passed away in privately run nursing homes.

The treating clinicians did not suspect clozapine to have caused the death in any of this large number of patients. When a cause of death was documented in the DHB file, the most common reason given was pneumonia/aspiration pneumonia (n = 31), followed by inanition (n = 12). Other documented causes of death included myocardial infarction (MI) (n = 5), metastatic cancer (n = 3), septicemia (n = 2), intracranial bleed (n = 2), CVA (n = 2), gastrointestinal (GI) bleed (n = 1), heart failure (n = 1), and ischemic colitis (n = 1). The mean age at death of the deceased patients in the study was 80.5 years (range 62.3–97.6 years).

Other reasons for discontinuation included neutropenia/agranulocytosis as outlined above (n = 11), hypotension (n = 5), oversedation (n = 4), dermatitis (n = 3), cardiomyopathy (n = 1), and interstitial pneumonitis (n = 1). Patients had routine baseline troponin and ECGs, but not an echocardiogram. Further cardiac investigation was only completed if a patient was symptomatic. One patient ceased clozapine as their symptoms (psychosis/delirium with Parkinson’s Disease) had completely remitted, and two patients ceased clozapine by choice. Two patients had their clozapine ceased as it was felt to be ineffective. These patients included a 72-year-old woman with a longstanding treatment-resistant somatic delusional disorder, and 67-year-old woman with a brittle, treatment resistant bipolar II disorder and delirium. Two patients did not have any reason for ceasing clozapine documented in their file.

Psychiatric hospitalization data were examined as a proxy measure of effectiveness, with the assumption that if more effective than previous treatments, clozapine would cause fewer admissions and shorter hospital stays. After excluding the hospital admission where clozapine was commenced, patients had an average of 0.31 admissions and 12.46 days in hospital in the 12 months before starting clozapine, and an average of 0.27 admissions and 12.18 days in hospital in the 12 months after starting clozapine. This is not significantly different.

HoNOS data in the 12 months before and after starting clozapine were available for only 47 patients, as either the HoNOS forms had not been completed or clozapine was started before HoNOS was introduced at CDHB in 2006. In these 47 patients, the HoNOS score had reduced by an average of 2.45 points in the 12 months after starting clozapine compared to the 12 months before. This was not clinically significant because there was no pattern of subscores being improved due to the small size of the data set (many patients had only one HoNOS score for the 12 month period).

Medical records were scanned for statements by the treating clinician regarding the effectiveness of clozapine. These were then classified as being either “positive,” “equivocal,” or “negative.” One hundred, forty-two statements were positive, with examples including “marked sustained treatment effect,” “much less distressed, nights more restful,” “psychotic features have been effectively addressed,” and “visual hallucinations much reduced in frequency and severity.” Six statements were equivocal “psychosis improved slightly but never completely remitted,” “modest benefit,” “mixed response,” “without significant response,” “delusions were muted, but persisted,” and five were negative, including “without treatment success after a five week trial,” “not done as well since switched to clozapine,” “no response,” “mental state generally deteriorated.” Seven patients had not been taking clozapine long enough for any statement to be made about effectiveness.

Discussion

This study is a retrospective case series analysis and, thus, limited in any firm conclusions. Further prospective research with a close emphasis on accurate recording of medical complications (including metabolic syndrome) and causes of death is warranted.

The results of this study demonstrate clozapine can indeed be used for a wide variety of psychogeriatric indications. In this study population, clozapine was commonly and successfully used for Parkinson’s disease/Lewy body dementia related psychoses and less frequently for behavioral and psychological symptoms related to other dementias. These indications are almost exclusive to psychogeriatrics; thus, the study results can helpfully inform psychogeriatric practice.

Clozapine was successfully initiated in nursing homes or in patient’s own residences for a small but significant group of the study population. While this would not be advocated for every patient commencing clozapine, the knowledge that this can be implemented safely for a select few is helpful for service planning and treatment delivery, particularly in under-resourced rural areas where specialist inpatient psychogeriatric beds are difficult to access.

Although serious medical complications due to clozapine may occur at higher rates in the elderly, this study shows clozapine can be used both safely and effectively in the majority of elderly patients. Our data regarding complication rates may prove useful when discussing the risks and benefits of prescribing clozapine to patients and their families, particularly the difficult decisions weighing quality versus quantity of life so often encountered in psychogeriatrics. Very few of the patients in the study stopped taking clozapine due to side effects (approximately 15%). The severe neutropenia/agranulocytosis rate (6.9%) was, as expected, higher than that seen in younger patients (Alvir et al., 1993) ; however, the normalization of all patients’ white cell counts (except one who was later found to have leukemia) was reassuring. The life expectancy of the study group (80.5 years) was also reassuringly consistent with the expected life expectancy for adults in New Zealand. However, due to the advanced age of the patients in the study, some may have died prior to developing certain medical complications possibly leading to an underestimation of complication rates.

The poor recording of the causes of death of patients in this study was disappointing, particularly those who had recently ceased clozapine. Antipsychotics in older adults are associated with increased all-causes mortality (Schneeweiss et al., 2007) and, more specifically, a significantly increased risk of pneumonia (Tolppanen et al., 2016), CVA (Shin et al., 2013), and sudden cardiac death (Ray et al., 2009). It is possible there is a link between use of clozapine and death by these mechanisms, particularly pneumonia since so many of the patients in the study had dementia, and there is significant concern about antipsychotics and pneumonia in older people with dementia (Tolppanen et al., 2016). No firm conclusion about this could be reached from these study data; further research needs to be conducted into this area. A routine monitoring system of all patients after ceasing clozapine to determine eventual cause of death would be helpful. This is not currently part of the routine monitoring in New Zealand, which requires only those patients who die while still taking clozapine have their cause of death monitored and recorded by the clozapine surveillance program.

As our study group did not receive routine annual echocardiogram, troponin, or ECG, this raises the possibility the rates of myocarditis and cardiomyopathy were underestimated. Patients did receive further cardiac investigation if they were symptomatic, which the authors feel makes it unlikely a clinically significant cardiac complication would be missed. We note the latest Royal Australian and New Zealand College of Psychiatrists guidelines suggest routine annual echocardiography adds little to the detection of cardiomyopathy (Galletly et al., 2016). As many of our patient group passed away without a clear recorded cause of death, undetected clozapine related cardiac complications could be a relevant factor. The utility of cardiac monitoring for elderly patients on clozapine would be a useful avenue for further research, especially as a number of these patients will already carry a burden of cardiac disease before starting clozapine.

Clozapine is known to be associated with metabolic syndrome in younger patients (Lamberti et al., 2006). Unfortunately, useful data about this could not be extracted in this study’s elderly patient group. This would also be an interesting area for future research and highlights that the OPMH service could be improved by setting up a simple recording and monitoring system of BMI, lipids, and fasting glucose/HbA1c. The prevalence of metabolic syndrome increases with age (Hildrum et al., 2007), suggesting this is a risk to be taken seriously. However, the medical consequences of metabolic syndrome (for example, five year risk increases for MI or CVA) may be less concerning for people with a limited life expectancy either due to age or a terminal illness such as dementia. Nevertheless, there is a relative paucity of data in general regarding elderly patients, antipsychotics, and metabolic syndrome that warrants further investigation.

The constipation rates were lower than expected; it was encouraging to note no serious complications due to clozapine-induced gastrointestinal hypomotility. The true constipation rate in the study population is likely to be higher than the results suggested as many patients likely experienced some constipation but it was not documented in their clinical records. Research in younger patients on clozapine has shown more deaths are caused by clozapine-induced ileus/megacolon than by agranulocytosis (Nielsen et al., 2013), with a mortality rate of 27.5% (Palmer et al., 2008). Serious clozapine-induced gastrointestinal hypomotility occurs in around 37 per 10,000 clozapine users (Every-Palmer and Ellis, 2017). It has been speculated that the elderly may be less prone to this due to visiting their general practitioner more regularly and, thus, receiving more frequent screening for early symptoms of constipation. Many of the patients in the present study were either residing in nursing homes or receiving daily assistance at home for activities of daily living, both of which add an extra layer of monitoring of bowel frequency. This could have implications for developing screening initiatives in younger patients on clozapine to prevent serious constipation-related medical events. It is also possible the elderly study population were less likely to have been prescribed concomitant anticholinergic medications (due to the risk of delirium and heightened awareness of risks from these drugs by OPMH prescribers), which in turn may have reduced their risk of significant clozapine-induced gastrointestinal hypomotility.

In conclusion, we found clozapine could be used safely and effectively in our elderly patient group, for a wider range of indications and at lower doses than younger patients. Clinicians need to be mindful of the risk of medical complications for elderly patients taking clozapine but these can be monitored and managed, and our data may prove helpful in discussions with patients and their families about clozapine treatment. In collaboration with other clinicians, we hope to eventually develop a clozapine initiation and monitoring protocol specifically for the elderly using our data.

Conflict of interest declaration

None.

Description of authors’ roles

A. Law designed the study, collected the data, and wrote the paper. M. Croucher supervised study design and data collection and provided feedback on the article prior to submission.

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