Microsoft word - article_letourneau_submission_2013.doc

Title : A naturalistic study on the follow up of guidelines regarding
antipsychotics prescriptions in long-term care units
Running head : antipsychotics prescription in long-term care units
Key words : antipsychotics, long-term care, dementia, behavioral and psychological
symptoms of dementia.
Name of authors :
1- Genevieve Létourneau
2- Nayfe Abdul-Hadi
3- Salam El-Majzoub
4- Marie-Andrée Bruneau
Institution :
Institut Universitaire de Gériatrie de Montréal
4565 Chemin Queen Mary
Montréal, Québec
H3W 1W5
Canada
Corresponding author : Genevieve Létourneau
Email address : genevieveletourneau@yahoo.ca
Phone number : (514) 944-4035
Fax: (514) 340-2832
Sponsors : none
Word count : 3491

A naturalistic study on the follow up of guidelines regarding
antipsychotics prescriptions in long-term care units

Geneviève Létourneau, Nayfe Abdul-Hadi, Salam El-Majzoub, Marie-Andrée Bruneau.
Introduction.

Antipsychotics are classically used to treat mental illnesses such as psychotic disorders or
other disorders associated with psychotic features. However with the development of new
antipsychotic medications with a favorable side effect profile antipsychotics are now
prescribed in several other clinical situations. Antipsychotic treatment in elderly patients
suffering from behavioral and psychological symptoms of dementia (BPSD) is the focus
of many studies.
A meta-analysis from 2006 revealed that atypical antipsychotics such as olanzapine and
risperidone were efficient in treating aggression in dementia and that risperidone was
effective to treat psychotic symptoms [1]. The authors of this paper also highlight the
risks and potential side effects associated with antipsychotic treatment in this population
and insist that antipsychotic treatment should never be a “routine” intervention in patients
suffering from dementia. The CATIE-AD study demonstrated that antipsychotics such as
risperidone and olanzapine could have modest positive impact on anger, aggression or
psychosis, but were not efficient in improving functioning or quality of life [2]. A recent
systematic review of pharmacological treatments for dementia in long-term care units
identified 15 studies that focused on atypical antipsychotics effects and concluded that
there were some evidence of efficacy for risperidone, olanzapine and aripiprazole on
BPSD in long-term care units [3].
Risks and side effects.
In 2005 Health Canada issued a warning after a retrospective review of 13 studies of
atypical antipsychotics treatment (risperidone, olanzapine, quetiapine) in dementia
revealed that dementia subjects treated with antipsychotics compared to placebo showed
a higher mortality risk, with an odds ratio of approximately 1,6. Mortality,was mostly
associated with cardiac or infectious causes. A subsequent meta-analysis confirmed an
increased mortality risk for dementia patients treated with atypical antipsychotics
(aripiprazole, olanzapine, risperidone, quetiapine) compared to placebo, (3,5% versus
2,3%). The odds ratio for mortality was 1,54 [4]. Several studies also associated higher
mortality rates with typical antipsychotics treatment in dementia patients [5, 6]. Finally
the DART-AD study that investigated the impact of withdrawing versus continuing
antipsychotics in patients suffering from dementia, confirmed decreased survival rates in
those patients who were kept on antipsychotics after 12 months to 36 months [7].
In 2002 a black-box warning was issued describing increased risks of stroke and
transitory ischemic events in dementia patients treated with risperidone. In 2004 the UK
Committee on Safety of Medicines published a meta-analysis stating an odds ratio of 3,32
for stroke-related events in dementia patients treated with risperidone or olanzapine.
Another meta-analysis from Herrmann and al. also found relative risks of 3,2 and 1,8 of
having a stroke for dementia patients treated respectively with risperidone and olanzapine
versus placebo [8].
Metabolic side effects can also be a concern for elderly patients suffering from dementia.
CATIE-AD showed that atypical antipsychotic treatment resulted in higher weight gain
than placebo [9]. Higher weight gain was also described in BPSD patients treated with
olanzapine compared to risperidone or placebo in a study by Deberdt and al [10] and
olanzapine treatment was associated with increased abdominal circumference, lowered
HDL [9] and increased risk of diabetes after 6 months, compared to placebo [11]. A
higher risk of hospitalization for hyperglycemia was also described in elderly patients
who were newly receiving a typical or atypical antipsychotic [12].
Typical and atypical antipsychotics can prolong the QT interval, as they modify the
function of cardiac potassium channels, increasing the risk of potentially lethal
arrhythmias. Known significant risk factors to develop a prolonged QT interval are,
among others, being over 65 years old and high dose of antipsychotic treatment [13]. A
case-control study has showed higher odds ratio of being hospitalized for
arrhythmia/cardiac arrest in elderly long-term care residents receiving typical or atypical
antipsychotics versus those not treated with antipsychotics [14]. Ray and al. also
described higher and dose-related relative risks of sudden death in elderly patients treated
with typical and atypical antipsychotics compared to those who were not [15].
Although the evolution of antipsychotics prescriptions for dementia patients was
influenced by the black-box warnings and raising awareness concerning side effects [16],
these medications still remain largely used, especially in long-term care units. In 2005, it
was evaluated that 25% of long-term care residents suffering from dementia living in the
Montreal area, in Canada [17] were treated with atypical antipsychotics. Between 2006
and 2009, a 13,3% increase in the number of antipsychotic prescriptions was described in
the province of Quebec, Canada [18] for all individuals with dementia. More recently, a
Swedish study also revealed that as much as 38% of the demented patients living in
specialized care units were receiving antipsychotic treatments [19].

Recommendations and guidelines.

The American Diabetes Association (ADA) established metabolic follow-up guidelines
for patients treated with atypical antipsychotics. Actual recommendations state that a
baseline work-up, including body weight, abdominal circumference, blood pressure,
fasting blood sugar and lipid profile, should be done. Body weight should be monitored
monthly for 3 months and then every 3 months, while fasting blood sugar should be
monitored after 3 months, then yearly, and lipid profile should be monitored after 3
months then every 5 years [20]. These guidelines rely on studies mostly made on young
adult populations and no specific recommendations have been made for elderly patients.
It has also been recommended to monitor the risk of antipsychotic-related arrhythmias
with an EKG within the first week of treatment, and to repeat it minimally every 6
months if the patient has a specific risk factor for QT prolongation or is treated with more
than one antipsychotic. These recommendations also concern the adult population of all-
age.
Some specific recommendations for antipsychotic treatment in elderly patients suffering
from dementia are available in the 3rd Canadian Consensus Conference on Diagnosis and
Treatment of Dementia, where it is clearly stated that after a 3 months period of
behavioral stability, attempts to reduce the dose of the medication against BPSD should
be done in order to withdraw that medication [21]. Bergh and Engedal [22] found that a
small sample of subjects suffering from dementia tolerated well the discontinuation of
antipsychotics medication over 24 weeks. Similarly Ballard and al. [23] demonstrated
that the majority of subjects remained clinically stable after the discontinuation of
neuroleptic medication, adding that higher scores on the NPI at baseline were associated
with greater risks of BPSD aggravation. Devanand and al. [24], on the other hand,
showed that Alzheimer’s disease subjects who had responded to risperidone had
significantly higher of relapse when this medication was stopped. A recent Cochrane
review on the topic concluded that antipsychotics withdrawal could generally be done
without significantly affecting patients behavior and that discontinuation programmes
could be incorporated into routine practice [25].
Objectives of the study

This study was elaborated in order to
- Monitor metabolic side effects in long-term care patients treated with - Evaluate the pertinence of metabolic follow-up in these antipsychotic-treated patients, considering that such side effects would possibly not be treated - Evaluate how and understand why guidelines are (or not) followed regarding indications to begin reevaluation and withdraw antipsychotic treatment in the long-term care population.
Methods.

We designed questionnaires that were sent to the physicians prescribing antipsychotics to
all the long-term care residents at the IUGM. These questionnaires were sent at the
beginning of the study (baseline), then 3 months and 6 months later. We asked physicians
to detail the initial indication for prescription, duration of the antipsychotic prescription
and presence of comorbidity with metabolic/cardiac illnesses (hypertension, diabetes,
dyslipidemia or arrhythmia). We also inquired if physicians were following up on the
evolution of metabolic parameters and if they would treat potential metabolic
complications. The 3rd and 6th months questionnaires investigated reasons for continuing
the antipsychotic prescription versus attempting drug withdrawal as well as the clinical
evolution of the patients when antipsychotics were withdrawn. At the same time as these
questionnaires were distributed, the IUGM pharmacy service issued a notice encouraging
physicians to reconsider the indication of the medication before renewing it. All
physicians involved in this study were invited to attend a conference about the
management of BPSD at the beginning of the study.

All statistical analyses were conducted using Excel programs.

Results.

Nine physicians participated in the study. At baseline (January 2012) 127 of the 367
residents (34,6%) of the long-term care units of the IUGM were prescribed at least one
antipsychotic medication. Information could be collected for 116 of these 127 patients
(see table 1). 90% of them were receiving regular antipsychotics while 10 % only
received medications “as needed”. The antipsychotics that were the most prescribed were
quetiapine and risperidone. Other prescribed antipsychotics were haloperidol,
olanzapine, aripiprazole and clozapine. Table 2 offers a summery of the ranges and
average daily doses for these medications. Regular median daily doses were of 50 mg for
quetiapine, 0,5 mg for risperidone and 4,4 mg for olanzapine. About two thirds (68%) of
all these prescriptions had been active for over a year. Only 17% of these prescriptions
had been active for less than 6 months. The indications were mostly related to BPSD
since «dementia and psychosis, agitation or aggression» was identified in more than 80%
of the cases. The remaining indications were refractory major depression (8%), bipolar
disorder (6%), schizophrenia (3%) and insomnia (1%).
The questionnaires revealed that metabolic parameters were not systematically
monitored. Blood pressure was the most regularly monitored parameter with more than
90% of the residents having at least monthly values available in their charts. More than
25% of them didn’t have a regular monitoring of their weight and less than 10% had
testing of fasting blood sugar, lipidic profile or EKGs in the 6 months duration of the
study. These results contrasted with the important rates of patients who suffered from
comorbid metabolic/cardiac illnesses. Fifty five percent of them had a diagnosis of
hypertension, 22% suffered from diabetes, 30% from dyslipidemia and 18% from cardiac
arrhythmia. The majority (64,3%) of them were also actively receiving treatments for
these conditions. The physicians were also asked whether they would consider
pharmacological treatment for metabolic/cardiac disorders that would appear while on
antipsychotic treatment. While nearly 100% of the physicians answered that they would
introduce a treatment for hypertension or diabetes, only 35% of them said they would
treat de novo dyslipidemia.
At 3 months (see figure 1), 12 of the original 116 subjects were deceased and one had
moved to another nursing home. About 50% of the baseline subjects were still receiving
unchanged doses of antipsychotics. In 11 % of these patients, all antipsychotics had been
discontinued and in an additional 16 % of them, antipsychotics doses had been reduced.
About 10% of the patients had required a dose increase or a modification of the
antipsychotic type.
Antipsychotics decreases or discontinuation resulted in clinical stability in 92%,of the
cases. In the remaining cases, a mild deterioration was noted and antipsychotic
medication was either increased to previous higher doses or a new antipsychotic
medication was introduced. The main explanations not to initiate medication withdrawal
were diverse: 17% of the cases were considered as “clinically unstable”, 21% as “chronic
mental illnesses” but in nearly 25% of the cases, the physicians admitted that “fear of
clinical deterioration” was the main reason not to withdraw antipsychotics. The
explanation was not specified by the physician in the remaining cases.
Considering the need to modify metabolic/cardiac conditions-related medications, only 4
patients saw their need for insuline change and 1 patient needed increased
antihypertensive medication doses.
After 6 months (see figure 2), 9 additional subjects were deceased. Nevertheless at this
time point, nearly 14% of the original cohort didn’t receive any antipsychotics anymore
and an additional 26% received diminished doses. Table 3 presents details information
about the frequencies of each antipsychotic at 6 months. Only 37% of the baseline
subjects were still receiving the original doses of antipsychotics and 4% of them had
needed doses increases or antipsychotics type changes between the 3rd and the 6th month
of follow-up. At this point time it was still reported that antipsychotics decreases or
discontinuation didn’t lead to BPSD aggravation in 92% of the cases, while the remaining
8% responded well to doses re-augmentation. The average regular doses of
antipsychotics given to the patients at 6 months didn’t change (see table 4), but the
median daily doses of both quetiapine and risperidone decreased (respectively at 43,75
mg and 0,375 mg after 6 months). Only one patient required readjustments of his insulin
doses.
Including all “new” patients who were hospitalized in the long-term care units of the
IUGM during the research project but who weren’t part of the baseline cohort, the
percentage of long-term care patients receiving antipsychotics at the IUGM went from
34.6% at baseline, to 28.6% at 3 months, to 31.0% at 6 months.
Discussion.

An important proportion of the patients hospitalized in the long-term care units of the
IUGM were prescribed antipsychotics medication. Coherent with prevalences found in
the literature, our results informed us that antipsychotics are still prescribed to a quarter to
a third of all patients suffering from dementia residing in long-term care units.
Furthermore, in most cases, these prescriptions aren’t short-termed as almost two thirds
of the patients in our cohort had received them for over a year. The reasons why these
medications were originally prescribed were in line with the Canadian guidelines
(agitation, psychosis or aggression related to dementia or from other chronic psychiatric
illnesses). It is interesting to point out that quetiapine was the most frequently prescribed
medication, while risperidone came second. Quetiapine is generally considered by
clinicians to have a more benign adverse effects profile even though the risk of
hypotension and sedation is not negligible in this population. Moreover quetiapine has
been shown to be less efficient in treating BPSD and only risperidone is officially
indicated in Canada to treat such symptoms.
Nevertheless, in our study, medical education aiming towards increased awareness about the issues regarding antipsychotics prescription in elderly patients, combined with the reminders from the hospital pharmacy every 3 months, were linked to a reduction of the percentage of antipsychotic prescription by 10% in the long-term care units of the IUGM over the 6 months of the study. In our original cohort, antipsychotics could be totally withdrawn in 14% of the patients and partially withdrawn in over 25% of the others. When excluding the patients who were deceased or moved away during the study, the proportions of antipsychotics discontinuation/partial withdrawal raise respectively to 16% and 32%, meaning that nearly 50% of the baseline patients for which information was available at 6 months had had reductions of their neuroleptic prescriptions. Moreover these antipsychotics reductions were well tolerated in most cases, while over 90% of the residents remained clinically stable. In the remaining cases, slight medication readjustments were sufficient to stabilize the clinical situation. Although the majority of the patients who continued antipsychotic therapy throughout the research project had chronic mental illnesses requiring continuous antipsychotic treatment or presumed severe BPSD, it is interesting to learn that many of them were kept on their antipsychotics mainly because their physician was afraid their mental state would deteriorate. Our study design did not include a tool to assess the intensity of the baseline BPSD and relate it to the possibility of withdrawing the medication. Nevertheless the average initial regular doses of quetiapine and risperidone received by patients who had successful antipsychotic discontinuation were much lower than those of the whole initial cohort (respectively 18,7 mg vs 78,4 mg for quetiapine and 0,2 mg vs 0,8 mg for risperidone), suggesting that those with lighter BPSD, who require less important doses, tolerated better medication withdrawal. This would be coherent with the findings from the Denavand and al. study suggesting that there is a subgroup of patients suffering from severe BPSD who benefits from prolonged antipsychotic treatment. Another important issue raised by this study is the difficulty to follow the guidelines for metabolic monitoring of patients treated with atypical antipsychotics. The majority of the subjects in our original cohort already had premorbid cardiovascular risk factors and received treatments for hypertension, diabetes, dyslipidemia or cardiac arrhythmias. Even though these patients could have been described as at “increased risk” for antipsychotics-related metabolic and cardiovascular adverse effects, in most cases, no EKG nor fasting blood glycemia or lipidic profile were made during the follow-up period (or at all). When we ask why, the physicians mentioned they would not prescribe these tests either because the patients were “too agitated” to go through them, because the patients’ families opposed invasive tests or because they thought they would not treat any anomalies they would find, since many of these patients were at a minimal level of intervention considering their prognostic. Especially considering the lipidic profile follow-up, it seemed indeed that the ADA recommendation isn’t appropriate for elderly patients suffering from dementia, considering the time to benefit of the statins and the life expectancy of the patient. On the other hand it was surprising that physician rarely monitored fasting glycemia as the majority of them confirm they would treat such an anomaly if it arose. About the tool provided by the hospital pharmacy, clinicians said that having it to remind them to review the indication of the prescription and try to decrease or discontinue the medication was helpful. Clinicians are often overload with work so time tracking is difficult without that kind of tool and reminder. Our study certainly has many limitations, mainly because of its design. First we don’t have any information about co-occurring prescriptions of other psychotropic medications (antidepressants, mood stabilizers, cholinesterase inhibitors, etc.) and were unable to establish if lower/discontinued doses of antipsychotics were well tolerated because other classes of psychotropic mediations had been introduced. We have not either assessed the presence or impact of non-pharmacological interventions although these approaches are increasingly supported by the literature. However, non-pharmacological interventions are often associated with costs and needs for additional resources that are not available in many long-term care settings in Quebec, which at least partly explains, unfortunately, why pharmacological interventions such as antipsychotics prescriptions are still so common in long-term care units. In regard to the results of our study, we suggest to revise some guidelines about the follow-up of antipsychotic medication in long term care patients with BPSD. First, the indication must be restricted to severe agitation, aggression or psychosis associated with dementia. Second, family and patient (if able) must receive information about the risks and benefits of the medication and give informed consent. Third, the minimal effective dose of evidenced-based efficacious antipsychotics must be prescribed and the level of intervention must be defined with the family and patient and metabolic and cardiac follow-up scheduled depending of the level decided i.e. follow ADA guidelines with full level of intervention to no follow up if minimal level of intervention. At this point, a discussion must take place about what would be best to maintain a good quality of end-of-life to the patient, even though it could mean increasing the risk of some complications. Dementia, unfortunately, is still a terminal illness and relieving psychotic symptoms or severe agitation can represent the main therapeutic objective to improve quality of life in a palliative care optic. Fifth, an alert tool should be available to clinicians every 3 months to remind them that it’s time to reassess the indication of the antipsychotic prescription and try to decrease the dose or cease the medication. This withdrawal should be done cautiously, by tapering by the minimal amount every week and evaluate the clinical status of the patient with the possibility to re-increase to previous dose if needed. Finally, long-term care units must be given the human and financial means to propose non-pharmacological interventions for BPSD, even if medication is needed, alongside all the international guidelines. Further research is needed to define which subgroup of BPSD would benefit from prolonged use of antipsychotics and which subgroups could be easily withdrawn from the medication. More studies about metabolic side effects of antipsychotics in the elderly must go on, as some differences emerge with younger patients. It would be also interesting to see if our recommandations could also apply to BPSD patients living at
home.
Conclusion.

Antipsychotics are widely used to treat BPSD in long-term care units, in about one
quarter to a third of patients. Although their adverse effects and their association with
increased risks of mortality and stroke has been well described, they remain a common
treatment of choice for clinicians. However, our study shows that regular and systematic
prescription reevaluation reminders led to high numbers of successful antipsychotics
withdrawals and were useful to assist physicians manage BPSD. We also documented
that side effects follow-up is rarely done as suggested by usual guidelines. In this sense,
antipsychotics adverse effects guidelines that were designed for a young adult population
seem unrealistic for the majority of the long-term care patients and are, in fact, not
applied. It therefore comes to the clinician to carefully ponder the risks and benefits
related to the prescription of the antipsychotics and choose, after multidisciplinary and
family discussions, the prescription and adverse effect follow-up that is more appropriate
in each specific case.
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