Excessive dosing and polypharmacy of antipsychotics caused by pro re nata in agitated patients with schizophrenia

Psychiatry and Clinical Neurosciences 2013; 67: 345–351
Excessive dosing and polypharmacy of antipsychotics causedby pro re nata in agitated patients with schizophrenia Junichi Fujita, MD,1,3* Atsushi Nishida, PhD,1,2 Mutsumi Sakata, BS,4 Toshie Noda, MD1 andHiroto Ito, PhD11Department of Social Psychiatry, National Institute of Mental Health, National Center of Neurology and Psychiatry,2Tokyo Institute of Psychiatry, Tokyo, 3Department of Child and Adolescent Psychiatry, Kanagawa Children's MedicalCenter, Kanagawa and 4Sasaguri Hospital, Fukuoka, Japan Aims: It has been recommended that for patients Results: Of 413 patients, 312 (75.5%) were pre- with schizophrenia, antipsychotics should be pre- scribed p.r.n. for agitated status. Of those, 281 scribed simply, using an optimal dose. However, pro (90.1%) were prescribed p.r.n. antipsychotics. The re nata (p.r.n., meaning to use on an as-needed basis) total doses were significantly higher and more com- antipsychotics may increase the risk of excessive pounded in case patients prescribed p.r.n. antipsy- dosing (defined as mean chlorpromazine-equivalent chotics than in those who were not. Seventeen doses above 1000 mg) and polypharmacy (combina- patients (4.1%) were actually administered p.r.n.
tion use of different antipsychotics). This study antipsychotics. Their total medication, including aimed to investigate the increased risk caused by p.r.n. on the current day, represented excessive dosing or polypharmacy of antipsychotics.
Method: The subjects included 413 patients with Conclusion: The use of p.r.n. antipsychotics may schizophrenia from 17 acute psychiatric wards in cause hidden excessive dosing and polypharmacy.
nine hospitals. Over a 24-h period on a survey day, Our results indicate the importance of careful moni- data on regular medication and the use of p.r.n. were toring of p.r.n. antipsychotics to agitated patients collected. The analysis focused on p.r.n. antipsychot- with schizophrenia.
ics in agitated patients. We used McNemar's test toevaluate differences in the proportions of patients Key words: acute mental health care, antipsychotics,
prescribed antipsychotics with excessive dosing or polypharmacy, pro re nata, schizophrenia.
polypharmacy before (i.e., regular medication only)and after prescribed p.r.n. antipsychotics were addedto regular medication (i.e., regular medication plusp.r.n. antipsychotics).
THERE IS NO evidence that a combination of shows that excessive dosing of antipsychotics antipsychotics is more effective than a single increases side-effects1,3 and mortality.4 Guidelines antipsychotic.1 In addition, combining antipsychot- and algorithms have recommended that antipsy- ics is a major cause of excessive dosing,2 and evidence chotic medications for patients with schizophreniabe prescribed simply, using an optimal dose.5,6However, there are discrepancies between these *Correspondence: Junichi Fujita, MD, Department of Child and guidelines or algorithms and actual prescription pat- Adolescent Psychiatry, Kanagawa Children's Medical Center, 2-138-4, terns, as excessive dosing and polypharmacy of antip- Mutsukawa, Minami-ku, Yokohama, Kanagawa 232-8555, Japan. sychotics are prevalent in East Asia.7,8 Within mental health care units, patients are Received 10 September 2010; revised 4 August 2012; accepted 11September 2012. often administered unscheduled medications. The 2013 The Authors Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology J. Fujita et al.
Psychiatry and Clinical Neurosciences 2013; 67: 345–351
unscheduled medications fall into two categories: stat prescribed and administered before regular antipsy- medication and p.r.n. medication. Although these chotic medications have had a chance to take effect.
categories are not clearly differentiated in previous In the present multi-center study, we investigated studies,9 stat medication usually refers to medication whether the prescription and administration of p.r.n.
prescribed and administered on the basis of doctors' antipsychotics to agitated patients with schizophre- decisions in addition to regularly prescribed medica- nia increased the risk of excessive dosing and polyp- tions, whereas p.r.n. medication refers to medication harmacy of antipsychotics in acute care settings.
prescribed by doctors in advance, and administrationon an as-needed basis according to nurses' clinicaljudgment under doctors' instructions. The use of p.r.n. psychotropic medication is a widespread butnot fully proven interim method of treating acute psychotic symptoms or behavioral disturbances Twelve psychiatric hospitals were invited to an thought to be secondary to psychotic illness.10 Antip- explanatory meeting regarding this survey. These sychotics are one class of drug used as a p.r.n. psy- hospitals were recruited at the research request of chotropic medication.11,12 A previous study showed the Japanese Psychiatric Nurses Association (JPNA).
that most psychotic patients are administered at least Of these recruited institutions, 17 acute psychiatric one dose of p.r.n. antipsychotic during their hospital wards in nine hospitals agreed to participate in this stay.13 Furthermore, patients with schizophrenia in survey. To relieve the burden on medical staff and to acute mental health-care settings may be given p.r.n.
encourage participation in the study, the survey was psychotropic medications frequently14 and at high conducted using a single-day method. Participating doses.9 The main disadvantage of this practice is the wards were asked to submit data for all patients who misuse of medication, that is, the administration of occupied a bed in the ward for a 24-h period, includ- too much medication or the administration of medi- ing both day and night shifts. The survey day was cation too quickly.15 This misuse may be caused by selected by the chief nurse in each ward from among variations in nurses' opinions regarding the need 5 weekdays in January 2008. The chief nurses in each for p.r.n. psychotics, punitive indications, or over- ward were asked to fill out the survey sheets and to reliance on medication.16 provide details of the prescription and administra- Recent studies revealed that cultural factors and the tion of regular medication and p.r.n. psychotropic practice of adding p.r.n. psychotropic medication to medication. All 17 participating psychiatric wards regular medicine might increase the risk for excessive were considered acute psychiatric wards as defined by dosing and polypharmacy of antipsychotics.17,18 the Ministry of Health, Labor and Welfare of Japan.
There are no published reports of prescription Figure 1 shows a flow diagram of the recruitment of surveys assessing the use of p.r.n. psychotropic medi- participants. Patients with a diagnosis of schizophre- cation, excessive dosing, or polypharmacy of antipsy- nia or related disorders (ICD-10, F21-29) who were chotics in East Asia. Previous studies have indicated prescribed at least one antipsychotic agent as regular that more Japanese patients with schizophrenia are therapy were included in the study. The total number prescribed antipsychotics at high doses than patientsin other East Asian countries.7,8 It is thus important toinvestigate the risk of excessive dosing and polyphar-macy of antipsychotics caused by p.r.n. psychotropic Invited to participate (24 wards in 12 hospitals) medication in Japan.
Declined (7 wards in 3 hospitals) Agreed to participate (17 wards in 9 hospitals) Aims of the study
All the inpatients in 17 wards at the survey day (n = 789) Agitation is commonly cited as the rationale for both Inpatients who did not meet the the prescription and administration of p.r.n. psycho- inclusion criteria (n = 376) tropic medication.19 Patients with schizophrenia or Inpatients who met the inclusion criteria (n = 413) related disorders who are admitted to acute psychiat-ric units may urgently require the reduction of agita- Figure 1. Inclusion criteria: ICD-10-F2 and prescribed at least
tion, and thus p.r.n. psychotropic medication is often one antipsychotic as regular medication.
2013 The AuthorsPsychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2013; 67: 345–351
Polypharmacy caused by p.r.n. medication of inpatients in the 17 wards on the survey day was dosing group,' regardless of whether the medication 789. Out of a total of 789 inpatients, 440 had schizo- administered was regular medication only or regular phrenia or related disorders. Of these, 10 patients were medication plus p.r.n. medication. All dosages of excluded from the analysis because of missing data, antipsychotic drugs were converted into chlorprom- and an additional 17 patients were excluded because azine equivalents to facilitate comparisons.20 they had not been prescribed antipsychotics as a We found that the maximum dose of p.r.n. psycho- regular medication. Thus, we used data from 413 tropic medication varied by nurse and ward. Simi- patients for our analysis. Of these 413 patients, the larly, the reasons that doctors prescribed p.r.n.
number (%) of male patients was 245 (59.3%). The psychotropic medication to patients also varied. To mean age of the patients was 49.1 (SD 15.6, range help control for these variations, our study group, 15–83). The number of patients who had undergone including one expert psychiatric nurse, one expert involuntary admission was 282 (68.3%). The median psychiatric pharmacologist, and one psychiatrist with length of stay in days of the 413 patients was 180.
sufficient clinical experience, first determined the keyreasons for the prescription and administration ofp.r.n. psychotropic medication; it was concluded that all of these reasons related to the reduction of patient In the present study, as part of a study carried out by ‘agitation.' Based on previous studies,16,17 the follow- the National Program of Drug Optimization for Psy- ing five terms were chosen to represent agitation: chiatric Services (P-DOPS), a cross-sectional survey ‘unstable mental status,' ‘distress,' ‘restlessness,' was conducted to clarify the current status of daily ‘physically or verbally threatening behavior,' and psychiatric medication use. This study was approved ‘loud/disruptive behavior.' Second, we focused on by the institutional review board of the National two aspects of antipsychotic therapy for patients with Centre of Neurology and Psychiatry.
schizophrenia: (i) initial prescription of p.r.n. antip- The following data were collected for each patient: sychotics; and (ii) administration of p.r.n. antipsy- demographic variables, age, sex, mental health act chotic therapy on the survey day. Although there were status, length of stay in days, and ICD-10 diagnostic 126 patients whose p.r.n. prescription included grouping. We collected the drug names and daily several medications (i.e., risperidone tablet 1 mg at dosage for each regular prescription, and the drug first, haloperidol tablet 5 mg next, and finally halo- name, route of administration, dose, indications for peridol 5 mg i.m. injection), we used the first p.r.n.
use and prescription dosage for each p.r.n. prescrip- prescription and administration in this study.
tion or administration. The data of patients with adiagnosis of schizophrenia or related disorders whose regular medication contained one or more In the present study, we used McNemar's test to antipsychotics were used.
evaluate differences in the proportions of patients In this survey, we operationally defined appropri- whose antipsychotic prescriptions met the criteria for ate prescribing patterns in two ways. First, a single excessive dosing or polypharmacy before (i.e., regular antipsychotic was recommended.5,6 We defined medication only) and after prescribed p.r.n. antipsy- patients who were prescribed a combination of two chotics were added to their regular medication (i.e., or more kinds of antipsychotics as the ‘polypharmacy regular medication plus p.r.n. antipsychotics). We group.' The polypharmacy group was divided into defined the level of significance at P < 0.05.
three subgroups: polypharmacy with first-generation Analyses were performed using SPSS 11.0 (SPSS, antipsychotics (FGA), referred to as type 1 polyphar- Chicago, IL, USA).21 macy; polypharmacy with second-generation antip-sychotics (SGA), referred to as type 2 polypharmacy; and polypharmacy with both FGA and SGA antipsy-chotics, referred to as type 3 polypharmacy. Second, Descriptive statistics regarding the use of
the standard daily dosage of an individual antipsy- antipsychotics with excessive dosing and
chotic is recommended to be less than a 1000-mg polypharmacy as regular medication
chlorpromazine-equivalent dose (mg CPZ eq.).3 Wedefined patients who were prescribed a 1000-mg CPZ Among 413 patients, the mean antipsychotics dosage eq. dose or more in a single day as the ‘excessive was 942.1 mg CPZ eq. (SD 805.6), and the mean 2013 The Authors Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology J. Fujita et al.
Psychiatry and Clinical Neurosciences 2013; 67: 345–351
number of antipsychotics was 2.2 (SD 1.2). With respect to prescriptions outside of the recommended prescription guidelines, the excessive dosing group included 150 patients (36.4%), and the polyphar- macy group included 276 patients (66.9%).
Patterns of prescribing p.r.n. for agitated
patients with schizophrenia
Out of the total of 413 patients, 312 (75.5%) wereprescribed at least one p.r.n. psychotropic medicationby doctors for agitation. Of these 312 patients, 281 Excessive dosing group* Polypharmacy group (90.1%) were prescribed antipsychotics, and 31(9.9%) were prescribed agents other than antipsy- Figure 2. Total number of patients prescribed pro re nata
chotics. The remaining 101 patients (24.2%) were (p.r.n.) antipsychotics was 281.*1000 mg chlorpromazine eq.
not prescribed p.r.n. medication for agitation.
Of the 281 agitated patients who were prescribed **McNemar-test, P < 0.001. , Regular only; , Regular + pre- p.r.n. with antipsychotics, 109 (38.8%) received scribed p.r.n. antipsychotics (not including benzodiazepinesand other psychotropics).
excessive dosing and 186 (66.2%) were administeredpolypharmacy due to the regular medications pre-scribed to them.
macy of antipsychotics increased to 257 (91.5%): Of the 281 agitated patients who were prescribed 196 (69.8%) with type 3 polypharmacy, 19 (6.8%) p.r.n. with antipsychotics, 171 (60.9%) were pre- with type 1, and 42 (14.9%) with type 2.
scribed risperidone, and 23 (8.2%) were prescribed When these 281 patients were administered only another SGA. Meanwhile, 36 (12.8%) were pre- their regular medication, the mean dosage of regular scribed haloperidol, and 52 (18.5%) were prescribed antipsychotics was 1016.7 mg CPZ eq. (SD 884.5), another FGA.
and the mean number of antipsychotics was 2.3 (SD1.3). When these patients were administered regularmedication together with p.r.n. antipsychotics for Risk of excessive dosing and polypharmacy
agitation, the mean dosage increased to 1220.0 mg caused by p.r.n.
CPZ eq. (SD 920.9), and the mean number of antip- sychotics increased to 2.8 (SD 1.2).
When p.r.n psychotropic medication for agitation is Actual administration on the survey day
added to the patient's regular medication by a nurse, Seventeen patients (4.1%) were actually adminis- the total daily dose of antipsychotic medications may tered p.r.n. psychotropic medication for agitation on increase. Figure 2 shows the changes in the number the day of the survey. After the administration of of patients in the excessive dosing group and the p.r.n. antipsychotics, the number of patients in the polypharmacy groups among the 281 patients who excessive dosing group increased from 10 (58.8%) to were prescribed p.r.n. antipsychotics. McNemar's test 13 (76.5%) patients, while that in the polypharmacy revealed a significant increase in the proportion of group increased from 14 (82.4%) to 17 (100.0%).
patients with excessive dosing (P < 0.001) and polyp- McNemar's test revealed no significant differences harmacy (P < 0.001) after p.r.n. psychotropic medi- between these groups. Of the 281 patients with an cation was added to regular medication.
antipsychotic p.r.n. prescription, the 17 patients actu- When these 281 patients were administered only ally administered p.r.n. had a median length of stay their regular medication, the total number of patients of 1622 days, while that for the 264 patients who with polypharmacy of antipsychotics was 186 were not administered any p.r.n. was 172 days.
(66.2%): 128 (45.6%) with type 3 polypharmacy, 31(11.0%) with type 1, and 27 (9.6%) with type 2.
When these patients were administered regularmedication together with p.r.n. antipsychotics for In the present study, at least one p.r.n. psychotropic agitation, the total number of patients with polyphar- medication for agitation was prescribed to three- 2013 The AuthorsPsychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2013; 67: 345–351
Polypharmacy caused by p.r.n. medication quarters of patients with schizophrenia. Of those without optimization of the practice of prescribing p.r.n. medications, nine-tenths were antipsychotics.
and administering p.r.n. psychotropic medication.
Of these antipsychotics, 70% were SGA. Among the Currently, regarding stat psychotropic medication 281 patients who were prescribed p.r.n. antipsychot- that is mainly the responsibility of doctors, we can ics for ‘agitation,' the numbers of patients with exces- refer to the guidelines for standard pharmacotherapy sive dosing and polypharmacy increased significantly for patients with schizophrenia5,6 and to the guide- after p.r.n. antipsychotics were added to the patients' lines for standard management of violence or regular medications, and the mean dosage and total agitation.26 These guidelines suggest that rapid tran- daily doses of antipsychotics increased by 20%.
quillization as an intervention for the short-term Actually, 4% of patients who were prescribed p.r.n.
management of agitation with benzodiazepines or antipsychotics for ‘agitation,' were administered at antipsychotics is both reasonably effective and safe.
least one p.r.n. psychotropic medication on only one However, regarding p.r.n. psychotropic medication survey day, and all the patients received excessive with which nurses' clinical decisions are closely dosing or polypharmacy of antipsychotics as a result.
involved, the guidelines suggest that the use of p.r.n.
These patients stayed longer than patients who were medication for the short-term management of agita- not actually administered p.r.n. antipsychotics on the tion in psychiatric in-patient settings is inconsistent and the medication may not be appropriately admin- The present study suggests that the prescription of istered or monitored.26 There is no high-quality evi- p.r.n. psychotropic medication may lead to the dence regarding the risks and benefits of p.r.n.
administration of antipsychotics outside of recom- mended prescription guidelines. In particular, there In many circumstances, there are no clear-cut clini- are serious problems related to the prescription of cal guidelines regarding p.r.n. psychotropic medica- p.r.n. psychotropic medications for agitated patients tion. It is possible that a non-pharmacological with schizophrenia who are vulnerable to repeated approach27 or a benzodiazepine28 may be a better dosing.9,14,22 In the present study, patients who were initial approach than p.r.n. antipsychotics in agitated administered p.r.n. antipsychotics on the survey day patients with schizophrenia who do not require rapid stayed longer in acute psychiatric wards and received tranquilization. However, a previous study14 found more excessive dosing and polypharmacy of antipsy- that barriers to the acute use of benzodiazepines chotic medication than other patients. The previous include doubts about their efficacy and concerns study showed that p.r.n. psychotropic medications about drug dependence, despite evidence showing are likely to be administered to patients in the first 4 the safety and effectiveness of these drugs.28 It is pos- days of admission, or to those who remain in hospi- sible that the present findings reflect the belief among tal for longer periods of time.19 The patients who Japanese psychiatrists and nurses that antipsychotics remain in hospital for longer periods may be refrac- are more effective than benzodiazepines for agitated tory cases, and may be more vulnerable to repeated patients with schizophrenia.
doses of p.r.n. psychotropic medication. In those In general, although SGA have fewer side-effects cases in which p.r.n. antipsychotics were prescribed than FGA,29,30 SGA should be prescribed carefully in and administered repeatedly and over a long term, terms of their additional use as p.r.n. psychotropic p.r.n. antipsychotics were shown to cause hidden medications. Evidence suggests that these drugs can excessive dosing and polypharmacy of antipsychotic cause adverse effects, such as Parkinson's-like syn- medication.17,18 The p.r.n. process in psychiatric drome, sexual dysfunction, and metabolic syndrome, wards is complicated and potentially allows nurses to which may affect treatment adherence.31,32 All three use their clinical judgment regarding the administra- types of polypharmacy of antipsychotics as described tion of p.r.n. medications prescribed by doctors.23 in the present study can alter the predicted efficacy The proper use of p.r.n. antipsychotics by nurses and adverse effects of medications through complex depends on several factors, including clinical set- pharmacokinetics.33–35 The risk-to-benefit ratio for tings,22 preference for medication,24 relationship with the use of SGA on a p.r.n. basis may not be accept- doctors,17,25 nursing experience, nursing technique, able.36 It is recommended that one antipsychotic and working environment.15 should be added to another antipsychotic only with The problems of hidden excessive dosing and careful consideration.34 However, the present study polypharmacy of antipsychotics cannot be solved suggests that the use of SGA as p.r.n. psychotropic 2013 The Authors Psychiatry and Clinical Neurosciences 2013 Japanese Society of Psychiatry and Neurology J. Fujita et al.
Psychiatry and Clinical Neurosciences 2013; 67: 345–351
medications is common, and this practice may researchers would also like to thank the hospital staff induce a high percentage of combination therapies, who assisted with the survey.
such as type 2 polypharmacy or type 3 polypharmacy.
No author reports that there is any conflict of inter- Some studies and expert-consensus statements rec- ests to declare.
ommend that both doctors and nurses should care-fully examine the necessity for the prescription andadministration of p.r.n. antipsychotics, and that psychiatric services should provide educationalprograms for mental health professionals and 1. Centorrino F, Goren JL, Hennen J, Salvatore P, Kelleher JP, reach consensus about the proper way to use p.r.n.
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Active International Research into Cardiometabolic and Liver Effects of a Proprietary Calabrian Bergamot Citrus Extract By James Ehrlich, MD and Jay Williams, PhD A team of Italian physicians and food scientists are leading an aggressive international research agenda into the salutary cardiovascular, metabolic, and hepatic properties of a juice extract of the bergamot citrus fruit (Citrus bergamia, Rutaceae), endemic to Calabria, Italy. After developing one of Europe's top medical research facilities at the Interregional Research Center for Food Safety and Health at the University of Catanzaro, the group has recruited academic physicians from Rome, Australia, and the United States to study the properties of a highly concentrated juice extract called(Bergamot Polyphenol Fraction/BPF 38%). Over the past few years, the group has organized international symposia, published book chapters, and has authored numerous publications concentrating its efforts on three key areas affecting at least 30% of western civilization -- high cholesterol, metabolic syndrome, and fatty liver disease. Safe and effective management of dyslipidemia (elevated cholesterol) with a "natural statin" It is well known that statin cholesterol medications have a long list of adverse side effects, including muscle aches, memory loss, and an elevated risk for diabetes. Finding a natural and safe lipid-lowering alternative is a topic of increased interest among clinicians and proactive citizens. Bergamot polyphenolic fraction (BPF) has been shown to lower LDL- cholesterol , raise HDL-cholesterol and favorably improve the dangerous lipoprotein particle characteristics seen in most Americans who consume excessive carbohydrates. Dietary polyphenols (especially bioflavonoids) may prevent atherosclerosis due to their anti-oxidative and anti-inflammatory proprieties. Among the citrus family (Rutaceae), bergamot fruits contain a very high content of flavonoids, including "statin-like" bruteridin and melitidin, two polyphenols which contain the same HMG-CoA reductase enzymatic activity found in all pharmacologic statins.

Design of the hiv prevention trials network (hptn) protocol 054: a cluster randomized crossover trial to evaluate combined access to nevirapine in developing countries

Design of the HIV Prevention Trials Network (HPTN) Protocol 054: A cluster randomized crossover trial to evaluate combined access to Nevirapine in developing countriesJim HughesUniversity of Washington, jphughes@u.washington.edu Robert L. GoldenbergUniversity of Alabama, Robert.Goldenberg@ccc.uab.edu Catherine M. WilfertElizabeth Glaser Pediatric AIDS Foundation/Duke University, wilfe001@mc.duke.edu