Correspondence: Junichi Fujita, MD, Department of Child and Adolescent Psychiatry, Kanagawa Children's Medical Center, 2-138-4, Mutsukawa, Minami-ku, Yokohama, Kanagawa 232-8555, Japan. Email: email@example.com
It has been recommended that for patients with schizophrenia, antipsychotics should be prescribed simply, using an optimal dose. However, pro re nata (p.r.n., meaning to use on an as-needed basis) antipsychotics may increase the risk of excessive dosing (defined as mean chlorpromazine-equivalent doses above 1000 mg) and polypharmacy (combination use of different antipsychotics). This study aimed to investigate the increased risk caused by p.r.n. antipsychotics.
The subjects included 413 patients with schizophrenia from 17 acute psychiatric wards in nine hospitals. Over a 24-h period on a survey day, data on regular medication and the use of p.r.n. were collected. The analysis focused on p.r.n. antipsychotics in agitated patients. We used McNemar's test to evaluate differences in the proportions of patients prescribed antipsychotics with excessive dosing or polypharmacy before (i.e., regular medication only) and after prescribed p.r.n. antipsychotics were added to regular medication (i.e., regular medication plus p.r.n. antipsychotics).
Of 413 patients, 312 (75.5%) were prescribed p.r.n. for agitated status. Of those, 281 (90.1%) were prescribed p.r.n. antipsychotics. The total doses were significantly higher and more compounded in case patients prescribed p.r.n. antipsychotics than in those who were not. Seventeen patients (4.1%) were actually administered p.r.n. antipsychotics. Their total medication, including p.r.n. on the current day, represented excessive dosing or polypharmacy of antipsychotics.
The use of p.r.n. antipsychotics may cause hidden excessive dosing and polypharmacy. Our results indicate the importance of careful monitoring of p.r.n. antipsychotics to agitated patients with schizophrenia.
THERE IS NO evidence that a combination of antipsychotics is more effective than a single antipsychotic. In addition, combining antipsychotics is a major cause of excessive dosing, and evidence shows that excessive dosing of antipsychotics increases side-effects[1, 3] and mortality. Guidelines and algorithms have recommended that antipsychotic medications for patients with schizophrenia be prescribed simply, using an optimal dose.[5, 6] However, there are discrepancies between these guidelines or algorithms and actual prescription patterns, as excessive dosing and polypharmacy of antipsychotics are prevalent in East Asia.[7, 8]
Within mental health care units, patients are often administered unscheduled medications. The unscheduled medications fall into two categories: stat medication and p.r.n. medication. Although these categories are not clearly differentiated in previous studies, stat medication usually refers to medication prescribed and administered on the basis of doctors' decisions in addition to regularly prescribed medications, whereas p.r.n. medication refers to medication prescribed by doctors in advance, and administration on an as-needed basis according to nurses' clinical judgment under doctors' instructions. The use of p.r.n. psychotropic medication is a widespread but not fully proven interim method of treating acute psychotic symptoms or behavioral disturbances thought to be secondary to psychotic illness. Antipsychotics are one class of drug used as a p.r.n. psychotropic medication.[11, 12] A previous study showed that most psychotic patients are administered at least one dose of p.r.n. antipsychotic during their hospital stay. Furthermore, patients with schizophrenia in acute mental health-care settings may be given p.r.n. psychotropic medications frequently and at high doses. The main disadvantage of this practice is the misuse of medication, that is, the administration of too much medication or the administration of medication too quickly. This misuse may be caused by variations in nurses' opinions regarding the need for p.r.n. psychotics, punitive indications, or over-reliance on medication.
Recent studies revealed that cultural factors and the practice of adding p.r.n. psychotropic medication to regular medicine might increase the risk for excessive dosing and polypharmacy of antipsychotics.[17, 18] There are no published reports of prescription surveys assessing the use of p.r.n. psychotropic medication, excessive dosing, or polypharmacy of antipsychotics in East Asia. Previous studies have indicated that more Japanese patients with schizophrenia are prescribed antipsychotics at high doses than patients in other East Asian countries.[7, 8] It is thus important to investigate the risk of excessive dosing and polypharmacy of antipsychotics caused by p.r.n. psychotropic medication in Japan.
Aims of the study
Agitation is commonly cited as the rationale for both the prescription and administration of p.r.n. psychotropic medication. Patients with schizophrenia or related disorders who are admitted to acute psychiatric units may urgently require the reduction of agitation, and thus p.r.n. psychotropic medication is often prescribed and administered before regular antipsychotic medications have had a chance to take effect. In the present multi-center study, we investigated whether the prescription and administration of p.r.n. antipsychotics to agitated patients with schizophrenia increased the risk of excessive dosing and polypharmacy of antipsychotics in acute care settings.
Twelve psychiatric hospitals were invited to an explanatory meeting regarding this survey. These hospitals were recruited at the research request of the Japanese Psychiatric Nurses Association (JPNA). Of these recruited institutions, 17 acute psychiatric wards in nine hospitals agreed to participate in this survey. To relieve the burden on medical staff and to encourage participation in the study, the survey was conducted using a single-day method. Participating wards were asked to submit data for all patients who occupied a bed in the ward for a 24-h period, including both day and night shifts. The survey day was selected by the chief nurse in each ward from among 5 weekdays in January 2008. The chief nurses in each ward were asked to fill out the survey sheets and to provide details of the prescription and administration of regular medication and p.r.n. psychotropic medication. All 17 participating psychiatric wards were considered acute psychiatric wards as defined by the Ministry of Health, Labor and Welfare of Japan.
Figure 1 shows a flow diagram of the recruitment of participants. Patients with a diagnosis of schizophrenia or related disorders (ICD-10, F21-29) who were prescribed at least one antipsychotic agent as regular therapy were included in the study. The total number of inpatients in the 17 wards on the survey day was 789. Out of a total of 789 inpatients, 440 had schizophrenia or related disorders. Of these, 10 patients were excluded from the analysis because of missing data, and an additional 17 patients were excluded because they had not been prescribed antipsychotics as a regular medication. Thus, we used data from 413 patients for our analysis. Of these 413 patients, the number (%) of male patients was 245 (59.3%). The mean age of the patients was 49.1 (SD 15.6, range 15–83). The number of patients who had undergone involuntary admission was 282 (68.3%). The median length of stay in days of the 413 patients was 180.
In the present study, as part of a study carried out by the National Program of Drug Optimization for Psychiatric Services (P-DOPS), a cross-sectional survey was conducted to clarify the current status of daily psychiatric medication use. This study was approved by the institutional review board of the National Centre of Neurology and Psychiatry.
The following data were collected for each patient: demographic variables, age, sex, mental health act status, length of stay in days, and ICD-10 diagnostic grouping. We collected the drug names and daily dosage for each regular prescription, and the drug name, route of administration, dose, indications for use and prescription dosage for each p.r.n. prescription or administration. The data of patients with a diagnosis of schizophrenia or related disorders whose regular medication contained one or more antipsychotics were used.
In this survey, we operationally defined appropriate prescribing patterns in two ways. First, a single antipsychotic was recommended.[5, 6] We defined patients who were prescribed a combination of two or more kinds of antipsychotics as the ‘polypharmacy group.’ The polypharmacy group was divided into three subgroups: polypharmacy with first-generation antipsychotics (FGA), referred to as type 1 polypharmacy; polypharmacy with second-generation antipsychotics (SGA), referred to as type 2 polypharmacy; and polypharmacy with both FGA and SGA antipsychotics, referred to as type 3 polypharmacy. Second, the standard daily dosage of an individual antipsychotic is recommended to be less than a 1000-mg chlorpromazine-equivalent dose (mg CPZ eq.). We defined patients who were prescribed a 1000-mg CPZ eq. dose or more in a single day as the ‘excessive dosing group,’ regardless of whether the medication administered was regular medication only or regular medication plus p.r.n. medication. All dosages of antipsychotic drugs were converted into chlorpromazine equivalents to facilitate comparisons.
We found that the maximum dose of p.r.n. psychotropic medication varied by nurse and ward. Similarly, the reasons that doctors prescribed p.r.n. psychotropic medication to patients also varied. To help control for these variations, our study group, including one expert psychiatric nurse, one expert psychiatric pharmacologist, and one psychiatrist with sufficient clinical experience, first determined the key reasons for the prescription and administration of p.r.n. psychotropic medication; it was concluded that all of these reasons related to the reduction of patient ‘agitation.’ Based on previous studies,[16, 17] the following five terms were chosen to represent agitation: ‘unstable mental status,’ ‘distress,’ ‘restlessness,’ ‘physically or verbally threatening behavior,’ and ‘loud/disruptive behavior.’ Second, we focused on two aspects of antipsychotic therapy for patients with schizophrenia: (i) initial prescription of p.r.n. antipsychotics; and (ii) administration of p.r.n. antipsychotic therapy on the survey day. Although there were 126 patients whose p.r.n. prescription included several medications (i.e., risperidone tablet 1 mg at first, haloperidol tablet 5 mg next, and finally haloperidol 5 mg i.m. injection), we used the first p.r.n. prescription and administration in this study.
In the present study, we used McNemar's test to evaluate differences in the proportions of patients whose antipsychotic prescriptions met the criteria for excessive dosing or polypharmacy before (i.e., regular medication only) and after prescribed p.r.n. antipsychotics were added to their regular medication (i.e., regular medication plus p.r.n. antipsychotics). We defined the level of significance at P < 0.05.
Analyses were performed using spss 11.0 (spss, Chicago, IL, USA).
Descriptive statistics regarding the use of antipsychotics with excessive dosing and polypharmacy as regular medication
Among 413 patients, the mean antipsychotics dosage was 942.1 mg CPZ eq. (SD 805.6), and the mean 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 polypharmacy 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%) were prescribed at least one p.r.n. psychotropic medication by doctors for agitation. Of these 312 patients, 281 (90.1%) were prescribed antipsychotics, and 31 (9.9%) were prescribed agents other than antipsychotics. The remaining 101 patients (24.2%) were not prescribed p.r.n. medication for agitation.
Of the 281 agitated patients who were prescribed p.r.n. with antipsychotics, 109 (38.8%) received excessive dosing and 186 (66.2%) were administered polypharmacy due to the regular medications prescribed to them.
Of the 281 agitated patients who were prescribed p.r.n. with antipsychotics, 171 (60.9%) were prescribed risperidone, and 23 (8.2%) were prescribed another SGA. Meanwhile, 36 (12.8%) were prescribed haloperidol, and 52 (18.5%) were prescribed another FGA.
Risk of excessive dosing and polypharmacy caused by p.r.n
When p.r.n psychotropic medication for agitation is added to the patient's regular medication by a nurse, the total daily dose of antipsychotic medications may increase. Figure 2 shows the changes in the number of patients in the excessive dosing group and the polypharmacy groups among the 281 patients who were prescribed p.r.n. antipsychotics. McNemar's test revealed a significant increase in the proportion of patients with excessive dosing (P < 0.001) and polypharmacy (P < 0.001) after p.r.n. psychotropic medication was added to regular medication.
When these 281 patients were administered only their regular medication, the total number of patients with polypharmacy of antipsychotics was 186 (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 regular medication together with p.r.n. antipsychotics for agitation, the total number of patients with polypharmacy of antipsychotics increased to 257 (91.5%): 196 (69.8%) with type 3 polypharmacy, 19 (6.8%) with type 1, and 42 (14.9%) with type 2.
When these 281 patients were administered only their regular medication, the mean dosage of regular antipsychotics was 1016.7 mg CPZ eq. (SD 884.5), and the mean number of antipsychotics was 2.3 (SD 1.3). When these patients were administered regular medication together with p.r.n. antipsychotics for agitation, the mean dosage increased to 1220.0 mg CPZ eq. (SD 920.9), and the mean number of antipsychotics increased to 2.8 (SD 1.2).
Actual administration on the survey day
Seventeen patients (4.1%) were actually administered p.r.n. psychotropic medication for agitation on the day of the survey. After the administration of p.r.n. antipsychotics, the number of patients in the excessive dosing group increased from 10 (58.8%) to 13 (76.5%) patients, while that in the polypharmacy group increased from 14 (82.4%) to 17 (100.0%). McNemar's test revealed no significant differences between these groups. Of the 281 patients with an antipsychotic p.r.n. prescription, the 17 patients actually administered p.r.n. had a median length of stay of 1622 days, while that for the 264 patients who were not administered any p.r.n. was 172 days.
In the present study, at least one p.r.n. psychotropic medication for agitation was prescribed to three-quarters of patients with schizophrenia. Of those p.r.n. medications, nine-tenths were antipsychotics. Of these antipsychotics, 70% were SGA. Among the 281 patients who were prescribed p.r.n. antipsychotics for ‘agitation,’ the numbers of patients with excessive dosing and polypharmacy increased significantly after p.r.n. antipsychotics were added to the patients' regular medications, and the mean dosage and total daily doses of antipsychotics increased by 20%. Actually, 4% of patients who were prescribed p.r.n. antipsychotics for ‘agitation,’ were administered at least one p.r.n. psychotropic medication on only one survey day, and all the patients received excessive dosing or polypharmacy of antipsychotics as a result. These patients stayed longer than patients who were not actually administered p.r.n. antipsychotics on the survey day.
The present study suggests that the prescription of p.r.n. psychotropic medication may lead to the administration of antipsychotics outside of recommended prescription guidelines. In particular, there are serious problems related to the prescription of p.r.n. psychotropic medications for agitated patients with schizophrenia who are vulnerable to repeated dosing.[9, 14, 22] In the present study, patients who were administered p.r.n. antipsychotics on the survey day stayed longer in acute psychiatric wards and received more excessive dosing and polypharmacy of antipsychotic medication than other patients. The previous study showed that p.r.n. psychotropic medications are likely to be administered to patients in the first 4 days of admission, or to those who remain in hospital for longer periods of time. The patients who remain in hospital for longer periods may be refractory cases, and may be more vulnerable to repeated doses of p.r.n. psychotropic medication. In those cases in which p.r.n. antipsychotics were prescribed and administered repeatedly and over a long term, p.r.n. antipsychotics were shown to cause hidden excessive dosing and polypharmacy of antipsychotic medication.[17, 18] The p.r.n. process in psychiatric wards is complicated and potentially allows nurses to use their clinical judgment regarding the administration of p.r.n. medications prescribed by doctors. The proper use of p.r.n. antipsychotics by nurses depends on several factors, including clinical settings, preference for medication, relationship with doctors,[17, 25] nursing experience, nursing technique, and working environment.
The problems of hidden excessive dosing and polypharmacy of antipsychotics cannot be solved without optimization of the practice of prescribing and administering p.r.n. psychotropic medication. Currently, regarding stat psychotropic medication that is mainly the responsibility of doctors, we can refer to the guidelines for standard pharmacotherapy for patients with schizophrenia[5, 6] and to the guidelines for standard management of violence or agitation. These guidelines suggest that rapid tranquillization as an intervention for the short-term management of agitation with benzodiazepines or antipsychotics is both reasonably effective and safe. However, regarding p.r.n. psychotropic medication with which nurses' clinical decisions are closely involved, the guidelines suggest that the use of p.r.n. medication for the short-term management of agitation in psychiatric in-patient settings is inconsistent and the medication may not be appropriately administered or monitored. There is no high-quality evidence regarding the risks and benefits of p.r.n. psychotropic medication.[10, 26]
In many circumstances, there are no clear-cut clinical guidelines regarding p.r.n. psychotropic medication. It is possible that a non-pharmacological approach or a benzodiazepine may be a better initial approach than p.r.n. antipsychotics in agitated patients with schizophrenia who do not require rapid tranquilization. However, a previous study found that barriers to the acute use of benzodiazepines include doubts about their efficacy and concerns about drug dependence, despite evidence showing the safety and effectiveness of these drugs. It is possible that the present findings reflect the belief among Japanese psychiatrists and nurses that antipsychotics are more effective than benzodiazepines for agitated patients with schizophrenia.
In general, although SGA have fewer side-effects than FGA,[29, 30] SGA should be prescribed carefully in terms of their additional use as p.r.n. psychotropic medications. Evidence suggests that these drugs can cause adverse effects, such as Parkinson's-like syndrome, sexual dysfunction, and metabolic syndrome, which may affect treatment adherence.[31, 32] All three types of polypharmacy of antipsychotics as described in the present study can alter the predicted efficacy and adverse effects of medications through complex pharmacokinetics.[33-35] The risk-to-benefit ratio for the use of SGA on a p.r.n. basis may not be acceptable. It is recommended that one antipsychotic should be added to another antipsychotic only with careful consideration. However, the present study suggests that the use of SGA as p.r.n. psychotropic medications is common, and this practice may induce a high percentage of combination therapies, such as type 2 polypharmacy or type 3 polypharmacy.
Some studies and expert-consensus statements recommend that both doctors and nurses should carefully examine the necessity for the prescription and administration of p.r.n. antipsychotics, and that psychiatric services should provide educational programs for mental health professionals and reach consensus about the proper way to use p.r.n. medications.[25, 37] Doctors and nurses should attempt various approaches to minimize the unnecessary use of unscheduled psychotropic medication. These approaches might be reviewing clinical indications, frequency of administration, therapeutic benefits and side-effects each week, for instance. Results in this study suggest that p.r.n. medication practice be listed as a quality indicator in psychiatric inpatient care. The careful monitoring of p.r.n. medication practice could improve the quality and safety of psychiatric care.
This study contains the limitation that few patients were administered p.r.n. due to the short-term study period. We could not identify the potential for the risk of excessive dosing and polypharmacy in patients who were actually administered p.r.n. antipsychotics. As this study was intended as a prescription survey, not as a survey of patients in an interventional manner, we could not gather complete profiles of patients, including the clinical characteristics of symptoms and co-morbidities.
In conclusion, p.r.n. antipsychotics may cause hidden excessive dosing and polypharmacy of antipsychotics. Our results indicate the importance of monitoring the prescription and administration of p.r.n. antipsychotic medication to patients with schizophrenia.
This study was conducted with the aid of Sponsored Research on Psychiatric and Neurological Diseases and Mental Health Research 2008, supported by the Ministry of Health, Labor and Welfare, Japan (Grant No; 20-8). The opinions expressed in this article are those of the authors and do not represent the official views of the Ministry. We are especially grateful to the members of the Japan Psychiatric Nurses Association, Keiko Matsumoto PhD, Mr Tamio Sueyasu MNSc, and Ms Sakae Nakano for data collection. The researchers would also like to thank the hospital staff who assisted with the survey.
No author reports that there is any conflict of interests to declare.