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Keywords:

  • antipsychotic agents;
  • perception;
  • prescriptions;
  • psychiatrists;
  • schizophrenia

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

Aims:  The objective of the present study was to identify schizophrenia inpatients who had their original regimen augmented with additional antipsychotics during acute inpatient care, and to clarify the factors associated with these additions.

Methods:  The subjects were 204 schizophrenia inpatients at 34 acute care hospitals, of whom 42 (20.6%) had further antipsychotics added to their medication regimen during hospitalization.

Results:  Compared with patients who were not prescribed additional antipsychotics, the subjects were typically discharged with higher dosages of antipsychotics, principally low-potency medications. Patients who exhibited aggressive behavior, who had no physical illness, or whose psychiatrists preferred typical antipsychotics, were more likely to be prescribed additional new antipsychotics.

Conclusions:  Alternative approaches such as intensive care for aggressive patients and educational intervention with psychiatrists may prove useful in stabilizing patients without adding new antipsychotics unless absolutely necessary, and in simplifying medication regimens.

PRESCRIPTION CHANGE FOR acute inpatients with schizophrenia is critical. During hospitalization, psychiatrists are able to overhaul prescription regimens in an environment with 24-h staff monitoring. The first aim of prescribing medication in the acute phase is sedation of positive symptoms. To that end, antipsychotics may be added and/or increased depending on the effect of initial treatment; a temporary addition and/or increase can be effective for acute treatment. However, if the additional or increased antipsychotics are still being taken after symptoms have subsided, long-term polypharmacy will result. Polypharmacy for schizophrenia patients remains prevalent,1,2 although the importance of simplifying prescription has been recognized.

Certainly, temporary addition in the acute phase or in the course of switching to newer antipsychotics is sometimes necessary. However, we should not forget that once new antipsychotics are added to a regimen, it is difficult to wean patients off additional medications and many become stuck in the supplementary regimen.3,4 If the addition of new antipsychotics potentiates polypharmacy, we must clarify the phenomenon and its related factors. As far as could be determined, no studies have examined the effect of new supplementary antipsychotics.

Previous studies suggested that prescription practices were associated with various factors. They noted that patient clinical and demographic factors and psychiatrist demographic factors and perception of medication were associated with prescription.5–8 We assume that these factors might also be related to the addition of antipsychotics. If these phenomena and related factors were clarified, important clues for avoiding needless addition of antipsychotics might be identified.

The aim of the present study was to identify those schizophrenic inpatients in acute inpatient care units for whom additional antipsychotics had been prescribed, and to clarify patient and psychiatrist factors associated with the addition of new antipsychotics.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

Participants

Every acute psychiatric care unit defined by the Japanese reimbursement system (n = 112), university hospital (n = 85), and national hospital (n = 16) in Japan was invited to participate in the present study. Forty-six hospitals agreed to participate and in each, the units that specialized in acute care were selected. Each patient who met the DSM-IV9 criteria for schizophrenia as well as the following criteria was asked to participate: (i) discharged from the participating units between 4 November and 25 December 2003; (ii) age ≤65 years; and (iii) treatment of psychiatric symptoms as principal reason for hospitalization.

Of 362 eligible patients, 260 (71.8%) agreed to participate. Written informed consent was obtained from all patients. If their admission had been involuntary, the family members responsible for admission also provided their written informed consent.

Of the 260 patients, 10 patients were excluded from the analysis because their psychiatrists did not answer the questionnaire. Ten patients who had not been prescribed antipsychotics at admission and, or discharge, and 36 patients whose data were missing were also excluded.

Thus, we used data for 204 patients in 34 hospitals for statistical analysis: 20 private hospitals, 11 university hospitals, and three national hospitals. The mean number of subjects per hospital was 6.0 ± 3.8 with no significant age or gender difference between the 204 patients analyzed and the 56 who were not.

One hundred and seventeen patients (57.4%) were male, and the mean age was 39.5 ± 14.0 years. The median stay in hospital was 71 days (25th percentile, 32 days; 75th percentile, 95 days) and the mean duration of illness was 13.5 ± 12.0 years. The mean GAF score was 31.3 at admission (SD = 14.3) and 59.3 at discharge (SD = 15.8). One hundred and twenty psychiatrists treated the patients.

Prescription data

Prescription data was collected at admission and discharge. The average daily dose was established for each antipsychotic medication, and was converted to a relative potency equivalent to 100 mg of chlorpromazine (CPZeq), based on information published in the literature.10–14 Polypharmacy was defined as co-prescription of two or more antipsychotic medications.

To identify patients for whom new antipsychotics had been added (the addition group), the prescription data at admission and discharge were analyzed. The addition group included patients who had an increase in the total number of antipsychotics at discharge compared with admission.

Patient factors

We confirmed each patient's demographic and clinical variables with their psychiatrist and nurses. For the clinical variables, the psychiatrists assessed the Global Assessment of Functioning (GAF) scale (DSM-IV Axis V) at both admission and discharge, with a lower GAF score signifying greater disability. To assess symptoms at admission or during hospitalization lasting >1 month, patients were evaluated for the five characteristic symptoms defined by the DSM-IV: delusion, hallucination, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms. In addition, the existence of severe confusion and severe agitation were taken into account. Other variables considered were age, gender, length of illness, involuntary admission, first episode, modified electroconvulsive therapy (m-ECT), and physical illness. Nurses were asked about the use of seclusion and physical restraint and the presence of aggression against objects, others, or themselves during hospitalization.

Psychiatrist factors

Psychiatrists were asked about their age, gender, length of clinical experience, perception of medication, and whether they were designated psychiatrists. Designated psychiatrists are permitted to initiate measures such as physical restraint and involuntary hospitalization. These questions were originally developed based on a consensus of experienced psychiatrists and on previous studies.5,6,15 The questions consisted of various factors affecting psychiatrist prescription practice such as cost, requests from other staff or patients, and knowledge of, or attitudes towards prescription. Each item was scored on a 4-point scale (1, strongly agree; 2, agree; 3, disagree; 4, strongly disagree); 1 and 2 were combined into ‘agree’, and 3 and 4 into ‘disagree’. For a list of the questions used, see Table 1.

Table 1.  Psychiatrist factors between the addition and the non-addition groups
 Addition (n = 42) n (%)Non-addition (n = 162) n (%)Test statistic
  • *

    < 0.05,

  • **

    < 0.10.

  • t test;

  • χ2 test.

  • Addition group, patients who had new antipsychotics added during hospitalization; non-addition group; patients who did not have new antipsychotics added during hospitalization.

Age (years) (mean ± SD)38.9 ± 10.138.4 ± 10.0−0.27
Length of clinical experience (years) (mean ± SD)11.3 ± 10.511.5 ± 9.50.10
Gender
 Male37 (88.1)137 (84.6)0.33
 Female5 (11.9)25 (15.4) 
Designated psychiatrist30 (71.4)104 (64.2)0.77
Psychiatrist perceptions
 Cost consideration24 (57.1)95 (58.6)0.03
 Receiving advice from other psychiatrists35 (83.3)133 (82.1)0.03
 Giving advice to other psychiatrists27 (64.3)101 (62.3)0.05
 Increasing dosage or adding new antipsychotics for the security of staff and other patients39 (92.9)151 (93.2)0.01
 Having patients for whom one can decrease the dose or take off drugs if one has sufficient time to spare27 (64.3)103 (63.6)0.01
 Prescribing drugs when patients request them20 (47.6)77 (47.5)0.00
 Decreasing or stopping drugs at a patient's request24 (57.1)104 (64.2)0.71
 Resistance from staff to decreasing or stopping drugs12 (28.6)52 (32.1)0.19
 Resistance to changing drugs from staff7 (16.7)35 (21.6)0.50
 Request by staff to increase the dosage or add drugs28 (66.7)87 (53.7)2.28
 Reading pamphlets from pharmaceutical industry41 (97.6)155 (95.7)0.33
 Consulting articles or conferences about prescription41 (97.6)151 (93.2)1.17
 Importance of practical experience in prescription of medication40 (95.2)154 (95.1)0.00
 Learning acquired in medical school is basis of prescription practices39 (92.9)138 (85.2)1.71
 Preference for atypical antipsychotics27 (64.3)132 (81.5)5.74*
 Have knowledge of algorithms16 (38.1)86 (53.1)3.00**

Statistical analysis

We compared prescribing patterns between the addition group and the patients who were not prescribed additional antipsychotics (the non-addition group) using t-tests and χ2 tests.

To clarify the difference between the two groups, we compared the demographic and clinical variables of the patients in both groups using t-tests and χ2 tests. Similarly, we compared their psychiatrists' factors. To assess the independent effect of the multiple factors that could contribute to the addition of new antipsychotics, generalized estimating equations logistic regression analysis (GEE) was performed.16 In the data, one psychiatrist was responsible for several subjects and the impact of psychiatrists who had many subjects tended to be bigger. In order to resolve this problem we used GEE logistic analysis.

Factors for the independent variables were selected, which were significant or tended to be different when the two groups were compared.

All tests were two-tailed, and the significance level was set at P < 0.05. The analyses were performed using SPSS version 14.0 (SPSS, Chicago, IL, USA) and SAS version 9.1 (SAS Institute, Cary, NC, USA).

This study was conducted as part of the National Center of Neurology and Psychiatry–Medication Algorithm project (NCNP-MAP) and was approved by the Institutional Review Board (IRB) of the National Center of Neurology and Psychiatry, Japan, and by the IRB or board of directors of each participating hospital.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

Identification of patients who had been prescribed new antipsychotics

Table 2 shows prescription patterns at admission and discharge. At admission 76 (37.3%) of the 204 subjects were prescribed monopharmacy. Twenty-six were prescribed a typical antipsychotic and 50 an atypical one. One hundred and twenty-eight (62.7%) were prescribed polypharmacy with combination patterns of two or more typical antipsychotics (n = 43), typical and atypical antipsychotics (n = 80), or two or more atypical antipsychotics (n = 5).

Table 2.  Prescription pattern at admission and discharge (n = 204)
At admissionAt discharge
Monopharmacy (n = 80)Polypharmacy (n = 124)
Typical (n = 20)Atypical (n = 60)Typical + Typical (n = 39)Typical + Atypical (n = 77)Atypical + Atypical (n = 8)
  1. [], addition group: patients who had new antipsychotics added during hospitalization.

Monopharmacy (n = 76)
 Typical (n = 26)1364 [4]3 [3]0
 Atypical (n = 50)43507 [7]4 [4]
Polypharmacy (n = 128)
 Typical + Typical (n = 43)1626 [4]10 [3]0
 Typical + Atypical (n = 80)2128 [2]56 [14]2
 Atypical + Atypical (n = 5)0111 [1]2

At discharge 80 (39.2%) of the 204 subjects were prescribed monopharmacy. Twenty of them (9.8%) were prescribed a typical antipsychotic and the rest an atypical one. One hundred and twenty-four (60.8%) were prescribed polypharmacy, with combination patterns of two or more typical antipsychotics (n = 39), typical and atypical antipsychotics (n = 77), or two or more atypical antipsychotics (n = 8).

The addition group consisted of 18 subjects being treated with monopharmacy at admission, who had been prescribed new antipsychotics by the time of discharge, and 24 subjects being treated with polypharmacy at admission, who had been prescribed new antipsychotics by the time of discharge. Age, gender, and length of illness were not significantly different between the 18 subjects treated with monopharmacy at admission and the 24 treated with polypharmacy.

Table 3 shows the prescription patterns of both the addition and non-addition groups. Regarding the number of antipsychotics, the difference between the two groups was not significant at admission, but by the time of discharge the addition group had been prescribed significantly more antipsychotics than the non-addition group. Regarding the total dosage of antipsychotics (CPZeq), the difference was not significant at admission, but by the time of discharge the addition group had been prescribed significantly higher dosages than the non-addition group, the mean dosage exceeding 1000 mg.

Table 3.  Comparison of prescriptions
 Addition group (n = 42) n (%)Non-addition group (n = 162) n (%)Test statistic
  • **

    < 0.01.

  • t test;

  • χ2 test.

  • Addition group, patients who had new antipsychotics added during hospitalization; non-addition group, patients who did not have new antipsychotics added during hospitalization.

  • CPZeq, chlorpromazine equivalent.

No. antipsychotics (mean ± SD)
 At admission1.8 ± 0.92.0 ± 1.01.19
 At discharge3.0 ± 1.11.7 ± 0.8−8.43**
Dosage of antipsychotics (CPZeq) (mean ± SD)
 At admission645.8 ± 518.5639.5 ± 504.5−0.07
 At discharge1065.2 ± 679.3695.4 ± 546.3−3.26**
Use of atypical antipsychotics
 At admission28 (66.7)107 (66.0)0.01
 At discharge32 (76.2)113 (69.8)0.67
Use of typical antipsychotics
 At admission30 (71.4)119 (73.5)0.07
 At discharge38 (90.5)98 (60.5)13.49**
Use of low-potency antipsychotics
 At admission24 (57.1)97 (59.9)0.10
 At discharge36 (85.7)72 (44.4)22.80**
Use of benzodiazepines
 At admission32 (76.2)121 (74.7)0.04
 At discharge36 (85.7)131 (80.9)0.53
Use of antidepressants
 At admission1 (2.4)9 (5.6)0.72
 At discharge2 (4.8)8 (4.9)0.00

Although the rate of atypical antipsychotic usage was not significantly different between the two groups at either admission or discharge, the percentage of typical antipsychotics at discharge – especially low-potency antipsychotics – was significantly higher for the addition group than for the non-addition one. The percentages of benzodiazepines and antidepressants were not significantly different between the two groups at either admission or discharge.

Factors associated with adding new antipsychotics

Table 4 compares patient demographic and clinical variables (patient factors) between the addition and non-addition groups. Except for delusion, there were no differences between the two groups on patient age, gender, length of illness, involuntary admission, first episode, use of physical restraint during inpatient care, or six symptoms: hallucination, disorganized speech, grossly disorganized or catatonic behavior, negative symptom, severe confusion, and severe agitation. However, the rate of delusion and aggression against objects, others, or themselves was significantly higher in the addition group than in the non-addition one. In addition, the rate of patients with a physical illness tended to be higher in the non-addition group than in the addition group. There was no significant difference in the GAF score between the two groups at admission, but by the time of discharge the mean score of the addition group was significantly lower than that of the non-addition group. The addition group had received significantly more m-ECT than had the non-addition group.

Table 4.  Patient factors
 Addition group (n = 42) n (%)Non-addition group (n = 162) n (%)Test statistic
  • *

    < 0.05,

  • **

    < 0.01,

  • ***

    < 0.10.

  • t test;

  • χ2 test.

  • Addition group; patients who had new antipsychotics added during hospitalization; non-addition group, patients who did not have new antipsychotics added during hospitalization.

  • GAF; Global Assessment of Functioning; m-ECT, modified electroconvulsive therapy.

Age (years) (mean ± SD)38.4 ± 14.539.8 ± 13.90.59
Length of illness (years) (mean ± SD)14.5 ± 11.613.3 ± 12.1−0.57
GAF score at admission (mean ± SD)30.4 ± 16.331.5 ± 13.80.42
GAF score at discharge (mean ± SD)54.5 ± 13.960.5 ± 16.02.19*
Gender
 Male25 (59.5)92 (56.8)0.10
 Female17 (40.5)70 (43.2) 
Involuntary admission34 (81.0)112 (69.1)0.13
First episode12 (28.6)33 (20.4)1.30
Physical restraint during inpatient care28 (66.7)86 (53.1)2.49
Delusions34 (81.0)102 (63.0)4.86*
Hallucinations18 (42.9)76 (46.9)0.22
Disorganized speech14 (33.3)38 (23.5)1.71
Grossly disorganized or catatonic behavior7 (16.7)23 (14.2)0.16
Negative symptoms21 (50.0)62 (38.3)1.90
Severe confusion3 (7.1)7 (4.3)0.57
Severe agitation5 (11.9)25 (15.4)0.33
Aggression against objects, others, or themselves19 (45.2)36 (22.2)8.97**
Physical illness4 (9.5)37 (22.8)3.68***
m-ECT4 (9.5)1 (0.6)11.07**

Table 1 compares psychiatrist demographic variables and perceptions of prescription practices (psychiatrist factors) for the addition and non-addition groups. No significant differences were found for the two groups regarding psychiatrist demographic factors of age, gender, length of clinical experience, and medical qualification. However, there were differences in psychiatrist perceptions of medication. When compared with psychiatrists for the non-addition group, those for the addition group were significantly less likely to agree with the statement ‘I prefer to prescribe atypical antipsychotics more often than typical antipsychotics [preference for antipsychotics]’, and tended to disagree with the statement ‘I know medication algorithms [knowledge of algorithms]’.

Table 5 shows the results of the GEE logistic regression analysis for the six independent factors that either proved significant or illustrated a significantly different tendency between the two groups. The variable m-ECT was excluded because the number of subjects who received this treatment was too small (addition group, n = 4; non-addition group, n = 1).

Table 5.  GEE logistic regression to determine why new antipsychotics were added
 Adjusted odds ratio95%CI
  • *

    < 0.05.

  • CI, confidence interval; GAF, Global Assessment of Functioning; GEE, generalized estimating equations.

Patient factors
 Delusion2.240.97–5.16
 Aggression2.81*1.21–6.49
 Physical illness0.24*0.07–0.79
 GAF score at discharge0.980.96–1.00
Psychiatrist factors
 Preference for atypical antipsychotics0.30*0.11–0.81
 Knowledge of algorithms0.660.30–1.46

GEE logistic-regression analysis showed that the addition group was significantly more likely to show aggression and less likely to have physical illness. The analysis also showed that the psychiatrists for the addition group were significantly less likely to agree with the statement ‘I prefer to prescribe atypical antipsychotics more often than typical antipsychotics [preference for antipsychotics]’.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

In the present multicenter study psychiatrists prescribed additional antipsychotics toapproximately 20% of inpatients during hospitalization. Results indicate that these patients exhibited aggressive behavior and had no physical illness. Interestingly, these patients were seen more frequently by psychiatrists who generally preferred to prescribe typical antipsychotics.

In the current study approximately 20% of the inpatients had new antipsychotics addition during hospitalization, a much higher rate than that in the Loosbrock et al. study in which 7% of the outpatients had their original antipsychotic therapy augmented with an additional antipsychotic within 1 year.17 This difference could be the effect of the present subjects being in acute inpatient care. Even so, the results of the present study suggest that the addition of new antipsychotics during acute care treatment is common in Japan. This may be because clozapine, an atypical antipsychotic effective for treatment-resistant schizophrenic patients, has yet to be approved for use in Japan. Other possible factors range from reluctance among Japanese psychiatrists to simplify prescription practices, to inadequate staffing.

In the present study there was no difference between dosage levels prescribed for the addition group and non-addition group at admission; but by the time of discharge the addition group had been prescribed significantly higher dosages of antipsychotics than the non-addition group. This result is consistent with the finding of Centorrino et al. who reported that inpatients with polypharmacy were prescribed higher dosages of antipsychotics than those with monopharmacy at discharge, while there was no difference between the groups at admission.18 It is impossible to make a simple comparison between the present study and the Centorrino et al. study because our study does not compare polypharmacy with monopharmacy. However, it does conclude that adding antipsychotics to a treatment regimen during acute care results in a significant increase in the total dosage of antipsychotics at discharge.

The rate of typical antipsychotic use, especially low-potency antipsychotics, was higher at discharge in the addition group than the non-addition group. This finding concurs with previous studies reporting that less frequent use of atypical antipsychotics was a predictor for polypharmacy.5,19,20 It is important to consider the risk of patients being prescribed additional low-potency antipsychotics after discharge: patients are more likely to be prescribed these after discharge, resulting in polypharmacy. Further research is required on the use of low-potency antipsychotic combinations.

In the present study the addition group was significantly more prone to aggression. As Brieden et al. suggested, pharmacological treatment of acute, persistent, and repetitive aggression poses a serious challenge for staff members as well as other patients.21 Some research has examined the use of pharmacological treatment to decrease aggression.22 However, the efficacy of adding new antipsychotics to the original antipsychotic regimen to control aggression is not currently recommended. Therefore, the urgent temporary addition of antipsychotics might be required in some situations. However, with patients prescribed new antipsychotics for the purpose of sedating aggression, psychiatrists need to avoid excessive consecutive polypharmacy.

Patients with physical illness had fewer new antipsychotics added during hospitalization. Psychiatrists have to pay attention to drug interactions and the side-effects of antipsychotics on physical illness when prescribing for patients with a physical illness such as hepatic, renal, or cardiovascular disease. The present study confirms that standard clinical practice is adhered to by Japanese psychiatrists. Physical illness can be an important criterion in deciding whether to add new antipsychotics to a regimen.

The study indicates that a psychiatrist's preference for typical antipsychotics predicts that they will add new antipsychotics to a patients' medication regimen; this means that the addition of antipsychotics depends on a preference for typical antipsychotics, regardless of a patient's actual clinical condition. This demonstrates the effect of psychiatrist factors on prescription practices and is consistent with some previous studies. For example, Ito et al. reported that multiple medications and excessive dosing were influenced by psychiatrist skepticism towards the use of algorithms.7 In a survey on long-acting depot antipsychotics, Patel et al. noted that psychiatrist knowledge about depots was positively associated with use.8

Recently, certain studies have emphasized the importance of educational intervention to disseminate evidence-based medication guidelines to improve pharmacological treatment.23–26 Given the results of the current study, educational programs for psychiatrists regarding their preference for typical or atypical antipsychotics is critical to facilitating more simplified prescription practices, especially with those psychiatrists who prefer typical antipsychotics.

These results should be interpreted cautiously because there are certain limitations. It could not be clarified when and why additional antipsychotics were prescribed during hospitalization. Prescription during hospitalization was examined, but could not be followed up after discharge; it is possible that some subjects' prescriptions are simplified after discharge; longitudinal follow up is needed in future studies. As to patient evaluation, psychiatric symptoms assessed by validated measures were not used, given the burden on psychiatrists. In addition, institutional factors such as staffing should have been examined. Finally, there might be different reasons for adding new antipsychotics and for psychiatrist attitudes toward prescription, according to whether subjects were experiencing their initial episode and had relapsed.

Further study is needed regarding effective non-pharmacological treatment of aggression such as temporary seclusion and restraint, special care nursing,27 and educational programs for psychiatrists regarding their antipsychotic preference in order to facilitate simplified prescription practices.

In conclusion, the present study shows that one-fifth of schizophrenia inpatients with aggressive behavior but no physical illness were prescribed additional antipsychotic medication by psychiatrists who preferred typical antipsychotics. It might be more useful to continue treatment regimens without additional antipsychotics, simplify prescription practices, use alternative approaches or intensive care for aggressive patients, and promote educational programs among psychiatrists.

ACKNOWLEDGMENT

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

This study was supported by a grant from the Ministry of Health, Labour, and Welfare, Japan (15050401-1).

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES
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