• non-adherence;
  • polypharmacy;
  • schizophrenia;
  • side-effects;
  • subjective opinions


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  2. Abstract

Aims:  Medical therapy is the cornerstone of schizophrenia, but >50% of patients do not adhere to medication regimens. In previous reports, the reasons for non-adherence were assessed only by medical staff. We think that patients have specific reasons for non-adherence. We researched whether there was an association between patients' subjective opinions and the number of antipsychotics used.

Methods:  A self-rating questionnaire survey was conducted on 252 outpatients with schizophrenia at five psychiatric hospitals in Japan. Based on patients' subjective opinions, we retrospectively analyzed the patients' medications: the number of antipsychotics, concurrently used agents, and dosages of antipsychotics.

Results:  There was no significant difference regarding attitudes toward medication between monotherapy and polypharmacy. The most common reason for not taking medications was ‘I sometimes forget’ followed by ‘side-effects’. Of the latter, weight gain was the most common, and dry mouth (P < 0.05) and sexual dysfunction (P < 0.01) were significantly higher in polypharmacy. The dosages of antipsychotics (P < 0.01), concurrent use of anti-Parkinsonian agents (P < 0.01), and the number of side-effects (P < 0.01) were also higher in polypharmacy.

Conclusions:  Patients had good attitudes toward medication but a higher prevalence of side-effects was seen in polypharmacy of antipsychotics. Hence, monotherapy may be a more appropriate prescription with respect to side-effects. By using monotherapy, patients may reduce feelings of discomfort due to side-effects.

ANTIPSYCHOTIC MEDICATIONS HAVE reduced the number of recurrent psychotic episodes among patients with schizophrenia.1 Multiple studies have shown that a low prevalence of adherence to medication use in schizophrenia is associated with worse outcomes with respect to physical and mental health.2,3 Therefore, understanding the factors underlying adherence is very important for therapeutic strategy and prevention of relapse.

Three risk factors for non-adherence have been conceptualized: medication (poor response and side-effects), patients (poor insight into illness), and environments (incorrect advice by significant others and high emotional expression).4,5 These factors should be assessed not only as objective measurements but also as the patients' subjective opinions. However, most studies have focused on adherence to treatment in schizophrenic patients, and the assessments were made only by medical staff. Few reports have focused on the patients' subjective opinions. We think that patients have specific reasons for not taking medication(s). Based on the patients' subjective opinions, we analyzed their medication history: the number of medications, concurrently consumed agents, and dosages of antipsychotics.


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  2. Abstract

Patient backgrounds and medical records

A total of 252 outpatients with schizophrenia at five psychiatric hospitals in Japan were enrolled. All patients provided written informed consent to participate in the study. Age, sex, social circumstances, illness duration, and prescription duration were recorded. ‘Prescription duration’ was defined as the period during which the primary antipsychotic agent was sustained without changing the type and amount of antipsychotic agent. If patients were given two or more antipsychotics, the largest amount of antipsychotic (calculated as the value of chlorpromazine equivalents) was as the primary antipsychotic. ‘Polypharmacy’ was defined as a situation in which the patient was prescribed two or more antipsychotics, even though they were at lower doses than if either were prescribed alone. We also recorded the contents of the prescription, dosages of antipsychotics (expressed as the values of chlorpromazine equivalents [if the patient was given two or more antipsychotics, the dosages were the total amount]), the number of antipsychotics, and the prevalence of concurrent use with anti-Parkinsonian agents and benzodiazepines.


A self-rating questionnaire survey was completed by patients. Three main questions needed to be answered.

Question (A) was concerned about attitudes toward medication: whether the patients liked or disliked taking medication, whether they adhered to medication use according to the prescription, and whether the number of medications they took was acceptable or too much.

Question (B) was concerned with the reasons for not taking medications. In this question, patients who answered ‘poor adherence’ in question (A) were the subjects. The items, which referred to a previous study,6 were the possible reasons for not taking the medication. That is: I sometimes forget; side-effects of the medications; condition is exacerbated by the medications; too many medications; taking the medications is bothersome; advice from significant other; it is not a natural disease; I felt well; the medications are insufficient; and I am more comfortable not taking medications.

Question (C) was based on the side-effects of medications. The items were: tremors; restless legs; excess salivation; sexual dysfunction; weight gain; weight loss; hunger; dry mouth; constipation; blurred vision; slurred speech; akathisia; and sedation.

Multiple answers were allowed for questions (B) and (C). For question (C), the number of side-effects patients chose as the item(s) in the questionnaire was also recorded.

Data analyses

All analyses were carried out using Microsoft excel (version 8.0; Redmond, WA, USA). We conducted a Fisher's probability test for the frequency of side-effects and concurrent use of agents. Dosages of antipsychotics (chlorpromazine equivalent) and the number of side-effects were evaluated using the Student's t-test. P < 0.05 was considered significant.


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  2. Abstract

Background of patients and data on antipsychotic agents

Table 1 shows the characteristics of the study group. The 252 participants had a mean age of 46.5 years (SD = 13.6), ranging from 19 years to 81 years. Most of the study population was male (64.7%).

Table 1.  Patients' characteristics
 All patients (n = 252)Monotherapy (n = 144)Polypharmacy (n = 108)
  1. Average ± SD.

Age (years)46.5 ± 13.645.6 ± 14.547.8 ± 12.1
Sex (Male / Female)163 / 8991 / 5372 / 36
Social circumstances: Alone / with family (non-responder 21)88 / 14348 / 8640 / 57
Illness duration (years)17.8 ± 12.516.4 ± 13.219.7 ± 11.3
Prescription duration (years)3.3 ± 3.03.2 ± 3.33.3 ± 2.5

The social circumstances were primarily classified as ‘with family’ (56.7%); 34.9% of patients were living alone. The mean duration of illness was 17.8 years (SD = 12.5), ranging from 0.2 years to 51.3 years. The mean duration of the prescription was 3.3 years (SD = 3.0). There are no significant differences with respect to patient characteristics between monotherapy and polypharmacy (Table 1).

With respect to data relating to antipsychotics, second-generation antipsychotics (SGA) were used in 87.4% of subjects, and the prevalence of monotherapy was 61.4%. First-generation antipsychotics (FGA) were used in 12.6% of patients, and the prevalence of monotherapy was 25.8%. The overall prevalence of monotherapy was 57.1%. Conversely, polypharmacy comprised 72 prescriptions using two medications (28 prescriptions in SGA + SGA; 35 prescriptions in SGA + FGA; and nine prescriptions in FGA + FGA). The remainder were more than three medications. The mean number of antipsychotics used and the mean dosage were 1.6 drugs (SD = 0.9) and 631.7 mg (SD = 406.1), respectively.

Attitudes toward medication

With regard to patients' attitudes toward medication, patients who answered that they ‘disliked’ taking medication were 22.2% in the monotherapy classification and 15.7% in the polypharmacy classification. The ratio of answers for subjects taking medication according to the prescription was 68.7% for monotherapy and 65.7% for polypharmacy. With respect to the number of medications, 79.9% of patients who were undergoing monotherapy and 75.9% of patients who were undergoing polypharmacy answered that their type of therapy was ‘acceptable’. There were no significant differences regarding attitudes toward medication between monotherapy and polypharmacy.

Reasons for not taking medication

Figure 1 shows the reasons for not taking medications. The most common reason was ‘I sometimes forget’, with which 49.4% of patients responded. The next most common answer was ‘side-effects of the medications’, with which 30.4% of patients responded. This was followed by ‘too many medications’, ‘the condition is exacerbated by the medications’ and ‘taking the medications is bothersome’.


Figure 1. Reasons for not taking medication.

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Frequency of side-effects and comparison between monotherapy and polypharmacy

Table 2 shows the frequency and comparison between monotherapy and polypharmacy for each side-effect. We asked the patients ‘what are the side-effects that you struggle with?’ in the questionnaire. Weight gain (42.1%) and sedation (41.7%) were the most common answers. This was followed by dry mouth (33.7%), akathisia (30.0%), sexual dysfunction (27.0%), and tremors (19.8%).

Table 2.  Frequency and comparison between monotherapy and polypharmacy for each side-effect
 FrequencyMonotherapy (n = 144)Polypharmacy (n = 108)Statistics
  1. P < 0.05, 0.01, Fisher's probability test.

  2. NS, not significant.

Weight gain42.1%40.3%43.5%NS
Dry mouth33.7%27.1%41.7%P < 0.05
Sexual dysfunction27.0%18.8%38.0%P < 0.01
Slurred speech16.3%14.6%17.6%NS
Excess salivation14.7%11.8%17.6%NS
Blurred vision10.3%10.4%10.2%NS
Restless legs7.5%7.6%7.4%NS
Weight loss6.0%4.9%7.4%NS

With respect to side-effects, dry mouth (P < 0.05) and sexual dysfunction (P < 0.01) had a significantly higher prevalence in polypharmacy compared with monotherapy.

Prescription data

Figure 2a shows the effects of polypharmacy on the dosage of antipsychotics, Figure 2b shows the prevalence of concurrent use with anti-Parkinsonian agents, and Figure 2c shows the prevalence of concurrent use with benzodiazepines. Dosages of antipsychotics (Fig. 2a) and the rate of concurrent use with anti-Parkinsonian agents (Fig. 2b) were significantly higher in polypharmacy than in monotherapy (both P < 0.01), but the prevalence of concurrent use with benzodiazepines was not (Fig. 2c). The number of side-effects in polypharmacy was higher than in monotherapy (P < 0.01).


Figure 2. Comparison between monotherapy and polypharmacy. (a) Dosage of antipsychotics. (b) Concurrent use with an anti-Parkinsonian agent. (c) Concurrent use with benzodiazepine. **P < 0.01, t-test; ##P < 0.01, Fisher's probability test.

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  2. Abstract

The purpose of this study was to discover if there was an association between patients' subjective opinions, certain side-effects, and the number of antipsychotics. To achieve this purpose, we undertook a survey in the form of a questionnaire to obtain patients' subjective opinions rather than objective assessments by medical staff.

There were no significant differences between polypharmacy and monotherapy with respect to patient attitudes toward medication. This result was in accordance with another report.7 It is thought that subjective opinions toward medication are related to patients' characteristics (age, illness duration, and sex), previous experience with medication, insight into the illness,8 psychosocial factors, and environmental factors. Kuroda et al. showed that subjective responses were positively correlated with illness duration, and that older patients who had been ill for a longer period of time had more positive attitudes toward medication.7 Slingsby suggested that it is a cultural characteristic for Japanese patients to be passive and rely upon the attending physician.9 It is well known that the ‘therapeutic alliance’ between physicians and patients promotes adherence to treatments in patients with schizophrenia.4,10–12 In the present study, all the subjects were Japanese, and the mean age was higher and the duration of illness was longer than in the report by Kuroda et al. Therefore, we thought that almost all patients might have good attitudes toward medication.

In the present study, the most common reason for not taking medication was ‘I sometimes forget’. There are a few reports demonstrating that ‘I sometimes forget’ is the most common reason for non-adherence.6,13,14 However, side-effects and/or poor insight into the illness have been stated as factors for non-adherence in other studies.5,15 This difference may be because in the present study, the reasons for not taking medication were not objective assessment by psychiatrists but patients' subjective opinions, whereas the reasons for non-adherence were evaluated only by psychiatrists in other studies.

When investigating side-effects, we found that the prevalence of weight gain, sedation, dry mouth, akathisia, and sexual dysfunction was quite high. These results are similar to those in expert consensus guidelines.16

With respect to side-effects, there were no significant differences between monotherapy and polypharmacy except for dry mouth and sexual dysfunction. In the present study, the data of side-effects were obtained by patients' subjective feelings, not by the judgment of medical staff. Patients were taking antipsychotics as well as benzodiazepines and anti-Parkinsonian agents. Consequently, most side-effects occurred at a similar level in monotherapy and polypharmacy. Conversely, the number of side-effects was significantly higher in polypharmacy than in monotherapy. Slight differences in each side-effect may result in the total differences of the number of side-effects being larger.

It is well-known that a higher dose of antipsychotics is associated with side-effects. However, side-effect(s) induced by antipsychotics are not always attributed to dose only. The side-effect(s) might be caused by the characteristics of the medications; ability to cross the blood–brain barrier; and dopamine D2 receptor-binding affinity.17 Previous studies have indicated that each antipsychotic has specific side-effects.18,19 Considering the information given above, it is not necessarily appropriate to suggest that a higher dose of an antipsychotic always leads to side-effects.

With respect to having a dry mouth as a side-effect, we thought that the major cause was use of a medication that possessed anticholinergic efficacy (e.g., anti-Parkinsonian agents and benzodiazepines). These medications are often treated with side-effects of extrapyramidal symptoms induced by antipsychotics. In polypharmacy, the antipsychotic dosage tended to be larger than in monotherapy in the present study. Therefore, the prevalence of concurrent use of anti-Parkinsonian agents was higher in polypharmacy. Other studies have also shown that antipsychotic combination treatment is associated with a higher prevalence of extrapyramidal side-effects, as well as increased use of anticholinergic agents.20–22 Taken together, these results suggest that the prevalence of the side-effect of dry mouth is higher in polypharmacy than in monotherapy.

There are many reports stating that polypharmacy and/or a high dosage of antipsychotics cause sexual dysfunction.23–25 However, this does not mean that sexual dysfunction will never occur during monotherapy. In the present study, antipsychotic dosage was significantly higher in polypharmacy than in monotherapy. Therefore, side-effects may be more frequent in polypharmacy than in monotherapy. In contrast, it is thought that sexual dysfunction is not dose-dependent on the antipsychotic agent, but instead due to a pharmacodynamic effect. In the present study, risperidone (which is very susceptible to the side-effects of antipsychotics) was the most commonly prescribed agent in 36.1% cases of monotherapy and 48.1% cases of polypharmacy (data not shown).

The present study had several limitations. Although the dosage of medications was determined by patient symptoms, we did not assess symptoms using rating scales. Subjects who participated in this study were outpatients with a relatively positive attitude towards medication; patients with poor adherence may have been excluded. Also, the study design was point estimation. Therefore, we think that subjective opinions and objective parameters as well as follow-up research are necessary.

In the present study, polypharmacy of antipsychotics did not cause differences in attitudes or reasons for not taking medications. However, several side-effects were exerted dependent upon the number of antipsychotics used. Regarding prescription data, polypharmacy increased the dosage and concurrent use of anti-Parkinsonian agents. Differences in the prevalence of side-effects might have been due not only to antipsychotics, but also to concurrent medications.


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  2. Abstract

We wish to extend our thanks for the cooperation we received from everyone involved at the institution, and all participants of the research. In this study, we did not receive any funding.


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