Discussion
This study is the first in the world to follow the same patients with schizophrenia for 20 years in terms of the antipsychotics prescribed. The results of this study showed a slow but steady substitution of FGAs for SGAs over time. In addition, the rate of FGA monotherapy prescription decreased, whereas the rate of SGA monotherapy prescription gradually increased, but by less than half. The fact that SGA prescription has become mainstream since 2016, although this study did not incorporate new patients and the study population was not likely to take SGAs, may be due to the guidelines and other educational activities. This result is particularly positive even in Japan, a conservative country that favors multidrug therapy. In addition, although the dosage of the antipsychotics did not change, ratio of SGAs to FGA dose was clearly elevated. This suggests that even if FGA were used in combination with SGA, the dosage would be kept small. Furthermore, this result is a corollary of the fact that SGA has replaced FGA as the mainstay of treatment, even for the same patients, over the past two decades.
A history of previous hospitalization was identified as a factor for switching to SGA. This is an understandable result, because it is safer to switch medications during hospitalization. Since there are still a certain number of outpatients treated with FGAs, it is necessary to develop a method to safely switch to SGAs in the outpatient setting in the future.
Although guidelines recommend monotherapy with antipsychotics, the most frequently chosen treatment strategy internationally was combination antipsychotic therapy, prescribed in 49% of all patients.7,21 Combination antipsychotic therapy is recommended only as a last resort when clozapine has not been successful,22,23 although the use rate of clozapine is low in Japan.24 Despite these recommendations, adjunctive treatment strategies are often used in schizophrenia before trial of clozapine.25 Combination antipsychotic therapy is prescribed to 10-20% of outpatients, and as many as 50% of inpatients require two or more antipsychotics.26Another study showed that combination antipsychotic therapy is prescribed to 10-20% of outpatients, and as many as 50% of inpatients require two or more antipsychotics. Furthermore, a study reported that combination therapy was prescribed to 42.5% of patients and augmentation therapy to 70% of patients.27Combination therapy for schizophrenia in the ”real world” may be aimed at enhancing the efficacy of antipsychotics and reducing side effects by utilizing the different receptor binding profiles of various medications.
The results of this study showed lower SGA and monotherapy rates than the results of other cross-sectional studies. The results of comparisons of combination antipsychotic therapy with monotherapy remain controversial. Combination antipsychotic therapy has shown little evidence of superior efficacy28,29 and is associated with a cumulative risk of adverse effects,30pharmacokinetic interactions, mortality31 and increased costs compared with monotherapy.32
In the EGUIDE study of hospitalized patients in Japan, an analysis of the prescription rate from 2017 to 2019 showed a 90% SGA prescription rate and a 50% SGA monotherapy prescription rate.33On the other hand, in the REAP study,34 which focused on outpatients, there was a significant decrease in the prescription rate of high-dose antipsychotics between 2001 and 2004, along with a decrease in the total daily dose of antipsychotics. In an international comparative pharmacoepidemiological study, overall rates of concomitant use of antipsychotics were shown to have declined over the past 20 years in Asia and to have slightly declined over the past 10 years in Europe.12 Nevertheless, the concomitant use rate was much higher in Asia and Europe than in other Western countries. This may be partly related to the fact that in Eastern traditional medicine, mixtures of different medicinal ingredients are believed to be superior to single compounds.35 On the other hand, the introduction of SGAs may have led to a decrease in concomitant use of antipsychotics, as concomitant use of FGAs was replaced with SGA monotherapy because of the expected or actual improved efficacy of SGAs.
Because concomitant use of anticholinergic drugs has been associated with many problems in cognitive function and peripheral side effects, such as constipation and urinary retention,36,37 the guidelines recommend that anticholinergic drugs should not be used in combination. In this study, the results showed that the concomitant use rate and the average dosage used have gradually decreased over a period of 20 years. This finding may reflect the increasing use of SGAs, which have fewer extrapyramidal side effects, in addition to the widespread use of guidelines.
On the other hand, concomitant use of antidepressants increased even though antidepressants are not recommended by the guidelines. The addition of antidepressants to antipsychotic therapy for the treatment of schizophrenia is rather routine in clinical practice,38 but evidence on the efficacy of antidepressants is still limited and inconsistent.39 A recent comparative effectiveness study using U.S. Medicaid national data found a reduced risk of psychiatric hospitalization and emergency room visits among outpatients with schizophrenia who were prescribed adjunctive antidepressants.40 In a recent meta-analysis, concomitant use of antidepressants proved to be partially effective.12 Another factor may be that the widespread use of mirtazapine, which is less likely to cause side effects, instead of antidepressants such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), which are more likely to cause activation syndrome, has reduced concerns about the concomitant use of antidepressants.
The prescribing rate of benzodiazepines did not change in this study. A recent systematic review did not test the efficacy of concomitant use of benzodiazepines with antipsychotics.41 Furthermore, a recent meta-analysis of 16 randomized controlled trials confirmed the lack of efficacy data.42 Therefore, in various guidelines, benzodiazepines were recommended for very short-term sedation of acutely agitated patients but not as an augmentation to antipsychotic therapy in the medium- to long-term pharmacotherapy of patients with schizophrenia and related disorders.
In a recent review, Carton et al. estimated that 40-75% of all antipsychotic prescriptions are for off-label use.43Mood disorders, anxiety disorders insomnia, and agitation were the main indications for antipsychotic use. A study in primary care in the United Kingdom found that a significant proportion of people prescribed antipsychotics had no record of psychosis or bipolar disorder, i.e., the ”classic” indications for antipsychotics.44 Similarly, only approximately 30% of antipsychotic prescriptions in Belgium were for psychotic disorders.45 In addition, a recent study of elderly patients in Taiwan suggested that approximately 80% of atypical antipsychotic users had a psychotic disorder, but only approximately 20% of typical antipsychotic users had a psychotic disorder. Only approximately 20% of atypical antipsychotic users had underlying psychiatric disorders.46 On the other hand, in our study, only schizophrenia was evaluated, the patients were followed in one hospital for 20 consecutive years, and the diagnosis and prescriptions were confirmed by their attending physicians. The findings from our study are more reliable than those of studies that include many patients that use antipsychotics for other psychiatric disorders.
There are several limitations to this study. First, our study looked at prescribing rates every 5 years; therefore, we cannot rule out the possibility that prescribing rates may have changed during the 5-year intervals. We also cannot rule out the possibility that the prescriptions were switched during that time. It is common in practice for patients to request to return to their original medications due to side effects after attempting to change to different medications. Second, in this study, we did not evaluate symptoms over a 20-year period. Therefore, the causal relationship between the reason for change and the change in prescription cannot be clarified because it is unclear whether the change in prescription was due to unchanged symptoms or side effects. Finally, there is a bias in that patients who were transferred to other hospitals or died during the 20-year study period were not tracked, which is called panel mortality. In addition, this study was retrospective in design, whereas in the majority of published studies, panel studies were performed prospectively. The retrospective design of the study was because only the past trends in prescribing rates were investigated. In the future, prospective trend studies and cohort studies are necessary.