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.