Factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20‐year period: Retrospective cohort study

Abstract Background Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20‐year period. Methods We enrolled patients with schizophrenia attending each hospital (n = 14) from April 1, 2021, and retrospectively examined all prescriptions as of April 1, 2016, 2011, 2006, and 2001, every 5 years starting in 2021, for this population. 716 participants with complete data were included in the analysis. The Cochran Q test followed by Bonferroni correction and the Cochran–Armitage trend test were used to determine the differences and trends of the frequency of each laxative. Multivariate logistic regression analysis was performed to assess the factors on the initiation of laxative use over a 20‐year period. Results Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021. The numbers of patients treated with any laxatives significantly differed over the 20‐year period, with a significant increasing trend. In all laxatives, the numbers of patients treated with magnesium oxide, lubiprostone and elobixibat differed with a significant increasing trend. Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20‐year period. Conclusions Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine. Optimizing prescriptions according to treatment guidelines could reduce antipsychotic‐induced constipation.


| INTRODUC TI ON
Constipation is defined by bowel disturbances (reduced frequency of bowel movements, hard stools, excessive straining to defecate, a sense of anorectal blockage, anal digitation, and a sense of incomplete evacuation after defecation). 1 The reported median prevalence of constipation was 16%. 2 In the elderly population aged 60-101 years, constipation was more frequent, and the median prevalence rate was 33.5%. 2 The reported risk factors for constipation are increasing age, female sex, lower socioeconomic status, lower parental education rates, less self-reported physical activity and use of certain medications. 3nstipation is a well-known adverse effect of antipsychotics, but there is a paucity of investigation regarding antipsychoticinduced constipation.De Hert and colleagues 4 investigated the prevalence of antipsychotic-induced constipation over a period of 22 months and reported that 36.3% of patients required laxatives.One of the neurotransmitter mechanisms involved in antipsychotic-induced constipation is the muscarinic anticholinergic effects of antipsychotics. 5Inappropriate treatment for antipsychotic-induced constipation can lead to severe complications, including paralytic ileus, aspiration pneumonia and bowel perforation. 6,7Because of the high case-fatality rate of clozapineinduced life-threatening gastrointestinal hypomotility (15%-27.5%), 8most previous studies regarding antipsychotic-induced constipation have focused on clozapine.Thus, little has been investigated regarding antipsychotic-induced constipation not focused on clozapine.Recently, Lin and colleagues 9,10 investigated the factors associated with regular laxative use at discharge in schizophrenia patients treated with second-generation antipsychotic (SGA) monotherapy.They reported that advanced age and higher antipsychotic or anticholinergic doses were associated with an increase in laxative use.Among SGAs, clozapine was associated with the highest rate of laxative use, followed by zotepine, quetiapine, olanzapine and risperidone. 9 study to date has examined the factors linked to antipsychotic-induced constipation in a longitudinal manner within individual patients.The existing studies on this topic have primarily been cross-sectional or descriptive in nature.Laxative use is a proxy major of antipsychotic-induced constipation.Therefore, we aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over 20 years of age.716 participants with complete data were included in the analysis.

| Participants
This study was initiated in April 2021 and was conducted in 14 psychiatric hospitals. 11Participants were selected based on the consecutive sampling method.To obtain an equivalent number of participants from each site, we set the number (n = 70) due to the feasibility.We enrolled up to 70 patients with schizophrenia attending each hospital from April 1, 2021, whose prescriptions could be traced over the past 20 years; for hospitals that did not reach 70 patients, all patients were enrolled.We excluded patients who had been off antipsychotic medication for more than 2 years in the past 20 years or who were untraceable because they had been treated at another hospital in the past 20 years.All patients included in this study were diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, or the International Classification of Disease, tenth revision.Patients with clinically significant medical illnesses or active psychotic symptoms related to comorbid substance use disorders were excluded (e.g., disturbance of consciousness due to a stroke or alcohol withdrawal delirium).The medical records of the patients were reviewed to obtain all medications, including laxatives, and demographic data (age and sex).Starting in 2021, we conducted a retrospective analysis of prescription records for this population at 5-year intervals, specifically Results: Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021.The numbers of patients treated with any laxatives significantly differed over the 20-year period, with a significant increasing trend.In all laxatives, the numbers of patients treated with magnesium oxide, lubiprostone and elobixibat differed with a significant increasing trend.Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20-year period.
Conclusions: Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine.Optimizing prescriptions according to treatment guidelines could reduce antipsychotic-induced constipation.

| Statistical analysis
The data are presented as the mean and standard deviation (SD) and number (%).A p-value of <0.05 indicated statistical significance.
The procedure for the statistical analysis of our research is shown in

| RE SULTS
The clinical and demographic characteristics of the participants are listed in Table 1, and the numbers of the prescribed antipsychotics and mood stabilizers in 2021 are listed in Table S1.The frequencies of prescribed laxatives and the numbers of patients treated with laxatives over 20 years are shown in Table 2 and Figure    Abbreviations: FGA, First-generation antipsychotics; SGA, Second generation antipsychotics.

TA B L E 2
The frequencies of prescribed laxatives and the numbers of patients treated with laxatives in the same patients with schizophrenia over 20 years.(36.3%) and Lin and their colleagues 9 (22.1%-33.7%)but smaller than that reported by Koizumi and their colleagues 14 (68.0%).Because antipsychotic-induced constipation is more common in inpatient settings than in outpatient and mixed settings, 15 the prevalence of laxative use in our survey differed from that in a previous study by Koizumi and their colleagues, 14 which involved inpatient settings.Compared to the previous study which reported that prevalence rate of constipation in elderly individuals was 33.5%, 2 the frequency of laxative use in patients with schizophrenia in this study was almost the same and not high.It might be due to oversight of constipation because patients with schizophrenia were less aware of constipation and less reported its presence to their psychiatrists. 14r results showed an increasing trend of laxative use over the past 20 years, and age in 2021 was a significant factor associated with the initiation of laxative use, which is in line with a previous study showing that increasing age is a risk factor for constipation. 3Female sex was a significant factor associated with the initiation of laxative use.This is natural since female sex is known as a risk factor for constipation. 3The total DZP equivalent dose in 2021 was a significant factor associated with the initiation of laxative use.This is in line with the reported adverse events of benzodiazepine, which are due to the anticholinergic effect of benzodiazepine. 16Among the antipsychotics used in our study, daily doses of levomepromazine maleate, olanzapine, quetiapine and zotepine in 2021 were significant factors associated with the initiation of laxative use.This is in line with a previous study showing that zotepine, quetiapine and olanzapine had the highest rates of laxative use in SGA, followed by clozapine, 9 and levomepromazine maleate was associated with severe constipation. 17In our survey, clozapine was not a significant factor associated with the initiation of laxative use.This is not consistent with previous studies that reported that clozapine-induced constipation is most prevalent and severe. 5,9,10,15This might be due to a lack of statistical power because only two participants were treated with clozapine in our survey in 2021.Daily doses of lithium and carbamazepine in 2021 were significant factors associated with the initiation of laxative use.This is consistent with a previous study that reported that lithium and carbamazepine were the medications associated with constipation. 3The biperiden equivalent of total anticholinergic drug in 2021 was smaller than that in 2001, as we previously reported. 11There was no significance between the initiation of laxative use and the daily dose of anticholinergic drugs in 2021 or 2001.This is not consistent with a previous study by Lin and their colleagues who reported that a higher dose of anticholinergic drugs was associated with increasing laxative use. 9However, in the elderly population (average age 66.3), they reported that antiparkinsonian agent use was not associated with laxative use, 10 which is in line with our results.
Osmotic laxatives such as magnesium oxide are recommended as a first-line treatment by several recent guidelines for chronic idiopathic constipation. 18,19The number of patients treated with magnesium oxide showed increasing trend over the past 20 years, which is in line with these guidelines.9][20][21] The number of patients treated with senna, sodium picosulfate hydrate or rhubarb showed no increasing trend over the past 20 years, which is in line with these guidelines.We did not assess the dose of laxatives and their acclimatizing effects in this study.Careful consideration of this point is needed.Lubiprostone and elobixibat, which are newer pharmacological agents, showed increasing trend over the past 20 years.
These agents are not recommended in the guidelines, because they 9][20][21] The number of patients treated with glycerin (enema) showed no increasing trend over the past 20 years.Several guidelines state the efficacy of enemas, 18,20,21 but mention that a trial is probably justified in patients in whom all other measures have failed. 20 reduce antipsychotic-induced constipation, one possible solution is to optimize the prescription according to treatment guidelines.
Previously in this survey, we reported a slow but steady substitution of SGAs for FGAs over time. 11Since many guidelines recommend that monotherapy with SGAs is the first-line treatment for schizophrenia, [22][23][24] polytherapy with benzodiazepine and mood stabilizers, including lithium and carbamazepine, should be minimized.6][27] In addition, to easily visualize the degree to which current prescriptions conform to the guidelines for the pharmacological treatment of schizophrenia, 24 the individual fitness score (IFS) is an effective tool, in which points vary in range from 0 to 100. 28To prevent severe complications due to antipsychoticinduced constipation, careful monitoring is needed for patients treated with high-risk antipsychotics for constipation such as levomepromazine maleate, olanzapine, quetiapine, zotepine and clozapine.
In cases of severe constipation, decreasing the dose of antipsychotics or switching to low-risk antipsychotics should be considered.
There are several limitations of this study.First, we adopted laxative use as a proxy measure for constipation.Some participants with constipation may not have been treated with laxatives in our study because patients with schizophrenia are less aware of constipation and less frequently report its presence to their psychiatrists. 14cond, our study did not assess the laxatives prescribed in other hospitals because our study was conducted in outpatient settings.
However, it is also a strength because most of the patients with schizophrenia were outpatients, and previous studies were inpatient settings. 4,9,10,14Third, there may be sampling bias because the participants were not randomized, and those who continued to visit the same hospital over 20 years were selected.Fourth, the coadministration of antipsychotics was not assessed.Fifth, the coadministration or dose of laxatives was not assessed.Sixth, several potential confounding factors, such as comorbidities, activities of daily living, fiber/fluid intake, duration of illness, and severity of illness, were not assessed in our study.Finally, the odds ratios for the factors associated with the initiation of laxative use, except for gender, are significant but very small.Careful consideration of this point is needed.

Figure 1 .
Figure 1.Data were obtained for 812 participants in total, but since there were 96 participants with missing data, 716 participants with complete data were included in the analysis.The Cochran Q test followed by Bonferroni correction and Cochran-Armitage trend test were used to determine the differences and trends of the frequency of each laxative among the five groups (n = 716).The paired t-test was used to determine the differences between the biperiden equivalent of total anticholinergic drug between 2001 and 2021 (n = 716).For multivariate logistic regression analysis, patients treated with laxatives in 2001 (n = 180) were excluded, and patients not treated with laxatives in 2001 (n = 536) were included.Multivariate logistic regression analysis with a forward selection method was performed to assess the effects of age, sex, chlorpromazine equivalent of total antipsychotics, total first generation antipsychotics (FGA) and total SGA, biperiden equivalent of total anticholinergic drugs, imipramine equivalent of total antidepressants, diazepam equivalent of total anxiolytics and hypnotics, daily dose of each antipsychotic (risperidone, olanzapine, aripiprazole, quetiapine, blonanserin, zotepine, brexpiprazole, perospirone, asenapine maleate, clozapine, lurasidone, haloperidol, levomepromazine maleate, chlorpromazine, paliperidone, sulpiride, bromperidol, fluphenazine maleate, perphenazine maleate, propericiazine, clocapramine hydrochloride hydrate, mosapramine, pipamperone hydrochloride, nemonapride) and mood stabilizers (valproate, lithium, carbamazepine, lamotrigine) in 2021 and biperiden equivalent of total anticholinergic drugs in 2001 on the initiation of laxative use over 20 years (those who were not treated with laxatives in 2001 but treated in 2021 were scaled as 1,

2 .
Laxatives prescribed in this study were magnesium oxide, senna, sodium picosulfate hydrate, lubiprostone, elobixibat, rhubarb, and glycerin (enema).The number of patients treated with any laxatives differed over the 20 years (Cochran Q = 44.3,df = 4, p < 0.001), with an increasing trend over the past 20 years (χ 2 = 16.83,df = 1, p = 0.028).Bonferroni's post hoc analysis of the Cochran Q test revealed that the number of patients treated with any laxatives in 2021 was significantly larger than the number in 2001, 2006, and 2011 (p < 0.001, p < 0.001, p = 0.020, respectively).The number of patients treated with any laxatives in 2016 was significantly larger than the number in 2001 and 2006 (p = 0.001 and p < 0.049, respectively).The number of patients treated with any laxatives in 2011 was significantly larger than the number in 2001 (p = 0.037).The number of patients treated with magnesium oxide differed over the 20 years (Cochran Q = 97.4,df = 4, p < 0.001), with an increasing trend over the past 20 years (χ 2 = 51.04,df = 1, p < 0.001).Bonferroni's post hoc analysis of the Cochran Q test revealed that the number of patients treated with magnesium oxide in 2021 was significantly larger than the number in 2001, 2006, 2011 and 2016 (p < 0.001, p < 0.001, p < 0.001, p = 0.027, respectively).The number of patients treated with magnesium oxide in 2016 was significantly larger than the number in 2001 and 2006 (p < 0.001 and p < 0.001, respectively).The number of patients treated with magnesium oxide in 2011 was significantly larger than the number in 2006 and 2001 (p = 0.041 and p = 0.001, respectively).The number of patients treated with senna did not differ over the 20 years (Cochran Q = 8.13, df = 4, p = 0.087), and did not show trend over the past 20 years (χ 2 = 2.00, df = 1, p = 0.157).The number of patients treated with sodium picosulfate hydrate did not differ over the 20 years (Cochran Q = 5.53, df = 4, p = 0.237), and did not show trend over the past 20 years (χ 2 = 0.74, df = 1, p = 0.389).The number of patients treated with lubiprostone differed over the 20 years (Cochran Q = 38.8,df = 4, p < 0.001), with an increasing trend over the past 20 years (χ 2 = 22.06, df = 1, p = 0.006).Bonferroni's post hoc analysis of the Cochran Q test revealed that the number of patients treated with lubiprostone in 2021 was significantly larger than the number in 2001, 2006, 2011, and 2016 (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively).The number of patients treated with elobixibat differed over the 20 years (Cochran Q = 16.0,df = 4, p = 0.003), with an increasing trend over the past F I G U R E 1 Procedure for statistical analysis.

| 63 KAWAMATA
et al. 20 years (χ 2 = 8.00, df = 1, p = 0.004).Bonferroni's post hoc analysis of the Cochran Q test revealed that the number of patients treated with elobixibat in 2021 was significantly larger than the number in 2001, 2006, 2011, and 2016 (p = 0.016, p = 0.016, p = 0.016, p = 0.016, respectively).The number of patients treated with rhubarb did not differ over the 20 years (Cochran Q = 4.00, df = 4, p = 0.406), and did not show a trend over the past 20 years (χ 2 = 0.16, df = 1, p = 0.683).The number of patients treated with glycerin did not differ over the 20 years (Cochran Q = 4.00, df = 4, p = 0.406), and did not show a trend over the past 20 years (χ 2 = 2.25, df = 1, p = 0.133).The biperiden equivalent of total anticholinergic drug in 2021 was smaller than that in 2001 (t = 16.0,df = 715, p < 0.001).Table 3 shows the factors associated with the initiation of laxative use over 20 years.With a multivariate logistic regression analysis with a forward selection method, female sex, age in 2021, total DZP equivalent dose in 2021, dose of levomepromazine maleate in 2021, dose of olanzapine in 2021, dose of quetiapine in 2021, dose of zotepine in 2021, dose of lithium in 2021, and dose of carbamazepine in 2021 were significantly associated with the initiation of laxative use over the 20-year period.TA B L E 1 Clinical and demographic characteristics (N = 716).

2
= 2.25, df = 1, p = 0.133 Numbers of patients treated with laxatives a (%)180/716 (25.1%) 192/716 (26.8%) 211/716 (29.5%) 222/716 (31.0%) 244/716 (34.1%) χ 2 = 16.83,df = 1, p = 0.028 a Coadministration of laxatives was not counted in duplicate.F I G U R E 2 Increased number of patients treated with laxatives.To the best of our knowledge, this is the first study to investigate the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period.Of the patients in our survey, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021.Female sex, age in 2021, total DZP equivalent dose in 2021, dose of levomepromazine maleate in 2021, dose of olanzapine in 2021, dose of quetiapine in 2021, dose of zotepine in 2021, dose of lithium in 2021, and dose of carbamazepine in 2021 were significant factors associated with the initiation of laxative use over a 20-year period.The prevalence of laxative use in this survey (25.1%-34.1%)was consistent with the previous study by De Hert and their colleagues 4

TA B L E 3
Factors associated with the initiation of laxative use in the same patients with schizophrenia over 20 years.
Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021.Female sex, age in 2021, the total DZP equivalent dose in 2021, the dose of levomepromazine maleate in 2021, the dose of olanzapine in 2021, the dose of quetiapine in 2021, the dose of zotepine in 2021, the dose of lithium in 2021, and the dose of carbamazepine in 2021 were shown to be associated with the initiation of laxative use over the 20-year period.Careful monitoring is needed for patients treated with high-risk antipsychotics for constipation such as zotepine, quetiapine, olanzapine and levomepromazine maleate.Optimizing prescriptions according to treatment guidelines could reduce antipsychotic-induced constipation.Further studies on the promotion of treatment guidelines are needed.