Relationship between clozapine exposure and the onset of appendicitis in schizophrenia patients: a retrospective cohort study

doi:10.21203/rs.3.rs-1771939/v1

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Relationship between clozapine exposure and the onset of appendicitis in schizophrenia patients: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-1771939/v1

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Objective:

Clozapine may cause serious side effects despite benefits in patients with schizophrenia. Thus, an accurate understanding of the side-effect profile of clozapine is extremely important in the management of its administration to patients with schizophrenia. Our aim was to validate the relationship between clozapine exposure and appendicitis onset in patients with schizophrenia.

Methods:

In this study, we retrospectively compared the incidence and cumulative incidence of appendicitis in patients with schizophrenia with and without a history of clozapine exposure. Among the patients with schizophrenia who visited our hospital between June 2009 and August 2021, we extracted those with a history of clozapine treatment. Patients with a history of taking clozapine were defined as the clozapine exposure group, while the others were defined as the clozapine non-exposure group. Patients with a history of appendectomy or clozapine use at other hospitals were excluded.

Results:

There were 65 patients in the clozapine exposure group and 400 patients in the clozapine non-exposure group who met the inclusion criteria. The exposure group exhibited a remarkably higher incidence of appendicitis during the observation period than the non-exposure group (863 cases vs. 124 cases per 100,000 person-years). In particular, if limited to the period of clozapine exposure, the incidence of appendicitis is extremely high, at 2,086 cases per 100,000 person-years. Moreover, the multivariable analysis showed that clozapine exposure during adolescence is a risk factor for appendicitis onset.

Conclusions:

Clozapine exposure is associated with appendicitis onset in patients with schizophrenia.

clozapine

appendicitis

antipsychotics

schizophrenia

Schizophrenia is a severe psychotic disorder that presents with positive, negative, and cognitive symptoms [1]. Treatment-resistant schizophrenia (TRS) has been clinically defined as the persistence of symptoms despite at least two trials of antipsychotic drugs of adequate dose and duration, and occurs in approximately one-third of all patients with schizophrenia [2, 3].

Clozapine is recognized as the “gold standard” drug for the management of TRS and is the only antipsychotic drug approved for TRS [4, 5]. Clozapine has widely accepted clinical benefits for TRS; however, it may cause serious side effects such as myocarditis, granulocytopenia, ileus, and glucose intolerance [4, 5]. Thus, an accurate understanding of the side-effect profile of clozapine is extremely important in the management of its administration to patients with TRS.

Appendicitis is one of the most common abdominal emergencies and one of the most frequent indications for emergency surgery [6]. The approximate incidence of appendicitis is 90 − 110 cases per 100,000 persons per year, although it varies slightly between countries, regions, races, and ages [6–11]. Appendicitis occurs frequently from adolescence to thirties, with the incidence peaking in teens and gradually declining over the years [6–11]. Appendicitis often causes peritonitis or abdominal abscess if prompt diagnosis and appropriate treatment are not undergone [6–8]. Meanwhile, patients with schizophrenia are known to often exhibit less pain sensitivity, called “analgesia,” which has been described by Kraepelin and Bleuler since the early 20th century [12, 13]. It has been reported that if a patient with schizophrenia develops appendicitis, the awareness and detection of abdominal symptoms are delayed owing to less pain sensitivity, which often leads to more severe conditions such as perforated appendicitis [14–16]. Regarding the association between clozapine use and the onset of appendicitis, a single-center retrospective observational study in Germany found that the incidence of appendicitis was remarkably high (2, 726 cases per 100,000 person-years) in patients with schizophrenia treated with clozapine [17]. To the best of our knowledge, this study is the only one that referred to this relationship; however, an analysis of its causality and a comparison between the incidence of appendicitis in patients treated with clozapine versus those treated with other antipsychotics, excluding clozapine, has not been performed. Verifying the relationship between clozapine exposure and the onset of appendicitis, and identifying risk factors for developing appendicitis during clozapine administration will enable the detection of patients at high risk of appendicitis, which will allow psychiatrists to more safely manage patients taking clozapine.

Therefore, the aim of this study was to validate the relationship between clozapine exposure and the onset of appendicitis, to identify risk factors for the onset of appendicitis in patients with schizophrenia, and to compare the incidence and cumulative incidence of appendicitis between schizophrenia patients with and without a history of clozapine exposure.

Study design and participants

This retrospective cohort study was approved by the ethics committee of Akita University (approval number: 2762). In this study, we compared the incidence and cumulative incidence of appendicitis in schizophrenia patients with and without a history of clozapine exposure. Among the patients with schizophrenia who visited our hospital between June 2009 and August 2021, we extracted those with a history of clozapine treatment at our hospital. Patients with a history of taking clozapine were defined as the clozapine exposure group, and the others were defined as the clozapine non-exposure group. Patients with a history of appendectomy or clozapine use at other hospitals were excluded. The diagnosis of schizophrenia was confirmed according to the DSM-IV text revision or DSM-5 criteria [18, 19]. The observation period was from the date of the first visit to our hospital until August 2021. The endpoint in this study was defined as the onset of appendicitis during the observation period, and dropout was defined as the discontinuation of follow-up due to transfer to other hospitals or interruption of hospital visits at the patient’s discretion.

Clozapine administration was limited to patients with TRS who exhibited poor response and poor tolerance criteria. A poor response was defined as failure to respond for a sufficient period (at least 4 weeks) of treatment with a sufficient dose of at least two well-tolerated antipsychotics (including at least one atypical antipsychotic, such as risperidone, perospirone, olanzapine, quetiapine, or aripiprazole, at an equivalent dose of over 600 mg/day chlorpromazine). Poor tolerance was defined as the failure to adequately respond to monotherapy with at least two atypical antipsychotics due to failure to increase the dose to a necessary level for any of the following reasons: occurrence or worsening of moderate or more severe tardive dyskinesia, tardive dystonia or other tardive extrapyramidal symptoms, occurrence of uncontrolled parkinsonian symptoms, akathisia, or acute dystonia [20]. As previously described, the clozapine dose was slowly increased to achieve the optimal dose (the maximum dose in Japan is 600 mg/day) [21]. In consideration of the established discontinuation criteria of the Japanese Guideline Pharmacological Therapy of Schizophrenia and Japanese Clozaril® Patient Monitoring Service, clozapine administration was discontinued due reasons such as hematological adverse events (neutropenia and leukopenia), cardiomyopathy, patient refusal due to drowsiness [20]. Patients who discontinued clozapine immediately resumed treatment with other antipsychotics and remained under observation until the final follow-up date. The diagnosis of appendicitis was confirmed by appendectomy and histopathological evaluation, except in one case. In one of the patients in the clozapine non-exposure group, appendicitis was diagnosed using computed tomography and treated with non-operative management.

Survey Methods

We retrospectively extracted the following demographic and clinical data from electronic medical records: age at the start of the observation, sex, date of developing appendicitis, date of diagnosis of schizophrenia, date of transfer to other hospitals, prescription status of clozapine, other antipsychotics, and the prescription status of concomitant drugs such as anticholinergic drugs, antidepressants (noradrenergic and specific serotonergic antidepressants (NaSSA), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCA)), benzodiazepines, corticosteroids, laxatives, mood stabilizers, and non-steroidal anti-inflammatory drugs (NSAIDs).

The incidence and cumulative incidence of appendicitis during clozapine administration were calculated in the clozapine exposure group, and those during the observation period from the initial visit until the final date of follow-up were also calculated in both groups. Moreover, multivariable analyses were used to examine the risk factors for the onset of appendicitis.

Statistical analysis

Values are expressed as the median (interquartile range). Differences between the two groups were analyzed using the Wilcoxon rank sum test for continuous variables and the Pearson χ² test or Fisher’s exact probability test for categorical variables. The event-free survival length was determined from the date at the start of the observation or clozapine administration to the onset date of appendicitis or the final date of follow-up. Cumulative incidence curves were derived using the Kaplan-Meier method, and differences between the curves were analyzed using the log-rank test. Odds ratios for developing appendicitis were assessed using multiple logistic regression models. Variables added to the multivariable analyses were determined using stepwise regression. Statistical analyses were performed using JMP 14.2 (SAS Institute, Cary, NC, USA). Statistical significance values of p < 0.05 (two-sided) were considered significant.

Patient characteristics of the clozapine exposure and non-exposure groups

Among the 492 patients with schizophrenia who visited our hospital between June 2009 and August 2021, 65 patients in the clozapine exposure group and 400 patients in the clozapine non-exposure groups. The characteristics of all the patients in both groups are summarized in Table 1. All appendicitis cases in the clozapine-exposed group were observed during clozapine administration. Moreover, the number of appendicitis cases was significantly higher in the clozapine-exposed group than in the clozapine-non-exposed group [5 (7.7%) vs. 5 (1.3%), p = 0.007). Correspondingly, the clozapine-exposed group exhibited a remarkably higher incidence of appendicitis during the observation period than the clozapine-non-exposed group (863 cases per 100,000 person-years vs. 124 cases per 100,000 person-years). In particular, if limited to the period of clozapine administration, the incidence of appendicitis is extremely high at 2,086 cases per 100,000 person-years. The age at the start of clozapine administration was 32.3 (23.1 − 50.4) years. The duration of disease at the start of clozapine administration and the duration of clozapine administration were 9.3 (2.9 − 16.6) years and 49 (9.3 − 80.4) months, respectively. Furthermore, the maximum administered dose of clozapine in the clozapine-exposed group was 300 (200 − 525) mg. Clozapine administration was discontinued in 18 (27.7%) of the 65 patients in the clozapine-exposed group owing to adverse events. Neither the length of disease duration nor the length of the observation period was significantly different between both groups [13.3 (7.3 − 20.8) years vs. 12.3 (4.7 − 23.3) years, p = 0.665, 7.4 (2.6 − 13.1) years vs. 6.7 (1.3 − 15.5) years, p = 0.665, respectively]. In contrast, both the age at the start of treatment for schizophrenia and the age at the first visit to our hospital were significantly lower in the clozapine exposure group than in the clozapine non-exposure group [20.5 (18.5 − 26.5) years vs. 25.2 (19.8 − 32.7) years, p < 0.001; 25.8 (19.9 − 35.3) years vs. 30.1 (23.0 − 40.9) years, p = 0.008, respectively]. Additionally, the rates of regular use of laxatives and mood stabilizers were significantly higher in the clozapine-exposed group than in the clozapine-non-exposed group [56 (86.2%) vs. 116 (29.0%), p < 0.001; 15 (23.1%) vs. 48 (12.0%), p = 0.029, respectively]. In contrast, the rate of regular anticholinergic drug use was significantly higher in the clozapine non-exposure group than in the clozapine exposure group [119 (29.8%) vs. 5 (7.7%), p < 0.001]. There were no significant differences in other characteristics. With regard to concomitant antipsychotics during clozapine administration, the top five drugs that were concomitantly administered for four or more weeks were quetiapine (23.1%), olanzapine (20.0%), risperidone (16.9%), levomepromazine (15.4%), and blonanserin (13.8%) (data not shown in Table 1).

Patient Characteristics Of The Appendicitis Cases In Both Groups

The characteristics of all appendicitis cases in both the groups are summarized in Table 2. The mean age at the start of clozapine administration was 20.9 (15.9 − 26.7) years old. The disease duration at the start of clozapine administration and the duration of clozapine administration were 3.8 (1.3 − 8.4) years and 16.7 (10.3 − 28.5) months, respectively. In addition, the maximum doses of clozapine and clozapine administered at the onset of appendicitis were 425 (250 − 600) mg and 400 (350 − 600) mg, respectively. No patients in the clozapine-exposed group discontinued clozapine owing to adverse events. Neither the age at the start of treatment for schizophrenia nor the age at the first visit to our hospital were significantly different between the two groups, although the clozapine exposure group tended to exhibit younger ages [16.1 (14.6 − 18.7) years vs. 21.6 (16.3 − 31.7) years, p = 0.117, 19.1 (15.7 − 25.8) years old vs. 26.1 (18.3 − 41.5) years, p = 0.175, respectively]. The length of the observation period was significantly shorter in the clozapine-exposed group than in the clozapine-non-exposed group [2.1 (1 − 3.8) vs. 7.3 (4.4 − 18.5), p = 0.028]. Similarly, the length of disease duration tended to be shorter in the clozapine exposure group than in the clozapine non-exposure group despite the lack of its statistical significance [5.2 (2.2 − 10.8) years vs. 7.5 (4.8 − 32.0) years, p = 0.251]. There were no significant differences in the rate of regular use of other drugs, except that the rate of regular use of laxatives was significantly higher in the clozapine exposure group (5 (100%) vs. 2 (40%), p = 0.038). Regarding concomitant antipsychotics during clozapine administration, there were no drugs that were commonly used among all 5 patients with appendicitis in the clozapine exposure group (data not shown in Table 2).

The Cumulative Incidences Of Appendicitis In Both Groups

To calculate the cumulative incidence of appendicitis in both groups, we used Kaplan-Meier analysis (Fig. 1). Figure 1a shows the cumulative incidence of appendicitis in the clozapine-exposed group starting from the initiation of clozapine administration, and Fig. 1b shows the cumulative incidence of appendicitis in both groups starting from the initial visit. In the former, dropout was defined as withdrawal of clozapine administration or discontinuation of follow-up; in the latter, dropout was defined as discontinuation of follow-up. The last onset of appendicitis in the clozapine-exposed group was observed approximately 32 months after the start of clozapine administration, after which the cumulative incidence plateaued at 11.2% (Fig. 1a). In contrast, Kaplan-Meier analysis showed that the cumulative incidence of appendicitis in the clozapine exposure group was significantly higher than that in the clozapine non-exposure group (log-rank p = 0.004; Fig. 1b). Approximately 30 years after the start of treatment for schizophrenia, the cumulative incidences reached plateaus of 9.4% and 7.5%, respectively (Fig. 1b).

Multivariable Analysis Of The Impact Of Clozapine On The Onset Of Appendicitis

To further analyze the impact of clozapine on the onset of appendicitis, we used multiple logistic regression models (Table 3). The cutoff value for each variable was set at the median based on the data shown in Table 2. In the univariate analyses, the presence or absence of a history of exposure to clozapine (p = 0.004), presence or absence of a history of exposure to clozapine at the age of 21 years or younger (p < 0.001), duration of clozapine administration (p = 0.039), and regular use of laxatives (p = 0.043) were all significant factors affecting the onset of appendicitis. The multivariable analysis showed that only the presence or absence of a history of exposure to clozapine at the age of 21 years or younger was an independent factor contributing to the onset of appendicitis (odds ratio = 7.525, 95% confidence interval 1.098 − 51.563, p = 0.040).

This retrospective study is the first to compare the incidence of appendicitis in patients with schizophrenia who were not exposed to clozapine. In this study, we found that the incidence of appendicitis during clozapine exposure was prominently higher, approximately 20 times that of patients treated with other antipsychotics and the general population [6–8]. Additionally, we clarified for the first time that clozapine exposure during adolescence is a risk factor for appendicitis onset. Regarding the rationale for supporting our results, all cases of appendicitis in the clozapine exposure group were observed during clozapine administration. Furthermore, none of the antipsychotics combined with clozapine that were commonly used by all patients with appendicitis in the clozapine exposure group were identified (data not shown). Additionally, patients with appendicitis in the clozapine-exposed group tended to have a shorter disease duration to appendicitis onset than those with appendicitis in the clozapine non-exposure group, although the difference was not significant (5.2 years vs. 7.5 years, p = 0.251). These findings support the hypothesis that clozapine exposure is associated with the onset of appendicitis in patients with schizophrenia, although the underlying pathological mechanism has not yet been elucidated.

Incidentally, the incidence of appendicitis during clozapine administration in our study was slightly lower than that reported in a previous research [17]. One possible explanation for this is that approximately 30% of patients in the clozapine exposure group were transferred back to the referring hospital after the introduction of clozapine was completed; therefore, it was not possible to monitor the subsequent onset of appendicitis. In a previous study, age at the start of clozapine administration in patients taking clozapine was not mentioned [17].

The proposed mechanism of appendicitis is increased intraluminal pressure due to luminal obstruction, often by a fecalith, impacted stool, lymphoid hyperplasia (LH), or malignancy, which leads to interference with circulation and ischemia of the appendiceal tissue, with consequent necrosis and bacterial invasion of the appendix [6–8, 22, 23]. Based on the above, three hypotheses can be considered for the mechanism by which clozapine causes appendicitis. Firstly, constipation is one of the typical side effects of antipsychotics, and is one of the major adverse events of clozapine [4, 5, 24]. A meta-analysis showed that clozapine is approximately three times more likely to cause constipation than other antipsychotics [25]. In contrast, a previous study found no obvious relationship between plasma clozapine concentration and constipation [25]. Consistent with previous research, the proportion of laxative users was significantly higher in the clozapine-exposed group than in the non-clozapine-exposed group (86.2% vs. 29.0%, p < 0.001). Steinert et al., who first reported the relationship between clozapine administration and appendicitis, also mentioned that two of six patients with appendicitis during clozapine administration exhibited subileus in the process of diagnosis [17]. Incidentally, constipation is a common side effect not only in clozapine users but also in other antipsychotic users. In fact, approximately 30% of the patients in the clozapine non-exposure group regularly used laxatives. However, the incidence of appendicitis in the non-clozapine exposure group was similar to that in the general population. Unfortunately, it cannot be further discussed in this study whether constipation is the main cause of appendicitis onset because the presence or absence of clinical constipation and its severity were not assessed in detail in each group.

Second, clozapine can cause inflammation, particularly myocarditis [26, 27]. Additionally, clozapine has been associated with other infections such as pneumonitis, hepatitis, pancreatitis, nephritis, and colitis [26, 27]. The mechanisms by which clozapine causes inflammation are not fully understood; nevertheless, it has been reported that pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), are elevated in patients with schizophrenia treated with clozapine [28, 29].

Third, considering the increase in inflammatory cytokines when taking clozapine into consideration, we can mention the potential involvement of LH. LH is recognized as a benign nodular lesion that may occur in various organs in response to specific antigens such as bacteria and viruses, and is characterized by remarkable proliferation of non-neoplastic, polyclonal lymphocytes forming follicles [30, 31]. Furthermore, LH is also known to be observed in Castleman’s disease, characterized by overproduction of IL-6, and in several animal models with IL-6 stimulation [32–34]. LH of the appendix is commonly identified in childhood and adolescence and is typically associated with inflammatory conditions, such as viral gastroenteritis [23, 35]. As described above, LH of the appendix is known to be one of the causes of appendicitis [6–8, 23, 35]. In addition, previous reports showed that the lymphoid follicles of the appendix were most developed in teens to twenties, which is could account for why appendicitis is often observed in adolescence and early adulthood [23, 35, 36]. In this study, most of the onset ages at which patients developed appendicitis in the clozapine exposure group ranged from teens to twenties, and the multivariable analysis showed that the presence or absence of a history of exposure to clozapine at the age of 21 years or younger was a risk factor for the onset of appendicitis. Hence, these findings suggest that the mechanism by which clozapine causes appendicitis might be that the appendiceal lumen is obstructed by the development of LH via IL-6 stimulation. In the current study, histopathological examination of the appendectomy specimens in the clozapine exposure group revealed that three of the five patients had gangrenous appendicitis and the other two patients had phlegmonous appendicitis. It was difficult to accurately evaluate the presence or absence of LH because the mucosal tissue of the appendectomy specimen was markedly necrotic or shed in four patients. However, in one patient with phlegmonous appendicitis, enlarged lymphoid follicles were observed; thus, the presence of LH was suspected.

Finally, this study has several limitations. First, our results have insufficient validity due to the small sample size of the subjects in this study. Second, because of the retrospective nature of our study, demographic data, such as disease duration, were not comparable between the two groups. Furthermore, details of the exposure doses and exposure durations of drugs such as other antipsychotics, excluding clozapine, have not been investigated. In particular, patients with TRS were expected to have been exposed to higher chlorpromazine-equivalent doses of antipsychotics than non-TRS patients. Third, we did not identify the pathological mechanism by which clozapine caused appendicitis. Specifically, the presence or absence of clinical constipation and its severity were not evaluated in either group, pro-inflammatory cytokine concentrations such as IL-6 and TNF-α in the clozapine-exposed group were not examined, and histopathological evaluation of the presence or absence of LH in appendectomy specimens was insufficient. Fourth, the plasma clozapine concentration at the onset of appendicitis was not measured in the clozapine exposure group, despite the fact that a few side effects are known to increase as clozapine concentration increases [37, 38]. To address these issues, prospective research is required.

Our data showed that the incidence of appendicitis in schizophrenic patients treated with clozapine was about 20 times higher than that in patients treated with other antipsychotics and the general population. Moreover, results clarified that clozapine exposure in adolescence was a risk factor for the onset of appendicitis in patients with schizophrenia. These findings support the hypothesis that clozapine exposure is associated with the onset of appendicitis in patients with schizophrenia, which highlights the importance of psychiatrists prescribing clozapine to manage their patients’ conditions with the risk of appendicitis in mind at all times.

TRS: Treatment-resistant schizophrenia; DSM: Diagnostic and Statistical Manual of Mental Disorders; NaSSA: noradrenergic and specific serotonergic antidepressants; SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin norepinephrine reuptake inhibitors; TCA: tricyclic antidepressants; NSAIDs: non-steroidal anti-inflammatory drugs; LH: lymphoid hyperplasia; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α.

Ethics approval and consent to participate

This retrospective cohort study was approved by the ethics committee of Akita University (approval number: 2762). All methods in the present study were carried out in accordance with relevant guidelines and regulations and the ethical standards laid down in the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all the study subjects in the form of opt-out on the website.

Consent for publication

Not applicable.

Availability of data and materials

The datasets analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Competing interests

Masahiro Takeshima has received speaker’s honoraria from Takeda Pharmaceutical, MSD, Daiichi Sankyo Company, Sumitomo Dainippon Pharma, Meiji Seika Pharma, Viatris Pharmaceuticals Japan, and Yoshitomi Pharmaceutical, and research grants from Otsuka Pharmaceutical, EISAI, Shionogi and the Japanese Ministry of Health, Labour and Welfare (R3-21GC1016) outside the submitted work. Kazuo Mishima has received speaker’s honoraria from EISAI Co., Ltd., Nobelpharma Co., Ltd., and MSD Inc., and research grants from the Japanese Ministry of Health, Labour and Welfare (19GC1012, 21GC0801) outside the submitted work. The other authors declare no conflicts of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions

Guarantors of integrity of entire study and Study concepts: Kawakita Y, Komatsu K, Takeshima M, Mishima K; Study design or data acquisition or data analysis: All authors; Statistical analysis, and manuscript editing, Kawakita Y, Takeshima M, Mishima K.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Authors’ information

¹Department of Neuropsychiatry, Akita City Hospital, Akita, Japan. ²Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan. ³Department of Neuropsychiatry, Noshiro Kousei Medical Center, Akita, Japan.

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Tables 1 to 3 are available in the Supplementary Files section

Competing interest reported. Masahiro Takeshima has received speaker’s honoraria from Takeda Pharmaceutical, MSD, Daiichi Sankyo Company, Sumitomo Dainippon Pharma, Meiji Seika Pharma, Viatris Pharmaceuticals Japan, and Yoshitomi Pharmaceutical, and research grants from Otsuka Pharmaceutical, EISAI, Shionogi and the Japanese Ministry of Health, Labour and Welfare (R3-21GC1016) outside the submitted work. Kazuo Mishima has received speaker’s honoraria from EISAI Co., Ltd., Nobelpharma Co., Ltd., and MSD Inc., and research grants from the Japanese Ministry of Health, Labour and Welfare (19GC1012, 21GC0801) outside the submitted work. The other authors declare no conflicts of interest.

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Relationship between clozapine exposure and the onset of appendicitis in schizophrenia patients: a retrospective cohort study

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Version 1

Abstract

Figures

Background

Methods

Study design and participants

Survey Methods

Statistical analysis

Results

Patient characteristics of the clozapine exposure and non-exposure groups

Patient Characteristics Of The Appendicitis Cases In Both Groups

The Cumulative Incidences Of Appendicitis In Both Groups

Multivariable Analysis Of The Impact Of Clozapine On The Onset Of Appendicitis

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1