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 . 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 .
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 . In contrast, a previous study found no obvious relationship between plasma clozapine concentration and constipation . 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 . 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.