Introduction

Clozapine is a second-generation antipsychotic and the only medication FDA-approved for treatment-resistant schizophrenia.^1–3 According to a meta-analysis on the comparative efficacy of first- or second-line treatments in schizophrenia, clozapine may exhibit superior efficacy compared to other antipsychotics.⁴ Despite its efficacy, clozapine continues to be underutilized, mainly due to the risk of life-threatening adverse effects including severe neutropenia, seizures, myocarditis, and severe constipation.^2,3 Clozapine-related constipation is dependent on serum concentration, affecting 15% to 60% of individuals undergoing clozapine treatment, establishing it as one of the most commonly reported adverse effects.^5,6 A meta-analysis of 32 studies reported a pooled prevalence of 31.2% for clozapine-related constipation.⁶ In addition, clozapine-related constipation can potentially lead to paralytic ileus and bowel obstruction, and thus be life-threatening.^7–12 It has been postulated that the anticholinergic properties of clozapine play a role in causing constipation.⁵ In addition to anticholinergic properties, other factors may influence constipation, and patient self-report has low sensitivity in this context.⁵ Therefore, instead of relying on patient self-reporting, a clozapine-induced constipation protocol is necessary.

Fulton State Hospital (FSH) is a 449-bed forensic psychiatric facility.¹³ Since 2017, a clozapine-induced constipation protocol has been implemented to improve the detection and treatment of clozapine-induced constipation (Appendix). The protocol emphasizes both proactive bowel management and close monitoring. Abdominal imaging is performed before starting clozapine treatment. A weekly report containing an updated list of patients on clozapine, organized by unit, is emailed to all unit clerks. Clerks print the weekly reports and place them with the flow sheets to identify patients who require monitoring. All patients on the protocol are required to have their bowel movements visualized daily by staff, who proceed to assign an appropriate Bristol Stool Chart (BSC) classification. Only 1 BSC is recorded per patient per day. The BSC is a tool to classify stools into 7 types based on appearance, ranging from very hard to watery, which is useful in identifying constipation and other bowel disorders.¹⁴ If there is no visualized bowel movement for 3 days, or a stool is visualized and reported as a BSC Type 1 or Type 7, patients are diagnosed with constipation or diarrhea and referred to an onsite medical clinic for an assessment. Approximately 1500 badge-size copies of the BSC were made for employees to wear on their badges to assist with the documentation process. All staff involved in direct patient care received the badge-size copies. All visualizations, types, referrals, medication adherence, and as-needed (PRN) medications are recorded in the hospital’s Electronic Medication Administration Record. PRN laxatives are not automatically ordered when clozapine is initiated, but may be ordered at the discretion of the provider at any time during the clozapine therapy.

A new coronavirus identified in December 2019 would later become known as COVID-19.¹⁵ This disease is transmitted by both symptomatic and asymptomatic carriers via direct contact, aerosol droplets, and the fecal-oral route.^16,17 In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic,¹⁸ and the United States began implementing stay-at-home orders as a quarantine. Accordingly, FSH began quarantining patients to minimize the spread of COVID-19 between units. As a result of these quarantines, the number of activities offered to patients was reduced, and sedentary behavior increased. As gastrointestinal motility is associated with physical activity,¹⁹ this study aimed to evaluate the impact of these quarantines on medical referrals for constipation, the BSC ratings, utilization of PRN laxatives, and adherence rates with scheduled constipation medication regimens.

Methods

Retrospective chart reviews were conducted for patients on the clozapine-induced constipation protocol from May 1, 2019 to December 31, 2020, were included, with a 10-month pre- and mid-quarantine implementation. Patients were excluded if they initiated clozapine after May 1, 2019, discontinued clozapine before December 31, 2020, did not participate in the clozapine-induced constipation protocol, or were transferred to another facility during the study period. All patients treated with clozapine were initially on the protocol, but the protocol might be discontinued if stool visualization resulted in aggression. The primary outcome was the number of medical referrals for constipation. This was selected as it represented the step in the protocol at which constipation was significant enough to require medical intervention. The secondary outcomes included the BSC ratings, utilization of PRN laxatives, and adherence rates with scheduled constipation medication regimens. Patients who were included served as their own control.

The BSC ratings were categorized as Types 0-7.¹⁴ Type 0 was no bowel movement documented. Medication administration history reports were used to identify medication refusals and the utilization of PRN laxatives. Referrals made to the medical clinic for constipation were documented. Other data collected included patient demographic variables (age, gender, and race) and primary psychiatric diagnosis. Disease states were identified by the International Classification of Diseases (ICD)-9 and ICD-10 codes. Descriptive statistics and paired t-tests were performed. The study was approved by the University of Missouri-Columbia Institutional Review Board and the State of Missouri Department of Mental Health Professional Review Committee.

Results

Fifty-three patients were identified during the study period, of which 31 met the inclusion criteria. The other 22 patients were excluded because they were transferred to another facility during the study period (n = 10), were transferred to the facility while taking clozapine after the start of the study period (n = 1), started taking clozapine after the start of the study period (n = 10), or discontinued clozapine before the end of the study period (n = 1). Most patients were male (93.5%), with a median age of 40 years, and Caucasian (58%) (Table 1). The most common primary diagnosis was schizophrenia (38.7%), followed by schizoaffective disorder, bipolar type (29.1%), and schizoaffective disorder, depressive type (9.8%).

TABLE 1 Baseline characteristics of total population (N = 31)

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The average number of medical referrals for constipation per person was 6.45 (±5.63) during the period of pre-quarantine implementation and 4.06 (±5.92) during the period of mid-quarantine implementation. The paired t-test demonstrated a statistically significant difference (P < .05) between the measures. The instances of BSC ratings were not statistically different between the periods of pre- and mid-quarantine implementation (Table 2). During the period of pre-quarantine implementation, milk of magnesia was utilized 589 times, magnesium citrate was utilized 17 times, lactulose was utilized 86 times, and bisacodyl was utilized once (a total of 693 times). During the period of mid-quarantine implementation, milk of magnesia was utilized 444 times, magnesium citrate was utilized 4 times, lactulose was utilized 104 times, and bisacodyl was utilized 60 times (a total of 612 times). Overall, the frequency of PRN laxative utilization was reduced by 11.6% during the mid-quarantine implementation period. Moreover, the adherence rate of scheduled constipation medication was 87% during the period of pre-quarantine implementation and 84% during the period of mid-quarantine implementation.

TABLE 2 Paired t-tests for instances of the Bristol Stool Chart (BSC) ratings (N = 31)

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Discussion

The results demonstrate fewer medical referral contacts per person during the mid-quarantine implementation period. In addition, no difference in the BSC ratings was observed. The results show that the clozapine-induced constipation protocol worked well during the quarantines, even though the quarantines dramatically changed patients’ daily routines and physical activity levels. The decline in PRN use indicates there was not an increased reliance on PRN laxatives by health care professionals. It was also possible that health care professionals were proactively addressing patient needs by conducting assessments and implementing treatments more quickly and informally, rather than relying solely on PRN laxatives or medical referrals. As described earlier, the protocol closely monitors patients prescribed clozapine and provides resources for managing constipation, such as medical referrals and the provision of PRN laxatives. However, it is possible that confounding factors were not fully measured. A number of factors contribute to constipation, including insufficient dietary fiber, dehydration, female gender, increasing age, socioeconomic status, educational level, physical activity, self-rated health, certain medical conditions, and certain medications.^20–22 In addition, there was a push on the wards to encourage activity and mobility, but this was not accounted for, so patients might have been physically active in the wards or their rooms. Another limitation is the small sample size (n = 31), located in a single practice setting, which can limit the generalizability of the results.

The clozapine-induced constipation protocol is innovative in 3 aspects. First, it takes a proactive approach to bowel management promoting early identification and treatment of constipation. Daily monitoring of bowel movements by trained staff helps detect any changes in bowel function and take appropriate measures to prevent constipation. These complications may require surgical interventions, which can be costly and have a significant impact on patient’s quality of life. Second, the protocol incorporates the BSC into the process. The BSC provides a standardized model for consistent reporting of bowel function across settings and populations. Based on our experience, the BSC is easy for staff to use and for patients to understand. In addition, the BSC has demonstrated benefit in diagnosing various bowel disorders. For example, Types 1 and 2 stools are indicative of constipation, while Types 5-7 stools are associated with diarrhea.¹⁴ Its diagnostic utility can also be used to monitor the effectiveness of a treatment. Third, the protocol engages patients and involves direct care staff, nurses, pharmacists, and physicians. It standardizes and includes medical referrals and the provision of PRN laxatives. It supports a multidisciplinary approach of regular bowel monitoring, medication management, dietary modification, and physical activity to address a potentially significant adverse event.

Conclusion

Compared with the pre-quarantine implementation period, there were fewer medical referrals per person during the mid-quarantine implementation period. Other factors that might impact the clozapine-induced constipation and patient self-report had low sensitivity in this context.