Korean J Schizophr Res.  2022 Oct;25(2):54-61. 10.16946/kjsr.2022.25.2.54.

Clinical Factors Affecting Constipation in Patients with Schizophrenia Taking Clozapine

• Lee MJ
• Kim SJ
• Moon JJ
• Jeon DW
• Jung DU

• KMID: 2535945
• DOI: http://doi.org/10.16946/kjsr.2022.25.2.54

Abstract

Objectives
To investigate clinical factors affecting constipation in patients with schizophrenia taking clozapine.
Methods
The participants were patients with schizophrenia taking clozapine and tested for the Therapeutic Drug Monitoring from September 1, 2020 to July 1, 2022 at a university hospital. To evaluate the effect of clozapine on constipation, clozapine dosage, clozapine concentration, and norclozapine concentration were investigated. To evaluate effects of drugs other than clozapine on constipation, dosage and type of other drug were investigated. Anticholinergic Drug Scale was used to evaluate anticholinergic action.
Results
A total of 56 patients were enrolled in the study. Clozapine daily dose, clozapine concentration, and norclozapine concentration were higher in the constipated patient group. Through logistic regression analysis, it was discovered that the risk of constipation increased as the norclozapine concentration increased, and the results remained similarly even after adjustments of related variables was performed.
Conclusion
It was discoverd that among patients taking clozapine, the higher the norclozapine concentration, the higher the probability of constipation. Among patients taking clozapine, patients with high norclozapine concentration may need additional evaluation and management of constipation.

Keyword

Cholinergic antagonists; Clozapine; Constipation; Drug monitoring; Schizophrenia; 변비; 약물농도감시; 조현병; 콜린성 길항제; 클로자핀

Reference

1. Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016; 209:385–392.

2. Young CR, Bowers MB Jr, Mazure CM. Management of the adverse effects of clozapine. Schizophr Bull. 1998; 24:381–390.

3. Alvir JMJ, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis--incidence and risk factors in the United States. New England Journal of Medicine. 1993; 329:162–167.

4. Raja M, Raja S. Clozapine safety, 40 years later. Current drug safety. 2014; 9:163–195.

5. Shirazi A, Stubbs B, Gomez L, Moore S, Gaughran F, Flanagan RJ, et al. Prevalence and Predictors of Clozapine-Associated Constipation: a Systematic Review and Meta-Analysis. Int J Mol Sci. 2016; 17:863.

6. Every-Palmer S, Nowitz M, Stanley J, Grant E, Huthwaite M, Dunn H, et al. Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: a cross sectional study. EBioMedicine. 2016; 5:125–134.

7. Chengappa KR, Pollock BG, Parepally H, Levine J, Kirshner MA, Brar JS, et al. Anticholinergic differences among patients receiving standard clinical doses of olanzapine or clozapine. Journal of Clinical Psychopharmacology. 2000; 20:311–316.

8. Taylor DM, Smith L, Gee SH, Nielsen J. Augmentation of clozapine with a second antipsychotic - a meta-analysis. Acta Psychiatr Scand. 2012; 125:15–24.

9. Nielsen J, Meyer JM. Risk factors for ileus in patients with schizophrenia. Schizophr Bull. 2012; 38:592–598.

10. Every-Palmer S, Inns SJ, Ellis PM. Constipation screening in people taking clozapine: a diagnostic accuracy study. Schizophr Res. 2020; 220:179–186.

11. West S, Rowbotham D, Xiong G, Kenedi C. Clozapine induced gastrointestinal hypomotility: a potentially life threatening adverse event. A review of the literature. Gen Hosp Psychiatry. 2017; 46:32–37.

12. Stubbs B, Thompson T, Acaster S, Vancampfort D, Gaughran F, Correll CU. Decreased pain sensitivity among people with schizophrenia: a meta-analysis of experimental pain induction studies. Pain. 2015; 156:2121–231.

13. Bickerstaff LK, Harris SC, Leggett RS, Cheah KC. Pain insensitivity in schizophrenic patients. A surgical dilemma. Arch Surg. 1988; 123:49–51.

14. De Hert M, Cohen D, Bobes J, Cetkovich-Bakmas M, Leucht S, Ndetei DM, et al. Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level. World Psychiatry. 2011; 10:138–151.

15. Seidel S, Aigner M, Ossege M, Pernicka E, Wildner B, Sycha T. Antipsychotics for acute and chronic pain in adults. Cochrane Database Syst Rev. 2008; CD004844.

16. Olsson E, Edman G, Bertilsson L, Hukic DS, Lavebratt C, Eriksson SV, et al. Genetic and Clinical Factors Affecting Plasma Clozapine Concentration. Prim Care Companion CNS Disord. 2015; 17:doi:10.4088/PCC.14m01704.

17. Albitar O, Harun SN, Zainal H, Ibrahim B, Sheikh Ghadzi SM. Population Pharmacokinetics of Clozapine: a Systematic Review. Biomed Res Int. 2020; 2020:9872936.

18. Ohlsen R, Williamson R, Yusufi B, Mullan J, Irving D, Mukherjee S, et al. Interrater reliability of the Antipsychotic Non-Neurological Side-Effects Rating Scale measured in patients treated with clozapine. Journal of Psychopharmacology. 2008; 22:323–329.

19. Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010; 167:686–693.

20. Bailey L, Varma S, Ahmad N, Gee S, Taylor DM. Factors predicting use of laxatives in outpatients stabilized on clozapine. Therapeutic Advances in Psychopharmacology. 2015; 5:256–262.

21. Lu ML, Lane HY, Lin SK, Chen KP, Chang WH. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry. 2004; 65:766–771.

22. Szegedi A, Wiesner J, Hiemke C. Improved efficacy and fewer side effects under clozapine treatment after addition of fluvoxamine. J Clin Psychopharmacol. 1995; 15:141–143.

23. Jakobsen M, Larsen J, Svensson C, Johansen SS, Linnet K, Nielsen J, et al. The significance of sampling time in therapeutic drug monitoring of clozapine. Acta Psychiatrica Scandinavica. 2017; 135:159–169.

24. Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The anticholinergic drug scale as a measure of drug - related anticholinergic burden: associations with serum anticholinergic activity. The Journal of Clinical Pharmacology. 2006; 46:1481–1486.

25. Eum S, Hill SK, Rubin LH, Carnahan RM, Reilly JL, Ivleva EI, et al. Cognitive burden of anticholinergic medications in psychotic disorders. Schizophrenia Research. 2017; 190:129–135.

26. Jun DW, Park HY, Lee OY, Lee HL, Yoon BC, Choi HS, et al. A population-based study on bowel habits in a Korean community: prevalence of functional constipation and self-reported constipation. Digestive Diseases and Sciences. 2006; 51:1471–1477.

27. Centorrino F, Baldessarini RJ, Kando JC, Frankenburg FR, Volpicelli SA, Flood JG. Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients. J Clin Psychopharmacol. 1994; 14:119–125.

28. Kuoppamaki M, Syvalahti E, Hietala J. Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists. Eur J Pharmacol. 1993; 245:179–182.

29. Tracy JI, Monaco CA, Abraham G, Josiassen RC, Pollock BG. Relation of serum anticholinergicity to cognitive status in schizophrenia patients taking clozapine or risperidone. Journal of Clinical Psychiatry. 1998; 59:184–188.

30. Lameh J, Burstein ES, Taylor E, Weiner DM, Vanover KE, Bonhaus DW. Pharmacology of N-desmethylclozapine. Pharmacol Ther. 2007; 115:223–231.

31. Weiner DM, Meltzer HY, Veinbergs I, Donohue EM, Spalding TA, Smith TT, et al. The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology (Berl). 2004; 177:207–216.

32. de Leon J, Odom-White A, Josiassen RC, Diaz FJ, Cooper TB, Simpson GM. Serum antimuscarinic activity during clozapine treatment. J Clin Psychopharmacol. 2003; 23:336–341.

33. Olianas MC, Dedoni S, Ambu R, Onali P. Agonist activity of N-desmethylclozapine at δ-opioid receptors of human frontal cortex. Eu-ropean Journal of Pharmacology. 2009; 607:96–101.

34. Chougule A, Praharaj SK, Bhat SM, Sharma P. Prevalence and factors associated with clozapine-related constipation: an observational study. Journal of Clinical Psychopharmacology. 2018; 38:42–46.

35. Park SC, Lee MS, Kang SG, Lee SH. Patterns of antipsychotic prescription to patients with schizophrenia in Korea: results from the health insurance review & assessment service-national patient sample. J Korean Med Sci. 2014; 29:719–728.

36. Kim CW, Lee TG, Kim JG. The Clinical Practice of clozapine in the Treatment of Inpatients with Schizophrenia and Other Psychotic Disorders: effect and Side Effect. J Korean Soc Biol Ther Psychiatry. 2003; 9:61–68.

37. Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tuck- er GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004; 24:70–78.