Paralytic ileus in a patient on clozapine therapy showing an inverted clozapine/norclozapine ratio after switching valproic acid to carbamazepine: a case report

Introduction: Clozapine and constipation/paralytic ileus

Clozapine is the most efficacious antipsychotic drug in treatment-resistant schizophrenia. ¹

Besides this superior efficacy it has a very complex adverse reaction profile. Clozapine has several potentially life-threatening side effects, such as agranulocytosis, diabetic ketoacidosis, constipation and myocarditis. Other side effects include weight gain, metabolic effects, sedation, and hypersalivation.

Constipation is often neglected and underestimated. A meta-analysis of 32 studies established a prevalence of clozapine-associated constipation of 31.2%. ² If left untreated, constipation can cause serious complications such as bowel obstruction, paralytic ileus, colon perforation, aspiration of faecal vomitus and bacterial sepsis. ³

Complications of constipation are among the major causes of death in clozapine patients. ⁴ Data from VigiBase, the World Health Organisation’s global database, showed that with 326 deaths out of 2814 cases of ‘broad constipation’ (constipation, toxic megacolon and paralytic ileus) the relative mortality was 12%. Inpatient setting ² and anticholinergic co-medication ⁵ are co-occurring risk factors for constipation.

Here, we present (following the CARE Guidelines ⁶ ) a patient on clozapine therapy who developed paralytic ileus after switching from valproic acid to carbamazepine. We describe how an altered clozapine metabolism resulting from a pharmacokinetic interaction could have contributed to the occurrence of paralytic ileus.

Case description

A 42-year-old male smoker of mixed African/Caucasian descent diagnosed with schizoaffective disorder (295.70A, DSM-V) had several admissions to a psychiatric hospital over the last 20 years. Since 2019, he stayed in a specialized long-term closed ward for patients with serious mental illness and extremely disruptive/aggressive or otherwise dangerous behaviour for whom treatment in a regular ward did not result in improvement. The schizoaffective disorder manifested as chronically present florid psychotic symptoms (auditory hallucinations, paranoid and grandiose delusions) and fluctuating mood states, often featuring a manic presentation characterized by an agitated mood. Profound impulse control disturbances were evident, marked by multiple incidents of aggression. Driven by psychotic convictions, the patient severely assaulted his mother.

Clozapine therapy was started in 2005 but several times discontinued, the last time in 2018, because the patient developed severe constipation, leading to hospitalization with suspected ileus. In January 2019, clozapine was restarted and titrated to therapeutic plasma levels. In 2019, plasma levels of clozapine fluctuated between 347 and 672 µg/l, and plasma levels of norclozapine were between 230 and 520 µg/l. Comedication at that time consisted of lithium carbonate (1200 mg at bedtime) and zuclopenthixol long-acting injection (LAI, 200 mg every 2 weeks). In 2020, higher clozapine plasma levels – even above 1000 µg/l – were reached, but severe psychotic symptoms persisted. Zuclopenthixol LAI was substituted with haloperidol LAI (225 mg every 2 weeks, later switched to oral haloperidol), yielding some reduction in dysphoria. Nevertheless, the patient’s psychotic state persisted unaltered. In September 2020, biweekly electroconvulsive therapy (ECT) was initiated. By May 2021, the lithium was stopped due to cognitive side effects, and in September 2021, valproic acid (2 g once daily) was introduced. In 2021, before valproic acid addition, the mean clozapine/norclozapine ratio was 1.99 (mean clozapine plasma levels 957 µg/l and mean norclozapine plasma levels 481 µg/l, n = 39). After switching to valproic acid, the mean clozapine/norclozapine ratio increased to 3.15 (mean clozapine plasma levels 716 µg/l and mean norclozapine plasma levels 227 µg/l, n = 62). After >1 year of biweekly sessions of ECT in combination with clozapine (plasma levels between 400 and 1300 µg/l), haloperidol (plasma levels between 10 and 15 µg/l) and valproic acid (plasma levels fluctuating around 80 mg/l), only minimal improvement was observed. There had been no further incidents of aggression; however, florid psychotic symptoms and fluctuating mood states persisted. The other drugs used were glycopyrronium 2 mg at bedtime, lactulose 30 ml and memantine 20 mg. Lorazepam and droperidol were used as needed. The patient is an intermediate CYP2D6 metabolizer (CYP2D6 *2/*3) and an extensive metabolizer of CYP1A2 (CYP1A2 *1/*1F), CYP2C9 (CYP2C9*1/*1), CYP2C19 (CYP2C19*1/*1) and CYP3A4 (CYP3A4*1/*1). Patient’s BMI is 22.5 (height 171 cm, weight 65.9 kg).

Because of the serious treatment-resistant symptoms, valproic acid was replaced by carbamazepine. As carbamazepine is a strong inducer of several CYP450 enzymes and can decrease clozapine levels, precautionary measures had to be taken. Firstly, fluvoxamine 25 mg was added to the medication to inhibit clozapine metabolism. Clozapine dose was adjusted from 600 to 500 mg once daily at the same time (Figure 1, arrow 1). Two weeks after starting fluvoxamine, carbamazepine (200 mg twice daily) was added and valproic acid was stopped (Figure 1, arrow 2). Clozapine levels decreased the next 2 weeks to 370 µg/l, which was below baseline (460 µg/l before adding fluvoxamine). Therefore, both fluvoxamine and clozapine doses were increased (to 50 mg and 550 mg once daily, respectively) (Figure 1, arrow 3). Patient took his pills under direct supervision of a nurse and always remained in sight for 30 min to avoid non-adherence.

OPEN IN VIEWER

Figure 1.

Clozapine and norclozapine levels in time.

A total of 5 weeks later, the patient was admitted to a general hospital after almost 1 week of no defecation, nausea and vomiting. On the day of admission, eight sachets of macrogol were given, but he immediately vomited. Patient was diagnosed with paralytic ileus caused by clozapine. All oral medication was stopped, metoclopramide (against the nausea) and haloperidol were given intravenously.

Drug concentration levels showed increasing norclozapine in the weeks before hospital admission, and an inverted clozapine/norclozapine ratio 2 days before admission was observed (Figure 1, arrow 4). Clozapine level was 410 µg/l and norclozapine level 510 µg/l.

Carbamazepine plasma levels fluctuated between 5.2 and 8.0 mg/l in the weeks before admission.

Treatment of the ileus was conservative with enemas and showed a good response. Clozapine was restarted the evening after admission, and the next day, the patient was dismissed from the hospital back to the psychiatric hospital. Clozapine dose was reduced to 450 mg once daily to lower the anticholinergic burden. Carbamazepine was continued, and the dose was increased to 600 mg daily because psychiatric symptoms, especially the mood, had improved on carbamazepine. Although the psychosis remained unabated, the patient could, for the first time in years, join a family weekend because he was very friendly and cooperative. An intensive laxative treatment (with macrogol, lactulose, bisacodyl and enemas as needed) was started to prevent constipation.

Two weeks later, the patient was readmitted to the general hospital, suspected of paralytic ileus and faecal vomiting. Again, there was an inverted ratio, with clozapine level being 270 µg/l and norclozapine level 280 µg/l (Figure 1, arrow 5). After admission, the patient had spontaneous defaecation and was dismissed the next day. Glycopyrronium was stopped in the hospital due to its contraindication paralytic ileus. No hypersalivation was observed after stopping the glycopyrronium tablets.

Discussion

Clozapine is metabolized by N-demethylation and N-oxidation, yielding norclozapine and the inactive metabolite clozapine-N-oxide. The main enzymes involved are CYP1A2 and CYP3A4, as shown in Figure 2. Other Cytochrome P450 enzymes also contribute to N-demethylation^7,8and N-oxidation. ⁸

OPEN IN VIEWER

Figure 2.

Clozapine metabolism.

Norclozapine is further metabolized by conjugation with sulfate and glucuronic acid and eliminated in urine. ⁹ It also undergoes tubular secretion ¹⁰ by an unknown renal transporter.

Carbamazepine, in addition to clozapine therapy, is not recommended in some countries due to its additive risk of agranulocytosis. In the Dutch guideline for the use of clozapine (Dutch Clozapine Collaboration Group ¹¹ ), carbamazepine is mentioned as relatively contraindicated. Our patient did not improve on other mood stabilizers, memantine and numerous ECT sessions. Therefore, carbamazepine was started with frequent haematologic monitoring.

Because carbamazepine is a potent inducer of CYP1A2 and CYP3A4, the dose of clozapine has to be increased by a factor of 1.5–2.^12,13 In this patient, this would have been a dose above 900 mg, which is the licenced maximum dose. Instead of increasing clozapine dose, fluvoxamine (a strong CYP1A2 inhibitor) was added to prevent clozapine levels to fall. Drug concentration levels were measured weekly, as shown in Figure 1.

Fluvoxamine strongly inhibited CYP1A2, increasing clozapine/norclozapine ratio (Figure 1, arrow 1). In this case clozapine/norclozapine ratio decreased and even inverted after addition of carbamazepine and increasing fluvoxamine dose to 50 mg. Norclozapine levels increased from 200 to 520 µg/l in 2 weeks.

Conclusion

Our patient developed paralytic ileus after substituting valproic acid with carbamazepine (+fluvoxamine) during clozapine therapy. Clozapine levels decreased, and norclozapine levels increased, resulting in an inverted clozapine/norclozapine ratio.

We discussed antagonism of M3 receptors by clozapine and norclozapine and agonism of delta-opioid receptors by norclozapine as possible mechanisms that have contributed to the occurrence of the paralytic ileus in our patient. We propose that both the clozapine/norclozapine ratio and the absolute norclozapine levels can be considered risk factors for constipation and paralytic ileus.

There is growing evidence that the clozapine/norclozapine ratio is important in cognition and metabolic side effects of clozapine, but this is the first report on the potential impact of the clozapine/norclozapine ratio on constipation and paralytic ileus.

Supplemental Material

Supplemental Material