by Megan K. Skelly, PharmD, BCPS; Tammie Lee Demler, BS, PharmD, MBA, BCGP, BCPP; and Claudia Lee, MD

Drs. Skelly, Demler, and Lee are with the State University at Buffalo (SUNY) School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacy Practice in Buffalo, New York and Drs. Demler and Lee are also with New York State Office of Mental Health, Buffalo Psychiatric Center in Buffalo, New York and SUNY School of Medicine, Department of Psychiatry (Demler) and Department of Medicine (Lee) in Buffalo, New York.

Funding: No funding was provided.

Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Abstract: Clozapine, a second-generation antipsychotic (SGA), is known for its superior efficacy in the treatment of refractory schizophrenia. Clozapine’s hallmark side effects are well-known, including, but not limited to, drug-induced seizures associated with daily goal doses greater than 600mg and rapid dose escalation, which can also contribute to significant risk of orthostatic hypotension, bradycardia, and syncope. However, less well-known is the potential withdrawal that can occur from its rapid discontinuation. Here, we describe a case of seizure-like activity that occurred 72 hours after an abrupt high-dose clozapine discontinuation in a patient with schizoaffective disorder, bipolar type. Seizures, although known to be a high-serum-concentration-dependent side effect of clozapine, could not be excluded as a possible withdrawal syndrome in this patient.

Keywords: Clozapine, seizure, psychopharmacology, withdrawal

Innov Clin Neurosci. 2019;16(7–8):22–24

Clozapine is a second-generation antipsychotic (SGA) with mixed receptor antagonism.¹ It exhibits its effect through antagonism at dopaminergic, serotonergic, adrenergic, cholinergic, muscarinic, and histaminergic receptors. Withdrawal syndromes from rapid discontinuation of clozapine are likely secondary to its mixed mechanism of action and pharmacokinetic properties. Abrupt discontinuation has been reported in the literature to cause rebound psychosis, cholinergic rebound, serotonin syndrome, and catatonia.² The discontinuation phenomena is thought to be related to clozapine’s short duration of action and its subsequent rapid dissociation from receptors.³

Clozapine is widely recognized for its many side effects, most notably for its propensity to cause blood dyscrasias along with other adverse reactions, which can also be life threatening. Seizures are a recognized adverse event that are dose-related in risk.¹ No literature currently exists, to our knowledge, of seizures occurring upon rapid clozapine discontinuation. We report a case of high-dose clozapine withdrawal causing possible seizure-like activity.

Case Report

A 57-year-old male patient with schizoaffective disorder, bipolar type, received clozapine while hospitalized at an inpatient psychiatric facility. In addition to clozapine, the patient’s medication regimen included divalproex extended release (ER) 500mg twice daily, levothyroxine 0.25mg daily, multiple vitamin daily, nicotine 14mg patch daily, and combination bowel regimen that contained docusate, senna, and polyethylene glycol (Miralax). His clozapine dose was 1,400mg per day with 500mg in the morning and 900mg in the evening, and his most recent clozapine level was 628ng/mL.

Given clozapine’s antagonistic activity on muscarinic 1 receptors and associated anticholinergic side effects, constipation is a known side effect; thus, patients taking clozapine require close monitoring of gastrointestinal function.⁴ The patient had severe constipation, and physical examination confirmed abdominal distention. He was transferred to a local medical center, where an abdominal x-ray showed distended colon with large stool burden. His potassium was also elevated at 5.8mEq/L, which was thought to be secondary to dehydration and constipation. The patient returned to the inpatient psychiatric facility once he was able to move his bowels with intravenous fluids and laxative intervention.

After four days, the patient continued having constipation and dizziness, with a sitting blood pressure of 87/54 and standing blood pressure of 76/44. Orthostasis and dizziness were thought to be due to dehydration and clozapine’s alpha 1 antagonism.⁴ Medical staff ordered lab work, which showed elevated potassium (6.7mEq/L), not hemolyzed.

The patient was again sent to the local medical center for potassium correction. The high potassium was then thought to be related to elevated magnesium from ingestion of magnesium citrate and milk of magnesia laxatives, which were subsequently discontinued. The patient returned to the inpatient psychiatric facility but continued to have constipation. Physical exam demonstrated palpable stool in the abdomen without impaction on rectal exam. It was then decided that clozapine would be discontinued as a “clozapine holiday” without a taper. The patient was continued on divalproex 500mg twice daily, which was originally initiated for seizure prevention while receiving the high dose of clozapine, as seizure risk is reported to increase with clozapine dose increases.⁴

Approximately 72 hours after clozapine discontinuation, the staff noted “seizure-like activity.” The patient was shaking his head and arms rhythmically and was not responding to verbal stimuli. He was answering questions intermittently. His body was not rigid or stiff. The patient urinated on himself and was hitting himself in the head and groin area with his right arm. He was unable to ambulate. It was unknown if the patient had fallen. The left side of the patient ‘s face appeared to droop. He had no prior history of seizures and had remained on divalproex 500mg twice daily, despite discontinuation of clozapine.

The patient was then transferred to a local vascular center for seizure and cerebrovascular accident (CVA). While at the vascular center, imaging was performed. Computed tomography (CT) showed a 4- to 5-millimeter-thick lateral convexity subdural hematoma with slight cortical mass effect but no midline-shift. No medical intervention was performed, and the patient was discharged from the vascular center taking levetiracetam 1,000mg twice daily for seizure prophylaxis, which was not continued upon readmission to the inpatient psychiatric facility. Possible seizure was noted as the patient’s differential diagnosis, and the patient was instructed to follow up with neurology.

Discussion

The etiology of this patient case remains unknown. The minor subdural hematoma could have resulted from a seizure secondary to the patient’s self-hitting behaviors. Arguably, clozapine is thought to have a dose-related seizure risk, and this etiology cannot be ruled out. Seizures associated with clozapine dose are not always apparent, nor do they have classic presentation; temporal lobe seizures can present as abnormal or strange behavior.⁵ Our patient was taking 1,400mg of clozapine daily; clozapine dose greater than 600mg/day has traditionally been accepted as a clinical threshold, with increased risk of seizures expected beyond that dose.⁶ However, the United States Food and Drug Administration (FDA) established the maximum daily dose of clozapine to be 900mg, and warned that seizures might still occur at lower doses. The therapeutic reference range of clozapine is 350 to 600ng/mL.¹ High clozapine serum levels (>1,000ng/mL) have been associated with increased risk of seizure; however, our patient’s most recent level was 628ng/mL, which is not above this threshold.⁷ There are no reports, to our knowledge, of clozapine withdrawal precipitating seizures.

Clozapine’s multireceptor action profile seems to account for withdrawal symptoms with a variety of suggested mechanisms: serotonergic influence, enhanced dopaminergic sensitivity, involvement of D4 receptors, cholinergic rebound, and possible gamma-aminobutyric acid (GABA)-ergic involvement.⁸ The magnitude of clozapine withdrawal symptoms has been reported to occur more rapidly and more severely than those that can occur following cessation of first generation antipsychotics (FGA).²

Serotonin syndrome, associated with clozapine withdrawal, can result from the abrupt withdrawal of 5-HT_2A antagonism.⁹ The symptoms of serotonin syndrome include, but are not limited to, clonus, hyperreflexia, agitation, restlessness, confusion, muscle rigidity, and diaphoresis. Life-threatening signs and symptoms of serotonin syndrome include high fever, seizures, irregular heartbeat, and unconsciousness. A theoretical mechanism for these symptoms could be that the abrupt discontinuation of clozapine causes a decrease in 5-HT_2A antagonism, which results in an upregulation of the 5-HT_2A receptor. A case report by Zesiewicz et al¹⁰ described a patient with advanced Parkinson’s disease who presented with symptoms of serotonin syndrome upon abrupt clozapine discontinuation. The patient’s symptoms resolved with cyproheptadine, a potent antihistamine and serotonin antagonist with anticholinergic effects, suggesting serotonergic rebound as a possible explanation for the patient’s symptoms.¹⁰

Rapid discontinuation of clozapine has been reported to cause rebound psychosis and worsening of symptoms within 24 to 48 hours of drug cessation.⁴ The rapid relapse of psychosis after discontinuation of clozapine is thought to be associated with enhanced dopamine sensitivity involving upregulation of D₄ receptors, for which clozapine has high affinity.^2,11,12 The most commonly reported symptoms include auditory hallucinations, persecutory ideation, and suicide attempts.¹¹ Discontinuation-induced enhanced sensitivity of dopamine receptors can lead to worsening severity of the mental illness with the appearance of new and more complex symptoms.¹³ Clozapine’s low D₂ affinity can result in the “loosely” bound drug being readily displaced by endogenous dopamine, upon drug cessation, which can cause a rapid relapse of psychosis.^2,14 Meltzer¹⁵ reported that cyproheptadine was effective in alleviating such psychotic relapses, suggesting that these symptoms could be related to excessive stimulation of the 5-HT₂ receptors.¹⁵

Based on these proposed pharmacodynamic consequences, if abrupt discontinuation of clozapine is necessary, the patient should be covered for cholinergic rebound.⁴ Cholinergic rebound, or withdrawal of the anticholinergic effects of clozapine, is due to clozapine’s uniquely potent antimuscarinic activity.¹⁶ Peripheral cholinergic rebound produces nausea, vomiting, diaphoresis, and rhinitis, whereas mild central cholinergic rebound produces restlessness and insomnia.¹⁶ Individuals with higher serum clozapine concentrations might need high doses of anticholinergic medications to prevent delirium and other rebound symptoms. The theory that cholinergic rebound is responsible for the majority of the withdrawal symptoms is supported by reports of successful use of anticholinergic agents, particularly trihexyphenidyl, for treating similar syndromes.¹³ De Leon et al¹⁷ effectively treated two patients, following abrupt clozapine withdrawal, with 1mg of trihexyphenidyl per 40mg clozapine to mitigate the emerging cholinergic symptoms.

Catatonia has also been reported following the abrupt discontinuation of clozapine.¹⁸ It is suggested that serotonergic hyperactivity, associated with cholinergic rebound, is involved in the pathogenesis of catatonia related to clozapine withdrawal. The catatonic syndrome has even been reported after missing one or two doses of clozapine. Such catatonia has been reported to resolve within seven days of clozapine reinstatement, thus supporting the theory of a clozapine withdrawal state. The reported successful treatment of catatonia with SGAs, including clozapine, olanzapine, and risperidone, further suggests a possible role of 5-HT₂ antagonism in the treatment of catatonia and serotonergic hyperactivity in the pathophysiology of catatonia.^19–21 A case report by Bilbily et al²² suggested that the dysregulation of GABA receptors might contribute to catatonia.Their findings indicate that clozapine might be a GABA agonist and that sudden clozapine withdrawal could explain a sudden decrease in GABA activity and the development of catatonic symptoms. The reported treatment for catatonia secondary to clozapine discontinuation is benzodiazepines and/or the reinitiation of clozapine. Sudden withdrawal from GABA-ergic agents is known to cause seizure activity.²³ The suggested GABA activity of clozapine supports possible seizure activity from rapid clozapine discontinuation.

If the discontinuation of treatment with clozapine is desired, it should be gradually tapered off over several weeks (50mg/week), rather than abruptly discontinued.⁸ Slow off-titration is preferred, if possible, to avoid withdrawal syndromes.⁴ To prevent relapse of psychosis, some advocate starting a new antipsychotic in therapeutic dosage before the discontinuation of clozapine is completed. There are no established guidelines for which antipsychotic to choose; however, an antipsychotic with high anticholinergic activity, such has thioridazine, might prevent withdrawal symptoms.¹⁶ In cases of emergency, such as severe neutropenia, abrupt discontinuation would require close monitoring in a hospital setting with concomitant coverage for cholinergic rebound. Prior to the revised risk evaluation and mitigation strategies (REMS) guidelines, requirements for abrupt discontinuation were more commonly based on low absolute neutrophil counts (ANC) and white blood cell count (WBC) threshold values. These new FDA-sponsored monitoring guidelines now offer a more flexible interpretation of an individual’s ANC at baseline and changes reported during ongoing clozapine treatment.²⁴

Limitations. There are several potential confounders that must be considered when suggesting alignment of the seizure that occurred in this patient with clozapine-associated withdrawal. The primary confounders include, but are not limited to, the patient’s multiple incidents of high serum potassium and dehydration, constipation with fecal impaction, and treatment with valproate for seizure prevention while receiving high-dose clozapine therapy. Of additional concern were the mutlple episodes of orthostasis, which might have led to an unobserved fall, the patient’s attempts at self-harm, and the observation of facial droop that was noted after a CT scan revealed a subdural hematoma. Although this case highlights robust explanations for the potential adverse neurophysiological consequences of abrupt discontinuation of clozapine, we cannot say with full confidence that what occurred in this subject’s case was truly a withdrawal seizure.

Conclusion

Our case report and supporting literature suggest that seizures might result from rapid clozapine discontinuation.²² One could argue that the patient’s presentation was severe serotonin syndrome; although, given that our patient was on a sizeable clozapine dose, an organic seizure cannot be exclusively ruled out. Notably, the prescribed clozapine doses in other published case reports of clozapine withdrawal were considerably lower than our patient’s dose of 1,400mg per day. It is important to remember that clozapine’s mechanism of action in exhibiting its unique therapeutic actions remains elusive and, therefore, so do the mechanisms involved in clozapine’s rapid discontinuation.² If the discontinuation of treatment with clozapine is desired, it should be gradually tapered off over several weeks, rather than abruptly discontinued. In cases of abrupt discontinuation, close monitoring in a hospital setting should be considered.

References

1. Clozaril (clozapine) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; January 2017.
2. Goudie AJ. What is the clinical significance of the discontinuation syndrome seen with clozapine? J Psychopharmacol. 2000;14(2):188–192.
3. Baldessarini RJ, Gardner DM, Garver DL. Conversions from clozapine to other antipsychotic drugs. Arch Gen Psychiatry. 1995;52(12):1071–1072.
4. Stahl S. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide, Revised and Updated Sixth Edition. New York, NY: Cambridge University Press.
5. Sacks O. Hallucinations. New York City, NY: Vintage Books; 2012.
6. Williams AM, Park SH. Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs. 2015;29(2):101–111.
7. Simpson GM, Cooper TA. Clozapine plasma levels and convulsions. Am J Psychiatry. 1978;135(1):99–100.
8. Szafranski T, Gmurkowski K. [Clozapine withdrawal. A review]. Psychiatr Pol. 1999;33(1):51–67.
9. Stevenson E, Schembri F, Green DM, Burns JD, et al. Serotonin syndrome associated with clozapine withdrawal. JAMA Neurol. 2013;70(8):1054–1055.
10. Zesiewicz TA, Borra S, Hauser RA. Clozapine withdrawal symptoms in a Parkinson’s disease patient. Mov Disord. 2002;17(6):1365–1367.
11. Ekblom B, Eriksson K, Lindstrom LH. Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal. Psychopharmacology (Berl). 1984;83(3):293–294.
12. Chouinard G, Jones BD, Annable L. Neuroleptic-induced supersensitivity psychosis. Am J Psychiatry. 1978;135(11):1409–1410.
13. Shiovitz TM, Welke TL, Tigel PD, et al. Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophr Bull. 1996;22(4):591–595.
14. Hartvig P, Eckernäs SA, Lindström L, et al. Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET). Psychopharmacology (Berl). 1986;89(2):248–252.
15. Meltzer HY. Clozapine withdrawal: serotonergic or dopaminergic mechanisms? Arch Gen Psychiatry. 1997;54(8):760–763.
16. Stanilla JK, de Leon J, Simpson GM. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. J Clin Psychiatry. 1997;58(6):252–255.
17. de Leon J, Stanilla JK, White AO, Simpson GM. Anticholinergics to treat clozapine withdrawal. J Clin Psychiatry. 1994;55(3):119–120.
18. Yeh AW, Lee JW, Cheng TC, et al. Clozapine withdrawal catatonia associated with cholinergic and serotonergic rebound hyperactivity: a case report. Clin Neuropharmacol. 2004;27(5):216–218.
19. Rommel O, Tegenthoff M, Widdig W, et al. Organic catatonia following frontal lobe injury: response to clozapine. J Neuropsychiatry Clin Neurosci. 1998;10(2):237–238.
20. Cassidy EM, O’Brien M, Osman MF, et al. Lethal catatonia responding to high-dose olanzapine therapy. J Psychopharmacol. 2001;15(4):302–304.
21. Valevski A, Loebl T, Keren T, et al. Response of catatonia to risperidone: two case reports. Clin Neuropharmacol. 2001;24(4):228–231.
22. Bilbily J, McCollum B, de Leon J. Catatonia secondary to sudden clozapine withdrawal: a case with three repeated episodes and a literature review. Case Rep Psychiatry. 2017;2017:2402731.
23. Hu X. Benzodiazepine withdrawal seizures and management. J Okla State Med Assoc. 2011;104(2):
    62–65.
24. Demler TL, Morabito NE, Meyer CE, Opler L. Maximizing clozapine utilization while minimizing blood dyscrasias: evaluation of patient demographics and severity of events. Int Clin Psychopharmacol. 2016;31(2):76–83.