Use of Clozapine in the General Hospital

Abstract

Patients with treatment-resistant schizophrenia receiving clozapine therapy are at risk of potentially serious complications in the general hospital setting, due to the complex pharmacokinetic and pharmacodynamic profile of clozapine. We summarize common clinical challenges that face clinicians who care for clozapine patients in the general hospital, and make recommendations based on the available literature and clinical experience. Early collaborative management between consultation-liaison psychiatry and other clinical teams in the general hospital is paramount to improve clinical outcomes and avoid serious complications in this patient group.

Introduction

Schizophrenia is a major neuropsychiatric disorder that is associated with increased physical health morbidity and mortality particularly from cardiovascular disease, diabetes, chronic obstructive pulmonary disease and pneumonia, which is likely to have multifactorial etiologies including genetic and environmental factors, lifestyle as well as iatrogenic effects of pharmacotherapy.^1–5 Furthermore, compared with the general population, people with schizophrenia have higher rates of general hospital admissions which tend to be more prolonged and have poorer outcomes.⁵ Patients receiving clozapine treatment are particularly at increased risk of serious complications when admitted to the general hospital.^6–10

Clozapine

Clozapine is the only pharmacological agent with proven efficacy in treatment resistant schizophrenia,^11,12 although its use is associated with various troublesome and potentially life threatening adverse effects including agranulocytosis (requiring mandatory regular monitoring of white cell counts), cardiomyopathy, constipation, hypersalivation, metabolic syndrome, myocarditis, sedation, seizures, tachycardia, urinary incontinence and weight gain.¹³

Clozapine should be initiated at a very low dose of 12.5 mg and uptitrated gradually over a period of weeks according to response and tolerance.¹⁴ Therapeutic response is usually observed within the dose range 150–900 mg per day¹⁵ (in two divided doses) and the trough plasma level of 350–600 ng/ml.¹⁶ Average dose in clinical practice is around 450 mg per day,¹⁴ albeit lower doses are required in the elderly, females, East Asians, non-smokers and those prescribed certain hepatic enzyme inhibitors.^14,17 Clozapine undergoes extensive hepatic metabolism, mainly by CYP1A2 and to a lesser extent by CYP3A4, CYP2D6 and CYP2C19.¹⁸ Thus, smoking tobacco (through polycyclic aromatic hydrocarbons) can reduce clozapine plasma levels via induction of CYP1A2, resulting in the need for higher doses of clozapine in smokers. In contrast, co-prescribing of CYP1A2 inhibitors (such as fluvoxamine and cimetidine) can increase clozapine plasma levels potentially resulting in severe adverse effects including seizures and excessive sedation, although clinicians may at times cautiously therapeutically exploit this drug-drug interaction to enhance plasma levels of clozapine in smokers or fast metabolizers without increasing the dose.

Clinical Challenges

Clinicians managing clozapine patients in the general hospital setting are faced with a number of common clinical challenges that are summarized here, together with some recommendations.

Interrupted Treatment

Upon admission to the general hospital clozapine may not be readily available, which could result in interrupting treatment for more than 48 hours (from the time of last dose before admission) potentially leading to loss of tolerance and development of serious and possibly fatal adverse reactions if clozapine was subsequently resumed at the original dose¹⁹ including severe hypotension, seizures and myocarditis. In such cases clozapine should be retitrated from 12.5 mg per day, although this might be done more rapidly than in clozapine-naïve patients if treatment was interrupted for less than a week.^14,20 Clinicians should also consider whether patients were compliant with their clozapine treatment prior to admission. White cell count monitoring should continue during hospitalization.

Tobacco Smoking

People with schizophrenia have high rates of tobacco use which enhances clozapine clearance. Smoking is usually discontinued or substantially reduced during admission, while patients may remain on the same clozapine dose resulting in increased plasma concentrations to potentially toxic level⁹ which cannot be mitigated by the use of nicotine replacement therapy. Thus, smoking patients should be closely monitored after admission for signs of toxicity, and consideration made for prophylactic dose reduction especially in heavy smokers on high dose clozapine. However, if clozapine toxicity is suspected (usually manifesting with excessive sedation and myoclonus) clozapine dose should be substantially reduced or suspended until clozapine plasma concentrations are available.^6,7,21 In those patients, cardiac and respiratory functions should be monitored and other central nervous system depressant drugs, such as benzodiazepines, should be avoided. Clinicians should also consider prophylactic anti-epileptic drugs due to the increased risk of seizures and should effectively treat hypersalivation and constipation in addition to assessing and managing the risk of aspiration.

Pneumonia and other Infections

Pneumonia has been found to be one of the main causes of death in patients receiving clozapine treatment.²² Association between clozapine and pneumonia is potentially bi-directional;^23,24 On the one hand, clozapine has been shown to be associated with significant reduction in immunoglobulin levels, thus increasing the risk of infections,²⁵ and it may also cause esophageal hypomotility and remarkable hypersalivation which could result in aspiration pneumonia.^26,27 On the other hand, pneumonia²⁸ and other severe infections²⁹ suppress clozapine metabolism through the inhibitory effects of pro-inflammatory cytokines on CYP1A2, resulting in elevated clozapine plasma levels²³ potentially leading to toxicity and perpetuating the risk factors for pneumonia. In those cases clozapine dose reduction or cessation may be necessary^6,7 in addition to monitoring for and managing adverse effects and the risk of toxicity, with particular emphasis on preventing aspiration.^24,26 The choice of antibiotic treatment should consider any potential interactions with clozapine.¹⁴

Severe Constipation

Constipation is a common, albeit under-reported and under-treated, adverse effect of clozapine which may be exacerbated by the co-prescribing of opioids or anticholinergic agents.³⁰ Bulk laxatives or stool softeners can be effective, although clinicians should consider clozapine reduction or suspension in patients hospitalized with treatment-refractory constipation or ileus, which could otherwise result in avoidable surgical interventions, and may rarely be fatal.^22,30

Drug–Drug Interactions

Due to clozapine’s complex metabolism and adverse effect profile, hospitalized patients are at increased risk of interaction between clozapine and other drugs commonly prescribed in hospital. For instance, the antibiotics erythromycin and ciprofloxacillin (hepatic enzyme inhibitors) may elevate clozapine plasma concentration to toxic levels, whereas corticosteroids and phenytoin could enhance clozapine clearance.¹⁶ Furthermore, the risk of agranulocytosis may increase if clozapine is prescribed simultaneously with drugs that can cause bone marrow suppression¹⁴ such as cytotoxic chemotherapy and carbamazepine. Co-prescribing sedatives and drugs that could cause QT interval prolongation should also be avoided if clinically possible.

Severe Medical Conditions

In patients with organ failure or other serious acute medical conditions such as stroke, myocardial infarction, or those admitted to intensive care units (ICUs), it may be inappropriate to continue with clozapine therapy, although decisions have to be made based on risk-benefit assessments for individual patients and in liaison with their medical or surgical teams, taking into consideration both their medical and psychiatric prognoses, and whether clozapine had caused or contributed to the development of those medical conditions.

General Anesthesia

In patients undergoing elective general anesthesia (GA), clozapine may need to be withdrawn 12 hours or more prior to GA due to its potential interactions with drugs that may be used during GA such as hypnotic or adrenergic agents. However, in cases when GA is performed non-electively for urgent surgical interventions or ICU procedures, anesthesiologists and intensivists should consider those interactions, and particularly the paradoxical vasodilatory effect of epinephrine in patients receiving clozapine, due to the latter’s alpha-1 adrenoreceptor antagonism.³¹ The timing of restarting clozapine should be agreed in liaison between the psychiatric and anesthetic teams depending on clinical recovery from GA.

Clozapine Withdrawal

Admissions to the general hospital are potentially associated with the risk of psychotic relapse or exacerbation owing to the significant psychological and physical stress of hospitalization and/or clozapine reduction or cessation, and it is therefore paramount that patients are supported and monitored by the local consultation-liaison psychiatry services. If clozapine is discontinued, a trial of an appropriate alternative antipsychotic drug could be considered in order to mitigate the risk of relapse.^14,32,33 Additionally, abrupt clozapine withdrawal may result in cholinergic rebound (vomiting, diarrhoea, diaphoresis, agitation and insomnia) that may be alleviated by anticholinergic agents.³⁴ Nonetheless, once sufficiently medically stable, it may be necessary to transfer those patients into an inpatient psychiatric unit for clozapine optimisation or re-titration, as per local protocols.

Conclusion

In summary, clozapine patients admitted to the general hospital may experience serious complications owing to the complex pharmacokinetic and pharmacodynamic profile of clozapine, in addition to the increased risk of psychotic relapse. Thus, it is imperative that those patients are referred to the local consultation-liaison psychiatry teams immediately upon admission, and that they are managed collaboratively throughout their hospitalization.