A Retrospective Multicenter Evaluation of Clozapine Use in Pediatric Patients Admitted for Acute Psychiatric Hospitalization

Abstract

Objectives:

Clozapine is the drug of choice for treatment-resistant schizophrenia. While pediatric clozapine use is not contraindicated, the literature describing its clinical application is limited. The primary objective of this study was to assess the use of clozapine in a child and adolescent population by characterizing the documented safety and clinical benefits of the medication.

Methods:

A multicenter retrospective study at sites in the United States and Australia included children and adolescents admitted to a psychiatric unit who were administered at least one dose of clozapine. Information related to demographics, patient history, past treatments, clozapine, and adverse events was collected.

Results:

Eighty-two patients from eight sites were included in this study. Patients were predominantly clozapine naive (76.8%), and most had a discharge diagnosis of a primary psychotic disorder (61%) or bipolar disorder (25.6%). Four clozapine discontinuations occurred during hospitalization due to severe neutropenia, ileus, need for diagnostic clarification, and significant psychomotor retardation. The remainder (n = 78) were discharged on a mean clozapine dose of 218.1 ± 142.2 mg. Sedation (26.8%) and sialorrhea (17.1%) were the most common documented adverse events. The mean number of previously trialed antipsychotics before clozapine was 3.5 ± 1.4 (range 1–10). Improvement with clozapine was documented as significant (31.7%), moderate (32.9%), minimal (12.2%), no improvement (2.4%), and not described (20.7%).

Conclusions:

In this cohort, 95% of pediatric patients admitted with or started on clozapine during an acute psychiatric hospitalization were discharged on the medication. The high incidence of adverse events should reinforce to clinicians the need for vigilant monitoring. Pediatric guidelines recommend clozapine for refractory schizophrenia but stress the critical need to ensure an accurate diagnosis. Limited data exist for the use of clozapine in pediatric patients with other diagnoses.

Introduction

Early-onset schizophrenia (EOS) occurs in roughly 5% of patients who develop the disease and is characterized by a diagnosis before 18 years of age (Clemmensen et al. 2012). When diagnosed under the age of 13 years, it is described as childhood-onset schizophrenia (COS) (McClellan and Stock 2013). Clozapine has proven to be superior when compared with other antipsychotics for managing treatment-resistant schizophrenia in adults, and the benefits have been clearly defined (Kane et al. 1988; Lewis et al. 2006). While the literature supporting clozapine use in pediatric populations remains sparse, guidelines recommend the careful initiation of this medication for treatment-resistant EOS (McClellan and Stock 2013). There have been three published prospective, double-blind, randomized controlled trials of clozapine in pediatric patients, with the largest sample consisting of 39 subjects (Kumra et al. 1996, 2008; Shaw et al. 2006). Two of the trials reported clozapine superiority over an alternative antipsychotic, whereas in the third, clozapine was only superior to olanzapine in regard to negative symptoms. All trials described significantly greater adverse events for subjects treated with clozapine. Retrospective studies involving clozapine use in pediatric patients also highlight a significant side effect burden (Frazier et al. 2003). However, when clozapine is initiated in pediatric patients, there is evidence to support that the medication may be even more effective with longer maintenance rates compared with adult outcomes (Kasoff et al. 2016). Overall, the sparse safety and efficacy data in part can explain the limited clinical use of clozapine in pediatric patients. Continued evaluation of this potentially life-saving medication is crucial to better understand the role of clozapine in pediatric populations. In an attempt to characterize the “real-world” use of clozapine in pediatric patients, a multisite retrospective chart review was conducted.

Methods

A multicenter retrospective chart review was approved by the Mayo Clinic's Institutional Review Board (IRB) and each contributing sites' IRB. Patients admitted to a child and adolescent psychiatric unit and administered at least one dose of clozapine between January 2003 and March 2015 were included. Information collected from medical records included demographic data, medical history, social history, mental illness age of onset, discharge diagnoses, metabolic parameters, use of electroconvulsive therapy, past antipsychotic trials, and medications at discharge. Clozapine-related information collected included whether the drug was a new initiation or a continued home medication, reasons contributing to discontinuation, whether rechallenge was conducted with outcome, need for increased blood count monitoring frequency, maximum dose achieved, and discharge dose. The primary objective was to characterize the documented safety and clinical benefits of clozapine utilization.

Results

A total of 82 patients with a mean age of 14.7 ± 2.7 years, from eight sites within the United States and Australia, were included in this study. Contributing sites included the University of Minnesota (n = 23, 28%), Cleveland Clinic (n = 17, 20.7%), Mayo Clinic-Rochester (n = 8, 9.8%), Virginia Commonwealth Health System (n = 8, 9.8%), Rutgers (n = 8, 9.8%), Shodair Children's Hospital (n = 7, 8.5%), Cambridge Health Alliance (n = 6, 7.3%), and the Royal Children's Hospital (n = 5, 6.1%).

Patients were predominantly clozapine naive (76.8%), whereas 23.2% of patients in the cohort were already prescribed clozapine at a mean dose of 294.7 ± 184 mg upon admission. For the 82 patients, the indication for clozapine was largely for a primary psychotic disorder (61%) or bipolar disorder (25.6%). Demographic and clinical characteristics are presented in Table 1. The mean number of documented previously trialed antipsychotics before clozapine was 3.5 ± 1.4 (range 1–10). Seventeen patients had clozapine augmentation with another antipsychotic (i.e., not as a part of a documented cross-taper): aripiprazole (n = 1), aripiprazole and quetiapine (n = 1), chlorpromazine (n = 2), haloperidol (n = 2), haloperidol and quetiapine (n = 1), molindone (n = 1), olanzapine (n = 3), quetiapine (n = 5), and risperidone (n = 1). The use of concomitant nonantipsychotic psychotropic medications was prevalent upon discharge, which included the following: mood stabilizers (51.2%), sedative/hypnotics (15.9%), psychostimulants (4.9%), anticholinergics (22%), prazosin (2.4%), antidepressants (22%), and alpha-2 antagonists (15.9%). Eight (9.8%) patients had electroconvulsive therapy (ECT) previously, one patient had ECT during the hospitalization before clozapine initiation, and two (2.4%) had ECT concomitantly with clozapine (one patient had 12 bilateral treatments and another patient had 6 bilateral treatments).

Table 1.

Patient Characteristics (n = 82, Unless Indicated)

Characteristic	n (%), unless noted otherwise
Male	42 (51.2)
Mean age on admission, years	14 ± 2.7
Mean age of illness onset, years (n = 72 documented)	11 ± 4.3
White	46 (56.1)
Non-white	36 (43.9)
Median length of stay (IQR), days	19 (9–39.5)
Discharge diagnosis
Primary psychotic disorder	50 (61)
Bipolar disorder	21 (25.6)
Neurodevelopment disorder	7 (8.5)
Major depressive disorder	1 (1.2)
Other	3 (3.7)
Clozapine dose at discharge, mg (n = 78)	218.1 ± 142.2

IQR, interquartile range.

In terms of adverse events, three patients had clozapine temporarily held for mild-to-moderate neutropenia, of which one of these patients also had a seizure while taking the medication. A forth patient had clozapine held for what was documented as significant hypertension and headache. All four of these patients were rechallenged with clozapine successfully. There were four additional patients with a clozapine discontinuation without rechallenge due to severe neutropenia, ileus, significant psychomotor retardation, or need for diagnostic clarification. Forty-five (54.9%) patients experienced at least one documented adverse effect, with 17 (20.7%) patients having at least two adverse events. Sedation (26.8%) and sialorrhea (17.1%) were the most common side effects. Twelve (14.6%) patients required increased blood count collection frequency based on monitoring guidelines secondary to a substantial white blood cell (WBC) and absolute neutrophil count (ANC) (i.e., old guidelines during the study time period required increased monitoring with a WBC drop ≥3000/μL or ANC drop ≥1500/μL). More information related to adverse events is listed in Table 2.

Table 2.

Documented Clozapine-Related Adverse Events

Adverse event	n (%)
Sedation	22 (26.8)
Sialorrhea	14 (17.1)
Gastrointestinal hypomotility	10 (12.2)
Increased appetite/metabolic effects	9 (11)
Tachycardia	5 (6.1)
Abnormal movements/extrapyramidal symptoms	4 (4.9)
Hypotension/dizziness/orthostasis	3 (3.7)
Neutropenia	3 (3.7)
Headache	2 (2.4)
Hypertension	2 (2.4)
Seizure/abnormal electroencephalogram	2 (2.4)
Eosinophilia	1 (1.2)
Nocturnal enuresis	1 (1.2)
QTc prolongation	1 (1.2)

Metabolic monitoring in the form of a fasting lipid panel was conducted in only 57.3% of patients. Weight upon admission and discharge was also not documented in all patients. The mean admission weight documented (n = 75) was 73.3 ± 23.9 kg, and the mean discharge weight documented (n = 64) was 72.8 ± 21.4 kg. Pharmacological management of hypercholesterolemia, glucose intolerance/diabetes mellitus, and constipation occurred in 1.2%, 17.1%, and 43.9% of patients, respectively, as indicated by discharge medication lists. Three (3.7%) were smokers and 43 (52.4%) patients were specifically documented to be nonsmokers. Therapeutic drug monitoring of clozapine serum concentration was conducted in 17 (20.7%) patients.

While no formal clinical improvement scales were systematically utilized, documented clinical improvement of mental status due to clozapine was collected as follows: significant (31.7%), moderate (32.9%), minimal (12.2%), no improvement (2.4%), and not described/unknown (20.7%). For patients discharged on clozapine (n = 78), the mean daily dose was 218.1 + 142.2 mg.

Discussion

COS is not common but is associated with a worse prognosis compared with patients with adult-onset schizophrenia (Gogtay and Rapoport 2008). Thus, the importance of clozapine as an available treatment option needs to be recognized for treatment-resistant EOS and potentially other severe psychiatric illness such as bipolar disorder that was diagnosed in nearly one-quarter of patients in this cohort. A barrier to clozapine use in pediatric patients may be related to limited efficacy data from randomized controlled trials. Substantial side effect burden, laboratory monitoring, patient/caregiver acceptance, and lack of clinician comfort with clozapine are barriers that have been described in adult patients and likely also apply to pediatric patients (Kelly et al. 2017). Additionally, accurate psychiatric diagnosis at an early age may be challenging, and clinicians may have trepidation about starting clozapine when guidelines specifically state the need for diagnostic clarification before medication initiation (McClellan and Stock 2013). Yet when there is a preponderance of evidence favoring a treatment-resistant psychotic (or bipolar) spectrum illness over other possible diagnoses, treatment with clozapine should not be delayed.

While clozapine's efficacy has been supported in part by three small, prospective, randomized controlled trials, accumulation of safety data is crucial to better understand anticipated adverse events and whether these differ from those events expected with adults. This study is unique as there were a significant number of patients with a diagnosis of bipolar disorder at the time of discharge, and the inclusion of samples from multiple sites offers a “real-world” assessment of clozapine use in clinical practice. In this study, there was documented benefit from clozapine in 76.8% of this pediatric population. Despite the characterization of clinical benefit being reliant on chart documentation, the fact that clozapine was prescribed in all but four patients at the time of discharge is suggestive of benefit by the discharging provider. Additionally, there were no discontinuations due to a documented lack of clozapine effectiveness. This is in agreement with a study conducted by Kasoff et al. (2016). In this study, a patient cohort (n = 120) from involvement in studies and/or follow-up care at the Child Psychiatry Branch of the National Institutes of Health were contacted if they would have been taking clozapine for at least 2 years. The authors reported that of the 120 reachable patients, 72.5% were maintained on clozapine, a rate much greater than reported to be with adults (32%–57%) (Kasoff et al. 2016).

The rate of adverse event in this study was found to be significant. This is not surprising based on information from other retrospective studies. A previously published chart review evaluated pediatric patients who were exposed to clozapine to assess the risk for neutropenia (Maher et al. 2013). The authors reported significantly higher rates of neutropenia compared with adult populations; and these results are congruent with two other retrospective evaluations of hematological adverse events in clozapine-treated children and adolescents (Sporn et al. 2007; Maher et al. 2013). Another review reported the occurrence of neutropenia as 2.7%, closer to the findings in this study (Yalcin et al. 2016). Comforting is the fact that the incidence of agranulocytosis, however, does not appear to be greater than adults treated with clozapine and emphasizes the importance of following the required hematological monitoring (Gerbino-Rosen et al. 2005; Maher et al. 2013). It should be noted that the three patients who developed mild-to-moderate neutropenia were successfully rechallenged in this study.

The need for medications to treat glucose intolerance or diabetes mellitus was prevalent in this cohort, and future studies should focus on the appropriate management of metabolic effects of clozapine, including the effects on lipids and weight. Given the short time frame of this study, as data reflect inpatient stays only, no conclusion can be drawn related to the metabolic influence of clozapine, yet this study does suggest that the overall metabolic monitoring rate is suboptimal. We unfortunately did not assess in the 43.1% of patients, whether the use of stool softeners or laxatives was prophylaxis or for management of ongoing/developing constipation. However, the incidence of clozapine-induced constipation in adults is reported to be as high as 60% (Palmer et al. 2008). The recognition of constipation is important given the possibility of progression to a more life-threatening condition, such as ileus, bowel obstruction, or bowel perforation. The incidence of sialorrhea reported in this study was 17.1% but has been reported as high as 54.1% in children and adolescents (Yalcin et al. 2016). Early detection of sialorrhea is important not only to reduce possible embarrassment that can contribute to nonadherence but also to prevent aspiration pneumonia (Kaplan et al. 2017).

This is the first pediatric cohort to describe clozapine use for the management of bipolar disorder and is a practice supported by the adult literature (Li et al. 2015). However, this is not the first description of clozapine use in psychiatric illness other than schizophrenia. A retrospective study by Yalcin et al. (2016) found that clozapine was effective in reducing psychotic symptoms not only with treatment-resistant schizophrenia but also in other psychotic disorders with or without autism spectrum disorders, which provides support for using clozapine for nonschizophrenic disorders. Clozapine use has also been described in patients with conduct disorder (Teixeira et al. 2013).

In adult populations, a number of studies indicate that it is common to have a significant delay in clozapine initiation despite documented failure of two antipsychotic trials (Grover et al. 2015). For adults, delayed clozapine initiation is associated with antipsychotic polypharmacy and a reduced clozapine response once prescribed (Ucok et al. 2015). Similar trends have been reported in pediatric populations (Schneider et al. 2015). Although one study found a high rate (40.2%) of antipsychotic polypharmacy (i.e., clozapine plus another antipsychotic), the mean time from the first hospitalization for EOS until clozapine therapy was only 1.1 years on average following a mean of 2.3 prior antipsychotic trials (Trinczek et al. 2016). In the presently studied cohort, the average number of antipsychotic trials before clozapine was 3.5 but as late as the 10th. Clozapine-related antipsychotic polypharmacy was used to treat 20.7% of patients in our cohort. The use of numerous other psychotropic medications indicates the presence of comorbidities but could also represent diagnostic uncertainty.

Study limitations include reliance on clinical documentation accuracy and absence of rating scales to assess efficacy. In clinical practice, scales to assess medication response or adverse effects may not be commonly employed. However, clinical documentation in addition to high clozapine continuation rates at discharge could indicate an acceptable clinical benefit. Also, the number of patients included is an aggregate of eight clinical practice sites over a 12-year period. Some retrospective studies involving one center with similar time frames have 10 times the number of clozapine patients compared with any given individual site included in this study (Gerbino-Rosen et al. 2005). Based on this, the overall clozapine use in pediatric patients at the contributing sites was not common.

Conclusion

Our report suggests clinical benefit with clozapine in pediatric patients with schizophrenia and bipolar disorder but reinforces the need to monitor and mitigate adverse effects that occur frequently. While pediatric schizophrenia guidelines recommend clozapine initiation following two previously failed antipsychotic trials, our results indicate that patients had as many as 10 previous antipsychotic trials before clozapine initiation. Continued research is needed to assess the barriers of clozapine use in both adult and pediatric populations. Future studies should focus on long-term benefits of clozapine in pediatric patients and therapeutic options and monitoring to offset potential adverse events.

Clinical Significance

Clozapine is an effective medication for treatment-resistant mood and psychotic disorders in adults. Although limited, data from randomized placebo-controlled trials support the use of clozapine in pediatric populations. Previous studies have noted a high incidence of adverse events with clozapine that may dissuade clinicians from initiating this medication despite the support also from clinical guidelines. A delay of clozapine initiation was evident in our cohort of patients and should be recognized among clinicians.

Footnotes

Disclosures

All authors are without any corporate/commercial relationships that might pose a conflict of interest in relation to any stage of this project. This project was not supported by a pharmaceutical company or any other sources of financial acquisition. Data were analyzed by authors L.M.S. and J.G.L. and reviewed by the remaining authors. L.M.S. and J.G.L. were responsible for the manuscript writing with the remaining authors providing review and/or expert opinion content on the topic.

References

Clemmensen

, Vernal

, Steinhausen

: A systematic review of the long-term outcome of early onset schizophrenia. BMC Psychiatry, 12:150, 2012.

Frazier

, Cohen

, Jacobsen

, Grothe

, Flood

, Baldessarini

, Piscitelli

, Kim

, Rapoport

: Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia. J Clin Psychopharmacol, 23:87–91, 2003.

Gerbino-Rosen

, Roofeh

, Tompkins

, Feryo

, Nusser

, Kranzler

, Napolitano

, Frederickson

, Henderson

, Rhinewine

, Kumra

: Hematological adverse events in clozapine-treated children and adolescents. J Am Acad Child Adolesc Psychiatry, 44:1024–1031, 2005.

Gogtay

, Rapoport

: Clozapine use in children and adolescents. Expert Opin Pharmacother, 9:459–465, 2008.

Grover

, Hazari

, Chakrabarti

, Avasthi

: Delay in initiation of clozapine: A retrospective study from a tertiary care hospital in North India. Psychiatry Res, 226:181–185, 2015.

Kane

, Honigfeld

, Singer

, Meltzer

: Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry, 45:789–796, 1988.

Kaplan

, Schwartz

, Ward

: Clozapine-associated aspiration pneumonia: Case series and review of the literature. Psychosomatics, 59:199–203, 2017.

Kasoff

, Ahn

, Gochman

, Broadnax

, Rapoport

: Strong treatment response and high maintenance rates of clozapine in childhood-onset schizophrenia. J Child Adolesc Psychopharmacol, 26:428–435, 2016.

Kelly

, Freudenreich

, Sayer

, Love

: Addressing barriers to clozapine underutilization: A National Effort. Psychiatr Serv, 69:224–227, 2017.

10.

Kumra

, Frazier

, Jacobsen

, McKenna

, Gordon

, Lenane

, Hamburger

, Smith

, Albus

, Alaghband-Rad

, Rapoport

: Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry, 53:1090–1097, 1996.

11.

Kumra

, Kranzler

, Gerbino-Rosen

, Kester

, De Thomas

, Kafantaris

, Correll

, Kane

: Clozapine and “high-dose”. olanzapine in refractory early-onset schizophrenia: A 12-week randomized and double-blind comparison. Biol Psychiatry, 63:524–529, 2008.

12.

Lewis

, Barnes

, Davies

, Murray

, Dunn

, Hayhurst

, Markwick

, Lloyd

, Jones

: Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull, 32:715–723, 2006.

13.

, Tang

, Wang

, de Leon

: Clozapine for treatment-resistant bipolar disorder: A systematic review. Bipolar Disord, 17:235–247, 2015.

14.

Maher

, Tan

, Tossell

, Weisinger

, Gochman

, Miller

, Greenstein

, Overman

, Rapoport

, Gogtay

: Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia. J Child Adolesc Psychopharmacol, 23:110–116, 2013.

15.

McClellan

, Stock

: Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry, 52:976–990, 2013.

16.

Palmer

, McLean

, Ellis

, Harrison-Woolrych

: Life-threatening clozapine-induced gastrointestinal hypomotility: An analysis of 102 cases. J Clin Psychiatry, 69:759–768, 2008.

17.

Schneider

, Papachristou

, Wimberley

, Gasse

, Dima

, MacCabe

, Mortensen

, Frangou

: Clozapine use in childhood and adolescent schizophrenia: A nationwide population-based study. Eur Neuropsychopharmacol, 25:857–863, 2015.

18.

Shaw

, Sporn

, Gogtay

, Overman

, Greenstein

, Gochman

, Tossell

, Lenane

, Rapoport

: Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry, 63:721–730, 2006.

19.

Sporn

, Vermani

, Greenstein

, Bobb

, Spencer

, Clasen

, Tossell

, Stayer

, Gochman

, Lenane

, Rapoport

, Gogtay

: Clozapine treatment of childhood-onset schizophrenia: Evaluation of effectiveness, adverse effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry, 46:1349–1356, 2007.

20.

Teixeira

, Celeri

, Jacintho

, Dalgalarrondo

: Clozapine in severe conduct disorder. J Child Adolesc Psychopharmacol, 23:44–48, 2013.

21.

Trinczek

, Heinzel-Gutenbrunner

, Haberhausen

, Bachmann

: Time to initiation of clozapine treatment in children and adolescents with early-onset schizophrenia. Pharmacopsychiatry, 49:254–259, 2016.

22.

Ucok

, Cikrikcili

, Karabulut

, Salaj

, Ozturk

, Tabak

, Durak

: Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. Int Clin Psychopharmacol, 30:290–295, 2015.

23.

Yalcin

, Kaymak

, Erdogan

, Tanidir

, Karacetin

, Kilicoglu

, Mutlu

, Adaletli

, Gunes

, Bahali

, Ayik

, Uneri

: A retrospective investigation of clozapine treatment in autistic and nonautistic children and adolescents in an inpatient clinic in Turkey. J Child Adolesc Psychopharmacol, 26:815–821, 2016.