Hematological and Cardiometabolic Safety of Clozapine in the Treatment of Very Early Onset Schizophrenia: A Retrospective Chart Review

Abstract

Objective:

There are very few studies in the literature regarding clozapine use in children <13 years of age. In this retrospective chart review, we compared the safety of clozapine – as determined by hematological and cardiometabolic changes – to that of non-clozapine antipsychotics used in the treatment of childhood-onset schizophrenia (COS).

Methods:

The clozapine treatment group (CTG) consisted of 17 COS patients (mean age 10.4±2 years) who were hospitalized in a psychiatric ward between the years 2005 and 2012. The control group consisted of 19 COS patients (mean age 10.1±1.4 years) who were hospitalized in the same ward during the same time period, and were treated with non-clozapine antipsychotics. A retrospective chart review was conducted. Hematological (white blood cells, absolute neutrophil count [ANC], red blood cells, platelets), metabolic (aspartate transaminase, alanine transaminase, triglycerides, total cholesterol, bilirubin) and cardiac (heart rate) values were extracted from the medical charts.

Results:

The average follow-up periods for the CTG and the control group were 332.9±200.5 days and 291.7±157 days, respectively. In the CTG, moderate neutropenia (ANC<1500/mm³) and mild neutropenia (1500/mm³<ANC<2000/mm³) were observed in two children (12%) and one child (6%), respectively. The neutropenia was transient in all cases. Treatment with clozapine was permanently discontinued only in one child (6%). There were no cases of agranulocytosis or severe infection in the CTG. In the control group, two children (11%) showed hematological abnormalities. Hyperlipidemia was observed in one child (6%) in the CTG at release from the hospital. Significantly more children (47%) in the CTG had tachycardia (heart rate>100 beats per minute) at release from the hospital, compared with only one child (5%) in the control group (p=0.006).

Conclusions:

It appears that clozapine use in very early onset schizophrenia is safe. Although hematological adverse effects did occur in our study, the rates were not much higher than those seen in the control group. We found that the hematological abnormalities in the CTG were mostly transient, and that treatment with clozapine can be safely continued or renewed.

Introduction

C hildhood-onset schizophrenia (COS) is a relatively rare form of schizophrenia (Remschmidt et al. 1994), defined by onset of psychosis before the age of 12 years. The prevalence in the general population is <1:10,000 children. Following puberty (ages 13–18 years), the incidence rises significantly. COS is clinically characterized, in children as well as in adults, by the appearance of psychotic symptoms and impaired functioning in different fields of life. It is not uncommon that even prior to the onset of psychotic symptoms, children with COS have high rates of premorbid developmental abnormalities, which appear to be nonspecific markers of severe early impaired neurodevelopment (Hollis 1995; Nicolson and Rapoport 1999; Nicolson et al. 2000; Sporn et al. 2004).

Children with COS are often diagnosed with other psychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD), various anxiety disorders, affective disorders, and behavioral disorders (Ross et al. 2006). Nevertheless, one should keep in mind that the prodromal stage of schizophrenia can also mimic the abovementioned disorders. Therefore, after the onset of psychosis, some of those disorders may remit following clinical improvement in the psychotic symptoms; but some of them may still pose a problem, in which case additional pharmacological treatment beyond antipsychotics should be considered.

The diagnostic criteria in children are identical to those in adults. The American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) does not separate COS from adult-onset schizophrenia, and it seems that COS is continuous with the adult disorder (Asarnow et al. 1994; Nicolson and Rapoport 1999; American Psychiatric Association 2000). However, the clinical manifestation of the disorder in childhood can be different. Some children may not achieve expected levels of social and academic functioning in the first place, whereas others may develop normally and then experience a decline in functioning – similar to adolescents and adults. The onset of psychotic symptoms is usually insidious, and the diagnostic criteria appear gradually over months to years (Asarnow et al. 1994).

COS is probably a more malignant form of schizophrenia (Asarnow et al. 1994; Gogtay and Rapoport 2008), and current treatments are based on very limited data. Research shows that children do not respond as well as adolescents or adults to antipsychotics, and the prognosis is poorer (Remschmidt and Theisen 2005).

Atypical antipsychotics, which block serotonin and dopamine receptors in the brain, are currently first line treatment in children with COS. These drugs have replaced the typical antipsychotics because of their more tolerable profile of adverse effects.

Clozapine, the first atypical antipsychotic to be discovered, was a landmark in the treatment of schizophrenia, not only because of its efficacy in treating resistant schizophrenia, but also because of its low propensity to induce extrapyramidal adverse effects (Luft and Taylor 2006). Although many atypical antipsychotics were developed later, some of which have a better profile of adverse effects (i.e., risperidone, olanzapine), clozapine remains the most efficient treatment for therapy-resistant schizophrenia (Luft and Taylor 2006).

The exact mechanism of action of clozapine is not well understood. Blocking dopamine receptors is one of the main mechanisms in schizophrenia treatment models. The dopamine D2 receptor occupancy is crucial for the balance between efficacy and adverse effects. Clozapine showed a much lower D2 occupancy than risperidone and olanzapine (Kapur and Zipursky 1999). The fast dissociation of clozapine from the dopamine D2 receptors permits an antipsychotic effect without motor side effects, prolactin elevation, or secondary negative symptoms (Kapur and Seeman 2001).

Clozapine also has an antagonistic effect on serotonin 5-HT2A receptors. The combined D2 and 5-HT2A receptor antagonism modulates dopamine release in the prefrontal cortex, which seems to be related to improvement in both positive and negative symptoms of schizophrenia (Horacek et al. 2006).

The use of clozapine is well established in cases of treatment-resistant schizophrenia in adults (McEvoy et al. 2006). In the past few decades, its use has been extended to the pediatric population as well (Gogtay and Rapoport 2008). It seems that clozapine may be highly beneficial for severely ill treatment-refractory young patients with schizophrenia (Gogtay and Rapoport 2008). Studies that have been conducted, both open (Frazier et al. 1994; Mozes et al. 1994; Turetz et al. 1997) and double-blind (Kumra et al. 1996; Shaw et al. 2006; Kumra et al. 2008; Fraguas et al. 2010) have shown clozapine to be superior in treatment-resistant COS, compared with other antipsychotics. However, the use of clozapine in the pediatric population remains limited because of its potentially serious adverse effects. Studies conducted on animals (Teicher et al. 1993) and humans (Frazier et al. 2003) have shown that children might be more susceptible to adverse effects caused by antipsychotics, especially to the most worrisome adverse effects, leukopenia and agranulocytosis (Alvir et al. 1993; Kennedy et al. 2007). The risk of agranulocytosis is 0.8% over 1 year in adults, and the majority of cases occur within 3 months after the start of treatment (Alvir et al. 1993).

A retrospective review of 172 children treated with clozapine showed a 13% incidence of neutropenia, with 1 case showing agranulocytosis (Gerbino-Rosen et al. 2005). A recent study found a 20% occurrence rate of moderate neutropenia in children with COS. Younger age, African-American ethnicity, and male gender were found to be risk factors (Maher et al. 2013). Ethnic background can affect the hematological baseline values and the tendency to develop hematological adverse effects during clozapine treatment (Alvir et al. 1993; Munro et al. 1999).

Significant weight gain and dyslipidemia are common adverse effects during treatment with clozapine, and are often the cause for discontinuation of treatment. Other adverse effects include hypersalivation, constipation, incontinence, sedation, lowered seizure threshold, akathisia, insulin resistance, QT prolongation on electrocardiogram (ECG), tachycardia, and, rarely, endocarditis (Gogtay and Rapoport 2008).

It is challenging to research COS, because of its rarity. There are very few randomized controlled trials that examined the use of clozapine (or other antipsychotics) in children.

In Israel, according to the Ministry of Health, in order to use clozapine in children with treatment-resistant schizophrenia, two other antipsychotics must have failed. Once treatment with clozapine is initiated, a weekly complete blood count needs to be taken for 18 weeks.

The present retrospective chart review study assessed the safety of clozapine treatment in COS.

Methods

Subjects

The medical charts of 36 children, 32 boys and 4 girls, were reviewed. All children were hospitalized at the Department of Child Psychiatry at the Ness-Ziona Mental Health Center (Ness-Ziona, Israel) between the years 2005 and 2012. All children met the DSM-IV-TR criteria for COS. Diagnosis was established by two senior child psychiatrists experienced in this field.

The study population (clozapine treatment) consisted of 17 children with COS, 15 boys and 2 girls, 6–13 years old (mean age 10.4±2 years). All started treatment with clozapine for the first time during the hospitalization (average therapeutic dose 307.35±81.73 mg/day, range 137.5–425 mg/day).

As clozapine is at least a third line treatment in Israel, all children had been treated with other antipsychotics prior to treatment with clozapine (risperidone, n=17; olanzapine, n=15; quetiapine, n=5; perphenazine, n=5).

The control group consisted of 19 children with COS, 17 boys and 2 girls, 7.5–13 years of age (mean age 10.1±1.4 years) who were treated with antipsychotics other than clozapine (risperidone, n=18; olanzapine, n=11; quetiapine, n=5; perphenazine, n=5).

In order to avoid the impact of ethnicity on hematological indices, patients of African origin were not included in this study.

The two groups were comparable in all baseline demographic data.

Comorbid medical conditions

In the clozapine treatment group (CTG), one child had ichthyosis and one child had glucose-6-phosphate dehydrogenase (G6PD) deficiency. In the control group, one child had atopic dermatitis, two children had asthma, and three children had epilepsy.

Assessment of hematological and biochemical adverse effects

A retrospective chart review was undertaken. All of the children received clozapine for the first time, and underwent weekly assessments of white blood cell counts (WBCs) and absolute neutrophil count (ANC) during the first 18 weeks of treatment. Red blood cell counts (RBCs) and platelet counts (PLT) were assessed prior to treatment initiation, during treatment, and prior to release from the hospital. Two of the children in the CTG were released from the hospital on week 14 of treatment. Follow-up was continued in regional outpatient clinics, and we could not trace data after their release.

Aspartate transaminase (AST), alanine transaminase (ALT), triglycerides, total cholesterol, bilirubin, and glucose were assessed prior to treatment initiation, during treatment, and prior to release from the hospital. Heart rate was measured prior to treatment, every day during treatment, and prior to release from the hospital.

Data analyses

Data were analyzed by Student's t test or Fisher's exact test, as appropriate. All results were expressed either as mean±SD, or as rates (%). The threshold for statistical significance was set at p<0.05 (two tailed).

Ethics

This study was approved by the Institutional Review Board of the Ness-Ziona Mental Health Center.

Results

The demographic and clinical characteristics are shown in Table 1.

Table 1.

Demographic and Clinical Characteristics of the Clozapine Treatment Group (n=17) and the Control Group (n=19)

	Clozapine n (%)	Control n (%)
Gender
Male	15 (88)	17 (89)
Female	2 (12)	2 (11)
Family history
Relatives with schizophrenia	6 (35)	9 (47)
Relatives with non-psychotic disorders	8 (47)	7 (37)
Premorbid developmental factors
Complicated pregnancy	8 (47)	5 (26)
Preterm birth	5 (29)	2 (11)
Difficult temperament	10 (59)	7 (37)
Delayed motor development	10 (59)^*	4 (21)
Delayed speech development	13 (76)	11 (58)
Intellectual disabilities	10 (59)^**	2 (11)
Attendance of special education programs	16 (94)^***	11 (58)
Psychiatric comorbidities
Obsessive-compulsive disorder	4 (24)	1 (5)
Attention-deficit/hyperactivity disorder	10 (59)	13 (68)
Oppositional defiant disorder	1 (6)	3 (16)
Anxiety NOS	2 (12)	4 (21)
Pervasive developmental disorder	4 (24)	2 (11)

p=0.038 versus control group, Fisher's exact test.

p=0.003 versus control group, Fisher's exact test.

***

p=0.019 versus control group, Fisher's exact test.

NOS, Not otherwise specified.

Family history of psychiatric conditions

In the CTG, six children (35%) had relatives (first and second degree) with schizophrenia, and eight (47%) had relatives with non-psychotic disorders (ADHD, n=3; obsessive-compulsive disorder [OCD], n=2; major depression, n=3; anxiety disorders, n=4; anorexia, n=1; bipolar disorder, n=1). In the control group, nine children (47%) had relatives with schizophrenia, and seven (37%) had relatives with non-psychotic disorders (ADHD, n=2; major depression, n=2; anxiety disorders, n=3; posttraumatic stress disorder [PTSD], n=1; drug abuse, n=1). Two children in the control group were adopted, and no data regarding their family medical history were available.

Premorbid developmental factors

In the CTG, 8 children (47%) were born following complicated pregnancy, 5 (29%) were born preterm, 10 (59%) were described (according to the medical history reviewed) as having a difficult temperament, 10 (59%) had delayed motor development, 13 (76%) had delayed speech development, 10 (59%) had intellectual disabilities (borderline mental functioning, n=8; mild mental retardation, n=2), and 16 (94%) attended special education programs.

In the control group, 5 children (26%) were born following complicated pregnancy, 2 (11%) were born preterm, 7 (37%) were described as having a difficult temperament, 4 (21%) had delayed motor development, 11 (58%) had delayed speech development, only 2 (11%) had borderline mental functioning, and 11 (58%) attended special education programs.

Statistically significant difference was found in the rates of delayed motor development (50% in the CTG, 21% in the control group, p=0.038), intellectual disabilities (59% in the CTG, 11% in the control group, p=0.003), and attendance of special education programs (94% in the CTG, 58% in the control group, p=0.019).

Psychiatric comorbidities

In the CTG, 4 children (24%) met the DSM-IV-TR diagnostic criteria for OCD, 10 (59%) met criteria for ADHD, 2 (12%) met criteria for anxiety disorders not otherwise specified (NOS), 1 (6%) met criteria for oppositional defiant disorder (ODD), and 4 (24%) met criteria for pervasive developmental disorder (PDD).

In the control group, 1 child (5%) met the DSM-IV-TR diagnostic criteria for OCD, 13 (68%) met criteria for ADHD, 4 (21%) met criteria for anxiety disorder NOS, 3 (16%) mt criteria for ODD, and 2 (11%) met criteria for PDD.

No significant statistical difference in the rates of psychiatric comorbidities was found between the two groups.

Duration of hospitalization

In the CTG, the average duration of time between initiation of clozapine treatment to release from the hospital was 332.9±200.5 days, range 100–803 days. In the control group, the average duration of hospitalization was 291.7±157 days, range 44–680 days. No significant difference was detected between the two groups (t=0.66, df=34).

Safety

Hematological effects

In the CTG, three children (18%) developed hematological adverse effects. One child (6%) developed moderate neutropenia (defined as ANC<1500/mm³; ANC=1200/mm³) on week 16 of treatment, and clozapine was discontinued in that child because of the neutropenia. Treatment was not renewed, because that child also had severe gastrointestinal adverse effects (see more details in Other effects). One child (6%) had transient mild neutropenia (defined as ANC<2000/mm³) in week 4 (ANC=1900/mm³) and in week 10 (ANC=1700/mm³) of treatment. Clozapine was not discontinued and the ANC returned to normal. Another child (6%) developed mild leukopenia (defined as WBC<3500/mm³; WBC=3400/mm³) and moderate neutropenia (ANC=1400/mm³) in week 10 of treatment, possibly because of a viral infection. In this case, treatment with clozapine was discontinued, and was renewed 1 week later when the child recovered from the presumed viral infection. There was no recurrence of the neutropenia later in the treatment. There were no cases of agranulocytosis or severe infection in the CTG. None of the children in the CTG were treated with carbamazepine.

In the control group, two children (11%) showed hematological abnormalities at release from the hospital (ANC=1700/mm³ in both children). Of these two children, one child was released from the hospital after 506 days, and the other after 102 days. One child in the control group had moderate neutropenia (ANC=900/mm³) on admission, which did not normalize during his hospitalization and probably represents a baseline value in this specific child. Two children in the control group were treated with carbamazepine for epilepsy. None of these children met the criteria for leukopenia or neutropenia. None of the children in the control group developed severe infectious illness.

None of the children in our sample were treated with lithium.

RBC count and PLT values were all within the normal range prior to treatment, during treatment, and prior to release from the hospital in both groups.

In summary, the rate of hematological abnormalities related to treatment was 3 out of 17 (18%) in the CTG, and 2 out of 19 (11%) in the control group.

Biochemical effects

As shown in Table 2, the rate of elevated ALT (normal range: 8–36 IU/L) values in the CTG was 18% on admission, remained the same during treatment, and was decreased to 12% on release from the hospital. Similar results were observed in the control group.

Table 2.

The Rates of Abnormal Biochemical and Heart Rate Values in the Clozapine Treatment Group (n=17) and in the Control Group (n=19)

	Admission		During hospitalization		Release
	Clozapine n (%)	Control n (%)	Clozapine n (%)	Control n (%)	Clozapine n (%)	Control n (%)
Elevated AST	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)	0 (0)
Elevated ALT	3 (18)	4 (21)	3 (18)	1 (5)	2 (12)	2 (11)
Elevated triglycerides	0 (0)	0 (0)	1 (6)	0 (0)	0 (0)	0 (0)
Elevated total cholesterol	1 (6)	0 (0)	0 (0)	0 (0)	1 (6)	0 (0)
Elevated bilirubin	0 (0)	0 (0)	1 (6)	0 (0)	0 (0)	0 (0)
Tachycardia^a	5 (29)	5 (26)	9 (53)	4 (21)	8 (47)^*	1 (5)

Tachycardia defined as heart rate>100 beats per minute.

p=0.006 versus control group, Fisher's exact test.

AST, aspartate transaminase; ALT, alanine transaminase.

The rates of children with elevated AST (normal range: 15–46 IU/L), triglycerides (normal values <200 mg/dL), total cholesterol (normal values <230 mg/dL), and bilirubin (normal values <1.5 mg.dL) values were low (up to 6%), and remained unaltered in both groups.

None of the children in the entire study population had high fasting blood glucose levels (normal values <100 mg/dL).

Cardiac effects

As shown in Table 2, the rate of children with tachycardia (defined as heart rate >100 beats per minute) was similar in the CTG and in the control group on admission. During treatment, there were more cases with tachycardia in the CTG, but the difference from the control group was not significant. At release, there were significantly more children with tachycardia in the CTG compared with the control group, with 47% and 5% respectively (Fisher's exact test, p=0.006).

ECG was normal in both the CTG and the control group during the entire follow-up period.

Other effects

One child in the CTG developed an epileptic seizure in week 10 of treatment. He started treatment with valproic acid up to a dose of 750 mg/day, and continued treatment with clozapine. There was no recurrence of seizures.

As stated before, one child in the CTG suffered from severe gastrointestinal adverse effects, including nausea, vomiting, and stomachache. Clozapine was discontinued in this child because of neutropenia, and was not renewed.

Discussion

In our study, we reviewed the medical charts of 36 children with COS. We found a large number of relatives with psychopathologies in the entire study population (both the CTG and the control group), including both psychotic and non-psychotic spectrum disorders. This finding supports the hypothesis that early-onset schizophrenia is associated with a greater genetic predisposition (Kumra and Schulz 2008). When comparing the children in the CTG with the children in the control group, there was no significant difference in the rates of psychiatric family history, abnormal pregnancy, and preterm births.

Our data are consistent with a previous study that demonstrated a significantly higher risk of premorbid social, motor, and language impairments in COS children than in children with non-psychotic psychiatric disorders (Hollis 1995). It is of note that significantly more CTG children had a history of delayed motor development and intellectual disabilities, and needed special education programs (Table 1). Therefore, it seems that these developmental problems are risk factors for antipsychotic-resistant COS that eventually requires clozapine intervention.

The rate of children in the CTG who attended special education programs (94%) was much higher than that found by Nicolson et al. in 2000 (30%). The discrepancy between the two studies may be related to differences in the criteria for referral to special education programs.

Clozapine treatment appeared to be relatively safe in children in this age group (6–13 years). Although 18% of the children in the CTG showed hematological adverse effects, the nature of these abnormalities was mostly transient. Of the three children who developed hematological adverse effects in the CTG, two children (12%) developed transient neutropenia which was later normalized. In only one child (6%), treatment with clozapine was permanently discontinued. The control group showed a slightly lower rate of hematological abnormalities (11%).

Our findings are similar to those reported recently by Maher et al. (2013), who found a 20% rate of moderate neutropenia during clozapine treatment in COS children. Similar to our study, in the latter study there were no cases of agranulocytosis or serious infection during clozapine treatment.

It appears in our 18 week study that hematological abnormalities are expected to occur in the time range of 4–16 weeks after the initiation of clozapine treatment.

Similar to adults (Casey 2004), there were very few cases (6%) with elevated triglycerides or total cholesterol blood levels following treatment in the entire study population (Table 2).

A previous prospective 12 week study found body composition to be affected significantly, relative to metabolic parameters. Unfortunately, in our study we do not have sufficient data regarding changes in body weight, fat mass, waist circumference and BMI Z scores. Although body composition may not have an effect in the immediate term, it is an important factor when considering the harm these medications can cause in the long run (Correll et al. 2009).

As expected, we found a higher rate of tachycardia in the CTG at release from the hospital, than in the control group; however, this is a well known adverse effect of clozapine (Safferman et al. 1991) and is easily and routinely treated with beta blockers. It is of note that the rate of tachycardia that we found in our study (12%) was lower than that described by Safferman et al. in an adult population (25%).

The major weaknesses of this study are the relatively small size of the study population, and the open-label and retrospective nature of the study. Despite those weaknesses, the strength of this study is in the inclusion of a comparative group of COS children treated with non-clozapine antipsychotics, the very young age of the study population, and the long follow-up (range 44–803 days).

Conclusions

In conclusion, it seems that clozapine treatment in young children (in our sample, age range 6–13 years) is relatively safe. We think that child psychiatrists should not avoid the use of clozapine in very early onset schizophrenia patients resistant to antipsychotics.

Clinical Significance

In the treatment of COS, clozapine is the medication of last resort. Although proven to be superior to other antipsychotics, its potentially serious adverse effects deter many child psychiatrists from prescribing it.

When treatment with clozapine is initiated, hematological monitoring is required during the first 18 weeks of treatment, because of the potential risk of neutropenia and agranulocytosis.

In our study, we did not see any cases of agranulocytosis, and all the cases of neutropenia in the CTG were transient during hospitalization. However, our sample size was very small; as the risk of agranulocytosis is 0.8% over 1 year in adults, assuming children share the same risk, the chance of encountering a case in the small group of our study was very low. That being said, in severe treatment-resistant COS, we do recommend the use of clozapine with weekly hematological follow-up.

Our study enhances the notion, which becomes more evident in recent years, that clozapine can be safely used in children.

Footnotes

Disclosures

No competing financial interests exist.

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