Clozapine in Severe Conduct Disorder

Abstract

Method: An open, naturalistic observational study design was used, in which a sample of seven boys between 10 and 14 years of age was assessed over 26 weeks. Results: The subjects were all diagnosed with conduct disorder (CD) and exhibited high levels of aggression that were refractory to psychosocial approaches (parent counseling, school counseling, and psychotherapy) and to more than three pharmacological treatments. Levels of aggression, side effects, and hematological parameters were evaluated weekly. Clinical response was evaluated using the standardized instruments Clinical Global Impressions (CGI) and Child Behavior Check List (CBCL) 6–18 before starting medication and after 26 weeks. Conclusion: We observed good tolerability of clozapine in doses from 100 to 600 mg/day with no significant side effects or hematological changes. The CGI and CBCL 6–18 scales indicated that clozapine led to a marked control of symptoms.

Introduction

T he disruptive behavior disorders, which include conduct disorder (CD), oppositional defiant disorder (ODD), and attention-deficit/hyperactivity disorder (ADHD), are the most common sources of referral to psychiatric services for children and adolescents (Garland et al. 2001). Severe cases may lead to serious personality disorders, mental disorders, and delinquency in adulthood (Mordre et al. 2011), deeply affecting personal and family life. Behavioral and socio-educational interventions are of central importance in most cases, but the availability and efficacy of such approaches, particularly in severe cases, remain limited (Steiner 1997). In order to control severe aggression in this heterogeneous diagnostic group, several studies were performed using lithium, first and second generation antipsychotics (Findling et al. 2007), and other agents (Ad-Dab'bagh et al. 2000). Although these drugs produced positive results, their impact was, in general, limited.

Clozapine, a second-generation antipsychotic drug (SGA), has been used in clinical trials for the management of aggression in patients with schizophrenia, bipolar disorder, and autism, among other diagnostic groups, with promising results (Kraus and Sheitman 2005). Despite the reported efficacy of clozapine for adult refractory patients and its relative tolerability and safety for children and adolescents (Sporn et al. 2007), the clinical use of this substance has nonetheless been limited in children and adolescents with severe and refractory forms of psychosis, mania, and other similar conditions (Kranzler et al. 2005; Sporn et al. 2007). To our knowledge, there are no reported uses of clozapine for treatment of CD.

Objective

The aim of this study was to evaluate whether clozapine was a safe, tolerable, and effective method for controlling levels of aggressive behavior in children and adolescents with severe forms of CD.

Methods

Design

This was an open naturalistic study in which a small sample was assessed during the regular course of psychiatric treatment. Subjects invited to participate were found at an outpatient clinic for children and adolescents (General Hospital, State University of Campinas/UNICAMP, Brazil). They had been diagnosed with CD coupled with a high level of aggression, were refractory to other treatments, and had been prescribed clozapine by the regular staff of psychiatrists. These were all serious cases that were referred to the university hospital after several unsuccessful attempts at treatment, involving patients who had faced various disciplinary and legal issues. The diagnosis of CD was made by two experienced psychiatrists using the American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) (American Psychiatric Association 1994), and the presence of significant conduct problems confirmed by the Child Behavior Check List (CBCL) 6–18 (Achenbach 2004).

Data were collected from the subjects themselves, from their parents or legal guardians, from physicians, and from their medical records. This study was developed with the approval of the Ethics Committee (CEP-FCM no. 728/2007) of the State University of Campinas. Informed consent was obtained from all participants and from their legal guardians. In Brazil, the age of majority is 18 years.

The subjects were evaluated using the standardized instruments Clinical Global Impressions (CGI) (Guy Weigold 1976) and CBCL 6–18 (Achenbach 2004) before starting medication and after 26 weeks. All interviews with the subjects were conducted by the first author of this article (Dr. Teixeira) after an initial period of training. For the CGI scale, it was determined that 1 or 2 was a positive response; for the CBCL scale, a score>70 was considered clinical, a score between 65 and 70 was considered subclinical, and a score<65 was considered normal.

Subjects

All comorbidity, earlier treatments, concomitant uses of medications, and side effects were recorded (Table 1). All subjects had a history of failed treatment with at least three antipsychotics of different chemical classes in clinically appropriate doses. The three boys with ADHD comorbidity had used methylphenidate in the past without response. Therapeutic response was evaluated based on accounts given by parents/guardians, reports and clinical observations of the subjects, written reports of teachers and school staff, and recorded decreases in the need for restraints, injectable medication, or hospitalization.

Table 1.

Medications Used Before and with Clozapine

Cases (age)	Diagnosis	Clozapine (average dose) mg/day	Medications used before clozapine	Medications used together with clozapine	Main side effect
10	CD+ADHD	600	Hal, Ris, Olz, Cbz, Meth, Lit, Parox	Hal, Clon, Cit, Imip	Sedation+weight gain
10	CD+ADHD	400	Hal, Queti, Olz, Cbz, Lit	Hal, Queti, Lit	Sedation+weight gain
11	CD+LD	150	Ris, Meth, Flu, Imip	Imip	Sedation
11	CD	100	Hal, Ris, Clon	Hal, Clon	None
12	CD+MR	150	Hal, Ris, Cbz, Meth, Lit, Diaz, Imip, Parox	Cbz	None
14	CD+ADHD	500	Ris, Thio, Meth, Lit, Clon	Clozapine only	Sedation
14	CD	450	Hal, Ris, Meth	Clozapine only	Sedation

CD, conduct disorder; MR, mental retardation; LD, learning disorder; ADHD, attention-deficit/hyperactivity disorder; Hal, haloperidol; Ris, risperidone; Olz, olanzapine; Queti, quetiapine; Thio, thioridazine; Cbz, carbamazepine; Meth, methylphenidate; Clon, clonidine; Lit, lithium; Imip, imipramine; Parox, paroxetine; Flu, fluoxetine; Sertr, sertraline; Cit, citalopran.

Seven boys, ages 10–14, diagnosed as having CD, who exhibited high level aggression and who were refractory to more than three pharmacological treatments and to psychosocial approaches (parent counseling, school counseling, and psychotherapy), were included. The selected subjects were outpatients from the Psychiatric Services for Children and Adolescents and were being treated to control high levels of aggression. Because of the lack of response, or minimal response, to first-line drugs in controlling their aggression and because of an elevated level of aggression, clozapine was considered as an alternative. The initial dose of clozapine was 25 mg/day, which was increased by 25 mg every other day. At the time the medical staff decided to start this medication, the subject and parents/legal guardians were asked to participate in this survey. Participation was contingent upon agreement by parents or legal guardians.

All subjects attended regular schools and lived at home. All were diagnosed as having a severe or very severe form of CD (CGI-S >6) and had shown no improvement in response to previous treatment (CGI-I=4). Regarding intellectual functioning, one patient had mild mental retardation (Wechsler Intelligence Scale for Children [WISC]=65) and another had a learning disorder without mental retardation. Of the other five patients, only three completed the tests, and their results were average. In none of the cases were there reports of substance abuse (neither from family, school, or health staff). Three had a history of psychiatric hospitalization and two had received court orders for treatment. Clozapine was given to control their aggression after all other therapeutic possibilities had failed, and in light of the serious psychosocial losses that were occurring in the absence of effective therapy.

The following is a summary of a case (case 6), offered as an example:

A boy, 14 years old, raised by his mother and stepfather, and who has never lived with his biological father, already had behavioral problems at the age of 3 years. He would set things on fire and needed to be closely monitored because he would not take direction. At school age, he manifested significant agitation and aggression toward teachers and classmates. He was frequently involved in fights at school and threatened peers. It was common for him to attack classmates with punches and kicks for no reason and without regard to the size or age of the other student. People avoided contact with him and requested that he be taken out of school. At 9 years of age, he ended up at a police station after physically attacking a teacher with punches and kicks. It was unclear why this attack happened. The teacher was not seriously hurt, despite the severity of the aggression. After this event and after the failure of treatments performed in primary healthcare settings, the patient was referred for treatment by the children's protection agency to the outpatient clinic for children and adolescents (UNICAMP) where this research was conducted. He was diagnosed with severe CD, ADHD, and mild mental retardation. Initially, various medications were prescribed, including methylphenidate, risperidone, clonidine, thioridazine, and lithium, in effective doses, associations and for satisfactory periods. The decision to start clozapine was because of the failure of previous treatment, as well as the type of impulsive aggression and the serious problems the patient was having in school. He had to be constantly monitored and showed progressive deterioration. With clozapine, he experienced a significant decrease in aggression and improved his academic performance and social and family relationships. His family reported never having seen such improvement with any other previous treatment.

Results

Health status and medication safety

Good tolerability of clozapine in doses from 100 to 600 mg/day with no serious side effects or hematological changes was observed.

The most commonly observed side effect was somnolence, followed by weight gain (Table 2), and hypersalivation. These side effects did not prevent continued treatment, despite having shown little improvement over the survey period. Based on regular and comprehensive evaluations by psychiatric staff, patients were treated with additional therapies as necessary. Somnolence and hypersalivation were managed through dose modification or time of administration. Patients with increased appetite and weight gain were referred to dieticians, and a satisfactory dietary management plan was implemented, as necessary, for each patient. All patients were regularly assessed for metabolic changes, and no clinically relevant changes were observed. Only in two cases was the weight gain >20%, and these patients received intensive nutritional treatment.

Table 2.

Parameters of Hematological Laboratory Tests During Treatment and Weight Before and After Treatment (6 Months)

	Leukocytes mean (mini/max)	Neutrophil mean (mini/max)	Plateletmean (mini/max)	Weight mean (mini/max)
Case 1	6.92	2.80	2.60	W₀=60
	(4.98/10.48)	(2.21–3.50)	(2.35–2.90)	W_f=83
Case 2	6.95	4.51	2.67	W₀=49
	(5.40/7.83)	(3.80/5.28)	(2.47/2.80)	W_f=59
Case 3	7.39	2.20	3.45	W₀=55
	(5.00/12.38)	(1.90/2.67)	(2.55/4.17)	W_f=58
Case 4	7.32	3.11	3.78	W₀=42
	(5.26/9.80)	(2.21/4.06)	(3.48/3.98)	W_f=43
Case 5	7.14	3.58	3.26	W₀=49
	(5.51/9.22)	(2.44/4.71)	(2.79/3.93)	W_f=54
Case 6	7.09	3.20	2.05	W₀=59
	(5.80/8.59)	(2.54/4.18)	(1.91/2.18)	W_f=60
Case 7	10.05	6.58	3.07	W₀=67
	(7.71/12.38)	(4.56/8.66)	(2.65/3.87)	W_f=73

Leukocytes (x10³ cell/mm³); Neutrophil (x10³ cell/mm³); Platelet (x10⁶ cell/mm³).

W_0, zero weight; W_f, final weight.

Hematological values and changes were, in all cases, within the normal range (Table 2). A reduction in total leukocytes and neutrophils was observed, which ranged from 10 to 30%, especially in the first 3 months, but these changes were within the safety limits established for this medication. In no case was it necessary to discontinue the medication. Moreover, the need for regular, thorough hematologic evaluation was not a limiting factor. All patients accepted the need to collect their blood every week.

Effectiveness

Considering the reports and perceptions of the patients and parents/guardians, the overall results were positive, with only one exception. A progressive decrease in the number of episodes of physical aggression was reported, as well as a significant impact on subjective quality of life of both the patients and their families. Verbal aggression remained present but of lesser intensity. Although antisocial behaviors remained present (lying, stealing, treating pets and people with cruelty), their intensity progressively lessened. The families reported improvement in social interactions (with friends, siblings, and parents) and resumption of educational activities.

In most of the cases, the other drugs used concurrently with clozapine were withdrawn. For six of the seven cases, the other treatments were reduced, and in two cases, clozapine was the only treatment used. In only one case the drugs used along with clozapine were withdrawn (risperidone, olanzapine, carbamazepine, methylphenidate, lithium, and paroxetine) and other drugs were included (clonidine, citalopram, and imipramine).

In six of the seven subjects, both the CGI and CBCL 6–18 scales (Table 3) indicated that clozapine led to a significant control of symptoms for the whole group. Significant statistical values were found (Table 4) for reduction in the subscales “aggression,” “rule-breaking,” and “conduct problems” in the CBCL scale. In one subject, no improvement was observed. There were no instances of hospitalization or physical restraint resulting from aggression for any subject, after the introduction of clozapine.

Table 3.

Scale Scores Before and After Clozapine Treatment

			CBCL 6–18 Aggression (50–100)		CBCL 6–18 Social problems (50–100)		CBCL 6–18 Rule-breaking (50–100)
Subjects age (all boys)	CGI-S (1–7)	CGI-I (1–7)	Before	After	Before	After	Before	After
10	6	1	92	73	78	70	74	71
10	7	4	92	92	69	70	72	72
11	6	2	86	76	65	62	83	72
11	7	1	76	62	57	56	77	64
12	6	2	81	76	75	77	80	66
14	7	2	83	79	70	69	68	64
14	6	2	91	81	75	70	76	76

CGI-S, Clinical Global Impressions – Severity (1-normal; 2-borderline; 3-mildly ill; 4-moderately ill; 5-strongly ill; 6-seriously ill; 7-extemely ill); CGI-I, Clinical Global Impressions – Improvement (1-greatly improved; 2-much improved; 3-improved a little; 4-no improvement; 5-worsened a little; 6-much worse; 7-extremely deteriorated); CBCL 6–18, Child Behavior Checklist (50–65: normal; 65–75: borderline clinical range; >70: clinical range).

Table 4.

CBCL and CGI-I Scale Scores Before and After Clozapine Treatment

CBCL variable	Before clozapine	After clozapine	p^*
Aggression	85.9±6.2	77.0±9.0	0.027^**
	median 86 (76–92)	median 76 (62–92)
Rule-breaking	75.7±5.0	69.3±4.6	0.043^**
	median 76 (68–83)	median 71 (64–76)
Social problems	70.0±6.9	67.7±6.75	0.127
	median 70 (58–78)	median 70 (56–77)
Oppositional Defiant problems	72.9±6.7	68.7±7.43	0.078
	median 77 (62–80)	median 70 (55–80)
Conduct problems	84.7±6.5	73.1±6.4	0.028^**
	median 86 (73–93)	median 72 (67–82)
CGI-I	4.0±0.	2.14±0.9	0.020^**
	median 4	median 2 (1–4)

Wilcoxon nonparametric test.

p<0.05, significant.

CGI-I, Clinical Global Impressions – Improvement; CBCL, Child Behavior Checklist.

Discussion

The use of clozapine has not yet been authorized in Brazil for children and adolescents, and parents/guardians were informed of this by the physicians responsible for treatment. In the present study, this off-label use may have been justified, as these seven boys had severe conditions and no other efficacious interventions were available (Pappadopulos et al. 2003).

The small number of subjects was a limiting factor of this study, and consequently it was not possible to evaluate the full impact of comorbidity on the results. However, a careful analysis of the results allowed us to observe significant changes in the level of aggression in six of the seven subjects. This change was assessed using the CBCL and CGI scales and was corroborated by reports from family members. The impact of treatment was evident from reports by family members of resumption of educational activities and of improved social interactions. Moreover, these changes allowed subjects to receive additional psychological or educational help appropriate to their age range (Steiner 1997). The reduction in need for hospitalization or physical restraint was also an important parameter used in evaluating improvement in aggression. This is important, considering that these interventions are demoralizing for the patient and family (Kranzler et al. 2005).

The diagnosis of the one subject who exhibited no improvement in aggression was called into question during the survey period, as he presented major behavioral disorganization. Subsequently, his diagnosis was changed to childhood-onset schizophrenia. Although clozapine is an effective antipsychotic, his disorganized behavior remained unchanged, and he maintained a high degree of aggression.

Side effects were present, but could be managed and were tolerable. Considering the benefits of clozapine and the fact that side effects are also common with other antipsychotic drugs, it is plausible that a risk–benefit case assessment will favor clozapine (Pappadopulos et al. 2003; Sporn et al. 2007). Regarding other drugs used with clozapine, the overall tendency was clearly to reduce other treatments. In this sense, it is highly unlikely that the improvement observed in six of the seven cases was the result of other drugs.

The cooperation by the patient and family in coming in for weekly examinations appears to have been a factor in treatment adherence; however, treatment would have been terminated had the medication not resulted in a positive response after ∼12 weeks.

The improvement in patterns of aggression in six of seven patients with severe CD reinforces previous studies that evaluated clozapine as a treatment for children and adolescents with aggressive behavior from schizophrenia (Kranzler et al. 2005), mental retardation (Cohen and Underwood 1994), and autism (Zuddas et al. 1996; Chen et al. 2001). This suggests that clozapine may be a useful medication for reducing aggression in general, and should not necessarily be limited to specific diagnostic groups.

Conclusions

We suggest that clozapine may be useful for decreasing high levels of aggression in different diagnostic groups in children and adolescents. It may represent an additional and important tool for controlling symptoms in severe cases of CD, a condition that urgently demands available and effective treatment options. Controlled studies with larger samples must be conducted in order to fully assess the tolerability, safety, and efficacy reported in this open and small sample survey.

Clinical Significance

In severe cases of CD in which aggression is difficult to manage, clozapine may be a safe and efficient treatment option.

Footnotes

Disclosures

Drs. Teixeira, Celeri, Jacintho, and Dalgalarrondo disclosed no conflicts of interest or financial ties.

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