JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 4, Number 1, 1994Mary Ann Liebert, Inc., PublishersPp. 53-62

Absence Status Seizures During Successful Long-TermClozapine Treatment of an Adolescent with Schizophrenia

JOSHUA E. FREEDMAN, M.D.,1'2 WILLIAM C. WIRSHING, M.D.,1'2ANDREW T. RUSSELL, M.D.,' MICHELE PALMER BRAY, B.S.,3 and

JERGEN UNUTZER, M.D.4

ABSTRACT

This article reports the appearance of complex partial seizures during the course of successfuluse of the atypical neuroleptic clozapine in a 15 year old with neuroleptic-resistant schizophre-nia. After 7 months of clozapine treatment, and 1 week after a gradual increase in dose to 550mg, the adolescent began to develop periods of nausea and a "spacey feeling" that lasted forseveral minutes to hours at a time. A diagnosis of absence status was confirmed byelectroencephalography (EEG). It was treated effectively by dose reduction (to 400 mg daily)without the use of anticonvulsant medications. A 3-year follow-up showed the generallysustained efficacy of this treatment, without recurrence of absence status seizures. Thisappears to be the first report of an absence seizure apparently associated with clozapinetreatment. Published reports on 80 adolescents suggest an estimated prevalence of clozapine-induced seizures at about 4% (compared to 1-5% in adults, depending on dose), whereas 60%developed mild to marked EEG abnormalities. The current data on the safety and efficacy ofclozapine for treating adolescents with schizophrenia remain preliminary. These data supportthe clinical recommendation that an EEG be obtained before adolescents are started on

treatment with clozapine.

DESPITE RELATIVELY EXTENSIVE DESCRIPTIVE AND PHENOMENOLOGICAL RESEARCH focusing Oil autismand pervasive developmental disorder, few carefully designed studies have focused exclusively on

schizophrenia that initially is diagnosed during adolescence or childhood. Childhood-onset schizophre-nia is a rare disease, with an estimated prevalence of identified cases of less than 14/100,000 (Kolvinet al. 1971, Kramer 1978, Beitchman 1983). Adolescent-onset is more common than child-onsetschizophrenia (Russell et al. 1989, Beitchman 1983), but is poorly studied (Werry et al. 1991). One ofthe major reasons accounting for the paucity of useful diagnostic research is that, prior to DSM-IIInomenclature (American Psychiatric Association 1990), studies employed relatively broad criteria for

'Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles,California 90024.

2Joint appointment at the West Los Angeles Veterans Affairs Medical Center, Los Angeles, California 90073.3West Los Angeles Veterans Affairs Medical Center, Los Angeles, California 90073."Neuropsychiatrie Institute, University of California at Los Angeles, Los Angeles, California 90024.

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FREEDMAN ET AL.

diagnosing "childhood schizophrenia." As a result, the earlier studies may have included subjects whosuffered from a variety of childhood psychoses, among them autism, schizophrenia, mental retardation,organic disorders, and possibly even major affective disorder (Beitchman 1985, Prior and Werry 1986).The heterogeneity of these sample populations renders interpretation of these earlier studies quitedifficult; however, more recent studies have taken care to maintain these diagnostic distinctions.

Even in these more recent studies, information regarding the prognosis and treatment of adolescent-onset schizophrenia must often be extracted from studies that include both childhood-onset andadolescent-onset patients, or extrapolated from young adult onset studies. It appears that all childhood-onset and adolescent-onset schizophrenias have prognoses as bad as, if not worse than, those inadulthood (Werry et al. 1991, Eggers 1978). Further, treatment with conventional neuroleptics appearsless effective than in adults (Kydd and Werry 1982, Carone et al. 1991) and is often marked by sideeffects (Realmuto et al. 1984, Polizos et al. 1973, McAndrew et al. 1972).

The prognosis of childhood-onset schizophrenia remains controversial. Only two studies of patientswith childhood-onset schizophrenia have included long-term follow-up, and they show somewhatdivergent findings regarding outcome. Eggers found that 50% of 57 patients with onset of illnessbetween age 7 and 13 years showed "improvement" at a follow-up that averaged 15 years, with 20% incomplete remission (Eggers 1978). Patients with a later onset did better, whereas all 11 who becamepsychotic before the age of 10 years had a "poor" outcome. Werry studied 30 patients with onset between7 and 17 years and found greater overall disability than did Eggers: only 17% had Global Assessment ofFunction Scale scores over 60 at a mean 5-year follow-up (Werry et al. 1991 ). Fifteen percent of Werry '

s

sample died of apparent suicide, as did 5% of Eggers' sample. A study of hospitalized young adults withschizophrenia, including several adolescent-onset patients, found a 78% rehospitalization rate, with38% having attempted suicide on 2- to 12-year follow-up (Breier et al. 1991).

Treatment of childhood-onset psychosis with conventional neuroleptics is frequently unsuccessful andis often impeded by side effects (Green et al. 1992), including neuroleptic malignant syndrome (NMS),the expected extrapyramidal side effects (EPS), tardive dyskinesia (TD), impaired learning, and ocularchanges (McAndrew et al. 1972, Polizos et al. 1973). In a study by Pool and colleagues (1976)evaluating the efficacy of loxitane and haloperidol in 75 psychotic adolescents (aged 13-18 years), bothhaloperidol (mean dose, 9.8 mg daily; n = 25) and loxitane (mean dose, 87.5 mg daily; n = 26) werefound to be significantly more effective than placebo in treating psychotic symptoms. Significantimprovements were observed for the symptoms of delusions, hallucinations, thought disorder, and socialwithdrawal. In an earlier study, Wolpert similarly found that 50% of a sample of children that met thethen extant criteria for schizophrenia had a poor response to conventional neuroleptics (Wolpert et al. 1967).Realmuto et al. ( 1984) found that only 12 of 21 chronic schizophrenic adolescents improved with a course ofeither thioridazine or thiothixene; but both medications caused intractible sedation in most patients.

Movement disorders associated with conventional neuroleptic treatment appear to be at least as

common in children as in adults and it is possible that NMS is common in children as well. Campbell, ina prospective study of long-term treatment with conventional neuroleptics in children with autism (i.e.,not schizophrenia), found that 21% developed TD, and 80% experienced withdrawal dyskinesia(Campbell et al. 1988). There has been no systematic study of NMS in children treated with conventionalneuroleptics but numerous cases have been reported (Latz and McCracken 1992, Steingard et al. 1992,Teicher and Glod 1990).

Although conventional neuroleptics certainly have their place in the treatment of childhoodpsychoses, early-onset schizophrenia is frequently characterized by a lack of responsivity to conven-tional neuroleptic agents (Crow 1980, Andreasen 1989).

Clozapine, the prototype of the so-called atypical antipsychotics, has demonstrated greater clinicalefficacy than conventional neuroleptics in treatment-refractory adults with schizophrenia (Kane et al.1988). In addition, it only infrequently causes TD and may even reduce preexisting TD in some instances(Small et al. 1987, Simpson et al. 1978). It rarely, if ever, induces dystonia or drug-inducedparkinsonism (Baldessarini and Frankenburg 1991). With the careful regulation of white blood cellcounts, the number of reported deaths apparently due to clozapine-induced agranulocytosis has beenlimited to nine patients since it became widely available in the United States in February 1990 (SandozPharmaceuticals, personal communication, November 1993).

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CLOZAPINE AND ABSENCE STATUS SEIZURES

The only completed studies examining the efficacy of clozapine in schizophrenic adolescents havebeen conducted by three research groups in Germany. In an open label study, Siefen and Remschmidt(1986) administered clozapine to 21 young schizophrenic patients (mean age, 18 years) who hadpreviously demonstrated an inadequate response to conventional neuroleptics or demonstrated signifi-cant extrapyramidal side effects. According to International Classification of Diseases (ICD) criteria, 15of the 21 patients were diagnosed with paranoid schizophrenia and the remaining subjects were

diagnosed with the other subtypes of schizophrenia or schizoaffective illness. When treated withclozapine, 11 of the 21 patients were observed to have an "excellent response," demonstrating markedimprovement or complete remission of psychotic symptoms, while 6 patients were reported as being"noticeably improved." In this particular sample, clozapine treatment reduced looseness of associations,hallucinations, and aggressiveness in 80% of the cases. Symptoms of ambivalence decreased at asomewhat lower rate, while psychomotor slowing and blunted affect either did not improve or worsenedin the majority of cases. The most commonly reported side effects were drowsiness, dizziness,orthostatic hypotension, pacing and sialorrhea; these occurred in up to 50% of the patients, but none

required stopping treatment. No significant hematological abnormalities were noted. Schmidt andcolleagues replicated these findings, reporting a similar frequency and pattern of side effects and efficacyin their sample of adolescent schizophrenics (Schmidt et al. 1990, Blanz and Schmidt, 1993).

In the third study examining the side effects associated with clozapine, Amminger et al. (1992)administered an 8-week trial of clozapine to 53 treatment-refractory psychotic patients between the agesof 13 and 18 years. On the basis of ICD criteria, 21 patients (40%) had schizoaffective disorder and 26of the patients (50%) were diagnosed with schizophrenia; 5 additional patients had nonschizophrenicdiagnoses. Forty-three patients completed the 8-week trial with doses ranging from 75 to 350 mg daily,which were reduced at discharge to doses ranging from 50 to 175 mg daily. Five patients discontinued themedication due to side effects, and five subjects were dropped from the study due to noncompliance orlack of efficacy. Reported side effects were minimal, and no cases of agranulocytosis were reported,although one case of leukopenia was noted. The authors concluded that clozapine was well tolerated bytheir adolescent patients and suggest that clozapine is a good alternative treatment for refractory patientsas long as leukocyte counts and liver function enzymes are carefully monitored.

The promising outcome of these three studies from Germany encouraged us to try clozapine whenfaced with a patient with treatment-refractory adolescent-onset schizophrenia. This case is reported withfull consent of the patient and his parents.

CASE REPORT

The patient is a 15-year-old foreign-born male with a medical history of uncomplicated rheumaticfever (for which he prophylactically takes penicillin 250 mg bid) and glucose-6-phosphate dehydroge-nase (G6-PD) deficiency. At age 5 years, he had enuresis, anxiety, and a transient tic (blink), and wastreated by a psychologist with 10 therapy sessions.

His family history is significant for (1) a paternal uncle with probable schizophrenia, who was treatedwith a combination of electroconvulsive therapy and fluphenazine and who is currently off medicationand described as odd and isolated, and (2) a maternal aunt, with an undetermined psychiatric diagnosis,was psychiatrically hospitalized once and showed a complete remission of symptoms.

The patient reported feeling increasingly distant from classmates starting 2'/2 years prior to admission,and feeling intermittently "attacked" by his classmates starting 6 months prior to admission. Four weeksbefore admission, he began school refusal and his parents noticed his mood fluctuating over the courseof minutes from pleasant and happy to depressed and agitated. He believed that his fellow students were

mocking him, and that he had to "do battle" with their thoughts because he lacked "the power" that theyall possessed. He began to believe that other people could read his mind, and felt that the television andradio were sending him messages. He felt he had to "be bad" to fight the thoughts of other people. He feltthat his father's influence forced him to be good, which made the patient feel weak, humiliated,and defenseless against these outside thoughts. He began to have daily episodes of feelings of despair

55

FREEDMAN ET AL.

lasting from minutes to several hours, and would sob and be angry on approach (once kicking the familydog and, on several occasions, pushing his father away). At other times, he complained of intensefeelings of "pressure" and would feel the need "to do something extreme," such as jump down a flight ofstairs, intending "maybe to break my ankles" but not to kill himself.

Ten days prior to admission, he was started on perphenazine (8 mg daily) and trihexiphenidyl (1 mgbid). The perphenazine was increased stepwise over 8 days to 32 mg daily, with minimal response.

Because of escalating agitation, he was hospitalized in a psychiatric unit. The mental statusexamination performed on admission showed that the patient had moderately blunted affect, but was ableto smile and joke during the interview. His mood was mildly dysphoric, and he showed no signs ofpressured speech, tangentiality, or loosening of associations. His thought processes were logical andcoherent, and cognitive functions were completely intact. He endorsed ideas of reference, thoughtbroadcasting, thought insertion, and paranoia. He denied hearing voices, but stated he experiencedothers as directing humiliating thoughts toward him in the form of "words," which he felt were "probablynot" real. He denied current depression or an overall change in mood, but admitted to daily moodfluctuations that generally correlated with the intensity of his psychotic thoughts. No clear-cut sleep or

appetite disturbances were noted. Physical examination was fully normal. A neurological examinationwas performed by the admitting psychiatrist of gait and station, rapid alternating movements, cranialnerves, light touch, deep tendon reflexes, and motor strength and were all completely normal.

Diagnoses considered on admission included schizophrenia, schizophreniform disorder, brief reactivepsychosis, mood disorder with psychotic features (particularly bipolar disorder), and an organic mentaldisorder. Routine laboratory tests, including thyroid function tests, were within normal limits. Drug andalcohol screening tests were negative. On the basis of the normal neurological examination, absence ofa history of seizures or loss of consciousness, negative urine toxicology screen, family history, andsymptoms typical of schizophrenia, it was felt that head imaging and electroencephalography (EEG)were not clinically indicated, and that an organic etiology was extremely unlikely. An affective etiologywas ruled out by the protracted prodromal history of social decline and isolative behaviors in the absenceof mood symptoms, as well as by the relatively euthymic affective presentation on admission. Althoughthe patient had some slight dysphoric symptoms on presentation, we considered it consonant with thestressful circumstances and far too mild for a depression with psychotic features. In light of the classicpresentation of symptoms, including the prodromal decline, as well as the exclusion of other etiologies,we diagnosed the patient as having schizophrenia.

In educational testing performed on admission, academic functioning was extremely impaired.Classroom performance was below grade level in all academic subjects, even when the patient was askedto perform highly structured and concrete tasks. He was observed to have difficulty in retaining newinformation and in focusing attention on classroom tasks. Performance on the Wide Range AchievementTest (Jastak and Jastak 1965) indicated delayed achievement in all academic areas. The same battery ofachievement tests performed when the patient was 6 years old indicated that he had been above averagein all areas. Throughout his hospitalization, the patient's performance in school consistently improved.At the time of discharge, he was able to earn A's in several of his classes.

While in hospital, the patient remained on perphenazine for a total of 6 weeks and showed a slightdecrease in his agitation (see Fig. 1). He continued episodically to have intensely dysphoric feelings of"pressure" that were partially relieved by lorazepam (1 mg po prn), which was administered an averageof once daily. He felt teased and humiliated by his fellow patients and increasingly accepted as real thebelief that others had a "power" that he and his father lacked, rendering him weak and vulnerable.Despite vigorous anticholinergic treatment, he developed drug-induced parkinsonism with akinesia,rigidity, and a mild upper extremity tremor. Because of a lack of clinical response to perphenazine, hewas switched to a different class of neuroleptics, starting with haloperidol (10 mg po daily). Hisdrug-induced parkinsonism worsened, requiring a temporary reduction in his dose of haloperidol to 7mg. His dose was gradually titrated back up to 10 mg of haloperidol daily, but his drug-inducedparkinsonism persisted, and his psychiatric symptoms remained essentially unchanged. After 3 weeks on

haloperidol, lithium carbonate (300 mg tid) was added (0.6 mEq/liter). After an additional 10 days oftreatment with both lithium and haloperidol, there was an increase in the patient's social withdrawal, a

slight reduction in anxiety and dysphoria, and no effect on the psychotic symptoms.

56

CLOZAPINE AND ABSENCE STATUS SEIZURES

1 ! Worsening Psychosis CIozap;„e 375 mg] Perphenazine-1 L Clozapine 550 mg Clozapine 300 mg_I Lorazepam v Clozapine 400 mg v Lithium N. yS ^w

_| AnticholinergicI I Haloneridol 'I \ Seizure-like episodes

/AI ^ Hospitalization l i

1111111111111M111111111111111111111111111 j 1111111111111111111111II11111 ^y^TT-rrr3 Clozapine

1111111111

10 20 30 40 50 60 70 120 140

Weeks Since Treatment Started

FIG. 1. The course ofpharmacotherapy. The anticholinergic medications were trihexiphenidyl, benztropine mesylate,and biperiden, used in order in nonoverlapping fashion.

Because of the patient's already protacted hospitalization, his marked EPS on conventionalneuroleptics, and a judgment that a more extended trial of lithium was unlikely to markedly affect core

psychotic symptoms, the decision was made to start a trial of clozapine. Lithium was discontinued inorder to avoid potentially confounding effects on leukocyte counts. Haloperidol was decreased to 5 mgdaily, and clozapine was started at 25 mg daily and increased over the course of 5 weeks to 500 mg daily,taken as 100 mg qAM and 400 mg qhs (see Fig. 1). Side effects experienced by the patient duringclozapine treatment were borderline hypertension (145/90), tachycardia (120), extreme sedation,sialorrhea, sinus congestion, and weight gain (9 kg).

No response was detected until the fourth week ofclozapine treatment when, at a dose of 100 mg qAMand 350 mg qhs, his anxiety decreased markedly and lorazepam was found to be no longer required. Inthe fifth week, he gradually began to feel "stronger" and less bothered by the feeling that he lacked a

special "power." Haloperidol was stopped, his drug-induced parkinsonism resolved completely, andbenztropine was tapered and discontinued. His clozapine dose was increased to 100 mg qAM and 400 mgqhs. He was increasingly interactive on the psychiatric unit, with improvement noted in all activities.After 6 weeks of clozapine treatment, elimination of the morning 100-mg dose led to reduced sedationwith no apparent worsening of symptoms.

The patient was discharged 7 weeks after the clozapine was started, which was 17 weeks afteradmission. After being treated with clozapine for 7 months, the patient remained much improved, butstill complained ofsome residual anxiety (which he rated as 90% improved) and persecutory experiences(which he rated as 50% improved). Because of these residual symptoms, the dose of clozapine was raisedto 100 mg qAM and 450 mg qhs over 2 weeks. After 1 week on this higher dose, the patient had an

episode ofright eye blinking and sialorrhea that lasted several seconds, followed by persistent nausea anda "spacey feeling" lasting for several minutes.

Three days later, he had another episode of nausea accompanied by a "spacey feeling" which lasted 15min. Over the next week, these episodes of nausea and "spaciness" became more frequent, occurring upto three times a day and increasing in duration up to several hours at a time. An EEG was obtained duringan episode, which showed absence status (see Fig. 2). Throughout the episodes, the patient remainedalert, oriented, and ambulatory, with no motor anomalies except during the original occurrence. Thedose of clozapine was reduced to 400 mg qhs, and the episodes became less frequent over the next 3weeks. Between episodes, a repeat EEG and an examination by a child neurologist were found to benormal. Seven weeks after restoring his clozapine dose to 400 mg qhs, these episodes ceased completely.A follow-up EEG 1 year later was also normal.

At the time of this writing, the patient has been on clozapine for 35 months. Because of moderatedaytime sedation, the clozapine dose was decreased to 350 mg daily at 23 months and to 300 mg daily at29 months. These reductions decreased both the daytime sedation and the length of nightime sleep. Hispsychotic symptoms continued to improve through month 31, at which point he was troubled only byoccasional transient sensations that others knew what he was thinking. He stated that he felt more

57

FREEDMAN ET AL.

FIG. 2. EEG montage obtained during absence status. EEG tracing obtained in week 40 of treatment, when the patientwas being treated with clozapine (550 mg daily). During the recording, the patient was alert and oriented, but complainedof nausea and a "spacey" sensation. The generalized 3-Hz spiking wave is pathognomonic for absence. Follow-up EEGson a reduced dose of clozapine were normal.

confident and comfortable around people than at any prior time in his life. Starting in month 32, thepatient had a further increase in the sensation that others could read his mind and felt that they were

sending messages to him. At month 33, his dose was titrated up to 375 mg daily with minimal increasein daytime sedation and marked improvement of his psychotic symptoms by 12 weeks after the doseincrease. He remains euthymic, and free of delusional thought content, describing his symptoms as "likean old knee problem acting up again. Most of the time I can ignore it, but it's irritating." He sleeps thesame 8 hr nightly that he did prior to hospitalization, and his weight has returned to baseline. Hissialorrhea, hypertension, and tachycardia have resolved. His weekly leukocyte counts have been stable.In the past year, the patient graduated from a special education high school with highest honors and was

a starting player on a varsity athletic team. He is now successfully attending junior college and is veryactive socially.

DISCUSSION

This rather successful experience with clozapine in an adolescent is consistent with the favorableoutcome reported in the three German studies using clozapine for adolescents with treatment-resistantschizophrenia (Amminger et al. 1992, Blanz and Schmidt 1993, Schmidt et al. 1990, Siefen andRemschmidt 1986). At the time of publication there were only two additional reports describing thetreatment of a total of four schizophrenic adolescents with clozapine, all with good clinical responses(Birmaher et al. 1992, Boxer and Davidson 1992). The current report is, to our knowledge, the longestfollow-up to date of the clozapine treatment of a patient with adolescent-onset schizophrenia.

Of particular interest in this case is the absence status, which occurred approximately 1 week after a

dose increase to 550 mg daily. To our knowledge, this is the first reported case of any type of absenceseizure in either an adolescent or adult with schizophrenia that appears to have been induced by clozapinetreatment.

To date, there have been few systematic studies of clozapine-induced seizures in adolescents withschizophrenia. Siefen et al. (1986) noted mild EEG changes in one-third of their adolescent patientstreated with clozapine. Braun-Scharm and Martinius (1991) performed EEGs on 32 adolescent patients(ages 14-19 years) with ICD-9 diagnoses of schizophrenia, before and after treatment with clozapine.Ten patients (31%) had an increase in mild EEG abnormalities, including irregular baseline rhythms,interruption of baseline rhythm by slow waves and marked high-voltage lability, as well as an overallincrease in slow wave activity. Fifteen subjects (47%) developed clearly abnormal EEGs with an overallincrease in dysrhythmic activity, occurring in combination with a slowing of baseline rhythm,pathological theta rhythms, or abnormal slow wave patterns. Three epileptiform seizures were observed.

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CLOZAPINE AND ABSENCE STATUS SEIZURES

The first case was a 16-year-old female with a history of premorbid epilepsy who had an apparently grandmal seizure while being treated with clozapine (700 mg daily). The second case was a 16-year-old male,with no prior history of seizures and a normal EEG prior to clozapine treatment, who had two witnessedgrand mal seizures at a dose of 700 mg daily. The third patient was a 19-year-old female with no priorhistory of seizure disorder who, following a normal preclozapine EEG, had one grand mal seizure on

clozapine (400 mg daily) after a night of sleep deprivation; a postseizure EEG displayed paroxysmalpotentials and irregular spike waves. In the latter two cases, the seizures resolved after dose reduction,and the EEG subsequently became less pathologic without the use of anticonvulsants.

Collectively, these studies indicate that 4% of the 80 clozapine-treated adolescents reported thus farhave experienced seizures, while 60% of 53 patients developed mild to marked EEG abnormalities. Theclozapine-induced EEG abnormalities presented in the Braun-Scharm and Martinius (1991) studyappeared to be dose related (p > 0.001). In those patients treated with 0-300 mg daily of clozapine, 14of 19 subjects maintained normal EEGs. In those receiving 300-600 mg daily, all of the EEGs developedat least mild dysrhythmia. All patients treated with more than 600 mg daily of clozapine developedmarkedly abnormal EEGs.

Clozapine, the only alternative to conventional neuroleptics that has until recently been available inthe United States, is both relatively free from the majority of the neuromotor side effects of conventionalagents, and is more efficacious in treatment-refractory cases in adults (Kane et al. 1988). Despite itsadvantages, it has remained a second-line agent due to the risk of agranulocytosis and seizures. The riskof agranulocytosis in adults, however, appears fairly minor with well-regulated blood monitoring(Gerson et al. 1991, Naber et al. 1992, Naber and Hippius 1990). The risk of seizures in adults appearsto be dose dependent, occurring in 1-2% ofpatients receiving less than 300 mg daily, 3-4% at 300-600mg daily, and 5% on doses greater than 600 mg daily (Haller and Binder 1990). In adults, both valproicacid and phenytoin have been shown to arrest clozapine-induced grand mal seizures (Devinsky et al.1991).

The almost complete symptom remission in this patient with clozapine suggests a potential value intreating certain cases of adolescent-onset schizophrenia, but it must be noted that there is extremely scantexperience using clozapine in adolescents and that use of clozapine is marked by a number of significantdifficulties. Similarly, the recently released atypical neuroleptic risperidone, which holds some promisefor increased efficacy compared to conventional agents and fewer adverse effects than clozapine in adults(Bollen et al. 1992), and which does not require weekly leukocyte counts, has been investigated inadolescents even less than clozapine.

In the very small samples studied, it appears that clozapine-induced seizures may be at least as likelyin adolescents as in adults, especially at clozapine doses above 600 mg daily. There are insufficient datato determine if the frequency of agranulocytosis is any different in adolescents or children than in adults.The less serious side effects of sedation, constipation, sialorrhea, hypertension, tachycardia, nausea, andweight gain appear to afflict adolescents similarly to adults.

Table 1. Seizure Rates during Clozapine Treatment in Three Studies on Adolescents"

Study

Number of clozapine-treated adolescentswith schizophrenia

Number andpercentage of

adolescents developingEEG abnormalities

on clozapine

Number andpercentage of

clozapine-relatedseizures Clozapine dose

Braun-Scharm andMartinius (1991)

Siefen and Remschmidt(1986)

Amminger et al. (1992)

32

21

27

25 (78%)

7 (33%)

Not measured

2 (6%) 1 on 400 mg/day1 on 700 mg/day

1 (5%) Dose not specified

0 (0%) 75-350 mg

"The data reflect only those patients with an ICD-9 or ICD-10 diagnosis of schizophrenia.

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FREEDMAN ET AL.

Despite these considerations, we believe that the extremely poor prognosis of adolescent- andchildhood-onset schizophrenia with conventional treatment (Green et al. 1992, Werry et al. 1991, Breieret al. 1991, Kydd and Werry 1982, Eggers 1978), as well as the long-term neurological side effects ofconventional agents (Campbell et al. 1983), justify consideration of alternative medication treatmentssuch as clozapine. Schizophrenia disrupts fragile developmental processes prior to an adult integration ofpersonality (Reinhard 1990). Too frequently, the drugs conventionally used to treat schizophrenicsymptoms induce blunting of affect and side effects, which themselves can be seriously disabling. It isuncommon for an adolescent with schizophrenia to have close to a normal life on conventionalneuroleptics. Clinicians must consider the risks of clozapine in the context of the treatment of an illnessthat has an expected suicide rate of at least 5% within 7 years and with a rate of significant disability inup to 80% of cases (Werry et al. 1991, Breieret al. 1991,Eggers 1978).

It is the authors' view that an adolescent who is an extremely poor responder to conventional agents(e.g., requiring repeated hospitalizations) deserves consideration for a trial of clozapine when the patienthas a stable and supportive family, is cooperative, and has no history of seizures or blood dyscrasias. Thepatient should first be given clinical trials of at least 6 weeks in duration on a minimum of two separateconventional neuroleptics, from two distinct chemical classes. The decision to use clozapine must becarefully discussed with patient, family, and others involved in the patient's care. It must be made clear to allinvolved that there are scant data concerning efficacy or risks in adolescents. For the intermediate responders(e.g., the patient who functions out of hospital but has significant social or academic impairment), thedecision is more complex, but clozapine still deserves consideration. An adequate responder to conventionalagents should not be switched to clozapine unless marked tardive dyskinesia becomes evident.

We believe the following are reasonable guidelines for administering clozapine to an adolescent. Priorto starting the drug, the patient should have a thorough physical examination, especially of thecardiovascular and neurological systems. Benzodiazepines should be reduced to low doses or elimi-nated, if possible. Laboratory tests should include at least a complete blood count with differential, liverfunction tests, thyroid function tests, renal function tests, and electrolytes, as well as an EKG. We concurwith the recommendations of Braun-Scharm and Martinius ( 1991 ) that obtaining a baseline EEG, beforestarting clozapine treatment, should be a standard of care for adolescents. Preferably, the EEG would beobtained in a medication-free state; however, an EEG while on a stable dose of conventional neurolepticswould still be useful.

In the absence of definitive data on clozapine treatment in adolescents, we employ a very conservativetreatment strategy. Until more data are gathered, we consider it prudent to start adolescents on clozapinein a hospital setting. We recommend starting clozapine at a dose of 12.5 mg daily and increasing the doseas tolerated at increments no greater than 25 mg/daily. The EEG should be repeated at a dose of 300 mgdaily, and with every increase of 100 mg daily beyond this level. In case moderate EEG abnormalitiesappear, a decision should be made in concert with a child neurologist whether to maintain or lower theclozapine dose, or to add valproic acid. Doses above 600 mg should be administered only inextraordinary circumstances, including at least 6 months on lower doses without adequate response andthe close involvement of a child neurologist with expertise in the use of clozapine and EEGs. Sleepdeprivation while on clozapine should be discouraged, because this may contribute to a lowering ofseizure threshold in some patients. Somatic complaints accompanied by transient perceptual distur-bances should be investigated by periodic EEGs throughout treatment. Weekly complete blood counts(CBCs) are mandatory, and in the United States must be conducted in concert with the Clozaril NationalRegistry. Weekly absolute neutrophil counts are prudent, and liver transaminases should be closelymonitored. The family should be involved in close supervision of potential side effects and ofcompliance with the stringent blood testing requirements. Finally, a psychiatrist experienced in usingclozapine should be involved in the treatment.

We note that the youngest patient to be reported to have received treatment with clozapine was a 13year old (Amminger et al. 1992). We feel that the use of clozapine in children younger than 13 yearsshould be attempted only by those with first-rank expertise in the use of clozapine.

Although the use of clozapine in adolescents is still novel, it may be considered in certaintreatment-resistant cases. Although the results thus far are promising, more clinical experience andcontrolled studies are necessary to establish the safety and efficacy of clozapine in adolescents.

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ACKNOWLEDGMENTS

Thanks to Ramin Sankar, M.D. for assistance with EEG interpretation and to Michael Kreutzer, M.D.for translation from German.

REFERENCES

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Third Edition. Washington,D.C., American Psychiatric Association, 1980

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Address reprint requests to:Joshua Freedman, M.D.

Department of Psychiatry11301 Wilshire Boulevard, Building 210

Los Angeles, California 90073

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