Clozapine Treatment in Very Early Onset Schizophrenia

CASE STUDY Clozapine Treatment in Very Early Onset Schizophrenia TAMAR MaZES, M.D., PAZ TOREN, M.D., NADEJDA CHERNAUZAN, M.D., ROBERTO MESTER, M.D., RaNI YORAN-HEGESH, M.D., RACHEL BLUMENSOHN, M.D., AND ABRAHAM WEIZMAN, M.D. ABSTRACT Very early onset schizophrenic patients only partially benefit from conventional antipsychotic treatment and are at increased risk for developing tardive dyskinesia (TD). Clozapine, which lacks extrapyramidal side effects including TD, has been proved effective for adult schizophrenic patients who are resistant to other neuroleptics. Clozapine, therefore, may offer an alternative treatment for these patients. The authors report four successful trials of clozapine in children aged 10 to 12 years old with schizophrenia, the youngest group reported on to date, who were unresponsive to conventional neuroleptic treatment. J. Am. Acad. Child Ado/esc. Psychiatry, 1994, 33, 1:65-70. Key Words: clozapine, schizophrenia, children. Very early onset schizophrenia (YEOS), defined as schizophrenia with onset before 13 years of age, is a debilitating illness with a chronic course (McClellan and Werry, 1992). These children spend years that are tremendously important to their cognitive and social development in an active state of illness, which includes positive symptoms of delusions and hallucinations and negative symptoms of apathy and lack of motivation, preventing them from functioning according to their potential. Neuroleptics are valuable for treating these patients, although younger schizophrenic patients appear to benefit less from them. In some studies, almost 40 to 50% of the children were nonresponders (King and Noshpitz, 1991). Moreover, neuroleptics generally do not change, and in some cases may worsen, negative Accepted June 15, 1993. Dr. Mozes is Director ofChildPsychiatric Department. Dr. Toren isa senior Child andAdolescent Psychiatrist and Director ofResearch, Dr. Chernauzan is a Child and Adolescent Senior Psychiatrist, Dr. Mester is Hospital Director, Dr. Yoran-Hegesh is Director of Child and Adolescent Psychiatric Outpatient Clinic, and Dr. Blumensohn is Director ofAdolescent Psychiatric Department, Ness-Ziona Mental Health Center, Seckler Faculty of Medicine, Tel-Aviv University. Dr. Weizman is Associate Professor in Psychiatry and Director of Research, Geha Psychiatric Hospital and Felsenstein MedicalResearch Center, Sackler Faculty ofMedicine, Tel-Aviv University. Correspondence and reprint requests to Paz Toren, MD., Ness-Ziona Mental Health Center, P.O.B. 1, Ness-Ziona, Israel 70450. 0890-8567/94/3301-0065$03.00/0©1994 by the American Academy of Child and Adolescent Psychiatry. J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:1, JANUARY 1994 symptoms such as apathy and anergia (Andreasen er al., 1990). During the past fewyears, there has been an increased interest in clozapine, a dibenzodiazepine antipsychotic that proved to be effective for schizophrenic patients, refractory to other antipsychotic medication (Kane, 1992). Clozapine is known to have a beneficial effect on both positive and negative symptoms of schizophrenia and has minimal extrapiramidal side effects (Meltzer, 1992b). Not only is the incidence of tardive dyskinesia on clozapine treatment minimal, but also there are some reports of a beneficial effect of clozapine on other neuroleptic-induced tardive dyskinesias (Lieberman et al., 1989). Tardive and withdrawal dyskinesias can occur in children after as few as 3 months on neuroleptic medications (Campbell, 1985). Children with VEOS have many years of antipsychotic treatment ahead of them, a major factor in developing tardive dyskinesia (Green, 1991). There are very few but promising reports by Birmaher et al. (1992) and Blanz and Schmidt (1993) on clozapine treatment in adolescents and young adults with schizophrenia (mean ages 17.3 and 16.8 years, respectively) . The risk of serious sequelae of clozapine-associated granulocytopenia, can be minimized by regular monitoring of white blood cells (Krupp and Barnes, 1992). 65 MOZES ET AL. All this has encouraged us to study the efficiency of clozapine for treating schizophrenic children resistant to other antipsychotic medication. The following are case studies of four trials with clozapine in VEOS patients who did not improve with conventional neuroleptic treatment. CASE STUDIES Before the initiation of clozapine treatment, risks and benefits were carefully explained to patients and to their parents, who signed an informed consent. The clozapine protocol included weeklyblood counts for the first 18 weeks and once a month thereafter to verify the absence of granulocytopenia. All patients were assessed weekly by one investigator (N.C.), using the Brief Psychiatric Rating Scale (BPRS)(Overall and Gorham, 1988) and its indices: 1. IPS-BPRS index for positive symptoms = mean value of the following BPRS items: conceptual disorganization, grandiosity, hostility, suspiciousness, hallucinatory behavior, unusual thought content, excitement. 2. INS-BPRS index for negative symptoms = mean value of the following BPRS items: emotional withdrawal, motor retardation, blunted affect. The investigator (N.C.) also used the Clinical Global Impression scale (CGI)(Guy, 1976) as an overall assessment of social function and mental status before, during, and after treatment. Case 1 S was hospitalized in the child psychiatric department at the age of 11 years. He is the third of four children of Persian origin parents. His mother is a chronic schizoaffective patient. There is no other psychopathology in the family. S's psychomotor development and early school years were normal. When he was 10 years old, he became increasingly isolated, refused to eat and lost seven kg in 2 months, had frequent bouts of insomnia, and reported multiple somatic complaints of headaches, dizziness, weakness, and abdominal pain. He was depressed and claimed that the world became "darker." S was hospitalized and treated with tricyclic antidepressants. While undergoing treatment, he became increasingly agitated and overtly psychotic. He was transferred to the hospital in an acute psychotic state with paranoid delusions that his "food was being 66 poisoned," that "people laughed at" him, and "did things on purpose in order to hurt" him. S displayed auditory hallucinations. He heard voices giving him orders and telling him to hurt himself and acted on these voices: he had two bizarre suicide attempts, one by hanging himself and the other by electrocution. There was no evidence of mood disorder during his hospitalization. There was no history of substance abuse. Neurological examination, electroencephalogram (EEG), brain computerized tomography (CT) and metabolic screening findings were all within normal ranges. S was treated with haloperidol followed by perphenazine, both in adequate amounts for a total duration of 1 year. He had partial remission while taking perphenazine, including lessening but not disappearance of the psychotic symptomatology and much less agitation and anxiety. He continued to display persecutory delusions and hallucinations, he was socially withdrawn, unmotivated, and showed blunted affect. Diagnosis of schizophrenia was made according to DSM-III-R criteria (American Psychiatric Association, 1987). However, the diagnosis of schizoaffective disorder cannot be ruled out. After experiencing a relapse that included intensification of psychotic symptoms in the absence of noncompliance to the abovementioned medication, clozapine was tried. The clinical data are summarized in Table 1. As shown, after several weeks of taking clozapine, S was free of delusions and hallucinations. He had no apparent disturbance in judgment and showed insight to his illness and to his capacities. He visited the hospital's school, showed motivation to study, and demonstrated capabilities in dealing with age-appropriate school material. He suffered minimal side effects (drooling only) and had no signs of tardive dyskinesia. He showed subclinical changes on follow-up EEGs. S was discharged from the hospital after 8 months of medication with clozapine. He livesat home and studies in a school for postpsychotic children. It has been 7 months since his discharge from the hospital. On routine follow-up examinations, his mental status was found to be stable. He functions well at home and at school. Clozapine dosage was reduced to 150 mg/day. Case 2 T is a 12-year-old boy, the second of two children of a father who is a residual schizophrenic patient and J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:1, JANUARY 1994 CHILDHOOD SCHIZOPHRENIA AND CLOZAPINE TABLE 1 Case 1 Weeks of Treatment 0 1.5 3 8 9 35 65 Total BPRS dBPRS in % IPS INS CGI (1-7) 0 50 57 37 0 -35 3.4 2.3 3.6 2.6 7 5 100 150 200 200 150 24 24 6 6 6 -35 0 -75 0 0 1.7 1.7 0 0 0 2.6 2.6 1.3 1.3 1.3 4 4 3 3 3 Czp mg/day Side Effects EPS++ EPS+/Drowsiness++/ Drooling+++ Drooling++ Drooling++ Drooling++/EEG' EEG EEG WBC( XlOOO) 7.6 12.6 65 5.6 4.4 6.2 65 Note: Czp = clozapine, dBPRS = % change in total Brief Psychiatric Rating Scale (BPRS) score between two consecutive time points, IPS = index of positive symptoms, INS = index of negative symptoms, CGI = clinical global impression, WBC = white blood cells . count (per mL), EPS = extrapyramidal side effects. 'On routine follow-up EEG, with no clinical epilepsy, paroxismal high-amplitude waves were found, scattered on both hemispheres. ++ = moderate, +++ = severe. a mother with borderline intellectual functioning. His brother has severeconduct disorder. There are a number of schizophrenic patients in the father's family. Twas diagnosed at age 6 years as suffering from mild mental retardation. At the age of 8 he went through a psychotic episode that lasted for a few months and was treated as an outpatient. When T was 9 years old, he was hospitalized showing paranoid delusions, auditory hallucinations, thought disorganization, and severe psychomotor agitation. Routine blood screen, EEG, and a complete neurological examination, were normal. A diagnosis of schizophrenia was established. Twas treated with haloperidol, pimozide, trifluoperazine hydrochloride, sulpiride, and thioridazine hydrochloride, all in suboptimal dosages, because of severe extrapyramidal side effects including akathisia, Parkinsonism, and perioral tardive dyskinesia. After 17 months of hospitalization, T was still actively psychotic, had paranoid delusional fears, and could not participate in the daily activities of either school or hospital department. Clozapine treatment was initiated, and the clinical response is shown in Table 2. After a few weeks on clozapine, T showed substantial improvement, including disappearance of hallucinations and reduction in persecutory fears. His thoughts and actions became more organized. He became more interested in his surroundings and even gradually attended the hospital's school. T still has blunted affect and is rather withdrawn in his social interactions. He experienced virtually no side effectson clozapine (except J . AM . ACAD. CHILD ADOLESC. PSYCHIATRY. 33:1, JANUARY 1994 for subclinical changes on follow-up EEG). Furthermore, tardive dyskinesia caused by former medications disappeared. Case 3 I, 10 years old, is the older son of Russian-origin parents. There is no psychopathology in his family. His early psychomotor development was normal and, apart from some difficulties in social interactions, he developed normally up to the age of 8 years. He then gradually became introverted and lost interest in all daily activities. He reported of visual and auditory hallucinations and showed bizarre delusions. He saw skeletons coming toward him ordering him to murder someone and then join them; he lived on a star whose king gave him instructions to do things. He had periods of depression and wanted to die. I was hospitalized in an active psychotic state when he was 9 yearsold. His blood routine, EEG, and neurological examination were all normal. I was treated with perphenazine 24 mg/day, followed by haloperidol 25 mg/day, and clothiapine 30 mg/day for a total duration of 10 months. The diagnosis of schizophrenia was established. I had partial remission for a few weeks, which included lessening of delusions and hallucinations. But then, however, he had an exacerbation with no response to the above-mentioned medications. He showed severe extrapyramidal side effects including tardive dyskinesia. 67 MOZES ET AL. TABLE 2 Case 2 Weeks of Treatment Czp mg/day Total BPRS dBPRS in % 0 1.5 4 10 18 20 28 30 60 0 25-50 150 175 175 225 225 275 275 66 36 24 19 27 19 33 19 19 0 -45 -33 -21 +42 -29 +73 -45 0 CGI IPS INS (1-7) 3.7 1.8 1.4 4.3 2.3 2.3 1.2 1.3 1.4 2.3 1.6 1.6 1.6 1.6 7 6 5 4 5 4 5 4 4 1.1 1.7 0.8 0.8 Side Effects EPS+++/TD+ EPS+/TD+ None None None None/EEG" None None/EEG" None WBC(XlOOO) 8.7 9.6 6.2 5 5.4 6 6.2 5.7 6 Note: Czp = clozapine, dBPRS = % change in total Brief Psychiatric Rating Scale (BPRS) score between two consecutive time points, IPS = index of positive symptoms, INS = index of negative symptoms, CGI = clinical global impression, WBC = white blood cells count (per mL), EPS = extrapyramidal side effects, TD = tardive dyskinesia. "On routine follow-up EEG, with no clinical epilepsy, paroxismal high-voltage bilateral frontotemporal waves were found. + = mild, +++ = severe. Clozapine was administered, with substantial improvement (Table 3). I is now 5 months on clozapine. He has no delusions nor hallucinations, he studies at the hospital's school according to his age and spends every weekend with his family. He is motivated to study, has only mild blunting of affect, and has insight to his illness. Extrapyramidal side effects of former medications disappeared all but mild tardive dyskinesia. I has occasional bouts of stereotype movements, which started after a few weeks of taking clozapine and improved spontaneously thereafter (obsessive compulsive symptoms?). I reported enuresis nocturna twice a week, which started around the third week on the clozapine regimen. Case 4 D, now a 13.5-year-old girl, is the second of three children of Russian-origin parents. The father, a lecturer at university, is described as having schizoid personality traits. There is no psychopathology in the family. D had neurodevelopmental delays in motor and social functioning, as an infant and toddler. When D was 2 years old, her mother noticed that she was "different" from other children and showed "bizarre behavior." D had virtually no social interactions, was aggressive toward other children, had severe sleep disturbances, and had unusual eating habits (ate sand, cigarettes, and paper). D was diagnosed at the age of 4 years at a child development center, as having a pervasive 68 developmental disorder (PDD). She attended a special kindergarten for PDD children from the age of 2 years and then a special school. At school, she was reported to have a wide range of behavioral concerns fluctuating from relatively appropriate to bizarre. Her developmental skills were scattered and were lowest in motorrelated tasks and highest in cognitive-academic-oriented tasks. She had restricted social interest but had relatively good academic achievements. At the age of 11 years, a psychotic episode with insidious onset began. Her performance at school deteriorated. She became aggressive, ran away from home severaltimes, ate tremendous amounts of food, gained weight substantially, and talked to herself. On psychiatric evaluation, she showed bizarre, mostly persecutory delusions, was continuously hallucinatory, and acted according to "voices" she heard that gave her orders to run, move, etc. D was hospitalized. Blood screen and EEG were normal. Neurological examination showed no sign of an orgamc cause. D was treated with 40 mgtday haloperidol and then with 150 mgtday levomepromazine for 7 months with temporary partial remission; the delusions and the hallucinations declined in intensity for a month. Nevertheless, there was a rebound of the psychotic production thereafter, with no additional improvement for 7 months ofhospitalization. For a year after the beginning of her deterioration, D was not able to learn anything at school, at home, or at the hospital's school; she was uncooperative, actively psychotic, and met, in addition J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:1, JANUARY 1994 CHILDHOOD SCHIZOPHRENIA AND CLOZAPINE TABLE 3 Case 3 Weeks of Treatment 0 1.5 Czp mg/day Total BPRS dBPRS In % IPS INS CGI (1-7) 0 37.5 40 40 0 -33 4.1 2.5 3.6 3.3 7 5 3 6 50 100 35 25 -12 -28 2.1 I.2 3.1 2.3 5 4 15 23 150 175 16 16 -36 0 0.6 0.6 1.3 1.3 3 3 Side Effects EPS+++/TD++ EPS+/TD++/ Drowsiness-e/Drooling-» TD+/Drooling++ TD+/Drooling+/ OCD-like symptomst/ Enuresis-" OCD-like symptoms EEG changes' WBC(XlOOO) 7.5 7 8.8 7.6 8 7.2 Note: Czp = clozapine, dBPRS = % change in total Brief Psychiatric Rating Scale (BPRS) score between two consecutive time points, IPS = index of positive symptoms, INS = index of negative symptoms, CGI = clinical global impression, WBC = white blood cells count (per mL), EPS = extrapyramidal side effects, TD = tardive dyskinesia. 'The patient reported enuresis nocturna appeared a few weeks after onset of clozapine treatment. Frequency of once a week reported. bOCD = obsessive-compulsive disorder. Patient has occasional bouts of stereotype movements that started a few weeks after beginning treatment with clozapine and improved spontaneously therafter. 'On routine follow-up EEG, with no clinical epilepsy, sharp high-amplitude waves were found scattered on both hemispheres, with fronto-temporal origin. + = mild, ++ = moderate, +++ = severe. to PDD, DSM-III-R criteria for schizophrenia. D was then treated with clozapine. Results are summarized in Table 4. D has now been taking clozapine for 17 months. For the past 15 months she has shown no delusions or hallucinations, and she has attended the hospital's school with motivation to study, as reported before the deterioration. She has no insight to her illness, has minimal social interaction, is a compulsive overeater, neglects her personal hygiene, and has blunted affect. She visits home regularly, and it is hoped she will be discharged soon from the hospital. DISCUSSION Presented above are four case histories of VEOS patients (aged 10 to 12 years), the youngest group reported on to date, successfully treated with clozapine. All were treated with other neuroleptic drugs earlier but without significant improvement. All four patients improved substantially while taking clozapine. A mean reduction of total BPRS score of 41 was achieved in a maximal period of 15 weeks. A significant reduction of symptomatology was noticed within fewer than 2 TABLE 4 Case 4 Weeks of Treatment 0 1.5 8 15 70 Czp mg/day Total BPRS dBPRS in % IPS INS CGI (0-7) 0 100 50 46 0 -8 2.1 1.7 3.3 3 7 7 200 300 300 30 28 28 -34 -6 0 1.1 1.1 2.6 2.6 2.6 6 5 4 1 Side Effects EPS++ EPS+ Drowsiness--e/ Fever' Drooling+++ Drooling++ Drooling++ WBC(X1000) 8.1 8.4 16.2 7.9 8 Note: Czp = clozapine, dBPRS = % change in total Brief Psychiatric Rating Scale (BPRS) score between two consecutive time points, IPS = index of positive symptoms, INS = index of negative symptoms, CGI = clinical global impression, WBC = white blood cells count (per mL), EPS = extrapyramidal side effects. aA Week after starting clozapine, D had a fever of 38°C for 2 days, with normal physical examination, no subjective complaints, and normal blood counts. ++ = moderate, +++ = severe. J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 33:1, JANUARY 1994 69 MOZES ET AL. weeks in three of the four patients. Another decrease, of both positive and negative symptoms then followed, toward 10 to 15 weeks of treatment. All four patients benefited from their remission ofsymptoms in all areas, including daily functioning, social interaction, and academic achievements. Compliance to the clozapine treatment regimen was good enough, despite the weekly blood sampling involved. Maximal dosages reached were 175 to 300 mgt day, a range similar to previous reports in adolescents (Birmaher et al., 1992; Blanz and Schmidt, 1993). On taking clozapine, extrapyramidal side effects caused by former neuroleptic drugs decreasedor even disappeared, including two cases of tardive dyskinesia. No Parkinsonism or tardive dyskinesia appeared while these patients were taking clozapine. After 3 weeks on clozapine, one patient developed bouts of psychomotor agitation, which improved spontaneously. A possibility of obsessive-compulsivedisorder-like symptoms caused by antiserotoninergic properties of clozapine (Baker et al. 1992; Meltzer, 1992a; Patil, 1992) was raised. The most common and troublesome side effect of clozapine was drooling, which diminished spontaneously. Drowsiness,noticed in three of the four patients, reached a peak within a week of onset of treatment and then gradually disappeared. Routine EEG at baseline and during treatment with clozapine were conducted as recommended (Blanz and Schmidt, 1993; Naber et al., 1992). Excitatory EEG changes were found in three of four patients. To prevent the emergence of seizures, we did not increase the dosage of clozapine in these patients. One patient displayed fever with a temperature of 38°C after 10 days of treatment with clozapine up to 100 mg/day. Her temperature returned to normal without reduction of clozapine dosage after 2 days. One patient developed mild enuresis nocturna while taking clozapine. No granulocytopenia developed in any of the four patients. In conclusion, clozapine may be a promising alternative treatment for VEOS patients who do not respond 70 to treatment with other neuroleptics. Clozapine may also be a promising alternative treatment for those children who do not tolerate side effects of other neuroleptics or for those who develop signs of tardive dyskinesia. REFERENCES American Psychiatric Association (1987), Diagnostic and Statistical Manual of MentalDisorders, 3rd edition-revised (DSM-III-R). Washington, DC: American Psychiatric Association Andreasen NC, Flaum M, Swayze VW 2nd, Tyrrell G, Arndt S (1990), Positive and negative symptoms in schizophrenia. Arch Gen Psychia- try 47:615-621 Baker RW, Chengappa KNR, Baired JW, Steingard S, Christ MAG, Schooler NR (1992), Emergence of obsessive compulsive symptoms during treatment with clozapine. 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