management of schizophrenia in children and adolescents

Management of Schizophrenia inChildren and AdolescentsThe Role of Clozapine

Helmut Remschmidt,1 Christian Fleischhaker,2 Klaus Hennighausen1 and Eberhard Schulz2

1 Department of Child and Adolescent Psychiatry, Philipps-University, Marburg, Germany2 Department of Child and Adolescent Psychiatry, Albert-Ludwigs-University, Freiburg, Germany

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2531. Pharmacological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2542. Review of the Literature of Acute and Maintenance Treatment with Clozapine . . . . . . . . . . 254

2.1 Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2542.2 Child and Adolescent Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

3. Indications in Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2564. Acute Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

4.1 Treatment Initiation and Transition From Classical Antipsychotics to Clozapine . . . . . . . . 2574.2 Dosage, Interactions and Plasma Concentrations . . . . . . . . . . . . . . . . . . . . . . . . . 2574.3 Adverse Effects and Their Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

5. Maintenance Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2596. Treatment Termination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2607. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

Abstract Clozapine is a dibenzodiazepine derivative with established antipsychotic ef-ficacy in adult patients with schizophrenic psychoses. There are more than 15studies that have also demonstrated the antipsychotic efficacy of clozapine inchildhood and adolescent schizophrenia.The main advantages of clozapine treatment in this age group in comparison

with typical antipsychotics are: (i) high antipsychotic efficacy during an acuteschizophrenic episode; (ii) better improvement in chronic cases with a high loadof negative symptoms; and (iii) markedly fewer extrapyramidal adverse effectsand, therefore, fairly good tolerability.However, because of its possible adverse effects on the haemopoetic system

(granulocytopenia, agranulocytosis), clozapine should not be used as first-lineantipsychotic medication. Other adverse effects are related to the cardiovascularsystem (hypotonia, tachycardia or arrhythmia), the central nervous system (epi-leptic seizures, fever) and liver function (transient increases in levels of hepatictransaminases). Two other frequent adverse effects are hypersalivation and body-weight gain, which may present a particular problem in adolescents and youngadults.Careful monitoring of haematological parameters and other adverse effects

are preconditions for a successful treatment programme.

DISEASE MANAGEMENT Paediatr Drugs 2000 Jul-Aug; 2 (4): 253-2621174-5878/00/0007-0253/$20.00/0

© Adis International Limited. All rights reserved.

Clozapine is an atypical antipsychoticmedicationwith established efficacy in adults with schizophre-nic psychoses.[1-4] The term ‘atypical antipsychotic’originated in the first clinical descriptions of thethen unique properties of clozapine.[5,6] Clozapinecould be differentiated from ‘typical antipsychotics’by the absence of extrapyramidal adverse effects(EPS), which were formerly thought to be insepa-rable from antipsychotic efficacy. More recently,other substances have been included in the groupof atypical antipsychotics.

1. Pharmacological Properties

Clozapine is a dibenzodiazepine derivativewhichshows, in spite of its structural similarity to imip-ramine, pharmacological aspects that are moreclosely related to those of chlorpromazine than ofimipramine. Clozapine differs from classical anti-psychotics in the following features:[7]• greater arousal-inhibiting activity• no inhibition of apomorphine- or amphetamine-induced stereotypic behaviour

• no induction of catalepsy• no dopaminergic or GABAergic supersensitivityon long term administration

• no depolarisation block of nigrostriatal dopamineneurons on chronic exposure

• relatively high serotonin 5-HT2 to dopamine D2blocking ratio

• less dopamine D2 but greater D1 and D4 receptorblockade.Clozapine reaches its plasma peak concentra-

tion within a few hours after administration. How-ever, the major portion of the drug is immediatelymetabolised and inactivated, mostly by liver en-zymes such as the cytochrome P450 system. Themain metabolites of clozapine (clozapine N-oxideand N-demethyl-clozapine) are likely to have onlylow pharmacological activity.

2. Review of the Literature of Acute andMaintenance Treatment with Clozapine

2.1 Adults

Data from several independent controlled clinical

trials provide evidence that adult patients withschizophrenia, including those who show mini-mal or no response to conventional antipsychoticdrugs, can benefit from clozapine treatment.[8] Fur-thermore, clozapine appears effective in treatingboth positive and negative symptoms of schizo-phrenia in adults.[4,9]From studies in adult patients with schizophre-

nia it is quite clear that clozapine treatment has atleast the same or a superior antipsychotic effectcompared with conventional antipsychotics. Insome studies,[10,11] clozapine was superior with re-gard to symptom reduction in patients with severeand acute schizophrenia. Other studies demon-strated a superiority of clozapine compared withchlorpromazine with regard to a reduction of neg-ative symptoms, such as emotional withdrawal andflattening affect, measured by Brief PsychiatricRating Scale (BPRS) scores.[12]Studies of maintenance treatment in adult pa-

tients with schizophrenia are particularly interesting,because most of the patients were nonresponders toconventional antipsychotics. These studies demon-strate a differential efficacy of clozapine as main-tenance treatment of schizophrenic psychoses com-pared with treatment with classical antipsychotics.Beyond that, it could be demonstrated that clozap-ine is effective in reducing recurrence rates and theduration of hospitalisation.[13-15]

2.2 Child and Adolescent Studies

Although there is a large amount of literature onclozapine in adult patients, there are only a fewreports on its use in childhood- and adolescent-onsetschizophrenia.The first study in this age group[16] was based

on a retrospective analysis of 21 patients, of whom12 were below 18 years of age (mean age 18.1years). Clozapine was offered to adolescents whohad shown inadequate clinical response to otherantipsychotic medications, for whom there wasconcern that the psychotic symptoms were becom-ing chronic, or who had extensive extrapyramidaladverse effects during treatment with other anti-psychotic agents. Clozapine was administered over

254 Remschmidt et al.

© Adis International Limited. All rights reserved. Paediatr Drugs 2000 Jul-Aug; 2 (4)

a mean period of 130 days with an average dosageof 415 mg/day (range 225 to 800 mg/day) and witha mean maintenance dosage of 363 mg/day (range150 to 800 mg/day). Marked or complete improve-ment was observed in 52% (11 out of 21) of theadolescents, and at least some degree of improve-ment in an additional 29% of the patients. Fourpatients did not respond to clozapine and showedno behavioural change. In general, positive symp-toms of schizophrenia showed more clinical im-provement on clozapine than did negative symp-toms. These patients had had a mean of 2.3 priorinpatient hospitalisations and had previously beenprescribed, on average, 2.8 different antipsychoticmedications. 10 patients out of 21 received clozap-ine alone and 11 patients also received small dosesof other antipsychotic drugs. Autonomic adverseeffects were typically transient and included day-time drowsiness, dizziness, orthostatic hypotoniaand hypersalivation. Persistent tachycardia wasalso observed in some of these adolescents. Serumenzyme changes remained within normal range orwere clinically insignificant (and transient) andwere no more frequent than with other antipsy-chotic agents. None of the patients developedagranulocytosis but transient haematologicalchanges were observed in about 50% of the pa-tients. One-third of the patients were found to haveelectroencephalogram (EEG) alterations, includ-ing pathological synchronisation and changes inbackground activity. Similar findings in youthswere reported by other studies.[17,18]As the guidelines[19] do not allow the use of

clozapine as a first-line drug, most patients havebeen treated with at least 2 other antipsychotics(typical or atypical) before clozapine is introduced.Our group[20,21] evaluated the short term effects ofclozapine in a prospective nonblind trial of 15 outof a total of 40 consecutively admitted (October1991 to May 1994) inpatients who fulfilled theDSM-III-R criteria[22] for schizophrenia. These pa-tients received clozapine because of nonresponseto earlier treatment with conventional antipsychot-ics. At the beginning of the prospective investiga-tion, the age range of the patients was 11 to 20

years, with a mean of 17.3 (standard deviation 2.2)years.Individual mean values of 2 measurements at

weeks 5 and 6 during treatment with typical anti-psychotics and at weeks 5 and 6 of clozapine treat-ment demonstrated a significant (p = 0.014) reduc-tion of positive symptoms according to the Scalefor the Assessment of Positive Symptoms (SAPS),a decline in BPRS-derived depressive symptoms(p =0.011) aswell as a decrease in total BPRS scores(p =0.012) during clozapine treatment. For the neg-ative symptoms of schizophrenia (Scale for the As-sessment of Negative Symptoms; SANS), a trendtowards lower scores could be observed during theclinical trial with clozapine (p = 0.127). With re-spect to the 2 response criteria (20% drop in totalBPRS scores and final minimumBPRS score of 34or less), 7 patients were classified as respondersand 8 as nonresponders to clozapine treatment.Compared with the symptomatology at intake, re-sponders to clozapine showed a decline in totalBPRS scores ranging from 39.3 to 63.4%.Several other studies listed in table I havemean-

while confirmed these results in principle. Beyondthese results, the following tendencies can be con-cluded from the literature.• Overall, more than 50% of patients treated withclozapine showed significant reduction of thesymptomatology. In some studies, there was animprovement in all of the treated cases (see ta-ble I). The improvement applies not only to pos-itive symptoms but also to negative symptoms,albeit to a lesser extent.[20,34] The only control-led double-blind study, which was a comparisonof clozapine with haloperidol in 21 patientsaged 14 ± 2.3 years,[34] found that clozapine wassuperior to haloperidol in all measures of psy-chosis. However, seizures and neutropenia weremajor concerns. For that reason, clozapinemed-ication had to be discontinued in 5 cases; a further3 patients discontinued because of nonresponse.

• The main indications for clozapine treatmentare nonresponse to conventional antipsychotictreatment, severe adverse effects, especially extra-

Clozapine in Child and Adolescent Schizophrenia 255


pyramidal symptoms that cannot be controlled,and the avoidance of chronicity.[25]

• As far as age is concerned, clozapine has alsobeen administered in children; most of the stud-ies, however, report on treatment in adolescentsusing similar dosages as in adults, starting withan initial dosage of 12.5 mg/day and maintain-ing an average daily dose of 285mg.[25]

• With careful professional observation and mon-itoring of haematological parameters and adverseeffects, clozapine is an effective medication thatcan be used in childhood- and adolescent-onsetschizophrenia.

3. Indications in Children and Adolescents

There are 3 main indications for clozapine treat-ment in childhood- and adolescent-onset schizophre-nia: (i) acute schizophrenic psychoses characterisedby delusions, hallucinations, thought disorders, ag-gressive and acting-out behaviour; (ii) chronic andtherapy-refractory schizophrenic psychoses; and(iii) symptom suppression and prophylaxis of re-lapse in acute and chronic schizophrenic psychosesduring long term treatment.[33]The guidelines[19] for clozapine treatment require,

however, that patients have not responded to other

(conventional) antipsychotic medications or do nottolerate them. In most countries, at least 2 other anti-psychotic agents have to be tested before clozapinetreatment may be introduced. A further requirementis the absence of anomalies in the haemopoetic sys-tem (white blood cell count >3500/mm3 and normaldifferential blood count).White blood cell count should be monitored

during treatment. Recommendations for the fre-quency and duration of monitoring depend on thecountry. Examples are: in the US, weekly duringthe entire treatment and 4 weeks after discontinua-tion; in the UK, weekly during the first 18 weeksand at least every other week for the first year, thenat least every 4 weeks and for 4 weeks after discon-tinuation; in Germany, weekly for the first 18weeks and subsequently every 4 weeks. Addition-ally, total and differential blood counts should beadministered if any symptoms or hints of agranu-locytosis occur (e.g. febrile infections).Absolute contraindications are: hypersensitivity

to clozapine; known dysfunction of the haemopoeticsystem under clozapine or other antipsychotics orother agents; acute intoxications or psychoses in-duced by other agents with an adverse effect on thecentral nervous system [especially alcohol (ethanol),antidepressants, other antipsychotics, hypnoseda-

Table I. Studies of clozapine in childhood- and adolescent-onset schizophrenia

Number of patients Age (years) Daily dosage (mg) Response Reference21 11-18 150-800 Marked improvement or remission in 11/21 1615 11-20 100-600 Symptom reduction (BPRS) of >20% in 47% (7/15) 2020 14-22 75-600 Symptom reduction in a special subgroup of responders 213 17-18 300-400 3/3 improved 231 17 600 Improved 24

57 10-21 75-800 Significant improvement in 67% (38/57) 252 14-16 40-600 2/2 improved 264 10-13 150-300 4/4 improved 272 13-18 500-600 2/2 improved 28

13 14-17 240 Significant improvement in 77% (10/13) 291 11 400 Moderate improvement 30

11 12-17 125-825 Improvement in CGI (58%) 316 NR 300 6/6 improved 32

36 18 50-800 Improvement in 75% (27/36) 3321 6-18 25-525 Clozapine superior to haloperidol 34BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression; NR = not reported.



tives and opioids]; severe diseases affecting thecardiovascular system, the gastrointestinal systemor kidney function; atonia of the gut; and therapy-refractory epileptic seizures.Relative contraindications and special risk fac-

tors for clozapine treatment are: pregnancy, braindysfunction, glaucoma, prostate adenoma, combi-nation with other medications that can induce dys-haematopoiesis, allergic reactions against othermedications and combination with depot antipsy-chotics, especially of the tricyclic type.

4. Acute Treatment

Treatment recommendations are in general thesame as in adult psychiatry, and should follow theguidelines of the manufacturer.[35] Age restrictionsfor the use of clozapine have been modified in thepast few years. However, as for many other anti-psychotics, use in children below the age of 16years is not generally recommended; data sheetsstate, for example, in the US and Australia that‘safety and effectiveness in pediatric patients havenot been established’. In the UK, the drug is ‘notrecommended for children’ and in Germany ‘chil-dren below 16 years are a relative contraindication’.We have modified these guidelines slightly for

the younger age group of patients with early-onsetschizophrenia. These guidelines[36] point out thatclozapine dosage must always be adjusted individ-ually for each patient. The lowest effective dosageshould be used. To establish this dosage, carefultitration is recommended. Clozapine is usually ad-ministrated orally. In some countries (e.g. Ger-many), ampoules for intramuscular injection areavailable but are used only in rare cases if neces-sary and can usually be replaced by oral adminis-tration after a few days.Some general recommendations for clozapine

treatment in childhood- and adolescent-onsetschizophrenia have been formulated by a consen-sus conference of 13 German child and adolescentpsychiatrists who have special expertise in clozap-ine treatment.[36] The main principles of theseguidelines are listed in table II.

At present, it is unclear if other atypical antipsy-chotics such as olanzapine[37] or risperidone havea similar antipsychotic effect or are comparable toclozapine in the other domains.

4.1 Treatment Initiation and Transition FromClassical Antipsychotics to Clozapine

As clozapine cannot be used as a first-line drug,treatment initiation usually has to start with dis-continuation of the previous medication. In pa-tients pretreated with classical antipsychotics, it isrecommended that this medication is discontinuedby lowering the dosage over a period of at least 1week and initiation of the clozapine treatment aftera complete drug-free interval of at least 24 hours.However, for some patients a complete discontin-uation of the previous medication can lead to rapidclinical deterioration and a crossover of antipsy-chotic medications may be necessary. In these pa-tients the concomitant antipsychotic medicationshould be restricted to 1 substance and the dosageshould be lowered and finally discontinued withthe increasing dosage of clozapine. The use of benzo-diazepines as comedication should be avoided be-cause of the risk of respiratory depression, espe-cially in the initial treatment phase.

4.2 Dosage, Interactions and Plasma Concentrations

Clozapine treatment can be started with a doseof 12.5mg once or twice on the first and the seconddays, followed by 1 or 2 doses of 25mg on the thirdday. If the drug is well tolerated, the daily dose can

Table II. Recommendation for clozapine treatment in childhood-and adolescent-onset schizophrenia[36]

1. Clozapine treatment is recommended in acute early-onsetschizophrenia in clinical conditions2. At least 1 traditional antipsychotic agent administered for 4-6weeks and in adequate dosage should have failed to improvethe positive and/or negative symptomatology3. A further indication is the occurrence of intolerable adverseeffects with classical antipsychotics4. Clozapine is also effective in chronic schizophrenia5. No recommendation can be given for relapse prevention(no adequate data)



be slowly increased in steps of 25mg with the aimof achieving a dosage of between 200 and 350mg/day within 3 weeks. Usually, these dosages areeffective. If not, it can also be recommended inadolescent patients to increase the daily dosage inincrements of 25 to 50mg at weekly intervals. Inour experience there are some adolescent patients,refractory to other antipsychotic medications (bothclassical and atypical), who can benefit fromhigher dosages of clozapine (600mg/day andmore).In these cases, extremely careful observation underinpatient conditions and monitoring of adverse ef-fects is necessary.As in adult schizophrenia, clozapine should be

administered to children and adolescents as mono-therapy. Some comedications are possible, but suchcombined therapy should take into account theknown interactions with clozapine and should berestricted to cases in which clozapine alone at anappropriate dosage is not effective and other anti-psychotics (typical and atypical) are not successful.Table III describes some of the known interac-

tions of clozapine with other agents. These interac-tions have mainly been described in adult patients,but some of them also in early-onset schizophre-nia.[21,38] One important key to the understandingof these interactions is the studyof clozapineplasmaconcentrations.In studies with adult patients, a relation between

clozapine plasma concentration and clinical re-sponse has been reported. Clozapine plasma con-centrations above 350 μg/L led to a clinical re-sponse in 64 to 86% of patients; the response ratewas 22 to 40% when the plasma concentration wasbelow 350 μg/L.[39,40] Another study showed re-sponse rates of 73% and 29% above and below,respectively, a plasma concentration threshold of420 μg/L.[41] In a receiver operation curve (ROC)analysis of plasma concentration and response rate,the optimal threshold for a clinical response wasestimated at 350 μg/L.[42] In adolescent patients alinear relationship between clinical improvementand clozapine concentration could be demonstra-ted.[43] However, the implementation of plasmaconcentrations in the clinical routine has also been

questioned[44] and there are marked individual dif-ferences in dose–plasma concentration relation-ships.The available data from adult and adolescent pa-

tients with schizophrenia can be summarised as fol-lows.[20,21,45]• Therapeutically relevant plasma concentrationshave been measured over a wide range. An op-timal response threshold is assumed for plasmaconcentrations between 350 and 420 μg/L.

• Serum concentrations of clozapine above 250μg/L may increase the risk of adverse effects.

• In case of comedication, the interactions de-scribed in table III have to be taken into account.As some adverse effects of clozapine are dose

related, for example epileptic seizures, plasma (orserum) concentration measurements, not only inadults but also in adolescent patients, have beenfound to be useful.[20,21,38] Especially in therapy-refractory cases, or when a comedication is used,the measurement of plasma concentrations can giveimportant hints to improve the treatment regimen.

4.3 Adverse Effects and Their Management

Many of the problems of tolerability and ad-verse effects are connected with the receptor pro-file of clozapine. Some of the adverse effects seemdose related (e.g. epileptic seizures), but others arenot (e.g. agranulocytosis). As in treatment with

Table III. Interactions of clozapine with other agents

Agent EffectAlcohol (ethanol) Intensifies effects of alcohol on blood

pressureBenzodiazepines Sedation, depression of respirationCarbamazepine Reduction of clozapine plasma

concentrations, reduction of clozapineeffects

Lithium Enhancement of extrapyramidaladverse effects

Nicotine Reduction of clozapine plasmaconcentrations

SSRIs Elevation of clozapine plasmaconcentrations, intensification ofclozapine effects

Tricyclic antidepressants Enhancement of anticholinergic effectsSSRIs = selective serotonin reuptake inhibitors.



other antipsychotic agents, there is a remarkableinterindividual variability in tolerability. This hasto be taken into account, and is an argument forcautious dosage titration, starting with low dosagesand gradual increase.There are no data on adverse effects in large

samples of children and adolescents with schizo-phrenia, but clinical experience shows that the sit-uation is similar to that in adults. Themost frequentadverse effects are EEG changes, dizziness, in-creased liver enzymes, orthostatic hypotension,leucocytosis or leucopenia, hypersalivation andbodyweight gain. Only in a few cases are theseadverse effects severe enough to warrant either areduced clozapine dosage or discontinuation. How-ever, especially in adolescents and young adults,hypersalivation and bodyweight gain are perceivedas major problems and may lead to reduced com-pliance.As the greatest danger is adverse effects of the

haemopoetic system, we will comment briefly onthis important issue. During the first weeks oftreatment, transient white blood count disorderscan occur.[46] Usually, these changes do not compeldiscontinuation of clozapine treatment, unless thewhite cell count drops down below 3000/mm3. Insome cases, thrombocytopenia was observed. Se-vere and life-threatening granulocytopenia (neu-trophilic granulocytes <1500/mm3) or agranulocy-tosis (neutrophilic granulocytes <500/mm3) haveto be distinguished from these milder disorders ofthe haemopoetic system. If agranulocytosis occurs,it is seen within the first 18 weeks of treatment in85% of cases.[47] The frequency of granulocytopeniawas calculated to be 2.8%; the frequency of agran-ulocytosis 0.6%.[48] The cumulative risk of agran-ulocytosis has been estimated in a large sample as0.8% after 1 year of treatment and 0.91% after 1.5years.[49] The risk increases with age and is higherin females than in males.Clozapine-induced granulocytopenia and agranu-

locytosis can be treated successfully if they are di-agnosed early enough. However, 2 out of 73 pa-tients with clozapine-induced agranulocytosis diedfrom infectious complications.[49] Thus, regular

blood counts according to the guidelines in section3 are extremely important, as well as strict consid-eration of the contraindications and detailed edu-cation of the patients and their parents.If the total white cell count drops below

3500/mm3, a total and differential blood count isrecommended twice weekly. A white cell bloodcount below 3000/mm3 or a granulocyte count be-low 1500/mm3 requires an immediate discontinu-ation of the medication and daily haematologicalmonitoring until the haematological parametershave recovered. For any patient with a white cellcount below 2000/mm3 or a granulocyte count be-low1000/mm3 a permanent discontinuation of cloza-pine is necessary. After withdrawal of clozapine,recovery can usually be observed.Braun-Scharm and Martinius[18], whose study

focused specifically on EEG changes with clozap-ine, pointed out an apparent correlation betweendosage and risk of seizures, a connection that hadalready been described in adults.[2,50] These find-ings underscore the clinical requirement for EEGexaminations, both before and during administra-tion of clozapine. Arelationship between clozapinedosage and incidence of seizures has been de-scribed.[51] These results are not unequivocal, butthere is evidence for an increased risk of seizuresat dosages above 600 mg/day and during the titra-tion period even at dosages below 300 mg/day.In order to cover the whole field of adverse ef-

fects, standardised monitoring procedures are rec-ommended, for instance the Dosage Record Treat-ment Emergent Symptom Scale (DOTES) of theNational Institute of Mental Health[52] or a similarinstrument.

5. Maintenance Treatment

As in adults, antipsychotic efficacy can beachieved in adolescent patients with daily dosesbetween 200 and 350mg. Higher dosages are pos-sible, but the larger proportion should then begiven at bedtime. Once antipsychotic efficacy isestablished and stability of the patient’s status isachieved, the lowest possible maintenance dosageshould be established by a careful downward titra-



tion until a dosage is reached at which a reactiva-tion of psychotic symptoms can be avoided andadverse effects are minimised. According to ourclinical experience this can be achieved for mostpatients with dosages around 200 mg/day.

6. Treatment Termination

In principle, there are 2 requirements for treat-ment termination: abrupt discontinuation becauseof leucopenia or other adverse effects, and plannedtermination of treatment because of a lack of re-sponse. In the first case, recurrence of psychoticsymptoms can be expected and another antipsy-chotic medication will probably be necessary. Inthe latter case, the introduction of another antipsy-chotic drug is recommended.At this point the necessity for, and benefits of,

long term treatment versus planned treatment ter-mination after a good response and an adequateperiod of maintenance treatment have to be dis-cussed. So far, there are insufficient empirical dataabout the necessity and duration of long term treat-ment with clozapine. The risk of a relapse, whichmight be even more difficult to treat, has led manyexperts to recommend continuous treatment whenthere is a good response and the drug is well toler-ated. However, the expectations and wishes of pa-tients and/or parents, and problems with compli-ance, might require a planned treatment termination.In this case, a gradual reduction in dosage over aperiod of 2 to 4 weeks is recommended. The patientshould then be seen at regular intervals in order tobe sure that his/her situation is stable. If psychoticsymptoms recur, reinitiation of clozapine treatmentis recommended, starting again with an initial dos-age of 12.5 mg/day but possibly with a quickerupward titration in order to reach the therapeuticlevel.

7. Conclusions

Clozapine can be used as an antipsychotic med-ication with established effects in childhood- andadolescent-onset schizophrenia. However, becauseof its possible severe adverse effects, it should notbe used as first-line medication. The guidelines re-

quire the administration of 2 classical antipsychot-ics before starting clozapine medication. As far asefficacy is concerned, the administration of thedrug can be recommended during the acute phaseof a schizophrenic disorder as well as in chroniccases with a predominantly negative symptomatol-ogy. Another indication for clozapine treatment issevere extrapyramidal adverse effects during treat-ment with conventional antipsychotics.In spite of the danger of adverse effects (agran-

ulocytosis or granulocytopenia, hypotonia, epilep-tic seizures, hypersalivation and bodyweight gain),clozapine can be used with good efficacy and tol-erability by closely adhering to the following prin-ciples:• thorough information of the patient and his/herfamily about the drug and the treatment regimen

• carefulmonitoring of haematological parameters• EEG recording before treatment initiation andduring maintenance treatment

• individual adjustment of the dosage for each pa-tient

• careful consideration of drug interactions ifclozapine is coadministered with other drugs(which is not recommended, but might be nec-essary in a few cases)

• possible use of blood concentration monitoringto establish the effective individual dosage or todetect anomalies of metabolism.

References1. Kane JM, Honigfeld G, Singer J, et al. Clozapine in treatment-

resistant schizophrenics. Psychopharmacol Bull 1988; 24: 62-72. Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for

clinical management. J Clin Psychiatry 1990; 50: 329-383. Naber D, Müller-Spahn F, editors. Clozapin. Pharmakologie

und Klinik eines atypischen Neuroleptikums: eine kritischeBestandsaufnahme. Stuttgart: Schattauer, 1992

4. Meltzer HY. Multiple-outcome criteria in schizophrenia: anoverview of outcome with clozapine. Eur Psychiatry 1995;10: 19-25

5. Angst J, Bente D, Berner P. Das klinische Wirkungsbild vonClozapin (Untersuchung mit dem AMP-System). Phar-makopsychiatrie 1971; 4: 200-11

6. Stille G, Hippius H. Kritische Stellungnahme zum Begriff derNeuroleptika (und von pharmakologischen und klinischenBefunden mit Clozapin). Pharmakopsychiatrie 1971; 4: 182-91

7. Coward DM. General pharmacology of clozapine. Br J Psychi-atry 1992; 160 Suppl. 17: 5-11



8. Kane JM. Clinical efficacy of clozapine in treatment-refractoryschizophrenia: an overview. Br J Psychiatry 1992; 160 Suppl.17: 41-5

9. Meltzer HY. The effect of clozapine and other atypical antipsy-chotic drugs on negative symptoms. In: Marneros A, An-dreasen NC, Tsuang MT, editors. Negative versus positiveschizophrenia. NewYork (NY): SpringerVerlag, 1991: 365-76

10. Gerlach J, Koppelhus P, Helweg E, et al. Clozapine and halo-peridol in a single-blind cross-over trial: therapeutic and bio-chemical aspects in the treatment of schizophrenia. ActaPsychiatr Scand 1974; 50: 410-24

11. Honigfeld G, Patin J, Singer J. Clozapine: antipsychotic activityin treatment-resistant schizophrenics. Adv Ther 1984; 1: 77-97

12. EkblomB, Haggstrom JE. Clozapine (Leponex) comparedwithchlorpromazine: a double-blind evaluation of pharmacologi-cal and clinical properties. Curr Ther Res 1974; 16: 945-57

13. Leon CA. Therapeutic effects of clozapine: a four-year follow-upof a controlled clinical trial. Acta Psychiatr Scand 1979; 60:471-80

14. Meltzer HY. Dimensions of outcome with clozapine. Br J Psy-chiatry 1992; 17: 46-53

15. Breier A, Buchanan RW, Irish D, et al. Clozapine treatment ofoutpatients with schizophrenia: outcome and long-term re-sponse patterns. Hosp Community Psychiatry 1993; 44: 1145-9

16. Siefen RG, Remschmidt H. Behandlung mit Clozapin beischizophrenen Jugendlichen. Z Kinder Jugenpsychiatr 1986;14: 245-57

17. Schmidt MH, Trott GE, Blanz B, et al. Clozapine medicationin adolescents. In: Stefanis CN, Rabavilas AD, Soldatos CR,editors. Psychiatry: a world perspective. Vol. 1. Proceedingsof the VIII World Congress of Psychiatry; 1989 Oct 12-19;New Jersey (NJ): Excerpta Medica, 1991: 1100-4

18. Braun-Scharm H, Martinius J. EEG-Veränderungen undAnfälle unter Clozapinmedikation bei schizophrenenJugendlichen. Z Kinder Jugenpsychiatr 1991; 19: 164-9

19. Farmer AE, Blewett A. Drug treatment of resistant schizophrenia:limitations and recommendations. Drugs 1993; 45: 374-83

20. Fleischhaker C. Die Bedeutung der biogenen Amine für diePharmakotherapie schizophrener Psychosen in der Adoleszenz[dissertation]. Marburg: University of Marburg, 1996

21. Schulz E, Fleischhaker C, Clement HW, et al. Blood biogenicamines during clozapine treatment of early-onset schizophre-nia. J Neural Transm 1997; 104: 1077-89

22. American Psychiatric Association. Diagnostic and statisticalmanual of mental disorders (DSM-III-R), 3rd ed. Washing-ton, DC: American Psychiatric Association, 1987

23. Birmaher B, Baker R, Kapur S, et al. Clozapine for the treat-ment of adolescents with schizophrenia. J Am Acad ChildAdolesc Psychiatry 1992; 31: 160-4

24. Boxer G, Davidson J. More on clozapine [letter]. J Am AcadChild Adolesc Psychiatry 1992; 31: 993

25. Blanz B, Schmidt MH. Clozapine for schizophrenia [letter]. JAm Acad Child Adolesc Psychiatry 1993; 32: 223-4

26. Mandoki M. Clozapine for adolescents with psychosis: litera-ture review and two case reports. J Child Adolesc Psy-chopharmacol 1993; 3: 213-21

27. Mozes T, Toren P, Chernauzan N, et al. Clozapine treatment invery early onset schizophrenia. J Am Acad Child AdolescPsychiatry 1994; 33: 65-70

28. Jacobsen LK, Walker MC, Edwards JE, et al. Clozapine in thetreatment of a young adolescent with schizophrenia. J AmAcad Child Adolesc Psychiatry 1994; 33: 645-50

29. Levkovitch Y, Kaysar N, Kronnenberg Y, et al. Clozapine forschizophrenia [letter]. J Am Acad Child Adolesc Psychiatry1994; 33: 431

30. Towbin KE, Dykens EM, Pugliese RG. Clozapine for earlydevelopmental delays with childhood-onset schizophrenia:protocol and 15-month outcome. J Am Acad Child AdolescPsychiatry 1994; 33: 651-7

31. Frazier JA, Gordon CT, McKenna K, et al. An open trial ofclozapine in 11 adolescents with childhood onset schizophre-nia. J Am Acad Child Adolesc Psychiatry 1994; 33: 658-63

32. Mandoki M. Anti-aggressive effects of clozapine in childrenand adolescents [abstract]. In: Proceedings of the AnnualMeeting, Society for Biological Psychiatry; 1994 May; Phil-adelphia. Biol Psychiatry 1994; 35 Suppl.: 469

33. Remschmidt H, Schulz E, Martin M. An open trial of clozapinein thirty-six adolescents with schizophrenia. J Child AdolescPsychopharmacol 1994; 4: 31-41

34. Kumra S, Frazier JA, Jacobsen LK, et al. Childhood-onsetschizophrenia: a double-blind clozapine-haloperidol compar-ison. Arch Gen Psychiatry 1996; 53: 1090-7

35. Bleeham T. Leponex® - Clozaril® (clozapine) literature reviewData on file, Sandoz Pharma Ltd, 1993

36. Elliger T, Englert E, Freisleder FJ, et al. Zur Behandlungschizophrener Psychosen des Kindes- und Jugendalters mitClozapin (Leponex). Konsensuskonferenz vom 4. März1994. Z Kinder Jugenpsychiatr 1994; 22: 325-27

37. Fulton B, Goa KL. Olanzapine: a review of its pharmacologicalproperties and therapeutic efficacy in the management ofschizophrenia and related psychoses. Drugs 1997; 53: 281-98

38. Schulz E, Fleischhaker C, Remschmidt H. Correlated changesin symptoms and neurotransmitter indices during mainte-nance treatment with clozapine or conventional neurolepticsin adolescents and young adults with schizophrenia. J ChildAdolesc Psychopharmacol 1996; 6: 119-31

39. Perry PJ, Miller DD, Arndt SV, et al. Clozapine and norclozap-ine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 1991; 148:231-5

40. Miller DD, Fleming F, Holman TL, et al. Plasma clozapineconcentrations as a predictor of clinical response: a follow-upstudy. J Clin Psychiatry 1994; 55 Suppl. B: 117-21

41. Potkin SG, Bera R, Gulasekaram B, et al. Plasma clozapineconcentrations predict clinical response in treatment-resistantschizophrenia. J Clin Psychiatry 1994; 55 Suppl. B: 133-6

42. Kronig MH, Munne RA, Szymanski S, et al. Plasma clozapinelevels and clinical response for treatment-refractory schizo-phrenic patients. Am J Psychiatry 1995; 152: 179-82

43. Piscitelli SC, Frazier JA, McKenna K, et al. Plasma clozapineand haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response. J Clin Psychi-atry 1994; 55 Suppl. B: 94-7

44. Olesen OV. Therapeutic drug monitoring of clozapine treat-ment. Therapeutic threshold value for serum clozapine con-centrations. Clin Pharmacokinet 1998; 34: 497-502

45. Lindenmayer JP, Apergi FS. The relationship between clozap-ine plasma levels and clinical response. Psychiatr Ann 1996;26: 406-12

46. Hummer M, Kurz M, Kurzthaler I, et al. Clozapine-inducedtransient white blood count disorders. J Clin Psychiatry 1994;55: 429-32

47. Dev VJ, Krupp P. Adverse event profile and safety of clozapine.Rev Contemp Pharmacother 1995; 6: 197-208



48. Krupp P, Barnes P. Clozapine-associated agranulocytosis: riskand aetiology. Br J Psychiatry 1992; 160: 38-40

49. Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-inducedagranulocytosis: incidence and risk factors in the UnitedStates. N Engl J Med 1993; 329: 162-7

50. Naber D, Hippius H. The European experience with the use ofclozapine. Hosp Community Psychiatry 1990; 41: 886-90

51. Pacia SV, Devinsky O. Clozapine-related seizures: experiencewith 5,629 patients. Neurology 1994; 44: 2247-9

52. National Institute of Mental Health (NIMH). DOTES-dosagerecord and treatment emergent symptom scale. In: Guy W,

editor. ECDU Assessment Manual for Psychopharmacology.Rockville (MD): National Institute of Mental Health, US De-partment of Health, Education and Welfare, 1976: 223-44

Correspondence and offprints: Professor Helmut Remschmidt,Department of Child and Adolescent Psychiatry, Philipps-University, D-35033 Marburg, Germany.E-mail: [email protected]



management of schizophrenia in children and adolescents

Documents