ManageMent issues

Paediatric psychopharmacology in schizophreniaanthony James

Abstractthe evidence for the use of antipsychotic medication in the treatment of

early-onset schizophrenia (onset at age less than 18 years), based on an

increasing number of randomized controlled trials, points to therapeutic

efficacy with moderate-to-large effect sizes. some of the trials, however,

were of short duration and a few were industry funded. Medication with

both first-generation (Fga) and second-generation (sga) antipsychotics

is also associated with considerable side effects. nevertheless, cautious

use alongside psychosocial interventions can be recommended, provided

there is continued, careful monitoring.

Keywords adolescent; antipsychotics; psychopharmacology; RCts;

schizophrenia

IntroductionEarly-onset schizophrenia (EOS), diagnosed according to Diag-nostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria, is a severe illness often with a poor prognosis. EOS is continuous with adult-onset schizophrenia, but generally has more premorbid and language abnormalities, a higher genetic loading, and is less responsive to treatment.1

A central feature of schizophrenia is overactivity of dopamine in the mesolimbic pathways. Current antipsychotics work by low-ering dopamine activity via blockade of D2 receptors. The ‘typical’ or first-generation antipsychotics (FGAs) were followed by ‘atypi-cal’ or second-generation antipsychotics (SGAs), designed to be similar to clozapine but with lower dopamine D2 receptor affinity and higher affinity for serotinergic 5-HT2A receptors. Aripiprazole, a novel mixed dopamine agonist and antagonist, is thought to reduce dopamine overactivity in the mesolimbic system while pur-portedly increasing dopamine underactivity in frontal lobe projec-tions. There are important maturational changes in the dopamine system in adolescence that may alter sensitivity to side effects.2

Schizophrenia

Recently there has been an increasing number of randomized con-trolled trials (RCTs) demonstrating the efficacy of antipsychotic

Anthony James MBBS MRCP MRCPsych MPhil MA is a Consultant Adolescent

Psychiatrist at the Highfield Adolescent Unit, Warneford Hospital,

Oxford, UK. He qualified at St Bartholomew’s Hospital, London, and

trained at the Maudsley Hospital, London. His research interests

include early-onset psychoses, OCD and ADHD. Conflicting interests:

none declared.

PsYCHiatRY 7:11 4

medication in the treatment of EOS. A Cochrane review3 of childhood-onset schizophrenia (age at onset less than 13 years), involving six studies with 256 children and adolescents, showed that antipsychotics were effective; however, no one drug was more effective than another, with the exception of clozapine over haloperidol.4 A systematic review and meta-analysis of 15 studies of antipsychotics in children and adolescents (up to the year 2003) showed an average response in 8 studies employing SGAs of 55.7%, compared with 72.3% in the 13 studies that used FGAs. The effect size of 0.36 in favour of the FGAs was not significant.

An 8-week RCT by Sikich et al.5 of 50 older children and ado-lescents aged 9–18 years with positive psychotic symptoms com-pared the efficacy of risperidone (6.3 mg/kg), olanzapine (7.4 mg/kg), and haloperidol (5.7 mg/kg). Improvement was seen in 88% of those taking olanzapine, 74% for risperidone, and 53% for haloperidol. Drop-outs were fairly common, largely due to extrapyramidal side effects. All the medications produced greater weight gain and more extrapyramidal side effects than typically seen with adults.

The efficacy of antipsychotics in treating EOS has been shown in five RCTs involving FGAs and nine RCTs involving SGAs (four with risperidone, three with clozapine, one with olanzapine, and one with aripiprazole) (Table 1). The results of a large multicen-tre RCT in the USA – Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS)19 – are awaited.

ClozapineIn a 12-week RCT, Kumra and colleagues18 found that clozapine was more effective than high-dose olanzapine in terms of reduc-ing both psychosis scores and negative symptoms. Sporn et al.20 undertook a double-blind, open-label clozapine trial with base-line and 6-week evaluations, and 2–6-year follow-up. Clinical improvement after 6 weeks of clozapine treatment was strongly associated with the N-desmethylclozapine/clozapine ratio at the 6-week timepoint. A previous RCT demonstrated a superiority of clozapine over haloperidol,4 and Shaw et al.14 found clozapine to be superior to olanzapine for negative symptoms, but with more adverse side effects (see Table 1). Overall, clozapine appears to be a uniquely beneficial second-line agent for treating children with refractory schizophrenia.21

Pharmacokinetics

For clozapine and olanzapine, the pharmacokinetic profile varies greatly between individuals and in those who smoke. The serum concentrations of olanzapine and olanzapine metabolites in ado-lescents show high intra-individual variability.22 Monitoring of plasma levels is indicated, especially when there is doubt about the therapeutic response.

Side effects

Extrapyramidal side effectsChildren and adolescents appear to be more likely to experience extrapyramidal side effects (EPSs) – parkinsonian side effects and dystonia – with FGAs and SGAs than adults.23 Clozapine and quetiapine appear to be associated with relatively low EPS rates in paediatric patients, as is the case in adults.

58 © 2008 elsevier Ltd. all rights reserved.

ManageMent issues

Randomized controlled trials of antipsychotic medication in the treatment of schizophrenia in children and adolescents

Reference Drugs and mean ± sD

daily dose

Duration Participants effectiveness adverse effects

Faretra et al.

(1970)6Fluphenazine: up to

1.25 mg t.d.s. (n = 30)

Haloperidol: up to 1.25

mg t.d.s.(n = 30)

8 weeks n = 60

age 5–12 years

87% childhood-

onset schizophrenia

Cgi: no differences

(fluphenazine vs

haloperidol)

engelhardt

et al. (1973)7Fluphenazine: mean

10.4 mg/day (n = 15)

Haloperidol: mean 10.4

mg/day (n = 15)

12 weeks n = 30

age range

6–12 years

Cgi and CDRs: no

differences (fluphenazine vs

haloperidol)

Pool et al.

(1976)8Loxapine: 87.5 mg

Haloperidol: 9.8 mg

Placebo

4 weeks n = 75

Mean age

15.5 years

Both treatments significantly

reduced BPRs total ratings

compared with placebo

no significant differences

observed between active

treatment groups

ePs (e.g. muscle rigidity)

noted in 19 subjects

(73%) of 26 receiving

loxapine and 18 (72%) of

25 receiving haloperidol

sedation also problematic

Realmuto et al.

(1984)9thiothixene: 16.2 mg

thioridazine: 178 mg

6 weeks n = 21

Mean age

15.5 years

Both treatments significantly

reduced BPRs total scores

Marked sedation

spencer et al.

(1992)10

Cross-over design:

Haloperidol: 1.8 mg vs

placebo

6 weeks n = 16

Mean age

8.9 years

Cgi-i much/very much

improved: 12 (75%) of 16;

marked reduction in severity

of persecutory ideation and

hallucinations

sedation

Kumra et al.

(1996)4Clozapine: 176 ± 149

mg Haloperidol: 16 ±

8 mg

6 weeks n = 21

Mean ± sD age

14.0 ± 2.3 years

Clozapine > haloperidol

in terms of positive (saPs

total) and negative (sans

total) symptoms

Clozapine: high rates of

neutropenia and seizures

Yao (2003)11 Risperidone: dose range

0.25–3 mg/day (n = 21)

Haloperidol: dose range

0.5–12 mg/day (n = 21)

6 weeks n = 42

Childhood-onset

schizophrenia.

Mean age 11 years

BPRs Risperidone fewer ePs

than haloperidol: relative

risk 0.10 (Ci 0.03–0.36);

nnt 2 (Ci 2–2)

sikich et al.

(2004)5Risperidone: 4 ± 1.2 mg

Olanzapine: 12.3 ± 3.5

mg Haloperidol: 5.0 ±

2.0 mg

8 weeks n = 50

Mean ± sD age

14.7 ± 2.7 years

Broad psychotic

disorders

BPRs-C reduction >20%

(risperidone 74%,

olanzapine 88%, haloperidol

54%) all Cgi-i much/very

much improved

ePs and weight gain

greater than that reported

in adult studies

Xiong (2004)12 Risperidone: dose range

0.5–5 mg/day (n = 30)

Chlorpromazine: dose

range 50–400 mg/day.

(n = 30)

8 weeks n = 60

age range 7–16 years

Mean age 13 years

Length of illness

9–9.5 years

BPRs: no difference

between risperidone and

chlorpromazine

Kryzhanovskaya

et al. (2006)13

Olanzapine: 11.1 ± 4.0

mg vs placebo

6 weeks n = 107

Mean ± sD age

16.2 ± 1.3 years

Olanzapine > placebo in

terms of improvement

from baseline to endpoint

on the BPRs-C

(P = 0.003) and Cgi-s

(P = 0.004), respectively

treatment response rate

not significantly different

between olanzapine (37.5%)

and placebo (25.7%)

Mean ± sD weight gain

with olanzapine 4.3 ±

3.3 kg

(continued)

PsYCHiatRY 7:11 459 © 2008 elsevier Ltd. all rights reserved.

ManageMent issues

shaw et al.

(2006)14

Clozapine: 327 ± 113

mg Olanzapine: 18.1 ±

4.3 mg

8 weeks n = 25

Mean age

12 years

Clozapine > olanzapine;

improvement in negative

symptoms (sans)

Marked weight gain at

4 kg during the 8-week

trial noted in both

groups, at 2-year follow-

up 6 (40%) of 15 patients

had dyslipidaemia

Haas et al.

(2007)15

Risperidone: 1–3 mg vs

risperidone 4–6 mg vs

placebo

6 weeks n = 160

Mean ± sD

age 15.6 ± 1.3

years

Both risperidone groups >

placebo on the Panss

total score: risperidone

1–3 mg, 19.9; risperidone

4–6 mg, 20.7; placebo,

7.8 (LOCF)

More ePs (dizziness)

with higher-dose

risperidone

Pandina et al.

(2007)16

Risperidone: low dose

(0.15–1.6 mg/day) vs

high dose (1.5–6.0

mg/day)

8 weeks n = 257 (high dose

125, low dose 132)

age range

13–17 years

Panss total score

improvement (mean ±

sD) significantly greater

(P <0.001) with high-dose

(−23.6 ± 22.8) vs low-dose

(−12.5 ± 20.3) risperidone

all adverse events

greater with high-dose

vs low-dose risperidone

(e.g. hypertonia 4.5% for

low dose vs 14.4 % for

high dose)

Robb et al.

(2007)17

aripiprazole: 10 mg vs

aripiprazole: 30 mg vs

placebo

6 weeks n = 02

Mean age 15.5

(range 13–17) years

aripiprazole (10- and

30-mg doses) > placebo

improvement from baseline

to end point on the Panss

Mild-to-moderate

severity adverse events:

extrapyramidal disorder,

somnolence, akathisia

Kumra et al.

(2008)18

Clozapine: 403.1 ±

201.8 mg Olanzapine:

26.2 ± 6.5 mg

12 weeks n = 39

Mean ± sD

age 15.6 ± 2.1

years

>30% BPRs reduction:

clozapine 66%, olanzapine

33% Clozapine > ‘high-

dose’ olanzapine in terms

of negative symptoms

(sans) Cgi much/very much

improved; and Robb et al,

58 Findlinggg et al 57

Weight gain

High incidence of

dyslipidaemia

BPRs, Brief Psychiatric Rating scale; CDRs-R, Child Depression Rating scale – Revised; Cgi, Clinical global impression; Ci, confidence interval; ePs, extrapyramidal symptoms; LOCF, last observation carried forward; nnt, number needed to treat; Panss, Positive and negative syndrome scale; sans, scale for assessment of negative symptoms; saPs, scale for assessment of positive symptoms; YMRs, Young Mania Rating scale.

Table 1

Randomized controlled trials of antipsychotic medication in the treatment of schizophrenia in children and adolescents (continued)

Akathisia occurs and may be triggered or aggravated by sero-tonin reuptake inhibitors. Children and adolescents seem to be at risk for developing withdrawal dyskinesia, yet these are fre-quently reversible – unlike the case in adults. A recent meta-analysis reported an annual incidence rate of 0.4% for tardive dyskinesia.24

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal medical emergency that can result from antipsychotic treat-ment. The clinical picture consists of severe (lead pipe) rigidity, tachycardia, fever, hypertension or hypotension, raised levels of creatinine phosphokinase, and increased white cell count. If NMS develops, referral to a physician is necessary.

Neurological adverse events: fitsChildren and adolescents taking clozapine may be at higher risk than adults for developing seizures or epileptiform discharges on electroencephalography (EEG).25 A pretreatment EEG may be useful, and a repeat EEG for overt or impending seizure activity,

PsYCHiatRY 7:11 46

a daily clozapine dose of 600 mg, or blood level greater than 600 ng/ml.

Weight gainThe weight gain potential of SGAs is greater in children and ado-lescents than in adults.26 Excessive weight gain is associated with significant medical morbidity and mortality. The potential for weight gain is as follows: olanzapine > clozapine > risperidone > quetiapine, aripiprazole, and ziprasidone.

There is little convincing evidence that dietary advice combined with exercise reduces weight in this situation, although a healthy lifestyle is always advocated.23 Two RCTs27,28 point to the benefit of metformin as an adjunctive treatment to stabilize weight.

Metabolic syndromeAs a potential result of significant weight gain, SGAs have been associated with lipid abnormalities in children and adoles-cents, for example increased triglyceride, total cholesterol and

0 © 2008 elsevier Ltd. all rights reserved.

ManageMent issues

low-density lipoprotein cholesterol levels, and/or decreased high-density lipoprotein cholesterol levels.23 The metabolic syndrome appears to result from insulin resistance, secondary to weight gain.

The Food and Drugs Administration in the USA has issued a ‘black box’ warning concerning the development of diabetes mellitus in patients receiving any SGA. Risk factors for the development of diabetes include obesity, rapid weight gain, and family history of diabetes or hyperlipidaemia.29

Prolactin-related side effectsSecretion of prolactin from the pituitary is regulated by tonic dopa-minergic inhibition; consequently the majority of FGAs and SGAs cause an increase in prolactin levels. Hyperprolactinaemia can result in sexual side effects, such as amenorrhoea, erectile dysfunc-tion, decreased libido, and breast symptoms, although prolactin levels are not closely correlated with these symptoms. Hyperpro-lactinaemia appears to be dose dependent, tends to normalize over time, and resolves after antipsychotic discontinuation.30 The relative potency of antipsychotic drugs to induce hyperprolactinaemia is as follows: risperidone > haloperidol > olanzapine > quetiapine > clozapine > aripiprazole. If the patient develops persistently high prolactin levels, switching to a drug with a lower risk is often help-ful. Aripiprazole may actually reduce prolactin levels.

Neutropenia and agranulocytosisThere is a risk of neutropenia and agranulocytosis with clozapine treatment – hence the need for regular monitoring. The cumula-tive 1-year probability of an initial adverse haematological event has been estimated at 16.1%31;however, 45% of these were suc-cessfully rechallenged, and only 5% had repeat adverse events. Over time, the bone marrow seems to adjust, and treatment can continue.32

MyocarditisClozapine has been associated with a small risk for myocar-ditis, which occurs early on in treatment. Blood pressure and pulse determinations are initially obtained daily to detect ortho-static changes and tachycardia. Some cardiomyopathies may be induced by tachycardia; these can be avoided by early detec-tion and then appropriate dose adjustments and/or addition of a β-blocker. Electrocardiography and estimation of myocardial creatine kinase levels should be undertaken monthly for about 3–6 months, then every 6 months. Clozapine should be discon-tinued if either myocarditis or cardiomyopathy develops.

Assessment and monitoring

At baseline and at regular 3–6-month follow-up intervals, weight, blood pressure, and blood tests (full blood count [at baseline only, except clozapine], liver function tests, fasting lipids, cho-lesterol, blood sugar, and prolactin) are recommended. Glucose, triglyceride, and low-density lipoprotein cholesterol levels are strongly affected by eating, so fasting blood values should be used. Ideally, measurement of insulin should be available. Meas-urement of haemoglobin A1C is not suggested as a screening test because it is insensitive and should be used only as a long-term monitoring in patients with diabetes. Prolactin levels should be measured in the morning as prolactin levels vary during the day

PsYCHiatRY 7:11 46

and can be increased by food, exercise, and stress, as well as medications.

Conclusion

Evidence is now accumulating to support the efficacy of antipsy-chotics. A caveat is that the evidence based upon RCTs is limited by trials of small size and short duration, and some have been funded by the pharmaceutical industry. The treatment of schizo-phrenia should involve antipsychotic medications only as part of a comprehensive treatment plan alongside appropriate psycho-educational, psychological (cognitive behavioural therapy and family therapy), and psychosocial interventions. ◆

REfERENCES

1 Rapoport J, addington a, Frangou s. the neurodevelopmental model

of schizophrenia: update 2005. Mol Psychiatry 2005; 10: 434–49.

2 Kumra s, Oberstar J, sikich L, et al. efficacy and tolerability of

second-generation antipsychotics in children and adolescents with

schizophrenia. Schizophr Bull 2008; 34: 60–71.

3 Kennedy e, Kumar a, Datta ss. antipsychotic medication for

childhood-onset schizophrenia. Cochrane Database Syst Rev 2007;

(3) CD004027.

4 Kumra s, Frazier Ja, Jacobsen LK, et al. Childhood-onset

schizophrenia: a double-blind clozapine-haloperidol comparison.

Arch Gen Psychiatry 1996; 53: 1090–97.

5 sikich L, Hamer R, Bashford R, sheitman B, Lieberman J. a pilot

study of risperidone, olanzapine, and haloperidol in psychotic youth:

a double-blind, randomized, 8-week trial. Neuropsychopharmacology

2004; 29: 133–45.

6 Faretra g, Dooher L, Dowling J. Comparison of haloperidol and

fluphenazine in disturbed children. Am J Psychiatry 1970; 126:

1670–73.

7 engelhardt D, Polizos P, Waizer J, Hoffman s. a double blind

comparison of fluphenazine and haloperidol in outpatient

schizophrenic children. J Autism Child Schizophr 1973; 3: 128–37.

8 Pool D, Bloom W, Mielke D, Roniger JJ, gallant D. a controlled

evaluation of loxitane in seventy-five adolescent schizophrenic

patients. Curr Ther Res Clin Exp 1976; 19: 99–104.

9 Realmuto g, erickson W, Yellin a, Hopwood JH, greenberg L.

Clinical comparison of thiothixene and thioridazine in schizophrenic

adolescents. Am J Psychiatry 1984; 141: 440–42.

10 spencer e, Kafantaris V, Padron-gayol M, Rosenberg C, Campbell M.

Haloperidol in schizophrenic children: early findings from a study in

progress. Psychopharmacol Bull 1992; 28: 183–86.

11 Yao H. a study of risperidone in the treatment of child

schizophrenia. J Clin Psychol Med 2003; 7468: 801.

12 Xiong Y. Comparison study of childhood schizophrenia treated with

risperidone and chlorpromazine. Guizhou Med J 2004; 28: 697–98.

13 Kryzhanovskaya La, schulz s, McDougle C, et al. Results from a

double-blind placebo-controlled trial of olanzapine in adolescents

with schizophrenia. 159th annual Meeting of the american

Psychiatric association, toronto, Canada, 2006 (abstract).

14 shaw P, sporn a, gogtay n, et al. Childhood-onset schizophrenia:

a double-blind, randomized clozapine-olanzapine comparison. Arch

Gen Psychiatry 2006; 63: 721–30.

1 © 2008 elsevier Ltd. all rights reserved.

ManageMent issues

15 Haas M, unis a, Copenhaver M, Quiroz s, Kushner s, Kusumakar V.

efficacy and safety of risperidone in adolescents with schizophrenia.

160th annual Meeting of the american Psychiatric association,

san Diego, Ca, May 2007 (abstract).

16 Pandina g, Kushner s, singer J, et al. Comparison of two risperidone

dose ranges in adolescents with schizophrenia. 54th annual Meeting

of the american academy of Child and adolescent Psychiatry,

Boston, Ma, 2007 (Poster).

17 Robb a, Findling R, nyilas M, et al. efficacy of aripiprazole in the

treatment of adolescents with schizophrenia. 160th annual Meeting

of the american Psychiatric association, san Diego, Ca, 2007.

18 Kumra s, Kranzler H, gerbino-Rosen g, et al. Clozapine and ‘high-

dose’ olanzapine in refractory early-onset schizophrenia: a 12-week

randomized and double-blind comparison. Biol Psychiatry 2008; 63:

524–29.

19 Frazier Ja, McClellan J, Findling RL, et al. treatment of early-onset

schizophrenia spectrum disorders (teOss): demographic and

clinical characteristics. J Am Acad Child Adolesc Psychiatry 2007; 46:

979–88.

20 sporn aL, Vermani a, greensteinn DK, et al. Clozapine treatment of

childhood-onset schizophrenia: evaluation of effectiveness, adverse

effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry

2007; 46: 1349–56.

21 gogtay n, Rapoport J. Clozapine use in children and adolescents.

Expert Opin Pharmacother 2008; 9: 459–65.

22 Bachmann C, Haberhausen M, Heizel-gutenbrunner M, Remschmidt

H, theisen F. Large intraindividual variability of olanzapine serum

concentrations in adolescent patients. Ther Drug Monit 2008; 30:

108–12.

23 Correll C. antipsychotic use in children and adolescents: minimizing

adverse effects to maximize outcomes. J Am Acad Child Adolesc

Psychiatry 2008; 47: 9–20.

PsYCHiatRY 7:11 4

24 Correll C, Kane J. One-year tardive dyskinesia rates in children

adolescents treated with second-generation antipsychotics: a

systematic review. J Child Adolesc Psychopharmacol 2007; 17:

647–55.

25 Findling RL, steiner H, Weller eB. use of antipsychotics in children

and adolescents. J Clin Psychiatry 2005; 66: 29–40.

26 Correll C, Kane J. One-year tardive dyskinesia rates in children

adolescents treated with second-generation antipsychotics: a

systematic review. J Child Adolesc Psychopharmacol 2007; 17:

647–55

27 Wu R, Zhao J, guo X, et al. Metformin addition attenuates

olanzapine-induced weight gain in drug-naive first-episode

schizophrenia patients: a double-blind, placebo-controlled study.

Am J Psychiatry 2008; 165: 352–58.

28 Klein D, Cottingham e, sorter M, Barton B, Morrison J. a randomized,

double-blind, placebo-controlled trial of metformin treatment of

weight gain associated with initiation of atypical antipsychotic

therapy in children and adolescents. Am J Psychiatry 2006; 163:

2072–79.

29 Correll C. antipsychotic use in children and adolescents: minimizing

adverse effects to maximize outcomes. J Am Acad Child Adolesc

Psychiatry 2008; 47: 9–20

30 Findling RL, Kusumakar V, Daneman D, Moshang t, De smedt D,

Binder C. Prolactin levels during long-term risperidone treatment in

children and adolescents. J Clin Psychiatry 2003; 64: 1362–69.

31 gerbino-Rosen g, Roofeh D, tompkins D, et al. Hematological

adverse events in clozapine-treated children and adolescents. J Am

Acad Child Adolesc Psychiatry 2005; 44: 1024–31.

32 Findling R, Frazier J, gerbino-Rosen g, Kranzler H, Kumra s,

Kratochvil C. is there a role for clozapine in the treatment of

children and adolescents? J Am Acad Child Adolesc Psychiatry 2007;

46: 423–28.

62 © 2008 elsevier Ltd. all rights reserved.