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East Asian Arch Psychiatry 2025;35:50-2 | https://doi.org/10.12809/eaap2465

CASE REPORT

Low-dose clozapine for first-episode, early onset, treatment-resistant schizophrenia in an adolescent female: a case report

Nga Yu Hui, Edwin Ho Ming Lee, Sherry Kit Wa Chan

Nga Yu Hui, Department of Psychiatry, Queen Mary Hospital, Hong Kong SAR, China
Edwin Ho Ming Lee, Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Sherry Kit Wa Chan, Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

Address for correspondence: Prof Sherry Kit Wa Chan, Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Email: kwsherry@hku.hk

Submitted: 24 December 2024; Accepted: 28 January 2025

pdf Full Paper in PDF

Introduction

Early-onset schizophrenia is associated with a higher risk of treatment resistance and a lower response rate to non- clozapine antipsychotics.1 A lower serum concentration of clozapine is considered sufficient for clinical effect in children and adolescents.2 Sex, smoking status, and heredity are factors affecting clozapine metabolism in adults,3 whereas only sex and smoking status were found to have such an effect in paediatric patients.2 We present a case of an adolescent female with early-onset, treatment-resistant schizophrenia who showed a favourable response to low- dose clozapine and had a high clozapine concentration- to-dose ratio. Our case report highlights the potential benefits of low-dose clozapine in younger patients and the possibility of slow clozapine metabolism in young female non-smokers of Asian ethnicity.

Case presentation

In 2022, a 14-year-old Chinese girl had an onset of psychotic symptoms of suspiciousness and irritability without obvious stressors. She was a non-smoker and non-drinker, had an unremarkable past medical history, and had satisfactory premorbid academic and social functioning. Within 2 weeks of symptom onset, she developed florid psychotic symptoms including delusions of persecution, grandeur, love, thought interference, and passivity, as well as Capgras and Fregoli delusions, third-person derogatory auditory hallucinations, disorganised behaviours and speech, and disrupted sleep and appetite. She was admitted to the psychiatric ward under the care of the Early Assessment Service for Young People with Psychosis team. She appeared preoccupied and inattentive and was giggling and muttering to herself. Her speech showed features of formal thought disorder such as loosening of associations. Physical examination and organic workup including computed tomography of the brain and electroencephalogram revealed no abnormalities. According to the DSM-5 criteria, a diagnosis of brief psychotic disorder was made.

As per recommendations of the Maudsley Prescribing Guidelines in Psychiatry4 on treatment of first-episode psychosis, the patient was started on a second-generation antipsychotic medication, and the dosage was adjusted according to therapeutic response and tolerability. She was assessed over 2 weeks to determine the efficacy of the medication. She showed some improvement after being treated with risperidone 5 mg/day for 2 weeks, but her psychotic symptoms persisted. In view of its adverse effects of sedation, hyperprolactinaemia, and extrapyramidal symptoms, risperidone was switched to oral paliperidone 9 mg/day. However, her mental state significantly worsened, with an increase in auditory hallucinations, requiring regular clonazepam. Paliperidone was thus cross- tapered to olanzapine 9 days after its initiation. She initially responded to olanzapine 20 mg/day, but her symptoms flared up after several days. Olanzapine was further increased to 30 mg/day, but she showed no improvement after taking an adequate dose for 4 weeks. Aripiprazole was added and increased to 25 mg/day, but no improvement was achieved after 4 weeks. Despite a combination of olanzapine 30 mg/day and aripiprazole 20 mg/day, she remained floridly psychotic with incessant muttering, incoherent speech, and disorganised behaviours.

The condition was considered treatment-resistant, and clozapine was commenced after discussion with the patient and her family. She showed rapid improvement on clozapine 12.5 mg/day. After 1 week, her psychotic symptoms had reduced significantly and her self-care improved. The clozapine was titrated slowly at 12.5 mg/week in view of her young age; the olanzapine and aripiprazole were gradually tapered off over 4 weeks and 12 weeks, respectively. At 4 weeks after clozapine was started, her hallucinations and disorganised behaviours subsided. At 8 weeks, she achieved a complete remission of psychotic symptoms with clozapine 50 mg/day. Her serum clozapine level was 173 μg/L at 50 mg/day. She tolerated clozapine well, except for developing transient mild liver function derangement during titration. After the remission of positive symptoms, her negative symptoms including blunted affect and reduced motivation became more manifest, and these were addressed by multidisciplinary rehabilitation. She was discharged from the psychiatric ward 6 months after admission on a clozapine dosage of 50 mg/day. Her diagnosis was revised to schizophrenia. At 18-month follow-up, she remained clinically remitted and functionally recovered. She was able to resume her education and continue to the next academic grade.

Discussion

Early-onset schizophrenia is defined as having an onset before the age of 18 years.5 It is associated with poor treatment response and lower antipsychotic response rates (34% to 50%).6 Clozapine is effective and tolerable in patients with early-onset schizophrenia7 but results in higher incidences of adverse drug reactions, probably because of pharmacokinetic and pharmacodynamic differences in paediatric patients.2 The suggested therapeutic clozapine levels are 350 to 600 μg/L for adults.8 In paediatric patients, clozapine serum levels vary, with a mean of 378.0 μg/L (mean clozapine dose, 4.9 mg/kg body weight) required to produce clinical improvement. Only 33.8% of paediatric patients had a clozapine serum level within the suggested adult range, and more than half had a level below this range. Therefore, a lower therapeutic concentration range for children and adolescents is appropriate.2 Furthermore, clozapine-induced cardiomyopathy is more common in younger people aged 15 to 44 years9 and is likely associated with rapid titration.3 A slower speed of clozapine titration in younger patients may minimise the risk of cardiac adverse effects.

Our patient achieved remarkable symptom remission on a low dose (50 mg) of clozapine. Her serum clozapine level was 173 μg/L, which is below the suggested therapeutic range for adults. The dosage of clozapine was not increased because of favourable clinical response. The relatively high serum clozapine level in relation to the dosage suggests a slow metabolism. A clozapine titration guideline suggests that female non-smokers require a lower dose of clozapine.3 The effects of sex and smoking status on clozapine serum concentration have also been reported in paediatric patients.2 In a review of 1408 samples of clozapine therapeutic monitoring from 454 paediatric patients, the clozapine serum levels are influenced by dose, smoking habits, sex, age, and body weight in similar ways as in adults.10 In addition, ethnicity is shown to affect clozapine metabolism in adults patients; patients of Asian and Native American descent have an average clozapine concentration-to-dose ratio of 2.12 μg/L per mg/day, which is higher than the 0.6 to 1.2 μg/L per mg/day among patients in the United States.3,11 In our patient, the clozapine concentration-to-dose ratio was 3.46 μg/L per mg/day, which is significantly higher than the average in patients of Asian descent. This may have been related to her young age and the resulting differences in pharmacokinetics and pharmacodynamics. The associations between ethnicity and clozapine metabolism among paediatric patients warrant further study.

This case report highlights the effectiveness of low- dose clozapine in paediatric patients with early-onset schizophrenia. Monitoring of the serum clozapine level during titration is important in female paediatric non- smokers of Asian ethnicity who may have a slow clozapine metabolism.

Contributors

All authors designed the study, acquired the data, analysed the data, drafted the manuscript, and critically revised the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

As editors of the journal, EHML and SKWC were not involved in the peer review process. The other author has disclosed no conflicts of interest.

Funding / support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analysed during the present study are available from the corresponding author on reasonable request.

Ethics approval

This study was approved by the Institutional Review Board of the University of Hong Kong / Hospital Authority Hong Kong West Cluster (reference: UW 24-684). The patient and her mother provided written informed consent for all treatments and procedures and for publication.

References

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  2. Wohkittel C, Gerlach M, Taurines R, et al. Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice. J Neural Transm (Vienna) 2016;123:1021-31. Crossref
  3. de Leon J, Schoretsanitis G, Smith RL, et al. An international adult guideline for making clozapine titration safer by using six ancestry- based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry 2021;55:73-86. Crossref
  4. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry, 14th ed. New York: Wiley-Blackwell; 2021:42. Crossref
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  7. Schneider C, Papachristou E, Wimberley T, et al. Clozapine use in childhood and adolescent schizophrenia: a nationwide population- based study. Eur Neuropsychopharmacol 2015;25:857-63. Crossref
  8. Hiemke C, Bergemann N, Clement HW, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: update 2017. Pharmacopsychiatry 2018;51:9-62. Crossref
  9. Merrill DB, Dec GW, Goff DC. Adverse cardiac effects associated with clozapine. J Clin Psychopharmacol 2005;25:32-41. Crossref
  10. Couchman L, Bowskill SV, Handley S, Patel MX, Flanagan RJ. Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged <18 years: data from a therapeutic drug monitoring service, 1994-2010. Early Interv Psychiatry 2013;7:122-30. Crossref
  11. de Leon J, Armstrong SC, Cozza KL. The dosing of atypical antipsychotics. Psychosomatics 2005;46:262-73. Crossref
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