A 6-year-old boy received treatment for ADHD at The Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public Health, Thailand. Written informed consent was obtained from the patient’s legal guardian for publication of this case report and accompanying images. The patient’s medical history was obtained from his grandparents, aunt, and his class teacher. The teacher reported that the patient was mischievous, disorderly, ignored people around him, answered questions incorrectly, created and spoke his own language, and did not know how to play with peers. Moreover, he was often absent from class, and was restless and mischievous. He was able to communicate, but only answered questions when directly addressed. However, there was no evidence of congenital disease, convulsion, or brain injury, or any known drug allergies, and there was no family history of psychiatric illness in any close relatives.
According to his mental status examination, the patient was mildly impulsive, mute and not answering the questions, and nodded his head as a response to communication, but made eye contact. The WISC-III (Wechsler Intelligence Scale for Children, 3rd Edition) is used to assess the intelligence quotient (IQ) in these children, and the patient’s IQ score was below average at 84. His nonverbal skills were better than his verbal skills. He was able to screen and analyze patterns, and follow the form of a pattern well. However, he lacked the overall ability to analyze images, his concentration was not sustained, and he would only do what interested him. Most recessive was his social intelligence (especially judgment and common sense) which affected his ability to adapt to daily life.
The psychiatrist diagnosed him as having ADHD with delayed language development, and recommended that most child-rearing problems in this patient would be resolved if he took methylphenidate 5 mg in the morning and at noon. On the first day of treatment, the patient’s grandfather gave him methylphenidate 5 mg at 7 am, and asked the patient’s class teacher to give the boy another dose after lunch. The patient’s school teacher reported that he became even more disobedient and mischievous thereafter, did not respond to discipline, had a poor appetite, and became increasingly disruptive. He did not go to sleep until midnight (his usual time of going to sleep being around 8.30 pm). His grandfather then stopped the methylphenidate, and observed that the boy went to sleep around 8.30 pm as usual.
Thereafter, the patient’s behavior returned to almost the same as it was before taking the drug. Two weeks after commencing treatment, his grandfather took him for an IQ test with the clinical psychologist, who advised the grandfather to consult with the pharmacist because he was concerned about the patient being more impulsive after taking methylphenidate. The temporal relationship between methylphenidate and emergence of adverse drug reactions in the patient (insomnia, hyperactivity, and poor appetite) indicated that the methylphenidate dose prescribed had been too high. The pharmacist suggested a new treatment plan to the patient’s grandfather, involving rechallenge with half a 10 mg tablet of methylphenidate to be taken once in the morning. After that, the patient became more mischievous, had difficulty sleeping, and would not go to sleep until around 11–12 pm. The patient was then taken to the hospital, where the physician suggested cessation of methylphenidate, instead prescribing half a 0.5 mg tablet of haloperidol and one 10 mg imipramine tablet before bedtime. After taking this prescription on the first night, the patient’s behavior was normal. However, on the second night, the patient started to become restless, sleepless, and impulsive, whereupon his grandfather stopped giving him the drugs. He then became better and was more able to communicate. After observing the improvement, his grandfather did not give the child any further haloperidol or imipramine.
An adverse reaction to haloperidol was suspected, with restlessness and agitation occurring because of a high drug plasma concentration, so a blood sample was sent to the Laboratory for Pharmacogenomics and Personalized Medicine, Department of Pathology, Somdech Phra Debaratana Medical Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, for pharmacogenetic testing with the All-In-One Pharmacogenetics for Antipsychotics test (All-In-One PGX; CYP2D6, CYP2C19, and CYP2C9) using microarray-based and real-time polymerase chain reaction techniques. Genotyping for CYP2D6 and CYP2C19 was performed using the AmpliChip® for 29 different alleles of CYP2D6 (including gene duplications and deletions) and two alleles of CYP2C19 (*2, splicing defect G681A single nucleotide polymorphism and *3, stop codon G636A single nucleotide polymorphism) genes. Testing for two single nucleotide polymorphisms for CYP2C9 (*2, C430T, exon 3 and *3, A1075C, exon 7) was also performed. Twenty-nine polymorphisms in CYP2D6 were also tested for: -1584C > G, 31G > A, 100C > T, 138 insT, 883G > C,1023C > T, 1039C > T, 1659G > A, 1661G > C, 1707T > del, 1758G > T, 1758G > A, 1846G > A, 1976G > A, *20 cluster, 2539-2542delAACT, 2549 A > del, 2613-2615delAGA, 2850C > T, 2935 A > C, 3183G > A, 3198C > G, 3277T > C, 4042G > A, *36GC, 4180G > C, 1863 repeats, gene deletion (*5) and gene duplication. In this study, AmpliChip data analysis software was used to infer the CYP genotype, and to predict the individual’s CYP2D6 enzyme activity. The algorithm from the AmpliChip package insert was used for assignment of the predicted phenotypes. There are four phenotypic categories according to allele-related enzyme activity: no enzyme activity alleles (ie, poor metabolizers), *3, *4, *5, *6, *7, *8, *11, *14A, *15, *19, *20, *36, *40, and *4XN; decreased enzyme activity alleles (ie, intermediate metabolizers), *9, *10, *17, *29, *41,*10XN, *17XN, and *41XN; normal enzyme activity alleles (extensive metabolizers), *1, *2, and *35; and increased enzyme activity alleles (ultrarapid metabolizers), *1XN, *2XN, and *35XN.
Pharmacogenetic testing showed that the child did not have CYP2C9 (*1/*1) or CYP2C19 (*1/*1) gene polymorphisms, a profile compatible with normal enzyme activity, indicating an extensive metabolizer phenotype. However, the patient was found to have a CYP2D6 *2/*10 genotype, so was an intermediate metabolizer for this enzyme (see ). This genetic profile may explain the patient’s reaction to methylphenidate, haloperidol, and imipramine, given that these antipsychotics are metabolized by CYP2D6.
Drug metabolizing genetic profile for this patient as determined by the All-In-One Pharmacogenetics for Antipsychotics test (CYP2D6, CYP2C19, and CYP2C9)
Finally, the patient’s psychiatrist suggested reducing the patient’s methylphenidate dose from half to one quarter of a tablet (2.5 mg) per day in the morning, and to monitor the clinical response. Haloperidol and imipramine were withdrawn. On the reduced dose of methylphenidate, there was no indication of adverse drug reactions or sleep disorder, and the patient could eat normally. The patient is still taking methylphenidate 2.5 mg/day in the morning. The relatives have been provided with a list of other drugs that are substrates for CYP2D6 and should be avoided in this patient.