Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.

BACKGROUND: Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS-TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS-TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition. METHODS: From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them for symptoms. We used the estimated historical incidence of SJS-TEN as a control. RESULTS: Mild, transient rash developed in 4.3% of subjects; more widespread rash developed in 0.1% of subjects, who were hospitalized. SJS-TEN did not develop in any of the HLA-B*1502-negative subjects receiving carbamazepine. In contrast, the estimated historical incidence of carbamazepine-induced SJS-TEN (0.23%) would translate into approximately 10 cases among study subjects (P<0.001). CONCLUSIONS: The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects was strongly associated with a decrease in the incidence of carbamazepine-induced SJS-TEN. (Funded by the National Science Council of Taiwan and the Taiwan Drug Relief Foundation.).

Acute hearing loss in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).

The mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare congenital disorder of mitochondrial DNA. Patients with this syndrome may present acute onset of sensorineural hearing loss, which is genetic in origin. An impression of the MELAS syndrome is favored because hearing loss is part of the syndrome for some patients with epilepsy. We report a 20-year-old man who suffered from acute onset of bilateral hearing loss with epilepsy and two stroke-like events which recovered without any sequela. Epilepsy with complex partial seizures was controlled by antiepileptic drugs. Brain magnetic resonance images showed high signal lesions in bilateral temporal lobes. Serum levels of pyruvate and lactate were elevated. Muscle biopsy showed ragged-red fibers and molecular genetic study showed a point mutation of the mitochondrial A3243G gene. Mitochondrial disease with the MELAS syndrome was diagnosed and then he was treated with Co-enzyme Q10 and carnitine. The symptoms recovered gradually.

Confusion or delirium in patients with posterior cerebral arterial infarction.

OBJECTIVE: To identify the possible anatomic sites and risk factors for the development of confusion or delirium in patients with posterior cerebral arterial (PCA) infarction. MATERIALS AND METHODS: Twenty-nine patients aged 34-86 years with PCA infarction were divided into two groups: one with and the other without perturbed mentation. The clinical and laboratory data, including neuroimages, were retrospectively reviewed. Student-t, chi-square and Fisher's exact tests were performed for data analysis. RESULTS: Confusion or delirium tended to develop in the left (10/13) or bilateral (5/5) PCA infarction as compared to the right PCA infarction (3/15) (P< 0.05) and medial occipital-temporal gyri involvement was crucial for its development (P< 0.05). The results were also noted in the patients with first-ever stroke. Diabetes mellitus was the sole biochemical factor to be associated with confusion or delirium (P< 0.01). CONCLUSIONS: The involvement of the medial occipito-temporal gyri, especially on the left side was the pivotal factor for the development of confusion or delirium in patients with PCA infarction. Higher prevalence of diabetes mellitus was also observed in the group with mental perturbation.

Risperidone-related weight gain: genetic and nongenetic predictors.

OBJECTIVE: A serious side effect of atypical antipsychotics is increased body weight, which leads to further morbidity and nonadherence to medication. It has been suggested that both genetic and nongenetic variables may influence antipsychotics-related weight gain. This study aimed to simultaneously explore the effects of multiple candidate genes and environment factors on body weight of schizophrenia patients who received risperidone, a commonly used atypical antipsychotic agent. METHODS: One hundred twenty-three ethnically Han Chinese inpatients with acutely exacerbated schizophrenia were given risperidone monotherapy for up to 42 days. Body weight and clinical manifestations were assessed biweekly. Drug efficacy was measured by the Positive and Negative Syndrome Scale (PANSS), and safety was evaluated by the Extrapyramidal Symptom Rating Scale (ESRS) and the UKU Side Effect Rating Scale. We collected body weight as the response value. Potential prognostic factors were baseline body weight, age, sex, diagnosis subtypes, risperidone dosage, PANSS total scores, treatment duration (weeks 0-6), and 15 genetic variants [across 10 candidate genes: 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, D1, D2, D3, and alpha1-adrenergic receptors, brain-derived neurotrophic factor (BDNF), and cytochrome P450 2D6 (CYP2D6)]. Because there were repeated assessments, multiple linear regression with the generalized estimating equation (GEE) method was used to adjust the within-subject dependence. RESULTS: Of 15 genetic polymorphisms examined, 5-HT2A 102-T/C, 5-HT2C -759-C/T, 5-HT6 267-C/T, BDNF 66-Val/Met, and CYP2D6 188-C/T significantly influenced body weight, and so did baseline body weight, age, gender, schizophrenia subtype, and treatment duration and efficacy. CONCLUSIONS: These results suggest that numerous genetic and nongenetic factors affect antipsychotics-related weight gain.

Effects of dopamine D2 receptor Ser311Cys polymorphism and clinical factors on risperidone efficacy for positive and negative symptoms and social function.

Risperidone is an atypical antipsychotic agent with efficacy for both positive and negative symptoms of schizophrenia. However, what makes an antipsychotic 'atypical' remains unclear. We recently found that the T102C polymorphism in the 5-HT2A receptor gene could affect risperidone's efficacy for negative symptoms. The present study investigated the effect of the Ser311Cys polymorphism in the dopamine D2 receptor (DRD2) gene on risperidone treatment response. A total of 123 Han Chinese patients with acutely exacerbated schizophrenia were given risperidone for up to 42 days. Clinical manifestations were measured bi-weekly with Positive and Negative Syndrome Scale (PANSS) and Nurses' Observation Scale for Inpatients Evaluation (NOSIE, for assessment of social function). For adjusting the within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was utilized to analyse the effects of Ser311Cys polymorphism and other covariates on clinical performance. Compared with patients who had the Ser311Ser genotype, patients with the Ser311Cys genotype had lower scores on PANSS Positive, Negative, General Psychopathology and Cognitive subscales and NOSIE, after adjustment for 5-HT2A T102C polymorphisms and other confounders. The 5-HT2A T102C polymorphism had marginal influences on PANSS Total and Negative subscale scores. Male gender, fewer previous hospitalizations, and higher risperidone dose predicted better treatment response after control for other variables. The preliminary results suggest that variations in the DRD2 gene influence risperidone treatment response for positive, negative, and cognitive symptoms, general psychopathology, and social functioning. Several clinical factors may also contribute to inter-individual differences in risperidone treatment response.