DOI: 10.1097/JCP.0b013e31814f4d82
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PMID: 17873692
Issn Print: 0271-0749
Publication Date: 2007/10/01
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Excerpt
Atypical antipsychotics show significant interindividual variation in therapeutic efficacy. The ability to predict response to specific antipsychotics would be of great value in making rational therapeutic choices for individualized patient treatment. Natural variation in genes involved in interactions between antipsychotic medications and their target receptors likely contributes to differential antipsychotic response. Identification of genotypes associated with response may provide the clinician with objective data for decision making.
Schizophrenia is a heterogeneous disorder with several symptom domains including positive, negative, and depressive symptoms.1 Variations in antipsychotic target receptor genes may be more likely to be associated with differential response in specific symptom domains than in an overall measure of psychopathology. Depressive symptoms in schizophrenia have been associated with increased rates of relapse and rehospitalization, poor response to pharmacological treatments, poor functioning, and increased risk of suicide.2
We examined genetic variations in target neuroreceptors of the atypical antipsychotic, olanzapine (dopamine, serotonin, and adrenergic receptor subtypes), for association with depressive symptom response and remission.
Subjects were adult outpatients or hospital inpatients from a randomized double-blind study comparing olanzapine with haloperidol treatment (study population and design previously reported).3 Because of small number of samples available from haloperidol-treated patients, only olanzapine-treated patient samples were used for this study. Relevant inclusion criteria included the following: patients who met Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnostic criteria for schizophrenia or schizoaffective disorder and had a minimum Brief Psychiatric Rating Scale score of 18 or were intolerant of current antipsychotic therapy, or both. For the present study, patients with a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of 15 or greater were included. Patients were randomly assigned treatment with 5 mg/d of olanzapine 2 to 9 days after discontinuation of prior antipsychotic treatment, and subsequently, doses could be increased or decreased in 5-mg/wk increments between 5 and 20 mg/d. The study protocol was approved by institutional review boards, and written informed consent was obtained from all participants before study entry.
A subset of patients enrolled in the clinical trial agreed to donate a DNA sample for genetic analysis (n = 34). Genotyping was performed by Genaissance Pharmaceuticals (New Haven, CT) using the MassARRAY platform4 for single nucleotide polymorphisms (SNPs) and polymerase chain reaction characterization for variable nucleotide tandem repeat polymorphisms. Depressive symptoms were assessed with the MADRS.5
An a priori determined sequence of analysis was used based upon candidate genes from the literature. Polymorphisms were analyzed in the following order: (1) 5-hydroxytryptamine (serotonin) receptor 1A (HTR1A) −1019C/G6; (2) 5-hydroxytryptamine receptor 2A (HTR2A) T102C37; (3) 5-hydroxytryptamine receptor 6 (HTR6) C267T8; (4) 5-hydroxytryptamine transporter (5HTT) promoter s/l variants9; (5) other olanzapine neuroreceptor gene polymorphisms; and (6) all other polymorphisms genotyped.
Hardy-Weinberg equilibrium was calculated for each genetic variant.10 Linkage disequilibrium was determined between the genotyped variants calculated using disequilibrium coefficient (r2). The assessment of mean change in baseline to 6-week end point in MADRS scores was assessed using analysis of variance of observed cases adjusted for baseline scores (SAS Proc Mixed; SAS Institute Inc, Cary, NC). Correlation between polymorphisms that were significantly associated with response was determined by Pearson correlation on the number of rare alleles. Categorical depressive symptom remission was defined as a last observation carried forward 6-week end point rating of 10 or lesser on the MADRS total score. Categorical analysis of remitters versus nonremitters was performed using logistic regression and Wald χ2 test on the number of responsive alleles. P values were not corrected for multiple testing.
One hundred seventy-eight SNPs and 3 variable nucleotide tandem repeat polymorphisms were successfully genotyped from 18 candidate genes.
