Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression.
OBJECTIVE
To evaluate common genetic variations for association with symptomatic improvement in bipolar I depression following treatment with olanzapine/fluoxetine combination (OFC) or lamotrigine.


METHODS
Symptom improvement was assessed in 88 OFC-treated and 85 lamotrigine-treated white patients with bipolar I depression in the 7-week acute period of a randomized, double-blind study comparing OFC (6/25, 6/50, 12/25, or 12/50 mg/d [olanzapine/fluoxetine]) with lamotrigine (titrated to 200 mg/d). The original study was conducted from November 2003 to August 2004. Single nucleotide polymorphisms (SNPs) were genotyped in a set of 19 candidate genes corresponding to known sites of activity for olanzapine and fluoxetine or previously associated with antidepressant or antipsychotic response. Primary outcome was the reduction in Montgomery-Asberg Depression Rating Scale (MADRS) total score as assessed by the difference by genotype from baseline to week 7 from a mixed-effects repeated measures analysis with terms for visit, genotype, genotype-by-visit interaction, and baseline MADRS score as a covariate.


RESULTS
SNPs within the dopamine D(3) receptor and histamine H(1) receptor (HRH1) genes were significantly associated with response to OFC. SNPs within the dopamine D(2) receptor, HRH1, dopamine beta-hydroxylase, glucocorticoid receptor, and melanocortin 2 receptor genes were significantly associated with response to lamotrigine.


CONCLUSIONS
SNPs in specific candidate genes were associated with symptomatic improvement in a treatment-specific fashion. These results suggest the importance of dopaminergic effects in the treatment of patients with bipolar I depression and the potential utility of genotyping in selection of pharmacologic treatments for bipolar depression.
Perlis
Roy H
RH
Bipolar Clinic and Research Program, 50 Staniford St, 5th Floor, Boston, MA 02114, USA. rperlis@partners.org
Adams
David H
DH
Fijal
Bonnie
B
Sutton
Virginia K
VK
Farmen
Mark
M
Breier
Alan
A
Houston
John P
JP
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000627:therapeutic use*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D000077152:Olanzapine; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D011969:Receptors, Histamine H1 / Q000235:genetics; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use*
D018687:Antidepressive Agents, Second-Generation; D004338:Drug Combinations; D044103:Receptor, Melanocortin, Type 2; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011965:Receptors, Glucocorticoid; D011969:Receptors, Histamine H1; D014227:Triazines; C492572:olanzapine-fluoxetine combination; D005473:Fluoxetine; D001569:Benzodiazepines; D004299:Dopamine beta-Hydroxylase; D000077152:Olanzapine; D000077213:Lamotrigine