A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression.
The multi-drug resistance gene ABCB1 (or MDR1) encodes a P-glycoprotein (P-gp) that regulates passage of many substances across the blood-brain barrier. The antidepressant amitriptyline and its metabolites (including nortriptyline) are substrates for P-gp, and in mice lacking P-gp, penetration of amitriptyline, but not fluoxetine, into the brain is enhanced. We reasoned that polymorphic variation of P-gp may contribute to differing responses of patients to antidepressant drugs. A single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) was recently correlated with expression levels and in vivo function of P-gp. We examined this SNP in patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine, and observed a significant association between nortriptyline-induced postural hypotension and 3435C>T (chi(2) = 6.78, df = 2, P = 0.034). Our results suggest that homozygosity for 3435T alleles of ABCB1 is a risk factor for occurrence of nortriptyline-induced postural hypotension (OR = 1.37, P = 0.042, 95% CI 1.01-1.86).
Roberts
R L
RL
Department of Pathology, Christchurch School of Medicine, Christchurch, New Zealand.
Joyce
P R
PR
Mulder
R T
RT
Begg
E J
EJ
Kennedy
M A
MA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects* / Q000627:therapeutic use*; D004247:DNA / Q000235:genetics; D003866:Depressive Disorder / Q000150:complications* / Q000188:drug therapy*; D005260:Female; D005473:Fluoxetine / Q000009:adverse effects / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D007024:Hypotension, Orthostatic / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D009661:Nortriptyline / Q000009:adverse effects* / Q000627:therapeutic use*; D012150:Polymorphism, Restriction Fragment Length; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D005473:Fluoxetine; D004247:DNA; D009661:Nortriptyline