ABSTRACT
Several studies have linked 5-HT1A C1019G and BDNF G196A (Val66Met) gene polymorphisms to major depressive disorder (MDD) and the actions of antidepressants. We attempt to show that the interaction between 5-HT1A and BDNF polymorphism predicts the risk of treatment-resistant depression. The sample consists of 119 patients with treatment-resistant MDD and 392 controls. 5-HT1A C1019G and BDNF G196A (Val66Met) polymorphisms were studied. The combination of 5-HT1A GG and BDNF GA + AA genotypes is associated with an increased risk of depression.
Subject(s)
Brain Chemistry/drug effects , Brain-Derived Neurotrophic Factor/genetics , Depressive Disorder/genetics , Drug Resistance/genetics , Genetic Predisposition to Disease/genetics , Receptor, Serotonin, 5-HT1A/genetics , Adult , Aged , Antidepressive Agents/pharmacology , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Brain Chemistry/genetics , DNA Mutational Analysis , Depressive Disorder/metabolism , Depressive Disorder/therapy , Electroconvulsive Therapy/statistics & numerical data , Female , Gene Frequency/genetics , Genetic Markers/genetics , Genetic Testing , Genotype , Humans , Male , Middle Aged , Polymorphism, Genetic/genetics , Risk Factors , Serotonin/metabolism , Treatment FailureABSTRACT
We studied the association between tryptophan hydroxylase 1 (TPH1) A218C and G-protein beta-3 subunit (GNB3) C825T polymorphisms and treatment response in electroconvulsive therapy (ECT). The sample consisted of 119 patients with major depressive disorder (MDD) and 398 controls. Neither TPH1 nor GNB3 polymorphisms are associated with treatment response. However, subjects carrying TPH1 CC genotype are more likely to belong to the patient sample than to the controls. In female subjects, T-allele of GNB3 polymorphism increases the risk of being a treatment-resistant patient with MDD. Moreover, in females the combination of TPH1 CC and GNB3 CT + TT genotype is associated with an increased risk of belonging to the patient group.
Subject(s)
Depressive Disorder, Major/genetics , Depressive Disorder, Major/therapy , Electroconvulsive Therapy , Heterotrimeric GTP-Binding Proteins/genetics , Polymorphism, Genetic , Tryptophan Hydroxylase/genetics , Female , Genotype , Humans , Linkage Disequilibrium , Male , Middle Aged , Polymerase Chain Reaction , Treatment OutcomeABSTRACT
The metabolism of melatonin to 6-sulphatoxymelatonin (aMT6S) and N-acetylserotonin (NAS) is catalyzed by cytochrome-P450 (CYP) isozymes CYP1A2 and CYP2C19 respectively. We studied the in vivo effect of CYP2C19 substrate (citalopram, omepratzole, or lansopratzole) on the metabolism of endogenous and exogenous melatonin by measuring the excretion of urinary aMT6S, the main metabolite of melatonin, and a reliable estimate of plasma melatonin in 15 insomniac psychogeriatric inpatients. The effect of melatonin treatment on sleep parameters was also assessed. The patients with or without CYP2C19 substrate were treated for 21 days randomly in a double-blind manner with placebo or 2 mg exogenous melatonin orally. aMT6S excretions were measured radioimmunologically from night urine at baseline (day 0), on day 21, and one day after the treatment was discontinued (day 22). Sleep parameters were assessed using the Sleep Assessment Scale and the Sleep Quality Scale. In the control patients receiving only melatonin, aMT6S excretion increased 72-fold and returned to baseline on day 22. In the patients receiving melatonin + CYP2C19 substrate, aMT6S excretion increased 156-fold and was, on day 22, still 6.4-fold higher than at baseline (p = 0.04). The 22/0 day aMT6S excretion ratio was 10-fold higher in the patients treated with melatonin + CYP2C19 substrate when compared with that in the subjects treated with placebo + CYP2C19 substrate (p = 0.02). CYP2C19 substrate did not affect the metabolism of endogenous melatonin. The sleep parameters in the patients on melatonin treatment did not differ from those in the patients treated with placebo. In conclusion, it may be inferred that CYP2C19 substrate slows the metabolism of exogenous melatonin and increases its bioavailability, as shown by the augmented excretion of aMT6S, probably by inhibiting the conversion of melatonin to NAS via CYP2C19 isozyme. Melatonin therapy may not affect the sleep parameters in our psychogeriatric inpatients.
