Estimation of CYP3A4*1B single nucleotide polymorphism in patients with recurrent Major Depressive Disorder.

BACKGROUND: Major depression is the most common mental illness in the world. Failures in treatment may occur due to the presence of a subtype of depression called TRD (Treatment- Resistant Depression). CYP3A4 polymorphism (rs2740574) can increase the activity of Cytochrome P450 3A4, contributing to faster metabolism of xenobiotics and reduced response to treatment. The aim of the study was to assess the distribution of CYP3A4*1B in study and control group and to estimate the influence of particular genotypes on parameters such as: age at onset, severity of symptoms before treatment and on the effectiveness of therapy. METHODS: Total of 192 patients were enrolled in this study (102 patients suffering from recurrent Major Depression Disorder, 90 healthy blood donors). PCR Restriction Fragment Length Polymorphism method with MboII enzyme was performed. The presence of CYP3A4*1B allele was evaluated on the basis of agarose gel electrophoresis. RESULTS: There was a tendency in frequency of genotypes distribution in the study group in comparison with the control group (p = 0.050). There were no statistically significant differences in the distribution mutant allele among these two groups, but there was a tendency for mutant allele to occur more often in the study group (p = 0.050). No significant correlations were found between the specific genotype and the studied parameters: age at onset (p = 0.232), severity of the symptoms (p = 0.946), and efficacy of treatment (p = 0.882). CONCLUSION: The study suggests that CYP3A4*1B polymorphism have no influence on the predisposition to depression, the severity of depressive symptoms and the efficiency of antidepressant therapy.

The role of GSK-3 in treatment-resistant depression and links with the pharmacological effects of lithium and ketamine: A review of the literature.

BACKGROUND: Since the discovery of antidepressants, new treatments have emerged with fewer side effects but no greater efficacy. Glycogen synthase kinase 3 ß (GSK-3ß), a kinase known for its activity on glycogen synthesis, has in the last few years raised growing interest in biological psychiatry. Several efficient treatments in major depression have an inhibitory effect on this kinase, which could be targeted in new mood disorder treatments. METHODS: The aim of this review is to summarize findings concerning the intracellular pharmacologic effects of GSK-3ß inhibitors on mood. After a brief description of the intracellular transduction pathways implicated in both GSK-3ß and mood disorders, we reviewed the results demonstrating GSK-3ß involvement in the effects of lithium and ketamine. RESULTS: GSK-3ß can be inhibited through several mechanisms such as serine phosphorylation or binding in a proteic scaffold and others. Its inhibition is implicated in numerous cellular pathways of interest involved in neuronal growth and architecture, cell survival, neurogenesis or synaptic plasticity. This inhibition appears to be both efficient and sufficient in improving mood in animal models. In human beings, several levels of evidence show GSK-3ß inhibition with antidepressant use. Crucially, strong inhibition has been shown with lithium via the proteic scaffold PP2A/ß-arrestin/AKT, and with the rapid antidepressant effect of ketamine via p70S6K. CONCLUSION: Our review focuses on mechanisms whereby the GSK-3ß pathway has a part in the antidepressant effect of lithium and ketamine. This article highlights the importance of translational research from cell and animal models to the clinical setting in order to develop innovative therapeutic targets.

Influence of Val108/158Met COMT Gene Polymorphism on the Efficacy of Modified Electroconvulsive Therapy in Patients with Treatment Resistant Depression.

Depression is a common emotional disorder associated with increased risk of suicide and rate of disability. In this double-blinded control study, we tested the efficacy of modified electroconvulsive therapy (MECT) in patients with treatment resistant depression (TRD) using the Hamilton Depression Rating Scale for Depression (HAMD). The total scores of HAMD were found to be significantly decreased after the treatment. The genotyping of catechol-O-methyltransferase (COMT) was carried out with polymerase chain reaction-based testing. Our results demonstrated that frequency of mutant COMT alleles in TRD patients was significantly higher than that of the controls indicating a correlation of the enzyme genotype to the occurrence of TRD. Moreover, the patients homozygous for wild-type COMT gene (G/G) were evidenced to be more sensitive to MECT treatment than those with an heterozygous mutant genotype (A/G).