Vascular endothelial growth factor and pigment epithelial-derived factor in the peripheral response to ketamine.

BACKGROUND: Ketamine is a rapid-acting antidepressant but its mechanism remains unclear. Vascular endothelial growth factor growth factor (VEGF) has been reported in the antidepressant action of ketamine in rodents. VEGF and pigment epithelial-derived factor (PEDF) signalling are closely linked and both are dysregulated in depression. We explored the effect of a single infusion of ketamine, with midazolam as comparison, on peripheral whole blood mRNA levels of vascular endothelial growth factor A (VEGFA) and PEDF, and the VEGFA/PEDF ratio, in patients with depression. METHODS: Twenty-five patients with depression were randomised to either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) infusions over 40 min. Blood plasma samples were taken 1 h before the first infusion and 4 h after the infusion start. mRNA was extracted and qRT-PCR performed to analyse gene expression. RESULTS: Single infusions of ketamine and midazolam both decreased depression scores (F(1,21) = 102.40, p < 0.000). There was a significant group × time interaction for VEGFA mRNA levels (F(1, 21) = 5.207, p = 0.029), with ketamine increasing VEGFA levels. There was no significant effect of either ketamine or midazolam on PEDF levels. There was a significant group × time interaction for VEGFA/PEDF mRNA ratio, with ketamine alone increasing this ratio (F(1, 11) = 12.085, p = 0.005). LIMITATIONS: Patients were on psychotropic medication and continued treatment as usual throughout the study. CONCLUSIONS: These preliminary results support a role for VEGF in the action of ketamine and suggest a novel role for VEGF/PEDF in the molecular response to ketamine.

Peripheral blood E2F1 mRNA in depression and following electroconvulsive therapy.

The E2F transcription factors are a group of proteins that bind to the promotor region of the adenovirus E2 gene. E2F1, the first family member to be cloned, is linked to functions including cell proliferation and apoptosis, DNA repair, cell senescence and metabolism. We recently performed a deep sequencing study of micro-RNA changes in whole blood following ECT. Two micro-RNAs (miR-126-3p and miR-106a-5p) were identified and gene targeting analysis identified E2F1 as a shared target of these miRNAs. To our knowledge, no studies have examined E2F1 mRNA levels in patients with depression. Peripheral blood E2F1 mRNA levels were therefore examined in patients with depression, compared to healthy controls, and the effects of a course of ECT on peripheral blood E2F1 mRNA was investigated. Depressed patient and healthy control groups were balanced on the basis of age and sex. E2F1 mRNA levels were significantly lower in depressed patients in comparison to controls (p = .009) but did not change with ECT. There was no relationship between baseline E2F1 levels and depression severity, response to treatment, presence of psychosis or polarity of depression. There were no significant correlations between E2F1 levels and mood scores based on the HAM-D24. These results indicate that reduced peripheral blood E2F1 mRNA could be a trait feature of depression.

Peripheral blood SIRT1 mRNA levels in depression and treatment with electroconvulsive therapy.

Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+) dependent enzymes that regulate cellular functions through deacetylation of protein targets. They have roles in both the periphery and central nervous system and have been implicated in depression biology. A recent genome-wide association study has identified a locus for major depression in the Sirtuin1 gene (SIRT1) and lower blood levels of SIRT1 mRNA in patients with depression have also been observed in two studies. To our knowledge, no studies have examined the effect of treatment on SIRT1 levels in patients with depression. We therefore examined SIRT1 mRNA levels in a well characterised group of patients with depression, compared to healthy controls, and characterised the effects of a course of electroconvulsive therapy (ECT) on peripheral blood SIRT1 mRNA. Depressed patients (n = 91) were matched to healthy controls (n = 85) on the basis of age and sex. In line with previous studies, blood SIRT1 mRNA levels were lower in depressed patients in comparison to controls (p = 0.005). However, ECT had no effect on SIRT1 levels (p = 0.67). There was no relationship between baseline pre-ECT SIRT1 levels and depression severity, change in mood scores, suicidality, depression polarity, presence of psychosis, or response to treatment. There was a trend for a negative association between an increase in SIRT1 mRNA and a decrease in HAM-D24 scores in ECT responders and remitters. These results indicate that reduced peripheral blood SIRT1 mRNA could be a trait feature of depression.