Polymorphisms of IKBKE gene are associated with major depressive disorder and panic disorder.

BACKGROUND: The immune system has been increasingly implicated in the development of mood and anxiety disorders. Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase epsilon (IKBKE) gene encodes IKKε protein that is involved in innate immunity, predominantly antiviral response generation. It also bears pro-inflammatory properties that could affect psychiatric outcomes. In order to investigate the possible role of IKBKE gene in major depressive disorder (MDD) and panic disorder (PD), we conducted a case-control genetic association study concerning these disorders. METHODS: In all, 14 SNPs of IKBKE gene were genotyped in groups of 391 patients with MDD and 190 patients with PD together with respective 389 and 371 healthy control individuals. The given groups were further divided by gender for additional analyses. RESULTS: Substantial genetic associations were revealed between IKBKE SNPs and MDD (multiple testing adjusted P < 0.05) and suggestive associations in case of PD (P(adj) > 0.05). In addition, two SNPs that were only associated with PD among males, also displayed significantly different allele frequencies compared to PD females. This may indicate a specific role of these SNPs in male PD, but caution should be applied here due to the small size of the studied PD males group. CONCLUSIONS: The results of this study confirm our initial findings and indicate a possible role of IKBKE gene in mood and anxiety disorders.

Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways.

BACKGROUND: The involvement of microRNAs (miRNAs) in neuronal differentiation and synaptic plasticity suggests a role for miRNAs in psychiatric disorders; association analyses and functional approaches were used to evaluate the implication of miRNAs in the susceptibility for panic disorder. METHODS: Case-control studies for 712 single-nucleotide polymorphisms (SNPs) tagging 325 human miRNA regions were performed in 203 Spanish patients with panic disorder and 341 control subjects. A sample of 321 anxiety patients and 642 control subjects from Finland and 102 panic disorder patients and 829 control subjects from Estonia was used as a replica. Reporter-gene assays and miRNA overexpression experiments in neuroblastoma cells were used to functionally evaluate the spectrum of genes regulated by the associated miRNAs. RESULTS: Two SNPs associated with panic disorder: rs6502892 tagging miR-22 (p < .0002), and rs11763020 tagging miR-339 (p < .00008). Other SNPs tagging miR-138-2, miR-488, miR-491, and miR-148a regions associated with different panic disorder phenotypes. Replication in the north-European sample supported several of these associations, although they did not pass correction for multiple testing. Functional studies revealed that miR-138-2, miR-148a, and miR-488 repress (30%-60%) several candidate genes for panic disorder--GABRA6, CCKBR and POMC, respectively--and that miR-22 regulates four other candidate genes: BDNF, HTR2C, MAOA, and RGS2. Transcriptome analysis of neuroblastoma cells transfected with miR-22 and miR-488 showed altered expression of a subset of predicted target genes for these miRNAs and of genes that might be affecting physiological pathways related to anxiety. CONCLUSIONS: This work represents the first report of a possible implication of miRNAs in the etiology of panic disorder.

Thyroid autoimmunity and treatment response to escitalopram in major depression.

BACKGROUND: There is evidence that immune alterations play an important part in the pathogenesis of major depression. Thyroid autoimmunity has been found in association with major depression in several studies. AIM: 1) to examine whether the prevalence of anti-thyroid peroxidase autoantibodies (anti-TPO) in depressive patients differs from that in healthy controls; 2) to investigate the possible relationship between thyroid autoimmunity, total T3, free T3, free T4, thyroid-stimulating hormone (TSH), clinical status and treatment outcome in depression. METHOD: The study group consisted of 129 outpatients (69.8% female; mean age 31.7+/-12.0 years) with major depressive disorder with a Montgomery-Azsberg Depression Rating Scale total score of 22 or higher and 72 healthy controls (62.5% female; mean age 31.7+/-13.1 years). The patients were treated with escitalopram 10-20 mg/day for 12 weeks using open-label placebo non-controlled design. Anti-TPO, total T3, free T3, free T4 and TSH were measured before the treatment. RESULTS: The anti-TPO was found in eight (8.9%) depressive and two (4.8%) healthy females without statistical difference between these groups. Since anti-TPO was not seen in males, all further statistical analyses were carried out in females. At the end of week 12 of the treatment, 60 female patients (66.7%) were defined as responders and 30 depressive females (33.3%) showed insufficient response to treatment. Although there were no significant differences in the measurements between responders and non-responders, the last group showed a trend for a higher prevalence of anti-TPO compared with responders. CONCLUSION: Thyroid autoimmunity might be a factor predicting treatment response to antidepressants in depressive patients.

Interleukin 10 family gene polymorphisms are not associated with major depressive disorder and panic disorder phenotypes.

Genetic regulation of immune system and inflammatory response may be related to the pathogenesis and manifestations of mood and anxiety disorders. In the present study we examined a range of single-nucleotide polymorphisms (SNP) in chromosomal region 1q32, the locus of interleukin 10 (IL10) gene, in patients with major depressive disorder (n=312) and panic disorder (n=210), and matched healthy controls (n=356). We found no significant associations of the SNPs in IL10 family genes with either diagnostic group. Haplotype analysis revealed seven haplotype blocks, but their frequencies did not differ between patients and controls. Significant associations were detected for SNP rs1539243 in IKBKE (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon) gene showing different allelic and genotypic distributions in the total as well as in separate diagnostic groups as compared to controls. IKBKE emerged as a candidate for further studies of genetic factors associated with panic disorder and major depressive disorder.

Soluble interleukin-2 receptor and tumor necrosis factor levels in depressed patients in Estonia.

Several studies have reported immune system alterations in depressed patients. Furthermore, correlations between some interleukins and specific depressive symptoms have been found, but results are ambiguous. It might be caused by heterogeneous patient population and concomitant administration of antidepressants. The aim of our study was to look at differences in the levels of soluble interleukin-2 receptor (sIL-2R) and tumor necrosis factor-alpha (TNFalpha) between currently depressed patients with first or recurrent episode of depression, patients in full remission and healthy controls. Secondly, we looked for correlations between sIL-2R and TNFalpha and different depressive symptoms. A total of 75 medication-free currently depressed patients (76% of females), 17 patients in the full remission phase of major depression (58.8% of females), and 55 healthy controls (58.2% of females) participated in this study. The results showed that the level of sIL-2R was significantly lower in depressed patients in remission phase compared to the healthy controls and subjects with recurrent depression. Drug-nalve patients with major depressive disorder with recurrent episode had higher levels of sIL-2R than previously treated or patients with the first episode. TNFalpha levels were higher in drug-nalve patients with major depressive disorder with recurrent episode compared with previously treated patients. Further analysis of patients revealed that sIL-2R was positively correlated with decreased activity and agitation. TNFalpha was associated with decreased activity and suicidality.

Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder.

Alterations in the immune system may have importance for the pathophysiology of depression. Several studies have linked increased production of pro-inflammatory cytokines to depression and depressive symptoms. There is growing evidence that antidepressive treatment may influence the production of pro-and anti-inflammatory cytokines. In the present study we aimed to find associations between the levels of soluble interleukin-2 receptor (sIL-2R), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) and the response to antidepressant treatment in patients with major depression. Our study group consisted of 100 patients (35 males and 65 females) who were treated with escitalopram 10-20 mg/day for 12 weeks. Responders and non-responders were identified according to Montgomery-Asberg's Depression Rating Scale (MADRS) scores. The levels of cytokines were measured at baseline and at 4th and 12th week of the treatment and compared to cytokine concentrations in healthy volunteers (n=45; 19 males and 26 females). Our data indicated that a higher level of TNF-alpha might predict a non-response to treatment with escitalopram and that changes in concentrations of sIL-2R during the treatment were different in responders and non-responders.