Virginia Soria

Differential Association of Circadian Genes with Mood Disorders: CRY1 and NPAS2 are Associated with Unipolar Major Depression and CLOCK and VIP with Bipolar Disorder

Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3′ near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.

A brain-derived neurotrophic factor (BDNF) haplotype is associated with antidepressant treatment outcome in mood disorders.

Brain-derived neurotrophic factor (BDNF) has been studied extensively in relation to the susceptibility to mood disorders (MD), although it remains to be clarified whether BDNF is a susceptibility locus for MD phenotypes, including therapeutic response to antidepressants. We have performed a single-marker and haplotype association study of eight TagSNPs polymorphisms in the genomic region containing the BDNF gene in 342 control subjects and 374 patients with MD, and have tested the association with antidepressant treatment outcome. None of the eight single nucleotide polymorphisms (TagSNPs) was significantly associated with MD phenotype after Bonferroni correction. In the single-marker analysis, a SNP was found to be associated with the patients state of ‘remitter’ after adequate trial with a single antidepressant phenotype (odds ratio (OR)=2.95; P=0.0025). We also identified a haplotype associated with this phenotype. This study supports the implication of BDNF in antidepressant treatment outcome in MD, with specific association with 5′ upstream region of BDNF gene.

Resequencing and association analysis of arylalkylamine N-acetyltransferase (AANAT) gene and its contribution to major depression susceptibility.

Abstract:  Circadian rhythms disruptions, including abnormalities of circadian phase position and melatonin secretion, have been described in major depression (MD). Arylalkylamine N‐acetyltransferase (AANAT) is a key enzyme of the melatonin pathway involved in circadian oscillations of melatonin levels. We assessed the contribution of AANAT gene variability to susceptibility to MD considering common and rare genetic variations through a sequential sequencing and single nucleotide polymorphism (SNP)‐based genotyping approach in a sample of 445 unrelated patients with MD (257 unipolar MD, 188 bipolar depression) and 440 community‐based screened control subjects. We identified 17 sequence changes, thirteen of which represented novel sequence variations. We did not observe an over‐representation of patients carrying rare variants compared with the healthy controls. Common variants (MAF > 2%) were included in a case–control association analysis that showed significant association after multiple testing correction of two SNPs located in the promoter region of AANAT with MD: rs3760138 (P = 0.00006) and rs4238989 (P = 0.005). Multimarker analysis found significant associations between two three‐marker protective haplotypes and a susceptibility three‐marker haplotype containing the rare alleles of rs3760138‐rs4238989‐rs8150 and MD. We present evidence of the association of genetic variability in the AANAT gene with susceptibility to MD. Our results support the hypothesis that the melatonin‐signaling pathway and circadian clock mechanisms may contribute to the pathophysiology of MD.

A haplotype of glycogen synthase kinase 3β is associated with early onset of unipolar major depression.

Recent findings suggest that glycogen synthase kinase 3β (GSK3β) may play a role in the pathophysiology and treatment of mood disorders. Various genetic studies have shown the association of GSK3β polymorphisms with different mood disorder phenotypes. We hypothesized that genetic variants in the GSK3β gene could partially underlie the susceptibility to mood disorders. We performed a genetic case–control study of 440 psychiatrically screened control subjects and 445 mood disorder patients [256 unipolar major depressive disorder (MDD) and 189 bipolar disorder (BD)]. We genotyped a set of 11 single nucleotide polymorphisms (SNPs) and determined the relative frequency of a known copy number variant (CNV) overlapping the GSK3β by quantitative real‐time polymerase chain reaction (PCR). We found no evidence of association with MDD or BD diagnosis, and we further investigated the age at onset (AAO) of the disorder and severity of depressive index episode. We found that rs334555, located in intron 1 of GSK3β, was nominally associated with an earlier AAO of the disease in MDD (P = 0.001). We also identified a haplotype containing three SNPs (rs334555, rs119258668 and rs11927974) associated with AAO of the disorder (permutated P = 0.0025). We detected variability for the CNV, but we could not detect differences between patients and controls for any of the explored phenotypes. This study presents further evidence of the contribution of GSK3β to mood disorders, implicating a specific SNP and a haplotype with an earlier onset of the disorder in a group of well‐characterized patients with unipolar MDD. Further replication studies in patients with the same phenotypic characteristics should confirm the results reported here.

VAL66MET BDNF GENOTYPES IN MELANCHOLIC DEPRESSION: EFFECTS ON BRAIN STRUCTURE AND TREATMENT OUTCOME

A brain‐derived neurotrophic factor (BDNF) prodomain single‐nucleotide polymorphism resulting in a valine to methionine substitution (Val66Met) has been associated with depression‐related phenotypes and brain alterations involving regions consistently associated with major depressive disorder (MDD).

A Brain-Derived Neurotrophic Factor Haplotype Is Associated with Therapeutic Response in Obsessive-Compulsive Disorder

BACKGROUND Several clinical and genetic studies have focused on the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of various mental disorders. Recent lines of evidence regarding the network hypothesis of treatment outcome point towards the involvement of BDNF variants in the pharmacologic response in mood disorders (MD). Furthermore, there is strong evidence of a role for the serotonergic system in the pathophysiology and treatment of OCD, and upregulation of BDNF has been observed with various classes of antidepressants, including selective serotonin reuptake inhibitors (SSRI). Thus, we hypothesized that the BDNF gene might also be associated with treatment outcome in OCD. METHODS We performed a single-marker and haplotype association study of eight tag single nucleotide polymorphisms in the BDNF genomic region and related this to pharmacologic response in a sample of 131 OCD patients. RESULTS We found an association for a haplotype containing two single nucleotide polymorphisms that have previously been reported to be associated with treatment outcome in MD (rs908867 and rs1491850). CONCLUSIONS Our results support the hypothesis that the BDNF gene is involved in the response to psychopharmacologic treatment even though these preliminary findings await replication in a follow-up sample.

Hypothalamic-pituitary-adrenal axis activity and cognition in major depression: The role of remission status.

OBJECTIVES Neuropsychological deficits and hypothalamic-pituitary-adrenal (HPA) axis dysfunction have been described in major depressive disorder (MDD). We conducted an exploratory study to investigate the role of remission status in the relationship between HPA axis and cognition in MDD. METHODS Ninety-seven MDD patients (44 remitted, 53 non-remitted) and 97 healthy controls (HC) were evaluated. We measured verbal and visual memory, working memory, processing speed, attention, and executive function. Three HPA axis measures were assessed: cortisol awakening response (CAR), diurnal cortisol slope, and cortisol suppression ratio with 0.25mg of dexamethasone (DSTR). Multiple linear regression analyses were performed to study the relationship between cortisol measures and cognition while controlling for potential confounders. We conducted an overall analysis in all participants to compare both MDD-remitted and MDD non-remitted groups with respect to HC. Another analysis including MDD patients only was used to explore a moderating effect by remission status. RESULTS MDD patients showed poorer cognitive performance compared with HC, without significant differences between remitters and non-remitters. Cortisol measures did not differ between remitters and non-remitters. Although most HPA axis measures were not associated with cognitive dysfunction, we found significant associations between cognitive performance in MDD-remitters and cortisol measures for visual memory, processing speed and executive function. A significant moderating effect for remission status was found between cortisol diurnal slope (but neither CAR nor DSTR) and performance in processing speed or executive function. CONCLUSIONS Remission status in MDD appears to moderate the association between some cognitive domains (processing speed and executive function) and HPA axis activity.

Long-term treatment strategies in major depression: a 2-year prospective naturalistic follow-up after successful electroconvulsive therapy.

Objective To describe a 2-year follow-up in a cohort of patients with major depressive disorder treated with pharmacotherapy plus a short-term course of electroconvulsive therapy (ECT) over the index episode. Methods This naturalistic study included 127 patients. After remission, the same pharmacotherapy regimen was maintained in all patients, whereas 44 also received continuation/maintenance ECT (C/M-ECT). Demographic and clinical data were reported for patients with pharmacotherapy and patients with pharmacotherapy and C/M-ECT. The clinical course of the disorder was compared two years before and after index episode remission. Results Continuation/maintenance ECT was more prescribed in men and in those patients with more previous episodes and admissions and higher treatment resistance. Longer duration of index episode and greater number of episodes in the previous 2 years were identified as risk factors for relapse/recurrence. Furthermore, in our sample, a significant improvement of the illness course after remission was observed after successful ECT. Conclusion Both treatments were effective as maintenance strategies for depressive patients who showed complete response to an acute ECT course. According to our observations, pharmacotherapy both alone and plus C/M-ECT may potentially be considered as long-term treatments after successful ECT in patients with severe major depressive disorder.

Electroconvulsive shock alters the rat overt rhythms of motor activity and temperature without altering the circadian pacemaker

The hypothetical relationship between circadian rhythms alterations and depression has prompted studies that examine the resultant effects of various antidepressants. Electroconvulsive therapy (ECT) exerts significant antidepressant effects that have been modelled in the laboratory via the use of electroconvulsive shock (ECS) in rats. However, data on the effects of ECT or ECS vis-à-vis the circadian rhythms remain scarce. Thus, we report here the effects of acute and chronic ECS administration on the temperature and motor activity circadian rhythms of rats. The motor activity and core body temperature of rats were continuously recorded to determine the circadian rhythms. We carried out three experiments. In the first, we analyzed the effects of acute ECS on both the phase and period when applied at different times of the subjective day. In the second and third experiments ECS was nearly daily applied to rats for 3 weeks: respectively, under dim red light, which allows a robust free-running circadian rhythm; and under light-dark cycles of 22 h (T22), a setting that implies dissociation in the circadian system. Acute ECS does not modify the phase or the period of circadian rhythms. Chronic administration of ECS produces an increase in motor activity and temperature, a decrease in the amplitude of circadian rhythms, although the period of the free-running rhythm remains unaffected. In conclusion, while chronic ECS does alter the overt rhythms of motor activity and temperature, it does not modify the functioning of the circadian pacemaker.

Patrón de uso de la terapia electroconvulsiva en España: propuestas para una práctica óptima y un acceso equitativo

OBJECTIVES The main aims of our study were to estimate the current rates and pattern of electroconvulsive therapy (ECT) use in Spain, as well as exploring the causes that may be limiting its use in our country. METHODS A cross-sectional survey was conducted covering every psychiatric unit in Spain as of 31 December 2012. RESULTS More than half (54.9%) of the psychiatric units applied ECT at a rate of 0.66 patients per 10,000 inhabitants. There are wide variations with regard to ECT application rates between the different autonomous communities (0.00-1.39) and provinces (0.00-3.90). ECT was prescribed to a mean of 25.5 patients per hospital that used the technique and 4.5 in referral centre (P=.000), but wide differences were reported in the number of patients who were prescribed ECT from hospital to hospital. CONCLUSIONS Although the percentage of psychiatric units applying ECT in our country is among the highest in the world, the ECT application rate in Spain is among the lowest within western countries. Large differences in ECT use have been reported across the various autonomous communities, provinces and hospitals. Thus, health planning strategies need to be implemented, as well as promoting training in ECT among health professionals, if these differences in ECT use are to be reduced.