Erika Martínez-Amorós

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.

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.

Eficacia y patrón de uso de la terapia electroconvulsiva de continuación y mantenimiento en el trastorno depresivo mayor

Patients with major depressive disorder (MDD) who require an acute course of electroconvulsive therapy (ECT) have high relapse rates. Therefore, an effective maintenance treatment strategy needs to be established. Continuation and maintenance ECT (C/M-ECT) could be an adequate treatment option, although the lack of controlled studies has led to its usefulness being questioned. This review includes a detailed description of studies on the effectiveness/efficacy of ECT in MDD. Despite their methodological limitations, the results appear to support the idea that C/M-ECT would be a safe and effective alternative, especially in patients with severe and recurrent disease. Nevertheless, more controlled studies are needed to provide new evidence and allow a more accurate assessment of the efficacy, safety and pattern of use of C/M-ECT.

Electroconvulsive Therapy Practice in Spain: A National Survey.

Objectives The use of electroconvulsive therapy (ECT) in Spain has not been systematically evaluated since 2000 to 2001. The aim of this study is to assess the current use of ECT in Spain. Methods A cross-sectional survey was conducted covering every psychiatric unit in Spain as of December 31, 2012. Results About 93.2% of the centers answered the questionnaire. About 54.9% of the psychiatric units applied ECT at a rate of 0.66 patients per 10,000 inhabitants. Wide variations existed among the different autonomous communities and provinces. Written informed consent was obtained in all the facilities. About 38.2% of ECT-treated patients were 65 years or older. About 55.7% were women. Depressive episodes were the main indication for ECT (80.2%). All the facilities applied modified ECT. No sine wave current devices are currently used in Spain. Bifrontotemporal ECT was elective in 85% of the hospitals, bifrontal in 13.3%, and unilateral in 1.8%. Stimulus titration methods were elective in 8.6% of the centers. The decision to end ECT relied on the psychiatrists clinical impression in 89.4% of the centers and on rating scales in 10.6%. The ECT training was mandatory in 56.5% of the centers. Conclusions The ECT practice has significantly improved in Spain in recent years. Overall, Spanish facilities seem to comply with established clinical guidelines; however, specific concerns were identified, meaning there is still further scope for improvement.

Propofol y pentotal como agentes anestésicos en la terapia electroconvulsiva: un estudio retrospectivo en el trastorno depresivo mayor

OBJECTIVE To determine the influence of propofol and thiopental as anesthetics in electroconvulsive therapy (ECT), as regards, seizure duration, electrical charge, clinical efficacy, cardiovascular profile, and presence of adverse cognitive effects. METHODS A retrospective design including 127 patients who received bilateral ECT for the treatment of a major depressive episode. RESULTS The mean seizure duration in the propofol group was significantly shorter than in the thiopental group (21.23±6.09 versus 28.24±6.6 7s, P<.001). The mean stimulus charge was 348.22 mC in the propofol group, and 238 mC in the thiopental group (P<.001). Propofol was associated with a lower increase in blood pressure. There were no differences between groups in treatment response or presence of adverse effects. CONCLUSIONS The anesthetic agent used in ECT might determine differences in parameters such as seizure duration or electrical charge. However, this does not seem to be translated into differences in clinical efficacy or the pattern of adverse effects observed.

Electroconvulsive therapy practice in Catalonia: a survey study comparing data from 1993 and 2010.

Objective The aim of this study was to assess the current use of electroconvulsive therapy (ECT) in Catalonia (Spain) as compared with ECT practice 17 years ago (1993). Methods This was a descriptive, cross-sectional study using a structured questionnaire to collect data regarding the use of ECT in Catalan psychiatric units in 2010. A comparative approach was used with respect to previously published data. Results Data were obtained from 25 of the 27 units (92.6%) surveyed. The ECT was used in 20 facilities (80%, as opposed to 60% in 1993), and in all cases, a brief-pulse device was used. The most commonly used anesthetic was propofol (65%), and most facilities recorded the seizure duration (95%). The ECT was always administered in combination with pharmacologic therapy, and the primary clinical indication was depression. Only 20% of the ECT procedures were performed in the inpatient unit. Written informed consent to administer ECT was obtained in all centers. Conclusions The ECT practice in Catalonia has changed since the 1990s, being administered more often, in a more standardized way and across a larger number of psychiatric units. The results indicate considerable consensus with regard to its indications and conditions of application, which comply with current clinical practice guidelines and standards.

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.

Bilateral posterior vitreous detachment after electroconvulsive therapy.

In this case report, we describe a patient with an acute bilateral posterior detachment of the vitreous, which developed during electroconvulsive therapy (ECT) under general anesthesia. The patient developed symptoms of posterior vitreous detachment immediately after recovery from the eighth ECT session. The ophthalmologist confirmed the clinical diagnosis and ECT was stopped. We review the literature and discuss the ocular side effects of ECT.

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.

The CORE system for sub-typing melancholic depression: Adaptation and psychometric properties of the Spanish version.

We report the development procedure for a Spanish version of the CORE measure for subtyping melancholic depression and its psychometric properties. The sample comprised two subsets of depressive patients: 117 in-patients clinically assessed after admission and before discharge; and 34 in- and out-patients who were video-recorded, with each recording being rated by independent raters and re-rated six months later. The internal consistency of the Spanish version of the CORE was high, with Cronbachs alpha coefficient of 0.93 for the total CORE score. High intra-class correlation coefficient for the total score (0.96) and the three subscales (around 0.8) indicate high inter-rater reliability. Baseline and six-month ratings of video-recordings showed high test-retest reliability. Regarding construct validity, the correlation between the CORE and the Newcastle endogeneity scale scores was 0.64. A ROC curve generated an optimal cut-off of 10 to predict the definition of endogeneity/melancholia based on the Newcastle score >=6 and the DSM-IV-TR definition of melancholia. The comparison between the CORE scores at admission and at discharge revealed large differences, indicating demonstrable sensitivity to change. The Spanish version of the CORE system is a reliable and valid instrument for sub-typing depression in terms of melancholic versus non-melancholic sub-types.