Dolors Puigdemont

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.

Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-μs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.

Ventromedial prefrontal spectroscopic abnormalities over the course of depression: a comparison among first episode, remitted recurrent and chronic patients.

Structural and neuropathological alterations in the ventromedial prefrontal cortex (vmPFC) described in depression (MDD) might become even more pronounced over the course of illness. Measurement of brain metabolites by means of Magnetic Resonance spectroscopy (MRS) can indirectly deliver information about glial and neuronal integrity or potential cellular loss. The aim of this study was to investigate whether Glutamate (Glu), Choline (Cho) and total N-acetylaspartate (total-NAA) levels in the vmPFC differed among MDD patients in distinct stages of illness and healthy controls. We hypothesized that high-past illness-burden would represent more metabolite abnormalities independently of mood state. A 3-Tesla MR facility was used to measure these metabolites in vmPFC of 45 depressive patients (10 first-episode-MDD, 16 remitted-recurrent-MDD and 19 chronic-MDD) and 15 healthy controls. Multivariate and correlation analyses were carried out to explore the influence of duration of illness, age at onset and mood-state. Levels of Glu were significantly decreased in remitted-recurrent and chronic patients compared with both first-episode and controls (up to 28% mean reduction; pxa0<xa00.001, Cohens dxa0=xa02.88) and were negatively correlated with illness duration (rxa0=xa0-0.56; pxa0<xa00.001). Cho levels showed an opposite pattern: highest values were detected in chronic patients, correlating positively with duration of illness (rxa0=xa00.32; pxa0=xa00.03). Total-NAA levels were significantly lowered in remitted-recurrent and chronic patients, which were associated with an earlier age at onset (rxa0=xa00.50; pxa0=xa00.001). Our data suggest that abnormalities in Glu, Cho and total-NAA levels are consistently related to the course of MDD, supporting the hypothesis that cellular changes would take place in vmPFC over time.

Augmentation of Fluoxetine's Antidepressant Action by Pindolol: Analysis of Clinical, Pharmacokinetic, and Methodologic Factors

In a controlled trial, the β-adrenoceptor/5-hydroxytryptamine-1A (5-HT1A) receptor antagonist pindolol accelerated and enhanced the antidepressant effect of fluoxetine. The median times to sustained response (≥50% reduction of baseline severity maintained until endpoint) were 19 days for fluoxetine plus pindolol (N = 55) and 29 days for fluoxetine plus placebo (N = 56) (p = 0.01). The response rate at endpoint was 16% greater in patients treated with the combination. The plasma concentration of pindolol remained stable between 3 days (first blood sampling) and 6 weeks. Mean values were ∼26 nM, a concentration higher than the Ki of (−)pindolol for human 5-HT1A autoreceptors (11 nM). Plasma fluoxetine and norfluoxetine concentrations increased steadily until the fourth week of treatment. Fluoxetine concentrations were lower in patients receiving the combination (p = 0.043), but there was no significant relationship to the clinical response in either group. A reanalysis of the data using a survival analysis revealed that significant differences in the time to sustained response between both groups would have also been detected (1) in a 2-week trial, (2) without a placebo lead-in phase, and (3) with less frequent visits. However, the use of response instead of sustained response as measure of clinically relevant change would have greatly diminished the difference between treatment arms (p = 0.08 instead of p = 0.01). This emphasizes the need of using stringent outcome criteria in antidepressant drug trials. A comparison of the data of all sustained responders (N = 27) in the fluoxetine-plus-placebo group with the first 27 responders in the fluoxetine-plus-pindolol group (of a total of 38) revealed a highly significant difference in the time to sustained response (18 and 10 days, respectively; p = 0.0002). This indicates that the faster response in the fluoxetine-plus-pindolol group is not a result of the greater proportion of responders.

Can We Really Accelerate and Enhance the Selective Serotonin Reuptake Inhibitor Antidepressant Effect? A Randomized Clinical Trial and a Meta-Analysis of Pindolol in Nonresistant Depression

OBJECTIVEnSince depression entails not only dramatic personal disruption but also a huge amount of medical and socioeconomic burden, slowness of antidepressant action and difficulties to attain remission are entangled issues to be solved. Given the controversial previous findings with enhancing strategies such as pindolol, we examined whether the speed of selective serotonin reuptake inhibitor (SSRI) action can be truly accelerated with optimized pindolol dosage. Additionally, we aimed at elucidating whether pindolol benefits emerge, particularly in a population with nonresistant depression.nnnMETHODnThirty outpatients with major depressive disorder (DSM-IV criteria) recruited between December 2002 and November 2005 were randomly assigned to receive citalopram + pindolol (5 mg tid) or citalopram + placebo for 6 weeks in a double-blind randomized clinical trial. A meta-analysis of randomized controlled trials of pindolol augmentation in patients with nonresistant depression was also performed. Outcome criteria were based on the 17-item Hamilton Depression Rating Scale. For the meta-analysis, efficacy was assessed by the number of treatment responders at 2 weeks and 4-6 weeks.nnnRESULTSnClinical trial outcomes: Repeated-measures analysis of variance showed a significant group-by-time interaction (P = .01). Cumulative percentage showed a trend for sustained response (odds ratio [OR] = 2.09; 95% CI, 0.914-4.780; P = .08) and a well-defined increased likelihood of sustaining remission (OR = 5.00; 95% CI, 1.191-20.989; P = .03) in pindolol receivers. Median survival time until first response was 65% less in the pindolol group (22 days vs 30 days; P = .03). The negative binomial regression model yielded different rates of response per person-day for pindolol and placebo groups (7.6% vs 4.7%, respectively; P = .03). Meta-analysis: Outcome favored pindolol at 2 weeks time (relative risk [RR] = 1.68; 95% CI, 1.18-2.39; P = .004) and also at 4-6 weeks time (RR = 1.11; 95% CI, 1.02-1.20; P = .02).nnnCONCLUSIONSnPresent findings represent further evidence of the acceleration and enhancement of efficacy with pindolol administered together with SSRIs, displaying a quicker and more pronounced decrease of symptoms in patients with nonresistant major depressive disorder.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00931775.

Microstructural white-matter abnormalities associated with treatment resistance, severity and duration of illness in major depression

BACKGROUNDnAlthough white-matter abnormalities have been reported in middle-aged patients with major depressive disorder (MDD), few data are available on treatment-resistant MDD and the influence of relevant variables related to clinical burden of illness is far from being well established.nnnMETHODnThe present study examined white-matter microstructure in a sample of 52 patients with MDD in different stages (treatment-resistant/chronic MDD, n = 18; remitted-recurrent MDD, n = 15; first-episode MDD, n = 19) and 17 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. Groups were comparable in age and gender distribution, and results were corrected for familywise error (FWE) rate.nnnRESULTSnWidespread significant reductions of fractional anisotropy (FA) - including the cingulum, corpus callosum, superior and inferior longitudinal fascicule - were evident in treatment-resistant/chronic MDD compared with first-episode MDD and controls (p < 0.05, FWE-corrected). Decreased FA was observed within the ventromedial prefrontal region in treatment-resistant/chronic MDD even when compared with the remitted-recurrent MDD group (p < 0.05, FWE-corrected). Longer duration of illness (β = -0.49, p = 0.04) and higher depression severity (at a trend level: β = -0.26, p = 0.06) predicted lower FA in linear multiple regression analysis at the whole-brain level. The number of previous episodes and severity of symptoms were significant predictors when focused on the ventromedial prefrontal area (β = -0.28, p = 0.04; and β = -0.29, p = 0.03, respectively). Medication effects were controlled for in the analyses and results remained unaltered.nnnCONCLUSIONSnOur findings support the notion that disruptions of white-matter microstructure, particularly in fronto-limbic networks, are associated with resistance to treatment and higher current and past burden of depression.

A short duration of untreated illness (DUI) improves response outcomes in first-depressive episodes.

BACKGROUNDnFew studies have addressed the implication of the duration of untreated illness (DUI) on the clinical outcome of mood disorders. Although not focusing on DUI, previous findings suggest that the longer it takes to start appropriate treatment, the worse will be the evolution of depressive disorder. We sought to determine the effect of the duration of untreated episode (DUE) on 1) rates of response to treatment, 2) time to attain a sustained response and 3) rates of remission of MDD, dealing specially with first-depressive episodes.nnnMETHODSn141 patients with MDD were grouped into long DUE (>8 weeks) and short DUE (< or =8). Statistical analyses were performed to determine differences in outcome variables. The same analyses were repeated by splitting the sample between first-episode and recurrent depression.nnnRESULTSnThe percentage of patients who achieved a sustained response was significantly higher in the group with a short DUE [OR=2.6; 95% CI 1.3-5.1]. Survival analyses showed that patients with a long DUE delayed longer time to attain a sustained response [39 vs. 20 days, p=0.012]. Once the sample was split, these results were even more pronounced in the subsample of first-depressive episode patients.nnnLIMITATIONSnGiven that the sample was originally recruited for two clinical trials, the follow-up period of this study is only six weeks long.nnnCONCLUSIONSnOur results indicate that response to antidepressant treatments is faster when the no-treatment interval is reduced. The earliest treatment of first-depressive episodes seems to be crucial since a shorter duration of untreated illness implies better response outcomes.

Regulation of platelet α2A-Adrenoceptors, Gi proteins and receptor kinases in major depression: Effects of mirtazapine treatment

Major depression is associated with the upregulation of α2A-adrenoceptors in brain tissue and blood platelets. The homologous regulation of these receptors by G-protein-coupled receptor kinases (GRKs) might play a relevant role in the pathogenesis and treatment of depression. This study was designed to assess the status of the complex α2A-adrenoceptor/Gαi/GRK 2 in the platelets of depressed patients (n=22) before and after treatment with the antidepressant mirtazapine, an antagonist at α2A-adrenoceptors (30–45 mg/day for up to 6 months). A second series of depressed suicide attempters (n=32) were also investigated to further assess the status of platelet GRK 2 and GRK 6. Platelet α2A-adrenoceptors and Gαi protein immunoreactivities were increased in depressed patients (49 and 35%) compared with matched controls. In contrast, GRK 2 content was decreased in the two series of depressed patients (27 and 28%). GRK 6 (a GRK with different properties) was found unchanged. In drug-free depressed patients, the severity of depression (behavioral ratings with two different instruments) correlated inversely with the content of platelet GRK 2 (r=−0.46, n=22, p=0.032, and r=−0.55, n=22, p=0.009). After 4–24 weeks of treatment, mirtazapine induced downregulation of platelet α2A-adrenoceptors (up to 34%) and Gαi proteins (up to 28%), and the upregulation of GRK 2 (up to 30%). The results indicate that major depression is associated with reduced platelet GRK 2, suggesting that a defect of this kinase may contribute to the observed upregulation of α2A-adrenoceptors. Moreover, treatment with mirtazapine reversed this abnormality and induced downregulation of α2A-adrenoceptor/Gαi complex. The results support a role of supersensitive α2A-adrenoceptors in the pathogenesis and treatment of major depression.

Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study

RationaleTo assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo 123I-ADAM SPECT.Objectives123I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc.Materials and methodsMeasures of SERT availability by means of 123I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20xa0mg/day. 123I-ADAM SPECT measures of SERT availability from a group of ten previously studied age-matched healthy volunteers were used for comparison. The relationship between percentages of SERTocc and paroxetine Cp was studied using an Emax model.ResultsMean SERTocc values were 66.4u2009±u20099.5% in midbrain, 63.0u2009±u20099.6% in thalamus, and 61.3u2009±u200910.9% in striatum. No significant differences in SERTocc were found among these three regions. No significant differences in mean SERT availability were found in any region between drug-free MDD patients (midbrainu2009=u20091.14u2009±u20090.15; thalamusu2009=u20090.85u2009±u20090.13; striatumu2009=u20090.70u2009±u20090.07) and healthy volunteers (midbrainu2009=u20091.19u2009±u20090.22; thalamusu2009=u20090.96u2009±u20090.14; striatumu2009=u20090.67u2009±u20090.15). The Emax model returned a SERToccmaxu2009=u200970.5% and a Cp50u2009=u20092.7xa0ng/ml.ConclusionsUsing 123I-ADAM SPECT, treatment with paroxetine 20xa0mg/day leads to more than 60% SERTocc on average in cerebral regions with known high SERT density. Data from this study do not support the existence of SERT availability differences between drug-free MDD patients and healthy volunteers. Finally, the Emax model is suitable for the study of paroxetine Cp relationship to 123I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic–pharmacodynamic relationships in drug development.

Preclinical and clinical characterization of the selective 5‐HT1A receptor antagonist DU‐125530 for antidepressant treatment

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5‐HT reuptake inhibitors (SSRI) and other 5‐HT‐enhancing drugs is compromised by a negative feedback mechanism involving 5‐HT1A autoreceptor activation by the excess 5‐HT produced by these drugs in the somatodendritic region of 5‐HT neurones. 5‐HT1A receptor antagonists augment antidepressant‐like effects in rodents by preventing this negative feedback, and the mixed β‐adrenoceptor/5‐HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5‐HT1A autoreceptors. However, it is unclear whether 5‐HT1A receptor antagonists not discriminating between pre‐ and post‐synaptic 5‐HT1A receptors would be clinically effective.