Rosario Pérez-Egea

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.

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

BACKGROUND Few 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. METHODS 141 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. RESULTS The 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. LIMITATIONS Given that the sample was originally recruited for two clinical trials, the follow-up period of this study is only six weeks long. CONCLUSIONS Our 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.

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.

Hippocampal abnormalities of glutamate/glutamine, N-acetylaspartate and choline in patients with depression are related to past illness burden.

BACKGROUND Smaller hippocampal volumes in major depressive disorder (MDD) have been linked with earlier onset, previous recurrences and treatment refractoriness. The aim of our study was to investigate metabolite abnormalities in the hippocampus associated with past depressive illness burden. METHODS Glutamate/glutamine (Glx), N-acetylaspartate (NAA) and choline (Cho), potential markers of glial/neuronal integrity and membrane turnover, respectively, were measured in adults with depression and healthy controls using a 3 T magnetic resonance spectroscopy scanner. Voxels were placed in the head of the right and left hippocampus. We controlled for systematic differences resulting from volume-of-interest (VOI) tissue composition and total hippocampal volume. RESULTS Our final sample comprised a total of 16 healthy controls and 52 adult patients with depression in different stages of the illness (20 treatment-resistant/chronic, 18 remitted-recurrent and 14 first-episode), comparable for age and sex distribution. Patients with treatment-resistant/chronic and remitted-recurrent depression had significantly lower levels of Glx and NAA than controls, especially in the right hippocampal region (p ≤ 0.025). Diminished levels of Glx were correlated with longer illness duration (left VOI r = -0.34, p = 0.01). By contrast, Cho levels were significantly higher in patients with treatment-resistant/chronic depression than those with first-episode depression or controls in the right and left hippocampus (up to 19% higher; all p ≤ 0.025) and were consistently related to longer illness duration (right VOI r = 0.30, p = 0.028; left VOI r = 0.38, p = 0.004) and more previous episodes (right VOI r = 0.46, p = 0.001; left VOI r = 0.44, p = 0.001). LIMITATIONS The cross-sectional design and the inclusion of treated patients are the main limitations of the study. CONCLUSION Our results support that metabolite alterations within the hippocampus are more pronounced in patients with a clinical evolution characterized by recurrences and/or chronicity and add further evidence to the potential deleterious effects of stress and depression on this region.

Pindolol augmentation enhances response outcomes in first depressive episodes.

Effectiveness of Pindolol addition to SSRIs is still a matter of debate. Recently, Geretsegger et al. [Geretsegger, C., Bitterlich, W., Stelzig, R., Stuppaeck, C., Bondy, B. and Aichhorn, W. (2008) Paroxetine with Pindolol augmentation: a double-blind, randomized, placebo-controlled study in depressed in-patients. Eur. Neuropsychopharmacol. 18, 141-146.] have found that never-medicated depressed patients showed a significant sustained response with Paroxetine + Pindolol treatment. Also, patients with a first depressive episode displayed a trend for higher sustained response rates with Pindolol co-administration. Re-analysing the data of a previous clinical trial of Fluoxetine + Pindolol [Pérez, V., Gilaberte, I., Faries, D., Alvarez, E. and Artigas, F. (1997). Randomised, double-blind, placebo-controlled trial of Pindolol in combination with Fluoxetine antidepressant treatment. Lancet 349, 1594-1597.], we have found that first depressive episodes are associated with a significant higher percentage of sustained responses when administering Fluoxetine + Pindolol (70.3%) compared to Fluoxetine + Placebo (44%). Moreover, based on a survival analysis, among the patients with a first depressive episode, those who received Fluoxetine + Pindolol achieved a sustained response significantly earlier (19 days) than those on Fluoxetine + Placebo (35 days). Interestingly, none of these effects were observed in the subsample of recurrent patients. The results suggest that Pindolol augmentation accelerates and enhances the action of SSRI at the beginning of the illness.

Cognitive functioning after deep brain stimulation in subcallosal cingulate gyrus for treatment-resistant depression: An exploratory study

Deep brain stimulation (DBS) is being investigated as a therapeutic alternative for patients with treatment-resistant depression (TRD), but its cognitive safety has been scarcely explored. The aim of this exploratory study is to evaluate cognitive function of patients before and after deep brain stimulation of the subgenual cingulate gyrus (SCG). Eight treatment-resistant depressed patients were implanted in subgenual cingulate gyrus. A neuropsychological battery was used to evaluate patients before surgery and 1-year after. A matched group of eight first-episode patients was also assessed. A MANOVA was performed for each cognitive domain and those tests showing main time effects were then correlated with depressive symptoms and with medication load. There were significant group and time effects for memory and a group effect for language. No significant interactions between groups or cognitive domains were observed. Medication load was negatively correlated with memory at time 1, and clinical change negatively correlated with memory improvement. These findings support the cognitive safety of DBS of subgenual cingulate gyrus, as cognitive function did not worsen after chronic stimulation and memory performance even improved. The results, though, should be interpreted cautiously given the small sample size and the fact that some treatment-resistant patients received electroconvulsive therapy (ECT) before implantation.

Immediate cerebral metabolic changes induced by discontinuation of deep brain stimulation of subcallosal cingulate gyrus in treatment-resistant depression

BACKGROUND Positron emission tomography (PET) studies have shown that the antidepressant effect of chronic deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) may be consequence of modifications of brain metabolism at key structures involved in depression. Like clinical benefits, these metabolic changes may reverse when the stimulation is discontinued, even preceding clinical worsening. However no data on immediate effects of DBS discontinuation are available. The aim of this study was to determine immediate cerebral metabolism changes during a short switch-off of electrical stimulation in implanted patients with treatment-resistant depression (TRD) who had achieved clinical improvement after a period of chronic DBS. METHODS Seven patients with TRD who had been previously implanted for DBS in SCG were included. After a period of clinical stabilization two consecutive FDG-PET were acquired, the first with active stimulation and the second after 48 h of inactive stimulation. A HAMD-17 to assess depressive symptoms was performed before both scans. Analyses were performed with SnPM8. RESULTS Inactive stimulation was characterized by metabolism decreases in dorsal anterior cingulate (Broadmann Area, BA24), premotor region (BA6) and putamen with respect to active stimulation. No clinical changes according to HAMD-17 were detected. LIMITATIONS The main limitation of this study is the small sample size. CONCLUSION Our results point to immediate effects of DBS discontinuation on metabolism of brain depressive network which precede clinical changes, helping to disentangle the rationale behind DBS efficacy in TRD.

P.2.b.013 Does the early response to deep brain stimulation in depression represent a placebo or electrode insertion effect

6 INTRODUCTION Deep Brain Stimulation (DBS) in the subgenual cingulated (Cg25) has revealed as a new and promising innovative technique that may be able to provide sustained remission in resistant major depressive disorder. The first clinical series have reported an initial large effect followed by a decay in the first month of treatment. However, this unexpected phenomenon, attributed to a potential placebo effect or a physiological response to probe insertion, remains poorly understood.

P.2.g.009 Early antidepressant response of deep brain stimulation for depression treatment: a translational study

provide sustained remission in resistant major depressive disorder. However, the first clinical series have reported an initial large effect followed by a decay in the first month of treatment . Thus, the aim of this study was to examine the effect of the electrical brain stimulation and the electrodes implantation in a traslational study. Perez-Caballero L, Pérez-Egea R, Puigdemont D, Molet J, Micó JA, Pérez V, Berrocoso E