M. Serra-Blasco

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

BACKGROUND Although 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. METHOD The 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. RESULTS Widespread 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. CONCLUSIONS Our 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.

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.

Effects of illness duration and treatment resistance on grey matter abnormalities in major depression

BACKGROUND Findings of brain structural changes in major depressive disorder are still inconsistent, partly because some crucial clinical variables have not been taken into account. AIMS To investigate the effect of major depressive disorder on grey matter volumes. METHOD Voxel-based morphometry was used to compare 66 patients with depression at different illness stages (22 each with first-episode, remitted-recurrent and treatment resistant/chronic depression) with 32 healthy controls. Brain volumes were correlated with clinical variables. RESULTS Voxel-based morphometry showed a significant group effect in right superior frontal gyrus, left medial frontal gyrus and left cingulate gyrus (P<0.05, family wise error-corrected). Patients whose condition was treatment resistant/chronic exhibited the smallest volumes in frontotemporal areas. Longer illness duration was negatively correlated with decreases in right medial frontal cortex and left insula. CONCLUSIONS Frontotemporolimbic areas are smaller in the patients with severe depression and are associated with duration of illness, but not with medication patterns, suggesting negative effects of long-lasting major depressive disorder on grey matter.

Volumetric MRI study of the habenula in first episode, recurrent and chronic major depression.

The habenula (Hb) can play an important role in major depressive disorder (MDD) as it is a key node between fronto-limbic areas and midbrain monoaminergic structures. In vivo neuroimaging studies have shown reductions in Hb volume in a post-mortem sample of patients with affective disorders but findings in unipolar MDD are not consistent. The current study aimed to investigate whether the Hb volume differed between patients with different stages of unipolar MDD and healthy subjects. We also explored differences in grey (GM) and white matter (WM) volumes and potential age and gender effects. High-resolution images were acquired using a 3T-scanner from 95 participants (21 with first-episode MDD; 20 with remitted-recurrent MDD; 20 with treatment-resistant/chronic MDD; and 34 healthy controls).Two researchers blinded to clinical data manually delineated habenular nuclei, with excellent inter-rater agreement. Multivariate analysis of covariance revealed a significant group-by-gender interaction (F9,258=2.22; p=0.02). Univariate effects emerged for Hb-WM volumes (F3,86=3.12; p=0.03) but not for total Hb volumes (F3,86=0.59; p=0.62) or Hb-GM volumes (F3,86=2.01; p=0.12). Women with a first-episode MDD had greater Hb-WM volumes than healthy controls and patients with treatment-resistant/chronic MDD (p<0.01). These findings remained unaltered when controlled for total intracranial volume or medication load. Our results do not support decreased total Hb volumes in unipolar MDD, in patients with first-episode or in patients with long-lasting recurrent or chronic depression. However, the increased Hb-WM volume we observed in women with a first-episode suggests involvement of Hb and its projections in early stages of the recovery process and in the course of MDD.

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.

NATURALISTIC COURSE OF MAJOR DEPRESSIVE DISORDER PREDICTED BY CLINICAL AND STRUCTURAL NEUROIMAGING DATA: A 5‐YEAR FOLLOW‐UP

Despite its high recurrence rate, major depression disorder (MDD) still lacks neurobiological markers to optimize treatment selection. The aim of this study was to examine the prognostic potential of clinical and structural magnetic resonance imaging (sMRI) in the long‐term MDD clinical outcomes (COs).

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.

Cognitive predictors of illness course at 12 months after first-episode of depression

Major Depressive Disorder (MDD) entails cognitive dysfunction in many cognitive domains, but it is still uncertain whether such deficits are present in the early stages. The purpose of the study is to determine the cognitive performance in first episode depression (FED) exploring the presence of different cognitive profiles, and the role of cognition in FED at baseline and long-term. Ninety subjects (18-50 years) were included, 50 patients with a FED and 40 healthy controls. Participants were assessed with a neuropsychological battery, covering language, attention, verbal memory, processing speed and executive domains. Neuropsychological group comparisons were performed with MANOVAs. A hierarchical cluster analysis was run to identify clusters of patients with similar neuropsychological performance. Two generalized linear models were built to predict baseline HDRS-17 and changes at 12 months. Patients performed significantly worse than healthy controls in language, attention/working memory, verbal memory, processing speed and executive functioning, with moderate to large effect sizes (0.5 - 1). Two clusters were found: cognitively preserved patients (n=37) and cognitively impaired patients (n=13). Large effect sizes of cognitive impairment in FED were observed between the two cognitive clusters (preserved and impaired). Depressive symptoms at baseline were predicted by verbal memory (p=0.003), while 12-month changes were predicted by executive function (p=0.041) and language (p=0.037). Cognitive performance predicted depressive symptoms at baseline and at follow-up, pointing to the usefulness of cognitive assessment even at the commencement of the illness.

P.2.b.021 Amygdala shape differences in patients with major depressive disorder

M. Serra-Blasco1 °, J. De Diego-Adelino1, D. Puigdemont1, Y. Vives-Gilabert2, A. Santos3, I. Crespo3, A. Martin-Blanco1, E. Alvarez1, V. Perez1, M.J. Portella1 1Institut d’Investigacio Biomedica Sant Pau (IIB Sant Pau) Universitat Autonoma de Barceona (UAB) Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Department of Psychiatry, Barcelona, Spain; 2INNDACYT, Department of Medical Imaging, Barcelona, Spain; 3Hospital de la Santa Creu i Sant Pau Universitat Autonoma de Barcelona (UAB) Institut d’Investigacio Biomedica Sant Pau (IIB Sant Pau) Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Department of Endocrinology, Barcelona, Spa