P.2.a.027 Decreased fronto-limbic volumes in treatment-resistant major depressive disorder

P.2.a. Affective disorders and antidepressants − Affective disorders (clinical) in ictal activity and postictal suppression in EEG. Ictal characteristics of seizures suggested being very similar pointing to the fact that the better side effect profile of MST might indeed be explained by the more focal seizure induction. References [1] Lisanby SH, Luber B, et al. (2003). Safety and feasibility of magnetic seizure therapy (MST) in major depression: randomized within-subject comparison with electroconvulsive therapy. Neuropsychopharmacology 28(10): 1852−65. [2] Kirov G, Ebmeier KP, et al. (2008). Quick recovery of orientation after magnetic seizure therapy for major depressive disorder. Br J Psychiatry 193(2): 152−5.

P.2.a.026 Significant clinical, cognitive and imaging findings of bilateral magnetic seizure therapy in 26 treatment-resistant depression patients S. Kayser1 ° , B.H. Bewernick1 , R. Hurlemann1 , T.E. Schlaepfer1 1 University Hospital of Bonn, Psychiatry and Psychotherapy, Bonn, Germany Purpose of the study: In approximately 30% of Major depression disorders, even four treatment steps yielded no antidepressant response [1]. The magnetic seizure therapy (MST) is a new brain stimulation method and it refers to a more focal form of convulsive therapy that leads to seizure induction in prefrontal cortex and relatively spares medial temporal structures [2]. Preliminary studies with small numbers of patients suggested that MST had significant antidepressant effects [3]. This study was designed to test the hypothesis that MST has good antidepressant effects, however with less cognitive side effects and suitable imaging changes. Methods: Twenty-six patients suffering from treatmentresistant uni- or bipolar depression (TRD) underwent full courses (10 to 12 treatments) bilateral MST. The following assessments each at baseline and post treatment were obtained: clinical assessments by Hamilton Rating Scale for Depression (HAMD28 ) (primary outcome measure) were raised at baseline, post treatment and again at latest at six months follow-up. Antidepressant response as 50% reduction of the depressive symptom and remission ˚ as score of less than 10 on HAMD28 or Montgomery–Asberg Depression Rating Scale (MADRS) (secondary outcome measure) were defined. Comprehensive neuropsychological tests were elevated before treatment and post treatment. In addition, [18 F]FDGPET from 12 patients was received, again at baseline and post treatment. The MST procedure were done with a MagPro MST device (MagVenture A/S, Denmark). The following stimulation parameters were used: high-dose MST with up to 800 pulses in a train, amplitude of 100%, frequency of 100 Hz and duration of stimulation up to 8 s. Statistical analysis: the level of statistical significance was set at 5%. The main variables were compared by using a paired-samples t-test. Results: 69% of the patients responded to bilateral MST. As primary outcome measures the HDRS28 score declining from 28.8 (±6.0) at baseline to 14.0 (±9.2) post treatment (p < 0.001). The MADRS scores as secondary outcome measures lowered from 29.7 (±6.5) at baseline to 14.0 (±10.3) post treatment (p < 0.001). 46.2% of the patients fulfilled a remission criterion. Furthermore, 50% of the responders fulfilled relapse criteria within 6 months after end of treatment concerning the HDRS28 . No significant cognitive side-effects were observed. Decrease of frontal metabolism at short term followed by relative increase at long term and constant decreases in striatum and subgenual anterior cingulate cortex were revealed by [18 F] FDG-PET in 12 patients.

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Conclusions: Our findings demonstrated significant antidepressant effects of bilateral MST and additionally persistent metabolic changes in the brain regions strongly implicated in the pathophysiology of TRD. The absence of cognitive side effects in combination with significant antidepressant efficacy appeared to be a major advantage of bilateral MST. Further studies to replicate the results are needed to decide whether MST would be a method for treatment-resistant depression. References [1] Rush AJ, Trivedi MH, et al. (2006). Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 354(12): 1231−42. [2] Lisanby, SH, Luber B, et al. (2003). Safety and feasibility of magnetic seizure therapy (MST) in major depression: randomized within-subject comparison with electroconvulsive therapy. Neuropsychopharmacology 28(10): 1852–1865. [3] Kayser S, Bewernick BH, et al. (2011). Antidepressant effects, of magnetic seizure therapy and electroconvulsive therapy, in treatmentresistant depression. J Psychiatr Res 45(5): 569–576.

P.2.a.027 Decreased fronto-limbic volumes in treatment-resistant major depressive disorder M. Serra-Blasco1 ° , M.J. Portella1 , J. De Diego-Adeli˜no1 , Y. Vives-Gilabert2 , B. G´omez-Ans´on3 , A. Santos4 , 1 , V. P´ ´ D. Puigdemont1 , E. Alvarez erez1 1 Institut d’Investigaci´o Biom`edica Sant Pau (IIB Sant Pau). Centro de Investigaci´on Biom´edica en Red de Salud Mental (CIBERSAM), Psychiatry, Barcelona, Spain; 2 Port d’Informaci´o Cient´ıfica (PIC), Medical imaging group, Bellaterra, Spain; 3 Institut d’Investigaci´o Biom`edica Sant Pau (IIB Sant Pau). Centro de Investigaci´on Biom´edica en Red para Enfermedades Neurodegenerativas (CIBERNED), Neuroradiology, Barcelona, Spain; 4 Institut d’Investigaci´o Biom`edica Sant Pau (IIB-Sant Pau). Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBER-ER), Endocrinology, Barcelona, Spain Purpose of the study: Gray matter is clearly reduced in Major Depression Disorder (MDD) [1], but still the specific brain structures remain to be defined. One of the reasons of inconsistent findings relies on the heterogeneity of depressive samples. Purpose: to measure brain volume differences of depressed patients as compared to healthy controls, taking into account the disease’s stage to partly overcome the clinical heterogeneity. Second, to determine whether clinical variables, including medication load, can account for brain volume differences. Methods: MRI technology of 3-Tesla was used to obtain images from 66 depressive patients (22 first-episode-MDD, 22 remittedrecurrent-MDD and 22 treatment-resistant chronic-MDD) and from 32 healthy controls matched by age, gender, lateralization and level of education. All patients were on medication. Images: 3D-MPRAGE whole-brain sequence; TR=6.7 ms, TE=3.2 ms, 170 slices. Voxel-based morphometry analysis (SPM8) was used to analyze the morphometric data. Analyses: ANOVA of four groups, and posthoc contrasts. Whole volumes of those areas showing a significant decrease were then obtained by means of FreeSurfer 4.3.1., in order to perform correlations with clinical variables (duration of illness, number of previous episodes, HDRS score and age at onset). Medication load at time of scanning was also registered for each patient following Sackeim [2] system code. Summary of results: General ANOVA showed a significant decrease of volume in right superior frontal gyrus, left medial

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P.2.a. Affective disorders and antidepressants − Affective disorders (clinical)

frontal gyrus and left cingulate gyrus (F = 11.10; df = 3, 94; p < 0.05, corrected for family-wise error [FWE]). Posthoc analyses revealed that treatment-resistant chronic patients had less grey matter volume than healthy controls surviving the FWE correction (p < 0.05, cluster size>100; see Table 1). Among the clinical variables only illness duration was significantly correlated with the right medial orbitofrontal gyrus (r = −0.34; p = 0.006) and the left insula (r = −0.3; p = 0.015). Conclusions: The findings show a volume reduction of frontal, temporal and limbic areas in the most severe group of patients compared to healthy controls, which give partial support to the latest meta-analysis [1]. Interestingly, the effect of being depressed for longer periods appeared to correlate negatively with key areas which are part of the brain network involved in the pathophysiology of depression [3]. Even though, a longitudinal study would be more appropriate to ascertain whether volume reductions in chronic patients are a result of enduring effects of the disease or having less grey matter causes a more severe disorder. Table 1. Brain areas with diminished volumes in chronic patients compared to healthy controls (p < 0.05 [FWE corrected]) Brain Area Right superior frontal gyrus (BA 8)‡ Right medial frontal gyrus (BA 10) Left cingulate gyrus (BA 24) Left medial frontal gyrus (BA 6) Left insula (BA 13) Left medial frontal gyrus (BA 8) Left parahippocampal gyrus (BA 35) Left transverse temporal gyrus (BA 41)

Cluster

MNI† Coordinates

size*

x

y

z

877

5 2 −14 −11 −48 −9 −24 −59

34 60 7 −5 12 38 −10 −20

49 17 36 65 0 46 −32 14

641 123 767 192 180 114

*Number of significant voxels. † Montreal Neurological Institute. ‡ Brodmann area. References [1] Du MY, Wu QZ, Yue Q, Li J, Liao Y, Kuang WH, Huang XQ, Chan RC, Mechelli A, Gong QY. 2012. Voxelwise meta-analysis of gray matter reduction in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 10;36(1): 11−6. [2] Sackeim HA., 2001. The definition and meaning of treatment-resistant depression. J Clin Psychiatry 62 Suppl 16: 10−7. [3] Phillips ML, Drevets WC, Rauch SL, Lane R., 2003. Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 54: 515−28.

P.2.a.028 Gene × environment interaction in depressive disorders: which environment is of risk? L. Mandelli1 ° , C. Petrelli1 , A. Serretti1 Institute of Psichiatry, Bologna, Italy

1 University

of Bologna,

Gene × environment interaction studies in depressive disorders have renewed interest in the investigation of the major environmental risk factors, particularly childhood traumas, that may increase the risk of a clinical episode of major depression in predisposed individuals. Many studies have been published, but to date, the effective role of childhood stressors is unclear. To clarify the role childhood stressors in mood disorders, we performed a systematic review and meta-analysis of the literature focused on exposure to different childhood stressors, including sexual, physical, and emotional abuse, early significant loss and

familiar adversity. Moreover, we preliminary analyzed 250 patients affected by both mood and anxiety disorders evaluated for stressful life events in childhood, the year before the onset of the first episode and current episode. Previously published papers were retrieved in literature through common databases such as PubMed and ISI Web of Science using keywords such as childhood trauma, sexual, physical, emotional, psychological abuse and neglect. The reference lists of retrieved studies were employed to detect further studies relevant for the topic. Meta-analysis of studies was conducted by the RevMan software. Our sample was composed by 250 subjects satisfying criteria for a mood disorder or anxiety disorder consecutively admitted to our psychiatric inpatients and outpatients Units of the Institute of Psychiatry of Bologna Italy. This sample was evaluated for stressful life events in childhood, the year preceding illness onset and current episode according to Brown & Harris interview. A number of other clinical and demographic variables were collected and considered in the analyses. Statistical analyses were conducted as appropriate employing the Statistica Software (StatSoft Italia), taking into account the distribution of variables and recurring to both linear and multivariate models. According to our preliminary meta-analysis, sexual abuse in childhood is a major risk factor for the development of a mood disorder in adulthood. Physical and emotional abuse, neglect, violence within the family also showed strong associations, while separation/divorce of parents or early losses showed only slight associations with the risk to develop a clinical episode of major depression. On our sample of patients suffering from depressiveanxiety disorders, we found strongest associations between childhood stressors and severity of disorders (in terms of hospitalization, illness duration, clinical picture, comorbidity for other axis I and II disorders) than stressful life events at onset and preceding current episode. However, stressful life event at onset had a significant role in the development of the first episode as well. These findings support the role of severe childhood trauma in the etiology of mood disorders. Therefore, gene × environment studies should focus more on severe childhood trauma instead of other mild or late in life stressful events. Moreover, it is likely that subjects having been exposed to childhood stressors are more likely to develop clinical symptoms of depression and anxiety if exposed to stressful life events in adulthood as well.

P.2.a.029 The role of serotonergic genes and environmental stress on the development of depressive symptoms and neuroticism L. Mandelli1 ° , N. Antypa1 , F.A. Nearchou2 , C. Vaiopoulos3 , C.N. Stefanis4 , A. Serretti5 , N. Stefanis6 1 University of Bologna Italy, Institute of Psychiatry, Bologna, Italy; 2 Aristotle University of Thessaloniki Thessaloniki Greece, Department of Psychology, Thessaloniki, Greece; 3 General Hospital of Xanthi Xanthi Greece, Department of Psychiatry, Xhanthi, Greece; 4 University of Athens Greece, Mental Health Research Institute, Athens, Greece; 5 University of Bologna, Institute of Psychiatry, Bologna, Italy; 6 University of Western Australia Perth WA Australia, School of Psychiatry and Clinical Neurosciences, Perth, Australia Background: Depression is one of the leading causes of disability affecting 5−7% of the population annually, and approximately