P.2.b.017 Defining endophenoypes in major depressive disorder: anhedonia, neuroticism and psychomotor speed

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P.2.b. Affective disorders and antidepressants − Affective disorders (basic)

students participating in a long-distance learning program, and communitiy-based population. The mean age of participants was 31.38±0.39 years. Participants completed six questionnaires: a background questionnaire, the Threatening Life Events Questionnaire (TLE), the Social Support Questionnaire (SSQ), the Social Problems Questionnaire (SPQ) and Childhood Trauma Questionnaire (CTQ) the Psychological Immune System Inventory (PISI) the Zung Self-Rating Depression Scale (ZSDS). We used Structural Equation Modeling (SEM) to analyse the effects in our sample. Results: We found a significant interaction between the three PISI subdimensions (MOB − mobilising, activating, and executive system; APP − approach system, SELF − self-regulation system) and Childhood Life Events and between PISI subscales and Lifetime Events as well, indicating that childhood and current life events have a significant effect on coping strategies. The interaction between PISI and Childhood Life events was independent from the number of events happened. Life events (LEQ) and Childhood life events (CTQ) influenced the Zung (ZSDS) depression scores both directly and indirectly via the mediating effect of psychological immune competencies (PISI). All three PISI subdimensions (MOB, APP and SELF) had a significant direct interaction with the ZSDS total score. Conclusion: We found that childhood and current life events influence susceptibility to depressive symptoms both directly and also indirectly via the mediating effects of coping strategies and psychological immune competencies. Our results indicate that the MOB subdimension, including psychological immune competencies related to mobilizing and activating resources and execution, plays the mediating role between life events and emergence of depressive symptoms. Our results are valuable also in the research for relevant endophenotypes for the genetic studies of depression. This work was supported by the 6th Framework Program of the EU, LSHM-CT-2004–503474. References [1] Wilhelm K, Wedgwood L, Parker G, Geerligs L, Hadzi-Pavlovic D. Predicting mental health and well-being in adulthood. J Nerv Ment Dis. 2010 Feb;198(2):85−90. [2] Green JG, McLaughlin KA, Berglund PA, Gruber MJ, Sampson NA, Zaslavsky AM, Kessler RC. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry. 2010 Feb;67(2):113−23.

the expression of these PDE4 variants has not been characterized in human brain. Moreover, whether these splice variants play any role in depression, is completely unknown, although, a few studies suggest that PDE inhibitors show antidepressant-like effects in rodents. Therefore, in the present study, we characterized expression of PDE4A1, PDE4A4, PDE4A10, PDE4B1, PDE4B2, PDE4B3, PDE4D3, PDE4D4, PDE4D5 and PDE4D9 variants in human prefrontal cortex (PFC) and hippocampus by quantitative RT-PCR using specific primers. In addition, we characterized subcellular distribution of splice variants by using splice variant-specific antibodies. To examine the role of PDE4 in human depression, we performed our PDE4 studies in PFC and hippocampus of 17 non-psychiatric normal controls and age-, postmortem brain interval (PMI)-, and sex-matched 17 antidepressant-free depressed suicide subjects. Depressed patients were diagnosed according to DSM IV criteria. Postmortem brain samples were obtained from the Maryland Psychiatric Research Center. We examined catalytic activity of total PDE4 by enzymatic assays using rolipram as PDE4 inhibitor as well as the expression levels of splice variants in PFC and hippocampus of depressed subjects and normal controls. When examined, we observed that all, except PDE4A10, PDE4B1, PDE4D4 or PDE4D5 variants, were highly expressed in human brain. PDE4D8 was not expressed in any of the brain areas. We also observed compartmentalized expression of specific splice variants of PDE4 such that PDE4B2, B3, D3 were expressed in membrane and A1, A4, B3, and D9 were expressed in cytosol fraction specifically. When depressed subjects were compared with normal controls, we found that catalytic activity of PDE4 was significantly decreased in PFC and hippocampus of depressed subjects. We also observed decreased expression of selective PDE4A1, DE4B2, and PDE4A4 variants in PFC and hippocampus of depressed subjects. The expression levels of these splice variants were not affected by age, PMI or gender. Our study for the first time provides evidence of variant specific alterations in PDE4 in brain of depressed subjects and indicates that these variants may be used as site-specific therapeutic target(s) to develop novel antidepressants. P.2.b.017 Defining endophenoypes in major depressive disorder: anhedonia, neuroticism and psychomotor speed

Illinois Chicago, Psychiatry, Chicago,

E. Vrieze1 ° , K. Demyttenaere1 , R. Bruffaert1 , M. Schmidt2 , P. de Boer2 , S. Claes1 . 1 University Hospital Gasthuisberg, Psychiatry, Leuven, Belgium; 2 Johnson & Johnson, Pharmaceutical Research and Development, Beerse, Belgium

cAMP-specific PDE4 are a family of enzymes capable of hydrolyzing cAMP to 5’AMP. cAMP plays a major role in synaptic plasticity, neurite outgrowth, and neuronal differentiation and survival and recent studies demonstrate involvement of cAMP in pathophysiology of depression. The cAMP-specific PDE4 can be differentiated from other PDE families by sequence identity in the catalytic region of the protein and by their ability to be inhibited by a specific class of drugs, of which rolipram is the prototype. PDE4 enzymes are also unique in having ‘signature’ regions of sequence, called upstream conserved regions (UCR1 and UCR2), located in the N-terminal region of the proteins. There are four PDE4 subfamilies, encoded by separate genes (PDE4A, PDE4B, PDE4C, PDE4D). All, except PDE4C, are expressed in brain. Each PDE4 gene produces a number of splice variants, however,

Rationale: The DSM-IV construct of Major Depressive Disorder (MDD) is based on clusters of symptoms and characteristics of clinical course that do not necessarily describe a homogenous disorder, but rather reflect a common final pathway of different pathophysiological processes. Most likely the MDD-concept consists of different endophenotypes[1] . Objective: The purpose of this study was to find non-correlated, uniform typologies or clinical endophenotypes within a depressed patient group based upon a collection of clinical and psychopathological findings. Method: Eighty inpatients, all within the first week of submission and meeting DSM-IV criteria for MDD, completed a series of questionnaires and tasks. Fourteen test-outcomes were used in the analysis of this study: Information on comorbidity and number of previous episodes was extracted from the SCID-I questionnaire,

P.2.b.016 Role of phosphodiasterase 4 variants in depression and therapeutic treatment Y. Dwivedi1 ° . USA

1 University

P.2.b. Affective disorders and antidepressants − Affective disorders (basic) which was conducted for the diagnosis of MDD. The Positive and Negative Affect Scale (PANAS) was used to measure positive affect and negative affect separately. The Snaith-Hamilton Pleasure Scale (SHAPS), a validated self-report questionnaire, measured anhedonia. The neurotic and openness subscale of the NEO-FFI was used to find specific vulnerable personality traits for MDD. Executive functioning was assessed by performance on the STROOP. The Trail Making Test (TMT), part A and B, evaluated psychomotor speed and subscales of the CORE-scale measured psychomotor retardation and non-interactiveness. The Structured Trauma Interview (STI) revealed early neglect and early separation in patients. Results: A principal component analysis (PCA) was used on the fourteen variables included in the model. Three factors were retained (cumulative eigenvalue: 47%). A varimax rotational strategy revealed a pattern of loadings on the three factors (Table 1). Using a cut-off load (= >0.4), the first factor (Cronbach’s a = 0.68) was marked by high loadings on ‘psychomotor’ items (TMTA+B scores, CORE-scale and STROOP performance). The second factor (Cronbach’s a = 0.53) was marked by high loadings on ‘neuroticism’ items (neurotic personality, Negative Affect, comorbidity, number of episodes and early neglect). The third factor (Cronbach’s a = 0.55) was marked by ‘anhedonic’ items (SHAPS scores, Positive Affect, early separation and lack of openness in personality). Table 1. Rotated Factor Pattern (varimax) factor1 TMTA TMTB CORE SCALE (retardation) CORE SCALE (non interactive) STROOP NEO NEUROTICISM NEGATIVE AFFECT COMORBIDITY # EPISODES EARLY NEGLECT SHAPS POSIVE AFFECT EARLY SEPARATION NEO OPENNESS

factor2

factor3

0.74271 0.73997 0.67223 0.62643 0.46508 0.75939 0.55792 0.55360 0.48245 0.44331 0.83653 0.59196 0.58357 0.48861

Conclusion: These results show that anhedonia, neuroticism and psychomotor speed are non-correlated symptom dimensions in MDD. Also, the items, loading within each factor, give a more detailed understanding of the composite of each typology. In the literature, both anhedonia and stress sensitivity (which is strongly related to neuroticism) are already indicated as the most promising endophenotypes in MDD[2] , strengthening our findings. Furthermore, this study adds psychomotor speed as a valid endophenotype in MDD. Further research should be conducted to define these clinical endophenotypes in more detail and link them to other features of MDD, such as course of illness or sociodemographical, biological and genetic characteristics. Disclosure statement: This paper is financially supported by a grant from Johnson & Johnson References [1] Hasler, G., Drevets, W.C., Manji, H.K., Charney, D.S., 2004 Discovering endophenotypes in major depression. Neuropsychopharmacology 29: 1765–1781.

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[2] Vrieze E., Claes S., 2009 Anhedonia and Increased Stress Sensitivity: Two Promising Endophenotypes for Major Depression. Cur. Psych. Res. 5(3): 143–152.

P.2.b.018 Mouse communal nest: early social enrichment blunts adult depression-like phenotype altering BDNF epigenetic structure I. Branchi1 ° , I. D’Andrea1 , S. Santarelli1 , F. Cirulli1 , N. Karpova2 , E. Castr´en2 , E. Alleva1 . 1 Istituto Superiore di Sanit`a, Dept. Cell Biology and Neuroscience, Rome, Italy; 2 University of Helsinki, Neuroscience Center, Helsinki, Finland During the early postnatal period, the brain is highly plastic and environmental factors have a major role in shaping its structure and function. A stimulating social environment is necessary for brain and behavioral development, as shown by the disrupting effects of its impoverishment or deterioration, which lead to higher risk for the emergence of psychopathologies, such as depression. In order to study the effects of the early experiences on adult vulnerability to depression and on antidepressant treatment efficacy, as well as the mechanisms mediating such effects, we exposed mouse pups to an early social enrichment: the Communal Nest (CN). CN, which consists in a single nest where three mothers keep their pups together and share care-giving behavior until weaning, is an highly stimulating social environment [1]. At adulthood, CN mice have been studied for a number of behaviors having face validity with depressive symptomatology, for response to antidepressant treatment and for possible epigenetic modifications as a potential mechanism mediating the effect of early experiences on adult phenotype. When compared to mice reared in standard laboratory conditions (SN), adult CN mice displayed an increased resilience to show depressive-like behavior. In particular, they displayed reduced anhedonia during social stress [F(1,14) = 6.333, p = 0.0247] and had lower corticosterone levels after acute and prolonged social stress [F(1,11) = 4.892; p = 0.0500]. By contrast, in the forced swim test, CN mice display longer floating time [F(1,34) = 7.775; p = 0.0086], usually considered as a depression-like response. The apparently discordant forced swim test results may be put coherently together when the test is performed according to the original pharmacological protocol. Indeed, while acute fluoxetine administration reduces immobility in both CN and SN mice [F(1,34) = 5.277; p = 0.0279], chronic fluoxetine administration − which is effective in humans − increases immobility in SN mice up to the level shown by CN group (post-hoc, p < 0.01), confirming that they appear less vulnerable to depression-like behavior. These behavioral and neuroendocrine modifications are accompanied by higher hippocampal BDNF levels [F(1,13) = 7.172, p = 0.0190]. Accordingly, we found that the epigenetic structure of the BDNF gene is modified, CN mice having a significantly more acetylated BDNF gene − i.e. a more permissive structure for gene expression − compared to SN mice (post-hoc, p < 0.01). Overall, our findings show that being reared in a CN profoundly changes developmental trajectories, reducing the display of endophenotypes of depression and modifying response to antidepressants at adulthood. Furthermore, the effects of early experiences appear to be, at least in part, mediated by epigenetic modifications, such as that concerning the BDNF gene. Finally, the present results suggest that, when FST is not carried out according to the original Porsolt’s protocol, i.e. after psychoactive drug administration, data interpretation should be performed cautiously.