Saturday, May 21: Plenary Session: pathogenesis

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Saturday Abstracts

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543. Early Markers of Alzheimer's Disease in Patients with Minimal to Mild Cognitive Impairment Davangere P. Devanand1,2, Gregory H. Pelton1,2, Matthias H. Tabert1,2, Diana Zamora2, Yaakov Stern3 1

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Psychiatry, Columbia University, New York, NY, Biological Psychiatry, New York State Psychiatric Institute, New York, 3 NY, Neurology, Columbia University, New York, NY Background: In cognitively impaired patients without dementia, the predictive utility of putative early markers of Alzheimer's disease (AD) is not established. Methods: 150 patients with minimal to mild cognitive impairment and 63 ageand sex-matched controls were evaluated systematically and followed for an average of 5 years. 40 of 150 patients converted to AD during follow-up. Results: Apolipoprotein E e4 carrier status did not differ in frequency between patients and controls, and predicted conversion to AD only in the older age group (> 70 years at initial evaluation) in Cox analyses after controlling for sex, education and baseline MMSE scores. MRI-defined hippocampal atrophy predicted conversion to AD in Cox survival analyses (p < .04) after controlling for age, sex, education and MMSE scores, but parahippocampal volume did not predict conversion to AD in similar analyses. On the 40-item UPSIT, an olfactory identification test, patients scored lower than controls (mean 31.3 SD 6.4 versus mean 34.8 SD 4.2). UPSIT scores were lower in converters to AD (mean 25.9 SD 8.2) compared to non-converters (mean 32.9 SD 4.6, t=6.5, p < .001), and this effect remained significant in Cox analyses after controlling for demographic and clinical covariates. The UPSIT's predictive accuracy was comparable to that obtained by neuropsychological testing, in which Selective Reminding Test (SRT) delayed recall was the strongest predictor. Conclusions: Low scores on olfactory identification and delayed recall were strong predictors, hippocampal atrophy was a moderately significant predictor, and apolipoprotein E e4 carrier status was a weak predictor of conversion to AD. Supported by National Institute of Aging R01AG17761

544. Mechanisms Mediating the Effects of Stress and Depression on Myocardial Dysfunction

Conclusions: These preliminary findings suggest that depression with a history of prior exposure to traumatic stress is associated with increased risk for stressinduced cardiovascular dysfunction. Supported by Charles A. Dana Foundation

545. Cortico-Limbic Responses to Harsh Faces in Patients with Impulsive Aggression Emil F. Coccaro, Michael S. McCloskey, Daniel A. Fitzgerald, K. Luan Phan Psychiatry, University of Chicago, Chicago, IL Background: Patients with intermittent explosive disorder (IED), characterized by impulsive aggression, exhibit poor affective regulation and impaired recognition of negative emotions in facial expressions, resembling behavioral patterns observed in humans with orbitofrontal (OFC) lesions. However, little is known about the functional neuroanatomy of these deficits, or the neural mechanisms of human aggression. Methods: The present study employed BOLD-sensitive whole-brain functional magnetic resonance imaging at 3Tesla (reverse spiral: TR=2s; TE=25ms) to examine the neural correlates of social-emotional processing. Subjects performed a gender identification task while viewing alternating 20-sec blocks of faces expressing discrete emotions (anger, fear, disgust, happy, sad, surprise, neutral) over six runs. Imaging data were analyzed with a standard, random effects model (p<0.05, SVC) using statistical parametric mapping software (SPM2). So far, 6 patients with IED (3 females; age 35.8±9.0 years) and 7 healthy controls (3 females; age 31.7±6.2 years) have been studied. Results: All subjects activated the left amygdala in response to emotional faces in contrast to neutral faces. However, patients with IED had exaggerated activation of the left amygdala ([-20, -8, -22], Z=2.42) and OFC ([10, 42, -10]; Z=2.47), and attenuated activation of the dorsal anterior cingulate cortex ([-6, 24, 16], Z=3.09) in response to faces expressing harsh emotions (anger, fear, disgust), relative to healthy controls. Conclusions: These preliminary findings suggest that altered responses in the amygdala, OFC, and anterior cingulate cortex, regions important for social cognition, threat perception, and emotion regulation, may contribute to the deficits in social-emotional processing observed in impulsive aggression. Supported by Brain Research Foundation

James Douglas Bremner1, Faiz A. Cheema1, Ali Ashraf1, Nadeem Afzal1, Negar Fani1, Lai Reed1, Dominique L. Musselman1, James C. Ritchie1, Tracy Faber1, John R. Votaw1, Charles B. Nemeroff1, Viola Vaccarino2

Elizabeth A. Young1, Delia Vazquez2, Cynthia R. Pfeffer3

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Psychiatry and Radiology, Emory University, Atlanta, GA, Medicine (Cardiology), Emory University, Atlanta, GA Background: Coronary heart disease (CHD) patients with depression exhibit increased mortality compared to equally ill cardiac patients without depression, however the mechanisms mediating this effect are unknown. The purpose of this study was to assess pathways through cortisol, heart rate variability, and the brain by which stress and depression mediate increased mortality in patients with CHD. Methods: Patients with CHD (N=26) underwent single photon emission computed tomography (SPECT) imaging of myocardial perfusion and positron emission tomographic (PET) imaging of the brain at rest and during a stressful cognitive challenge. Severity of ischemia was measured by summing perfusion defect scores across myocardial segments and subtracting out rest from stress scores. Plasma cortisol concentrations and heart rate variability (HRV) were measured at baseline and in response to the stressful challenge. Subjects with CHD, depression, and a history of psychological trauma (N=5) were compared to subjects with CHD and depression without psychological trauma (N=8), and subjects with CHD without depression or psychological trauma (N=13). Results: Eighty percent of CHD/depression trauma exposed subjects had stress-induced ischemia as opposed to 38% of CHD/depression subjects without trauma exposure and 23% of subjects with CHD (F=8.51; df=2,23; p=0.007). There were no differences in cortisol response to the cognitive stress challenge between the groups. Data on brain activation and HRV will be presented.

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546. Saliva Cortisol and Response to Dexamethasone in High Risk Prepubertal Children

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Psychiatry, MHRI, University of Michigan, Ann Arbor, MI, Pediatrics, 3 University of Michigan, Ann Arbor, MI, Psychiatry, Weill Medical College, White Plains, NY Background: Major depression is heritable and children of depressed parents are at higher risk for the development of depression. However, depression in a parent may also act as a stressor leading to increased activation of stress circuits. To address this question, we examined saliva cortisol in children with a parent with a history of major depression. Methods: We recruited 15 families with one parent with major depression (26 prepubertal children) and 16 control families (32 prepubertal children). All families underwent SCID and K-SADS interviews. Both parents were interviewed with the SCID. Families were asked to collect morning, afternoon and bedtime saliva samples for 4 days for 2 weeks. On the evening of the 3rd day, dexamethasone was administered. Two doses (high and low) were used. Results: Parents with history of depression (n=10) showed a tendency to higher saliva cortisol that was not significant. The majority of children demonstrated no psychiatric diagnosis. Children showed higher cortisol in the evening basally and higher post dex cortisol to both 0.25mg and 0.5 mg dexamethasone. (p=0.04 for group). There were strong correlations between cortsiol in parents and children. (r=0.52 in depressed; r=0.499 in control) Conclusions: High-risk offspring show elevated cortisol, particularly postdexamethasone and this occurs even if parent is no longer depressed. Elevated cortisol and impaired feedback appears to predate onset of depression. Supported by Pritzker Foundation

Saturday Abstracts

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Saturday Abstracts amplitude than that in SAL animals, suggesting that synaptic plasticity was abnormally augmented in the PFC of MAM animals. In addition, acute stress produced by placing animals in a cold room differently affected LTP induction. LTP in SAL animals was enhanced with short duration (10 minutes) stress exposure, whereas longer durations (30 and 120 minutes) impaired it, resulting in the inverted U-shape relationship between the amount of stress exposure and PFC plasticity. On the other hand, 10 and 30 minutes of stress exposures moderately and severely disrupted LTP induction in MAM animals, resulting in the shift of the inverted U-shape relationship toward greater stress vulnerability. Conclusions: These results suggest that the early cortical developmental disruption model of schizophrenia induces alterations in synaptic plasticity in the PFC, suggesting abnormal dopamine and glutamate interactions in the PFC. Supported by NIH and NARSAD

555. Working Memory: Genetic Influences on Prefrontal Information Processing as Revealed by BOLD fMRI Joseph H. Callicott Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, NIMH, Bethesda, MD Background: Neuroimaging studies of working memory (WM) have been a popular means of exploring individual and group differences in information processing strategies in the dorsolateral prefrontal cortex (DLPFC). Relating group differences in activation to a rapidly expanding list of genes of particular relevance to DLPFC neuronal function is a new challenge for this field. Methods: In schizophrenic patients, several studies have suggested that even when patients perform reasonably well on a WM task, the DLPFC fails to handle WM load efficiently resulting in areas of increased activation in comparison to healthy subjects. This pattern has also been observed in unaffected siblings of schizophrenic patients further suggesting that this information processing abnormality arises from shared susceptibility genes. Results: Given the relative importance of optimal dopamine tone in DLPFC, it is perhaps not surprising that the COMT val158met polymorphism that has been associated with schizophrenia has also been found to modulate DLPFC efficiency during WM even in healthy subjects. Like dopamine, glutamate may be of particular importance to schizophrenia in particular and DLPFC function in general. Like COMT, the synaptic metabotropic glutamate receptor GRM3 has an association to the illness and to inefficient DLPFC function. However, not all putative susceptibility genes, for example DISC1 and RGS4, impact DLPFC activation, although their effects appear at other nodes within the WM network. Conclusions: The integration of in-vivo neuroimaging with genetics may be a particularly useful way of rapidly expanding our knowledge of DLPFC function in illness and in health. Supported by Intramural Research Program, NIMH, NIH

556. The Role of the Mesocortical Pathway and Local Connections in Persistent Activity in Prefrontal Cortex: Implications for Working Memory and Schizophrenia Jeremy K. Seamans Neurscience Institute, MUSC, Charleston, SC Background: The prefrontal cortex (PFC) is thought to hold and manipulate information in working memory through persistent activity patterns. This activity is strongly modulated by the mesocortical dopamine system. Since working memory is critical for cognition and appears to be deficient in schizophrenia, we investigated persistent activity and its modulation by dopamine. Methods: In vivo field and intracellular recordings, patch-clamp recordings and Ca2+ imaging in organotypic co-cultures as well as computational modeling were used to investigate persistent activity patterns in PFC and their modulation by dopamine. Results: A fast EPSP is generated in the mesocortical pathway that is blocked by glutamate but not dopamine antagonists and is removed by 6OHDA lesions,

BIOL PSYCHIATRY 2005;57:1S-212S 153S indicating it is due to glutamate release from dopamine axons. This EPSP can evoke persistent activity that depend on local mechanisms within the PFC. Dopamine exerts very long-lasting effects on PFC neurons and appears to work in a concentration dependent manner to make persistent activity more or less robust. Conclusions: We suggest that the fast glutamatergic EPSP in the mesocortical pathway transmits temporally precise information to the PFC. This signal informs the PFC an event is important and to initiate persistent activity states that hold this information in working memory. In contrast, co-release of dopamine alters the processing mode of working memory buffers in PFC, making them more or less robust to distraction. Alterations in glutamate or dopamine signaling in PFC could lead to a variety of deficits observed in schizophrenia. Supported by NIMH, NARSAD

SYMPOSIUM Brain and Behavioral Development Occurinig during the Late Juvenile and Adolescent Periods: Relevance to the Prodrome and Onset of Schizophrenia Saturday, May 21, 2:30 PM - 5:00 PM Location: Georgia 5 Chair: Holly M. Moore* Co-Chair: Cheryl Corcoran * Supported by NARSAD; The Lieber Center for Schizophrenia Research at Columbia University; The Stanley Foundation

557. Postnatal Development of Local Circuits and Dopaminergic Inputs to the Primate Prefrontal Cortex David A. Lewis Psychiatry, Departments of Psychiatry and Neuroscience, University of Pittsburgh, Pittsburgh, PA Background: The typical appearance of the clinical features of schizophrenia during late adolescence or early adulthood suggests that adolescence-related neurodevelopmental events may contribute to the pathophysiology of this disorder. Thus, understanding the maturation of the neural circuits in the dorsal lateral prefrontal cortex (DLPFC) that subserve working memory, a core cognitive process that matures late and that is disturbed in schizophrenia, is particularly important. Methods: We used employed anatomical, molecular biological and electrophysiological techniques to quantify developmental changes in the functional architecture of the DLPFC in macaque monkeys. Results: These experiments demonstrate (1) that certain pre- and postsynaptic markers of excitatory and inhibitory neurotransmission in the monkey DLPFC exhibit striking changes during adolescence, and (2) that these same markers are selectively altered in the DLPFC of subjects with schizophrenia. Conclusions: Postnatal refinements in specific elements of the functional architecture of primate DLPFC, particularly changes in GABA transmission occurring during the late juvenile/periadolescent period, may be an important mechanism contributing to the clinical onset of schizophrenia. The implications of these findings for treatment and prevention strategies will be discussed. Supported by MH043784

558. Developmental Changes in Social Behavior, Novelty-Seeking and Reward Attribution during the Peripubescent Period in a Rodent Model Linda P. Spear Department of Psychology, Department of Psychology and Center for Developmental Psychobiology, Binghamton University, NY, Binghamton, NY

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154S BIOL PSYCHIATRY 2005;57:1S-212S Background: For successful negotiation of the developmental transition from childhood to adulthood, organisms must acquire and/or express behaviors that allow the organism to be self-sufficient. Behavioral characteristics of this developmental period that bear similarity across diverse species include an increase in risk taking or novelty-seeking and an increase in the value attributed to social interactions with individuals outside the natal family unit. Although these behavioral transitions overlap in time with the transition to sexual maturity, they likely represent a distinct aspect of the childhood-to-adult transition. Tied to these changes in social and risk-taking behavior are developmental changes in the reward properties and motor effects of psychoactive drugs. Methods: In a subset of our studies, we have used a variety of behavioral paradigms to study interactions between age, sex, and early-life experience on social behavior, novelty-seeking and reward attribution during the periadolescent period. In addition we have examined how these factors, particularly age, affect pharmacological mechanisms modulating reward attribution change across the periadolescent period. Results: We have found that behavior directed towards social stimuli, novelty, and other rewards, and the rewarding properties of these stimuli and psychoactive drugs such as nicotine change significantly during periadolescence. Moreover, early juvenile experiences, such as social isolation, appear to affect rewarding properties of incentive stimuli differentially across age. Conclusions: These studies will provide insight into the behaviors that emerge or change rapidly during the periadolescent (late juvenile-adult) period, which is associated with the prodrome to schizophrenia and onset of other psychiatric illnesses. Supported by PHS grants DA00140, AA10228, AA12150 , AA12525 and DA04478

559. Structural and Functional Changes during Late Childhood and Adolescence: Relevance to Schizophrenia Judith L. Rapoport NIMH, Child Psychiatry Branch, Bethesda, MD Background: Brain imaging advances created a new era in the study of developmental psychopathology. However, large scale parallel prospective studies of healthy and psychiatrically disturbed populations were needed. Methods: An integrated prospective anatomic brain imaging study compared healthy (n=200) and psychotic (n=100) children. Over 3000 scans have been collected. Automated analyses were developed by the Montreal Neurological Institute (MNI) and UCLA. . Results: Normal development shows a pattern of back to front "wave" of cortical loss, paralled by posterior increase and anterior hippocampal decrease (in preparation). Ongoing age-matched twin studies indicate genetic control is increasing for some brain regions (white matter) while decreasing for others (gray matter) (- unpublished data). Children with schizophrenia show an exaggeration of this pattern of cortical loss which plateaus by age 21 . Psychotic children also have exaggeration of normal developmental change in the hippocampus (unpublished data, Dr. Nitin Gogtay). These abnormal brain developmental patterns are related to specific genetic influence (GAD1) (Addington et al 2004), and to the 22q11 deletion syndrome. Conclusions: There is a time limited, diagnostically specific exaggeration of normal development during late adolescence. These developmental measures appear useful endophenotypes for genetic studies. Supported by Intramural Research Program, NIMH

560. Clinical Profile of Adolescents at High Risk for Schizophrenia Cheryl Corcoran Psychiatry, Columbia University Department of Psychiatry and the New York State Psychiatric Institute, New York, NY Background: Rodent models of schizophrenia provide an opportunity to explore emerging pathophysiology over development that underlie the symptoms of schizophrenia. The MAM model for schizophrenia is especially valid in that prenatal perturbations lead to overt behavioral pathology in the

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Saturday Abstracts adult (but not the juvenile) that are good proxies for schizophrenia symptoms. However, clinical studies of the prodrome now demonstrate subtle abnormalities before frank psychosis that include neuropsychological deficits, negative symptoms and attenuated psychotic-like symptoms. The challenge is to translate these clinical findings into behavioral proxies that could be evaluated developmentally in the juvenile phase in valid rodent models of schizophrenia. Methods: Adolescents and young adults identified as at clinical high risk or prodromal to psychosis were evaluated at baseline for positive and negative symptoms, stress sensitivity and neuropsychological function. Results: Prodromal patients have significant levels of negative symptoms, subjective stress sensitivity, enhanced cortisol secretion in response to a psychosocial stressor, and deficits in attention and memory. Conclusions: Behavioral, neuroendocrine and cognitive abnormalities exist in prodromal patients, and may be related to neural and behavioral changes during prepubescence and pubescence in a rodent model of schizophrenia. Supported by K23 (NIMH), NARSAD Young Investigator, Sackler Award

SYMPOSIUM Schizophrenia Endophenotypes: Specific to Schizophrenia or to Psychosis? Saturday, May 21, 2:30 PM - 5:00 PM Location: Georgia 6 Chair: Carol A. Tamminga* Co-Chair: Godfrey D. Pearlson * Supported by MH01180, MH 45156, MH 43687, MH62236, MH63439

561. Neurobehavioral Features of Schizophrenia and Bipolar Disorder John A. Sweeney Psychiatry, University of Illinois at Chicago, Chicago, IL Background: Multiple putative neurobehavioral endophenotypes for psychotic disorders have been proposed. These include abnormalities on oculomotor, electrophysiological and neuropsychological testing. This presentation will summarize findings from a series of oculomotor and neuropsychological studies in patients with schizophrenia and affective psychoses that were conducted, in part, with the aim of determining whether different deficits were associated with different disorders. Methods: Pursuit eye tracking data was collected in two samples of unmedicated patients with schizophrenia or psychotic affective disorders. Neuropsychological studies were conducted with four samples of patients with bipolar disorder or schizophrenia. Results: In both oculomotor studies, similar deficits were observed in patients with bipolar disorder and schizophrenia. In neuropsychological studies, robust neuropsychological deficits in executive and memory systems were observed in patients with bipolar disorder. These are similar domains that are impaired in patients with schizophrenia. In neuropsychological and pursuit eye movement studies, young adult patients with unipolar psychotic disorders had qualitatively similar but more modest deficits. Conclusions: Findings of these studies indicate that bipolar disorder and schizophrenia have overlap in their associated neurobehavioral deficits. This may have impact on their use in family studies, where they may be markers of risk for psychosis rather than a specific disorder. Research is needed to delineate the neurobehavioral deficits specific to different psychotic disorders in patients and their unaffected family members. Supported by MH62134, MH01433, MH45156 and NARSAD

562. MRI Neuroanatomy Across Schizophrenia and Bipolar Disorder Matcheri S. Keshavan Psychiatry, Wayne State University, Detroit, MI Background: Bipolar disorders (BPD) and schizophrenia have both intriguing similarities and differences in neurobiology. Understanding them may be very instructive in developing testable pathophysiological models. Attentional

Saturday Abstracts impairment, which is often a precursor of later emergence of BPD, may also characterize the premorbid phase of schizophrenia. Methods: We reviewed the literature pertaining to common and distinct alterations in neuroanatomic circuits that might explain such similarities and differences outlined above. Results: Increased amygdala volume and activation are seen in adult patients with BPD. These findings contrast those which report decreased amygdala volumes in patients with schizophrenia, and in those at risk for this disorder. Conclusions: Different developmental trajectories may emerge during late childhood and adolescence following common neurodevelopmental precursors (such as attentional impairments) in childhood. These developmental trajectories may be related to differential pathoplastic responses of the subcortical brain structures, such as the amygdala, and may mediate the emergence of distinct symptomatic presentations. Enlargement of amygdala, which are critically involved in affect regulation, might represent a pathological hyperplasia in that region related to repeated activation in the context of highly valenced emotional states, such as the manic and depressive episodes. On the other hand, the failure of optimum functioning of amygdala may underlie the deficits in diminished affective responsivity leading to blunted affect in schizophrenia. Longitudinal follow-up studies of children at risk for a variety of major psychiatric disorders allow us to further clarify the common and distinct neurodevelopmental alterations across disorders. Supported by MH01180;MH 43687; MH 46614

BIOL PSYCHIATRY 2005;57:1S-212S 155S memory (WM) task and fMRI activation at 3T during performance of a Sternberg WM paradigm. Study 2: We compared 30 community controls, 12 bipolar and 18 SZ who underwent fMRI while performing an auditory oddball task at 1.5T. Results: Study 1: For these two WM markers, subject percentages having abnormal (>1) z-score values, were: fMRI activation: Sternberg task, left minus right DLPFC: Controls 17%, Schizophrenia 86%, Relatives 67%. Cognitive: Nback, (2-back): Controls 16%, Schizophrenia 61%, Relatives 39%. Study 2: Compared to controls, a) SZ exhibited diminished activation in bilateral frontal, superior temporal gyral, parietal, middle temporal, cerebellar and thalamic regions. b) Bipolars exhibited diminished hemodynamic activation in bilateral frontal, orbitofrontal, superior parietal and cerebellar regions; and increased activation in middle temporal and right anterior superior temporal gyrus. Relative to SZ, bipolar activation was diminished in cerebellum and motor cortex and increased in bilateral middle and superior temporal gyrus, thalamus and anterior cingulate. Conclusions: Study 1: These putative biomarkers are abnormal in schizophrenia and in many of their unaffected relatives. Study 2: Patients with psychotic disorders (SZ and bipolars) can be discriminated from healthy controls based on frontal, temporal and subcortical hemodynamic patterns, while SZ and bipolars differ most in lateral temporal regions. Supported by NIMH to GP, KAK and VDC

563. Eye Tracking, PPI and P50 Mark Independent Aspects of Psychosis Liability Gunvant K. Thaker Psychiatry, University of Maryland School of Medicine, Maryland Psychiatric Research Center, Baltimore, MD Background: Schizophrenia and bipolar disorders are complex disorders and overlap in symptoms (i.e., psychosis). Our ongoing project asked the following questions: what aspects of these disorders run true in families? What marks the psychosis liability? Do different endophenotypes mark different aspects of risk, and what are the associated candidate genes? Methods: In preliminary studies, we evaluated several endophenotypes in schizophrenia probands and their families to examine which one of these measures mark risk for positive psychotic or negative symptoms. Results: We observed that both negative symptoms and positive psychotic symptoms independently run true in families. On predictive pursuit gain, healthy controls (0.60 + 0.19) significantly differed from the relatives of schizophrenia patients with positive psychotic-like symptoms (0.48 + 0.16), but not from relatives without positive symptoms (0.55 + 0.18). Examination of three endophenotypes (prepulse inhibition, PPI, P50, and pursuit) among probands showed that there was a significant association between the predictive pursuit and P50 abnormality (r = -0.50, p<0.01); there were no other significant correlations (r values ranging between -0.1 to 0.1). Our earlier studies found significant association of schizophrenia with DRP2, COMT and SNAP 29 genes. Preliminary examination of these genes showed significant effects of SNAP 29 on PPI (p<0.05; G allele associated with worse performance), and COMT on predictive pursuit (p < 0.05; Met allele associated with poor predictive pursuit in patients, but good performance in healthy controls). Conclusions: These data suggest that different endophenotypes mark different aspects of psychosis risk and are associated with different candidate genes. Supported by MH-49826

564. Putative Functional Endophenotypes in Psychotic Bipolar Illness, Schizophrenia and Schizophrenia Siblings Godfrey D. Pearlson Psychiatry, Yale University/Institute of Living, Hartford, CT Background: We examined putative biological markers in schizophrenia (SZ) subjects and their first-degree unaffected relatives to determine validity and specificity versus psychotic bipolar disorder. Methods: Study 1: We assessed 69 screened healthy community controls, 20 SZ probands and 16 of their first-degree unaffected relatives on an N-back working

SYMPOSIUM The Role of the Hypothalamic-Pituitary-Adrenal Axis in Psychiatric Disorders: Recent Developments Saturday, May 21, 2:30 PM - 5:00 PM Location: Georgia 10 Chair: Carmine M. Pariante Co-Chair: Andrew H. MIller 565. HPA-Axis Function Regulating Genes and Treatment Response in Depression Elisabeth B. Binder Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA Background: The stress hormone regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. Methods: To investigate a possible association between genes regulating the HPA-axis and response to antidepressants and susceptibility for depression, we genotyped single nucleotide polymorphisms (SNPs) in eight of these genes in depressed patients and matched controls. Results: We found significant associations between response to antidepressants and the recurrence of depressive episodes and SNPs in FKBP5, a glucocorticoid receptor (GR)-regulating co-chaperone of hsp-90, in two independent samples. These SNPs were also associated with increased intracellular FKBP5 protein expression which triggers adaptive changes in GR and thereby HPA-axis regulation. Patients carrying the associated genotypes displayed less HPA-axis hyperactivity during the depressive episode. A rare functional variant in the GR itself, leading to GR resistance, was also found to be associated with faster response to antidepressant treatment. The association of FKBP5 and GR with polymorphisms with response to antidepressant drugs appears to be independent of the primary pharmacological profile of antidepressants. Conclusions: We propose that the FKBP5 and GR variant dependent alterations in HPA-axis regulation could be related to a faster response to antidepressant drug treatment. These findings support a central role of genes regulating the HPA-axis in the causality of depression and the mechanism of action of antidepressant drugs. Supported in part by the German Ministry of Education and Research (BMBF) within the National Genome Research Network (NGFN) and the Bavarian Ministry of Commerce

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566. Animal Studies and the Role of Vasopressin and Corticotropin-Releasing Hormone in Anxiety Martin E. Keck Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Munich, Germany Background: New putative strategies for the treatment of patients with mood and anxiety disorders have in common that they act at neuropeptidergic systems such as CRF and vasopressin (AVP), which are believed to be closely linked to the pathology of anxiety and depression. Methods: A series of experiments further elucidated the neuroendocrine and behavioral impact of both the high-affinity non-peptide CRF1 receptor antagonist R121919/NBI 30775 and the well-established antidepressant paroxetine. Results: Robust anxiolytic effects in response to R121919/NBI 30775 and changes in stress coping after chronic paroxetine treatment were dependent on the innate emotionality of the animal models used. At the neuroendocrine level, paroxetine-induced behavioral changes were accompanied by a normalization of the CRF-stimulated increase in corticotropin and corticosterone secretion in the DEX/CRF test. Concomitantly, the hypothalamic vasopressinergic gene expression was found to be reduced. It is still unclear, however, whether or not AVP neuronal circuits, which are known to be involved in the regulation of emotionality, are affected by R121919/NBI 30775. We, therefore, investigated the effects of chronic social defeat as a psychosocial stress paradigm and concomitant treatment with R121919/NBI 30775 in mice on behavior and expression of AVP mRNA in the hypothalamic paraventricular nucleus, amygdala and hippocampus. The behavioral changes were accompanied by alterations in AVP gene expression in the paraventricular nucleus and could be reversed via chronic treatment with R121919/NBI 30775. Conclusions: These findings provide direct evidence that modulation of the vasopressinergic and CRH systems is likely to be critically involved in the behavioral and neuroendocrine effects of antidepressant drugs.

567. Glucocorticoid Resistance across Psychiatric Diagnoses: Evidence from Novel Neuroendocrine and Neuroimaging Methods to Assess the HPA Axis Carmine M. Pariante Psychological Medicine, Clinical Neuropharmacology, Institute of Psychiatry, London, London, United Kingdom Background: Depressed patients may have a hyperactive hypothalamicpituitary-adrenal (HPA) axis because their brain is resistant to the effects of circulating cortisol (glucocorticoid resistance). Indeed, depressed patients do not suppress cortisol following administration of dexamethasone, a probe of glucocorticoid receptor (GR) function. However, brain sensitivity to cortisol is also regulated by the mineralocorticoid receptor (MR). Furthermore, it is still unclear whether HPA hyperactivity is a specific feature of major depression or could also be present also in other psychiatric disorders. Methods: We present our novel work using the prednisolone suppression test and the measurement of pituitary volume (using MRI brain imaging) as methods to evaluate the HPA axis in a clinical setting. Results: Using the suppression test with prednisolone, a probe of both the GR and the MR, we find that the same depressed patients show impaired GR sensitivity but normal MR sensitivity. Furthermore, we find that antidepressant treatment increases the brain sensitivity to glucocorticoids in healthy volunteers after as little as 4 days of treatment. In a separate series of studies, we also find that the acute phase of development of a psychosis - both affective and nonaffective psychosis - is associated with a larger pituitary volume, again suggesting glucocorticoid resistance. Conclusions: Our findings may indicate that glucocorticoid resistance is a common feature in different severe psychiatric disorders, possibly as a consequence of the distress and arousal linked to the dramatic psychological experience. This resistance seems largely to be mediated by the GR, and could be reverted by antidepressant treatment. Supported by UK Medical Research Council, UK Wellcome Trust, National Alliance for Research in Schizophrenia and Depression, the Rosetrees Trust

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Saturday Abstracts

568. Molecular Mechanisms Linking Inflammation and the HPA Axis in the Pathogenesis of Depression Andrew H. Miller Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Atlanta, GA Background: Glucocorticoids play an essential role in shaping and restraining physiological responses to environmental stressors. A number of diseases including autoimmune, infectious and inflammatory disorders, as well as certain neuropsychiatric disorders such as major depression, have been associated with decreased responsiveness to glucocorticoids and impaired functioning of the glucocorticoid receptor (GR). One potential mediator of disrupted GR function in these diseases is proinflammatory cytokines. Proinflammatory cytokines and their signaling pathways have been shown to impair GR translocation and function. Methods: Using a variety of in vitro techniques and neuronal cell lines, we have examined the impact of various cytokines and their signaling pathways on GR function. Special attention has been paid to downstream targets of mitogen activated protein (MAP) kinases including p38, JNK and ERK as well as COX1 and -2 signaling pathways. Results: The data indicate that activation of p38 MAP kinase is responsible for IL-1-induced decreases in GR function, which is reversible by pharmacologic inhibitors and antisense oligonucleotides. In addition, we have found that constitutive expression of JNK plays a tonic inhibitory role in GR function, consistent with findings that activation of JNK pathways inhibits GR. Finally, we have shown that inhibition of COX-2 (but not COX-1) significantly increases GR nuclear localization, increases GR-DNA binding and enhances GR-mediated gene transcription in association with inhibition of p38 MAP kinase. Conclusions: Taken together, these results expand the intracellular targets of GR regulation and suggest novel approaches for the treatment of disorders associated with inflammation and impaired GR function including major depression. Supported by NIMH

SYMPOSIUM Neurobiological Mechanisms of Risk and Plasticity in Developmental Psychopathology: Evidence from Animal Models and Human Neuroimaging Saturday, May 21, 2:30 PM - 5:00 PM Location: Georgia 11 Chair: Daniel S. Pine* Co-Chair: Christopher S. Monk * Supported by NIMH

569. Developmental Role of 5-HT in the Establishment of Normal Emotional Behavior in Adult Mice Jay A. Gingrich Psychiatry and Developmental Psychobiology, Columbia University, New York, NY Background: Reduced serotonin transporter (SERT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents but the mechanism of this effect is unknown. Methods: We examined the behavior of adult mice with a reduced genetic complement of SERT in a variety of paradigms that assess depression and anxiety-related behaviors. We also treated mixed litters of wild-type, heterozygous, and knockout mice with fluoxetine during early life (P4-21) to establish whether developmental inhibition of the SERT was involved in the behavioral abnormalities seen in SERT mutant mice. Results: Adult SERT knockout mice showed an increase in latency to feed in a novel situation, more immobility in a forced swim, and increased escape latency

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Saturday Abstracts in a shock escape paradigm. SERT knockout mice exhibit a 50% reduction in serotonergic cell number and a fourfold decrease in firing rate in the DRN. The adult behavioral deficits seen in SERT knockout mice were largely mimicked by postnatal fluoxetine treatment of wild-type or heterozygous mice. Conclusions: Developmental loss of SERT produces altered behaviors in models of depression that are generally opposite to those produced by antidepressant action in a mature nervous system. The reduced serotonergic cell number and firing rate in the DRN of adult SERT KO mice suggest a mechanism for these altered behaviors. Supported by Sackler Institute for Developmental Psychobiology, NARSAD, Mather's Foundation

570. Preclinical Efficacy of Antidepressants in Developing Animals: Behavioral and Neurochemical Evidence Susan L. Andersen Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA Background: Responsiveness to most drugs changes with maturation, but in no instance is this more striking than with antidepressants. Clinically, the efficacy of the SSRI fluoxetine is greater in adults (78% responder rate) relative to children (56%), although both ages have comparable placebo:responder rates (57%). We propose that the poor response to SSRIs in children and adolescents may be related to an underlying pharmacodynamic factor, given that the brain is changing rapidly between childhood, adolescence, and adulthood. Serotonin utilization drops precipitously during puberty, before climbing to adult levels. Methods: We assessed the effects of fluoxetine (2, 5, 10, and 20 mg/kg) on depressive-like behaviors in Sprague-Dawley rats at ages estimated to represent childhood (postnatal day 21; P21), adolescence (P35), and early adulthood (P60). Results: Fluoxetine effectively increased the latency to become immobile in the forced swim test (FST) at 5 mg/kg, i.p., at P35 and P60, but not at P21. Chronic administration of 2 mg/kg fluoxetine between P20-35 did not produce enduring alterations when subjects were tested in the FST at P60. However, when a separate group of juvenile-exposed rats were tested as adults in the inescapable shock paradigm of learned helplessness, their latencies to escape shock were significantly shorter than vehicle controls. Conclusions: Taken together, these data suggest that fluoxetine increases in effectiveness between childhood and adolescence, and juvenile exposure during this period produces antidepressant actions that endure into adulthood. Furthermore, these results suggest that an age-appropriate battery of tests is needed for screening antidepressants in younger animals. Supported by NARSAD

571. Attention-Related Brain Activation to Emotional Facial Expressions in Adolescents at Risk for Psychopathology Christopher S. Monk Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, MD Background: Pronounced distress from adverse events is a key feature of adult and pediatric depression and anxiety disorders. Recent evidence suggests that such distress may tap underlying risk for these forms of psychopathology: diagnosis-free adolescents, who are nevertheless at risk for depression and anxiety based on family history, report heightened fear when viewing negative emotional faces. In the present investigation, we used the same fear-inducing task and functional MRI (fMRI) to examine a sample of diagnosis-free adolescents who are at risk for anxiety or depression due to the presence of depression in one or both parents. The use of an at-risk sample facilitates disentangling the behavioral and neurophysiological markers associated with risk from clinically significant symptoms of the disorder. Methods: Subjects viewed faces varying in intensity for two emotions: happiness and fear. Across blocks of trials, subjects alternately directed attention to personal subjective fear and a nonemotional aspect of the face. We hypothesized that the high- relative to low-risk adolescents would report greater subjective fear as faces became more fearful and show greater engagement of

emotion-related brain regions, including the amygdala and ventral prefrontal cortex. Results: As faces became more fearful, high-risk adolescents reported increased subjective fear, indicating that this task differentiates those at low and high risk. The parametric fMRI analysis will compare neurophysiological activation between the low- and high-risk groups. Conclusions: Findings from this study will indicate which brain regions show altered activation, suggesting a neural marker for risk for anxiety and depression. Supported by 1K22MH068017

572. Effects of Treatment on Attention-Modulated Brain Activation to Emotional Faces in Youth with Anxiety Disorders Erin B. McClure Section on Development and Affective Neuroscience, NIMH, Bethesda, MD Background: Recent fMRI studies of adults with mood/anxiety disorders demonstrate marked effects of both pharmacological and psychotherapeutic treatment on patterns of brain activation during symptom-relevant cognitive/emotional tasks. In particular, contrasts of pre- and post-treatment activation reveal reduced activation in frontal and limbic structures (e.g., ventrolateral prefrontal cortex (vPFC) and amygdala) within the “fear circuit.” We have shown that anxious/depressed adolescents, like anxious/depressed adults, show abnormal patterns of fear circuit activation during symptomrelevant face processing tasks. Little is known, however, about effects of successful treatment on brain activation in anxious/depressed youth. In light of the ongoing controversy about the efficacy and safety of standard treatments in youth, it is critical to elucidate neural mechanisms underlying symptoms and their resolution. Methods: We used fMRI to examine fear circuit activation in adolescents with mood/anxiety disorders (n=15) and healthy controls (n=15) while they attended alternately toward and away from threat cues in emotional faces. Patients were scanned both before and after 8 weeks of treatment with either fluoxetine or cognitive-behavioral therapy (CBT); controls also underwent two scanning sessions separated by 8 weeks. Results: Data analysis is currently underway examining the hypothesis that effective treatment will ameliorate amygdala and vPFC dysfunction in adolescents with successfully treated anxiety/depressive disorders. We expect that healthy controls will show no changes in patterns of amygdala or vPFC activation between their two scans. Conclusions: By identifying effects of successful treatment on neural dysfunction in anxious/depressed youth, the current work is designed to provide new insights for safer, more effective therapeutics.

SYMPOSIUM White Matter Matters: New Methods and Findings in Schizophrenia Saturday, May 21, 2:30 PM - 5:00 PM Location: Georgia 9 Chair: Monte S. Buchsbaum Co-Chair: Erin A. Hazlett 573. Multiple Methods of Assessing White Matter in Schizophrenia Kelvin O. Lim Psychiatry, University of Minnesota, Minneapolis, MN Background: Recently there has been much interest in examining white matter in schizophrenia because of intriguing neurobiological post mortem data and in vivo neuroimaging human studies. Studies of gene expression have found reductions in myelination related genes in frontal cortex. Reduced density of oligodendrocytes has been observed in the white matter of the superior frontal gyrus and Layer III of area 9.

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Saturday Abstracts

Methods: In vivo imaging studies, using diffusion tensor imaging, have found evidence of altered white matter organization and integrity as indicated by reductions in fractional anisotropy. Results: Additional imaging techniques for the in vivo assessment of white matter are now available. Methodologies to be discussed will include magnetization transfer imaging, T2 relaxography and magnetic resonance spectroscopy. Conclusions: Each of these techniques provides complementary information about white matter composition. Supported by MH060662

and traced to the frontal lobe were counted and a disturbed pattern of frontal lobe tract arrival observed. Conclusions: These data suggest that gray matter volume decrease in schizophrenia is more marked than white matter volume decrease, but the white matter is more disorganized as assessed by anisotropy measures. Age-related effects are more prominent than expected. Supported by MH60023 MH66392

574. Quantitative Neuropathology of Anterior Cingulate Cortex in Schizophrenia

Erin A. Hazlett

Patrick R. Hof Neuroscience, Mount Sinai School of Medicine, New York, NY Background: Abnormalities of the anterior cingulate cortex (ACC) have been frequently reported in schizophrenia, yet an integrative view of the neuropathology of ACC is still lacking. Methods: We have re-examined the neuropathology of ACC in schizophrenia in postmortem brains from 13 male schizophrenics and 13 age-matched male controls. Our analysis focused on the total cortical gray matter volume of area 24 based on established cytoarchitectural criteria, its thickness, and the morphology of the specialized spindle cells of layer Vb. All analyses were performed using stereologic methods. Results: We observed a significantly reduced total cortical gray matter volume (9%; p < 0.05) in schizophrenics compared to controls, as well as disturbances in the cytoarchitecture of area 24 particularly within the left hemisphere, a significant decrease in cortical thickness (12%; p < 0.05). We also found alterations in the morphology of layer Vb spindle cells in that they were less elongated and appeared less mature than in control cases, pointing to a possible developmental deficit. Conclusions: These data suggest that a constellation of factors likely contributes to the dysfunction of this cortical region in schizophrenia. Of particular importance was the finding of alterations in the morphology of the spindle cells, confirming the hypothesis of the possible involvement of these unique neurons in the pathogenesis of schizophrenia and other neuropsychiatric disorders. Importantly, our results are in line with the hypothesis of alterations of the normal development of brain asymmetry in schizophrenia and confirm brain imaging evidence of the involvement of the ACC in the disease. Supported by NIH grant MH66392 and the Stanley Medical Research Institute

575. Frontotemporal Circuitry and DT in Schizophrenia Monte S. Buchsbaum Psychiatry, Mount Sinai School of Medicine, New York, NY Background: Diffusion tensor (DT) imaging allows assessment of white matter organization and direction in circuits hypothesized to be defective or miswired in schizophrenia. Methods: DT/white matter morphometry acquired in three samples: 1)adult schizophrenics (n=106) and normals (n=42); patients were divided into goodoutcome (n=52) and poor-outcome (n=54) subtypes 2) 37 adult schizophrenics and 30 adolescents (mean age=16.07, range=13-21) experiencing their first psychotic episode and age and sex-matched normal adolescents, and 3) a cohort of 50 patients with schizophrenia and 42 normals rescanned after a 5-year interval. We are not aware of other longitudinal DT studies. Results: Both early and late onset patients had volumetric reductions in the frontal and temporal lobe compared to normals. Early-onset schizophrenia showed more marked volumetric deficits than older patients, especially in left temporal gray matter. White matter was most decreased in the medial frontal lobe, cingulate, and frontal pole. DT showed lower than normal frontal and cingulate anisotropy in adults with schizophrenia but higher values than normal in adolescents with schizophrenia. Adults tended to have lower frontotemporal anisotropy than adolescents, especially in more dorsal portions of the frontal lobe, and this pattern was lost in patients. Tracts arising in the internal-capsule

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576. Gray and White Matter Volumes of Cortical Brodmann Areas in the Schizophrenia Spectrum Department of Psychiatry, Mount Sinai School of Medicine, New York, NY Background: Previous magnetic resonance imaging (MRI) studies have revealed cortical gray matter volume reductions in frontal and temporal lobe regions in schizophrenia. Whether schizotypal personality disorder (SPD) patients share some or all of the structural brain-imaging characteristics of schizophrenia has received comparatively little study. Methods: We used high-resolution MRI to examine cortical gray and white matter volumes in SPD patients (n=51) and age- and sex-matched healthy comparison subjects (n=51). The MR images were reoriented to standard position parallel to the anterior-posterior commissure line and segmented into gray and white matter tissue types. The tissue types were assigned to Brodmann areas (BAs) using the Perry postmortem histological atlas. Results: A significant Diagnostic group x Temporal Lobe Regions (BA 20, 21, 22) x Matter type (Gray, White) interaction showed that compared with healthy participants, SPD patients had significantly reduced gray, but not white matter volume in the middle temporal gyrus (BA 21). Gray and white matter volumes in all other temporal lobe regions did not differ between groups. In the frontal cortex, a significant Diagnostic group x Region (anterior, dorsolateral, orbital) x BA (anterior: BA8-9-10, dorsolateral:BA44-45-46, orbital: BA11-12-47) interaction indicated that SPD patients had reduced overall (gray/white) volume in the anterior frontal region, especially BA 9, while dorsolateral and orbital regions were spared. Conclusions: These findings resemble, but are less widespread, particularly in the frontal lobe, than recent observations with the same methods in poor outcome schizophrenia. Additional analyses comparing a large group of schizophrenia patients will also be presented. Supported by Independant Investigator Award (NARSAD) to Dr. Hazlett

SYMPOSIUM New Insights on Unipolar Depression: Therapeutic Implications Saturday, May 21, 2:30 PM - 5:00 PM Location: Georgia 7 Chair: Julio Licinio Co-Chair: Charles B. Nemeroff 577. Antidepressants, and Suicidality in Children and Adolescents: An Update Cynthia R. Pfeffer Psychiatry, Weill Medical College of Cornell University, White Plains, NY Background: Suicide among children and adolescents has decreased in recent years. The specific reasons for this are not clear but increased recognition of youth at risk and more effective treatments may account for this trend. This presentation reviews prevention methods for youth suicide. Methods: Review of empirical research regarding risk factors and treatments of youth suicide will be highlighted. Results: Specific psychosocial and psychopharmacological treatments for children and adolescents have been shown to be effective in reducing risk factors for suicidal behavior. However, adverse effects of some psychopharmacological agents have increased concern about their applicability for youth populations.

Saturday Abstracts Conclusions: Additional research on youth suicide is required to improve efficacy of interventions. Increased monitoring of psychopharmacological treatments are required to identify adverse effects and prevent youth suicidal behavior.

578. Depression and Cardiovascular Disease: Pathophysiology and Treatment Charles B. Nemeroff Psychiatry and Behavioral Sciences, Emory Universitry, Atlanta, GA Background: A multitude of studies have revealed a remarkable relationship between depression and cardiovacular disease: depression is an important risk factor for the development of ischemic heart disease and depressed patients have a markedly poor outcome post MI. Methods: The biological basis for this relationship, including studies documenting alterations in platelet function and heart rate variability in depressed patients, will be reviewed. Results: Depressed patients exhibit reduced heartrate variability, increased platelet hyperactivity and increased markers of inflammatory processes. Conclusions: The alterations that appear to underlie the effect of depression on cardiovasular disease and the effect of treatment of depression on these alterations will be described. Supported by NIMH, Pfizer, GSK

BIOL PSYCHIATRY 2005;57:1S-212S 159S cause for which prediction of treatment response and identification of new targets for therapeutics is of crucial importance. Pharmacogenomic approaches to psychiatric disorders offer (1) the possibility to identify a network of genes that may underlie the mechanisms of psychotropic drugs, and (2) the possibility of identifying groups of individuals who are more likely to respond to specific drugs or to suffer from side effects. The corticotropin-releasing hormone receptor 1 (CRHR1) gene is a logical candidate as it is involved in signal transduction relevant to depression and antidepressant treatment, as well as to anxiety, which is a common feature of depression. Methods: We genotyped three single nucleotide polymorphisms (SNPs) of the CRHR1 gene in 80 depressed Mexican-Americans who were stratified according to their baseline level of anxiety and response to double-blind, structured, prospective treatment with either desipramine or fluoxetine. Patients underwent weekly assessments for 8 weeks. Results: We found that only in highly-anxious depressed patients a specific CRHR1 haplotype could significantly predict antidepressant treatment response. Conclusions: Pharmacogenetic/pharmacogenomic strategies can contribute to individualize antidepressant in clinically-defined subgroups of patients. We will present these novel results in the context of existing data for other candidate genes in pharmacodynamic pathways relevant to antidepressant treatment response. Supported by NIH grants GM61394, RR000865, HL04526, RR16996, RR017365, MH062777, HG002500, DK063240, and DK58851, and by an award from the Dana Foundation

579. Recent Neurobiological Developments in LateLife Depression Anand Kumar Psychiatry abd Behavioral Sciences, UCLA, Los Angeles, CA Background: The role of the white matter in the pathophysiology of major psychiatric disorders is receiving increasing recognition. Preliminary neuroimaging studies indicate that MRI detected high intensity lesions in the white matter predispose to late-life major depression (MDD). However, the role of normal appearing white matter (NWM) in the pathophysiology of mood disorders remains unknown. Our group has been investigating the neurobiological basis of late-life MDD using both neuroimaging and neuropsychological approaches to probe brain structure and function. Methods: Patients with MDD and a comparison sample of elderly nondepressed subjects were studied using Magnetic resonance spectroscopy (MRS) and magnetization transfer (MT). These are complementary neuroimaging approaches used to examine phospholipid metabolism and the status of myelin in the white matter of the brain in both groups. In addition, a comprehensive battery of neuropsychological tests were used to characterize cognitive functioning in all subjects. Results: Patients with MDD had higher levels of Choline and Myoinositol in the frontal white matter when compared with controls. MT ratios (indicative of demyelination) were also lower in multiple white matter regions and subcortical nuclei in the MDD group. The relationship between specific metabolites and cognitive measures was significantly weaker in patients with MDD when compared with our controls. Conclusions: These data demonstrate that biological impairments in NAWM and critical subcortical nuclei may lead to altered connectivity between brain regions and thereby contribute to mood disorders in late-life. Biochemical impairments may also contribute to the cognitive aberrations frequently observed in patients with mood disorders. Supported by MH-55115, MH 61567 and MH-02043

580. Pharmacogenomic and Pharmacogenetic Strategies in Antidepressant Treatment Julio Licinio Neuropsychiatric Institute, UCLA, Los Angeles, CA Background: Pharmacogenomics is a new area of medicine that uses the data emerging from the sequencing of the human genome to predict drug responses and to identify new targets for treatment. Pharmacogenomics is of particular relevance to depression, which is a common and complex disorder of unknown

POSTER SESSION Mixed Topics Saturday, May 21, 5:30 PM - 7:00 PM Location: Capitol Ballroom 581. Suicidal Ideation and Mixed Depression Franco Benazzi Dept. Psychiatry, NHS, Forli (Italy), Dept. Psychiatry, University of Szeged (Hungary), University of California (USA), Hecker Psychiatry Research Center, Forli (Italy), Castiglione Cervia RA, Italy Background: Following FDA warning about possible antidepressants-induced suicidal behavior, study aim was to find cross-sectional major depressive episode (MDE) and intra-MDE hypomanic symptoms associated with suicidal ideation. Methods: Consecutive 348 bipolar II disorder (BP-II) and 254 major depressive disorder (MDD) outpatients, presenting (off psychoactive drugs) for MDE treatment, were interviewed by a senior psychiatrist using the Structured Clinical Interview for DSM-IV and the Hypomania Interview Guide. Mixed depression was defined as an MDE with > 3 hypomanic symptoms (a validated definition). Results: Mean (SD) age was 43.7 (14.0) years, females were 65.1%, mean (SD) GAF score was 50.4 (9.4), 62.3% BP-II had mixed depression, 33.4% MDD had mixed depression, 49.6% had suicidal ideation (BP-II=52.0%, MDD=46.4%). Multiple logistic regression of MDE symptoms versus suicidal ideation found worthlessness significant independent predictor (OR=3.3). Multiple logistic regression of intra-MDE hypomanic symptoms versus suicidal ideation found significant independent predictors psychomotor agitation (OR=1.9) and racing/crowded thoughts (OR=1.9). Conclusions: Racing/crowded thoughts and psychomotor agitation were independent predictors of suicidal ideation. However, cross-sectional associations cannot show the direction of a causal association. Controlled trials should be designed to compare the effects of antidepressants in mixed versus non-mixed depression, and test if mood stabilising agents (especially lithium) may be needed to treat the hypo-manic symptoms (psychomotor agitation, racing thoughts) of mixed depression (and possibly, by this way, to treat or reduce suicidal ideation/behavior). Meanwhile, clinicians may find it useful screening for hypomanic symptoms during depression, as mental and behavioral activation may be linked to suicidal ideation.

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