using a measure adopted from studies of parkinsonian bradykinesia. There is a general consensus that parkinsonian bradykinesia stems from an inability to modify, or scale, velocity during movement. In the present study, we hypothesized that a substantial proportion of MD patients would exhibit deficits in velocity scaling. Our measure of velocity scaling quantifies the extent to which a subject programs or scales movement velocity in anticipation of increasing target distance. We studied 54 patients who met DSM-IV criteria for major depression and 26 age and gender comparable healthy comparison subjects. All MD patients were unmedicated at the time of testing. An instrumental measure of wrist movement was developed to quantify several aspects of movement including reaction time (RT), peak velocity (PV), and velocity scaling (VS). Subjects were instructed to flex their wrist when a target box appeared on the computer screen and to reach the target as quickly and as accurately as possible. Results indicated that MD patients exhibited significantly (p,0.001) longer mean RT (477 ms) than comparison subjects (391 ms). There was a trend (p50.07) for MD patients to have lower scores on the VS measure (2.68 deg/sec/deg) compared with comparison subjects (3.33 d/s/d). 53.7% of the MD patients had VS scores lower than the 95th percentile of the comparison subjects. These findings suggest that MD patients as a group exhibit delayed reaction times. Nevertheless, a significant proportion of MD patients also exhibit distur-bances in the programming of movement velocity reflective of a putative dopaminergic disturbance, similar to that seen in parkinsonism.
Research supported by the VA Healthcare System VISN-22 MIRECC and USPHS Grant MH30914
39. INHIBITORY EFFECTS OF OMEGA-3
FATTY ACIDS ON PROTEIN KINASE C
ACTIVITY IN VITRO
H.F. Kim (1), E.J. Weeber (2), J.D. Sweatt (2),
A.L. Stoll (3), L.B. Marangell (1)
(1) Department of Psychiatry, Baylor College of Medicine, Houston, TX 77030; (2) Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030; (3) Psychopharmacology Research Laboratory, McLean Hospital, Belmont, & Department of Psychiatry, Harvard Medical School, Boston, MA
Preliminary data indicate that omega-3 fatty acids may be effective mood stabilizers for patients with bipolar disorder. Both lithium and valproic acid are known to inhibit protein kinase C (PKC) activity after subchronic administration in cell culture and in vivo. The current study was undertaken to determine the effects of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C phosphotrans-ferase activity in vitro. Various concentrations of DHA, EPA, arachidonic acid, lithium and valproic acid were incubated with the catalytic domain of protein kinase C beta from rat brain, as well as the alpha and epsilon isozymes of protein kinase C. Protein kinase C activity was measured by quantifying incorporation of32P-PO
4into a synthetic peptide substrate. Both DHA and EPA, as well as the combination of DHA and EPA, inhibited activity of the catalytic subunit of PKC beta at concentrations as low as 10 micromoles/L. In contrast, lithium, valproic acid and arachidonic acid had no effect on PKC activity. Results of the effects of omega-3 fatty acids, lithium, and depakote on the alpha and epsilon isozymes of PKC will also be reported. DHA and EPA significantly inhibit the activity of the catalytic domain of PKC beta in a manner distinct from lithium and valproic acid. Hence, PKC represents a potential site of action of omega-3 fatty acids in their effects on treatment of bipolar disorder.
40. SMOKING AND PANIC DISORDER: AN
EPIDEMIOLOGIC INVESTIGATION
(1) N. Breslau, (2) D.F. Klein
(1) Henry Ford Health System, Detroit, MI; (2) Columbia University, College of Physicians and Surgeons, New York, NY
Epidemiologic studies have reported a lifetime association between smoking and panic disorder. In this study we examine potential expla-nations for this association. Analysis was conducted on data from two epidemiologic studies, the Epidemiologic Study of Young Adults in southeast Michigan (N51,007) and the National Comorbidity Survey, Tobacco Supplement (public use data) (n54,411). Cox proportional hazards models with time-dependent covariates were used to estimate the risk for onset of panic disorder associated with prior daily smoking and vice versa, controlling for history of major depression. The role of lung disease in the smoking—panic association was explored. Parallel analy-ses of the two epidemiologic data sets revealed that daily smoking signaled an increased risk for first occurrence of panic attack and disorder; the risk was higher in active smokers than in past smokers. These relationships held in both males and females with no evidence of sex interactions. No significant risk was detected for onset of daily smoking in persons with prior panic attack or disorder. Exploratory analyses suggest that lung disease might be one of the mechanisms linking smoking to panic attacks. The evidence that the association between smoking and panic disorder might result primarily from an influence in one direction, i.e., from prior smoking to first panic attack, and the possibility of a higher risk in active than in past smokers suggest a causal hypothesis for the smoking—panic relationship.
41. FAMILIAL SCHIZOPHRENIA
SPECTRUM DISORDERS IN
CHILDHOOD-AND ADULT-ONSET SCHIZOPHRENIA
R. Nicolson (1), M. Lenane (1), S.I. Usiskin (1),
F.B. Brookner (1), P. Gochman (1), M.F. Egan (2),
D. Pickar (3), D.R. Weinberger (2),
J.L. Rapoport (1)
(1) Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland 20892-1600; (2) Clinical Brain Disorders Branch, National Institute of Mental Health; (3) Experimental Therapeutics Branch, National Institute of Mental Health
Preliminary evidence suggests an increased rate of schizophrenia spectrum disorders in the relatives of patients with childhood-onset schizophrenia when compared with relatives of control children. In this study, the rates of schizophrenia spectrum disorders were compared in parents of onset and adult-onset schizophrenics. Eighty-nine parents of 49 childhood-onset schizophrenia patients and 53 parents of 32 adult-childhood-onset schizophrenics were interviewed using structured instruments to determine the presence of schizophrenia spectrum disorders. Information on a further six parents of adult-onset patients was obtained through structured interviews of family members. Parents of the adult-onset patients were significantly older than parents of the childhood-onset patients. Despite this, and without correction for age differences, the interviewed parents of the childhood-onset patients had significantly more schizophrenia spectrum disorders (20: 1 schizophre-nia, 10 schizotypal personality disorder, 9 paranoid personality disorder), whether when compared with only those parents of adult-onset patients who had been interviewed in person (3: 1 schizotypal personality disorder, 2 paranoid personality disorder) (x257.1, df5 1, p50.008) or if the relatives about whom information was obtained from family members were included (6: 1 schizotypal personality disorder, 5 paranoid personality disorder) (x253.8, df51, p50.05). Among interviewed reatives, the risk
12S BIOL PSYCHIATRY Thursday Abstracts
for a schizophrenia spectrum disorder in parents of childhood-onset patients was 4.9 times greater than for parents of adult-onset patients. These data are consistent with the hypothesis that a childhood-onset of schizophrenia is due, at least in part, to a greater genetic diathesis for the disorder.
Brain Imaging I
Thursday, May 11, 2:30 PM–5:00 PM
Location: New Orleans
Chair: Robert M. Cohen
42. THE CONTRIBUTION OF
ORBITOFRONTAL CORTEX TO EPISODIC
MEMORY IMPAIRMENT IN OCD
C.R. Savage (1), T. Deckersbach (1),
S. Heckers (1), S. Wilhelm (1), A.D. Wagner (2),
D.L. Schacter (3), L. Baer (1), M.A. Jenike (1),
S.L. Rauch (1,2)
(1) Dept. of Psychiatry and (2) Radiology, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129; (3) Dept. of Psychology, Harvard University, Cambridge, MA
Biological studies of obsessive-compulsive disorder (OCD) provide consis-tent evidence of dysfunction in orbitofrontal cortex (OFC). We have used the California Verbal Learning Test (CVLT) in behavioral studies to examine episodic memory in OCD. In two separate investigations, we found that OCD patients failed to spontaneously apply semantic organizational strate-gies during encoding and this led to problems in delayed recall. We will present new data from a PET study in normal subjects examining the neural systems underlying semantic organization using a verbal memory paradigm patterned after the CVLT. Eight normal subjects listened to lists of 24 words, in three conditions: 1) Unrelated: words were semantically unrelated; 2) Spontaneous: words were related in four semantic categories, and subjects were not instructed of this beforehand; 3) Directed: same as (2) but subjects were explicitly instructed to notice the relationships and use them to improve memory. Behavioral data included a Semantic Clustering score, measuring active regrouping of words into semantic categories during recall. In a graded PET contrast (Directed.Spontaneous.Unrelated), two distinct activations were found in left inferior prefrontal cortex and left dorsolateral prefrontal cortex. Correlation analyses in the Spontaneous condition indi-cated that blood flow in OFC during encoding predicted the use of semantic clustering strategies during immediate recall. These results indicate that OFC plays a role in episodic memory by supporting the mobilization of effective strategic processes, mediated in other regions of PFC. Disruptions in learning strategies in OCD are likely related to OFC dysfunction. Supported by NIMH MH01230 and MH50275.
43. MRI ANALYSIS OF CHILDREN AT RISK
FOR BIPOLAR DISORDER
M.P. DelBello, C.A. Soutullo, P. Ryan,
S.M. Graman, M.E. Zimmerman, G.E. Getz,
K.A. Lake, S.M. Strakowski
The University of Cincinnati College of Medicine, Cincinnati, OH 45267-0559
Studies of adults with bipolar disorder suggest abnormalities in the neuroanatomic pathways thought to modulate mood. To our knowledge, there have been no studies examining these neuroanatomic structures in
children at risk for bipolar disorder. We hypothesized that compared with healthy volunteers, children with a parent with bipolar disorder (high-risk) would exhibit abnormalities in brain regions that regulate mood.
Children (ages 8 –12 years) with at least one parent with bipolar disorder (N517) and children of healthy parents without any DSM-IV Axis I disorder (N513), matched for age, sex, socioeconomic status, handedness, and Tanner stage, were assessed using the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS). Parents were evaluated using the Structured Clinical Interview for DSM-IV (SCID-P). Contiguous 1 mm axial T1-weighted MRI slices were obtained using a GE 1.5 Tesla scanner. Morphometric analyses were performed by raters blind to subject diagnosis. Regions of interest (ROIs) included whole brain, hippocampus, amygdala, thalamus, striatum, globus pallidus, cerebellum, and prefrontal cortex.
MANCOVA adjusting for Tanner stage and education revealed the high-risk children demonstrated significantly different overall ROI vol-umes as compared to the healthy volunteers [Wilks lambda 5 0.51, F(7,19)52.6, p50.05]. The differences between groups in hippocam-pal volumes contributed the only large effect size (f 5 0.6) and hippocampal volumes were larger in high-risk children than in volunteers.
Our results suggest that children at risk for bipolar disorder may have neuroanatomic abnormalities similar to those found in adults with bipolar disorder, suggesting that these abnormalities may be present prior to the onset of bipolar disorder. We are continuing to collect data in effort to increase power so that additional differences in structural volumes may be detected.
44. REDUCED LEFT HESCHL’S GYRUS
VOLUME IN SCHIZOTYPAL PERSONALITY
DISORDER
C.C. Dickey, M.E. Shenton, S. Fraone,
M.A. Niznikiewicz, M.M. Voglmaier,
L.J. Seidman, Y. Hirayasu, J.S. Kwon,
I.A. Fischer, J. Anderson, M. Frumin,
R.W. McCarley
Harvard Medical School/Brockton VA Medical Center, Department of Psychiatry, Brockton, MA 02401
Schizotypal personality disorder (SPD) shares the same genetic diathesis as the schizophrenia spectrum disorders, yet persons with SPD are not psychotic and generally have not been prescribed neuroleptics. There-fore, they may represent an ideal group to study the underlying structural abnormalities in the spectrum disorders. Previously we showed SPD subjects to have enlarged CSF volumes, parahippocampal aysmmetry, and reduced left superior temporal gyrus (STG) gray matter volumes compared with normal control subjects. The STG consists anatomically of the anterior pole, Heschl’s gyrus (primary auditory sensory cortex) and planum temporale (auditory unimodal association cortex). In order to better define this STG abnormality, we examined Heschl’s gyrus and planum temporale in an extended group of subjects. Subjects: SPD subjects were all right-handed males (N524) and age-matched within 3 years to the comparison subjects (N523)), with no difference in IQ, years of education or parental socio-economic status. SPD subjects did have lower socioeconomic status. Image processing: The STG was manually drawn on the acquired coronal images consisting of 124 slices. To correct for the effects of head tilt, the images were realigned and resegmented to form a new set of images with over 200 slices and isotropic voxels. The drawings were edited as necessary and the boundaries were extended to their anterior and posterior most extent with high interrator reliability (intraclass r.0.99). The effect of brain volume on region size was accounted for using a regression procedure. The resultant residual volume for left Heschl’s gyrus was not normally
Thursday Abstracts BIOL PSYCHIATRY 13S
