- Email: [email protected]
325. Serotonin displacement of 3H-ketanserin binding to platelet 5-HT2A receptors in normal controls and depressed patients
Saturday Abstracts
322. TRANSCRANIAL MAGNETIC STIMULATION IN TREATMENTREFRACTORY DEPRESSION
BIOLPSYCHIATRY 1998;43:1S-133S
97s
reductionin the letl SVPCcomparedto those affective withoutfamily history(n=lO) (ANOVA,p=.017). These findingssuggestthat abnormalityof the SVFCare presentat diseaseonsetand are associatedwith a tirat degreefamilyhistoryof affectivedisorder.
R.M. Berman, N. Boutros, M. Narasimhan, G. Sanacora & D.S. Charney Yale UniversitySchoolof Medicine;ConnecticutMentalHeafth Center,New HavenCT 06519;and, West HavenVA MedicalCenter, West HavenCT 06516 Multiple groups have reported that repetitive transcranial magnetic stimulation (rTMS) may be an eftlcacious treatment for treatmentrefractorymajordepression.To date,these publishedstudiesare limited by eitheropen-labeldesignor inclusionof medicateddepressedsubjects. The purposeof this ongoingstudyis to assess the eftlcacy of rTMSin unmedicated,treatment-refractorypatientswho meet criteria for major depression.Depressedsubjects,whohadfailedto respondto at leastfour treatmenttrials, were assignedin a randomizeddouble-blindmannerto receiveeitheractive(n=6; twenty2-seetrainsof 20 Hz stimulationwith 58-see intervals;deliveredat 80% motor thresholdwith the figure-ofeight coil positioned5 cm anteriorto the left Ml site) or sham (n=6; similarconditionswith the coil elevatedand angled45 degreestangentially to the scalp) rTMS. These sequenceswere applied doring 10 consecutiveweekdays.The group mean 25-itemHamiltonDepression Rating Scafe (HDRS)scores was 40.3 (2.7 SEM).Mean decreasesin HDRS scores were 13.5(5.9 SEM) and 3.0 (5.9 SEM)points for the active and control groups, respectively(p=O.24).One of 6 subjects receiving active treatment demonstrateda fill remission (i.e., HDRS decreased from 47 to 7 points). Two of 6 subjects receiving sham treatmentdiscontinuedearlybecauseof lackof response(i.e.,after3 and 5 sham treatments).These preliminaryresults are consonantwith the hypothesisthat active rTMS may have greater antidepressantactivity than shamrTMS.
323. SUBGENUAL PREFRONTAL CORTEX REDUCTION IN FIRST EPISODE AFFECTIVE PSYCHOSIS Y. Hirayasul, M.E. Shentonl, D.F. Salisbury2, C.G. Wiblel, I.A. Fischerl, T. Kislerl, J.S. Kwonl, C.C. Dickeyl, D.A. Yurge1un-Todd2,M. Tohen2 & R.W. McCarleyl ‘BrocktonVA MedicalCenter,Brockton,MA 02401and 2McLean Hospitaf,Belmont,MA 02178,Departmentof Psychiatry,Harvard MedicalSchool Decreasedactivityof the left prefrontalcortexventralto the genuof the corpus callosum was reported in familial bipolar/unipdar reeurrent depressivesusingPETimages.Thisfindingwaspartiallyexplainedby a correspondinggraymattervolumereductionin the sameregions(Drevets et rd. 1997).However,it remainedunclearwhetherthese findingswere resulted from recurrent illness, and/or whether were associated with heritability.In order to determineif the subgenualventraf prefrontal cortex (SVPC)abnormalitieswere presentat disease onset, SPGRMR imagingwasacquiredfromfirstepisodepatientswitbaffeetivepsychosis (n=23, 20 bipolar and 3 unipolar), schizophrenia(n=16), and agematchednormrdcontrolsubjects(n= 19).There was no volumedifference among the three groups in either left SVPC or right SVPC. However,the afftitive psychoticpatients with a positive fust degree family historyof affectivedisorder(n=13) showedsignificantvolume
324. IMPLICATIONS OF A SIGNIFICANT TREATMENT BY COUNTRY INTERACTION J.D. Lightfoot, J.M. Herrera, R. Landin, D.J. Debrota, W. Offen, M.A. Demitrack & W.Z. Potter Lilly ResearchLaboratories,Lilly CorporateCenter,Indianapolis,IN 46285 Establishingefficacyof novelpsychotropicagentshas beeomeincreasinglydifficult.A potentialcontributoris the increasinguse of complex intemationrdclinicaltrials.Emergingevidencesuggestsdifficultieswith such studiesbut, traditionholdsthat increasedvariabilityis of minimal concern.We presentevidencethat sugges- site differencesmay have a significantinfluenceon the interpretabilityof suchtriafs. Subjectswere a subset of patients (N = 121) who met DSM-IVcriteria for major depressionin a phaseII clinicaltrial conductedin the U.S. and Canada. Thestudydesignincludeda randomizeddouble-blindplacebo-controlled trial with a l-week placebolead-in,and 6 week acute treatmentperiod comparingan establishedantideprwsrmtwith placebo.Clinicalchange was measuredusing the HamiltonDepressionScafe, 17 item version (1-IAM-D17). Demographicandbaselinevariablesrevealedno significant differencesbetween subjects,raters or sites, however,when the sites were groupedby country, there were significantvariations in study outcome.Forexample,afthoughHAM-D17changefrombaselinefor the antidepressantwas consistentacrosscountries,the magnitudeof placebo responsedifferedby 8.2points,a highfysignificanttreatmentby country effect (p=.0026). Several factors could contribute to these results including nationrddifferences in disease phenomenologyor clinical technique,but we believe this to be unlikelybecause of the lack of baseline differences and the socird, economic, and clinical practice similaritiesof the 2 countries.We believethe data are more consistent with significantdifferencesin specific site attributes(eg., recruitment practice,localclinicaftrainingmethods)or idiosyncraticclinician-patient interaction effects (eg., expectationbias). The nature of these sitespecificinfluencesis poorlyunderstoodyet, the results presentedhere suggest that their effe@smay be profound.Further study is clearly needed.
325. SEROTONIN DISPLACEMENT OF 3HKETANSERIN BINDING TO PLATELET 5HT2A RECEPTORS IN NORMAL CONTROLS AND DEPRESSED PATIENTS G.N.M. Gurguisl’2, S.P. Phan2, J.E. Blakeleyl, E.J. Dikis2 & A.J. Rush2 ‘Departmentof VeteransAffairsMedicalCenter,DrdlasTX 75216 ‘Universityof Texas SouthwesternMedicalSchool,Daflas,TX 72235 We have demonstratedpreviouslythat agonist displacementof 3Hketanserinbindingto platelet5-HT2~receptorsrevealsthat theyexist in high-andlow-atlhity statesandthat agonistbindingto 5-I-I’Tm receptor is regulatedby G protein.Abnormal5-HT2~receptor&nsity has been
98S
SaturdayAbstracts
BIOLPSYCHIATRY 1998;43:1S-133S
reported in major depression.However,earlier studies have focused primarily on measuringtotal receptor density. We arc not aware of previousstudiesinvestigatingpossibledysregulationin agonistaft%tity to the 5-HT2~receptorin the high-andlow-affinitystatesor the relative distributionof receptordensitybetweenthese two states. We arc currently investigating5-HT2Areceptor function in normal controls and patients with major depression, using both antagonist saturationand agonistdisplacementexperiments.Effectsof imipramine treatmentalso are being investigatedin a subsetof depressedpatients. We will presentour findingsregardingcouplingmeasuresof G. protein in patients and controls and the effects of inripraminetreatment on 5-HTMreceptorcoupling.These tindingswill be discussedin view of existingliteratureon the roleof 5-HT2~receptorsin the pathophysiology of depressionand mechanismsof actionof antidepressants.
326. EFFECTS OF VENLAFAXINE ON BLOOD PRESSURE: A META-ANALYSIS OF ORIGINAL DATA IN DEPRESSION M.E. Thase WesternPsychiatricInstituteand Clinic,Pittsburgh,PA 15213 Venlafaxine hydrochloride, the first nontncyclic serotonin-norepinephrinereuptake inhibitor,is a safe and effective antidepressantbut is associated with sustained elevation of supine diastolic blood pressure (SDBP). This meta-analysis of original data used both a randomeffects model and a multivariatesurvivalanalysis method.A sampleof 3,744patientswith majordepressionwhohad been enrolled in phase II and phase HI controlledclinical trials comparingvenlafaxine, imipramine, or placebo were treated for 6-12 weeks of acute phase therapy; somerespondersreceived up to 1 year of continuation phase tberapy. Venlafaxine and imipramine were associated with small but statistically significant increases in SDBP during acute phase therapy. Venlafaxine’seffect was highly dose-dependent,and the incidenceof cases of sustainedelevationof SDBPwas statistically and clinically significant only at dosages exceeding 300 mghlay. At lower dosages, the risk of elevated SDBPduring venlafaxinetherapy was comparable to that with placebo and somewhat lower than observed during imiprarninetherapy. Venlafaxinetreatment did not significantly increase BP in patients with treated hypertension,and SDBPvaluesdecreasedslightlyamongpatientswith elevatedbaseline values. About one-half of the cases of treatment-emergent SDBP elevation during venlafaxine therapy remitted spontaneouslyduring continuation therapy. These data compare favorably with those of Feighner (1995) and those reported in the package labeling. Vigilant monitoring of blood pressure is probably not indicated when venlafaxine is prescribed at low and intermediatedoses.
327. CYTOKINES AND ACUTE PHASE PROTEINS IN MAJOR DEPRESSION: ARE THERE GENDER DIFFERENCES? Z. Kronfol, V.K. Singh, J. Boura & M.B. Brown Departmentsof Psychiatry,Pharmacyand Biostatistics,Universityof MichiganMedicalCenter,AmtArbor,MI 48109 As the interest in the psychoneuroimmunologyof affective disorders continuesto grow,there has recentlybeen renewedinterest in tbe role
of cytokines and acute p@se proteins in the psychobiologyof major depression.Reportsof cytokineand acute phase protein abnormalities in depressive illness, however, remain scattered and sometimes contradictory.Furthermore,tbe effects of clinical variables such as age, gender, snd/or severity of depression have only rarely been addressed. In the present study, we compared the plasma levels of specific cytokinesand acute phase proteins in 38 patients with major depression and 38 matched controls. These included Alpha-1 Acid Glycoprotein(AGP), Cortisol-BindingGlobulin(CBG),Haptoglobin (Hp), Trsnsfernn (Tf), C-Reactive Protein (CRP), interletrkin-1(IL1), interleukin-2(IL-2), solubleinterleukin-2Receptors (sIL-2R)and soluble CDS Receptors (sCD8R).Patients had significantly higher levels of HP. IL-2 and sCDSRthan controls, and significantly lower levels of CBG. Females had significantlyhigher levels of CRP than males; they also had marginallyhigher levels of Tf. Femalesalso had higher levels of Hp among controls, but not among patients. These differences add to the growing list of gender differences in the regulation of biological factors involved in the pathophysiologyof major depression.More research is needed to address the biological and/or clinical significanceof these findings.
328. PULSATILE AND CIRCADIAN ANALYSES OF THE HPA AXIS IN DEPRESSED WOMEN E.A. Young The Departmentof Psychiatryand MentalHealthResearchInstitute, Universityof Michigan,AnnArbor,MI 48109 Increased activation of cortisol secretion is one of the most robust tindingsin majordepression.Our workwithmetyraponesuggestedthat this increasedsecretionwas more prominentin the late afternoonand evening,whenthe circadiandriveto the HPAaxis shouldbe suppressed. To extend these findingswe conductedstudies examiningACTHand cortisolpulsatilitywithq 10min. samplingfor 24 hoursin 11dmg free untreatedwomenwithmajordepressionand 11age andmenstmrd-cycleday matchedcontrol subjects. All subjects were pre-menopausal.We examinedmeanACTHand cortisolover24 H, numberof pulsesper 24 H and puke amplitudefor both hormonesfor both groups.In addition, usingart algorithmfrom van Cauteret al, we determinedthe onset and offset of the quiescent phase for cortisol. Onset was defined as 6 consecutivesamples(onehour)below5@U andoffsetas 6 consecutive samplesabove51LgM1. Mestt ACTHand cortisoldid not differ significantly betweendepressedpatients and control subjects.We found 18 pulses of ACTHin each group.ACTHpulse amplitudedid not differ betweendepressedpatientsand controls(1.96t0.25 PMin controlsand 206~0.3 PM in depressedpatients).Corrisolshowed21* 1.8Pulsesin controlsand 24*0.79 pulsesin depressedpatientswhichdid nor differ significantly.Cortisolpulse amplitudedid not differ between groups. Despitethe similsrfindingsbetweengroups,cortisolwasclearlyelevated in the quiescentperiod(7PMto 1AM)in depressedpatientscomparedto controls(meancortisol2.8 pgkll in controlsand 3.6 p,gldlin patients). Depressedpatientsdemonstrateda later onset on the quiescentperiod (19:23t 24 min. vs. controlsat 19:00t 30 min.) and an earlier offset of the quiescentperiod (2:20140 min. vs. controlsat 3:25~24 min.). These data conthn our earlier findingsthat increasedHPA activation duringthe circadiannadirperiodmaybe morecommonthangeneralized hypercortisolemiain depressionand again suggests dysregtdationof circadian elements responsible for restraining the HPA axis in the evening. Acknowledgments: The authorwouldliketo acknowledgeMH 50030as well as the contributionsof MortonBrownPh.D and WenshengGuo Ph.D.arrdShariMessangerfor biostatisticrdmodellitrgof pulse pammetcrs.
322. TRANSCRANIAL MAGNETIC STIMULATION IN TREATMENTREFRACTORY DEPRESSION
BIOLPSYCHIATRY 1998;43:1S-133S
97s
reductionin the letl SVPCcomparedto those affective withoutfamily history(n=lO) (ANOVA,p=.017). These findingssuggestthat abnormalityof the SVFCare presentat diseaseonsetand are associatedwith a tirat degreefamilyhistoryof affectivedisorder.
R.M. Berman, N. Boutros, M. Narasimhan, G. Sanacora & D.S. Charney Yale UniversitySchoolof Medicine;ConnecticutMentalHeafth Center,New HavenCT 06519;and, West HavenVA MedicalCenter, West HavenCT 06516 Multiple groups have reported that repetitive transcranial magnetic stimulation (rTMS) may be an eftlcacious treatment for treatmentrefractorymajordepression.To date,these publishedstudiesare limited by eitheropen-labeldesignor inclusionof medicateddepressedsubjects. The purposeof this ongoingstudyis to assess the eftlcacy of rTMSin unmedicated,treatment-refractorypatientswho meet criteria for major depression.Depressedsubjects,whohadfailedto respondto at leastfour treatmenttrials, were assignedin a randomizeddouble-blindmannerto receiveeitheractive(n=6; twenty2-seetrainsof 20 Hz stimulationwith 58-see intervals;deliveredat 80% motor thresholdwith the figure-ofeight coil positioned5 cm anteriorto the left Ml site) or sham (n=6; similarconditionswith the coil elevatedand angled45 degreestangentially to the scalp) rTMS. These sequenceswere applied doring 10 consecutiveweekdays.The group mean 25-itemHamiltonDepression Rating Scafe (HDRS)scores was 40.3 (2.7 SEM).Mean decreasesin HDRS scores were 13.5(5.9 SEM) and 3.0 (5.9 SEM)points for the active and control groups, respectively(p=O.24).One of 6 subjects receiving active treatment demonstrateda fill remission (i.e., HDRS decreased from 47 to 7 points). Two of 6 subjects receiving sham treatmentdiscontinuedearlybecauseof lackof response(i.e.,after3 and 5 sham treatments).These preliminaryresults are consonantwith the hypothesisthat active rTMS may have greater antidepressantactivity than shamrTMS.
323. SUBGENUAL PREFRONTAL CORTEX REDUCTION IN FIRST EPISODE AFFECTIVE PSYCHOSIS Y. Hirayasul, M.E. Shentonl, D.F. Salisbury2, C.G. Wiblel, I.A. Fischerl, T. Kislerl, J.S. Kwonl, C.C. Dickeyl, D.A. Yurge1un-Todd2,M. Tohen2 & R.W. McCarleyl ‘BrocktonVA MedicalCenter,Brockton,MA 02401and 2McLean Hospitaf,Belmont,MA 02178,Departmentof Psychiatry,Harvard MedicalSchool Decreasedactivityof the left prefrontalcortexventralto the genuof the corpus callosum was reported in familial bipolar/unipdar reeurrent depressivesusingPETimages.Thisfindingwaspartiallyexplainedby a correspondinggraymattervolumereductionin the sameregions(Drevets et rd. 1997).However,it remainedunclearwhetherthese findingswere resulted from recurrent illness, and/or whether were associated with heritability.In order to determineif the subgenualventraf prefrontal cortex (SVPC)abnormalitieswere presentat disease onset, SPGRMR imagingwasacquiredfromfirstepisodepatientswitbaffeetivepsychosis (n=23, 20 bipolar and 3 unipolar), schizophrenia(n=16), and agematchednormrdcontrolsubjects(n= 19).There was no volumedifference among the three groups in either left SVPC or right SVPC. However,the afftitive psychoticpatients with a positive fust degree family historyof affectivedisorder(n=13) showedsignificantvolume
324. IMPLICATIONS OF A SIGNIFICANT TREATMENT BY COUNTRY INTERACTION J.D. Lightfoot, J.M. Herrera, R. Landin, D.J. Debrota, W. Offen, M.A. Demitrack & W.Z. Potter Lilly ResearchLaboratories,Lilly CorporateCenter,Indianapolis,IN 46285 Establishingefficacyof novelpsychotropicagentshas beeomeincreasinglydifficult.A potentialcontributoris the increasinguse of complex intemationrdclinicaltrials.Emergingevidencesuggestsdifficultieswith such studiesbut, traditionholdsthat increasedvariabilityis of minimal concern.We presentevidencethat sugges- site differencesmay have a significantinfluenceon the interpretabilityof suchtriafs. Subjectswere a subset of patients (N = 121) who met DSM-IVcriteria for major depressionin a phaseII clinicaltrial conductedin the U.S. and Canada. Thestudydesignincludeda randomizeddouble-blindplacebo-controlled trial with a l-week placebolead-in,and 6 week acute treatmentperiod comparingan establishedantideprwsrmtwith placebo.Clinicalchange was measuredusing the HamiltonDepressionScafe, 17 item version (1-IAM-D17). Demographicandbaselinevariablesrevealedno significant differencesbetween subjects,raters or sites, however,when the sites were groupedby country, there were significantvariations in study outcome.Forexample,afthoughHAM-D17changefrombaselinefor the antidepressantwas consistentacrosscountries,the magnitudeof placebo responsedifferedby 8.2points,a highfysignificanttreatmentby country effect (p=.0026). Several factors could contribute to these results including nationrddifferences in disease phenomenologyor clinical technique,but we believe this to be unlikelybecause of the lack of baseline differences and the socird, economic, and clinical practice similaritiesof the 2 countries.We believethe data are more consistent with significantdifferencesin specific site attributes(eg., recruitment practice,localclinicaftrainingmethods)or idiosyncraticclinician-patient interaction effects (eg., expectationbias). The nature of these sitespecificinfluencesis poorlyunderstoodyet, the results presentedhere suggest that their effe@smay be profound.Further study is clearly needed.
325. SEROTONIN DISPLACEMENT OF 3HKETANSERIN BINDING TO PLATELET 5HT2A RECEPTORS IN NORMAL CONTROLS AND DEPRESSED PATIENTS G.N.M. Gurguisl’2, S.P. Phan2, J.E. Blakeleyl, E.J. Dikis2 & A.J. Rush2 ‘Departmentof VeteransAffairsMedicalCenter,DrdlasTX 75216 ‘Universityof Texas SouthwesternMedicalSchool,Daflas,TX 72235 We have demonstratedpreviouslythat agonist displacementof 3Hketanserinbindingto platelet5-HT2~receptorsrevealsthat theyexist in high-andlow-atlhity statesandthat agonistbindingto 5-I-I’Tm receptor is regulatedby G protein.Abnormal5-HT2~receptor&nsity has been
98S
SaturdayAbstracts
BIOLPSYCHIATRY 1998;43:1S-133S
reported in major depression.However,earlier studies have focused primarily on measuringtotal receptor density. We arc not aware of previousstudiesinvestigatingpossibledysregulationin agonistaft%tity to the 5-HT2~receptorin the high-andlow-affinitystatesor the relative distributionof receptordensitybetweenthese two states. We arc currently investigating5-HT2Areceptor function in normal controls and patients with major depression, using both antagonist saturationand agonistdisplacementexperiments.Effectsof imipramine treatmentalso are being investigatedin a subsetof depressedpatients. We will presentour findingsregardingcouplingmeasuresof G. protein in patients and controls and the effects of inripraminetreatment on 5-HTMreceptorcoupling.These tindingswill be discussedin view of existingliteratureon the roleof 5-HT2~receptorsin the pathophysiology of depressionand mechanismsof actionof antidepressants.
326. EFFECTS OF VENLAFAXINE ON BLOOD PRESSURE: A META-ANALYSIS OF ORIGINAL DATA IN DEPRESSION M.E. Thase WesternPsychiatricInstituteand Clinic,Pittsburgh,PA 15213 Venlafaxine hydrochloride, the first nontncyclic serotonin-norepinephrinereuptake inhibitor,is a safe and effective antidepressantbut is associated with sustained elevation of supine diastolic blood pressure (SDBP). This meta-analysis of original data used both a randomeffects model and a multivariatesurvivalanalysis method.A sampleof 3,744patientswith majordepressionwhohad been enrolled in phase II and phase HI controlledclinical trials comparingvenlafaxine, imipramine, or placebo were treated for 6-12 weeks of acute phase therapy; somerespondersreceived up to 1 year of continuation phase tberapy. Venlafaxine and imipramine were associated with small but statistically significant increases in SDBP during acute phase therapy. Venlafaxine’seffect was highly dose-dependent,and the incidenceof cases of sustainedelevationof SDBPwas statistically and clinically significant only at dosages exceeding 300 mghlay. At lower dosages, the risk of elevated SDBPduring venlafaxinetherapy was comparable to that with placebo and somewhat lower than observed during imiprarninetherapy. Venlafaxinetreatment did not significantly increase BP in patients with treated hypertension,and SDBPvaluesdecreasedslightlyamongpatientswith elevatedbaseline values. About one-half of the cases of treatment-emergent SDBP elevation during venlafaxine therapy remitted spontaneouslyduring continuation therapy. These data compare favorably with those of Feighner (1995) and those reported in the package labeling. Vigilant monitoring of blood pressure is probably not indicated when venlafaxine is prescribed at low and intermediatedoses.
327. CYTOKINES AND ACUTE PHASE PROTEINS IN MAJOR DEPRESSION: ARE THERE GENDER DIFFERENCES? Z. Kronfol, V.K. Singh, J. Boura & M.B. Brown Departmentsof Psychiatry,Pharmacyand Biostatistics,Universityof MichiganMedicalCenter,AmtArbor,MI 48109 As the interest in the psychoneuroimmunologyof affective disorders continuesto grow,there has recentlybeen renewedinterest in tbe role
of cytokines and acute p@se proteins in the psychobiologyof major depression.Reportsof cytokineand acute phase protein abnormalities in depressive illness, however, remain scattered and sometimes contradictory.Furthermore,tbe effects of clinical variables such as age, gender, snd/or severity of depression have only rarely been addressed. In the present study, we compared the plasma levels of specific cytokinesand acute phase proteins in 38 patients with major depression and 38 matched controls. These included Alpha-1 Acid Glycoprotein(AGP), Cortisol-BindingGlobulin(CBG),Haptoglobin (Hp), Trsnsfernn (Tf), C-Reactive Protein (CRP), interletrkin-1(IL1), interleukin-2(IL-2), solubleinterleukin-2Receptors (sIL-2R)and soluble CDS Receptors (sCD8R).Patients had significantly higher levels of HP. IL-2 and sCDSRthan controls, and significantly lower levels of CBG. Females had significantlyhigher levels of CRP than males; they also had marginallyhigher levels of Tf. Femalesalso had higher levels of Hp among controls, but not among patients. These differences add to the growing list of gender differences in the regulation of biological factors involved in the pathophysiologyof major depression.More research is needed to address the biological and/or clinical significanceof these findings.
328. PULSATILE AND CIRCADIAN ANALYSES OF THE HPA AXIS IN DEPRESSED WOMEN E.A. Young The Departmentof Psychiatryand MentalHealthResearchInstitute, Universityof Michigan,AnnArbor,MI 48109 Increased activation of cortisol secretion is one of the most robust tindingsin majordepression.Our workwithmetyraponesuggestedthat this increasedsecretionwas more prominentin the late afternoonand evening,whenthe circadiandriveto the HPAaxis shouldbe suppressed. To extend these findingswe conductedstudies examiningACTHand cortisolpulsatilitywithq 10min. samplingfor 24 hoursin 11dmg free untreatedwomenwithmajordepressionand 11age andmenstmrd-cycleday matchedcontrol subjects. All subjects were pre-menopausal.We examinedmeanACTHand cortisolover24 H, numberof pulsesper 24 H and puke amplitudefor both hormonesfor both groups.In addition, usingart algorithmfrom van Cauteret al, we determinedthe onset and offset of the quiescent phase for cortisol. Onset was defined as 6 consecutivesamples(onehour)below5@U andoffsetas 6 consecutive samplesabove51LgM1. Mestt ACTHand cortisoldid not differ significantly betweendepressedpatients and control subjects.We found 18 pulses of ACTHin each group.ACTHpulse amplitudedid not differ betweendepressedpatientsand controls(1.96t0.25 PMin controlsand 206~0.3 PM in depressedpatients).Corrisolshowed21* 1.8Pulsesin controlsand 24*0.79 pulsesin depressedpatientswhichdid nor differ significantly.Cortisolpulse amplitudedid not differ between groups. Despitethe similsrfindingsbetweengroups,cortisolwasclearlyelevated in the quiescentperiod(7PMto 1AM)in depressedpatientscomparedto controls(meancortisol2.8 pgkll in controlsand 3.6 p,gldlin patients). Depressedpatientsdemonstrateda later onset on the quiescentperiod (19:23t 24 min. vs. controlsat 19:00t 30 min.) and an earlier offset of the quiescentperiod (2:20140 min. vs. controlsat 3:25~24 min.). These data conthn our earlier findingsthat increasedHPA activation duringthe circadiannadirperiodmaybe morecommonthangeneralized hypercortisolemiain depressionand again suggests dysregtdationof circadian elements responsible for restraining the HPA axis in the evening. Acknowledgments: The authorwouldliketo acknowledgeMH 50030as well as the contributionsof MortonBrownPh.D and WenshengGuo Ph.D.arrdShariMessangerfor biostatisticrdmodellitrgof pulse pammetcrs.