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Neuroendocrine profiles of antipsychotic drugs in schizophrenic patients
THURSDAI~,MAYI9
123. GH RESPONSE TO TRH IN MULTICASE FAMILIES WITH SCHIZOPHRENIA P. Sirota, I. Gil-Ad, H. Hermesh, H. Muniz, Z. Laron, & R. Weizman Abarbanel Mental Health Center, Bat-Yam, Israel, Geha Psychiatric Hospital, Petah Tiqwa, Beilinson Medical Center, Petah Tiqwa and Sackler School of Medicine, Tel Aviv University, Israel Can abnormal growth hormone (GH) response to TSH releasing hormone (TRH) differentiate between schizophrenic probands, their affected first degree relatives and phenotypicaily healthy family members? Five multicase families with schizophrenia were studied - each family consisted of two chronic schizophrenic patients and one first degree healthy relative, TRH tests were performed between 8:00 9:00 am. Thirty minutes after IV line was inserted a basal blood sample was drawn, and thereafter synthetic TRH was administered. Additional blood samples were drawn at 15, 30 and 60 minutes. Plasma GH was carried out by double antibody RIA. The results were: One proband exhibited high basal GH levels (20 ng/ml) and was excluded. The mean baseline GH plasma levels did not differ significantly between the three groups and the controls. Abnormal GH response was observed in 3/4 probands; 3/5 schizophrenic relatives and 3/5 healthy relatives, but in 0/8 of the healthy non.related controls. The magnitude of the abnormal GH response did not differ significantly between the three groups of the families. The frequency of abnormal GH response was significantly higher in the schizophrenic patients (6/9) when compared to healthy non-related control subjects. A trend towards increased frequency of abnormal GH response was observed in healthy family members (3/5) as compared to control subjects. This study confirmed our previous observation of abnormal GH release after TRH challenge in about 50% of the schizophrenic patients with positive family history. The additional finding is increased frequency of GH response to TRH in healthy related controis.
124. HYPOTHALAMIC-PITUITARY-ADRENAL ACTIVITY IN PANIC DISORDER
J. L. Abelson, George C. Curtis, Oliver G. Cameron, & Michael Bronzo University of Michigan Anxiety Disorders Program, Ann Arbor, MI, 48109 It has been proposed that I) oversecretion of corticotropin-releasing hormone (CRH) from rite hypothalamus plays a pathophysiological role in panic disorder; and 2) the ability of alprazolam to inhibit CRH release contributes to this drug's efficacy in treating panic. Blunted corticotropin (ACTH) responses to CRH infusion have been reported in panic, but other evidence for hypothalamic-pituitsry adrenal (HPA) axis abnormality remains weak. To explore the above hypotheses and more definitively define HPA axis activity in panic disorder, we examined 24 hour profiles of ACTH and cortisoi secretion and conducted CRH stimulation tests in 20 panic patients before and during treatment with alprazolam and in 12 control subjects. Patients were diagnosed by structured clinical interview and DSM-Ill-R criteria. Subjects were studied in a clinical research center where blood samples were drawn (via an indwelling veinous catheter) every ! 5 minutes from 6 p.m. on day i until 6 p.m. on day 2, at which time i Itg/kg of ovine CRH was infused in I minute. Additional samples were drawn immediately before and for 2 hours after the infusion. Patients entered an open, flexible dose treatment trial with alprazolam and had a repeat HPA evaluation after 10 weeks of treatment, while still on drag. Preliminary analyses suggest the following: !) panic patients have normal 24
BIOL PSYCHIATRY 649 ! 994;35:615-747
hour ACTH secretion and normal ACTH responses to CRH; 2) neither basal ACTH secretion nor CRH stimulation test results are altered by treatment with alprazolam; 3) panic patients have normal total 24 hour cortisol secretion, but significantly elevated overnight (11 p.m. to 6 am.) cortisol secretion prior to treatment; 4) the pre-treatment elevation in overnight cortisol secretion is normalized with successful alprazolam treatment. Symptom severity interacted with HPA activity. Prior to treatmerit patients with greater panic attack frequency (> 2/wk) had lower 24 hour ACTH secretion than those with less frequent attacks, though both groups had elevated overnight cortisol secretion. AIprazolam corrected the elevated ovemight cortisol secretion in both groups, but the high fre. quency panic attack patients appeared more resistant to its cortisoi suppressive effects. ACTH levels increased during treatment in the high frequency group and decreased in the low frequency group. Implications of these findings for the role of the HPA axis in panic disorder will be discussed.
125. NEUROENDOCRINE PROFILES OF ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIC PATIENTS F. Duval !,2, M.C. Mokrani 2, M.A. Crocq 1,2, P. Bailey 2, T.S. Diep I, E. E. Andrade I, & J.P. Macher 1,2 tCentre Hospitalier, Rouffach, 68250, France; 2Research Center for Applied Neuroscience in Psychiatry (FORENAP), Rouffach, 68250, France inpatients meeting DSM-Iil-R criteria for schizophrenia were treated for at least one month with: the typical neumleptic chlorpmmazine (n-i 5); a dopamine (DA) D2 partial agonist, either SDZ HDC-912 or OPC 4392 (n-17); or the atypical neuroleptic clozapine (n-7). The effect of these treatments on the activity of the hypothalamic-pituitary dopaminergic system was evaluated by means of challenge with a DA agonist. Plasma adrenocorticotmpic hormone (ACTH), cortisol (COR), prolactin (PRL), and growth hormone (GH) levels before and after challenge with apomorphine (APO, 0.75 mg subcutaneous) were determined at baseline (medication free) and after I month of treatment. Chlorpromazine significantly decreased APO.induced ACTH and COR stimulation (both p<0.03) and PRL suppression (p<0.005), and increased baseline PRL secretion. The DA D2 partial agonists induced a significant decrease in APO-induced ACTH and GH stimulation (respectively !~0.03 and p~.002), and a nonsignificant decrease in APO-induced COR stimulation (p-0.08), and in baseline PRL (p-0.08). Clozapine induced a non significant increase in baseline PRL (p,,0.06) - which remained within the physiological range and APO-induced PRL suppression (p-0.06) but had no effect on GH, ACTH, or COR, either baseline or stimulated. The neuroendocrine profiles of these compounds agree with their dopaminergic properties, and differentiate atypical from typical antipsychotic agents.
126. GONADOTROPlN-RELEASINGHORMONE AGONIST INDUCES DEPRESSION IN WOMEN P. Toren !,6, J. Dor2.6, R. Mester3,6, T. Mozes 3,6, R. Blumensohn 3,6, M. Rehavi 4,e, & A. Weizman 5'e ~TeI-Aviv Community Mental Health Center, 21n Vitro Fertilization Unit, Sheba Medical Center, 3Ness-Ziona Mental Health Center, 4Departmont of Physiology and Pharmacology; SGeha Psychiatric Hospital; 6Tel Aviv University
123. GH RESPONSE TO TRH IN MULTICASE FAMILIES WITH SCHIZOPHRENIA P. Sirota, I. Gil-Ad, H. Hermesh, H. Muniz, Z. Laron, & R. Weizman Abarbanel Mental Health Center, Bat-Yam, Israel, Geha Psychiatric Hospital, Petah Tiqwa, Beilinson Medical Center, Petah Tiqwa and Sackler School of Medicine, Tel Aviv University, Israel Can abnormal growth hormone (GH) response to TSH releasing hormone (TRH) differentiate between schizophrenic probands, their affected first degree relatives and phenotypicaily healthy family members? Five multicase families with schizophrenia were studied - each family consisted of two chronic schizophrenic patients and one first degree healthy relative, TRH tests were performed between 8:00 9:00 am. Thirty minutes after IV line was inserted a basal blood sample was drawn, and thereafter synthetic TRH was administered. Additional blood samples were drawn at 15, 30 and 60 minutes. Plasma GH was carried out by double antibody RIA. The results were: One proband exhibited high basal GH levels (20 ng/ml) and was excluded. The mean baseline GH plasma levels did not differ significantly between the three groups and the controls. Abnormal GH response was observed in 3/4 probands; 3/5 schizophrenic relatives and 3/5 healthy relatives, but in 0/8 of the healthy non.related controls. The magnitude of the abnormal GH response did not differ significantly between the three groups of the families. The frequency of abnormal GH response was significantly higher in the schizophrenic patients (6/9) when compared to healthy non-related control subjects. A trend towards increased frequency of abnormal GH response was observed in healthy family members (3/5) as compared to control subjects. This study confirmed our previous observation of abnormal GH release after TRH challenge in about 50% of the schizophrenic patients with positive family history. The additional finding is increased frequency of GH response to TRH in healthy related controis.
124. HYPOTHALAMIC-PITUITARY-ADRENAL ACTIVITY IN PANIC DISORDER
J. L. Abelson, George C. Curtis, Oliver G. Cameron, & Michael Bronzo University of Michigan Anxiety Disorders Program, Ann Arbor, MI, 48109 It has been proposed that I) oversecretion of corticotropin-releasing hormone (CRH) from rite hypothalamus plays a pathophysiological role in panic disorder; and 2) the ability of alprazolam to inhibit CRH release contributes to this drug's efficacy in treating panic. Blunted corticotropin (ACTH) responses to CRH infusion have been reported in panic, but other evidence for hypothalamic-pituitsry adrenal (HPA) axis abnormality remains weak. To explore the above hypotheses and more definitively define HPA axis activity in panic disorder, we examined 24 hour profiles of ACTH and cortisoi secretion and conducted CRH stimulation tests in 20 panic patients before and during treatment with alprazolam and in 12 control subjects. Patients were diagnosed by structured clinical interview and DSM-Ill-R criteria. Subjects were studied in a clinical research center where blood samples were drawn (via an indwelling veinous catheter) every ! 5 minutes from 6 p.m. on day i until 6 p.m. on day 2, at which time i Itg/kg of ovine CRH was infused in I minute. Additional samples were drawn immediately before and for 2 hours after the infusion. Patients entered an open, flexible dose treatment trial with alprazolam and had a repeat HPA evaluation after 10 weeks of treatment, while still on drag. Preliminary analyses suggest the following: !) panic patients have normal 24
BIOL PSYCHIATRY 649 ! 994;35:615-747
hour ACTH secretion and normal ACTH responses to CRH; 2) neither basal ACTH secretion nor CRH stimulation test results are altered by treatment with alprazolam; 3) panic patients have normal total 24 hour cortisol secretion, but significantly elevated overnight (11 p.m. to 6 am.) cortisol secretion prior to treatment; 4) the pre-treatment elevation in overnight cortisol secretion is normalized with successful alprazolam treatment. Symptom severity interacted with HPA activity. Prior to treatmerit patients with greater panic attack frequency (> 2/wk) had lower 24 hour ACTH secretion than those with less frequent attacks, though both groups had elevated overnight cortisol secretion. AIprazolam corrected the elevated ovemight cortisol secretion in both groups, but the high fre. quency panic attack patients appeared more resistant to its cortisoi suppressive effects. ACTH levels increased during treatment in the high frequency group and decreased in the low frequency group. Implications of these findings for the role of the HPA axis in panic disorder will be discussed.
125. NEUROENDOCRINE PROFILES OF ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIC PATIENTS F. Duval !,2, M.C. Mokrani 2, M.A. Crocq 1,2, P. Bailey 2, T.S. Diep I, E. E. Andrade I, & J.P. Macher 1,2 tCentre Hospitalier, Rouffach, 68250, France; 2Research Center for Applied Neuroscience in Psychiatry (FORENAP), Rouffach, 68250, France inpatients meeting DSM-Iil-R criteria for schizophrenia were treated for at least one month with: the typical neumleptic chlorpmmazine (n-i 5); a dopamine (DA) D2 partial agonist, either SDZ HDC-912 or OPC 4392 (n-17); or the atypical neuroleptic clozapine (n-7). The effect of these treatments on the activity of the hypothalamic-pituitary dopaminergic system was evaluated by means of challenge with a DA agonist. Plasma adrenocorticotmpic hormone (ACTH), cortisol (COR), prolactin (PRL), and growth hormone (GH) levels before and after challenge with apomorphine (APO, 0.75 mg subcutaneous) were determined at baseline (medication free) and after I month of treatment. Chlorpromazine significantly decreased APO.induced ACTH and COR stimulation (both p<0.03) and PRL suppression (p<0.005), and increased baseline PRL secretion. The DA D2 partial agonists induced a significant decrease in APO-induced ACTH and GH stimulation (respectively !~0.03 and p~.002), and a nonsignificant decrease in APO-induced COR stimulation (p-0.08), and in baseline PRL (p-0.08). Clozapine induced a non significant increase in baseline PRL (p,,0.06) - which remained within the physiological range and APO-induced PRL suppression (p-0.06) but had no effect on GH, ACTH, or COR, either baseline or stimulated. The neuroendocrine profiles of these compounds agree with their dopaminergic properties, and differentiate atypical from typical antipsychotic agents.
126. GONADOTROPlN-RELEASINGHORMONE AGONIST INDUCES DEPRESSION IN WOMEN P. Toren !,6, J. Dor2.6, R. Mester3,6, T. Mozes 3,6, R. Blumensohn 3,6, M. Rehavi 4,e, & A. Weizman 5'e ~TeI-Aviv Community Mental Health Center, 21n Vitro Fertilization Unit, Sheba Medical Center, 3Ness-Ziona Mental Health Center, 4Departmont of Physiology and Pharmacology; SGeha Psychiatric Hospital; 6Tel Aviv University