- Email: [email protected]
CNS roles of CRF and urocortin, their receptors and binding protein
S-26 Pharmacotherapy ofAffective Disorders in Women - Part 1
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has also been obtained for some treatmen ts., including non-adrenergic imidazoline binding sites on platelet s. None of these measures, however. has proven closel y related to therapeutic response. One if left, therefore, without a firm bas is for developing specific classes of agents as more likely to produce rapid antidepressant response. Two recent "leads". reports of accelerated respon se using the mixed SHT/noradrenalin uptake inhibitor, venlafazine, and using the combination of pindolol and selective 5HT uptake inhibitors sugge st a "SHT plus" strategy. The problem with this interpretation is that there is. to date, no clear supportive biochem ical data in human s. The ability to more fully characterize agents in terms of their molecular specificity and the recognition that in addition to membrane related sites there are multiple specific intracellular ones which may prove to be even more essential targets raises the notion of exploratory clinical studies to test these concepts. Thus, agents could be evaluated in terms of their ability to produc e rapid changes in mood with ratings every two to three days accompanied by biochem ical or physiological measures to show that a presumed effect has indeed been achieved. Methods for "imaging" the acute biochemical and/or functional effects of new agents should aid in this task but require validation.
alternative splice variants. The first receptor binds (CRF-R l) binds CRF with high affinity, is coupled to adenylate cyclase and is distributed in pituitary corticotropes and throughout the CNS. Two variants of the second receptor (CRF-R2) differ from CRF-Rl with respect to anatomi c distribution and pharmacologic specificity: particularly, the structurally related lower vertebrate peptides sauvagine and urotensin-I are more potent than CRF on CRF-R2 . Fish urotensin I and amphibian sauvagine were considered to be homologs of CRF until peptides even more closely related to CRF were identified in these same vertebrate classes. Lookin g for an additional mammal ian member of this family, we have identified a novel urotensin CRF-like peptide, named urocortin , in the rat brain and the human genome that has very high affinity for CRF-RI and R2 as well as for CRF-BP. Synthetic urocortin has potnet biological action s on both CRF-Rl (pituitary ACTH release) as well as R2 (vasodilation, reduction of vascular permeabilit y) mediated events. The coincidence of urocortinlike projections with CRF-R2 and observations that synthetic urocortin is more potent than CRF for binding and activating these receptors, as well as for inducing c-Fos in regions enriched in CRF-R2, are consistent with the hypothesis that this novel peptide is an endogenous ligand for CRF type 2 receptors.
15-261Pharmacotherapy of Affective
I8-26-3 \ Gender Differences in the Response to
Disorders in Women - Part 1
I5-26-1 I The Continuum of Affective Disorders In Women - Diagnostic andTherapeutIc Implications
Uriel Halbreich. State University of New York at Buffa lo Depression is a common denominator of a wide range of affective disorders that differ from each other in the character of symptoms and time course that are required for meeting typological criteria for their descriptive diagnoses. It has been demonstrated that various affective disorders and related states may be effectively treated by same antidepressants. Drug response and its associa ted symptoms dimensions might shed some light on possible underlying mechanisms of affective disorders. We have been analyzin g data on over 2000 depressed subjects , with diagnoses ranging from severe episode s of major depressi ve disorder (MOD) and chroni c MOD . to dysthym ia and premen strual dysphoric disorders. Ages ranged from early 20's to old geriatric people. All patients participated in studies of the SSRI sertraline. Emphasis here is on gender differences across the affective disorders. The target variables are diagnostic symptoms, severity of depre ssion, life time history and family history, quality of life and social support, as well as side effects. Results of the affective disorders group are compared to a large group of patients with inclusion diagnosi s of obsessive-compulsive disorder. The similarities, differences and gender differences across the spectrum of various affective disorde rs might have diagnostic, therapeutic and heur istic implications.
I8-26 -2 \ CNS Rolesof CRFand Urocortln, their Receptors and Binding Protein W. Vale, J. Vaughan , C. Donaldson, M. Perrin, S. Sutton, J. Bittencourt, 1. Rivier, P. Sawchenk o. The Salk Institute fo r Biological STUdies. La Jolla, CA 92037 Corticotropin releasing factor (CRF) is the key neuroregulator of the hypothalamic-pituitary-adrenal cortical axis (HPA) and mediates numerous complementary stress-related endocrine, autonomic and behavioral respon ses. The broad central and peripheral distribution of the peptide and its receptors when considered with many biological actions support the notion that CRF is an important local regulator within the centra l nervous, immune and other systems. CRF antagonists block many stress-induced physiologic and pathoph ysiologic responses in experimental animal s and perturbations of the CRF system or HPA have been reported in human affective disorders. The effects of CRF within the CNS may be anatomically and temporally limited by a high aftinity binding protein (CRF-BP) . Thc actions of CRF are mediated by 7 transmembrane domain G-protein coupled receptors (CRF-R) derived from 2 genes, each of which have
Pharmacotherapy among Early OnsetDysthymics
K.A. Yonkers, A.J. Rush, S. Kornste in, U. Halbreich, T. Pearlstein, A. Stone. The University of Texas Sou thwestern Medical Cemer, St. Paul Prof essional Bldg. I, #5205959 Harry Hines Blvd. Dallas, TX 75235-9101 Dysthymia is a "subsyndrornal" mood disorder that is dominat ed by psychological symptoms of low, gloomy mood , poor self-esteem, guilt and hopelessness. Although historically the various psychotherapies have been considered treatments of choice, recent work has found efficacy for antidepressants. In this report , we present gender differences in the response to antidepressant therapy. Methods: Eligible patient s had earlyonset dysthymia, no lifetime history of psychotic illness, no MOD or other primary Axis I diagnoses within the last 6 months. All women used an adequate means of birth co ntrol. Excluded were patients with antisocial or severe borderl ine personality disorder, patients who had failed 2 previous adequate antidepressant treatment trials, and patients with medical contraindications to participation. After I week placebo washout , non-responders were randomi zed to 12 weeks of treatment with either sertraline (SO- 200 mgs daily), imipramine (SO- 300 mg daily) or placebo . Efficacy was evaluated with the Hamilton Rating Scale for Depressi on, Clinical Global Impression Scale, Inventory of Depressive Symptomatology, and Montgomery Asberg Depression Scale . Results: 144 men and 266 women had at least I post randomization visit. Baseline scores on all rating scales were equivalent for men and wome n. Women were more likely than men to discontinue regardless of treatment cond ition. Using a response criterion of ~ SO% decrease in HRS-D , there was a trend for women to be more likely to respond to any active treatment. Compared with men, significantly more women respo nded to sertraline (chi sq = 6.31, P = 0.012). More women respon ded to sertraline than either placebo or imipramine. Using all 4 outcome instruments, the highest response rate to active treatment and the lowest response rate to placebo was among women. There were no significant differences between any active treatme nt and placebo for the men in the study. Conclusion: Women with chronic milder depressions such as dysthymia may have a higher response rates to serotonin reuptake inhibitors.
I5-26-41 -Mood Effects of Hormonal Interventions Comparisons to ConventIonal Antidepressants E.W. Freeman, K. Rickels, S.J. Sondh eimer. Department s of Psychiatry and Obstetrics/Gynecology, University ofPennsylvania, Philadelphia, PA Comparisons of the efficacy of hormonal and anti-depressant medications in treating premenstrual symptoms (PMS) provide insight into the relative importance of hormonal and CNS effects on mood and behavioral symptoms in cycling women . Method: A series of treatment samples in placebo-controlled (progesterone, alprazolam, leuprolide) and open-label studies (desipramine, nefazodone , sertraline, lIuvoxamine) had the same
87
has also been obtained for some treatmen ts., including non-adrenergic imidazoline binding sites on platelet s. None of these measures, however. has proven closel y related to therapeutic response. One if left, therefore, without a firm bas is for developing specific classes of agents as more likely to produce rapid antidepressant response. Two recent "leads". reports of accelerated respon se using the mixed SHT/noradrenalin uptake inhibitor, venlafazine, and using the combination of pindolol and selective 5HT uptake inhibitors sugge st a "SHT plus" strategy. The problem with this interpretation is that there is. to date, no clear supportive biochem ical data in human s. The ability to more fully characterize agents in terms of their molecular specificity and the recognition that in addition to membrane related sites there are multiple specific intracellular ones which may prove to be even more essential targets raises the notion of exploratory clinical studies to test these concepts. Thus, agents could be evaluated in terms of their ability to produc e rapid changes in mood with ratings every two to three days accompanied by biochem ical or physiological measures to show that a presumed effect has indeed been achieved. Methods for "imaging" the acute biochemical and/or functional effects of new agents should aid in this task but require validation.
alternative splice variants. The first receptor binds (CRF-R l) binds CRF with high affinity, is coupled to adenylate cyclase and is distributed in pituitary corticotropes and throughout the CNS. Two variants of the second receptor (CRF-R2) differ from CRF-Rl with respect to anatomi c distribution and pharmacologic specificity: particularly, the structurally related lower vertebrate peptides sauvagine and urotensin-I are more potent than CRF on CRF-R2 . Fish urotensin I and amphibian sauvagine were considered to be homologs of CRF until peptides even more closely related to CRF were identified in these same vertebrate classes. Lookin g for an additional mammal ian member of this family, we have identified a novel urotensin CRF-like peptide, named urocortin , in the rat brain and the human genome that has very high affinity for CRF-RI and R2 as well as for CRF-BP. Synthetic urocortin has potnet biological action s on both CRF-Rl (pituitary ACTH release) as well as R2 (vasodilation, reduction of vascular permeabilit y) mediated events. The coincidence of urocortinlike projections with CRF-R2 and observations that synthetic urocortin is more potent than CRF for binding and activating these receptors, as well as for inducing c-Fos in regions enriched in CRF-R2, are consistent with the hypothesis that this novel peptide is an endogenous ligand for CRF type 2 receptors.
15-261Pharmacotherapy of Affective
I8-26-3 \ Gender Differences in the Response to
Disorders in Women - Part 1
I5-26-1 I The Continuum of Affective Disorders In Women - Diagnostic andTherapeutIc Implications
Uriel Halbreich. State University of New York at Buffa lo Depression is a common denominator of a wide range of affective disorders that differ from each other in the character of symptoms and time course that are required for meeting typological criteria for their descriptive diagnoses. It has been demonstrated that various affective disorders and related states may be effectively treated by same antidepressants. Drug response and its associa ted symptoms dimensions might shed some light on possible underlying mechanisms of affective disorders. We have been analyzin g data on over 2000 depressed subjects , with diagnoses ranging from severe episode s of major depressi ve disorder (MOD) and chroni c MOD . to dysthym ia and premen strual dysphoric disorders. Ages ranged from early 20's to old geriatric people. All patients participated in studies of the SSRI sertraline. Emphasis here is on gender differences across the affective disorders. The target variables are diagnostic symptoms, severity of depre ssion, life time history and family history, quality of life and social support, as well as side effects. Results of the affective disorders group are compared to a large group of patients with inclusion diagnosi s of obsessive-compulsive disorder. The similarities, differences and gender differences across the spectrum of various affective disorde rs might have diagnostic, therapeutic and heur istic implications.
I8-26 -2 \ CNS Rolesof CRFand Urocortln, their Receptors and Binding Protein W. Vale, J. Vaughan , C. Donaldson, M. Perrin, S. Sutton, J. Bittencourt, 1. Rivier, P. Sawchenk o. The Salk Institute fo r Biological STUdies. La Jolla, CA 92037 Corticotropin releasing factor (CRF) is the key neuroregulator of the hypothalamic-pituitary-adrenal cortical axis (HPA) and mediates numerous complementary stress-related endocrine, autonomic and behavioral respon ses. The broad central and peripheral distribution of the peptide and its receptors when considered with many biological actions support the notion that CRF is an important local regulator within the centra l nervous, immune and other systems. CRF antagonists block many stress-induced physiologic and pathoph ysiologic responses in experimental animal s and perturbations of the CRF system or HPA have been reported in human affective disorders. The effects of CRF within the CNS may be anatomically and temporally limited by a high aftinity binding protein (CRF-BP) . Thc actions of CRF are mediated by 7 transmembrane domain G-protein coupled receptors (CRF-R) derived from 2 genes, each of which have
Pharmacotherapy among Early OnsetDysthymics
K.A. Yonkers, A.J. Rush, S. Kornste in, U. Halbreich, T. Pearlstein, A. Stone. The University of Texas Sou thwestern Medical Cemer, St. Paul Prof essional Bldg. I, #5205959 Harry Hines Blvd. Dallas, TX 75235-9101 Dysthymia is a "subsyndrornal" mood disorder that is dominat ed by psychological symptoms of low, gloomy mood , poor self-esteem, guilt and hopelessness. Although historically the various psychotherapies have been considered treatments of choice, recent work has found efficacy for antidepressants. In this report , we present gender differences in the response to antidepressant therapy. Methods: Eligible patient s had earlyonset dysthymia, no lifetime history of psychotic illness, no MOD or other primary Axis I diagnoses within the last 6 months. All women used an adequate means of birth co ntrol. Excluded were patients with antisocial or severe borderl ine personality disorder, patients who had failed 2 previous adequate antidepressant treatment trials, and patients with medical contraindications to participation. After I week placebo washout , non-responders were randomi zed to 12 weeks of treatment with either sertraline (SO- 200 mgs daily), imipramine (SO- 300 mg daily) or placebo . Efficacy was evaluated with the Hamilton Rating Scale for Depressi on, Clinical Global Impression Scale, Inventory of Depressive Symptomatology, and Montgomery Asberg Depression Scale . Results: 144 men and 266 women had at least I post randomization visit. Baseline scores on all rating scales were equivalent for men and wome n. Women were more likely than men to discontinue regardless of treatment cond ition. Using a response criterion of ~ SO% decrease in HRS-D , there was a trend for women to be more likely to respond to any active treatment. Compared with men, significantly more women respo nded to sertraline (chi sq = 6.31, P = 0.012). More women respon ded to sertraline than either placebo or imipramine. Using all 4 outcome instruments, the highest response rate to active treatment and the lowest response rate to placebo was among women. There were no significant differences between any active treatme nt and placebo for the men in the study. Conclusion: Women with chronic milder depressions such as dysthymia may have a higher response rates to serotonin reuptake inhibitors.
I5-26-41 -Mood Effects of Hormonal Interventions Comparisons to ConventIonal Antidepressants E.W. Freeman, K. Rickels, S.J. Sondh eimer. Department s of Psychiatry and Obstetrics/Gynecology, University ofPennsylvania, Philadelphia, PA Comparisons of the efficacy of hormonal and anti-depressant medications in treating premenstrual symptoms (PMS) provide insight into the relative importance of hormonal and CNS effects on mood and behavioral symptoms in cycling women . Method: A series of treatment samples in placebo-controlled (progesterone, alprazolam, leuprolide) and open-label studies (desipramine, nefazodone , sertraline, lIuvoxamine) had the same