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Temperament and pharmacological response in depression
5-22 New Advances in the Biology of Corticosteroid Receptors: Relevance to Development, Neurotransmission and Behaviour
I8-21-41 Tempera.ment and Pharmacological Response in DepreSSion
H.S. Akiskal. Department of Psychiatry, University of California, San Diego, USA Standard psychopharmacologic methodology typically mandates comparing response rates of clinically depressed patients to new compounds versus placebo versus a reference antidepressant. Clinicians, however, are interested to know whether different types of antidepressants could be useful in specified subtypes of depression. Such efforts have generally failed to convince the research establishment; there seems to be meager data, if any, to argue for selectivity of certain antidepressants for "agitated", "melancholic", "dysthymic", "atypical", "retarded", or "even "bipolar" depressives. Building on a retrospective analysis of clinical databases, the present paper presents the hypothesis that commonly observed clinical phenomenologic subtypes of depression - double-depressive, anxious, bipolar II, pseudo-unipolar, hostile, and psychotic - arise from diverse temperamental bases and respond differentially to TCAs, MAOIs, SSRls, bupropion, lithium, anticonvulsants, and neuroleptic.
1
8-21-51 Clinical Predictions of Response to Treatments in MoodDisorders
S.A. Montgomery. Department of Psychiatry, Imperial College of Science, Technology and Medicine, London The core symptoms of depression have been shown to correlate with different severities of depression and to be sensitive to treatment with effective agents. These symptoms were defined by sensitivity studies in the development of rating scales such as the MADRS but there are other important issues. The duration of illness is probably important. Brief depressions do not apparently respond to antidepressants whereas those with a more prolonged duration of around a month or longer do. In major depression the severity cut-offs which predict response have been investigated by several groups and a survey of results suggests that scores of around 15 or higher predict response. In dysthymia or chronic depression these are lower which suggests that chronicity itself is an important factor in predicting a reliable drug placebo difference.
83
functions. Mice with a disrupted mineralocorticoid receptor gene die approximately one week after birth with severe kidney dysfunction. [I] ColeTJ, Blendy JA,Monaghan AP, Kriegelstein K, Schmid W. Aguzzi A, FantuzziG, Hummler E, Unsicker K.Schiiitz G. Genes Dev. 9 (1995), 1608-1621.
1
8-22-21 Brain Corticosteroid Receptors and Stress System Disorders
E.R. de Kloet. Division ofMedical Pharmacology, LACDR, Leiden University, Leiden, The Netherlands A fundamental question in stress research is when stress hormones stop being essential for survival and become damaging to health. Why some individuals suffer from stress, while others under the same conditions do not, is another important question. How stress triggers the expression of noxious genetic information is also unresolved, and which genes are involved is unknown. New insights in the biology of receptors for the stress hormones, i.e. the corticosteroid hormone receptors, may provide the answer to these questions. These answers are relevant for development of new leads towards intervention in pathogenesis of stress system disorders. Here we will discuss briefly 5 approaches commonly used to further understand the function of brain corticosteroid receptors in protection and damage of the hippocampus, a brain structure involved in regulation of mood and cognition. These approaches include: (i) Genetic selection of rat lines with extreme differences in coping with stress, (ii) Generation of mutants by transgenesis and ablation of genetic risk factors, (iii) Programming of brain stress circuitry by traumatic early life events, (iv) Screening for corticosteroid responsive genes in brain, (v) Blockade of receptor function by selective receptor antagonists. The outcome of experiments using these approaches suggests that a dysbalance in brain corticosteroid receptor types (mineralocorticoid and glucocorticoid receptors) increases vulnerability to disease. Supported by the Netherlands Organization for Scientific Research (NWO) grants 546-092; 100-007 and 554-45.
I
8-22-3 1 Regeneration and Inactivation of Bioactive Corticosteroids: Windows for Neuro-Pharmaceuticallntervention
Z.S. Krozowski, Baker Medical Research Institute, Melbourne, 1
5-221 New Advances in the Biology of Corticosteroid Receptors: Relevance to Development, Neurotransmission and Behaviour
I 8-22-1 I Consequences of Corticosteroid Receptor Ablation TJ. Cole 1, I.A. Blendy, A.P. Monaghan, K. Krieglstein, S. Berger, W. Schmid, K. Unsicker, G. Schutz. German Cancer Research Center, lm Neuenheimer Feld 280,69120 Heidelberg, Germany; 1 Present address: Baker Medical Research Institute, Commercial Rd., Prahran, 3181, Australia To understand the role of glucocorticoid signaling during development and in the adult, we disrupted the glucocorticoid receptor and mineralocorticoid receptor gene by homologous recombination in mouse embryonic stem cells. Most mice with a disrupted glucocorticoid receptor gene die within the first hours after birth due to severe atelectasis of the lungs, possibly resulting from deficient surfactant synthesis [I]. Regulation of glucocorticoid synthesis via the hypothalamic-pituitary-adrenal axis is perturbed leading to increased corticosterone and ACTH levels, and extensive hypertrophy and hyperplasia of the adrenal cortical zones. The adrenal medulla is severely reduced in size: no cells capable of epinephrine synthesis can be detected. A small number GR-ablated mice survive and are currently being analysed for alterations in higher brain
Australia.
The enzyme l l d-hydroxysteroid dehydrogenase type I (l1.8HSDl) is a bidirectional enzyme which is thought to inactive glucocorticoids in the brain, and to convert the biologically inactive cortisone to cortisol in the liver with micromolar Km. In contrast, II.8HSD2 is a unidirectional glucocorticoid inactivating enzyme with a low nanomolar Km for its substrate. It has been shown to confer specificity on the mineralocorticoid receptor in peripheral tissues, and may play an important role centrally given that intracerebroventricular administration of enzyme inhibitors has been shown to produce hypertension [J]. Mutations in the HSDIIB2 gene give rise to the syndrome of apparent mineralocorticoid excess, a congenital condition characterized by sodium retention, low-renin hypertension, and often by growth retardation. The II.8HSD2 enzyme has previously been localized immunohistochemically to the distal nephron and vascular smooth muscle cells, and more recently to a wide range of sodium transporting epithelia in man. In situ studies in the rat have demonstrated message for J I.8HSD1 in the hippocampus, hypothalamus and cortex, and for ll.8HSD2 in the commissural portion of the nucleus tractus solitarius, subcommissural organ and ventrolateral medial hypothalamus [2]. While the physiological consequences of these enzymes in many peripheral tissues is now well known it remains to be determined whether their central actions modulate blood pressure, salt appetite and the hypothalarno-pituitary-adrenal axis. [I] Gomez-Sanchez et a!. AmJ Physio!. 263, EI 125 (1992) [2] Roland et a!.Endocrino!. 136,4697 (1995)
I8-21-41 Tempera.ment and Pharmacological Response in DepreSSion
H.S. Akiskal. Department of Psychiatry, University of California, San Diego, USA Standard psychopharmacologic methodology typically mandates comparing response rates of clinically depressed patients to new compounds versus placebo versus a reference antidepressant. Clinicians, however, are interested to know whether different types of antidepressants could be useful in specified subtypes of depression. Such efforts have generally failed to convince the research establishment; there seems to be meager data, if any, to argue for selectivity of certain antidepressants for "agitated", "melancholic", "dysthymic", "atypical", "retarded", or "even "bipolar" depressives. Building on a retrospective analysis of clinical databases, the present paper presents the hypothesis that commonly observed clinical phenomenologic subtypes of depression - double-depressive, anxious, bipolar II, pseudo-unipolar, hostile, and psychotic - arise from diverse temperamental bases and respond differentially to TCAs, MAOIs, SSRls, bupropion, lithium, anticonvulsants, and neuroleptic.
1
8-21-51 Clinical Predictions of Response to Treatments in MoodDisorders
S.A. Montgomery. Department of Psychiatry, Imperial College of Science, Technology and Medicine, London The core symptoms of depression have been shown to correlate with different severities of depression and to be sensitive to treatment with effective agents. These symptoms were defined by sensitivity studies in the development of rating scales such as the MADRS but there are other important issues. The duration of illness is probably important. Brief depressions do not apparently respond to antidepressants whereas those with a more prolonged duration of around a month or longer do. In major depression the severity cut-offs which predict response have been investigated by several groups and a survey of results suggests that scores of around 15 or higher predict response. In dysthymia or chronic depression these are lower which suggests that chronicity itself is an important factor in predicting a reliable drug placebo difference.
83
functions. Mice with a disrupted mineralocorticoid receptor gene die approximately one week after birth with severe kidney dysfunction. [I] ColeTJ, Blendy JA,Monaghan AP, Kriegelstein K, Schmid W. Aguzzi A, FantuzziG, Hummler E, Unsicker K.Schiiitz G. Genes Dev. 9 (1995), 1608-1621.
1
8-22-21 Brain Corticosteroid Receptors and Stress System Disorders
E.R. de Kloet. Division ofMedical Pharmacology, LACDR, Leiden University, Leiden, The Netherlands A fundamental question in stress research is when stress hormones stop being essential for survival and become damaging to health. Why some individuals suffer from stress, while others under the same conditions do not, is another important question. How stress triggers the expression of noxious genetic information is also unresolved, and which genes are involved is unknown. New insights in the biology of receptors for the stress hormones, i.e. the corticosteroid hormone receptors, may provide the answer to these questions. These answers are relevant for development of new leads towards intervention in pathogenesis of stress system disorders. Here we will discuss briefly 5 approaches commonly used to further understand the function of brain corticosteroid receptors in protection and damage of the hippocampus, a brain structure involved in regulation of mood and cognition. These approaches include: (i) Genetic selection of rat lines with extreme differences in coping with stress, (ii) Generation of mutants by transgenesis and ablation of genetic risk factors, (iii) Programming of brain stress circuitry by traumatic early life events, (iv) Screening for corticosteroid responsive genes in brain, (v) Blockade of receptor function by selective receptor antagonists. The outcome of experiments using these approaches suggests that a dysbalance in brain corticosteroid receptor types (mineralocorticoid and glucocorticoid receptors) increases vulnerability to disease. Supported by the Netherlands Organization for Scientific Research (NWO) grants 546-092; 100-007 and 554-45.
I
8-22-3 1 Regeneration and Inactivation of Bioactive Corticosteroids: Windows for Neuro-Pharmaceuticallntervention
Z.S. Krozowski, Baker Medical Research Institute, Melbourne, 1
5-221 New Advances in the Biology of Corticosteroid Receptors: Relevance to Development, Neurotransmission and Behaviour
I 8-22-1 I Consequences of Corticosteroid Receptor Ablation TJ. Cole 1, I.A. Blendy, A.P. Monaghan, K. Krieglstein, S. Berger, W. Schmid, K. Unsicker, G. Schutz. German Cancer Research Center, lm Neuenheimer Feld 280,69120 Heidelberg, Germany; 1 Present address: Baker Medical Research Institute, Commercial Rd., Prahran, 3181, Australia To understand the role of glucocorticoid signaling during development and in the adult, we disrupted the glucocorticoid receptor and mineralocorticoid receptor gene by homologous recombination in mouse embryonic stem cells. Most mice with a disrupted glucocorticoid receptor gene die within the first hours after birth due to severe atelectasis of the lungs, possibly resulting from deficient surfactant synthesis [I]. Regulation of glucocorticoid synthesis via the hypothalamic-pituitary-adrenal axis is perturbed leading to increased corticosterone and ACTH levels, and extensive hypertrophy and hyperplasia of the adrenal cortical zones. The adrenal medulla is severely reduced in size: no cells capable of epinephrine synthesis can be detected. A small number GR-ablated mice survive and are currently being analysed for alterations in higher brain
Australia.
The enzyme l l d-hydroxysteroid dehydrogenase type I (l1.8HSDl) is a bidirectional enzyme which is thought to inactive glucocorticoids in the brain, and to convert the biologically inactive cortisone to cortisol in the liver with micromolar Km. In contrast, II.8HSD2 is a unidirectional glucocorticoid inactivating enzyme with a low nanomolar Km for its substrate. It has been shown to confer specificity on the mineralocorticoid receptor in peripheral tissues, and may play an important role centrally given that intracerebroventricular administration of enzyme inhibitors has been shown to produce hypertension [J]. Mutations in the HSDIIB2 gene give rise to the syndrome of apparent mineralocorticoid excess, a congenital condition characterized by sodium retention, low-renin hypertension, and often by growth retardation. The II.8HSD2 enzyme has previously been localized immunohistochemically to the distal nephron and vascular smooth muscle cells, and more recently to a wide range of sodium transporting epithelia in man. In situ studies in the rat have demonstrated message for J I.8HSD1 in the hippocampus, hypothalamus and cortex, and for ll.8HSD2 in the commissural portion of the nucleus tractus solitarius, subcommissural organ and ventrolateral medial hypothalamus [2]. While the physiological consequences of these enzymes in many peripheral tissues is now well known it remains to be determined whether their central actions modulate blood pressure, salt appetite and the hypothalarno-pituitary-adrenal axis. [I] Gomez-Sanchez et a!. AmJ Physio!. 263, EI 125 (1992) [2] Roland et a!.Endocrino!. 136,4697 (1995)