- Email: [email protected]
Research strategies at the interface of medicine and psychiatry
Research Strategies at the Interface of Medicine and Psychiatry David R. Rubinow, M.D. Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland
Abstract: The rapid growth of the neurosciences in the past decade has served to blur the differences and enhance the similarities between research in medicine and in psychiatry. As the number of relevant biological variables and the questions asked in relation to them has expanded, so has the number of medical disorders of interest to the clinical researcher in psychiatry. In addition to these new areas of common interest, consultation-liaison psychiatry and clinical psychiatric research share a common conceptual foundation based upon model development and testing.It is proposed, therefore, that research at the interface between medicine and psychiatry represents a new frontier for both consultation-liaison psychiatry and clinical psychiatric research. Goals and strategies for research at the interface are discussed with specific reference to current research efforts at the National Institutes of Health.
Consultation liaison psychiatry and clinical psychiatry research are related disciplines to the extent that both rely heavily on explanatory models. Research, in fact, is very much a process of model building and model testing and, thus, shares a common conceptual foundation with consultation- liaison psychiatry. Given this orientation, the medical disorders that we are in the process of studying provide not rival explanatory paradigms for depression or psychosis, but rather models that are manipulable and capable of teaching us about psychiatric syndromes that, in all likelihood, represent common pathways of expression for a variety of disorders. The demonstration in clincial medicine of a number of disorders (in addition to the classical endocrinopathies) that have relevance to psychiatry is in many ways the natural outgrowth of the expanding scope of psychiatric research over the last 20 years. General Hospital Psychiatry
5, W-103, 1983 0 EIsevier Science Publishing Co., Inc. 1983 52 Vanderbilt Avenue, New York, NY 10017
This expanded scope reflects an increase in the number of relevant biological variables studied, in the types of studies performed, including dynamic studies to clarify mechanisms of physiological regulation, and in our ability to observe and identify possible roles for these biological variables in symptom development and modulation. In psychoendocrine studies today, for example, a fairly impressive number of biological variables are being examined. While 20 years ago psychoendocrine studies were largely confined to adrenal and thyroid activity, we are now very actively engaged in examining the psychological and behavioral activities of a whole host of neuropeptides that are localized in discrete regions throughout the brain and appear to have profound effects on a variety of different behaviors. While disturbances in the activity of these neuropeptides have classically been associated with “medical conditions,” they are clearly of relevance to psychiatric studies as they relate to and dramatically affect learning and behavior in animals, and perhaps in humans, and as they relate to or reflect changes of state in psychiatric disorders. For example, two disorders of interest to psychiatric researchers are diabetes insipidus and Cushing’s disease, involving dysregulation of arginine vasopressin and cortisol, respectively. Both vasopressin and cortisol affect cognitive processing (l-3), and, in common with another hormone, somatostatin, both display state-related alterations in their activity in affective illness (4-6). This then represents an extension of the number of variables that we are studying in behavioral research currently. A second expansion of the scope of psychiatric 99
ISSN 0163~8343/83/.$3.00
D. R. Rubinow research derives from the observation that a peptide examined under stimulated conditions may display abnormalities not apparent during basal observation. This is represented clinically by the TIU-I stimulation test, with a variable percentage of depressed patients reported as manifesting a blunted thyroid stimulating hormone response to thyrotropin releasing hormone stimulation despite normal basal levels of TSH, T,, and T,(7,8). While 20 years ago static measurements of basal hormone concentrations were performed, we now challenge the system in order to detect evidence of dysregulation that would otherwise remain unobserved. Thus, we become involved in basic physiology and pose questions such as, “How does the system work?” and “What are the regulatory processes that influence the variables under study?” Finally, as a product of the morphological revolution of the 1960s and a renewed interest in descriptive psychiatry, we recognize that psychiatric syndromes are in fact syndromes characterized by rather dramatic and widespread systemic dysfunction. Depression then is clearly not simply a disorder of mood, but is, as well, a disorder of a variety of physiological processes and behaviors, including appetite, sleep, activity, pleasure, cognition, and circadian rhythm, among others. While there may not be a single convincing biochemical explanation for the syndrome, there may in fact be physiological or endocrinological concomitants of certain symptoms of these syndromes that may increase our understanding of the etiopathogenesis of the symptoms. For example, in a recent study (6) we found that CSF somatostatin appears significantly and inversely correlated with duration of sleep in patients with affective disorders. This is fully consistent with the arousal properties of somatostatin as described in a number of animal studies (9, lo), and we are currently attempting to confirm this finding with EEG recordings. Thus, not only does the number of variables that we consider expand, but we become more interested in the juncfioning and physiology of these variables as well as how they interact with the specific symptoms of the syndromes under study. Rather than just looking at the syndrome as an indivisible entity, we recognize it as a complex disorder reflecting dysfunction in a variety of different systems. If we were capable of identifying these sources of dysfunction, we might ultimately be able to more fully understand the pathophysiology of psychiatric disturbances. Lest I give the impression that we are interested in studying these disorders through a conviction 100
that biological variables unilaterally account for behavior, it is important that I mention the work of Friedman, Wolff, and Mason (11,12). They very effectively demonstrated the profoundly interactive relationship between biological and behavioral processes where the meaning of events clearly played a role in determining the biological response. They observed that parents of children with leukemia display a spectrum of cortisol values from high to quite low and further that those who had high cortisol tended to react to stress by elevufing their cortisol while those who had low cortisol tended to react by diminishingtheir cortisol. The factor that seemed to best identify those people who responded to stress by lowering their cortisol was the effective utilization of denial. Thus, they were able to demonstrate that there was no standard endocrine response to stress because stress was largely an interpretive phenomenon. The work done by Grau et al. (13), Visintainer et al. (14), and Weiss et al. (15) with learned helplessness and inescapable shock has convincingly demonstrated the powerful effect of the perception of loss of control on a variety of biological measures, including opiate activation, noradrenergic regulation, and tumor rejection. As a final demonstration of the impact of psychological and perceptual activities on biological function, Mason (16) reported that if you observed small, closely organized groups of subjects, within a relatively short period of time each group demonstrated remarkably little variation in their urinary 17-hydroxycoricosteroid levels. The intergroup variation of mean 17-hydroxycorticosteroids, however, remained quite high. This suggests the potential impact of group process on biological entrainment, a phenomenon also described in terms of synchronization of menstrual cycles in women in college dormitories (17). The bidirectional nature of the interaction between biochemical processes on one hand and cognitive, affective and perceptual processes on the other hand suggests that consultation-liaison research may play a critical role in future attempts to uncover the pathophysiological mechanisms of a multitude of medical disorders. Given the current complexity of the field, how can we best conceptualize the different goals of interface research, and what specific strategies can we employ? There are three types of studies that we are currently performing. First, we can perform phenomenological studies describing the psychological response to illness, i.e., how do people react when they have an illness? What is their ill-
Research Strategies
ness behavior? As an example of this first type of phenomenological study, we are interviewing and administering psychiatric symptom self-rating forms longitudinally to patients with cystic acne who are admitted to Dr. Gary Peck’s Cystic Acne Program at the National Cancer Institute. Patients are seen before, during, and following treatment with isotretonoin, a vitamin A derivative that is extraordinarily efficacious in the treatment of cystic acne (18). By so doing, we hope to better appreciate the impact of a disfiguring illness and its treatment on patients in terms of their ability to function, their self-image, and their self ratings of depression and anxiety. This study has interesting implications not only in terms of understanding illness behavior or the behavioral response to illness, but as well in increasing the awareness of physicians of the psychiatric concomitants of a variety of medical disorders, i.e., they can learn to anticipate which difficulties their patients will experience and how best to deal with them. Additionally, this study may also provide information to help refute or confirm the postulated psychoactive properties of vitamin A (19). A second type of phenomenological study we perform describes the psychological or behavioral symptoms that are part of the illness and that are a direct expression of the disease process rather than a response to the illness. This type of study can both develop a behavioral vocabulary for describing certain illnesses and also has the potential to uncover some of the pathophysiological mechanisms involved in psychiatric disorders. An example of this approach is a study investigating the incidence of depression and manic-depressive disorder in Type V hyperlipidemia. This study is based on clinical observations of NHLBI physicians who have noted that a large number of people with this specific type of hyperlipidemia present with depressed and/or manic symptoms. An opportunity exists, therefore, to expand the descriptive phenomenology of a disease entity as well as to hopefully uncover clues as to the pathogenesis of certain behavioral symptoms. This potential etiopathogenetic commonality is emphasized in the third type of study investigating the relationship between biochemical abnormalities and psychiatric symptoms in a medical illness that characteristically presents with psychiatric symptoms. The objective is to illuminate the pathophysiological mechanisms involved in the development of similar symptoms in traditional psychiatric disorders. One example of this is the work that Drs. Gold
and Becker are pursuing with Cushing’s patients. (See paper in this special section.) We have examined cognitive functioning in depression on the affective disorder unit and have determined that a large number of depressed patients experience profound cognitive deficits as measured by the Halstead Categories Test (20), and further that the number of errors committed on the Halstead Categories Test is significantly correlated with the level of mean urinary free cortisol excreted (21). Disorder of the cortisol system at this time appears to be found in about 50% of patients with depression (22). This figure, however, is somewhat in question, as it reflects utilization of only one measure of pituitary-adrenal activity, the dexamethasone suppression test, which is not sensitive to all forms of hypothalamic-pituitary-adrenal dysregulation (23). What is the relationship between the elevated cortisol and the cognitive deficit that we see in depression? Is the hypercortisolemia of etiological relevance, or is it an associated disorder of no causal significance, but perhaps reflecting, as does the cognitive disorder, a fundamental dysregulation produced by a more central CNS lesion? One way to attempt to answer these questions is to use a disorder that has elevated cortisol as a model. Cushing’s disease is the obvious candidate since it often presents with rather dramatic neuropsychiatric disturbances, including depression and cognitive defects that usually take the form of word finding disorders, lack of attention, concentration and memory (24,25). We are currently attempting to determine whether the neuropsychiatric disturbances in Cushing’s disease are state or trait properties and what relationship they manifest to plasma and urinary free cortisol values. In addition to the three types of studies already mentioned, we also have the opportunity to perform a number of related pharmacological and phenomenological investigations. We can observe and describe behavioral effects attendant upon the use of a wide spectrum of new and investigational pharmacological agents. We can attempt to determine the effect of the premenstruum on the mood and cognition of women who complain of mood disturbances as well as its effect on symptom exacerbation in patients with periodic disorders as, for example, seizures or angioedema. The NIH Clinical Center is a particularly fertile ground for the development of an interface research program. First, the NIH is a tertiary care facility, thus, one can readily gain exposure to patients with a variety of diverse and often esoteric 101
D. R.
Rubinow
illnesses who appear in large enough numbers to permit the accumulation of meaningful ns. Secondly, research is the coin of the realm at the NIH. Therefore, patients expect to participate in research and view themselves rightfully as collaborators. Third, the machinery for performing research, from protocol review committees to nursing raters, is largely in place. Additionally, we are able to capitalize on this research opportunity for our consultation liaison service by initiating research meetings to generate hypotheses, design research methodologies, coordinate the collection of behavioral ratings and circadian and endocrine measures, and to review and organize clinical and research data. We can, in fact, tap the richness of the Clinical Center by utilizing it as a huge research ward in which we will be able to generate and answer a number of specific questions. As we attempt to employ many of the fascinating disease processes that we see as probes, we will enhance our understanding of the illnesses with which we deal and additionally provide information that may lead to the production of more homogenous diagnostic groupings or result in identification of new therapeutic agents. Simultaneously, we increase the level of awareness of many of our medical colleagues as to the critical importance of behavioral and mood disturbances as symptoms that must receive attention for both therapeutic and theoretical reasons. In sum, good research and good clinical care are complementaryand mutually reinforcing enterprises. Therefore, I hope that, at the very least, the development of interface research in consultation-liaison psychiatry serves to open an exciting and challenging chapter in the continued unfolding of the neurobiology of psychiatric disturbances.
References 1. Weingartner H, Gold PW, Ballenger JC, Smallberg SA, Summers R, Rubinow DR, Post RM, Goodwin FK: Effects of vasopressin on human memory functions. Science 211:601-603, 1981 2. Gold PE: Hormonally-mediated noradrenergic modulation of memory processes. In Usdin E, Kopin IJ, Barchas J (eds). Fourth International Catecholamine Symposium. New York, Pergamon Press, 1978, pp 1714-1716 3. Carpenter WT Jr, Gruen PH: Cortisol’s effects on human mental functioning. J Clin Psychopharmacol 2:91-101, 1982 4. Gold PW, Rubinow DR, Post RM, Ballenger JC: CSF vasopressin function in affective illness. Submitted to Arch Gen Psychiatry, 1982 5. Rubinow DR, Post RM, Gold PW, Ballenger JC, Wolff EA: The relationship between cortisol and clinical 102
6.
7.
8.
9.
phenomenology of affective illness. In Post RM, Ballenger JC (eds). Neurobiology of the Mood Disorders. Baltimore, Williams and Wilkins, 1982. In press Rubinow DR, Gold PW, Post RM, Ballenger JC, Cowdry R: Somatostatin in patients with affective illness and in normal volunteers. In Post RM, Ballenger, JC (eds). Neurobiology of the Mood Disorders. Baltimore, Williams and Wilkins, 1982. In press Prange AJ Jr, Wilson IC, Lara PP, Alltop LB, Breese GR: Effects of thyrotropin-releasing hormone in depression. Lancet 11:999-1002, 1972 Loosen ET, Prange AJ Jr, Wilson IC, Lara PP: Pituitary responses to thyrotropin releasing hormone in depressed patients: A review. Pharmacol Biochem Behav 5:95-101, 1976 Rezek M, Havlicek V, Hughes KR, Friesen H: Cortical administration of somatostatin (SRIF): Effect on sleep and motor behavior. Pharmacol Biodhem Behav
5~73-77, 1976
10. Havlicek V, Rezek M, Friesen H: Somatostatin and thyrotropin releasing hormone: Central effect on sleep and motor system. Pharmacol Biochem Behav 4~455-459, 1976 11. Friedman SB, Mason JW, Hamburg DA: Urinary 17hydroxycorticosteroid levels in parents of children with neoplastic disease. Psychosom Med 25:364-376, 1963 12. Wolff CT, Friedman SB, Hofer, MA, Mason JW: Relationship between psychological defenses and mean urinary 17-OHCS excretion rates. I. A predictive study of parents of fatally ill children. Psychosom Med 26:576-591, 1964 13. Grau JW, Hyson RL, Maier SF, Madden J IV, Barchas JD: Long-term stress-induced anal esia and activa213:1409-1411, tion of the opiate system. Scien 1981 $ 14. Visintainer MA, Volpicelli JR, Sehgman NEP: Tumor rejection in rats after inescapable or escapable shock. Science 216:437-439, 1982 15. Weiss JM, Stone EA, Harrell M: CoRing behavior and brain norepinephrine level in rats. J Comp Physiol Psycho1 72:153-160, 1970 16. Mason J: Psychological influences on the pituitaryadrenal cortical system. Recent Prog Horm Res 15:345-389, 1959 17. McClintock MK: Menstrual synchrony and suppression. Nature 229:244-245, 1971 18. Peck GL, Olsen TG, Yoder FW, Stauss JS, Downing DT, Pandya M, Butkus D, Arnaud-Battandier J: Prolonged remissions of cystic and conglobate acne with 13-CIS-retinoic acid. N Engl J Med 300:329-333,1979 19. Windhorst DB, Nigra T: General clinical toxicology of oral retinoids. J Am Acad Dermatol6:675-682, 1982 20. Savard RG, Rey AC, Post RM: Halstead-Reitan Category Test in bipolar and unipolar affective disorders. J Nerv Ment Dis 168:297-304, 1980 21. Rubinow DR, Post RM, Savard RS, Gold PW: Relationship between cortisol secretion and a measure of cognitive dysfunction in affective illness. Unpublished manuscript. 22. Carroll BJ, Curtis JC, Mendels J: Neuroendocrine regulation in depression. II. Discrimination of depressed from nondepressed patients. Arch Gen Psychiatry 33:1051-1058, 1976
Research Strategies
23. Asnis GN, Sachar EJ, Dackis CA, Halbreich U, Mathan RS, Halpem FS: The dexamethasone suppression test (DST) and cortisol hyersecretion in endogenous depression. Abstract, Psychoneuroendocrinology Symposium, McMaster University, Hamilton, Ontario, Canada, June 1981 24. Carroll BJ: Psychiatric disorders and steroids. In
Usdin E, Hamburg DA, Barchas JD (eds). Neuroregulators in Psychiatric Disorders. New York, Oxford University Press, 1977, pp. 276-283 25. Starkman MN, Schteingart OE, Schonk MA: Depressed mood and other psychiatric manifestations of Cushing’s Syndrome: Relationship to hormone levels. Psychosom Med 43:3-18, 1981
103
Abstract: The rapid growth of the neurosciences in the past decade has served to blur the differences and enhance the similarities between research in medicine and in psychiatry. As the number of relevant biological variables and the questions asked in relation to them has expanded, so has the number of medical disorders of interest to the clinical researcher in psychiatry. In addition to these new areas of common interest, consultation-liaison psychiatry and clinical psychiatric research share a common conceptual foundation based upon model development and testing.It is proposed, therefore, that research at the interface between medicine and psychiatry represents a new frontier for both consultation-liaison psychiatry and clinical psychiatric research. Goals and strategies for research at the interface are discussed with specific reference to current research efforts at the National Institutes of Health.
Consultation liaison psychiatry and clinical psychiatry research are related disciplines to the extent that both rely heavily on explanatory models. Research, in fact, is very much a process of model building and model testing and, thus, shares a common conceptual foundation with consultation- liaison psychiatry. Given this orientation, the medical disorders that we are in the process of studying provide not rival explanatory paradigms for depression or psychosis, but rather models that are manipulable and capable of teaching us about psychiatric syndromes that, in all likelihood, represent common pathways of expression for a variety of disorders. The demonstration in clincial medicine of a number of disorders (in addition to the classical endocrinopathies) that have relevance to psychiatry is in many ways the natural outgrowth of the expanding scope of psychiatric research over the last 20 years. General Hospital Psychiatry
5, W-103, 1983 0 EIsevier Science Publishing Co., Inc. 1983 52 Vanderbilt Avenue, New York, NY 10017
This expanded scope reflects an increase in the number of relevant biological variables studied, in the types of studies performed, including dynamic studies to clarify mechanisms of physiological regulation, and in our ability to observe and identify possible roles for these biological variables in symptom development and modulation. In psychoendocrine studies today, for example, a fairly impressive number of biological variables are being examined. While 20 years ago psychoendocrine studies were largely confined to adrenal and thyroid activity, we are now very actively engaged in examining the psychological and behavioral activities of a whole host of neuropeptides that are localized in discrete regions throughout the brain and appear to have profound effects on a variety of different behaviors. While disturbances in the activity of these neuropeptides have classically been associated with “medical conditions,” they are clearly of relevance to psychiatric studies as they relate to and dramatically affect learning and behavior in animals, and perhaps in humans, and as they relate to or reflect changes of state in psychiatric disorders. For example, two disorders of interest to psychiatric researchers are diabetes insipidus and Cushing’s disease, involving dysregulation of arginine vasopressin and cortisol, respectively. Both vasopressin and cortisol affect cognitive processing (l-3), and, in common with another hormone, somatostatin, both display state-related alterations in their activity in affective illness (4-6). This then represents an extension of the number of variables that we are studying in behavioral research currently. A second expansion of the scope of psychiatric 99
ISSN 0163~8343/83/.$3.00
D. R. Rubinow research derives from the observation that a peptide examined under stimulated conditions may display abnormalities not apparent during basal observation. This is represented clinically by the TIU-I stimulation test, with a variable percentage of depressed patients reported as manifesting a blunted thyroid stimulating hormone response to thyrotropin releasing hormone stimulation despite normal basal levels of TSH, T,, and T,(7,8). While 20 years ago static measurements of basal hormone concentrations were performed, we now challenge the system in order to detect evidence of dysregulation that would otherwise remain unobserved. Thus, we become involved in basic physiology and pose questions such as, “How does the system work?” and “What are the regulatory processes that influence the variables under study?” Finally, as a product of the morphological revolution of the 1960s and a renewed interest in descriptive psychiatry, we recognize that psychiatric syndromes are in fact syndromes characterized by rather dramatic and widespread systemic dysfunction. Depression then is clearly not simply a disorder of mood, but is, as well, a disorder of a variety of physiological processes and behaviors, including appetite, sleep, activity, pleasure, cognition, and circadian rhythm, among others. While there may not be a single convincing biochemical explanation for the syndrome, there may in fact be physiological or endocrinological concomitants of certain symptoms of these syndromes that may increase our understanding of the etiopathogenesis of the symptoms. For example, in a recent study (6) we found that CSF somatostatin appears significantly and inversely correlated with duration of sleep in patients with affective disorders. This is fully consistent with the arousal properties of somatostatin as described in a number of animal studies (9, lo), and we are currently attempting to confirm this finding with EEG recordings. Thus, not only does the number of variables that we consider expand, but we become more interested in the juncfioning and physiology of these variables as well as how they interact with the specific symptoms of the syndromes under study. Rather than just looking at the syndrome as an indivisible entity, we recognize it as a complex disorder reflecting dysfunction in a variety of different systems. If we were capable of identifying these sources of dysfunction, we might ultimately be able to more fully understand the pathophysiology of psychiatric disturbances. Lest I give the impression that we are interested in studying these disorders through a conviction 100
that biological variables unilaterally account for behavior, it is important that I mention the work of Friedman, Wolff, and Mason (11,12). They very effectively demonstrated the profoundly interactive relationship between biological and behavioral processes where the meaning of events clearly played a role in determining the biological response. They observed that parents of children with leukemia display a spectrum of cortisol values from high to quite low and further that those who had high cortisol tended to react to stress by elevufing their cortisol while those who had low cortisol tended to react by diminishingtheir cortisol. The factor that seemed to best identify those people who responded to stress by lowering their cortisol was the effective utilization of denial. Thus, they were able to demonstrate that there was no standard endocrine response to stress because stress was largely an interpretive phenomenon. The work done by Grau et al. (13), Visintainer et al. (14), and Weiss et al. (15) with learned helplessness and inescapable shock has convincingly demonstrated the powerful effect of the perception of loss of control on a variety of biological measures, including opiate activation, noradrenergic regulation, and tumor rejection. As a final demonstration of the impact of psychological and perceptual activities on biological function, Mason (16) reported that if you observed small, closely organized groups of subjects, within a relatively short period of time each group demonstrated remarkably little variation in their urinary 17-hydroxycoricosteroid levels. The intergroup variation of mean 17-hydroxycorticosteroids, however, remained quite high. This suggests the potential impact of group process on biological entrainment, a phenomenon also described in terms of synchronization of menstrual cycles in women in college dormitories (17). The bidirectional nature of the interaction between biochemical processes on one hand and cognitive, affective and perceptual processes on the other hand suggests that consultation-liaison research may play a critical role in future attempts to uncover the pathophysiological mechanisms of a multitude of medical disorders. Given the current complexity of the field, how can we best conceptualize the different goals of interface research, and what specific strategies can we employ? There are three types of studies that we are currently performing. First, we can perform phenomenological studies describing the psychological response to illness, i.e., how do people react when they have an illness? What is their ill-
Research Strategies
ness behavior? As an example of this first type of phenomenological study, we are interviewing and administering psychiatric symptom self-rating forms longitudinally to patients with cystic acne who are admitted to Dr. Gary Peck’s Cystic Acne Program at the National Cancer Institute. Patients are seen before, during, and following treatment with isotretonoin, a vitamin A derivative that is extraordinarily efficacious in the treatment of cystic acne (18). By so doing, we hope to better appreciate the impact of a disfiguring illness and its treatment on patients in terms of their ability to function, their self-image, and their self ratings of depression and anxiety. This study has interesting implications not only in terms of understanding illness behavior or the behavioral response to illness, but as well in increasing the awareness of physicians of the psychiatric concomitants of a variety of medical disorders, i.e., they can learn to anticipate which difficulties their patients will experience and how best to deal with them. Additionally, this study may also provide information to help refute or confirm the postulated psychoactive properties of vitamin A (19). A second type of phenomenological study we perform describes the psychological or behavioral symptoms that are part of the illness and that are a direct expression of the disease process rather than a response to the illness. This type of study can both develop a behavioral vocabulary for describing certain illnesses and also has the potential to uncover some of the pathophysiological mechanisms involved in psychiatric disorders. An example of this approach is a study investigating the incidence of depression and manic-depressive disorder in Type V hyperlipidemia. This study is based on clinical observations of NHLBI physicians who have noted that a large number of people with this specific type of hyperlipidemia present with depressed and/or manic symptoms. An opportunity exists, therefore, to expand the descriptive phenomenology of a disease entity as well as to hopefully uncover clues as to the pathogenesis of certain behavioral symptoms. This potential etiopathogenetic commonality is emphasized in the third type of study investigating the relationship between biochemical abnormalities and psychiatric symptoms in a medical illness that characteristically presents with psychiatric symptoms. The objective is to illuminate the pathophysiological mechanisms involved in the development of similar symptoms in traditional psychiatric disorders. One example of this is the work that Drs. Gold
and Becker are pursuing with Cushing’s patients. (See paper in this special section.) We have examined cognitive functioning in depression on the affective disorder unit and have determined that a large number of depressed patients experience profound cognitive deficits as measured by the Halstead Categories Test (20), and further that the number of errors committed on the Halstead Categories Test is significantly correlated with the level of mean urinary free cortisol excreted (21). Disorder of the cortisol system at this time appears to be found in about 50% of patients with depression (22). This figure, however, is somewhat in question, as it reflects utilization of only one measure of pituitary-adrenal activity, the dexamethasone suppression test, which is not sensitive to all forms of hypothalamic-pituitary-adrenal dysregulation (23). What is the relationship between the elevated cortisol and the cognitive deficit that we see in depression? Is the hypercortisolemia of etiological relevance, or is it an associated disorder of no causal significance, but perhaps reflecting, as does the cognitive disorder, a fundamental dysregulation produced by a more central CNS lesion? One way to attempt to answer these questions is to use a disorder that has elevated cortisol as a model. Cushing’s disease is the obvious candidate since it often presents with rather dramatic neuropsychiatric disturbances, including depression and cognitive defects that usually take the form of word finding disorders, lack of attention, concentration and memory (24,25). We are currently attempting to determine whether the neuropsychiatric disturbances in Cushing’s disease are state or trait properties and what relationship they manifest to plasma and urinary free cortisol values. In addition to the three types of studies already mentioned, we also have the opportunity to perform a number of related pharmacological and phenomenological investigations. We can observe and describe behavioral effects attendant upon the use of a wide spectrum of new and investigational pharmacological agents. We can attempt to determine the effect of the premenstruum on the mood and cognition of women who complain of mood disturbances as well as its effect on symptom exacerbation in patients with periodic disorders as, for example, seizures or angioedema. The NIH Clinical Center is a particularly fertile ground for the development of an interface research program. First, the NIH is a tertiary care facility, thus, one can readily gain exposure to patients with a variety of diverse and often esoteric 101
D. R.
Rubinow
illnesses who appear in large enough numbers to permit the accumulation of meaningful ns. Secondly, research is the coin of the realm at the NIH. Therefore, patients expect to participate in research and view themselves rightfully as collaborators. Third, the machinery for performing research, from protocol review committees to nursing raters, is largely in place. Additionally, we are able to capitalize on this research opportunity for our consultation liaison service by initiating research meetings to generate hypotheses, design research methodologies, coordinate the collection of behavioral ratings and circadian and endocrine measures, and to review and organize clinical and research data. We can, in fact, tap the richness of the Clinical Center by utilizing it as a huge research ward in which we will be able to generate and answer a number of specific questions. As we attempt to employ many of the fascinating disease processes that we see as probes, we will enhance our understanding of the illnesses with which we deal and additionally provide information that may lead to the production of more homogenous diagnostic groupings or result in identification of new therapeutic agents. Simultaneously, we increase the level of awareness of many of our medical colleagues as to the critical importance of behavioral and mood disturbances as symptoms that must receive attention for both therapeutic and theoretical reasons. In sum, good research and good clinical care are complementaryand mutually reinforcing enterprises. Therefore, I hope that, at the very least, the development of interface research in consultation-liaison psychiatry serves to open an exciting and challenging chapter in the continued unfolding of the neurobiology of psychiatric disturbances.
References 1. Weingartner H, Gold PW, Ballenger JC, Smallberg SA, Summers R, Rubinow DR, Post RM, Goodwin FK: Effects of vasopressin on human memory functions. Science 211:601-603, 1981 2. Gold PE: Hormonally-mediated noradrenergic modulation of memory processes. In Usdin E, Kopin IJ, Barchas J (eds). Fourth International Catecholamine Symposium. New York, Pergamon Press, 1978, pp 1714-1716 3. Carpenter WT Jr, Gruen PH: Cortisol’s effects on human mental functioning. J Clin Psychopharmacol 2:91-101, 1982 4. Gold PW, Rubinow DR, Post RM, Ballenger JC: CSF vasopressin function in affective illness. Submitted to Arch Gen Psychiatry, 1982 5. Rubinow DR, Post RM, Gold PW, Ballenger JC, Wolff EA: The relationship between cortisol and clinical 102
6.
7.
8.
9.
phenomenology of affective illness. In Post RM, Ballenger JC (eds). Neurobiology of the Mood Disorders. Baltimore, Williams and Wilkins, 1982. In press Rubinow DR, Gold PW, Post RM, Ballenger JC, Cowdry R: Somatostatin in patients with affective illness and in normal volunteers. In Post RM, Ballenger, JC (eds). Neurobiology of the Mood Disorders. Baltimore, Williams and Wilkins, 1982. In press Prange AJ Jr, Wilson IC, Lara PP, Alltop LB, Breese GR: Effects of thyrotropin-releasing hormone in depression. Lancet 11:999-1002, 1972 Loosen ET, Prange AJ Jr, Wilson IC, Lara PP: Pituitary responses to thyrotropin releasing hormone in depressed patients: A review. Pharmacol Biochem Behav 5:95-101, 1976 Rezek M, Havlicek V, Hughes KR, Friesen H: Cortical administration of somatostatin (SRIF): Effect on sleep and motor behavior. Pharmacol Biodhem Behav
5~73-77, 1976
10. Havlicek V, Rezek M, Friesen H: Somatostatin and thyrotropin releasing hormone: Central effect on sleep and motor system. Pharmacol Biochem Behav 4~455-459, 1976 11. Friedman SB, Mason JW, Hamburg DA: Urinary 17hydroxycorticosteroid levels in parents of children with neoplastic disease. Psychosom Med 25:364-376, 1963 12. Wolff CT, Friedman SB, Hofer, MA, Mason JW: Relationship between psychological defenses and mean urinary 17-OHCS excretion rates. I. A predictive study of parents of fatally ill children. Psychosom Med 26:576-591, 1964 13. Grau JW, Hyson RL, Maier SF, Madden J IV, Barchas JD: Long-term stress-induced anal esia and activa213:1409-1411, tion of the opiate system. Scien 1981 $ 14. Visintainer MA, Volpicelli JR, Sehgman NEP: Tumor rejection in rats after inescapable or escapable shock. Science 216:437-439, 1982 15. Weiss JM, Stone EA, Harrell M: CoRing behavior and brain norepinephrine level in rats. J Comp Physiol Psycho1 72:153-160, 1970 16. Mason J: Psychological influences on the pituitaryadrenal cortical system. Recent Prog Horm Res 15:345-389, 1959 17. McClintock MK: Menstrual synchrony and suppression. Nature 229:244-245, 1971 18. Peck GL, Olsen TG, Yoder FW, Stauss JS, Downing DT, Pandya M, Butkus D, Arnaud-Battandier J: Prolonged remissions of cystic and conglobate acne with 13-CIS-retinoic acid. N Engl J Med 300:329-333,1979 19. Windhorst DB, Nigra T: General clinical toxicology of oral retinoids. J Am Acad Dermatol6:675-682, 1982 20. Savard RG, Rey AC, Post RM: Halstead-Reitan Category Test in bipolar and unipolar affective disorders. J Nerv Ment Dis 168:297-304, 1980 21. Rubinow DR, Post RM, Savard RS, Gold PW: Relationship between cortisol secretion and a measure of cognitive dysfunction in affective illness. Unpublished manuscript. 22. Carroll BJ, Curtis JC, Mendels J: Neuroendocrine regulation in depression. II. Discrimination of depressed from nondepressed patients. Arch Gen Psychiatry 33:1051-1058, 1976
Research Strategies
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