CLINICAL CHEMISTRY
Psychological Disorders Donald L. Warkentin Department of Pathology, Overlook Hospital, 99 Beauuoir Avenue, Summit, New Jersey 07902-0220 The clinical laboratory has indeed been challenged to aid in the diagnosis, prognosis, and treatment of psychological disorders. One of the major stumbling blocks has been the categorization of the various syndromes and diseases, and although this has improved by using the DSM-IIIR, much work remains (HI-H4). The inabilityto do more researchon the human brain has resulted in a reliance on animal data and the eventual extrapolation to the human system. Although most assays that are performed in the clinical laboratory rely on using peripheral measurements to assess what is hap ening a t the tissue level, this process is further complicatefin mental disorders by the blood-brain barrier. For this reason, the cerebrospinal fluid (CSF) has been a considerable source of information as a "window into the brain", although on a routine basis, it is not likely that these assays will be used, because of the difficulty of obtaining the specimen. Other assays that have been studied include latelet uptake studies with serotonin and imipramine, brain iopsies, . and postmortem analyses ( H 5 - H n . Underlying the evaluation of mental disorders is the increasingly complex nature of the brain. Neurotransmitters such as serotonin, norepinephrine, and dopamine often have multiple receptors scattered throughout the brain (H8, H 9 ) . These receptors exist in different states and can be either up or down regulated, based on the concentration of the neurotransmitters or drugs and/or the underlying disorder (Ha-HI1). The interrelationship between various neurotransmitter-receptor systems is complex and poorly understood. One of the combined affects of the neurotransmitters and their receptors is the modulation of the hypothalamus-pituitary-end organ axes. This review will cover the time period from 1987 to 1992, concentrating on those analytes where there is a significant amount of laboratory data available. The hypothalamus-pituitarythyroid (HPT)axiswill bestudiedbyinvestigatingthethyroid releasing hormone stimulation test (TRH-ST)and additional thyroid function markers (H12-HIn. The hypothalamuspituitary-adrenal (HPA) axis will be looked a t by concentrating on the dexamethasone suppression test (DST) as it relates to a variety of psychological disorders (H13, H18H21). The neurotransmitters serotonin, nore inephrine, somatostatin, and corticotropin releasing factor ( RF)(CRH) will he examined and the various hypotheses explored as they relate to the laboratory data (H6, H8, H21-HZ6).
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THE HYPOTHALAMUS-PITUITARYADRENAL AXIS The dexamethasone suppression test (DST) has been studied for several decades as a measure of the HPA axis in the evaluation of a variety of psychological disorders (H27H31). It hasbeenutilizedinevaluatingpatientswithprimary depression, posttraumatic stress disorder, anorexia nervosa, obsessive comoulsive disorder. and schizoohrenia in addition to depression secondary to &min Blt heficiency, thyroid dysfunction, dementia, cancer, and stroke (H13, H18. H32H 3 4 ~ .Hypercortisdism and the inability of the HPAaxis to suppresscortisol levelsafterexposure todexamethasone have become biochemical markers in the diagnosis, prognosis, and treatment of these diseases. Many patients who show nonsuppression during major depressive episodes will revert to normal suooression when thev have recovered (H35). The DST'& initiated by gihnp; the patient 1 mg of dexamethasone by mouth at 11:W p.m. Blood samples are subvequentlydrawn in varying combinations over t he ensuing 24 h a t 7:OO a.m., 400 p.m., and 11:OO p.m., and cortisol levels are measured. Dexamethasone is a powerful lucocortocoid that will normally suppress the cortisol pro%uction by the adrenals for a period of 24 h to serum values less than 5.0 IH36-H38). If the neeative feedback mechanism is .ueidL working properly, the dexaLethasone will interact with receptors in the pituitary gland, causing a reduction in the release of ACTH, thereby decreasing steroid hiorynt hesis and release from the adrenals. When the cortisol is greater than 5.0 pgldL, the test is considered positive for nonsuppression ~~~~~~
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Donald L Warkentln b Dkecta of Clinical Chemisbyand Laboratmy Developmentat Overlook Hos~italin Summit N.J. He received his 6.A. from Yale University In 1961 and his Ph.D.in biochemisby from Syracuse University in 1972. Alter postdoctoral work at Syracuse Universky. he completeda postdodual training program in cllnicalchemlsbyat TheMedicalCollege of Virginia In 1974. Ha has held posnbns as a Clinical Chemist at Metpath Laboratcfies In Hackensack. KI. from 1974 to 1977 andRollingHillHosptial inElklnsPark.
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(H21). This occurs with sensitivities varying from as low as 8% for anxiety disorders and 13%for schizophrenia to 67 % and 78%. resrtiyely,,for psychoticand mixed bipolar major depression. pecificities vary from 77 % for nonendogenous depression to 93% for major depression, due mainly to the low false positivity rate of 7% in normal patients (H5, H36, H 3 n . Within depression, there is a significant increase in the nonsuppression of cortisol as one proceeds from depressive symptoms to major depression without melancholia, major depression with melancholia, and finally to major depression with psychoses (H13). There are many factors that influence the results of the DST. Dexamethasoneisanexogenoussteroidandis thought to interact only with the pituitary rece tors, in contrast with cortisol, which in addition to its feeBback to the ituitary also hinds to receptors in the hypothalamus. Stucfies have been performed using cortisol as the suppressing steroid, instead of dexamethasone, hut the results have been essentially identical in regard to cortisol levels. It has been shown that @-endorphin,which like ACTH is a breakdown product of the precursor proopiomelanocortin, is not suppressed by cortisol for depressed patients, in contrast to its suppression by dexamethasone (H19). The pharmacokinetics of dexamethasone are not well understood, and levels are not assayed as part of the DST. Some reports suggest that there are differences up to 100-fold between patients and that the resultsoftheDSTvarywiththedexamethasonelevels (H41H44). This is a very important consideration that should be better controlled. Most cortisol assays are performed by radioimmunoassay, although the older competitive binding assays have shown comparable results. Taking allasaaysintoconsiderationfrom a variety of studies, there are only minor differences in nonsuppression rates (H45). Corticosterone has also been measured, instead of cortisol, with virtually the same results (H21). In summary, the DST has been used as an aid in the diagnosis and prognosis of a variety of mental disorders, hut must be used in the overall context of the clinical picture. The test should not be used as a sine qua non diagnostic tool for depression.
THE HYPOTAALAMUS-PITUITARYTHYROID AXIS The hypothalamus-pituitary-thyroid (HPT) axis, including both increases and decreases of various thyroid function testa, hasbeenimplicated indepresaion (H13,H15, H46, H 4 n . I t is of interest to note that elevated basal TSH levelscorrelate with the nonsuppression of cortisol in the DST, suggesting an association of the HPT and HPA axes (H13). Because of the association of the thyroid gland with the metabolic rate, andduetothe fact thereare weightdisturbancesindepression, it is not surprising that some investigators have also found changes in the metabolic rate in depression (H12). Because of the heterogeneity of the clinical symptoms of depression, it is not surprising that there may he multiple causes. The differing results regarding T4 and free T4 levels in depression, i.e., higher, lower, and not different from controls, depending on which study was performed, serve to demonstrate the underlying complexity of thedisease process. ANALYTICAL CHEMISTRY, VOL. 65. NO.
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should certainly be able to differentiate patients in the 3-7 It has been suggested that these types of differences are often punitslml range. based on very subtle changes in a variety of neurotransmitters and that different studies control different variables (H12). The thyrotropin releasing hormone stimulation test (TRHSEROTONIN ST) is a challenge test that has been used as an indication of The serotonergic hypothesis, i.e., relating to the neurons thyroid involvement in patients with depression. Many of which synthesize serotonin, is a plausible explanation for these patients either have abnormal thyroid function tests or have normal thyroid function tests, Le., T4, T3 uptake, and A reduction in several psychological disorders (H59-H62). TSH, yet fail to produce an appropriate TSH response to function of the brain serotonergic neurons is one of the As a corollary to this situation where depression TRH (H48). postulated mechanisms for depression and mania. Other is often first diagnosed and the thyroid function results are psychological disorders that involve serotonin dysfunction abnormal as a secondary finding, patients with rimary include schizophrenia, panic attacks, obsessive compulsive hwothvroidism. Le.. low T4 results and elevated T8Hs. are Because of the innerdisorder, and aggression (H63-H66). vation of the hypothalamus with serotonergic neurons, it is o%en dipressed’“ 4 ) . certainly possible that endocrine function can be regulated To initiate the TRH-ST, 500 pg of TRH is given IV with via the affect of these neurons on the hypothalamwpituitaryblood samdes beinst drawn for TSH levels for 60-120 min at end organ axes. Hormones known to be affected by serotonin varying intervals, Gost commonly every 15 min (H15, H49, release include ACTH, prolactin, renin, vasopressin, and H50). Normal patients will stimulate their TSH values a One of the common approaches in trying oxytocin (H67-H69). minimum of 5 or 7 punits/mL over baseline. Positive to understand the complexities of psychological dysfunction responders are defined as those patients who do not stimulate is to treat the disorder with certain drugs, measure the the TSH more than 5 or 7 punits/mL and in major depression hormones of interest, and identify which receptors are targeted this yields respectively sensitivities of 26-33% versus 50% in the brain; e.g., antidepressants cause a downregulation of and s ecificities of 96-100% versus 90% (H51-H53).It 5HT2 serotonin receptors which in turn affect renin and shoulfbe pointed out that these sensitivity figures are affected vasopressin levels in the blood. by whether the DSM-I11or the Research Diagnostic Criteria for depression are used. The blunting of the TSH response Serotonin is synthesized in the neurons by hydroxylating also occurs in mania, abstinent alcoholics, and anorexia tryptophan to 5-hydroxytryptophan (5-HTP) and decarboxnervosa. Due to the fact that the sensitivity of the TRH-ST ylating 5-HTP to 5-hydroxytryptamine (serotonin), utilizin is no more than 50%, it is not generally recognized as an the enzymes tryptophan hydroxylase (rate-limiting) and There is a ade uate screen for depressive disorders (H54). aromatic acid decarboxylase,respectively. The intraneuronal smJ1 subgroup of atients that have an increased response metabolism, and eventual inactivation, of sertonin proceeds of TSH to the TgH-ST, possibly representing increased via monoamine oxidase and aldehyde reductase to form sensitivity to TSH in the thyroid gland (HSS). This increased 5-hydroxyindoleacetic acid (5-HIAA). This metabolite is sensitivity at the end organ has been postulated in the HPA much more stable than serotonin and is often used to assess axis as an explanation for the elevated cortisol levels seen the As a “window”into the central nervous serotonin levels (H26). DST. system (CNS), cerebrospinal fluid (CSF) has been assa ed Of 250 patients who complained of depression, 8% disfor a number of neurotransmitter metabolites, i n c l d n 5-HIAA in depression. Althou h some studies have reported played hypothyroidism in varying stages and a totalof 7 were lower levels of 5-HIAA in CS%in depression, the results in treated either by thyroid replacement alone or in combination Variables that have with a tricyclic antidepressant. There was no apparent many cases have been inconsistent (H6). not been adequately controlled include time of day, season, corrleation with severity of depression and degree of hygender, weight, e, height, and spinal metabolism of seropothyroidism. Patients who had a rapid cycling bipolar tonin. Addition%y, there is also a poor correlation between disorder showed a 92% correlation with some form of CSF 5-HIAAlevelsand the responseto various antidepressant hypothyroidism, in comparison to nonrapid cyclers who only H71).Thus, in addition to being a difficult medications (H70, showed a 32% prevalence. However, these patients do not specimen to obtain, the CSF 5-HIAA has been ina propriate seem to respond as well to thyroid therapy (H56). for diagnosis and monitoring the treatment of epression. In addition to hyperthyroidism, the following conditions Because of the fact that there are serotonin receptors in can be responsible for false positives: acute starvation, bein male, chronic renal failure, Klinefelter’s syndrome, TRIf platelets as well as brain, several assays have been develo ed administered repeatedly, somatostatin, dopamine, thyroid in platelets, with the assumption that the binding in platereta will reflect what occurs in the CNS. Although this aesumption hormones,and neurotensin. Baseline TSH levels are virtually may not be completely valid, a significant reduction in identical in normals as compared with depressed subjects, even though bluntin does occur in some of the patients in serotonin uptake occurs in major depressive disorders. the latter category. 4he degree to which the TSH is blunted However, due to the large variation within normal patients, does not appear to correlate with the degree of hypothythe test is not a good diagnostic tool and also cannot be used as an indicator for response to medications (H26). roidism, but patients with rolon ed depression tend to blunt their TSH response to TZH wit! a higher frequency. The The tricyclic antidepressant imipramine has been used in underlying cause for a blunted TSH reponse to TRH is not platelet binding assays, with inconsistent results in patients understood from an endocrinological standpoint (HI7). suffering from depression, possibly due to the fact that the Since cortisol levels tend to be higher in depressed patients binding sites are heterogeneous. Studies have also been and because cortisol can reduce the TSH response in normal performed on postmortem brain tissue showing a decline in However, there is some uncerand depressed patients, it was thought that there might be serotonergic activity (H26). tainty as to the affect of premortem medications. Both of a correlation between those patients who had a blunted these approaches to looking at the serotonergic system response and their cortisol levels, although this has not been illustrate the underlying problem of working with brain tissue. shown by several investigators (H57). In the case of imipramine, a drug is being utilized to evaluate Regarding the pharmacokinetics of TRH, the peak cona platelet receptor in vitro, with the hope that it is somehow centrations occurred 2 min after the intravenous infusion at levels ranging from 8.1 to 75.1 ng/mL, in contrast to peak related to its in vivo function in brain tissue. For postmortem evaluation of brain tissue, it is another attempt at a %on in levels in two depressed patients of 104 and 140 ng/mL, vivo” window to evaluate a complex living process. respectively. This would suggest that the receptors in the thyrotrophs (pituitary) are less responsive to TRH, possibly bein downregulated due to a chronic hypersecretion of the NOREPINEPHRINE T R I ~( ~ 1 7 ) . Regardless of which medications were used to treat the The enzymatic synthesis of norepinephrine occurs intraneuronally by the following pathway: tyrosine is converted underlyin depression, there was an apparent correlation between bfunting of the TSH response and recovery, although to 3,4-dihydroxyphenylalanine(DOPA) b the enzyme tyit has been pointed out that this may have been a result of rosine hydroxlyase (rate-limiting) followeg by a conversion to do amine by aromatic amino acid decarboxylase (DOPAdifferent doses of TRH, assay variation in the low ran e of decarioxylase),followed by the roduction of norepinephrine measuring TSH, or medication schedule (H58).The &SH by dopamine-&hydroxylase. &e metabolism and eventual methods that are presently available are quite sensitive and
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inactivation of norepinephrine (NE) occurs by two pathways. The first occurs within the presynaptic neurons; the mitochondrial enzyme monoamine oxidase (MAO)converts NE to its dihydroxymandelic aldehyde, followed in the CNS by subsequent conversion to 3,4dihydroxyphenylglycol (DOPEG) via aldehyde reductase, eventually yielding the final product 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) via the enzyme catechol-0-methyltransferase (COMT). Vanillylmandelic acid (VMA)is also an end product of norepinephrine metabolism in the peripheral nervous system. In the second pathway, COMT catalyzes the conversion of NE to normetanephrine (NM), which is oxidized to an intermediate aldehyde by MAO, finally yielding VMA via an aldehyde dehydrogenase (H26, H72). The original catecholamine hypothesis in 1965stated that there was a functional deficiency of neurotransmitters in depression and excess in manic episodes (H73). This proposal was related to a serendipitous finding that reserpine, an anithypertensive medication,caused depressionas a side effect and also depleted NE levels in tissue (H74). Subsequently, the originalhypothesishas been modified to reflect laboratory findings that were not always consistent with a reduction in neurotransmitter function. When MHPG was analyzed, the laboratory data were inconsistent,showing either no changes,increases,or decreases in depression. This was possibly due to the differences in methodology, from the fluorometric analyses in earlier data to mass spectrophotometic determinations most recently (H26). Other posssibilities for the differences include different patient pools, Le., patients not having the same behavioral changes from one stud to the next, samples being drawn at different times of the d y or year, reflecting wellknown diurnal and annual variations, in addition to the episodicsecretionsof some of the hypothalamic and pituitary hormones and neurotransmitters. In order to resolve some of the above differences in results from one study to the next, it will be necessary to standardize how patients are grouped clinically, i.e., based on behavioral parameters, degree of severityof underlying condition,clinical response to different antidepressant medications, history of reoccurrence of symptoms, etc. From a laboratory standpoint, the specimen becomes critically important, as to how and when it was obtained, particularly regardin time of day, season, posture, activity, which CSF tube, mecfications, fasting, etc. Additionally,the methodology should be standardized and results comparable regardless of whether or not HPLC, GC, mass spectroscopy, or immunoassays were utilized. In studying anxiety and panic attacks, increased levels of NE and MHPG have been found in both CSF and plasma, indicating increased noradrenergic activity, i.e., a functional stimulation of the NE-containing neurons. Not all studies have corroborated these fiidings, with the differencespossibly attributed to venous samples, where muscle metabolism may explain the variability (H75). Urinary MHPG has been used routinely to assess noradrenergicfunction in the brain. Even though it has been known that MHPG is also derived from NE in peripheral tissue, the assumption was that urinary determinations would be useful in grouping patients asto whether or not the MHPG increased, decreased, or stayed the same. Prognosis was in part based on the urinary MHPG response to various medications. During the past few years, attention has become focused on the type of conjugation that occurs with MHPG, specifically the glucuronide and the sulfate. It appears that the primary conjugation product that occurs in the brain is the MHPGsulfate, although approximately half of the total MHPG is free. Therefore, the more specific assay for brain NE metabolism should be the urinary MHPG-sulfate, in contrast to many of the prior studies where MHPG was assayed as a combination of the free and two different bound forms. Additional evidence to support this comes from studies that peripheral sympathetic activity only changes the MHPGlucuronide levels in the urine. The original studies may still e somewhat valid using total urinary MHPG to monitor treatment, because the difference in levels before and after medication would be attributable to MHPG-sulfate, only if the mechanism of action occurred in the brain and not in the peripheral tissues as well (H75, H76).
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SOMATOSTATIN Somatostatin,the growth hormone release-inhibitingfactor (GHR-IF), is a tetradecapeptide that is found widely distributed in brain tissue, with the highest concentrationsfound in the hypothalamus (H22,H230). Its receptors are scattered throughout the brain, and in addition to its inhibitory action on growth hormone, it appears to have a eneral inhibitory affect on a variety of hormones such as TSIf CRF, and ACTH (H77). Somatostatin is derived from prosomatostatin and preprosomatostatin, with the additional presence of other somatostatin peptides involved in its overall metabolism (H78-HBl). If in fact some of these other pe tides are found in the CSF or peripheral circulation, it wille! important to determine their ratios in normal and pathologic specimens. CSF somatostatin levels have provided much of the information regardin the association of somatostatin with psychological disorhrs. As with other analytes in the CSF, the assumption is made that the somatostatin originates in the brain. The CSF in Alzheimer’s disease shows a decrease in somatostatin-14 and an increase in the 15-kDa precursor, indicating a probable posttranslational modification (H82). There are some reports showing that the degree of cognitive im airment is inverselyrelated to the CSF somatostatinlevels, an$ upon treatment and imprownent in these patients, the CSF somatostatin levels are increased. Other than in the depressed patients, where the results are similar to Alzheimer’s disease, there are inconsistent fiidin s in other psychological disorders (H23). The fact that the iifferences between the control oups and depressed patients are more marked when the C S f i s analyzed on morning samples suggests a disturbance in the circadian rhythm, a finding suggested by other reports, rather than the total somatostatin secretion. Administration of somatostatin into the CNS increases learning andmemory, whereas a reduction reverses these affects (H83). Increased levels of CSF somatostatin are observed in destructive neurological disorders such as tumors, spinal cord disease, nerve root compression, meningitis, and metabolic encephalopathy and should be ruled out as false negatives when the test is evaluated (H84). CORTICOTROPIN-RELEASING FACTOR Corticotropin-releasingfactor (CRF) (CRH) is a 41 amino acid eptide that stimulates the pituitary release of ACTH, 8-en orphin, etc., from the prohormone proopiomelanocortin. CRF itself is a product of a prohormone cleavage and, in addition to bein found in many different areas of the brain, is alsorecognizef by s ecific receptors in these locations (H24, H25). Because of e!t lack of suppression of cortisol by dexamethasone and also hi her baseline blood cortisollevels, it is not surprising that ChF levels in CSF and plasma are elevated in depression (H85-H87). Specifically, the CRF levels are more elevated in those patients who are dexamethasone nonsu ressors than in the su pressor subpopulation. ElevatefERF has also been found% CSF in anorexia nervosa, but not in schizophrenic patients (HBB-HM). In addition to direct assays of CRF and plasma, CRF has been administeredto atients as challenge tests, with resulting measurements of ACFH. A normal response to intravenous CRF would be an increase in the peripheral ACTH, but in de ressed patients and atients with panic disorder, the A8TH response is blunted! The mechanism for this is tho ht to be a downregulation of the pituitary receptors for 8 F due to a chronic exposure of these receptors to CRF. Additionall , it is thought that the adrenals might respond more to A8TH in depressed patients versus the normal controls (H25). As is the case with both the dexamethasone suppression test and the TRH stimulation test, the pharmacokinetics of the administered compound, in this case CRF, is not well understood and may in fact explainwhy some patients reapond and others do not. With CRF, since it is formed from a prohormone, it will be important to determine levels of all CRF-related eptides in both CSF and plasma. The ma’ority of these stulies are performed in CSF, but it would be informative and certainly easier to do if plasma assays were readily available. It becomes apparent from the information presented that the laboratory’s involvement in diagnosing and monitoring
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psychological disorders is a small but owing one. The vast amount of data that has become avaiEble from neurotransmitter and hormone assa s of the CSF and blood will some day be better understood( For the present, there is a need for sensitive neurotransmitter assays in the peripheral circulation,so that the cumbersome spinal tap will not be a deterrent for a particular assay. Many of the tests that were discussedare not even availablein the reference laboratories, much less to the average clinical laboratory. Although not much success has occurred with the geneticmapping of mental disorders, this would ap ear to be an area that could unravel some of the conflicting fata in the literature. In this regard, it will be interesting to see how some of the present work with schizophrenia and manic-depressive illness progresses over the next few years. LITERATURE CITED (Hl) van Praap. H. Neruopsychobbb# 1989, 22, 181-193. (H2)Nutt,D. phemwl. Ther. 1990,47,233-288; Chem. Abstr. 1990. 7 7321): 188946s. (H3) Gottfrles, C. 0. J. Newoscl. Res. 1990,27,541-547; Chem. Abstr. 1990, 7 749):79409u. (H4)Gold, P. W.; Goodwln, F. K.; Chrousos, M. D. New€ngl. J. M.1988,379, 348-353. (H5) Schnelder, L. S.; Chui, H. C.; Severson, J. A.; Sloane, R. B. BW. Psychlaby 1988, 24, 348-351. (H6)Grahame-Smlth,D.G. ActaPsychlatr. Sand. 1989, 80(Suppl. 350), 7-12. (H7) Hrdlna, P. D. Inf. J. Clln. Rwm. Res. 1989, 42), 119-122. (Ha) Meltzer, H. Y. Ann. N.Y. A a d . Sd. 1990, 800, 486-500. (HP)PIaznlk,A.; Kostowski, W.; Archer. T. Rog.Neumpsyctwphamwl. BW, PsYChlaby1989, 73, 623-833; Chem. Ab&. 1989, 777(19): 171773~. (HIO) Seeman, P.; Nlznik, H. B. FASEB J. 1990, 4, 2737-2744; Chem. Abstr. 1990, 71313): 1130981. (Hll) Fuxe, K.; Agnatl, L. F.; von Euk, 0.; Tanganelli, S.; O'Connor, W. T.; Ferre, S.; Hediund, P.; 2011, M. Newochem. Inf. 1992, 20, (Suppl.), 215s 2245; chem. Ab&. 1992, 778(21): 211993~. (H12) Zach, J.; Ackerman, S. H. Psychosomtk Med. 1988, 50, 454-488. (Hl3) Evans, D. L.; Stern, R. A.; Golden, R. N.; Haggetly, J. J.; Perklns, D. 0.; Slmon, J. S.; Nemeroff, C. B. Pmg. Psychlaby 1991, 29, 279-298. (H14) Nemeroff, C. B.; Evans, D. L. Ann. N.Y. A a d . Scl. 1989, 553,304-310. (H15)Arana,G.;Zarzar,M. N.; Baker,E. E&/. Psychlaby1990,28(8), 733-737. (H18) Rothschild, A. J. M.Clln. North Am. 1988, 7a4), 765-790. (H17) Loosen, P. T. Endocrfnol. Mefab. clln. North Am. 1988, 77(1), 55-82. (H18)Yshuda,R.; Olller, E. L.; Southwick, S. M.; Lowy, M. T.; Mason, J. W. Bbl. Psychlaby 1991, 30, 1031-1046. (H19)Qlspen-De-Wled,C. C.; Westenberg, H. G. M.; Thussen, J. H. H.; van Ree, J. M. Psydwlnewoendocrtn~l987.72(5), 355-386; Chem. Ab&. 1987, 7041 1): 92588~. (H20) McCracken, J. T.; Rubin, R. T.; Poland, R. E. PsychlabyRes. 1988,26(1), 69-78; Chem. Absfr. 1988, 77q5): 37373q. (H21) Arana, 0. W.; Mossman, D. Endocrfnol. Mefab. Clln. North Am. 1988, 77(1), 21-39. (H22) Rublnow, D. R.; Davls, C. L.; Post, R. M. Rog. New-Psyctwphamwl. Psychlaby1988,72(Suppl.), 51374155 Chem.Abstr. 1988, 7 7 7(3):17779~. (H23) Rublnow, D. R.; Post, R. M.; Davis, C. L. Rog. Psychlaby 1991. 29, 29-49. (H24) Bond, P. E.; Owens, M.J.; Butler, P. D.; Blssette, G; Nemeroff, C. B. UCLA Symp. Mol. Cell. Bbl. New Ser. 1989, 97, 87-78. (H25) von Bardeleben, U.; Holsboer, F. Rog. Newo-Psyctwphamwl. Bbl. Psychlaby 1988, 72 (Suppl.), 5185-5187; Chem. Abstr. 1988, 777(3): 17781~. (H26) Caldecott-Hazard, S.; Morgan, D. E.; DeLeonJones. F.; Overstreet, D. H.; Janowsky. D. Synapse 1991, 44), 251-301. (H27) Carroll, B. J. J. Clln. Psychlaby 1985, 46, 13-24. (H28) Rubin, R. T.; Poland. R. E. B h ~ b ~ IPsychiatry: a l~. Recent Sfudles:John . ~bbey:London, 1984. (H29) Asnls. 0. M.; Sachar, E. J.; Halbrelch, U.; et el. Am J. Psychlaby 1981, 738, 1218-1221. (H30) Brown, W. A.; Johnston, R.; Mayfleld, D. Am. J. Psychlaby 1979, 736, 543-547. (H31) Stokes, P. E.; Stoll, P. M.; Mattson, M. R.; et ai. /+omones, Behaviorend PsYdwpathdogy, Raven Press: New York, 1976 pp 225-229. (H32) GwMsman, H.; Gerner, R. BW. Psychlsby 1981, 76, 991-995. (H33) Insel, T. R.; Kalln. N. H.; Guttmacher, L. 8.; Cohen, R. M.; Murphy, D. L. Psychlaby Res. 1982, 6, 153-160. (H34) Dewan. J. M.; Pandurangi, A. K.; Boucher, M. L.; Levy, B. F.; MaJor, L. F. Am J. Psychlaby 1982, 77, 1501-1503. (H35) Evans, D. L.; Nemeroff, C. B. Am. J. Psychlaby1984, 747, 1485-1467. (H38) Asteldt, V. H. Acfa Endowlno/. Sand. 1989, 67, 219-231. (H37) Keiler-Wood, M. E.; Dallman, M. F. €ndocrfnology 1984, 5, 1-24. (H38) Kraus, R. P.; Hux, M.; &of, P. Am. J. Psychhby 1987. 744. 82-85. (H39) Arana. G. W.; Baldessarlni, R. J.; Ornsteen, M. Arch. Gen. Psy&&by 1985, 42, 1193-1204.
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