Stress Neurobiology and Corticotropin-Releasing Factor

Sponsored by CME LLC for 1.5 Category 1 credits. Original release date 09/06. Approved for CME credit through August 2007. Educational Objectives: After reading this article, you will be familiar with: The evidence linking hypothalamicpituitary-adrenal axis abnormalities andpsychiatric symptoms. The role of corticotropin-releasing factor(CRF) in depressed patients. Extrahypothalamic CRF circuits and theirimpact on depression. Who will benefit from reading this article? Psychiatrists, primary care physicians,neurologists, nurse practitioners, psychiatricnurses, and other mental health care professionals.Continuing medical education creditis available for most specialties. To determinewhether this article meets the CE requirementsfor your specialty, please contact yourstate licensing board. Dr Gutman is a resident in the department of psychiatry;Ms Gutman is an MD, PhD candidate; Dr Owens is associateprofessor in the department of psychiatry and behavioralsciences and associate director of the laboratoryof neuropsychopharmacology; and Dr Nemeroff isReunette W. Harris Professor and chair of the departmentof psychiatry and behavioral sciences at Emory UniversitySchool of Medicine in Atlanta. Dr Gutman and Ms Gutman report that they are consultantsfor WebMD. Dr Owens reports that he has receivedresearch grants from Pfizer, GlaxoSmithKline, Merck, andLundbeck. He is a consultant for Bristol-Myers Squibb,Cielo Institute, Cypress Bioscience, Pfizer, Lundbeck,Sepracor, and Johnson & Johnson, and he has receivedspeaker's honoraria from Forest Laboratories, Glaxo-SmithKline, and Pfizer. Dr Nemeroff reports that he hasreceived research grants from the American Foundationfor Suicide Prevention (AFSP), AstraZeneca, Bristol-MyersSquibb, Forest Laboratories, Janssen, National Alliancefor Research on Schizophrenia and Depression, NIMH,Pfizer, and Wyeth. He is a consultant for Abbott Laboratories,Acadia Pharmaceuticals, Bristol-Myers Squibb,Corcept Therapeutics, Cypress Bioscience, Cyberonics,Eli Lilly, Entrepreneurs Fund, Forest Laboratories, Glaxo-SmithKline, i3 DLN, Janssen, Lundbeck, Otsuka, Pfizer,Quintiles, UCB, and Wyeth. He is on the SpeakersBureau for Abbott Laboratories, GlaxoSmithKline,Janssen, and Pfizer. In addition, he is a stockholder inAcadia Pharmaceuticals, Corcept Therapeutics, CypressBioscience, and NovaDel Pharma; and on the Board ofDirectors of AFSP, the American Psychiatric Institute forResearch and Education, the George West MentalHealth Foundation, NovaDel Pharma, and the NationalFoundation for Mental Health; and he holds equity inReevax, BMC-JR LLC, and CeNeRx. This work was supported in part by MH-58922 (SylvioO. Conte Center for the Neuroscience of Mental Disorders)and MH-42088. The concept that stressful life events mayrender one vulnerable to psychiatric diseasehas been a mainstay of the psychiatric literaturefor more than a century. This idea wasinitiated, in part, by the pioneering work of SigmundFreud,who used psychoanalytic methods to explorethe relationship between stressful life events andpsychopathology. These concepts slowly evolvedinto more biologically based theories with the earlywork of Hans Selye, who studied the relationshipbetween stress, illness, and emotions. The occurrenceof depression, anxiety, and other psychiatricsymptoms in both Cushing and Addison diseases,which are associated with excessive or markedlyreduced levels of circulating glucocorticoids, respectively,served as a further impetus for researchersto scrutinize hypothalamic-pituitary-adrenal (HPA)axis function in psychiatric disorders. HPA axis abnormalitiesin depression Evidence linking HPA axis abnormalities and psychiatricsymptoms dates back over 100 years, andnumerous studies have been conducted in this area.Some of the earliest controlled clinical studies inpsychiatry, dating back to the 1950s, demonstrateda number of abnormalities in glucocorticoid (ie, cortisol)function in depressed patients, including elevatedplasma cortisol concentrations,1,2 increased 24-hoururinary free cortisol concentrations, and increasedlevels of cortisol metabolites in urine.3 Elevated cortisolsecretion in depression is among the most reproduciblefindings in all of biologic psychiatry. Structural changes in the components of the HPAaxis have also been documented in depressedpatients, including pituitary gland enlargementdemonstrated by MRI4 and enlargement of the adrenalglands, presumably due to adrenocorticotropichormone (ACTH) hypersecretion in depressedpatients postmortem5,6 and in suicide victims.7 Theadrenal gland enlargement seen in depression hasbeen confirmed using MRI, and it appears to bestate-dependent,8,9 waxing and waning in parallelwith exacerbation and resolution of depressivesymptoms, respectively. Corticotropin-releasing factor Although Saffran and colleagues10 identified a crudeextract that promoted the release of ACTH from thepituitary in 1955, the ultimate regulator of ACTHand cortisol release--corticotrophin-releasing factor(CRF)--was not isolated and chemically characterizeduntil 1981. Working with extracts derivedfrom 500,000 sheep hypothalami, Vale andcolleagues11 at the Salk Institute isolated, synthesized,and elucidated the structure of CRF. Thisdiscovery led to the availability of synthetic CRF,which allowed for a comprehensive assessment ofthe HPA axis. Based on findings from numerousstudies, it is clear that CRF coordinates the endocrine,immune, autonomic, and behavioral responses ofmammals to stress (Figure).12,13 In the hypothalamus, CRF is synthesized primarilyin the parvocellular neurons of the paraventricularnucleus (PVN). These PVN CRF neurons receive input from a variety of brain regions, includingthe amygdala, the bed nucleus of the stria terminalis,and the brain stem.14 Hypothalamic CRFcontainingneurons project to the median eminence.15 In response to stress, this neural circuit becomesactivated, thereby releasing CRF from medianeminence nerve terminals into the hypothalamohypophysealportal system, where it activates CRFreceptors on corticotrophs in the anterior pituitaryto promote the synthesis of pro-opiomelanocortinand the release of its major posttranslation products,ACTH and .-endorphin. ACTH, released fromthe anterior pituitary, stimulates the production andrelease of cortisol from the adrenal cortex. Thesesame hypothalamic CRF neurons also project to thespinal cord16 and brainstem nuclei,17 including thelocus caeruleus (LC), the major noradrenergicnucleus in the brain.18 Shortly after the isolation and characterizationof CRF, a standardized intravenous CRF stimulationtest was developed to assess HPA axis activity.In this paradigm, CRF is administered intravenously(usually at a dose of 1 µg/kg or a fixeddose of 100 µg) and the ACTH and cortisol responsesare measured at 30-minute intervals over a 2- to3-hour period.19 Numerous studies have now documenteda blunted ACTH and ß-endorphin responseto exogenously administered ovine CRF or humanCRF in depressed patients compared with nondepressedpersons; the cortisol response in depressedpatients and nondepressed control subjects did notconsistently differ.20-24 It has been hypothesized that the attenuatedACTH response to CRF is due to chronic hypersecretionof CRF from nerve terminals in the medianeminence,which results in down-regulation of CRFreceptors in the anterior pituitary, and/or to chronichypercortisolemia and its associated negative feedback.CRF receptor down-regulation results in areduced responsivity of the anterior pituitary toCRF, as repeatedly demonstrated in laboratoryanimals.25-29 Two CRF receptor subtypes, CRF1 and CRF2,with distinct anatomic localization and receptor pharmacology,have been identified in rats andhumans.11,14,15 Both receptors are G-protein coupledreceptors (GPCRs) and are positively coupled toadenylyl cyclase via the protein Gs. The CRF1 receptoris predominantly expressed in the pituitary, cerebellum,and neocortex in the rat.30 Considerableevidence from laboratory animal studies has shownthat CRF1 receptors may specifically mediate someof the anxiogenic-like behaviors observed afteradministration of CRF.31-34 In agreement with these findings, mice withtargeted knockouts of the CRF1 receptor were foundto have an impaired stress response.35 The CRF1receptor knockout mice were less anxious than theirwild-type litter mates when tested in the elevatedplus maze, a paradigm commonly used to assessanxiety-like behavior. In addition, data in these transgenicmice showed a significant reduction in stressinducedrelease of ACTH and corticosterone. CRF2 receptor knockout mice have also beengenerated.36,37 Deletion of the CRF2 receptor geneduring development provided an ambiguous profile,showing increased anxiety in some but not all anxietytasks36,37: in males, but not females37; in malesand females36; or not at all.38 Thus these studiessuggest CRF2 receptor blockade may lead to statesof increased anxiety, although it is likely that boththe environment and the genetic background onwhich the knockouts were bred significantly contributeto the behavioral phenotype of these animals. Research using selective CRF2 receptor agonistsand antagonists has been even more inconsistent.Several studies have used the selective CRF2 receptorantagonist antisauvagine-30 (ASV-30),39 whichhas been reported to be between 100- and 1000-fold selective for the CRF2 receptor, depending onwhether the radiolabeled ligand is sauvagine39 orASV-30,40 respectively. Intraseptal administration ofASV-30 was shown to reduce anxious behaviorinduced by immobilization stress in the plus mazetask or by previous association with foot shock inmice.41 These behavioral data were corroborated inrats, where intracerebroventricular ASV-30 reducedanxious behavior in the plus maze, defensive withdrawal,and a conditioned anxiety paradigm.32,42 Selective agonists at the CRF2 receptor have alsobeen discovered. The peptides urocortin II and urocortinIII are structurally and ancestrally related toCRF but show between 100- and 1000-fold selectivityat the CRF2 receptor versus the CRF1 receptor.43,44Urocortin III has been shown to mildly suppresslocomotion and has an anxiolytic-like profile inmice.45 However, another study from the same groupdemonstrated that urocortin II was inactive in themice in the plus maze after acute administration butincreased their exploratory behavior in the plus maze4 hours later. Thus, compounds reported to be bothselective agonists and antagonists at the CRF2 receptorhave shown anxiolytic-like effects, makingthe exact role of this receptor in modulating stress-inducedbehaviors ambiguous. Extrahypothalamic CRFcircuits and depression Although initially investigated for its role as one ofthe key modulators of the HPA axis, further researchhas revealed that CRF controls not only the neuroendocrinebut also the autonomic, immune, and behavioralresponses to stress in mammals. Results fromboth clinical studies and a rich body of literatureconducted primarily in rodents and lower primateshas highlighted the importance of extrahypothalamicCRF neurons.12,46,47 In rodents, primates, andhumans, CRF and its receptors have been heterogeneouslylocalized in a variety of regions, includingthe amygdala, thalamus, hippocampus, and prefrontalcortex, among others.48-51 These brain regionsare important in regulating many aspects of the mammalianstress response and affect. The presence of CRF receptors in both the dorsalraphe and LC, the origin of the major serotonergicandnoradrenergic-containing perikarya, respectively,also deserves comment because most availableantidepressants, including the tricyclics and SSRIs,are believed to act via modulation of the serotonergicand/or noradrenergic systems. The neuroanatomicproximity of CRF and monoaminergicsystems provides evidence for an interaction betweenCRF systems and antidepressants, thereby suggestinga mechanism by which antidepressants may effectthe CRF system. The involvement of extrahypothalamic CRFsystems in the pathophysiology of depression issuggested by numerous studies that have demonstratedelevated CRF concentrations in the cerebrospinalfluid (CSF) of depressed patients,52-56 althoughdiscrepant results have been reported.57 Elevated CSFCRF concentrations have also been detected indepressed suicide victims.55 A reduction in concentrationsof CRF in CSF has been reported in healthyvolunteers treated with the tricyclic antidepressantdesipramine58 and in depressed patients followingtreatment with fluoxetine59 or amitriptyline,60 providingfurther evidence of an interconnection betweenantidepressants, monoamine neurons, and CRFsystems. Similar effects have been reported afterelectroconvulsive therapy in depressed patients.59,61 Elevated CSF CRF concentrations appear to representa state, rather than a trait, marker of depression(ie, a marker of current depression rather thana marker of vulnerability to depression).61 Furthermore,high and/or increasing CSF CRF concentrationsdespite symptomatic improvement of majordepression during antidepressant treatment may bea harbinger of early relapse.62 Elevated CSF concentrationsof CRF are believed to be due to CNS neuronalCRF hypersecretion,63 which may be actingat sites throughout the brain and contribute to manyof the behaviors characteristic of depression. Consistent with altered concentrations of CRFfound in clinical studies of depression, CRF bindingsite density and messenger RNA (mRNA) expressionhave shown alterations in both preclinicaland clinical studies, presumably in response tochanges in CRF availability. Our group has previouslyreported a marked (23%) reduction in thenumber of CRF binding sites in the frontal cortexof suicide victims compared with controls64; we havenow replicated this finding in a second study. Twolater studies demonstrated an increase in CRFmRNAexpression in the PVN of depressed patientscompared with controls.65,66 Increased CRF mRNA and decreased CRF1mRNA have also been detected in the brains ofsuicide victims in subregions of the frontal cortex.67Although conducted in different laboratories and ondifferent tissue, and keeping in mind the relativedifficulty in obtaining and analyzing human tissue,the general pattern of increased CRF concentrationsand/or CRF mRNA and the relative decrease in CRFbinding sites is consistent with the well-documentedphenomenon of receptor up- and down-regulation. While the exact mechanism contributing to CRFhyperactivity remains obscure, studies from ourgroup and others have documented long-term persistentincreases in HPA axis activity and extrahypothalamicCRF neuronal activity after exposure toearly untoward life events, for example, neglect andchild abuse, respectively, in both laboratory animals(rats and nonhuman primates) and patients.68,69 Earlylife stress apparently permanently sensitizes the HPAaxis and extrahypothalamic CRF neurons and leadsto a greater risk of depression developing later inlife. In several paradigms, early sensitization of CRFsystems results in heightened responses to stresslater in life. To measure HPA axis responsivity to stress inhumans, the Trier Social Stress Test (TSST) wasdeveloped. This laboratory paradigm involves a simulated10-minute public speech and a difficult mentalarithmetic task. The TSST has been validated as apotent activator of the HPA axis in humans.70Recently, our group reported increased HPA axisresponsivity (ie, elevated plasma ACTH and cortisolconcentrations), presumably due to hypersecretionof CRF, after exposure to the TSST in bothdepressed and nondepressed women who wereexposed to severe physical and emotional traumaas children.71 These data provide evidence that CRFsystems are particularly sensitive to the effects ofearly adverse life events. Small-molecule CRF antagonists Although space constraints do not permit an extensivereview of the preclinical literature, several additionalpoints are worth noting. Findings from numerousstudies have shown that when CRF is directlyinjected into the CNS of laboratory animals it produceseffects reminiscent of the cardinal symptomsof depression, including decreased libido, reducedappetite, weight loss, sleep disturbances, andneophobia.13 Certainly by the late 1980s, a numberof research groups, including our own, had hypothesizedthat a lipophilic, small-molecule CRF receptorantagonist that readily penetrates the blood-brainbarrier after oral administration would represent anovel class of antidepressant and/or anxiolyticagents. CRF1 receptor antagonists have elicited activityin animal models of anxiety and depression. CRFreceptor antagonists have been tested in many differentparadigms, including the elevated plus maze,foot shock, restraint stress, and defensive withdrawal.Pretreatment with CRF receptor antagonists decreasesmeasures of anxiety induced by stressors.There is also some evidence that CRF receptor antagonistsmay reduce the effects of drug withdrawaland stress-induced relapse to drug seeking inrats.47,72-74 Based on this premise, newly developedCRF1 receptor antagonists represent a novel putativeclass of antidepressants. Such compounds showactivity in nearly every preclinical screening test forantidepressants and anxiolytics. Despite the rich preclinical and clinical literaturesupporting a potential role for CRF1 receptorantagonists, there has only been 1 published studyinvestigating the effects of a CRF1 receptor antagonistin humans. A small open-label study examiningthe effectiveness of R121919, a CRF1 receptorantagonist, in major depression was completed morethan 5 years ago.75 This study of 20 patients showedthat R121919 (5 to 40 mg/d or 40 to 80 mg/d for30 days) was well tolerated by patients and did notsignificantly affect plasma ACTH or cortisol concentrationsat baseline or following CRF challenge. Itis important that the use of any potential CRF antagonistnot lead to complete HPA axis blockade andadrenal insufficiency, which can, of course, resultin a severe medical emergency. Hamilton DepressionRating Scale and Hamilton Anxiety Scale severityscores were both significantly reduced following30-day treatment with this drug. Although this smallopen-label study does not provide unequivocalproof, it does provide further evidence that a selec-tive CRF-receptor antagonist may provide antidepressantand antianxiety properties in humans.75Although this drug is no longer in clinical developmentbecause of hepatotoxicity, several novel CRF1antagonists are currently under investigation. Conclusions and future directions Since the discovery of CRF more than 25 years ago,evidence has accumulated indicating a preeminentrole for this peptide in the pathophysiology of depressionand anxiety. The recent introduction ofsmall-molecule CRF receptor antagonists as a novelclass of antidepressant and anxiolytic drugs remainsvery promising. These compounds block the actionsof exogenous and endogenous CRF in a variety ofin vivo models, supporting a putative role for theseagents in the treatment of stress and/or anxiety andaffective disorders. The promising clinical resultsin patients with depression in the completed opentrial of R121919 is of great interest and the resultsof further studies are eagerly awaited. As we await the results of additional clinical trialsexamining the efficacy of CRF 1 receptor antagonistsin anxiety and mood disorders, it should bepointed out that these compounds may be beneficialin a broad array of neuropsychiatric disorders(including eating disorders, child abuse, and drugabuse), as well as irritable bowel syndrome andinflammatory diseases. Whether these drugs will beeffective as monotherapy or whether they representan important class of augmenting agents remains tobe determined. Furthermore, the development ofsingle photon emission CT and positron emissiontomography ligands from these lead compounds foruse in neuroimaging studies are likely to be usefulin furthering our understanding of the pathophysiologyof these mood and anxiety disorders. 76,77 Drugs mentioned in this article: Amitriptyline (Limbitrol) Desipramine (Norpramin, Pertofrane) Fluoxetine (Prozac, Serafem) References 1.Gibbons JL,McHugh PR.Plasma cortisol in depressive illness.J PsychiatrRes. 1962;1:162-171. 2. Carpenter WT Jr, Bunney WE Jr. Adrenal cortical activity in depressiveillness. Am J Psychiatry. 1971;128:31-40. 3. Sachar EJ, Hellman L, Fukushima DK, Gallagher TF. Cortisol productionin depressive illness. A clinical and biochemical clarification. ArchGen Psychiatry. 1970;23:289-298. 4. Krishnan KR, Doraiswamy PM, Lurie SN, et al. Pituitary size in depression.J Clin Endocrinol Metab. 1991;72:256-259. 5. Amsterdam JD, Marinelli DL, Arger P, Winokur A. Assessment of adrenalgland volume by computed tomography in depressed patients andhealthy volunteers: a pilot study. Psychiatry Res. 1987;21:189-197. 6. Nemeroff CB, Krishnan KR, Reed D, et al. Adrenal gland enlargementin major depression.A computed tomographic study. Arch Gen Psychiatry.1992;49:384-387. 7. Dorovini-Zis K, Zis AP. Increased adrenal weight in victims of violentsuicide. Am J Psychiatry. 1987;144:1214-1215. 8. Rubin RT, Phillips JJ, Sadow TF, McCracken JT. Adrenal gland volumein major depression. Increase during the depressive episode and decreasewith successful treatment. Arch Gen Psychiatry. 1995;52:213-218. 9. Nemeroff CB, Krishnan KR, Reed D, et al. Adrenal gland enlargementin major depression.A computed tomographic study. Arch Gen Psychiatry.1992;49:384-387. 10. Saffran M, Schally AV, Benfey BG. Stimulation of the release of corticotropinfrom the adenohypophysis by a neurohypophysial factor. Endocrinology.1955;57:439-444. 11. Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residueovine hypothalamic peptide that stimulates secretion of corticotropin andbeta-endorphin. Science. 1981;213:1394-1397. 12. Steckler T, Holsboer F. Corticotropin-releasing hormone receptor subtypesand emotion. Biol Psychiatry. 1999;46:1480-1508. 13.Owens MJ,Nemeroff CB.Physiology and pharmacology of corticotropinreleasingfactor. Pharmacol Rev. 1991;43:425-473. 14. Hauger RL, Dautzenberg FM. Regulation of the stress response by corticotropin-releasing factor receptors. In: Conn PM, Freedman ME, eds.Neuroendocrinology in Physiology and Medicine. Totowa, NJ: HumanaPress; 2000:261-286. 15. Swanson LW, Sawchenko PE, Rivier J, Vale WW. Organization of ovinecorticotrophin-releasing factor immunoreactive cells and fibers in therat brain: an immunohistochemical study. Neuroendocrinology. 1983;36:165-186. 16. Kiss JZ, Martos J, Palkovits M. Hypothalamic paraventricular nucleus:a quantitative analysis of cytoarchitectonic subdivisions in the rat. J CompNeurol. 1991;313:563-573. 17. Swanson LW, Kuypers HG. The paraventricular nucleus of the hypothalamus:cytoarchitectonic subdivisions and organization of projectionsto the pituitary, dorsal vagal complex, and spinal cord as demonstratedby retrograde fluorescence double-labeling methods. J Comp Neurol.1980;194:555-570. 18. Reyes BA,Valentino RJ, Xu G,Van Bockstaele EJ. Hypothalamic projectionsto locus coeruleus neurons in rat brain. Eur J Neurosci. 2005;22:93-106. 19. Hermus AR, Pieters GF, Smals AG, et al. Plasma adrenocorticotropin,cortisol, and aldosterone responses to corticotrophin-releasing factor:modulatory effect of basal cortisol levels. J Clin Endocrinol Metab. 1984;58:187-191. 20. Gold PW, Chrousos G, Kellner C, et al. Psychiatric implications of basicand clinical studies with corticotropin-releasing factor. Am J Psychiatry.1984;141:619-627. 21. Holsboer F, Muller OA, Doerr HG, et al.ACTH and multisteroid responsesto corticotropin-releasing factor in depressive illness:relationship to multisteroidresponses after ACTH stimulation and dexamethasone suppression.Psychoneuroendocrinology. 1984;9:147-160. 22. Amsterdam JD, Maislin G, Winokur A, et al. The oCRH stimulation testbefore and after clinical recovery from depression. J Affect Disord. 1988;14:213-222. 23. Kathol RG, Jaeckle RS, Lopez JF, Meller WH. Consistent reduction ofACTH responses to stimulation with CRH, vasopressin and hypoglycaemiain patients with major depression. Br J Psychiatry. 1989;155:468-478. 24. Young EA, Watson SJ, Kotun J, et al. Beta-lipotropin-beta-endorphinresponse to low-dose ovine corticotropin releasing factor in endogenousdepression. Preliminary studies. Arch Gen Psychiatry. 1990;47:449-457. 25. Wynn PC, Aguilera G, Morell J, Catt KJ. Properties and regulation ofhigh-affinity pituitary receptors for corticotropin-releasing factor.BiochemBiophys Res Commun. 1983;110:602-608. 26. Wynn PC, Hauger RL, Holmes MC, et al. Brain and pituitary receptorsfor corticotropin releasing factor: localization and differential regulationafter adrenalectomy. Peptides. 1984;5:1077-1084. 27. Aguilera G, Wynn PC, Harwood JP, et al. Receptor-mediated actionsof corticotropin-releasing factor in pituitary gland and nervous system.Neuroendocrinology. 1986;43:79-88. 28. Holmes MC, Catt KJ, Aguilera G. Involvement of vasopressin in thedown-regulation of pituitary corticotropin-releasing factor receptors afteradrenalectomy. Endocrinology. 1987;121:2093-2098. 29. Wynn PC, Harwood JP, Catt KJ, Aguilera G. Corticotropin-releasingfactor (CRF) induces desensitization of the rat pituitary CRF receptoradenylatecyclase complex. Endocrinology. 1988;122:351-358. 30. Primus RJ, Yevich E, Baltazar C, Gallager DW. Autoradiographic localizationof CRF1 and CRF2 binding sites in adult rat brain. Neuropsychopharmacology.1997;17:308-316. 31. Heinrichs SC, Lapsansky J, Lovenberg TW, et al. Corticotropin-releasingfactor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior.Regul Pept. 1997;71:15-21. 32. Takahashi LK. Role of CRF(1) and CRF(2) receptors in fear and anxiety.Neurosci Biobehav Rev. 2001;25:627-636. 33. Bale TL, Picetti R, Contarino A, et al. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impairedstress response and display sexually dichotomous anxiety-like behavior.J Neurosci. 2002;22:193-199. 34. Risbrough VB, Hauger RL, Roberts AL, et al. Corticotropin-releasingfactor receptors CRF1 and CRF2 exert both additive and opposing influenceson defensive startle behavior. J Neurosci. 2004;24:6545-6552. 35. Timpl P, Spanagel R, Sillaber I, et al. Impaired stress response andreduced anxiety in mice lacking a functional corticotropin-releasing hormonereceptor 1. Nat Genet. 1998;19:162-166. 36. Bale TL, Contarino, A, Smith GW, et al. Mice deficient for corticotropinreleasinghormone receptor-2 display anxiety-like behaviour and are hypersensitiveto stress. Nat Genet. 2000;24:410-414. 37. Kishimoto T, Radulovic J, Radulovic M, et al. Deletion of crhr2 revealsan anxiolytic role for corticotropin-releasing hormone receptor-2.Nat Genet.2000;24:415-419. 38. Coste SC, Kesterson RA, Heldwein KA, et al. Abnormal adaptations tostress and impaired cardiovascular function in mice lacking corticotropinreleasinghormone receptor-2. Nat Genet. 2000;24:403-409. 39. Ruhmann A, Bonk I, Lin CR, et al. Structural requirements for peptidicantagonists of the corticotropin-releasing factor receptor (CRFR): developmentof CRFR2beta-selective antisauvagine-30. Proc Natl Acad SciU S A. 1998;95:15264-15269. 40. Higelin J, Py-Lang G, Paternoster C, et al. 125I-Antisauvagine-30: anovel and specific high-affinity radioligand for the characterization ofcorticotropin-releasing factor type 2 receptors. Neuropharmacology.2001;40:114-122. 41. Radulovic J, Ruhmann A, Liepold T, Spiess J. Modulation of learningand anxiety by corticotropin-releasing factor (CRF) and stress: differentialroles of CRF receptors 1 and 2. J Neurosci. 1999;19:5016-5025. 42. Takahashi LK, Ho SP, Livanov V, et al. Antagonism of CRF(2) receptorsproduces anxiolytic behavior in animal models of anxiety. Brain Res.2001;902:135-142. 43. Lewis K, Li C, Perrin MH, et al. Identification of urocortin III, an additionalmember of the corticotropin-releasing factor (CRF) family withhigh affinity for the CRF2 receptor. Proc Natl Acad Sci U S A. 2001;98:7570-7575. 44. Reyes TM, Lewis K, Perrin MH, et al. Urocortin II: a member of thecorticotropin-releasing factor (CRF) neuropeptide family that is selectivelybound by type 2 CRF receptors. Proc Natl Acad Sci U S A. 2001;98:2843-2848. 45. Valdez GR, Inoue K, Koob GF, et al. Human urocortin II: mild locomotorsuppressive and delayed anxiolytic-like effects of a novel corticotropinreleasingfactor related peptide. Brain Res. 2002;943:142-150. 46. Gutman DA, Owens MJ, Nemeroff CB. Corticotropin-releasing factorantagonists as novel psychotherapeutics. Drugs of the Future. 2000;25:921-931. 47. Gutman DA, Owens MJ, Nemeroff CB. Corticotropin-releasing factorreceptor and glucocorticoid receptor antagonists:new approaches to antidepressanttreatment. In: den Boer JA, George MS, ter Horst GJ, eds.Current and Future Developments in Psychopharmacology. Amsterdam:Benecke NI; 2005:133-158. 48. Suda T, Tomori N, Tozawa F, et al. Distribution and characterization ofimmunoreactive corticotropin-releasing factor in human tissues. J ClinEndocrinol Metab. 1984;59:861-866. 49. Charlton BG, Ferrier IN, Perry RH. Distribution of corticotropin-releasingfactor-like immunoreactivity in human brain. Neuropeptides. 1987;10:329-334. 50. Sanchez MM, Young LJ, Plotsky PM, Insel TR. Autoradiographicand in situ hybridization localization of corticotropin-releasing factor 1and 2 receptors in nonhuman primate brain. J Comp Neurol. 1999;408:365-377. 51. Van Pett K, Viau V, Bittencourt JC, et al. Distribution of mRNAs encodingCRF receptors in brain and pituitary of rat and mouse. J Comp Neurol.2000;428:191-212. 52. Banki CM, Bissette G,Arato M, et al. CSF corticotropin-releasing factorlikeimmunoreactivity in depression and schizophrenia. Am J Psychiatry.1987;144:873-877. 53. France RD, Urban B, Krishnan KR, et al. CSF corticotropin-releasingfactor-like immunoactivity in chronic pain patients with and without majordepression. Biol Psychiatry. 1988;23:86-88. 54. Nemeroff CB. The role of corticotropin-releasing factor in the pathogenesisof major depression. Pharmacopsychiatry. 1988;21:76-82. 55. Arato M, Banki CM, Bissette G, Nemeroff CB. Elevated CSF CRF insuicide victims. Biol Psychiatry. 1989;25:355-359. 56. Risch SC, Lewine RJ, Kalin NH, et al. Limbic-hypothalamic-pituitaryadrenalaxis activity and ventricular-to-brain ratio studies in affectiveillness and schizophrenia. Neuropsychopharmacology. 1992;6:95-100. 57. Roy A, Pickar D, Paul S, et al. CSF corticotropin-releasing hormonein depressed patients and normal control subjects. Am J Psychiatry. 1987;144:641-645. 58. Veith RC, Lewis N, Langohr JI, et al. Effect of desipramine on cerebrospinalfluid concentrations of corticotropin-releasing factor in humansubjects. Psychiatry Res. 1993;46:1-8. 59. De Bellis MD, Gold PW, Geracioti TD Jr, et al. Association of fluoxetinetreatment with reductions in CSF concentrations of corticotropinreleasinghormone and arginine vasopressin in patients with major depression.Am J Psychiatry. 1993;150:656-657. 60. Heuser I, Bissette G, Dettling M, et al. Cerebrospinal fluid concentrationsof corticotropin-releasing hormone, vasopressin, and somatostatinin depressed patients and healthy controls:response to amitriptyline treatment.Depress Anxiety. 1998;8:71-79. 61. Nemeroff CB, Bissette G, Akil H, Fink M. Neuropeptide concentrationsin the cerebrospinal fluid of depressed patients treated with electroconvulsivetherapy. Corticotrophin-releasing factor, beta-endorphin andsomatostatin. Br J Psychiatry. 1991;158:59-63. 62. Banki CM, Karmacsi L, Bissette G, Nemeroff CB. CSF corticotropinreleasinghormone and somatostatin in major depression: response toantidepressant treatment and relapse. Eur Neuropsychopharmacol. 1992;2:107-113. 63. Post RM, Gold P, Rubinow DR, et al. Peptides in the cerebrospinal fluidof neuropsychiatric patients:an approach to central nervous system peptidefunction. Life Sci. 1982;31:1-15. 64. Nemeroff CB, Owens MJ, Bissette G, et al. Reduced corticotropinreleasing factor binding sites in the frontal cortex of suicide victims. ArchGen Psychiatry. 1988;45:577-579. 65. Purba JS, Raadsheer FC, Hofman MA, et al. Increased number of corticotropin-releasing hormone expressing neurons in the hypothalamicparaventricular nucleus of patients with multiple sclerosis. Neuroendocrinology.1995;62:62-70. 66. Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, et al. Corticotropinreleasinghormone mRNA levels in the paraventricular nucleus of patientswith Alzheimer's disease and depression. Am J Psychiatry. 1995;152:1372-1376. 67. Merali Z, Du L, Hrdina P, et al. Dysregulation in the suicide brain:mRNA expression of corticotropin-releasing hormone receptors andGABA(A) receptor subunits in frontal cortical brain region. J Neurosci.2004;24:1478-1485. 68. Coplan JD, Trost RC, Owens MJ, et al. Cerebrospinal fluid concentrationsof somatostatin and biogenic amines in grown primates rearedby mothers exposed to manipulated foraging conditions. Arch GenPsychiatry. 1998;55:473-477. 69. Nemeroff CB. The preeminent role of early untoward experience onvulnerability to major psychiatric disorders: the nature-nurture controversyrevisited and soon to be resolved. Mol Psychiatry. 1999;4:106-108. 70. Kirschbaum C, Pirke KM, Hellhammer DH. The 'Trier Social StressTest'--a tool for investigating psychobiological stress responses in alaboratory setting. Neuropsychobiology. 1993;28:76-81. 71. Heim C, Newport DJ, Bonsall R, et al. Altered pituitary-adrenal axisresponses to provocative challenge tests in adult survivors of childhoodabuse. Am J Psychiatry. 2001;158:575-581. 72. Erb S, Shaham Y, Stewart J. The role of corticotropin-releasing factorand corticosterone in stress- and cocaine-induced relapse to cocaineseeking in rats. J Neurosci. 1998;18:5529-5536. 73. Shaham Y, Erb S, Leung S, et al. CP-154,526, a selective, non-peptideantagonist of the corticotropin-releasing factor1 receptor attenuates stressinducedrelapse to drug seeking in cocaine- and heroin-trained rats.Psychopharmacology (Berl). 1998;137:184-190. 74. Skelton KH, Nemeroff CB, Knight DL, Owens MJ. Chronic administrationof the triazolobenzodiazepine alprazolam produces opposite effectson corticotropin-releasing factor and urocortin neuronal systems.J Neurosci. 2000;20:1240-1248. 75. Zobel AW, Nickel T, Kunzel HE, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in majordepression: the first 20 patients treated. J Psychiatr Res. 2000;34:171-181. 76. Martarello L, Kilts CD, Ely T, et al. Design, synthesis and evaluationof amino-anilino-pyrimidines as potential SPECT ligands for the CRF1receptor. International Society of Psychoneuroendocrinology Abstracts.Orlando, USA; 1999:53. 77. Martarello, L, Kilts CD, Ely T, et al. Design, synthesis and characterizationof fluorinated- and iodinated-pyrrolo[2,3-d]pyrimidines as candidatesfor CRF1 receptor PET/SPECT ligands.J Labelled Comp Radiopharm. 42(supp 1):S312-S314. 78. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety disorder. J Endocrinol.1999;160:1-12. Evidence-based References Steckler T, Holsboer F. Corticotropin-releasing hormone receptor subtypesand emotion. Biol Psychiatry. 1999;46:1480-1508. Strohle A, Holsboer F. Stress responsive neurohormones in depressionand anxiety. Pharmacopsychiatry. 2003;36(suppl 3):S207-S214. Psychiatric Times- Category 1 Credit If you are a first-time user, you must update your profile. If you are not on the Lifelong Learning site, click here. You must keep your own records of this activity. Copy this information and include it in your continuing education file for reporting purposes. CME LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CME LLC designates this educational activity for a maximum of 1.5 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits actually spent on the educational activity. CME LLC is an approved provider of continuing medical education for physicians, nurses and physician assistants in the State of Florida and is registered with CE Broker. CME LLC is approved by the California Board of Registered Nursing, Provider No. CEP12748, and designates this educational activity for 1.5 contact hours for nurses. The American Nurses Credentialing Center (ANCC) accepts AMA category 1 credit toward recertification requirements.