Stress Neurobiology and Corticotropin-Releasing Factor
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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.
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.
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.
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.
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.
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
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.
Desipramine (Norpramin, Pertofrane)
Fluoxetine (Prozac, Serafem)
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