REVIEW Neuropsychological functioning in health and mood disorder: Modulation by glucocorticoids and their receptors Peter Gallagher * , Keith S. Reid, I. Nicol Ferrier Institute of Neuroscience, Newcastle University, UK Received 17 April 2009; received in revised form 21 May 2009; accepted 26 May 2009 Contents 1. Introduction ............................................................... S197 1.1. The HPA axis ........................................................... S197 1.2. Cortisol and corticosteroid receptors ........................................... S197 2. HPA axis dysfunction in mood disorders .............................................. S197 3. Neuropsychological impairment in mood disorders ....................................... S198 4. Glucocorticoids, HPA axis function and cognition ........................................ S198 4.1. Clinical conditions ....................................................... S199 5. Effects of GR manipulation on cognition ............................................. S200 5.1. Effects of GR agonists on memory ............................................. S200 Psychoneuroendocrinology (2009) 34S, S196—S207 KEYWORDS Neuropsychology; Memory; Cortisol; Glucocorticoids; HPA axis; Mood disorders; Depression Summary Numerous studies have shown that disturbances in hypothalamic—pituitary—adrenal (HPA) axis function and consequent hypercortisolaemia occur in a significant proportion of patients with mood disorders. This dysfunction has been proposed to be an exacerbating factor of depressive symptoms and may predict symptomatic relapse. Glucocorticoids are also known to have a specific role in learning and memory processes. In this review we present a brief overview of the relationship between HPA axis dysfunction and neuropsychological impairment in mood disorders and the specific links between glucocorticoids and cognition in health and illness states. Finally we examine the neuropsychological effects of drugs that specifically target glucocorticoid receptor function. # 2009 Elsevier Ltd. All rights reserved. * Corresponding author at: Institute of Neuroscience, Newcastle University, Leazes Wing (Psychiatry), Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK. Tel.: +44 0191 282 4065; fax: +44 0191 222 6162. E-mail address: [email protected](P. Gallagher). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/psyneuen 0306-4530/$ — see front matter # 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2009.05.018
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REVIEW
Neuropsychological functioning in health and mooddisorder: Modulation by glucocorticoids and theirreceptors
Peter Gallagher *, Keith S. Reid, I. Nicol Ferrier
Institute of Neuroscience, Newcastle University, UK
Received 17 April 2009; received in revised form 21 May 2009; accepted 26 May 2009
Summary Numerous studies have shown that disturbances in hypothalamic—pituitary—adrenal(HPA) axis function and consequent hypercortisolaemia occur in a significant proportion ofpatients with mood disorders. This dysfunction has been proposed to be an exacerbating factorof depressive symptoms and may predict symptomatic relapse. Glucocorticoids are also known tohave a specific role in learning and memory processes. In this review we present a brief overviewof the relationship between HPA axis dysfunction and neuropsychological impairment in mooddisorders and the specific links between glucocorticoids and cognition in health and illness states.Finally we examine the neuropsychological effects of drugs that specifically target glucocorticoidreceptor function.# 2009 Elsevier Ltd. All rights reserved.
* Corresponding author at: Institute of Neuroscience, Newcastle University, Leazes Wing (Psychiatry), Royal Victoria Infirmary, Newcastleupon Tyne NE1 4LP, UK. Tel.: +44 0191 282 4065; fax: +44 0191 222 6162.
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1. Introduction
There is a wealth of evidence demonstrating both neurop-sychological impairment and hypothalamic—pituitary—adre-nal (HPA) axis dysfunction in patients with mood disorders.However, a direct causal relationship remains difficult toestablish. In this review we will first present a brief overviewof this evidence before reviewing the literature from healthysubjects and clinical populations in which the direct effectsof glucocorticoid manipulation have been examined. Finallywe focus on the neuropsychological effects of drugs thatdirectly target glucocorticoid receptors, an area of develop-ing therapeutic research.
1.1. The HPA axis
The HPA axis is one of the primary systems mediating physicaland psychological stress responses in humans. Neuroneslocated in the paraventricular nucleus of the hypothalamussecrete corticotropin releasing hormone (CRH) which istransported via the hypothalamo—pituitary portal circulationto the anterior pituitary where adrenocorticotropic hormone(ACTH) is secreted through stimulation of pituitary cortico-trophs. ACTH then stimulates the adrenal cortex to secreteglucocorticoids: corticosterone in rats and cortisol inhumans.
1.2. Cortisol and corticosteroid receptors
Under basal conditions in healthy humans, cortisol secretionfollows a 24-h circadian rhythm where levels are highest atwaking and slowly decline to a nocturnal low (Weitzmanet al., 1971). As with many hormones cortisol is releasedin a pulsatile manner throughout this cycle (Young et al.,2004b). A great deal of individual variability can be seen inthe secretion of both ACTH and cortisol. Although secretionof the two hormones is not quantitatively linked throughoutthe day, ACTH has been shown to be the stimulating factor ofcortisol release under basal conditions (Follenius et al., 1987;Bornstein et al., 2008). Time-series analysis identifying theperiods of the oscillations in plasma levels of cortisol andACTH in healthy individuals has shown an average periodicityin the oscillations of between 55 and 140 min for ACTH but95—180 min for cortisol, indicating that a single cortisol peakmay be initiated by more than one ACTH peak (Folleniuset al., 1987).
Cortisol is involved in the regulation of fat, protein andcarbohydrate metabolism, electrolyte balance, body waterdistribution, blood pressure and has an immunosuppresantanti-inflammatory action (Berne and Levy, 1998). It is also akey regulator of the neuroendocrine stress response, throughnegative-feedback actions at specific corticosteroid recep-tors. Two corticosteroid receptor sub-types have been
identified; the mineralocorticoid receptor (MR; Type I) andthe glucocorticoid receptor (GR; Type II). Both receptorshave been implicated in mediating glucocorticoid feedback(Reul and de Kloet, 1985). However there are several differ-ences in the distribution, occupancy and binding propertiesof the two receptors that affect their physiological role.
GR have been shown to be widely expressed in the centralnervous system with highest densities in cortical regionsincluding prefrontal cortex, in limbic areas including hippo-campus and amygdala, and in the thalamus and hypothala-mus. In the cortex expression is concentrated in pyramidalcells, while in the hippocampus both pyramidal and granulecells express GR (Fuxe et al., 1987; Ahima et al., 1991; Cintraet al., 1994; Patel et al., 2000). Mapping of MR in the CNS hasbeen less comprehensive and data are less consistent. How-ever, a widespread distribution has been noted (Ahima et al.,1991) with particularly high MR density in hippocampal,thalamic and hypothalamic regions (Ahima et al., 1991;Agarwal et al., 1993; Ito et al., 2000). Glucocorticoids bindto the MR with around a 6—10-fold greater affinity than to GR(de Kloet et al., 1999). At basal levels, near completeoccupation of MRs occurs while GRs are minimally occupiedat this point and only during times of high cortisol secretion,such as the circadian peak or during stress, do MRs becomesaturated and GR occupancy increases (Reul and de Kloet,1985; de Kloet and Reul, 1987) (but also see Pace andSpencer, 2005).
2. HPA axis dysfunction in mood disorders
Since the work of Board and colleagues (Board et al., 1956,1957) over half a century ago, many studies have replicatedthe findings of raised cortisol levels and HPA dysfunction inpatients with mood disorders (Gibbons and McHugh, 1962;Gibbons, 1964; Gallagher et al., 2007b). With more refinedtechniques it has been established that not only is overallcortisol production increased (Carroll et al., 1976), but alsothe diurnal profile is altered (Linkowski et al., 1985) withgreater waking levels observed during the morning peak(Bhagwagar et al., 2005) and increased levels at the eveningnadir, resulting overall in a flattened diurnal rhythm(Deuschle et al., 1997; Posener et al., 2000; Wong et al.,2000).
The most sensitive tests of HPA axis function, however,are ‘activating’ tests whereby neuroendocrine responses aremeasured following pharmacological challenge. These arepreferred not only because of their increased sensitivity, butalso because they elucidate functional changes in the HPAaxis at the receptor level (Watson et al., 2006a). The GRagonist dexamethasone has been used widely to examine HPAaxis negative-feedback integrity (Rush et al., 1996). Anabnormal (non-suppressed) cortisol response to dexametha-sone administration has been described in patients withmood disorder (Rush et al., 1996) and may be more
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pronounced in those with psychotic features (Duval et al.,2000). The combined dexamethasone/corticotropin releas-ing hormone (dex/CRH) test (Heuser et al., 1994) is alsoabnormal during relapse (Heuser et al., 1994; Modell et al.,1997) and persists in recovery, particularly in bipolar disorder(Rybakowski and Twardowska, 1999; Watson et al., 2004,2007). Furthermore, corticosteroid receptor abnormalitieshave been observed in post-mortem studies which showevidence of regionally specific changes in MR and GR mRNAexpression in post-mortem brain tissue samples from patientswith mood disorders (Knable et al., 2001; Webster et al.,2002; Lopez et al., 2003).
It has been suggested that raised cortisol is a marker ofprognosis and that HPA axis dysfunction and persistenthypercortisolaemia are likely to identify those patientswho are either not improving or are likely to be vulnerableto relapse. In a study of depressed patients treated with theSSRI fluoxetine (Young et al., 2004c), non-respondersshowed abnormal HPA axis reactivity, while responders didnot differ from healthy controls. A meta-analysis of thedexamethasone suppression test (DST) as a predictor oftreatment outcome concluded that although DST status atbaseline was not predictive of response to antidepressanttreatment, persistent DST non-suppression after treatmentwas associated with high risk of early relapse and pooroutcome after discharge from hospital (Ribeiro et al.,1993). Several studies have examined neuroendocrineresponses to the dex/CRH test in depression and have foundrelationships with relapse or treatment response (Isinget al., 2007). For example, it has been shown that in clini-cally remitted major depression, post-treatment responsesto the dex/CRH were significantly higher among patientswho relapsed (Appelhof et al., 2006; Aubry et al., 2007). Ithas been argued that early improvement, early treatmentresponse and beneficial treatment outcome are associatedwith a lower HPA axis activity (assessed using the dex/CRH)and that, in the longer-term, HPA axis dysregulationincreases in parallel with the number of previous episodes(Hatzinger et al., 2002).
In summary, there seems to be strong evidence thatthere are abnormalities at multiple levels of HPA axisfunctioning in mood disorders in a significant proportionof patients. These abnormalities also predict to somedegree the clinical course of the disorder and responseto treatment.
3. Neuropsychological impairment in mooddisorders
It has long been recognized that in addition to lowering ofmotivation and affect, mood disorders are associated withneuropsychological impairment (Kiloh, 1962). There is now awealth of literature examining the effects of major depres-sion on neuropsychological function (Burt et al., 1995; Veiel,1997; Zakzanis et al., 1998; Gallagher and Porter, 2004). Theheterogeneity of the disorder results in a great deal ofvariability in the extent and profile of the deficits and isaffected by numerous demographic and clinical features(Porter et al., 2007; Thomas et al., 2009). It has beendemonstrated that these deficits are not secondary to theeffects of psychotropic medications (Porter et al., 2003;Taylor Tavares et al., 2007).
By comparison, relatively fewer studies have focused ondepression within bipolar disorder. There is a large degree ofoverlap in the neuropsychological profiles of unipolar andbipolar depression, however in general it appears that thereis greater severity of neuropsychological impairment in thelatter (Wolfe et al., 1987; Borkowska and Rybakowski, 2001).For example, Borkowska and Rybakowski (2001) comparedthe performance of patients with bipolar or unipolar mooddisorders during acute episodes of depression. A greaterextent of executive dysfunction — including poorer perfor-mance in non-verbal problem solving, response inhibition,verbal fluency and set-shifting — was found in bipolar com-pared with unipolar depressed patients. Other studies havereported executive dysfunction in depressed patients withbipolar disorder (Calev et al., 1986; Martinez-Aran et al.,2004), although it should be noted that others have foundonly selective impairments in immediate spatial memory and‘hot’ (i.e. emotionally laden) cognition (Roiser et al., 2009).
Neuropsychological impairments persist into euthymia inbipolar disorder (Bearden et al., 2001; Robinson et al., 2006;Bora et al., 2009). In unipolar disorders, evidence of thepersistence of deficits is less consistent with the majority ofdomains improving in remission, although some studies havefound executive impairments persisting in the absence ofmemory deficits (Trichard et al., 1995; Clark et al., 2005).Our own work in patients with major depression who wereassessed at baseline (when all were medication-free) andfollowed up within 6 months found that there was signifi-cantly greater improvement in verbal memory but not execu-tive function in those who remitted compared to those whodid not (Gallagher et al., 2007a).
As is the case with major depression, a number of demo-graphic and clinical characteristics are associated with amore impaired neuropsychological profile in euthymic bipo-lar patients (Robinson and Ferrier, 2006). There is a generalconsensus that both executive functions and declarativememory are impaired (van Gorp et al., 1998; Ferrieret al., 1999; Martinez-Aran et al., 2000, 2002, 2004; El-Badriet al., 2001; Clark et al., 2002; Torrent et al., 2006). How-ever, a recent study suggested that the verbal declarativememory deficits may be entirely accounted for by a generalexecutive impairment (Thompson et al., 2009).
In summary, there is substantial evidence of both HPA axisdisturbance and neuropsychological impairment in mooddisorders, both during and following episodes; the linkbetween the two remains to be elaborated.
4. Glucocorticoids, HPA axis function andcognition
In the following section we examine the evidence for thedirect relationship between cortisol and cognition. We shallbriefly discuss the work from animal studies and then focus onthe extension of this to healthy human subjects and clinicalconditions, particularly mood disorders. It should be notedthat this will broadly examine the topic as more detailedreviews are available elsewhere, such as the acute effects ofglucocorticoids on cognition (Lupien and McEwen, 1997; Hetet al., 2005), the effects of stress on cognitive function(Sauro et al., 2003), and the modulatory effects of emotionalcontent on memory (Roozendaal et al., 2008).
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Much of the work from animal models brings together twolines of study–—the known effects of corticosteroids on hip-pocampal function and the role of the hippocampal forma-tion in learning and memory. Lupien and McEwencomprehensively reviewed the literature on the acuteeffects of corticosteroids on memory in animals and humans(Lupien and McEwen, 1997). The overall pattern of resultshighlight that there are clear dose-related effects that eliciteither facilitation in memory, as doses rise from sub-optimalto optimal levels, or impairment at higher doses and there-fore show an inverted ‘‘U’’-shape relationship. The role ofthe specific receptor sub-types in different stages of memoryformation can be separated from the effects glucocorticoidshave on general arousal. The model proposes that the dose—response relationship emerges because of differential acti-vation of MR or GR, especially in the hippocampus, with MRbeing involved in the processes of sensory integration and GRwith acquisition and consolidation of the memory trace(Lupien and McEwen, 1997).
It is noteworthy that some of these effects may occur viainteraction with neurotransmitter/hormone complexes,such as sex hormones (Symonds et al., 2004; Kuhlmannand Wolf, 2005), endocannabinoid (Campolongo et al.,2009) and noradrenergic (Quirarte et al., 1997; Roozendaalet al., 2006) or serotonergic (McAllister-Williams et al.,1998; Porter et al., 2002, 2004) systems. For example,chronic elevation of glucocorticoid levels, by corticosteroneadministration or stress, causes functional desensitizationof the 5-HT1A autoreceptor (Lanfumey et al., 1999; Fairchildet al., 2003). Functional 5-HT1A autoreceptor desensitiza-tion also occurs when corticosterone rhythm is flattened at alevel around the mid-diurnal level (Gartside et al., 2003;Leitch et al., 2003). In healthy human subjects administra-tion of the 5-HT1A agonist buspirone has been shown to resultin a negative shift in the frequency spectrum of the electro-encephalogram (EEG) (McAllister-Williams and Massey,2003). Following administration of hydrocortisone (20 mg/day for 7 days) the effect of buspirone is significantly atte-nuated, supporting of the notion that corticosteroids mayhave similar effects on somatodendritic 5-HT1A autorecep-tors in humans as seen in rodents (McAllister-Williams et al.,2007). It should be noted that, to date, studies using PET toexamine 5-HT1A receptor binding potential following admin-istration of hydrocortisone or prednisolone have found noeffect (Montgomery et al., 2001; Bhagwagar et al., 2003).However a recent review has suggested that methodologicalfactors, such as the timing of assessment or receptor spe-cificity may explain the lack of effect and more studies areneeded in this area (Drevets et al., 2007). Similarly, fMRIparadigms have been used to examine the effects of gluco-corticoids (van Stegeren, 2009) or serotonin on memory(particularly emotional memory) (Fusar-Poli et al., 2006)although more data is needed, especially on the interactionbetween these systems.
It has been suggested that the distinction be made inhumans between the effect of corticosteroids on generalarousal or attention and their effect on specific memoryprocesses, paralleling that described in the animal litera-ture (Lupien and McEwen, 1997). Several studies havedemonstrated verbal declarative memory deficits followingadministration of hydrocortisone (Wolkowitz et al., 1990;Newcomer et al., 1999). Those that have examined
different stages of information processing have arguedthat this is specifically an effect on memory retrieval(de Quervain et al., 2000, 2003). This appears discrepantfrom the findings in rodents where the effects are onacquisition and consolidation. However de Quervain andcolleagues suggest that it is the delay interval (24 h) that iscrucial to this difference. Although memory is impaired inhumans by pre-learning administration of cortisol (e.g.Newcomer et al., 1999) glucocorticoid levels may remainelevated at the time of testing in these experiments. Thusit is possible that such results actually reflect impairedmemory retrieval rather than altered memory acquisitionor consolidation. A recent review has also highlighted theeffect of diurnal changes in cortisol levels on the memoryeffects of glucocorticoids (Het et al., 2005). It is worthnoting that all of these studies have used declarativeverbal recall to assess performance, although it has beenproposed that verbal working memory may be more sensi-tive than declarative memory to the acute effects ofglucocorticoids (Lupien et al., 1999). There is also evi-dence that after sub-chronic doses of hydrocortisone,spatial working memory is also impaired (Young et al.,1999). This introduces interesting opportunities to parallelthe work in animals which has a focus on spatial memoryand the hippocampus. Including emotional content into theword lists can further affect the pattern of impairment andfacilitation following cortisol elevation (for more detailedprimary data and reviews see for example Wolf et al.,2004; Smeets et al., 2008; Wolf, 2008).
A meta-analysis has suggested a more complex picture ofthe effects of stress on memory (i.e. when memory isassessed following acute laboratory stress or long-term expo-sure to rising basal levels of glucocorticoids) compared withthat found after pharmacological manipulation (Sauro et al.,2003). This highlights the difficulty of generalising resultsacross differing methods of HPA axis manipulation, and aneven greater degree of complexity when attempting to applythese models of glucocorticoid—cognition interactions toclinical conditions in which cortisol levels/receptor dysfunc-tion may be present over long periods of time. Broadly,clinical studies can be separated into those that have lookedfor direct associations between cortisol levels and cognitiveperformance and those that have usedmarkers of the generalmagnitude of HPA disturbance and neuropsychologicalimpairment.
4.1. Clinical conditions
That hypersecretion of cortisol may be causative in thedevelopment of depression is suggested by findings inpatients with Cushing’s disease/syndrome (CD/CS). Typically,individuals have plasma cortisol levels that are threefoldthose of healthy subjects, and within this group the preva-lence of depression is higher than in the normal population(Cohen, 1980; Kelly et al., 1983). Furthermore, depressivesymptoms resolve on treatment of the primary endocrinedisorder (Cohen, 1980; Kelly et al., 1983). Importantly, thereis also clear impairment in neuropsychological functioning inthese individuals. A number of studies have now demon-strated impairments in learning and memory, delayed recall,and visual-spatial ability (Whelan et al., 1980; Mauri et al.,1993; Forget et al., 2000; Starkman et al., 2001).
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Particular focus has also been placed on the effects ofhypercortisolaemia in CS/D on hippocampal structures,where volume reductions have been noted in a significantproportion of patients (Starkman et al., 1992). These reduc-tions are noted to be strongly correlated with impairment ontasks of verbal learning and recall — tasks known to besensitive to hippocampal complex/temporal lobe dysfunc-tion — and also with the degree of hypercortisolaemia (Stark-man et al., 1992). Multiple mechanisms by whichglucocorticoids induce these morphological changes in thebrain have been posited, including decreased glucose utiliza-tion, increased actions of excitatory amino acids, inhibitionof long-term potentiation and decreased neurotrophic fac-tors, and decreased neurogenesis (Patil et al., 2007). Itshould be noted that in CS/D, the temporal relationshipbetween treatment and recovery of neuropsychological func-tioning is not always coincident (Forget et al., 2002).
Zobel and colleagues found that antidepressant treat-ment-associated changes in the cortisol response to thedex/CRH test in patients with major depression were corre-lated with improvements in working memory but not withimprovements in episodic memory, sustained attention orglobal severity of symptoms (Zobel et al., 2004). This isconsistent with the results of studies in healthy subjectsdiscussed above (Lupien et al., 1999). However this findinghas not yet been replicated. In contrast, Reppermund andcolleagues assessed neuropsychological performance andadministered the dex/CRH test to a group of 75 depressedinpatients of which 51 (68%) were in remission at the point ofdischarge. Despite a significant reduction of depressive symp-toms between admission and discharge, high rates of neu-ropsychological impairment were still observed. Selectiveattention did improve in remitted and non-remitted patients,while speed of information processing improved only in thosewho had remitted. The cortisol response to the dex/CRH testdecreased significantly only in remitted patients, but this wasnot correlated with neuropsychological performance. In non-remitted patients, severity of depression was significantlycorrelated with information processing while improvement inshort-term memory was negatively associated with the cor-tisol response at discharge. Thus, it appears that HPA axisdysregulation and symptom severity have differential effectson verbal short-term memory and speed of informationprocessing (Reppermund et al., 2007).
The potential importance of the association between theconsequences of HPA axis dysregulation and neuropsycholo-gical performance was indirectly illustrated recently in astudy by Gorwood and colleagues exploring the hypothesisof the ‘toxic’ effects of depression on the hippocampus.Using verbal declarative memory (the delayed paragraphrecall index from the Wechsler Memory Scale-Revised) as asurrogate marker of hippocampal function, 8229 patientswere assessed twice over an average 42-day period andStructural Equation Modelling used to assess the clinicaland demographic factors predicting performance. At presen-tation, current illness severity was an important determinantof performance, while previous depressive history (the num-ber and length of past episodes) was not. At the follow-upafter significant clinical response, the intensity of previousdepressive history was more significant than current symp-toms. Crucially, an inverse relationship was found betweenperformance and recurrence whereby each additional
episode (up to 4 episodes) impaired verbal declarative mem-ory performance by 2—3% (Gorwood et al., 2008). The directrelationship of this finding to measures of HPA axis dysregula-tion and hypercortisolaemia requires further study.
Higher levels of morning salivary cortisol have beenshown to be associated with post-encoding memory retrie-val and storage deficits and executive dysfunction in majordepression, in the absence of any relationship with symp-toms (Egeland et al., 2005). This is consistent with thefindings of Reppermund and colleagues described above. Inpsychotic major depression, relationships between ele-vated mean cortisol levels (18:00—01:00 h) and poorerverbal memory and psychomotor speed performance havebeen found, while the cortisol slope over this period sig-nificantly correlated with both verbal memory and workingmemory (Gomez et al., 2006). Inverse relationshipsbetween peripheral cortisol levels and general intellectualfunctioning, but not verbal declarative memory have alsobeen reported in major depression (van Londen et al.,1998). Such studies highlight the need for careful consid-eration of the known effects of corticosteroids on specificstages of information processing and the subtleties of HPAaxis dysfunction. Given the complexity of these relation-ships, it is not surprising that it is difficult to establish asimple (and replicable) linear or monotonic model relatingperipheral cortisol levels to general neuropsychologicalfunctioning.
5. Effects of GR manipulation on cognition
Although the co-occurrence of HPA axis dysfunction andneurocognitive impairment has frequently been described,examining a direct causal link has proved more difficult. Asnoted above, there are a number of possible reasons for this,not least of whichmay be that the complexity of the relation-ship centrally between the two phenomena may not beaccurately modelled or measured by peripheral hypercorti-solaemia. In this final section we examine those studies thathave used more direct probes of glucocorticoid receptorfunction to assess effects on learning and memory.
5.1. Effects of GR agonists on memory
Numerous studies have examined the effects of GR agonistson cognitive function, both in animal and human studies.Generally, two approaches have been adopted: the first is touse the cortisol response to specific GR agonists, such asdexamethasone, and the relationship of post-administrationcortisol levels with memory; the second is to assess the directeffects of GR agonists/antagonists within the stages of infor-mation processing and memory formation.
The use of dexamethasone (and the dexamethasone sup-pression test; DST) as an assay of GR function has a longhistory in the assessment of patients with mood disorders(Carroll, 1982a,b; Ribeiro et al., 1993; Nelson and Davis,1997; Raison and Miller, 2003). Relating this to memoryfunction (Wauthy et al., 1991) has produced mixed results.In elderly depressed patients, contrary to expectations apositive correlation has been observed between global cog-nitive performance and post-dexamethasone cortisol levelsi.e. a failure to dexamethasone suppresswas associatedwithbetter performance (Adler and Jajcevic, 2001). In contrast,
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a study from our group found, in bipolar disorder, dexa-methasone non-suppression was correlated with poorerworking memory function (Watson et al., 2006b). Interest-ingly, in a series of three studies across which a consistentverbal memory task was used, performance deficits wereseen: in healthy subjects following 5 days of prednisolone (anon-specific MR and GR agonist) administration, or followinga single dose of dexamethasone; and in patients with majordepression, were associated with dexamethasone non-sup-pression (Wolkowitz et al., 1990). Together these findingsare consistent with the inverted ‘‘U’’-shape relationshipbetween plasma glucocorticoid levels and cognitive functionposited earlier. This was shown more clearly recently inpatients with major depression using a verbal declarativememory task (paragraph recall) administered twice, withdexamethasone or placebo administered in-between (Brem-ner et al., 2004). In healthy controls,memory improved frombaseline to day 3 with placebo but was unchanged withdexamethasone, whereas in MDD patients memory functionshowed a pattern of decreasing with placebo and improvingwith dexamethasone (Bremner et al., 2004).
Studies in clinical populations using specific MR and GRprobes would be of great interest in examining the hypothesisof MR/GR balance and optimal memory performance (Tyther-leigh et al., 2004).
5.2. Effects of GR antagonists on memory
The recent therapeutic interest in anti-glucocorticoids forthe treatment of mood disorders has provided a furthervaluable opportunity to examine the effects of GR manipula-tion on neuropsychological functioning (Gallagher et al.,2008a). In this final section we will provide an overview ofthe findings in the animal literature before examining theparallels in clinical studies in humans.
5.2.1. Rodent studiesDouma and colleagues examined the effects of repeated MR(RU28318), GR (RU38486), or combined antagonism onaspects of spatial learning in the rat. Repeated administra-tion of the MR antagonist impaired reference memory (in thehole-board learning paradigm). Combined MR/GR antagon-ism similarly reduced reference memory performance whileGR blockade alone had no effect. These results highlight theimportance of MRs in this process. Working memory acquisi-tion rates were also suppressed in the initial phase of thetraining period with MR blockade, although they wereimpaired throughout the whole training period with com-bined MR/GR blockade suggesting modulation by both(Douma et al., 1998). Such results highlight the importanceof considering the specific processes within a cognitivedomain when examining the relative contribution of receptorfunction.
As with the human literature discussed above, the pat-tern of HPA interventions and the timing of assessment ofmemory processes are crucial. In a series of studies, Oitzl andcolleagues have examined the effect of GR blockade onspatial memory function in the rat. Acute intracerebroven-tricular (i.c.v.) injection of the GR antagonist RU38486 wasfound to result in spatial memory impairment (Oitzl and deKloet, 1992). However more localized administration(10 and 100 ng) intrahippocampally was found to improve
performance in a water maze 24 h after treatment. Thiseffect occurred following either unilateral or bilateral injec-tion and appeared to be dose-related (Oitzl et al., 1998a).Interestingly the authors note that opposite effects onneuroendocrine regulation of pituitary ACTH release occurwith RU38486. While i.c.v. administration increases plasmaACTHand corticosterone levels, administration locally in thedorsal hippocampus suppresses the circadian rise of thesehormones (van Haarst et al., 1997). Chronic administrationalso has effects that are dependent on the administrationregimen. Phasic GR blockade (RU38486: 10 and 100 ng/mLi.c.v. administered pre-training over 3 consecutive days)impaired spatial memory in a dose-dependent fashion whilecontinuous blockade (10 and 100 ng/0.5 mL per hour over 10days) facilitated spatial performance, continuing severaldays after training in the case of the higher dose (Oitzlet al., 1998b).
The use of such compounds in recent clinical trials offersan important avenue of research into the role of the GR inhuman memory. Of particular interest is in determining ifeffects seen in the non-human literature can be replicated.
5.2.2. Human studiesThere is little information of the effects of GR antagonists onmemory function in humans. Most data comes from treat-ment studies using RU38486 (mifepristone). Pomara andcolleagues examined the use of mifepristone in the treat-ment of Alzheimer’s disease in a small randomized, placebo-controlled trial (Pomara et al., 2002). Some subtests ofcognition were improved following RU486 on an intention-to-treat analysis. At 12 h after the first dose, the changefrom baseline in the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) (Rosen et al., 1984) totalscorewas not statistically different between the two groups.However, patients treated with mifepristone performedsignificantly better on the ADAS-Cog Word Recall subtest.At week 6, the mean change from baseline in ADAS-Cog totalscore among completers revealed that patients treatedwithmifepristone tended to improve (by 2.67 points) whereaspatients treated with placebo tended to worsen (by 1.67points). However, this difference of 4.3 points failed to reachstatistical significance and the use of completers rather thanan intention-to-treat may raise issues of bias (Pomara et al.,2002).
Our own pilot work exploring the effects of mifepristone(RU-486) in the treatment of mood disorder highlights someinteresting parallels with the rodent work. The trial wasdesigned as a crossover study, examining both symptomsand neurocognitive function. Based on the known effectsof corticosteroids on cognition, and the effects of GR antago-nists, we selected spatial working memory (assessed by theCambridge Neuropsychological Test Automated Battery;CANTAB) and verbal declarative learning and memory(assessed by the Rey-Auditory Verbal Learning Test; Rey-AVLT(Rey, 1964)); as primary outcomes (Young et al., 2004a). Theprimary end-point for the study was 2 weeks after cessationof the 7-day treatment periods, with mifepristone or pla-cebo. Significant improvement in spatial working memoryperformance (over placebo) was found. Secondary measuresof spatial recognition memory and verbal fluency alsoimproved significantly from baseline although the advantageover placebo was not statistically significant. No significant
Figure 1 Correlation between baseline cortisol (AUC: 1—4 p.m.) and spatial working memory improvement followingmifepristone (data from Young et al., 2004a,b,c).
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change was observed in verbal declarative memory or othersecondary neuropsychological measures. This improvementwas independent of changes in symptoms, which did notdiffer at this point. Correlational analysis also revealed thatthe area-under-the-curve (AUC 1—4 p.m. Halbreich et al.,1985) afternoon cortisol levels at baseline correlated withthe degree of improvement (i.e. the percentage reduction inerror scores) in spatial working memory following activetreatment (see Fig. 1). A similarly designed study was carriedout in patients with schizophrenia but no significant changeson any measure were detected (Gallagher et al., 2005). Apooled analysis of the HPA axis data from these studiessuggested that there was a subtle but statistically significantreduction in peripheral cortisol levels from baseline, 2 weeksafter cessation of active treatment–—the time-point at whichthe effects on spatial memory were observed (Gallagheret al., 2008c).
Comparing results of the treatment studies using GRantagonists with studies of the effect of HPA axis manipula-tion in animals and in healthy humans, the effect on workingmemory — particularly spatial working memory — is consis-tent. Apparent incongruence in the data on other domainssuch as verbal declarative memory may be attributable tomethodological differences. For example, the typical use ofparagraph recall or other word lists with a larger number ofitems, when examining the effects of corticosteroids in thehealthy human literature, may explain the lack of effects onverbal declarative memory seen in the Young et al. study(which used the 15-item Rey-AVLT) while subtle but positiveeffects were seen on word recall in the Pomera et al. study.
It is important to consider the treatment regimen used inthese trials. Although the administration of mifepristone wasonce daily, more chronic receptor occupancy was likely bythe end of the treatment period because mifepristone, hasrapid absorption, a long half-life (of 25—30 h) andmicromolarserum concentrations following typical doses (Heikinheimo
et al., 2003). This may explain the positive effects found inspatial memory processes, akin to those found in chronic (butnot phasic) administration in rodents (see Oitzl et al.,1998a,b). It should also be noted that, although it is typicallyreferred to as an antagonist, evidence indicates that mife-pristone is a partial agonist at the GR (Bourgeois et al., 1984;Laue et al., 1988). A recent paper has reported that mife-pristone exerted partial agonistic effects, while blocking theeffects of glucocorticoids, on mitochondrial GR translocationand mitochondrial membrane potential. These results arediscussed in the context of the biphasic (inverted ‘‘U’’-shaped) effects of glucocorticoids on neural functions,including memory (Du et al., 2009). Further studies aretherefore needed to understand the effects seen on humancognition.
6. Conclusions, implications and futuredirections
From the data reviewed it is clear that there is now asignificant literature on the co-occurrence of HPA axisdysregulation and neuropsychological impairment in mooddisorders. Studies directly linking hypercortisolaemia or GRdysfunction as a specific cause of this impairment are lessconsistent in terms of which neuropsychological domainsare affected, but the evidence is increasing. To date,studies have mostly involved relating overall degree ofHPA disturbance (e.g. magnitude of response to the dex/CRH or dexamethasone non-suppression) to neuropsycho-logical performance. However, in healthy subjects investi-gating the direct association of glucocorticoids withmemory performance, and the subtle manipulation of cor-tisol levels or GR ant-/agonism at specific stages of infor-mation processing, have all highlighted the complexity ofthe relationship between the HPA axis and discrete memoryprocesses. Further investigation of the effects of glucocor-ticoid manipulation on the discreet steps of cognition inpatients with mood disorders are required and are likely toprove of great interest. However, factoring in the degree ofHPA/GR disturbance which occurs in patients and medica-tion/illness factors further increases the difficulty of thisstrategy.
It appears that theremay be a dual mechanism that shouldbe considered: first, the atrophic effects that chronic HPAaxis disturbance and hypercortisolaemia has on brain struc-ture and second, the activational effects of glucocorticoidson the formation and processes of memory within this sys-tem. The effects on neuropsychological processes need to beconsidered in the context of the inverted ‘‘U’’-shaped curve;the effects glucocorticoids have in a healthy, functioningsystem may not directly translate to a system in a hyper-activated state with an elevated homeostatic set-point (par-ticularly given the importance of relative MR:GR balance deKloet et al., 1998).
Studies are currently underway, including by our owngroup, to examine in more depth the effects of GR antago-nists on neuropsychological functioning and symptoms inmood disorders. A particular focus is in fractionating thefindings on spatial memory into sub-processes to establish thespecificity of these effects in humans (Gallagher et al.,2008b; Watson et al., 2009). It would also be desirable toexamine these effects in healthy subjects to understand the
Neuropsychological functioning in health and mood disorder S203
role of corticosteroid receptors under phasic or chronicblockade. Also needed are studies using the more selectiveGR antagonists which are currently in development and havebeen piloted in human subjects (Høyberg et al., 2002;Peeters et al., 2008). Such drugs offer an interesting oppor-tunity to better understand the direct modulatory role ofglucocorticoids and their receptors on neuropsychologicalfunctioning in patients with mood disorders and also thehope that such interventions will be of therapeutic andfunctional benefit to such patients.
Author disclosures
INF is a co-applicant for a patent for use of GR antagonists asan SSRI augmentation treatment in depression.
Role of funding source
PG and INF are currently conducting a trial of a GRantagonist (mifepristone) in bipolar disorder funded bythe Medical Research Council and Stanley Medical ResearchInstitute.
Conflict of interest
None declared.
References
Adler, G., Jajcevic, A., 2001. Post-dexamethasone cortisol level andmemory performance in elderly depressed patients. Neurosci.Lett. 298, 142—144.
Agarwal, M.K., Mirshahi, F., Mirshahi, M., Rostene, W., 1993. Immu-nochemical detection of the mineralocorticoid receptor in ratbrain. Neuroendocrinology 58, 575—580.
Ahima, R., Krozowski, Z., Harlan, R., 1991. Type I corticosteroidreceptor-like immunoreactivity in the rat CNS: distributionand regulation by corticosteroids. J. Comp. Neurol. 313,522—538.
Appelhof, B.C., Huyser, J., Verweij, M., Brouwer, J.P., van Dyck, R.,Fliers, E., Hoogendijk, W.J.G., Tijssen, J.G.P., Wiersinga, W.M.,Schene, A.H., 2006. Glucocorticoids and relapse of major depres-sion (dexamethasone/corticotropin-releasing hormone test inrelation to relapse of major depression). Biol. Psychiatry 59,696—701.
Aubry, J.-M., Gervasoni, N., Osiek, C., Perret, G., Rossier, M.F.,Bertschy, G., Bondolfi, G., 2007. The DEX/CRH neuroendocrinetest and the prediction of depressive relapse in remitteddepressed outpatients. J. Psychiatr. Res. 41, 290—294.
Bearden, C.E., Hoffman, K.M., Cannon, T.D., 2001. The neuropsy-chology and neuroanatomy of bipolar affective disorder: a criticalreview. Bipolar Disord. 3, 106—150.
Bhagwagar, Z., Hafizi, S., Cowen, P.J., 2005. Increased salivarycortisol after waking in depression. Psychopharmacology (Berl.)182, 54—57.
Bhagwagar, Z., Montgomery, A.J., Grasby, P.M., Cowen, P.J., 2003.Lack of effect of a single dose of hydrocortisone on serotonin1Areceptors in recovered depressed patients measured by positronemission tomography with [11C]WAY-100635. Biol. Psychiatry 54,890—895.
Board, F., Persky, H., Hamburg, D.A., 1956. Psychological stress andendocrine functions; blood levels of adrenocortical and thyroid
hormones in acutely disturbed patients. Psychosom. Med. 18,324—333.
Board, F., Wadeson, R., Persky, H., 1957. Depressive affect andendocrine functions; blood levels of adrenal cortex and thyroidhormones in patients suffering from depressive reactions. AMAArch. Neurol. Psychiatry 78, 612—620.
Bora, E., Yucel, M., Pantelis, C., 2009. Cognitive endophenotypes ofbipolar disorder: a meta-analysis of neuropsychological deficits ineuthymic patients and their first-degree relatives. J. Affect.Disord. 113, 1—20.
Borkowska, A., Rybakowski, J.K., 2001. Neuropsychological frontallobe tests indicate that bipolar depressed patients are moreimpaired than unipolar. Bipolar Disord. 3, 88—94.
Bornstein, S.R., Engeland, W.C., Ehrhart-Bornstein, M., Herman,J.P., 2008. Dissociation of ACTH and glucocorticoids. TrendsEndocrinol. Metab. 19, 175—180.
Bourgeois, S., Pfahl, M., Baulieu, E.E., 1984. DNA binding propertiesof glucocorticosteroid receptors bound to the steroid antagonistRU-486. EMBO J. 3, 751—755.
Bremner, J.D., Vythilingam, M., Vermetten, E., Anderson, G., New-comer, J.W., Charney, D.S., 2004. Effects of glucocorticoids ondeclarative memory function in major depression. Biol. Psychia-try 55, 811—815.
Burt, D.B., Zembar, M.J., Niederehe, G., 1995. Depression andmemory impairment–—a metaanalysis of the association, its pat-tern, and specificity. Psychol. Bull. 117, 285—305.
Calev, A., Korin, Y., Shapira, B., Kugelmass, S., Lerer, B., 1986. Verbaland non-verbal recall by depressed and euthymic affectivepatients. Psychol. Med. 16, 789—794.
Campolongo, P., Roozendaal, B., Trezza, V., Hauer, D., Schelling, G.,McGaugh, J.L., Cuomo, V., 2009. Endocannabinoids in the ratbasolateral amygdala enhance memory consolidation and enableglucocorticoid modulation of memory. PNAS 106, 4888—4893.
Carroll, B.J., 1982a. Clinical applications of the dexamethasonesuppression test for endogenous depression. Pharmacopsychiatria15, 19—25.
Carroll, B.J., 1982b. The dexamethasone suppression test for mel-ancholia. Br. J. Psychiatry 140, 292—304.
Cintra, A., Zoli, M., Rosen, L., Agnati, L.F., Okret, S., Wikstrom, A.C.,Gustaffsson, J.A., Fuxe, K., 1994. Mapping and computer assistedmorphometry and microdensitometry of glucocorticoid receptorimmunoreactive neurons and glial cells in the rat central nervoussystem. Neuroscience 62, 843—897.
Clark, L., Iversen, S.D., Goodwin, G.M., 2002. Sustained attentiondeficit in bipolar disorder. Br. J. Psychiatry 180, 313—319.
Clark, L., Sarna, A., Goodwin, G.M., 2005. Impairment of executivefunction but not memory in first-degree relatives of patients withbipolar I disorder and in euthymic patients with unipolar depres-sion. Am. J. Psychiatry 162, 1980—1982.
Cohen, S.I., 1980. Cushing’s syndrome: a psychiatric study of 29patients. Br. J. Psychiatry 136, 120—124.
de Kloet, E.R., Oitzl, M.S., Joels, M., 1999. Stress and cognition: arecorticosteroids good or bad guys? Trends Neurosci. 22, 422—426.
de Kloet, E.R., Reul, J.M.H.M., 1987. Feedback action and tonicinfluence of corticosteroids on brain function: a concept arisingfrom the heterogeneity of brain receptor systems. Psychoneur-oendocrinology 12, 83—105.
de Kloet, E.R., Vreugdenhil, E., Oitzl, M.S., Joels, M., 1998. Braincorticosteroid receptor balance in health and disease. Endocr.Rev. 19, 269—301.
de Quervain, D.J., Henke, K., Aerni, A., Treyer, V., McGaugh, J.L.,Berthold, T., Nitsch, R.M., Buck, A., Roozendaal, B., Hock, C.,2003. Glucocorticoid-induced impairment of declarative memoryretrieval is associated with reduced blood flow in the medialtemporal lobe. Eur. J. Neurosci. 17, 1296—1302.
S204 P. Gallagher et al.
de Quervain, D.J., Roozendaal, B., Nitsch, R., McGaugh, J., Hock, C.,2000. Acute cortisone administration impairs retrieval of long-term declarative memory in humans. Nat. Neurosci. 3, 313—314.
Deuschle, M., Schweiger, U., Weber, B., Gotthardt, U., Korner, A.,Schmider, J., Standhardt, H., Lammers, C.H., Heuser, I., 1997.Diurnal activity and pulsatility of the hypothalamus—pituitary—adrenal system in male depressed patients and healthy controls.J. Clin. Endocrinol. Metab. 82, 234—238.
Douma, B.R.K., Korte, S.M., Buwalda, B., la Fleur, S.E., Bohus, B.,Luiten, P.G.M., 1998. Repeated blockade of mineralocorticoidreceptors, but not of glucocorticoid receptors impairs foodrewarded spatial learning. Psychoneuroendocrinology 23,33—44.
Du, J., Wang, Y., Hunter, R., Wei, Y., Blumenthal, R., Falke, C.,Khairova, R., Zhou, R., Yuan, P., Machado-Vieira, R., McEwen,B.S., Manji, H.K., 2009. Dynamic regulation of mitochondrialfunction by glucocorticoids. Proc. Natl. Acad. Sci. U.S.A. 106,3543—3548.
Duval, F., Mokrani, M.C., Crocq, M.A., Bailey, P.E., Diep, T.S., Correa,H., Macher, J.P., 2000. Dopaminergic function and the cortisolresponse to dexamethasone in psychotic depression. Prog. Neu-ropsychopharmacol. Biol. Psychiatry 24, 207—225.
Egeland, J., Lund, A., Landro, N.I., Rund, B.R., Sundet, K., Asbjorn-sen, A., Mjellem, N., Roness, A., Stordal, K.I., 2005. Cortisol levelpredicts executive and memory function in depression, symptomlevel predicts psychomotor speed. Acta Psychiatr. Scand. 112,434—441.
El-Badri, S.M., Ashton, C.H., Moore, P.B., Marsh, V.R., Ferrier, I.N.,2001. Electrophysiological and cognitive function in young euthy-mic patients with bipolar affective disorder. Bipolar Disord. 3,79—87.
Fairchild, G., Leitch, M.M., Ingram, C.D., 2003. Acute and chroniceffects of corticosterone on 5-HT1A receptor-mediated autoin-hibition in the rat dorsal raphe nucleus. Neuropharmacology 45,925—934.
Ferrier, I.N., Stanton, B.R., Kelly, T.P., Scott, J., 1999. Neuropsycho-logical function in euthymic patients with bipolar disorder. Br. J.Psychiatry 175, 246—251.
Follenius, M., Simon, C., Brandenberger, G., Lenzi, P., 1987. Ultra-dian plasma corticotropin and cortisol rhythms: time-series ana-lyses. J. Endocrinol. Invest. 10, 261—266.
Forget, H., Lacroix, A., Cohen, H., 2002. Persistent cognitive impair-ment following surgical treatment of Cushing’s syndrome. Psy-choneuroendocrinology 27, 367—383.
Forget, H., Lacroix, A., Somma, M., Cohen, H., 2000. Cognitivedecline in patients with Cushing’s syndrome. J. Int. Neuropsychol.Soc. 6, 20—29.
Fusar-Poli, P., Allen, P., McGuire, P., Placentino, A., Cortesi, M.,Perez, J., 2006. Neuroimaging and electrophysiological studiesof the effects of acute tryptophan depletion: a systematicreview of the literature. Psychopharmacology (Berl.) 188,131—143.
Fuxe, K., Cintra, A., Agnati, L.F., Harfstrand, A., Wikstrom, A.C.,Okret, S., Zoli, M., Miller, L.S., Greene, J.L., Gustafsson, J.A.,1987. Studies on the cellular localization and distribution ofglucocorticoid receptor and estrogen receptor immunoreactivityin the central nervous system of the rat and their relationship tothe monoaminergic and peptidergic neurons of the brain. J.Steroid Biochem. 27, 159—170.
Gallagher, P., Porter, R.J., 2004. The neuropsychology of mooddisorders. In: Joyce, P.R., Mitchell, P.B. (Eds.), Mood Disorders:
Recognition and Treatment. University of New South Wales Press,Sydney, pp. 139—150.
Gallagher, P., Robinson, L.J., Gray, J.M., Porter, R.J., Young, A.H.,2007a. Neurocognitive function following remission in majordepressive disorder: potential objective marker of response?Aust. N. Z. J. Psychiatry 41, 54—61.
Gallagher, P., Smith, M.S., Watson, S., Young, A.H., Ferrier, I.N.,Gray, J.M., 2008b. Fractionation of spatial memory impairmentsin bipolar depression and relationship with HPA axis function. J.Psychopharmacol. (Oxf.) 22 (Suppl.), A71.
Gallagher, P., Watson, S., Dye, C.E., Young, A.H., Ferrier, I.N., 2008c.Persistent effects of mifepristone (RU-486) on cortisol levels inbipolar disorder and schizophrenia. J. Psychiatr. Res. 42, 1037—1041.
Gallagher, P., Watson, S., Smith, M.S., Ferrier, I.N., Young, A.H.,2005. Effects of adjunctive mifepristone (RU-486) administrationon neurocognitive function and symptoms in schizophrenia. Biol.Psychiatry 57, 155—161.
Gartside, S.E., Leitch, M.M., Young, A.H., 2003. Altered glucocorti-coid rhythm attenuates the ability of a chronic SSRI to elevateforebrain 5-HT: implications for the treatment of depression.Neuropsychopharmacology 28, 1572—1578.
Gibbons, J.L., 1964. Cortisol secretion rate in depressive illness.Arch. Gen. Psychiatry 10, 572—575.
Gibbons, J.L., McHugh, P.R., 1962. Plasma cortisol in depressiveillness. J. Psychiatr. Res. 2, 162—171.
Gomez, R.G., Fleming, S.H., Keller, J., Flores, B., Kenna, H., DeBat-tista, C., Solvason, B., Schatzberg, A.F., 2006. The neuropsycho-logical profile of psychotic major depression and its relation tocortisol. Biol. Psychiatry 60, 472—478.
Gorwood, P., Corruble, E., Falissard, B., Goodwin, G.M., 2008. Toxiceffects of depression on brain function: impairment of delayedrecall and the cumulative length of depressive disorder in a largesample of depressed outpatients. Am. J. Psychiatry 165, 731—739.
Halbreich, U., Asnis, G.M., Shindledecker, R., Zumoff, B., Nathan,R.S., 1985. Cortisol secretion in endogenous depression. I. Basalplasma levels. Arch. Gen. Psychiatry 42, 904—908.
Hatzinger, M., Hemmeter, U.M., Baumann, K., Brand, S., Holsboer-Trachsler, E., 2002. The combined DEX—CRH test in treatmentcourse and long-term outcome of major depression. J. Psychiatr.Res. 36, 287—297.
Heikinheimo, O., Kekkonen, R., Lahteenmaki, P., 2003. The phar-macokinetics of mifepristone in humans reveal insights intodifferential mechanisms of antiprogestin action. Contraception68, 421—426.
Het, S., Ramlow, G., Wolf, O.T., 2005. A meta-analytic review of theeffects of acute cortisol administration on human memory. Psy-choneuroendocrinology 30, 771—784.
Heuser, I., Yassouridis, A., Holsboer, F., 1994. The combined dex-amethasone/CRH test: a refined laboratory test for psychiatricdisorders. J. Psychiatr. Res. 28, 341—356.
Høyberg, Ø.J., Wik, G., Mehtonen, O.P., Peeters, B.W.M.M., Sennef,C., 2002. ORG 34517, a selective glucocorticoid receptor antago-nist with potent antidepressant activity: first clinical results. Int.J. Neuropsychopharmacol. 5, S148.
Ising, M., Horstmann, S., Kloiber, S., Lucae, S., Binder, E.B., Kern, N.,Kunzel, H.E., Pfennig, A., Uhr, M., Holsboer, F., 2007. Combineddexamethasone/corticotropin releasing hormone test predictstreatment response in major depression–—a potentialbiomarker? Biol. Psychiatry 62, 47—54.
Ito, T., Morita, N., Nishi, M., Kawata, M., 2000. In vitro and in vivoimmunocytochemistry for the distribution of mineralocorticoidreceptor with the use of specific antibody. Neurosci. Res. 37,173—182.
Neuropsychological functioning in health and mood disorder S205
Kelly, W.F., Checkley, S.A., Bender, D.A., Mashiter, K., 1983. Cush-ing’s syndrome and depression–—a prospective study of 26patients. Br. J. Psychiatry 142, 16—19.
Knable, M.B., Torrey, E.F., Webster, M.J., Bartko, J.J., 2001. Multi-variate analysis of prefrontal cortical data from the StanleyFoundation Neuropathology Consortium. Brain Res. Bull. 55,651—659.
Kuhlmann, S., Wolf, O.T., 2005. Cortisol and memory retrieval inwomen: influence of menstrual cycle and oral contraceptives.Psychopharmacology (Berl.) 183, 65—71.
Lanfumey, L., Pardon, M.-C., Laaris, N., Joubert, C., Hanoun, N.,Hamon, M., Cohen-Salmon, C., 1999. 5-HT1A autoreceptor desen-sitization by chronic ultramild stress in mice. Neuroreport 10,3369—3374.
Laue, L., Gallucci, W., Loriaux, D.L., Udelsman, R., Chrousos, G.P.,1988. The antiglucocorticoid and antiprogestin steroid RU 486: itsglucocorticoid agonist effect is inadequate to prevent adrenalinsufficiency in primates. J. Clin. Endocrinol. Metab. 67, 602—606.
Leitch, M.M., Ingram, C.D., Young, A.H., McQuade, R., Gartside,S.E., 2003. Flattening the corticosterone rhythm attenuates 5-HT(1A) autoreceptor function in the rat: relevance for depres-sion. Neuropsychopharmacology 28, 119—125.
Linkowski, P., Mendlewicz, J., Leclercq, R., Brasseur, M., Hubain, P.,Golstein, J., Copinschi, G., Van Cauter, E., 1985. The 24-hourprofile of adrenocorticotropin and cortisol in major depressiveillness. J. Clin. Endocrinol. Metab. 61, 429—438.
Lopez, J.F., Little, K.Y., Lopez-Figueroa, A.L., Lopez-Figueroa, M.O.,Watson, S.J., 2003. Glucocorticoid and mineralocorticoid recep-tor mRNA levels in the hippocampus and prefrontal cortex ofsubjects with mood disorders and schizophrenia. Biol. Psychiatry53 (Suppl. 1), S173.
Lupien, S.J., Gillin, C.J., Hauger, R.L., 1999. Working memory ismore sensitive than declarative memory to the acute effects ofcorticosteroids: a dose—response study in humans. Behav. Neu-rosci. 113, 420—430.
Lupien, S.J., McEwen, B.S., 1997. The acute effects of corticoster-oids on cognition: integration of animal and humanmodel studies.Brain Res. Brain Res. Rev. 24, 1—27.
Martinez-Aran, A., Vieta, E., Colom, F., Reinares, M., Benabarre, A.,Gasto, C., Salamero, M., 2000. Cognitive dysfunctions in bipolardisorder: evidence of neuropsychological disturbances. Psy-chother. Psychosom. 69, 2—18.
Martinez-Aran, A., Vieta, E., Colom, F., Reinares, M., Benabarre, A.,Torrent, C., Goikolea, J.M., Corbella, B., Sanchez-Moreno, J.,Salamero, M., 2002. Neuropsychological performance indepressed and euthymic bipolar patients. Neuropsychobiology46, 16—21.
Martinez-Aran, A., Vieta, E., Reinares, M., Colom, F., Torrent, C.,Sanchez-Moreno, J., Benabarre, A., Goikolea, J.M., Comes, M.,Salamero, M., 2004. Cognitive function across manic or hypoma-nic, depressed, and euthymic states in bipolar disorder. Am. J.Psychiatry 161, 262—270.
Mauri, M., Sinforiani, E., Bono, G., Vignati, F., Berselli, M.E., Atta-nasio, R., Nappi, G., 1993. Memory impairment in Cushing’sdisease. Acta Neurol. Scand. 87, 52—55.
McAllister-Williams, R.H., Ferrier, I.N., Young, A.H., 1998. Mood andneuropsychological function in depression: the role of corticos-teroids and serotonin. Psychol. Med. 28, 573—584.
McAllister-Williams, R.H., Massey, A.E., 2003. EEG effects of buspir-one and pindolol: a method of examining 5-HT1A receptor func-tion in humans. Psychopharmacology (Berl.) 166, 284—293.
McAllister-Williams, R.H., Massey, A.E., Fairchild, G., 2007.Repeated cortisol administration attenuates the EEG responseto buspirone in healthy volunteers: evidence for desensitizationof the 5-HT1 A autoreceptor. J. Psychopharmacol. 21, 826—832.
Modell, S., Yassouridis, A., Huber, J., Holsboer, F., 1997. Corticoster-oid receptor function is decreased in depressed patients. Neu-roendocrinology 65, 216—222.
Montgomery, A.J., Bench, C.J., Young, A.H., Hammers, A., Gunn,R.N., Bhagwager, Z., Grasby, P., 2001. PET measurement of theinfluence of corticosteroids on serotonin-1A receptor number.Biol. Psychiatry 50, 668—676.
Nelson, J.C., Davis, J.M., 1997. DSTstudies in psychotic depression: ameta-analysis. Am. J. Psychiatry 154, 1497—1503.
Newcomer, J.W., Selke, G., Melson, A.K., Hershey, T., Craft, S.,Richards, K., Alderson, A.L., 1999. Decreased memory perfor-mance in healthy humans induced by stress-level cortisol treat-ment. Arch. Gen. Psychiatry 56, 527—533.
Oitzl, M.S., de Kloet, E.R., 1992. Selective corticosteroid antagonistsmodulate specific aspects of spatial orientation learning. Behav.Neurosci. 106, 62—71.
Oitzl, M.S., Fluttert, M., Sutanto, W., de Kloet, E.R., 1998b. Con-tinuous blockade of brain glucocorticoid receptors facilitatesspatial learning and memory in rats. Eur. J. Neurosci. 10,3759—3766.
Pace, T.W., Spencer, R.L., 2005. Disruption of mineralocorticoidreceptor function increases corticosterone responding to a mild,but not moderate, psychological stressor. Am. J. Physiol. Endo-crinol. Metab. 288, E1082—E1088.
Patel, P.D., Lopez, J.F., Lyons, D.M., Burke, S., Wallace, M., Schatz-berg, A.F., 2000. Glucocorticoid and mineralocorticoid receptormRNA expression in squirrel monkey brain. J. Psychiatr. Res. 34,383—392.
Peeters, B.W., Ruigt, G.S., Craighead, M., Kitchener, P., 2008. Dif-ferential effects of the new glucocorticoid receptor antagonistORG 34517 and RU486 (mifepristone) on glucocorticoid receptornuclear translocation in the AtT20 cell line. Ann. N. Y. Acad. Sci.1148, 536—541.
Porter, R.J., Bourke, C., Gallagher, P., 2007. Neuropsychologicalimpairment in major depression–—its nature, origin and clinicalsignificance. Aust. N. Z. J. Psychiatry 41, 115—128.
Porter, R.J., Gallagher, P., Thompson, J.M., Young, A.H., 2003.Neurocognitive impairment in drug-free patients with majordepressive disorder. Br. J. Psychiatry 182, 214—220.
Porter, R.J., Gallagher, P., Watson, S., Lunn, B.S., Young, A.H., 2002.Effects of sub-chronic administration of hydrocortisone on hor-monal and psychological responses to l-tryptophan in normalmalevolunteers. Psychopharmacology (Berl.) 163, 68—75.
Porter, R.J., Gallagher, P., Watson, S., Young, A.H., 2004. Corticos-teroid—serotonin interactions in depression: a review of thehuman evidence. Psychopharmacology (Berl.) 173, 1—17.
Posener, J.A., DeBattista, C., Williams, G.H., Kraemer, H.C., Kaleh-zan, B.M., Schatzberg, A.F., 2000. 24-hour monitoring of cortisoland corticotropin secretion in psychotic and nonpsychotic majordepression. Arch. Gen. Psychiatry 57, 755—760.
Quirarte, G.L., Roozendaal, B., McGaugh, J.L., 1997. Glucocorticoidenhancement of memory storage involves noradrenergic activa-tion in the basolateral amygdala. Proc. Natl. Acad. Sci. U.S.A. 94,14048—14053.
Raison, C.L., Miller, A.H., 2003. When not enough is too much: therole of insufficient glucocorticoid signaling in the pathophysiologyof stress-related disorders. Am. J. Psychiatry 160, 1554—1565.
Reppermund, S., Zihl, J., Lucae, S., Horstmann, S., Kloiber, S.,Holsboer, F., Ising, M., 2007. Persistent cognitive impairment indepression: the role of psychopathology and altered hypothala-
S206 P. Gallagher et al.
mic—pituitary—adrenocortical (HPA) system regulation. Biol. Psy-chiatry 62, 400—406.
Reul, J.M., de Kloet, E.R., 1985. Two receptor systems for corticos-terone in rat brain:microdistribution and differential occupation.Endocrinology 117, 2505—2511.
Rey, A., 1964. L’Examen Clinique en Psychologie. Press Universitairede France, Paris.
Ribeiro, S.C., Tandon, R., Grunhaus, L., Greden, J.F., 1993. The DSTas a predictor of outcome in depression: a meta-analysis. Am. J.Psychiatry 150, 1618—1629.
Robinson, L.J., Ferrier, I.N., 2006. Evolution of cognitive impairmentin bipolar disorder: a systematic review of cross-sectional evi-dence. Bipolar Disord. 8, 103—116.
Robinson, L.J., Thompson, J.M., Gallagher, P., Goswami, U., Young,A.H., Ferrier, I.N., Moore, P.B., 2006. Ameta-analysis of cognitivedeficits in euthymic bipolar subjects. J. Affect. Disord. 93, 105—115.
Roiser, J.P., Cannon, D.M., Gandhi, S.K., Tavares, J.T., Erickson, K.,Wood, S., Klaver, J.M., Clark, L., Zarate Jr., C.A., Sahakian, B.J.,Drevets, W.C., 2009. Hot and cold cognition in unmedicateddepressed subjects with bipolar disorder. Bipolar Disord. 11,178—189.
Roozendaal, B., Barsegyan, A., Lee, S., 2008. Adrenal stress hor-mones, amygdala activation, and memory for emotionally arous-ing experiences. Prog. Brain Res. 167, 79—97.
Roozendaal, B., Okuda, S., Van der Zee, E.A., McGaugh, J.L., 2006.Glucocorticoid enhancement ofmemory requires arousal-inducednoradrenergic activation in the basolateral amygdala. PNAS 103,6741—6746.
Rosen, W.G., Mohs, R.C., Davis, K.L., 1984. A new rating scale forAlzheimer’s disease. Am. J. Psychiatry 141, 1356—1364.
Rush, A.J., Giles, D.E., Schlesser, M.A., Orsulak, P.J., Parker Jr., C.R.,Weissenburger, J.E., Crowley, G.T., Khatami, M., Vasavada, N.,1996. The dexamethasone suppression test in patients with mooddisorders. J. Clin. Psychiatry 57, 470—484.
Rybakowski, J.K., Twardowska, K., 1999. The dexamethasone/cor-ticotropin-releasing hormone test in depression in bipolar andunipolar affective illness. J. Psychiatr. Res. 33, 363—370.
Sauro, M.D., Jorgensen, R.S., Teal Pedlow, C., 2003. Stress, gluco-corticoids, and memory: a meta-analytic review. Stress 6, 235—245.
Smeets, T., Otgaar, H., Candel, I., Wolf, O.T., 2008. True or false?Memory is differentially affected by stress-induced cortisol ele-vations and sympathetic activity at consolidation and retrieval.Psychoneuroendocrinology 33, 1378—1386.
Starkman, M.N., Gebarski, S.S., Berent, S., Schteingart, D.E., 1992.Hippocampal formation volume, memory dysfunction, and corti-sol levels in patients with Cushing’s syndrome. Biol. Psychiatry 32,756—765.
Symonds, C.S., Gallagher, P., Thompson, J.M., Young, A.H., 2004.Effects of the menstrual cycle on mood, neurocognitive andneuroendocrine function in healthy premenopausal women. Psy-chol. Med. 34, 93—102.
Taylor Tavares, J.V., Clark, L., Cannon, D.M., Erickson, K., Drevets,W.C., Sahakian, B.J., 2007. Distinct profiles of neurocognitivefunction in unmedicated unipolar depression and bipolar IIdepression. Biol. Psychiatry 62, 917—924.
Thomas, A.J., Gallagher, P., Robinson, L.J., Porter, R.J., Young, A.H.,Ferrier, I.N., O’Brien, J.T., 2009. A comparison of neurocognitiveimpairment in younger and older adults with major depression.Psychol. Med. 39, 725—733.
Torrent, C., Martinez-Aran, A., Daban, C., Sanchez-Moreno, J.,Comes, M., Goikolea, J.M., Salamero, M., Vieta, E., 2006. Cog-nitive impairment in bipolar II disorder. Br. J. Psychiatry 189,254—259.
Trichard, C., Martinot, J.L., Alagille, M., Masure, M.C., Hardy, P.,Ginestet, D., Feline, A., 1995. Time course of prefrontal lobedysfunction in severely depressed in-patients: a longitudinalneuropsychological study. Psychol. Med. 25, 79—85.
Tytherleigh, M.Y., Vedhara, K., Lightman, S.L., 2004. Mineralocorti-coid and glucocorticoid receptors and their differential effects onmemory performance in people with Addison’s disease. Psycho-neuroendocrinology 29, 712—723.
van Gorp, W.G., Altshuler, L., Theberge, D.C., Wilkins, J., Dixon, W.,1998. Cognitive impairment in euthymic bipolar patients with andwithout prior alcohol dependence: a preliminary study. Arch.Gen. Psychiatry 55, 41—46.
van Haarst, A.D., Oitzl, M.S., de Kloet, E.R., 1997. Facilitation offeedback inhibition through blockade of glucocorticoid receptorsin the hippocampus. Neurochem. Res. 22, 1323—1328.
van Londen, L., Goekoop, J.G., Zwinderman, A.H., Lanser, J.B.,Wiegant, V.M., De Wied, D., 1998. Neuropsychological perfor-mance and plasma cortisol, arginine vasopressin and oxytocin inpatients with major depression. Psychol. Med. 28, 275—284.
van Stegeren, A.H., 2009. Imaging stress effects onmemory: a reviewof neuroimaging studies. Can. J. Psychiatry 54, 16—27.
Veiel, H.O., 1997. A preliminary profile of neuropsychological deficitsassociated with major depression. J. Clin. Exp. Neuropsychol. 19,587—603.
Watson, S., Gallagher, P., Porter, R.J., Smith, M., Elmslie, J.L.,Ogilve, A., Harikumar, T.R., Menon, A., Carlile, J., Makhoul,S., Ferrier, I.N., Young, A.H., 2009. Efficacy of mifepristone(RU-486) in the treatment of bipolar depression. Biol. Psychiatry64 (Suppl.), 135—136S.
Watson, S., Gallagher, P., Ritchie, J.C., Ferrier, I.N., Young, A.H.,2004. Hypothalamic—pituitary—adrenal axis function in patientswith bipolar disorder. Br. J. Psychiatry 184, 496—502.
Watson, S., Gallagher, P., Smith, M.S., Ferrier, I.N., Young, A.H.,2006a. The dex/CRH test–—is it better than the DST? Psychoneur-oendocrinology 31, 889—894.
Watson, S., Owen, B.M., Gallagher, P., Hearn, A.J., Young, A.H.,Ferrier, I.N., 2007. Family history, early adversity and thehypothalamic—pituitary—adrenal (HPA) axis: mediation of thevulnerability to mood disorders. Neuropsychiatr. Dis. Treat. 3,647—653.
Watson, S., Thompson, J.M., Ritchie, J.C., Ferrier, I.N., Young, A.H.,2006b. Neurocognitive impairment in bipolar disorder: the rela-tionship with glucocorticoid receptor function. Bipolar Disord. 8,85—90.
Wauthy, J., Ansseau, M., von Frenckell, R., Mormont, C., Legros, J.J.,1991. Memory disturbances and dexamethasone suppression testin major depression. Biol. Psychiatry 30, 736—738.
Webster, M.J., Knable, M.B., O’Grady, J., Orthmann, J., Weickert,C.S., 2002. Regional specificity of brain glucocorticoid receptormRNA alterations in subjects with schizophrenia and mood dis-orders. Mol. Psychiatry 7, 985—994.
Weitzman, E.D., Fukushima, D., Nogeire, C., Roffwarg, H., Gallagher,T.F., Hellman, L., 1971. Twenty-four hour pattern of the episodicsecretion of cortisol in normal subjects. J. Clin. Endocrinol.Metab. 33, 14—22.
Whelan, T.B., Schteingart, D.E., Starkman, M.N., Smith, A., 1980.Neuropsychological deficits in Cushing’s syndrome. J. Nerv. Ment.Dis. 168, 753—757.
Wolf, O.T., 2008. The influence of stress hormones on emotionalmemory: relevance for psychopathology. Acta Psychol. (Amst.)127, 513—531.
Wolf, O.T., Kuhlmann, S., Buss, C., Hellhammer, D.H., Kirschbaum,C., 2004. Cortisol and memory retrieval in humans: influence ofemotional valence. Ann. N. Y. Acad. Sci. 1032, 195—197.
Neuropsychological functioning in health and mood disorder S207
Wolfe, J., Granholm, E., Butters, N., Saunders, E., Janowsky, D.,1987. Verbal memory deficits associated with major affectivedisorders: a comparison of unipolar and bipolar patients. J.Affect. Disord. 13, 83—92.
Wolkowitz, O.M., Reus, V.I., Weingartner, H., Thompson, K., Breier,A., Doran, A., Rubinow, D., Pickar, D., 1990. Cognitive effects ofcorticosteroids. Am. J. Psychiatry 147, 1297—1303.
Wong, M.L., Kling, M.A., Munson, P.J., Listwak, S., Licinio, J., Prolo,P., Karp, B., McCutcheon, I.E., Geracioti, T.D., DeBellis, M.D.,Rice, K.C., Goldstein, D.S., Veldhuis, J.D., Chrousos, G.P., Old-field, E.H., McCann, S.M., Gold, P.W., 2000. Pronounced andsustained central hypernoradrenergic function in major depres-sion with melancholic features: relation to hypercortisolism andcorticotropin-releasing hormone. Proc. Natl. Acad. Sci. U.S.A. 97,325—330.
Young, A.H., Gallagher, P., Watson, S., Del-Estal, D., Owen, B.M.,Ferrier, I.N., 2004a. Improvements in neurocognitive function andmood following adjunctive treatment with mifepristone (RU-486)in bipolar disorder. Neuropsychopharmacology 29, 1538—1545.
Young, A.H., Sahakian, B.J., Robbins, T.W., Cowen, P.J., 1999. Theeffects of chronic administration of hydrocortisone on cognitivefunction in normal male volunteers. Psychopharmacology (Berl.)145, 260—266.
Young, E.A., Abelson, J., Lightman, S.L., 2004b. Cortisol pulsatilityand its role in stress regulation and health. Front. Neuroendo-crinol. 25, 69—76.
Young, E.A., Altemus, M., Lopez, J.F., Kocsis, J.H., Schatzberg, A.F.,deBattista, C., Zubieta, J.-K., 2004c. HPA axis activation in majordepression and response to fluoxetine: a pilot study. Psychoneur-oendocrinology 29, 1198—1204.
Zakzanis, K.K., Leach, L., Kaplan, E., 1998. On the nature andpattern of neurocognitive function in major depressive disorder.Neuropsychiatry. Neuropsychol. Behav. Neurol. 11, 111—119.
Zobel, A.W., Schulze-Rauschenbach, S., von Widdern, O.C., Metten,M., Freymann, N., Grasmader, K., Pfeiffer, U., Schnell, S.,Wagner, M., Maier, W., 2004. Improvement of working but notdeclarative memory is correlated with HPA normalization duringantidepressant treatment. J. Psychiatr. Res. 38, 377—383.
