Journal of Psychiatric Research 35 (2001) 127145 www.elsevier.

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Corticosteroids and cognition

Joseph K. Belanoa, Kristin Grossb,*, Alison Yagera, Alan F. Schatzberga
b a Stanford University School of Medicine, Department of Psychiatry, Stanford, CA 94305, USA Pacic Graduate School of Psychology (PGSP), 940 East Meadow Drive, Palo Alto, CA 94303, USA

Received 3 July 2000; received in revised form 23 February 2001; accepted 10 April 2001

Abstract The brain is a major target organ for corticosteroids. It has been observed that excessive circulatory levels of endogenous and exogenous corticosteroids are frequently associated with cognitive impairment in a wide variety of clinical disease states. Cognition and low levels of corticosteroids have been less well studied. In this paper we review the literature on glucocorticosteroid eects on cognition and delineate specic functions that appear to be causally aected. We draw a possible connection to specic areas of brain perturbation, including the hippocampus and frontal lobe regions. The possibility that cognitive dysfunction caused by glucocorticoids can be pharmacologically managed is introduced. # 2001 Published by Elsevier Science Ltd.
Keywords: Cognition; Glucocorticoids; Cortisol; Hippocampus; Memory; Glucocorticoid receptor antagonists

1. Introduction The brain is a major target organ for corticosteroids (McEwen et al., 1968). More than 40 years ago, the administration of ACTH or cortisone was often noted to cause emotional and behavioral eects including frank psychosis (Quarton et al., 1955). More recently, research has focused on observations that excessive circulating levels of corticosteroids are frequently associated with cognitive impairment in normal subjects as well as in patients with Cushings syndrome, major depression, schizophrenia, Alzheimers disease, anorexia nervosa, Korsakos psychosis, and cerebrovascular brain injury (Carpenter & Gruen, 1982; Reus, 1984; Wolkowitz et al., 1990; Martignoni et al., 1992; Mitchel, 1995; Mitchell & Dening, 1996). Both global and specic cognitive eects have been reported with recent emphasis placed on the hippocampus, in part because of observations in rats that glucocorticoids can damage hippocampal neurons. In this paper, we review the literature on glucocorticoid eects on cognition in man and attempt to delineate specic functions that appear

to be causally aected (Tables 1 and 2). Several areas of cognitive functioning that are believed to be controlled by areas of the brain other than the hippocampus are highlighted. The possibility that cognitive dysfunction caused by glucocorticoids can be pharmacologically managed is introduced.

2. Corticosteroids, the hippocampus, and cognition Glucocorticoids, such as cortisol, are released by the adrenal cortex in response to a wide range of stressors. Through negative feedback inhibition, circulating glucocorticoids regulate the production and release of hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH). In addition, glucocorticoids modulate neurotransmitter systems and regulate the plasticity and circuitry of many brain regions (McEwen, 1999). It is likely that they play a role in the death and survival of neurons, dendritic branching and synapse formation, the abundance of certain structural proteins in glia cells, and the operation of various second messenger systems (Orchinik and McEwen, 1995). In addition, glucocorticoids are believed to suppress myelin content in the brain (Meyer, 1985), aect serotonin biosynthesis, and increase the uptake of norepinephrine in the brain (De Kloet, 1991).

* Corresponding author at present address: 3883 18th Street, San Francisco, CA 94114, USA. Tel.: +1-415-437-2621; fax: +1-415-4371881. E-mail address: belano@leland.stanford.edu (J.K. Belano).

0022-3956/01/$ - see front matter # 2001 Published by Elsevier Science Ltd. PII: S0022-3956(01)00018-8

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Table 1 Eects of corticosteroids on cognitive functioning Study Van Londen et al. (1998) Sample size Criterion group (criterion/control) 56/0 MDD Design Post-test Steroid N/A Tests/measures Plasma cortisol; vasopressin; oxytocin; WAIS-R; WMS-R; list learning tests MRI; Hamilton; MMSE; CAMCOG; MADRAS Word Recognition Test; measures of attention Neuropsych battery; CT scan Findings Neg. correlation between intellectual and memory functioning and baseline cortisol Increased HPA axis dysregulation related to depression and cognitive performance Pos. relationship between cortisol levels and errors of commission in depressed patients Greater VBR, atrophy and cortisol levels for psychotic depressives; nonpsychotic depressives did worse on frontal lobe measures; correlation between VBRs and specic neuropsych functions Signif. relationship between test errors and increased UFC Signif. decreased performance on memory, attention, verbal and performance IQ, visual and spatial processing Signif. impairment in all facets of memory but not in other cognitive functions Decreases performance on concentration tasks, verbal and non-verbal explicit memory, but not dependent on DST/UFC Association between reduced hippocampal formation, memory function and elevated cortisol levels Neg. correlation between cortisol levels and depression; and pos. correlation between cortisol levels, ACTH, memory and concentration Signif. impairment in visual memory and spatial-constructional functions

OBrien, Ames, et al. (1996a)

51/32

MDD

Correlational

Dexamethasone (DST) Dexamethasone (DST) Dexamethasone (DST)

Wolkowitz et al. (1990)

21/12

MDD

Between group

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Rothschild et al. (1989)

15 vs. 15

Psychotic vs. nonpsychotic

Correlational

Rubinow et al. (1984) Forget et al. (2000)

56/31 19/19

Aective Disorder Correlational Cushings Between group

N/A N/A

UFC; Halstead Category Test Extensive neuropsychological battery

Mauri et al. (1993)

25/25

Cushings

Between group

N/A

Extensive neuropsychological battery Neuropsychiatric battery; UFC

Martignoni et al. (1992)

24/24

Cushings

Between group

Dexamethasone (DST)

Starkman et al. (1992)

12/39

Cushings

Correlational

N/A

MRI; UFC; subtests of WMS

Starkman et al. (1986)

23/0

Cushings

Pre/post-test

Whelan et al. (1980) Aisen et al. (2000)

13/0 69/69

Cushings Alzheimers

Correlational Between group placebo-controlled Correlational

Dexamethasone (DST); pituitary irradiation; Mitotane N/A Prednisone

ACTH levels; Hamilton; neuropsychological battery

Michigan neuropsychological battery UFC; ADAS-cog CDR-SOB, BDRS, Hamilton, BPRS

Carlson et al. (1999)

52/52

Alzheimers

N/A

No dierence in cognitive between groups, treatment group showed behavioral decline Association between higher cortisol Plasma cortisol, plasma dehydroepiandrosterone sulfate, levels and decreased performance on Rivermead Behavioral Memory delayed route recall Test

Table 1 (continued) Study Weiner et al. (1997) Sample size Criterion group (criterion/control) 9/0 Alzheimers Design Correlational Steroid N/A Tests/measures Plasma cortisol; MMSE; DRS mADAS-COG Findings

OBrien, Schweitzer et al. (1996b) 16/18

Alzheimers

Post-test

ACTH (0.05 mg/kg once)

OBrien, Ames, et al. (1996a)

49/32

Alzheimers

Correlational

Dexamethasone (DST) Dexamethasone (DST) Dexamethasone (DST) Dexamethasone (DST) Prednisone (5 to 10 mg once) Prednisone for one year as therapeutic dose Hydrocortisone

Lawlor et al. (1992)

29/0

Alzheimers

Correlational

Davis et al. (1986) Balldin et al. (1983)

16/19 32/14

Alzheimers Alzheimers and Multinfarct dementia Chronic asthma (children) Systemic disease

Correlational Correlational

Association between hypercortisolemia and disease progression and cognitive decline Plasma cortisol; CAMCOG Relatioship between ACTH treatment and cortisol levels neg. correlation between cortisol and cognitive performance MRI; Hamilton; MMSE; HPA axis changes related to CAMCOG; MADRAS depression and dementia and hippocampal atrophy Alzheimers Disease Assessment Nonsignif. ndings for cortisol Scale levels and memory functions, but pos. correlation with aggitation DRS; Blessed Scale Correlation between severity of dementia and corsitol levels EEG; CT scan; GBS scale Correlation between elevated cortisol levels and severity of dementia Peabody Picture Voc.; Children Global Assessment Scale Tests of explicit and implicit memory Brief verbal memory test Increased corticosteroids caused increased anxiety and depression and decreased verbal memory Long-term drug tx showed signif. decline of explicit or declaritive memory Decline of free recall memory but not of recognition Signif. dose-dependent decrease in verbal memory;

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Bender et al. (1991)

22/0

Correlational

Keenan et al. (1995)

25/25

Between group

De Quervain et al. (2000)

36/0

Normals

Newcomer et al. (1999)

51

Normals

Placebo-controlled double-blind within-subject Placebo-controlled double-blind Placebo-controlled double-blind between group Correlational Placebo-controlled

Schmidt et al. (1999)

12/12

Normals

Hydrocortisone (160 or 40 mg/day for 4 days) Prednisone

Paragraph recall; Stroop CW test; Line orientation; Vigilance task EEG; memory recall; attention measures

Kirschbaum et al. (1996) Kirschbaum et al. (1996)

13/0 40/0

Normals Normals

N/A Hydrocortisone (10 mg once)

Newcomer et al. (1994)

19/0

Normals

Placebo controlled within subject

Wolkowitz et al. (1990)

30/19

Normals

Dexamethasone (0.5, 1, 1, 1 mg for 4 days) Placedo controlled; Dexamethasone between group (1 mg once)

Signif. increase in negative emotion and decline in recall performance in treatment group Social Stress Test Declarative Neg. correlation between stess, high memory test cortisol and decrease memory Memory test; Spatial Reasoning Neg. correlation between cortisol level and declaritive memory and spatial reasoning Paragraph recall test; serial Pos. correlation between cortisol levels addition task; vigilance task and decrease in both immediate and delayed free recall task Word Recognition Test; Pos. relationship between cortisol measures of attention, levels and errors of commision and intrusions into free recall

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Table 1 (continued) Study Wolkowitz et al. (1990) Sample size Criterion group (criterion/control) 11/0 Normals Design Within subject Steroid Prednisone (80 mg daily for 5 days) Tests/measures Word Recognition Test; measures of attention, Findings Pos. relationship between prednisone and errors of commision; eects vanished after discontinuation of drug administration Increased cortisol levels decreased ability to attend dierentially to visual stimuli Signicant relationship between high levels of cortisol and decreased working memory only Signicant relationship between high levels of cortisol and decreased visuo-spatial memory and executive function Cognitivie decits with higher dosage: confusion forgetfulness; distractability

Kopell et al. (1970)

18/0

Normals

Within subject

Lupien et al. (1999)

40/0

Normal (men only) Normals (men only)

Between group

Young et al. (1999)

20/0

Placebo-controlled double-blind within-subject

Cortisol (>3 mg/day 3-eld tachistoscope depending on body weight) Hydrocortisone (40, Working memory test; 12 word 300 or 600 mg/kg/h) declarative memory test; continuous performance test Hydrocortisone tests for spatial free recall and (20 mg twice for recognition memory; Tower of 10 days) London Hamilton; BDI; BPRS MMSE

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Su et al. (1993)

20/0

Normal (men only)

Fehm-Wolfsdorf et al. (1993)

18/0

Normal (men only) Normal elderly Normal elderly

Placebo controlled; Methyltestosterone within subject (placebo, 40 or 240 mg/day for 3 days) Within-subject Hydrocortisone

Plasma cortisol; brief memory task MMSE UFC; measures of visual and verbal memory; spatial ability; language Plasma cortisol; neuropsych battery CAMCOG

Kalmijn et al. (1998) Seeman et al. (1997)

189/0 1189/0

Longitudinal Longitudinal

Dexamethasone (DST) N/A

Lupien et al. (1995)

51/0

Normal elderly

Longitudinal

N/A

OBrien et al. (1994)

33/0

Normal elderly

Correlational

Dexamethasone (DST)

Hall et al. (1979)

14/0

Several medical conditions

Case observations

Several neuropsychological Prednisone 40 mg measures, clinical observations daily as therapeutic dose (length of treatment varied with medical condition)

Hydrocortisone treatment suppresses circadian variations in recall performance Neg. correlation between elevated cortisol levels and cognitive decits Correlation between elevated cortisol levels and memory functions only for female subjects Pos. correlation between age, cortisol, and decits in explicit memory and selective attention Pos. correlation between advancing age, impaired glucocorticoid feedback and decreased cognitive functions Psychotic symptoms (steroid psychosis); memory impairment; distractability

MDD, major depressive disorder; WAIS-R, Wechsler Adult Intelligence ScaleRevised; WMS-R, Wechsler Memory ScaleRevised; DST, Dexamethasone Suppression Test; MRI, magnetic resonance imaging; MMSE, mini mental status exam; CAMCOG, Cambridge Cognitive Examination; MADRAS, Montgomery and Asberg Depression Rating Scale; VBR, ventricle to brain ratio; UFC, urinary free cortisol; ACTH, adrenocorticotrophic hormone; DRS, Depression Rating Scale; mADAS-COG, Modied Alzheimers Disease Assessment ScaleCognitive; EEG, electroencephalogram; GBS, Gottes, Brane and Steen Dementia Rating Scale; Stroop CW Test, Stroop Color-Word Test; ADAS-cog, Alzheimers Disease Assessment Scale; CDR-SOB, Clinical Dementia Rating Scale sum of boxes; BDRS, Blessed Dementia Rating Scale.

Table 2 Eects of corticosteroids Study Thase et al. (1996) Sample size (criterion/control) 29/0 Criterion group MDD Design CBT treatment outcome study between group Correlational Pre/post-test Correlational Steroid Dexamethasone (DST) Dexamethasone (DST) Dexamethasone (DST) Dexamethasone (DST) Tests/ measures UFC; Hamilton; GAS MRI DSM-III CT scan Findings Inverse relationship CBT and pretreatment UFC J.K. Belano et al. / Journal of Psychiatric Research 35 (2001) 127145 Correlation between high cortisol levels and ventricular brain ratio Signif. correlation between increased cortisol and level of depression Abnormatities in brain anatomy (enlargement of 3rd ventricle) for subgroup of male patients with elevated cortisol levels Pos. correlation between cortisol levels and ventricular size Correlation between increased HFV and decreased UFC High cerebral and cerebellar cortical atrophy; ventricular enlargement Reduced plasma cortisol in hippocampus in treatment group Neuronal loss, esp. in hippocampus ACTH was not signif. between groups Antiglucocorticoid eect with increased cortisol and adrenocorticotropic hormone levels Substantial neuronal loss in subiculum and hilus of dentate gyrus with age Association between prolonged cortisol elevations and reduced hippocampal volume

Rao et al. (1989) Ferrier et al. (1988) Schlegel and Kretschmar (1987)

46/0 13/16 60/60

MDD MDD Aective Disorders

Kellner et al. (1983) Starkman et al. (1999) Momose et al. (1971) De Leon et al. (1997) Ball et al. (1985) Ferrier et al. (1988) Kettel et al. (1991)

10/0 22/0 31/0 8/7 20/0 15/16 60/0

Bipolar I Cushings Cushings Alzheimers Alzheimers Alzheimers Normals

Correlational Correlational Correlational Placebo-controlled between group Correlational Pre/post-test Longitudinal

N/A N/A N/A Hydrocortisone (35mg on 2 days) N/A Dexamethasone RU486 (2 mg/kg/day for 3 months) N/A

CT scan; UFC MRI scan after surgery; UFC Pneumoencephalopathy; proton-beam therapy PET Necrosy DSM-III Plasma cortisol and adrenocorticotropic hormone levels Brain autopsy

West (1993)

32/0

Normals (men only) Normal elderly

N/A

Lupien et al. (1998)

Longitudinal

N/A

MRI

CBT, cognitive-behavioral therapy; DST, Dexamethasone Suppression Test; UFC, urinary free cortisol; GAS, Global Assessment Scale; MRI, magnetic resonance imaging; DSM-III, Diagnostic and Statistical Manual of Mental DisordersIII; ACTH, adrenocorticotrophic hormone; HFV, Hippocampal Formation Volume.

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Adrenal steroids have been postulated to expect two distinct types of physiologic eects: a fairly rapid eect, inuencing membrane receptor sites, and a more longlasting eect on gene expression with subsequent changes in the regulation of neurotransmitter receptors and enzymes (Mauri et al., 1993). There are at least two distinct types receptors in the brain, Type I and Type II, that bind with glucocorticoids (Reul and De Kloet, 1985; De Kloet, 1991). Type I, also referred to as MR, binds to aldosterone with high anity as well, and MR, despite its anity for glucocorticoids, is often considered a mineralocorticoid receptor. The two classes of receptors may represent a bi-level recognition system, with Type I receptors showing a higher anity for glucocorticoids than do Type II receptors. This bi-level system may enable the brain to distinguish between two types of glucocorticoid secretion, namely stress-dependent release and circadian release (De Kloet, 1991). Chronic exposure of the limbic regions of the brain to glucocorticoids has been associated with neuropsychiatric changes, neurophysiological changes (as evidenced by alterations in EEG), neurotransmitter eects, and a variety of neuroanatomical changes (including cortical atrophy, ventricular enlargement, and hippocampal degeneration) (Sapolsky et al., 1985; 1986). Several of these changes, particularly ventricular enlargement and cerebral atrophy, have been linked to cognitive impairment (Rothschild et al., 1989). In addition, the association between glucocorticoids, calcium ions, and excitatory amino acids suggest that additional factors may contribute to the pathological consequences of glucocorticoids (McEwen, 1988). The hippocampal formation (HF) is an important receptor site for glucocorticoids in the CNS. Type I receptors are found predominantly in the hippocampus, while type II receptors are found not only in the hippocampus but are also widely distributed in other brain regions (Joels and DeKloet, 1992; McEwen et al., 1992). The HF is often described as the cognitive arm of the limbic system, since it plays an important role in memory as well as in determining how expectations match with actual events (Eichenbaum et al., 1992). The hippocampus is essential for declarative or explicit memory in particular, which refers to the conscious or voluntary recollection of information. There are numerous inhibitory eects of glucocorticoids that are site-preferential to the hippocampus, including inhibition of glucose transport into hippocampal neurons and glia at high concentrations of glucocorticoids (Horner et al., 1990), involution of dendritic processes of hippocampal neurons (Woolley et al., 1990), inhibition of long-term potentiation in an experiment using stress (restraint and restraint plus shock) paradigms (Foy et al., 1987), and inhibition of primed burst potentiation in the urethaneanesthetized rat (Bennett et al., 1991). Glucocorticoid eects may also further vary within dened structural

domains of the hippocampal formation (Herman et al., 1989). Glucocorticoid receptors in the hippocampus are lost as part of the normal aging process, and both hippocampal damage and hippocampal receptor loss are associated with learning impairments. Numerous studies suggest that there is a strong association between elevated cortisol levels and hippocampal and/or glucocorticoid receptor damage. Sapolsky et al. (1986) argued that, in rats, both elevated levels of glucocorticoids as well as cumulative exposure of normal concentrations of the hormone leads to hippocampal degeneration. Rats exposed to daily restraint stress, or given daily corticosterone injections for 21 days, developed atrophy of the apical dendrites in hippocampal CA3 pyramidal cells. The administration of phenytoin prevented this atrophy, suggesting a role of excitatory amino acids in the atrophic process. With severe stress, or extended daily administration of corticosterone for 12 weeks, the rats developed a permanent depletion in glucocorticoid receptors, resulting from destruction of the host neurons themselves. This neuronal loss was similar to that seen in aging (Sapolsky et al., 1986). Furthermore, the presence of NMDA receptors appears to be essential for the development of glucocorticoid-induced dendritic atrophy in CA3 pyramidal neurons (Magarinos and McEwen, 1996). Cumulative exposure to glucocorticoids over a lifetime may mediate the death of hippocampal neurons. Furthermore, elevated basal levels of glucocorticoids, insensitivity to the normal glucocorticoid negative feedback loop, and a delayed recovery from stress are consistently related to decreased binding of glucocorticoids in the hippocampus and/or frank hippocampal damage. The damage may result from a disruption of hippocampal neuronal energy metabolism, because glucocorticoids can inhibit the uptake and utilization of glucose in the hippocampus. This has been shown in both rats (Landgraf et al., 1978; Horner et al., 1990; Veirgin et al., 1991; Freo et al., 1992) and healthy humans (De Loen et al., 1997). Stress or corticosterone injections result in the release of both serotonin and glutamate, which may interact pre- or post-synaptically and contribute to the destructive eects. High doses of corticosterone in rats reduce the mRNA levels of brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in the hippocampus. Both are substances thought to be involved in the regulation of neuronal survival. There is also a negative correlation between plasma cortisol levels and long-term potentiation, a process involved in memory storage (Pavlides et al., 1993). According to Sapolskys Glucocorticoid Cascade Hypothesis, periods of stress or excessive glucocorticoid secretion result in the down-regulation of glucocorticoid receptors in hippocampal neurons. A critical

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point is eventually reached, where the decreased receptor number interferes with the hippocampal feedback inhibition of the adrenocortical axis. A hypersecretion of glucocorticoids develops as a result of this disrupted feedback process, which in turn leads to more receptor down-regulation and glucocorticoid hypersecretion. Ultimately, there is permanent destruction of the hippocampal neurons, at which point the cycle of destruction is irreversible (Sapolsky et al., 1986). Further work has to some extent challenged Sapolskys original work. West (1993), using highly accurate stereological methods for estimating the total number of neurons in brain structures, found that across the age range of 1385, there was a substantial loss of neurons in the subiculum (52%) and in the hilus of the dentate gyrus (31%). In the remaining subdivisions of the hippocampus, signicant changes with age were not observed. He felt that these regionally specic neuronal losses in the aging human hippocampus qualied as potential morphological correlates of the decline in relational memory seen with aging (Perlmutter et al., 1981; Park et al., 1983). He also noted that the regional pattern of neuron loss was fundamentally dierent from the pattern associated with Alzheimers disease (West, 1993). Further, a recent study that used unbiased stereological counting techniques to determine the eects of a 28 day psychological conict stress paradigm on the hippocampal neuronal number in the tree shrew, a phylogenetic intermediate between insectivores and primates (Martin, 1990) did not conrm stress-induced hippocampal neuronal loss (Vollman-Honsdorf et al., 1997). Leverenz et al. (1999) reported that aged monkeys (Macaca nemenstrina) given long-term (12 months) glucocorticoid treatment (46 mg/kg/day) did not result in a reduction in hippocampal volume, total neuronal number or neuronal density. They concluded that, unlike in the rat, chronically elevated glucocorticoid concentrations, in the absence of stress, do not injure the hippocampus in old nunhuman primates. One possible explanation is that maximal decline may have occurred prior to the administration of glucocorticoids. The nding of hippocampal atrophy does not necessarily imply a permanent loss of cells since pharmacologic or surgical treatment may reverse the process (McEwen, 1997). Starkman et al. (1999) demonstrated that changes in hippocampal formation volume associated with sustained hypercortisolemia (in patients with Cushings disease) are reversible, at least in part, once cortisol levels had decreased. They had previously reported that hippocampal formation volume was negatively correlated with plasma cortisol concentrations in patients with Cushings syndrome (Starkman et al., 1992). Luine (1994) found that 21 days of restraint stress prior to maze training impaired performance in rats.

However, the stress eect was reversible. Moreover, stress eects were prevented by prior treatment with phenytoin (Watanabe et al., 1992) or tianeptine (Conrad et al., 1996). These pharmacological agents may prove to be clinically useful in humans where hippocampal atrophy is suspected. Gould et al. (1998) reported that neurons were produced in the dentate gyrus in adult marmoset monkeys, challenging the accepted paradigm that there was no neurogenesis in the aging brain, although the rate of precursor cell proliferation was aected by a stressful experience. However, there is also evidence that acute glucocorticoid treatment can be memory enhancing. In animals, corticosterone is released during learning and appears to be necessary to establish enduring memories (De Kloet et al., 1998). Tests of both simple associative learning and more complex tasks involving the integration of various stimuli indicate that administration of exogenous corticosterone at the time of training potentiated memory in a dose-related fashion (Flood et al., 1978; McEwen et al., 1986; Sandi and Rose, 1994; Lupien and McEwen, 1997). Sandi and Rose (1997) reported that corticosterone, administered in amounts similar to the amounts seen during stress, in other words, at high enough levels to stimulate GR, facilitated spatial memory, if the exogenous corticosterone was given immediately after the test. De Kloet et al. (1999) argue that while the detrimental eects of corticosteroids in the brain have received a great deal of attention, corticosteroids are also essential in interpreting and storing new information. Ecient interplay between MR, the high anity corticosteroid receptor, and GR, the low anity corticosteroid receptor, is essential for maximal learning. Environmental input, which may result in elevated corticosteroid levels, can have signicant but not necessarily negative consequences. MR has a major role in behavioral reactivity towards stimuli (approaching and investigating) while GR is involved in consolidating learned information. Inappropriate behavioral reactivity in rats is seen after adrenalectomy as well as with high doses of corticosterone (Oitzl et al., 1994). Low doses of corticosterone, which lead to predominant MR activation normalize behavioral reactivity. In one study, MR antagonists aected the birds pecking pattern, an example of behavioral reactivity. Interference with memory only took place when a GR antagonist was given (Sandi and Rose, 1994), which indicates that levels of corticosteroids must be high enough to signicantly activate GR for maximal memory function to occur. Corticosterone activation has dierent outcomes depending on the concurrent environmental context. While exogenous corticosterone given immediately after training facilitates memory performance, memory in a radial maze is impaired when an unrelated stressor

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interrupts the task, resulting in a further increase in corticosterone levels (Sandi and Rose, 1997). Although corticosterone levels high enough to activate GR are needed for consolidation of information, additional GR activation, particularly when triggered by a stressor that is out of context with respect to the original task, disrupts ongoing consolidation (De Kloet et al., 1999). Brief periods of stress usually enhance the formation of new memory (Shors et al., 1989). Similarly, single injections of moderate doses of corticosterone or the synthetic glucocorticoid dexamethasone enhance memory for inhibitory avoidance training when administered after training (Kovacs et al., 1977; Flood et al., 1978; Roozendaal and McGaugh, 1996; Roozendaal et al., 1999). Although there is debate as to whether dexamethasone administration creates a high or low cortisol/corticosterone eect in the brain (see later), glucocorticoid eects on memory enhancement for inhibiting avoidance follow an inverted U-shape dose response relationship (Roozendaal, 2000). Similar biphasic eects of post-training corticosteroids in rats have been observed in a contextual-cue fear conditioning paradigm (Pugh et al, 1997; Cordero & Sandi, 1998), as well as in an avoidance task in 1-day-old chicks (Sandi and Rose, 1994). However, Sandi and Rose (1997) did not nd a biphasic dose dependent eect of corticosterone on hippocampal related learning using a water maze paradigm. At no point, even with stress and physiologic cortisol injections, did the descending part of the inverted U become apparent. Moreover, Sandi and Rose have shown that corticosterone injections are eective in enhancing consolidation processes for avoidance learning in chicks when given up to 60 min after training. Dexamethasone enhanced memory for avoidance learning in mice when injected up to 150 min after training (Flood et al., 1978). Although the time courses dier slightly between these studies, which were done in dierent species, they both illustrate the timedependent characteristics of glucocorticoids in inuencing memory consolidation processes (Roozendaal, 2000). Other areas of the brain may also be aected signicantly by corticosteroids. A recent study found that very low levels of GR mRNA were observed in the rhesus monkey hippocampal formation (Mar Sanchez et al., 2000, in contrast to the well-established pattern in the rat brain (Jacobsen and Sapolsky, 1991). Mar Sanchez et al. reported that in contrast to the rat brain, where GRs are widely distributed and particularly dense in the hippocampus, GR mRNA is only weakly detected in the dentate gyrus and cornu ammonis of the macaque hippocampus. In fact, GR was far more readily detected in the macaque pituitary, cerebellum, hypothalamic paraventricular nucleus and neocortex. Similarly, immononistochemical stains indicated a very

low density of GR-like immunoreactive cells within the macaque hippocampal formation in contrast to the high density observed within the hypothalamic paraventricular nucleus, prefrontal and entorhinal cortices, and cerebellar cortex. In this study, a human antibody for GR was employed, raising questions regarding the levels of GR recorded in the hippocampus. Overall, these results suggest that, in primates, neocortical and hypothalamic areas may be more important targets for GR-mediated eects of glucocorticoids than the hippocampus. In contrast, our group has recently reported on an experiment where we used a specic squirrel monkey antibody and found that GR receptors were well expressed in the hippocampus, but were more prominently found in the prefrontal cortex (Patel et al., 2000). Sapolsky et al.s (1986) paper was a landmark in that it put forth both the important concept that stress via its biological intermediary, glucocorticoids, is potentially detrimental to thinking and memory, as well as the possibility that this problem fed on itself is a positive feedback loop. However, these studies in rats have painted a less than complete picture, particularly as more recent work has shown that nding neuronal cell death in the hippocampus is technically dicult, particularly in primates. More recent studies have downplayed the importance of neuronal death as opposed to declining neuronal function and eects on structural plasticity. In addition, other modulators, including excitatory amino acids may have correspondingly signicant eects on the hippocampus. Recent evidence oers a more optimistic viewpoint that, while sustained elevated cortisol may have detrimental eects, the brain has a greater degree of plasticity than previously known and neuroregeneration oers real possibility for repair (McEwen, 1999).

3. Exogenous glucocorticoid administration 3.1. Terminology This section of the paper will cite empirical studies that investigate the eects of corticosteroids on cognition, especially memory impairment. Therefore, dening dierent aspects of memory seems appropriate in order to familiarize the reader with the terminology used hereafter. There are several independent memory systems, thought to be a result of dierent neural networks within the brain (Lishman, 1997). For example, a somewhat arbitrary division is made into recent and remote memory. Recent memory or short-term memory is the ability to acquire and retain new information over short periods of time and depends on a process of registration and consolidation. Remote

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memory or long-term memory is reected in the ability to recall acquired knowledge after a considerable time delay and depends on a process of retrieval of information that has been held in long-term storage (Lishman, 1997). Further terms that dene dierent aspects of memory include working memory, episodic-semantic memory, as well as declarative-procedural memory. Working memory emphasizes those components that can hold information in recent memory storage and at the same time perform some kind of mental operation on the retained information. Episodic memory is experiencebased and refers to memory of specic events or episodes in an individuals past. In contrast, semantic memory is less personal but is acquired knowledge about the world, objects, labels, vocabulary, principles and concepts early in life. Finally, declarative or explicit memory is accessible to conscious awareness and refers to knowledge of facts obtained by processing information. It essentially embraces both episodic as well as semantic memory. On the other hand, procedural or implicit memory is the capacity to perform a certain task without necessarily knowing when or where one learned to do such a task. It is expressed in performance, not knowledge, and is not directly accessible to conscious recollection (Lishman, 1997). 3.2. Experimental studies in healthy human subjects In order to elucidate the specic cognitive impairments associated with glucocorticoids, numerous studies have examined the cognitive eects of glucocorticoids in normal healthy subjects. Wolkowitz and Weinberger (1988) reported that glucocorticoids in normal controls caused a signicant increase in intrusion errors and errors of commission (incorrectly identifying a distracter as a target word), which reversed when steroid treatment was discontinued. Wolkowitz et al. (1990) later reported that two groups of healthy volunteers given dexamethasone (in a single dose) or prednisone treatment (80 mg/day for 5 days) both made signicantly more errors of commission in verbal memory tasks, with no signicant rise in their errors of omission, as compared to controls. He concluded that corticosteroids might impair selective attention, hampering an individuals ability to distinguish relevant and important inputs from irrelevant and unimportant ones. A similar decit is often noted during presumed normal aging, or during treatment with methamphetamines (Mewalt and Ghoneim, 1979; Pomara et al., 1988). These ndings support the work of Kopell (1970), who reported that acute administration of cortisol to human subjects reduced the average evoked potential response to relevant but not to irrelevant stimuli. Newcomer et al. (1994) found that performance on a paragraph recall test declined signicantly in normal

subjects who were given four successive daily doses of dexamethasone orally (5, 1, 1, 1 mg), while the performance of the placebo group actually improved throughout the trial. The performance decits found on the paragraph recall task did not appear to reect a generalized decit in attention or arousal although attention was measured in a limited fashion. In a second study of similar design, Newcomer et al. (1999) conrmed these preliminary results with further evidence on reversible decreases in declarative memory (paragraph recall) after high doses (40 or 60 mg) of cortisol treatment for 4 days orally given. This study also demonstrated that cortisol levels do not appear to signicantly impact nonverbal memory, sustained or selective attention, or executive functions as measured by a number of neuropsychiatric scales. However, performance on the paragraph recall test is also dependent on other cognitive functions such as intact organizational and learning capacities. While the neurobiological mechanism underlying the impairment in delayed recall performance during dexamethasone and cortisol addition remains largely unstudied, this declarative memory deficit is consistent with a glucocorticoid eect on hippocampal neurons (Newcomer et al., 1994). Newcomer et al. (1999) have postulated that this eect may be because glucocorticoids disrupt glucose transport into neurons. In support of Newcomer et al.s (1994, 1999) idea is work by De Leon et al. (1997) who found that among normal individuals in the presence of a pharmacological dose of cortisol, the glucose utilization of the hippocampus is specically reduced. This result suggests a glucocorticoid inhibition of cerebral glucose uptake or metabolism in the brain that parallels the classical inhibition found in peripheral tissues. More recently, Kirschbaum et al. (1996) reported ndings of two studies that looked at the correlation between cortisol levels and memory performance in healthy adults. The results of the rst study, in which 13 subjects were exposed to brief psychosocial laboratory stress, demonstrated a signicant negative correlation between stress-induced cortisol levels and declarative memory performance, indicating that endogenous production of cortisol may lead to the same cognitive deciencies as exogenous exposure to glucocorticoids. The ndings of the second study, in which 40 subjects were given either 10 mg of cortisol orally or placebo orally, showed that subjects who received cortisol demonstrated signicant declarative memory and spatial thinking task impairment. Lupien et al. (1999) found that working memory was even more sensitive than was declarative memory to the acute eects of corticosteroids. Four groups of 10 young men were given infusions of varying doses of hydrocortisone (40 mg/kg/h, 300 mg/kg/h, and 600 mg/ kg/h). During the infusion, participants were given an

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item-recognition working memory task and a pairedassociate declarative memory task. A continuous performance task was added in order to control for possible confounding eects of corticosteroids on vigilance. Results revealed signicant eects of hydrocortisone on working memory functions, but not on declarative memory functions or arousal-vigilance performance. This data point to eects on frontal cortical regions. In addition, Lupien et al. (1999) reported that while high dose hydrocortisone infusion impaired various measures of working memory, low dose hydrocortisone infusion actually improved performance. Interestingly, there are little data describing cognition in low cortisol states in humans. Fehm-Wolfsdorf et al. (1993) found that cognitive performance was superior in the morning (when cortisol levels are high) as opposed to the evening (when cortisol levels are low). They followed this experiment with one in which they measured the eects of oral administration of 50 mg of hydrocortisone on a free recall test in young normal controls in the morning and at night. Adding hydrocortisone did not systematically inuence recall performance. However, circadian variation in performance disappeared following treatment with hydrocortisone. While there are certainly alternative explanations, these two studies seem to imply that an inverted U-shape curve may best describe the relationship between cortisol and cognition. Lupien and McEwen (1997) in an elegant exposition, point out that the administration of dexamethasone may actually create a low cortisol state and that the impaired cognition seen after dexamethasone administration is in fact low cortisol impairment. There is good evidence that lower doses of dexamethasone gain sucient access to the pituitary gland to suppress ACTH and subsequently cortisol but do not eectively gain access to the type II (GR) receptors in the brain (DeKloet et al., 1975). If dexamethasone administration can be considered as producing a low cortisol state, then further support is granted for the concept that an inverted U-shape could be describing the relationship between cortisol and cognition. The issue of whether dexamethasone administration creates a high or low cortisol state in the brain is not settled. Of interest are Plihal and Borns (1999) and Plihal et al.s (1999) studies, which indicate that both dexamethasone and cortisol administered before or during early sleep impaired declarative memory (consolidation of paired associate words) but not non-declarative memory (visuomotor skills). Schmidt et al. (1999) conducted a double-blind study in order to examine the eects of high doses of prednisone on memory and attention in humans. Twentyfour healthy young men received either 100 mg of prednisone or placebo for 4 days. Subjects treated with prednisone recalled fewer objects on a memory task (remembering common household items placed in front

of them for 1 min on the last day of treatment) 4 days post-treatment. Young et al. (1999) found that 20 mg given twice a day for 10 days to healthy men caused impairments of visuo-spatial working memory. Hydrocortisone treatment was also associated with higher error rates for both spatial working memory and paired associates learning tests, although no eect was found on the Tower of London test. Cortisol improved reaction time in tests of pattern and spatial recognition memory. Overall, the pattern of neuropsychological impairment produced by chronic (10 day) administration of cortisol did not particularly suggest hippocampal involvement. Instead, it more strongly implicated (pre)frontal lobe dysfunction. De Kloet et al. (1999) have pointed out that corticosteroids should not be merely classied as bad guys. Corticosteroid hormones can protect the brain against adverse eects (Holsboer and Barden, 1996) and are essential for cognitive performance (Sandi and Rose, 1994, 1997). De Kloet et al. (1999) also argue that the context in which corticosteroid-receptor activity takes place is crucial in determining steroid-mediated eects. The disruption in memory caused by corticosteroids found in studies (Newcomer et al., 1994; Kirschbaum et al., 1996; Lupien and McEwen, 1997) can be partly explained by limitations in experimental design. These experiments did not allow dierential receptor manipulation nor were the steroids given in context, with appropriate consideration to the natural order of environmental input during information processing. They argue that what these investigations are observing are not decits, but in fact, more opportune responses to an out of context steroid stimulation. High corticosteroids are essential, but if experienced repeatedly out of context, they may stimulate disease factors or genetic vulnerabilities to which an individual is predisposed. De Kloet et al. (1999) argued that in order to assess the eects of corticosteroids on human cognition accurately, studies of attenuated levels of endogenous corticosteroids rather than studies of administration of high doses of exogenous corticosteroids are essential. Methods for targeting steroid-responsive sites in the human brain and delivering selective synthetic steroid-receptor antagonists to them will also be key steps. By employing such procedures and methods, the coordinated type I(MR) and type II-(GR) mediated actions in information processing can be discerned in the context of a specic event. 3.3. Glucocorticoid therapy Glucocorticoids are often used therapeutically for their potent anti-inammatory and immunosuppressive properties in the treatment of medical conditions,

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including allergic, rheumatologic, neurologic, and autoimmune disease. The most common cause of hypercortisolemia among all age groups, in fact, is the excessive administration of glucocorticoids as anti-inammatory agents (Martignoni et al., 1992). Treatment with steroids can result in psychosis, as well as cognitive disturbances including diculties in attention and concentration, loss of memory, and impaired logical thinking. In their pioneering study, Rome and Braceland (1952) evaluated over 100 patients who were being treated with ACTH, cortisone, hydrocortisone and related substances for various medical diseases. The authors noted thinking disturbances as a common symptom of corticosteroid therapy in these patients. In 1979, Hall et al. examined 14 patients being treated with steroids for a variety of medical conditions, including rheumatoid arthritis, ulcerative colitis, and asthma. Cognitive and memory impairment, as well as psychotic symptoms (e.g. aective lability, sensory ooding, auditory and visual hallucinations, and delusions), were common during steroid treatment. Keenan et al. (1995) compared 25 patients who had been taking prednisone for at least a year to closely matched controls, and concluded that the patients receiving long-term treatment with glucocorticoids performed signicantly worse on tests of hippocampal-dependent explicit or declarative memory. Furthermore, the results indicated that selective impairment in verbal explicit memory was not due to inattention, aective disturbance, or a generalized decline in cognition. There have also been case reports of impaired concentration in children using inhaled corticosteroids for the treatment of asthma (Barnes and Pederson, 1993). Bender et al. (1991) reported a decreased verbal memory performance in asthmatic children associated with higher prednisone doses.

4. Cushings syndrome and Addisons disease Cushings syndrome is an endocrine disorder characterized by sustained hypercortisolemia, either due to an endogenous overproduction of cortisol or treatment with exogenous steroids. Patients with Cushings syndrome also demonstrate impaired cognitive function. Whelan et al. (1980) evaluated 35 patients with Cushings syndrome (30 of whom had Cushings disease) with the Michigan Neuropsychological Test Battery, and found varying degrees of diuse bilateral cerebral dysfunction in two-thirds of the patients tested. Impairment in visual memory and non-verbal visual-ideational functions were the most pronounced and the most frequent, and there was a consistent pattern of progressive decline over time in almost all tests of cognitive function. Starkman et al. (1986) interviewed 23 patients with Cushings syndrome, and found that 66% had diculty

in concentration, and 83% had memory diculties. Furthermore, the severity of the patients overall impairment was directly correlated with their levels of cortisol or ACTH, and their cognitive decits improved with a reduction in their plasma cortisol levels using mitotane (Schteingart et al., 1980). In a later study of 12 patients with Cushings syndrome, Starkman et al. (1992) found an association between reduced HF volume (based on MRI results), short- and long term verbal but not visual memory dysfunction (based on neuropsychological testing), and elevated cortisol levels. There were signicant correlations between HF volume and verbal recall and verbal learning indices, and HF volume was negatively correlated with mean plasma cortisol. The relationship between HF volume and cognitive functioning was memory-specic in that HF volume was not correlated with IQ, psychomotor performance, educational level, or age. Previous studies using CT scans have demonstrated ventricular enlargement and cortical atrophy in hypercortisolemic patients with Cushings syndrome (Momose et al., 1971). In an early study of a Cushings syndrome, Trethowan and Cobb (1952) described signs of limbic atrophy at autopsy. Martignoni et al. (1992) evaluated 24 patients with Cushings syndrome, 22 of whom had pituitary adenomas. Signicant decits were found in both short and long-term logical memory and visual reproduction. The authors also administered measures of attention, language, visuo-spatial and reasoning abilities. Subjects showed poorer performance on the digit span and digit symbol substitution tests, indicating impairment in both verbal and non-verbal working memory. Interestingly, seven patients were re-tested 7 months after surgical treatment and all showed a signicant recovery of verbal memory. In a study of 25 patients with Cushings syndrome and matched controls, Mauri et al. (1993) also found signicant impairment in all facets of memory in the Cushings group, but not in other cognitive functions. Furthermore, patients re-tested 6 months after surgical ablation of their tumors showed signicant improvement in memory with a reduction of cortisol levels. The results of these studies suggest that not only is elevated plasma cortisol in patients with Cushings syndrome associated with cognitive impairment, but that this impairment may be reversed with a lowering of cortisol levels. Most recently, Forget et al. (2000) compared 19 patients with chronic hypercortisolemia due to Cushings syndrome and matched controls on an extensive neuropsychological battery. As has been shown in previous studies, signicant dierences between Cushings syndrome patients and normal controls were found on nonverbal memory and attention tasks, reasoning, concept formation, and language functions, as well as on measures of visual and spatial information processing.

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In addition, this study focused on dierentiating between cognitive functions that either depend on or are largely independent of memory functions. The strong evidence of non-memory related decits in a number of cognitive functions found in this study led to the conclusion that extrahippocampal eects of glucocorticoids may lead to cognitive impairments distinct from the typically reported eects on memory and learning in patients with chronic hypercortisolemia. In fact, hippocampal plasticity may be signicantly more robust than was previously anticipated. As indicated previously, in a study of 22 patients with Cushings disease who were treated with transsphenoidal microadrenomectomy hippocampal volume increased by as much as 10% following treatment (Starkman et al., 1999). Overall, data from patients with Cushings disease/ syndrome indicates that while cognitive impairment is prominent in the untreated disease state, treatment leads to a return of function that can sometimes be complete or nearly complete. There has been no systematic study of cognitive changes in patients with Addisons disease. One early study found that adrenal insuciency results in a change of threshold perception (Henkin et al., 1967) but a clinical correlate has not been described.

5. Normal aging Several studies of glucocorticoids and cognition have specically examined healthy older populations. Existing human studies of basal cortisol level changes as a function of advancing age show inconsistent results (Lupien et al., 1995). OBrian et al. (1994) measured cortisol levels, dexamethasone suppression and cognition in 33 healthy older subjects (ages 5196). They found a signicant correlation between high cortisol levels and impaired performance on the CAMCOG (Cambridge cognitive examination), as well as signicant correlations between dexamethasone resistance, advancing age, and declining cognitive function. Kalmijn et al. (1998) also investigated the relationship between cortisol levels and cognition, as measured by the Mini-Mental State Examination (MMSE), in 189 healthy elderly subjects (ages 5580). A signicant association between free cortisol levels and impairment of cognitive function was observed; higher cortisol levels after administration of dexamethasone (as a measure of HPA axis negative feedback sensitivity) correlated with an increased risk of decline in cognitive function. In a long-term study, Lupien et al. (1995) followed cortisol levels and neuropsychological performance in a group of 51 healthy elderly subjects (ages 6090) over a 3- to 6-year period. The results showed that the slope of the change in basal cortisol levels over time was the best

predictor of cognitive decits, rather than the basal cortisol levels themselves. Aged subjects, showing a signicant increase in cortisol levels throughout the study period, demonstrated impairment on tasks measuring declarative memory and selective attention in comparison to those subjects who had either decreasing cortisol levels, or moderately increasing cortisol levels. This suggests that increasing levels of cortisol play an important in altering cognitive functions. The cognitive performance of those subjects with a steeply increasing cortisol slope was comparable to the performance of patients with an amnestic syndrome resulting from hippocampal damage. In contrast, those subjects with a negative cortisol slope had a cognitive performance similar to healthy young subjects. Lupien et al. (1998) followed this work by studying whether cortisol levels during human aging predict hippocampal atrophy and memory decits. They found that aged humans with signicant cortisol elevations showed reduced hippocampal volume and decits in hippocampus-dependent memory tasks compared to normal cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and the current basal cortisol levels. Similar results were reported from the ndings of a larger, community-based study. Seeman et al. (1997) measured urinary free cortisol excretion and tested the memory performance of 194 subjects, ages 7079. The study found that for the women, higher levels of cortisol excretion correlated to poorer baseline memory performance and larger increases in cortisol excretion over the 2.5-year follow-up period were associated with declines in memory functions as measured by verbal free recall and spatial recognition performance. Signicant associations were not observed in men, perhaps because men show lesser increases in cortisol excretion over time, while also experiencing smaller declines in memory performance as compared to women. Because these authors measured memory functions in dierent modalities (i.e. free recall vs. recognition memory), it is difcult to compare the results obtained from verbal and spatial memory tasks since problems with the free recall of new information represents an encoding decit, whereas poor performance on recognition tasks indicates decits in retrieval of information.

6. Major depression A proportion of patients suering from major depression can be characterized by perturbation of their hypothalamic-pituitary adrenal axis, both basally and following dexamethasone suppression (Carroll, 1982; Thase et al., 1996). Sapolsky et al. (1986) speculated that the dexamethasone resistance present in many depressed patients may result from a transient stress-induced

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down-regulation of glucocorticoid receptors in the hippocampus. Steroids may play a role in the etiology and perpetuation of depression (Murphy, 1991). Standard antidepressants, known to act mainly on catecholaminergic and serotonergic neurotransmission also seem to have eects that are independent of their eects on biogenic amine metabolism or receptors, which involve normalization of initial HPA dysregulation. The time course of these neuroendocrine actions on HPA activity and, more specically, on corticosteroid receptors, follows closely that of clinical improvement, and supports the hypothesis that there is a causal link between HPA activity and antidepressant eect (Holsboer et al., 1996). Experiments with transgenic mice (using a partial GR gene knock-down) indicate that numerous antidepressants decrease HPA axis-drive (Pepin et al., 1992). Furthermore, steroid suppression may improve the symptoms of some patients with major depression. ACTH levels in these patients are not clearly elevated, and interestingly, while these patients may have higher cortisol levels, they do not develop Cushingoid symptoms and generally maintain their diurnal rhythm of cortisol secretion (Thase et al., 1996). However, patients with psychotic major depression may indeed have signicant alterations in both cortisol and ACTH levels (Schatzberg et al., 2000). They may also have more prominent cognitive impairment and it may be much more common than in patients with non-psychotic depression. Several studies have indicated that patients with depression (earlier studies tended to not dierentiate between patients with non-psychotic and psychotic depression) exhibit a variety of decits in cognitive functioning, including decrements in simple and complex attentional tasks, verbal and visual memory, encoding, storage, and retrieval (Weingartner et al., 1981; Cohen et al., 1982; Roy-Bryne et al., 1986). Furthermore, evidence exists that depressed patients with hypercortisolemia, or those who fail to suppress cortisol in response to dexamethasone, show particularly pronounced cognitive decits. Rubinow et al. (1984) reported that mean urinary free cortisol levels in depressed patients signicantly correlated with the number of errors made on the Halstead Category tests, and that all of the cortisol hypersecreters in that study were cognitively impaired. The cognitive impairment was most severe in those tasks that required a sustained cognitive eort by the patient. Wolkowitz et al. (1990) found that depressed patients who were dexamethasone non-suppressors made signicantly more errors of commission in verbal memory tasks as compared to controls. Recently, Van Londen et al. (1998) reported that in patients with major depression, better global cognitive performance (with a focus on memory impairment and the ability to learn new information) correlated

negatively with mean baseline plasma cortisol concentrations. A plausible contribution to the cognitive impairment in this subset of depressed patients may be glucocorticoid-induced cortical atrophy. The rst studies in this area used CT. For example, Rothschild et al. (1989) conducted a study of 30 depressed patients, 15 with psychotic symptoms and 15 without any psychotic symptomatology. He found that patients with psychotic major depression had higher pre and post-dexamethasone cortisol levels. In fact, their degree of hypercortisolemia approached that seen in Cushings syndrome. Of note, psychotically depressed patients had signicantly greater left and right inferior parietal brain atrophy, and signicantly larger anterior pole and sella media ventricle-to-brain ratios (VBRs). Patients with non-psychotic depression who were DST non-suppressors also demonstrated enlarged VBRs. Schlegel and Kretschmar (1987) found that in depressed patients, mean plasma cortisol levels were positively correlated with elevated VBRs as measured by computed axial tomography. Similarly, Rao et al. (1989), using CT, found that brain ventricular size was directly correlated with post-dexamethasone plasma cortisol levels in a group of depressed patients, and Kellner et al. (1983) showed a signicant correlation between urinary free cortisol and ventricular dilatation in patients with both unipolar and bipolar depression. Similarly, Rubinow et al. (1984) found that MUFC in depressed patients correlated with decreased performance on a measure of cognitive abstract thinking (Halstead Category Test). Kellner et al. (1983) raised the question whether large ventricles, high cortisol, or other factors are responsible for the documented cognitive impairment in these patients. In a very recent publication, Lucassen et al. (2001) challenge the concept that the reduced hippocampal volumes commonly seen in major depression are caused by substantial neuronal degeneration. In a post-mortem analysis of 15 patients with major depression, they found that cell loss was rare. Of particular interest is that apoptosis was not found in areas known to be at risk for glucocorticoid overexposure (e.g. CA3). This study supports the possibility that a shift in water content instead may be responsible for the observed hippocampal volume reductions (Starkman et al., 1986). Actual hippocampal neuron loss may not be necessary to cause the cognitive dysfunction seen in major depression. Murphy (1991) noted the signicant dierence in psychiatric symptoms associated with endogenous overproduction of glucocorticoids, and those associated with the exogenous administration of ACTH or glucocorticoids. With disorders of endogenous hypercortisolemia (Cushings syndrome), a euphoric state is rare while depression is very common. With exogenous

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steroid excess, however, depression is unusual while a euphoric state is quite common. As described above, reports of memory and cognitive decits are common both in patients with major depression and those with Cushings syndrome. Interestingly, in individuals receiving exogenous ACTH or cortisone, there may be an improved ability to concentrate, acceleration of thinking and increased ability to think creatively, as well as improvements in memory (Rome and Braceland, 1952; Murphy, 1991), suggesting that both high and low cortisol levels may be associated with less than optimum cognitive performance. In fact, acute rises in cortisol may be cognitively enhancing, while chronically elevated cortisol may be detrimental. Belano, Kalehzan et al. (submitted for publication) in their study of patients with non-psychotic major depression found that a portion of patients have lower than normal cortisol and the lower the patients cortisol levels the more errors of omission they made in a word recognition test. Wolkowitz and Reus (1999) reviewed the treatment of depression with antiglucocorticoid drugs. They reported that while it was often found that cortisol-lowering treatment may be of benet in select individuals with major depression, these results must be interpreted with caution as the reviewed studies were heterogeneic, had small sample sizes, and most were open-label. Unfortunately, these studies did not specically address the relationship between improved mood and change in cognition.

7. Alzheimers disease and non-Alzheimers dementia The role of the HPA axis in altering cognition in Alzheimers disease (AD) is currently being investigated. Results from Sapolsky et al.s (1986) studies with animals show that cortisol levels and HPA axis activation may accelerate neuronal loss in the hippocampus and contribute to cognitive decline, both characteristics associated with AD. Ball et al. (1985) found that in AD signicant neuronal loss occurs in the hippocampus, and several other studies have noted the correlation between AD, hypercortisolemia, and reduced negative feedback inhibition of cortisol secretion (Balldin et al., 1983; Davis et al., 1986; Hollander et al., 1986; Ferrier et al., 1988). Some have also found increased behavioral problems in AD patients with elevated cortisol levels (Lawlor et al., 1992). In addition, there is evidence that sustained higher cortisol levels may lead to non- Alzheimers dementia. Hippocampal sclerosis is a neuropathologic nding characterized by neuronal loss and gliosis in the CA-1 and subiculum of the hippocampus. It is a signicant cause of dementia in the community (Leverenz et al., 1999). Although the links between higher cortisol and hippocampal damage are tenuous, in the context of our increasing aging population, further research into these connections are clearly warranted.

OBrien et al. (1996a) investigated adrenal sensitivity in 16 non-depressed subjects with AD (meeting NINCDS/ADRDA criteria), and 18 control subjects. Cortisol response to exogenous ACTH was measured using two values: peak level (the dierence between baseline and maximum cortisol level) and area under the cortisol response curve above baseline (AUC). Both measurements were signicantly higher in AD subjects in comparison to controls, implying enhanced HPA axis sensitivity to ACTH. Moreover, AUC correlated signicantly and negatively to cognitive performance (as measured by CAMCOG score). In another study, published in the same year, OBrien et al. (1996b) found that on 49 subjects with AD, higher post-dexamethasone cortisol levels correlated with greater hippocampal atrophy. Weiner et al. (1997) explored the relationship between serum cortisol levels, measured by the Afternoon Cortisol Test (ACT), and cognitive function, measured by a modied version of the Alzheimers Disease Assessment Scale-Cognitive (mADAS-COG), in nine AD subjects. Baseline 12:00 hours cortisol levels were signicantly associated with changes in mADASCOG score per month, and that over time, as the mADAS-COG scores increased (indicating increasing cognitive impairment), so did ACT. Finally, Carlson et al. (1999) found that while there were no dierences in cortisol levels between patients with Alzheimers disease and aged matched healthy control subjects, Alzheimer disease patients with higher cortisol levels performed worse on Delayed Route Recall than those with lower levels. De Leon et al. (1997) found a lower baseline hippocampal glucose utilization in Alzheimers patients that was not further reduced by hydrocortisone administration, perhaps indicating that prominent physiological damage takes place relatively early in Alzheimers disease. Exploring the anti-inammatory eects of corticosteroids, Aisen et al. (2000) completed a large randomized study of prednisone for the treatment of Alzheimers disease. Preliminary open label studies seemed to indicate that prednisone suppresses peripheral markers of the acute phase response and complement activation in Alzheimers disease, without signicant systemic or neuropsychiatric toxicity. Unfortunately, not only was there no dierence in cognitive decline between the prednisone and placebo treatment groups in the larger, blinded study, but subjects treated with prednisone showed additional behavioral decline compared to those in the placebo group.

8. Discussion The eects of cortisol upon cognition have proved to be both more complicated and perhaps, more interesting,

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than was presumed at the time of Sapolskys landmark 1986 paper. Animal models have indicated that acute administration of corticosteroids may have cognitively enhancing qualities; while the human data are more sparse and more in debate, it does appear that not all increases in cortisol have detrimental consequences. Chronic hypercortisolemia does seem to produce signicant negative eects but, encouragingly, these eects seem to be more reversible than was anticipated. Of interest is that the manifestations of chronic hypercortisolemia do not appear to be limited to the hippocampus; in fact, many of the eects noted by clinicians may relate to altered function in the pre-frontal cortex. The specic areas of thinking and memory aected by glucocorticoids increasingly have been studied (see later) Modulation of cortisol in clinical disease by pharmacologic means is problematic, particularly in non-Cushings cases, where the perturbations in cortisol are more subtle. De Quervain (2000) found that the treatment of healthy people with cortisol at acute-stress levels specically impaired retrieval (as opposed to acquisition and consolidation) of declarative long term memory for a word test. The eects of stress and glucocorticoids on memory consolidation appear to follow an inverted U-shape dose-response curve: extremely low and high levels impair consolidation (Luine et al., 1993; Luine et al., 1994; Newcomer et al., 1994; Conrad et al., 1996; Kirschbaum et al., 1996; Lupien and McEwen, 1997; Lupien et al., 1997) but intermediate doses enhance memory (Shors et al., 1992; Luine et al., 1996; Roozendaal & McGaugh, 1996; Lupien and McEwen, 1997; Sandi and Rose, 1997). In addition, de Quervain et al. (1998) demonstrated that once memories are consolidated in rats the accuracy of the information retrieved remains vulnerable to glucocorticoids at the time of recall. The retrieval impairment was found as soon as 31 min after corticosterone injection which is probably too fast to point towards the classic genomic eect via intracellular receptors (McEwen, 1994). However, as Angelucci (2000) points out, another interpretation of de Quervains data is that the increase in cortisol provided exogenously results in signicant negative feedback at the CRF and ACTH level and that this suppression could be the cause of the decits observed. Whatever the exact mechanism, glucocorticoid inuences on retrieval memory seem to be exclusively negative (de Quervain et al., 1998). In fact, the same treatments that enhance memory consolidation when administered immediately post training (Shors et al., 1992; Roozendaal and Gaugh, 1996; Sandi and Rose, 1997) impaired memory retrieval in the present study when given shortly before testing. Elevations of corticosteroids eect the acquisition and consolidation of information (Lupien et al., 1999),

which essentially is a function of attentional, encoding, and working memory abilities. These processes may be impaired by perturbations in the HPA axis and may also involve brain structures other than the hippocampus. For example, perturbation of the HPA axis in rats who have undergone transection of the fornix as well as transection of the eerents from the hippocampus creates reversible cognitive decits (Osborne et al., 1987). Increased corticosteroid levels in Sprague Dawley rats produced faster running on early extinction trials in a food-reinforced runway response test, a change unlikely to have been mediated by the hippocampus (Hennessy et al., 1973). Similarly, we have found (Schatzberg et al., unpublished study) that elevated cortisol levels in healthy controls are strongly correlated with decits on the Stroop Test, a measure of prefrontal functioning, as well as on the Paragraph Recall Test. Studies have not yet extensively examined associations between cortisol, cognition and MRI scans in a contemporaneous fashion. Hormonal treatments aimed at altering cortisol activity may become very important in ameliorating cognitive impairment or even psychosis in states associated with endogenous hypercortisolemia. This is particularly true in light of recent ndings that a true reversal of cognitive impairment may take place with the resolution of abnormalities in the HPA axis. There are three medications in current clinical use which inhibit cortisol biosynthesis: metyrapone, aminoglutethimide and ketoconazole (ketconazole is also a relatively weak glucocorticoid receptor antagonist). Each has its pragmatic diculties. Metyrapone frequently causes gastrointestinal symptoms, aminoglutethimide is sedating and can cause orthostatic hypotension, and ketoconazole can be both sedating and hepatotoxic. In addition, cortisol synthesis inhibition is a homeostatic emergency for the body because cortisol is essential for survival. Therefore, although each drug causes a decrease in adrenocortical function, the eects are often transient because the HPA axis compensates for the drop in cortisol by stimulating ACTH production. Cortisol then returns to its original level fairly rapidly (Wolkowitz and Reus, 1999). Interestingly, dexamethasone may be a potent antiglucocorticoid, at least in the brain. Since dexamethasone does not readily cross the blood brain barrier, its suppression of the HPA axis occurs at the level of the pituitary gland. This leaves the brain depleted of its endogenous corticosteroid. Ironically, it may result in an amplication of the CRH overdrive mechanism, which may perpetuate symptoms of depression (Meijer et al., 1998). Mifepristone (RU 486) is a powerful blocker of the glucocorticoid type II receptor, as well as progesterone receptors. It appears to be well tolerated, with reported side eects of occasional nausea, rash and headache. It

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J.K. Belano et al. / Journal of Psychiatric Research 35 (2001) 127145 Barnes PJ, Pederson SS. Ecacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993;148:S10S26. Belano JK, Flores BH, Kalezhan M, Sund B, Schatzberg AF. Rapid reversal of psychotic depression using Mifepristone. J. Clin Psychopharm 2001, in press. Belano JK, Kalehzan M, Sund B, Schatzberg AF. Cognitive changes in psychotic major depression. Am J Psychiarty 2001, in press. Bender BG, Lerner JA, Poland JE. Association between corticosteroids and psychological change in hospitalized asthmatic children. Ann Allergy 1991;66:4149. Bennett MC, Diamond DM, Fleshner M, Rose GM. Serum corticosterone level predicts the magnitude of hippocampal primed burst potentiation and depression in urethane-anesthetized rats. Psychobiol 1991;19:3017. Carlson LE, Sherwin BB, Chertkow HM. Relationship between dehydroepiandrosterone sulfate (DHEAS) and cortisol (CRT) plasma levels and everyday memory in Alzheimers disease patients compared to healthy controls. Horm Behav 1999;35:25463. Carpenter WT, Gruen PH. Cortisols eects on human mental functioning. J Clin Psychopharmacology 1982;2:91101. Carroll B. The dexamethasone suppression test for melancholia. Br J Psychiatry 1982;140:292304. Cohen RM, Weingartner H, Smallberg S, Pickar D, Murphy DL. Eort and cognition in depression. Arch Gen Psychiatry 1982;39:5937. Conrad CD, Galea LAM, Kuroda Y, McEwen BS. Chronic stress impairs rat spatial memory on the y maze, and this eect is blocked by tianeptine pretreatment. Behav Neurosci 1996;6:132134. Cordero MI, Sandi C. A role for brain glucocorticoid receptors in contextual fear conditioning: dependence upon training intensity. Brain Res 1998;786:1117. Davis KL, Davis BM, Greenwald BS, Mohs RC, Mathe AA, Johns CA, Horwath TB. Cortisol and Alzheimers disease: I. basal studies. Am J Psychiatry 1986;143:3005. De Kloet ER. Brain corticosteroid receptor balance and homeostatic control. Frontiers Neuroendocrinol 1991;12:95164. De Kloet ER, Wallach G, McEwen BS. Dierences in corticosterone and dexamethasone binding to rat brain and pituitary. Endocrinology 1975;96:598609. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocrine Rev 1998;19:269 301. De Kloet ER, Oitzl MS, Joels M. Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 1999;22:4226. De Leon MJ, Rusinek Mc RH, de Santi S, Convit A, Tarshish C, Golomb J, Volkow N, Daisley K, Orentreich N, McEwen BS. Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimers disease. J Clin Endocrinol Metab 1997;82:32519. De Quervain DJF, Roozendaal B, De Quervain DJF, Roozendaal B, Nitsch RM, McGaugh JL, Hock C. Acute cortisone administration impairs retrieval of long-term declarative memory in humans. Nature Neurosci 2000;3:3134. De Quervain DJF, Roozendaal B, McGaugh JL. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature 1998;394:7807. Eichenbaum H, Otto T, Cohen NJ. The hippocampus what does it do? Behav Neural Biol 1992;57:236. Fehm-Wolfdorf G, Reutter D, Zenz H, Born J, Lrenz-Fehm H. Are circadian variations in taste thresholds cortisol-dependent? J Psychophysiol 1993;7:6572. Ferrier IN, Pascual J, Charlton BG, Wright C, Leake A, Griths HW, Fairbairn AF, Edwardson JA. Cortisol, ACTH, and dexamethasone concentrations in a psychogeriatric population. Biol Psychiatry 1988;23:25260. Flood JF, Vidal D, Bennett EL, Orme AE, Vasquez ME, Jarvik ME. Memory facilitating and anti-amnestic eects of corticosteroids. Pharm Biochem Behav 1978;8:817.

has been used in high doses for relatively short periods, and low doses for relatively long periods without creating hypoadrenalism (Kettel et al., 1991). We have studied the ecacy of RU 486 as a treatment for psychotic major depression in a small double-blind placebo controlled study, and obtained very promising results (Belano, Flores et al. in press). A larger study is now being conducted. We think that RU 486 may also be useful in the treatment of major depression with prominent cognitive impairment (pseudodementia). Because mifepristone is a glucocorticoid type II receptor antagonist, its presence in the body does not interfere with the normal cortisol homeostasis that is maintained through glucocorticoid type I receptor transmission. Mifepristones glucocorticoid blockade only aects the receptor activated by high (often stressrelated) levels of cortisol, the receptors that when excessively activated may be responsible for the bulk of the clinical pathology. Therefore, mifepristones action is at the margin of normal cortisol activity, and the fact that normal cortisol homeostasis is maintained through glucocorticoid type I transmission may account for its apparent very benign side eect prole.

9. Conclusion There is now compelling evidence that the brain is a major target for glucocorticoid hormones, and that cognition can be adversely aected by too low or high sustained glucocorticoid levels. While further study is certainly necessary to understand the precise mechanisms of glucocorticoid-induced brain injury, treatment strategies aimed at regulating abnormal levels of circulating glucocorticoids are currently worth examining. Acknowledgements This work was supported by the National Alliance for Research on Schizophrenia and Depression, Pritzker Foundation, RO-1 NIMH MH 47573 grant, NIMHfunded T-32 Biobehavioral Research Training Program. References
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