the neurobiology of the stress cascade and its potential ... · this review explores the...

Journal of Psychiatric Practice January 2001 3

This review explores the neurobiology of stressand its possible role in the etiology of schizophre-nia. Major life events may play a role in onset andrelapse in schizophrenia. Other data suggest thatearly stress exposure increases schizophrenia risk,especially in individuals with latent vulnerability.Animal research has led to an elucidation of themechanisms by which stress and cortisol are toxicto the hippocampus and impair cognition.Associations among these factors have been foundin a variety of human conditions, including psychi-atric illness and normal aging. These mechanismsare plausible in schizophrenia, which is character-ized by a degree of cortisol dysregulation, hip-pocampal abnormality, and cognitive impairment.Characterization of the role of the stress cascadein schizophrenia has implications for novel phar-macologic and other treatment, especially for cog-nitive symptoms, which are debilitating andlargely refractory to treatment. (Journal ofPsychiatric Practice 2001;7:3–14)

KEY WORDS: schizophrenia, stress, animal research,cortisol dysregulation, hippocampal abnormality, cogni-tive impairment

tressful life events can worsen symptoms and pre-cipitate relapse in a host of psychiatric conditions,including postpartum mood and psychotic disor-ders,1 affective illness,2–5 and alcohol dependence.6, 7

However, stress may be particularly deleterious forpatients with schizophrenia; the death of a parent, achange in therapist, a move from one apartment to anoth-er—these events seem to trigger multiple symptoms,such as anxiety, depression, and increasing psychosis,

which may lead to hospitalization. Even seemingly mildstressors, such as a job interview or a date, may have aprofound effect in some patients with schizophrenia, sug-gesting that such patients may be more vulnerable to lifeevents. In this article, we will explore the biological mech-anisms that may underlie the role of stress in the patho-physiology of schizophrenia.

The idea that stress and schizophrenia are inextricablylinked is well supported in the literature, beginning withBrown and Birley’s seminal paper from 1968, whichargued that stress may precipitate the onset of schizo-phrenia.8 These authors found that 46% of 50 patientswith acute-onset schizophrenia had been exposed tostressful life events in the preceding 3 months as com-pared to only 14% of 325 controls: the difference was mostpronounced in the 3 weeks leading up to hospitalization.In their 1993 review, Norman and Malla found a signifi-cantly higher incidence of recent life events in patientswith schizophrenia as compared with healthy controls in43% of all the studies they examined.9 A salient critiqueof these reviews is that the authors establish association,not causation (i.e., schizophrenia may increase vulnera-bility to life events). However, exposure to life events doesnot appear to simply be an effect of having schizophrenia,since the association between stressful life events andrelapse persists when patients with schizophrenia aretheir own controls (relapse versus baseline) and when“relapsing” patients are compared with “nonrelapsing”patients.10

The association between stress and illness is certainlynot unique to schizophrenia. A wealth of evidence fromanimal and human research shows that stress can lead topersistent biological changes via the stress hormone, cor-tisol, which at high levels can be harmful to many organsin the body, including the brain. There are physical andpsychological sequelae/costs/repercussions involved inthe adaptation to stress, termed the “allostatic load’ ofstress by Bruce McEwen, an expert in stress research.11

For example, psychological stress is associated withrelapse or exacerbation in a variety of medical illnesses,including ulcerative colitis,12 genital herpes,13 asthma,14

vaginal candidiasis,15 multiple sclerosis,16 psoriasis,17

and “tension-type” headaches.18

In this article, we review what is known about the biol-ogy of stress and its impact on the brain and cognition,provide further evidence of an association between stress

CHERYL CORCORAN, MDAMELIA GALLITANO, MD, PhD

DAVID LEITMAN, BSDOLORES MALASPINA, MD, MSPH

The Neurobiology of the Stress Cascadeand Its Potential Relevance for Schizophrenia

CORCORAN, GALLITANO, LEITMAN, and MALASPINA: New YorkState Psychiatric Institute and Columbia University College ofPhysicians and Surgeons, Department of Psychiatry.

Copyright © Lippincott Williams & Wilkins Inc.

Please send correspondence and reprint requests to: Dolores Malaspina,MD, New York State Psychiatric Institute, 1051 Riverside Drive, NewYork, NY 10032.

Acknowledgements: This work was supported by the G. Harold and LeilaY. Mathers Foundation and by NIMH 1K24 MH01699 (DM).

SS

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and schizophrenia risk, present models for mechanismsthat may underlie this association, and, finally, discusspossible novel pharmacological and nonpharmacologicalinterventions.

THE NEUROBIOLOGY OF STRESSAn intact stress response is adaptive and enhances sur-vival, but an unrestrained physiological stress responsecan injure the brain. Recently, a great deal of scientificeffort has been devoted to teasing apart the molecularand cellular events in the stress response that can lead toneural damage (Figure 1). The cascade of events initiatedby the perception of stress includes the release of corti-cotropin-releasing hormone (CRH) throughout the brain,especially in the hypothalamus and in the locus coeruleusand sympathetic nervous systems located in the brain-stem. Physiological effects from sympathetic nervous sys-tem output include increased cardiac output, shunting ofblood from the digestive system, and the release of nor-epinephrine by the adrenal medulla, in preparation forthe “fight or flight” reaction to acute danger. CRH stimu-lates norepinephrine release within the brain, enhancingarousal and vigilance. CRH release in turn triggersadrenocorticotrophic hormone (ACTH) release from thepituitary, which induces secretion of cortisol by the adre-nal cortex. Cortisol is the major mediator of the physio-logic effects of stress. In addition to its myriad effectsthroughout the body, cortisol acts centrally to inhibitserotonin, norepinephrine, and dopamine, which ulti-mately results in the inhibition of further cortisol release.The hippocampus (Figure 2), which is crucial for encodingand retrieving memory, is also an important modulator ofthe hypothalamic-pituitary-adrenocortical (HPA)response to stress.19 The hippocampus sends neuronalprojections to the hypothalamus to initiate the cascade ofcortisol release and is itself a major target organ for glu-cocorticoid action in the brain.20 Although basal levels ofcortisol are required for the health and normal function-ing of the hippocampus, an ongoing stress response (andconsequent elevation of cortisol) is associated with hip-pocampal dysfunction and volume reduction, as well asdeficits in hippocampus-dependent memory.

Animal Models

Our initial understanding of the toxic effects of stress andcortisol on the hippocampus derived from preclinicalstudies in diverse species. These findings were firstobserved in primates: vervet monkeys that died sponta-neously following severe stress from poor and overcrowd-ed housing had damage to the CA3 hippocampalsubfield.21 This damage was subsequently related to cor-tisol,22 which across species has been demonstrated todecrease dendritic branching23 and cause neuron loss24 ina steroid- and tissue-specific manner.25, 26 In rats, stressfrom physical restraint likewise causes atrophy of the

apical dendrites in CA3 hippocampal pyramidal cells(Figure 3)27 and leads to impairments in spatial memory,which is hippocampus-dependent.28 Exposure to high lev-els of cortisol in rats also causes the same hippocampal29

and spatial memory deficits,30 demonstrating that the

THE NEUROBIOLOGY OF THE STRESS CASCADE AND SCHIZOPHRENIA

Journal of Psychiatric Practice4 January 2001

Figure 1. Molecular and cellular events in thestress response that can lead to neural damage.

HIPPOCAMPUS

HYPOTHALAMUS

PITUITARY

ADRENAL

TO BODYfor energy usage,reproduction, and

inflammatoryresponse

CRF affects cognition and stimulates fear-related behaviors

through direct brain effects

CRF

ACTH

Cortisol


effects of stress are mediated by cortisol. Further, reduc-ing cortisol exposure prevents the hippocampal cell lossinduced by chronic stress.31, 32 The degree of hippocampalcell loss in rats is correlated with cognitive deficits: thedegree of impairment in new learning of maze escape

behaviors is related to the extent of damage to the CA3region of the hippocampus.33 A putative mechanism forthese deficits may be stress-induced impairment in long-term potentiation (LTP),34 which is the neurophysiologi-cal process that underlies memory and learning. The



Figure 2. The hippocampus, which is crucial for encoding and retrieving memory, is also an importantmodulator of the hypothalamic-pituitary-adrenocortical (HPA) response to stress.Reprinted with permission from Squire LR, Kandel ER. Memory: From mind to molecules. New York: Scientific AmericanLibrary; 2000.


impairments in hippocampus-dependent memory thatresult from stress can persist beyond the resolution of thestress response and the normalization of cortisol levels.35

While damaging effects of cortisol on CA3-specificsynapses36 and inhibition of neurogenesis in the dentategyrus37 are potentially reversible in the rat hippocampus,prolonged stress or exogenous cortisol can cause neuronaldeath in rats and primates.21, 22 High levels of cortisolaccelerate energy loss38 and inhibit glucose transport,39

causing the hippocampus to be energetically limited andvulnerable to damage. Excessive excitatory amino acids(EAAs), particularly glutamate, accumulate in thesynapse,40 where they activate glutamate receptors andpathologically mobilize free calcium in the postsynapticneuron. This process has been shown to be NMDA-dependent.41 Decreases in neurotrophic factors andchanges in serotonin, precipitated by stress, also mayplay a role. In rats, stress from physical restraint or highlevels of cortisol suppress serotonin 5HT1A receptorbinding,42 so that serotonin is not taken up into the neu-ron. This increase in extracellular serotonin43 further ele-vates glutamate levels and potentiates toxicity.41, 44

The degree of physiological response to a stress is relat-ed to genetic differences and to exposure to stressfulevents early in life. Early life sensitization to stress inrats and primates is related, in part, to maternal behav-ior towards the animals. Rat pups that are not vigorous-

ly licked by their mothers after short periods of separa-tion have, as adults, more cortisol dysregulation, greaterstress reactivity, more avoidant behavior, and poorer per-formance in maze tests.45 In contrast, rat pups that arevigorously licked after short separations are largely pro-tected from developing these abnormalities as adults.However, prolonged maternal separation leads to HPAdysfunction in nearly all rat pups, independent of mater-nal licking after separation. Although there is a geneticbasis for maternal licking rate, cross fostering demon-strates intergenerational nongenetic transmission, sug-gesting a protective effect of high licking even for pupsfrom low-licking lines.46, 47 Levine and his colleagues haveshown similar effects of maternal separation in mon-keys.48

Stress, Cortisol, Memory, and the Hippocampus inHuman Conditions

A number of studies in the last several years have alsodemonstrated strong associations among stress, high cor-tisol levels, hippocampal integrity, and memory inhumans. These data complement the animal studies insuggesting that these elements may likewise be linked ina causal pathway that is initiated by perceived psycho-logical and/or physiological threat in humans. There is aremarkable consistency in research on these elementsacross a wide range of human conditions, including expo-sure to steroid medications, Cushing’s disease, normalaging, depression, posttraumatic stress disorder (PTSD),and Alzheimer’s dementia.

Many psychiatric illnesses are known to be associatedwith cortisol dysregulation. While abnormal basal levelsof cortisol may indicate an abnormality, the more sensi-tive test of cortisol function is the dexamethasone sup-pression test (DST). This test examines the level ofcortisol released by the adrenal cortex into the blood inresponse to the exogenous steroid dexamethasone.Normally, dexamethasone inhibits cortisol secretionthrough feedback inhibition of the HPA axis. Patientswith psychiatric illness are more likely to have persist-ently elevated cortisol levels following administration ofdexamethasone, indicating a failure of inhibition of corti-sol secretion. Abnormal DST results are seen in a signifi-cant percentage of patients suffering from depression andhave been found to be associated in depression with small



Figure 3. Camera lucida drawings of representa-tive Golgi-impregnated CA3 pyramidalneurons from control and stress rats.Reprinted with permission from Watanabe Y,Gould E, Cameron HA, et al. Phenytoin preventsstress- and corticosterone-induced atrophy of CA3pyramidal neurons. Hippocampus 1992;4:431–6.

ControlStress

Many psychiatric illnesses are known tobe associated with cortisol dysregulation.


hippocampal size.49 In depression, baseline levels of corti-sol in the urine are correlated with cognitive impair-ment.50 Further, middle-aged patients with chronicrefractory depression have smaller hippocampi than doage-matched healthy controls51 and the total lifetimeduration of depression (but not age) correlates withsmaller bilateral hippocampal volumes and lower verbalmemory scores.52 Patients with depression have beenreported to have a statistically significant 16% smallerleft hippocampus than comparison subjects.53

Individuals with PTSD, who, by definition, have had asignificant exposure to stress, show associations amongcortisol, hippocampal volume, and cognition. Veteranswith PTSD score significantly lower on hippocampal-dependent memory measures, such as the WechslerMemory Scale and the Selective Reminding Test54 andthese deficits correlate with reduction in right hippocam-pus volume.55 Adult survivors of childhood abuse alsoshow deficits in immediate and delayed verbal recall56

and smaller hippocampi, but no difference in size of theamygdala, temporal lobe, or caudate,57 suggesting a neu-ral specificity to the volume reduction. However, unlikethe elevated and unregulated cortisol levels seen indepression and other conditions, cortisol levels inpatients with PTSD are reduced.58 One hypothesis toexplain this puzzling finding is that stress may cause anacute hypercortisolemia at the time of trauma and thensubsequent chronic cortisol dysregulation, which later, atthe time of diagnosis, is characterized by low serum cor-tisol but high CRF and ACTH.11

HPA dysfunction is related to the hippocampal atrophyof Alzheimer’s dementia (AD), even though it is not etio-logic for the condition. Patients with AD have elevatedbaseline cortisol levels and relative insensitivity to theeffect of glucocorticoids on glucose metabolism.59 Thedegree of hippocampal atrophy in AD is correlated withDST nonsuppression60 and with cortisol levels followingthe glucose tolerance test.61 However, only a few studieshave shown a link between cognitive impairment and

HPA dysfunction in AD;62 most studies have been nega-tive.60 It is likely that HPA-related cognitive changes inAD are small compared to those resulting from the dis-ease process itself.

Glucocorticoids may impair hippocampus-dependentmemory in humans. This effect is demonstrated in indi-viduals who chronically take 5–40 mg/day of prednisonefor medical indications63 and in healthy research subjectsadministered fixed doses of dexamethasone or prednisonefor just 4 days.64 In Cushing’s disease, a condition markedby high levels of endogenously released cortisol, patients’hippocampal volumes are inversely correlated with plas-ma cortisol levels (r = –0.73, p < 0.05). These reductionsin hippocampal volume are also correlated with lowerscores in verbal memory, specifically paired associatedlearning and recall corrected for full-scale IQ.65 Of note,memory deficits that occur in patients with Cushing’sdisease have been shown to be reversible.66

Associations among stress, cortisol, hippocampal vol-ume, and cognition are also demonstrated in normalaging. Healthy elderly individuals with increasing/highcortisol levels (measured annually) were found to haveimpairments in hippocampus-dependent explicit memoryand in selective attention, as measured by Wechslerscales, cued recall, and a visual search task.67 In an anal-ogous study, another group with increasing or high corti-sol over time demonstrated a 14% reduction inhippocampal volume (p < 0.001);52 the annual rate of cor-tisol increase correlated negatively with hippocampal vol-ume (r = –0.8, p < 0.01). Hippocampal size is alsoinversely related to delayed memory performance in nor-mal human aging.68 Explicit memory impairments inaging individuals can be transiently induced by stress:when healthy elderly subjects were assigned the stressfultask of giving a videotaped public presentation, thoseindividuals who secreted more cortisol in anticipation didmore poorly on explicit memory.69 However, these tran-sient effects may be a consequence of impaired workingmemory and thus poor encoding, rather than a deficit in



Hippocampal Atrophy and Memory Impairment Hippocampal Atrophy and Conditions Abnormal Cortisol and Abnormal Cortisol Memory Impairment

Cushing’s cortisol65 cortisol65 (+)65

Aging cortisol52 cortisol67 (+)68

Depression Abnormal DST49 Abnormal DST50 Both correlate withduration of illness52

PTSD (+)55

Alzheimer’s Abnormal DST,60 GTT61 (+),62 (–)60 (+)70

DST = Dexamethasone Suppression Test GTT = Glucose Tolerance Test (+) = positive findings (–) = negative findings

Table 1. Associations among hippocampal volumes, cortisol, and memory in various conditions


memory recall. The associations described in this sectionare summarized in Table 1.

STRESS, CORTISOL, MEMORY, AND THEHIPPOCAMPUS IN SCHIZOPHRENIAThese elements of the stress cascade—cortisol dysregula-tion, reduced hippocampal volumes, and impairment inhippocampus-dependent memory—occur in a significantnumber of patients with schizophrenia. Nonetheless, thesame type of comprehensive studies examining the rela-tionships among these elements—stress, cortisol, hip-pocampal integrity, and cognition—have not yet beendone in schizophrenia as they have for several other con-ditions.

Cortisol Dysregulation and Schizophrenia

Cortisol dysregulation occurs at a higher rate than nor-mal in schizophrenia even though the abnormalities arenot specific for schizophrenia. A meta-analysis of 46 stud-ies yielded an overall rate of 26.4% of DST nonsuppres-sion in schizophrenia versus 5% in controls71 and anothermeta-analysis of 25 studies found DST nonsuppression in19% of subjects with schizophrenia and 7% of healthysubjects, compared with 51% of those with depression.72

The varying rates of DST nonsuppression found in schiz-ophrenia may result from differences in the types of pop-ulations studied and variance in their illness stage andcourse. Dexamethasone nonsuppression in schizophreniahas been associated with negative and cognitive symp-toms,73 ventricular enlargement,74 poorer prognosis,75

and movement abnormalities.76 Of interest, most authorsdo not find depressive symptoms to be associated withdexamethasone nonsuppression in schizophrenia.Cortisol dysregulation may be related to fluctuations insymptomatology and may vary over time in a given indi-vidual. In a prospective study, Sachar et al. found thatcortisol levels increased by 250% immediately precedingpsychotic exacerbation and then decreased to a levelbetween that of pre-episode and recovery.77 Two studiesreported a normalization of cortisol function as psychoticsymptoms abated, with DST nonsuppression declining

from 71% to 20% in one study78 and from 39% to 20% inthe other.74 The large variance in cortisol dysregulation inpatients with schizophrenia is also consistent with theconcept of schizophrenia as a heterogeneous illness, sothat the mechanism may characterize distinct subgroupswithin the schizophrenia diagnosis.

Hippocampal Abnormalities and Schizophrenia

Patients with schizophrenia have smaller hippocampithan comparison subjects.79 In addition to volume loss,there are neurochemical indices of hippocampal damagethat have been observed using magnetic resonance spec-troscopy (MRS): reduction in N-acetyl aspartate (NAA), amarker of neuronal integrity, has been significantly asso-ciated with illness in a study of 23 patients with schizo-phrenia and 18 controls.80 Likewise, functional imagingshows reduced hippocampal activation in schizophreniaduring verbal episodic memory retrieval81 and odor dis-crimination.82 Postmortem studies also demonstrateabnormal cytoarchitecture, lower cell counts, disorienta-tion of pyramidal cells, and smaller neurons in the hip-pocampi of patients with schizophrenia.83, 84 Suchhippocampal findings could result from the effects ofstress and cortisol. Neuropathology in the hippocampalCA3 region, which is related to stress or glucocorticoidexposure in animal models, would be consistent with theneurotoxicity of glucocorticoids. In schizophrenia, post-mortem studies have found abnormal dendrites onpyramidal cells in another part of the hippocampus, thesubiculum (A. Dwork, personal communication, 2000),but to our knowledge the CA3 region has not yet beenexamined.

Impairment in Hippocampus-DependentCognition and Schizophrenia

Although cognitive deficits are not listed as specific crite-ria for schizophrenia in the DSM-IV, it has becomeincreasingly clear that cognitive impairment is pervasivein schizophrenia. Often refractory to treatment, cognitivedeficits are frequently evident very early in the course ofillness. Cognitive deficits in schizophrenia exist acrossmany domains, including executive functioning andmemory. A recent meta-analysis of 70 studies that exam-ined cognition in schizophrenia showed consistent mod-erate-to-large effect sizes across studies for memoryimpairment (specifically recall):85 impairment was pres-ent in hippocampus-dependent verbal and nonverbalmemory, both immediate and delayed. Indeed, cognitivefunction, specifically hippocampus-dependent verbalmemory, is a strong predictor of functional outcome inschizophrenia.86

Stress and Dopamine

The dopaminergic system is a mechanism through whichstress may interact with schizophrenia vulnerability. In a



These elements of the stress cascade—cortisol dysregulation, reduced hippocampalvolumes, and impairment in hippocampus-dependent memory—occur in a significantnumber of patients with schizophrenia.


recent model that focuses on the possibility of an abnor-mal dopamine response to stress, Walker and Diforio87

proposed that stress augmentation of the HPA axis couldincrease dopamine synthesis and release. Neural systemsneeded for adaptation to stressors may be damaged bymaturation-related abnormal synaptic pruning or myeli-nation or by earlier congenital defects. These defectsmight not be manifest unless they are called upon to reg-ulate critical neural elements in the stress response, suchas subcortical dopamine. In support of this idea, aug-mented prefrontal dopamine release is found only duringthe active symptom phase of schizophrenia, which is pre-sumably a time of stress.88 Preclinical studies support astress-dopamine relationship in schizophrenia: in an ani-mal model of schizophrenia, rats with neonatal hip-pocampal excitotoxic damage show greatly increasedmesolimbic release of dopamine in response to stress.Consistent with the relationship of dopamine to stress,psychosis reactivation in those with a history of metham-phetamine psychosis is more likely following major lifeevents, such as divorce, unwanted pregnancy, or physicalor sexual abuse.89

Stress and Schizophrenia

The association of schizophrenia with cortisolemia, hip-pocampal abnormalities, and impairment of hippocam-pal-dependent cognition suggests that these indices maybe causally related to the disease. Further support forthis relationship comes from data that show a relation-ship between stress/life events and illness course andrelapse. But what evidence exists that stress plays a rolein the etiology of schizophrenia? Interestingly, both pre-natal insults and early postnatal psychosocial stress havebeen linked to schizophrenia risk, even though the dis-ease becomes manifest and diagnosable years later, usu-ally during late adolescence or early adulthood. High-riskchildren are more likely to develop schizophrenia if theyare exposed to parental maltreatment90 or live in institu-tional settings.91 The adopted children of affected moth-ers are similarly more likely to develop schizophrenia iftheir adoptive families are “dysfunctional.”92 Recently,patients with schizophrenia have been found to have afourfold increased rate of early parental loss (death orpermanent separation) compared to controls, particularlyif parental loss occurred before 9 years of age.93

Thus far, we have principally focused on postnatal andadult effects of stress/cortisol in the induction of neuraldamage, but stress in utero is also associated with schiz-ophrenia risk. Offspring whose mothers were informed oftheir husband’s death during the second trimester havean increased risk of psychosis.94 Animal studies of prena-tal stress demonstrate several findings in parallel withschizophrenia. Exposure to stress or stress hormones inutero is associated with elevated cortisol and stressresponsiveness, reduced hippocampal weight, and

decreased brain N-acetyl-aspartate in rat pups95–98 andin primates.99 Some of the most promising animal modelsfor schizophrenia involve excitotoxic hippocampal insultduring development: in the rat, this lesion leads to behav-ioral abnormalities and hyperresponsivity to stress inadults.100 Similarly, early hippocampal injury in primatesleads to long-lasting impairment of the prefrontal cortexwith related abnormal behavior and cognition.101 In uterostress in primates leads to dermatoglyphic abnormali-ties,102 neuromotor and attentional deficits, and socialimpairment.103 The analogous findings in schizophreniaare evident as early as the premorbid phase, long beforethe development of frank psychotic symptoms. Neonatalhippocampal injury seems to be a workable primatemodel of schizophrenia, in that it impairs long-termsocioemotional behavior, with loss of social affiliation anda protracted emergence of abnormal behaviors, as well asmemory impairment. Hippocampal abnormalities inschizophrenia have been ascribed to early neurodevelop-mental events: it is conceivable that glucocorticoid toxici-ty is a final common pathway through which a variety ofstressors that have been associated with schizophrenia(prenatal infection, poor nutrition, obstetric complica-tions, and traumatic brain injury) may injure the hip-pocampus.

Stress is ubiquitous, but schizophrenia is uncommon. Itis therefore likely that some other latent vulnerability(either from faulty genes or adverse prenatal events) isessential for stress to cause schizophrenia. The finding ofan association between early psychosocial stress andschizophrenia only in high-risk individuals suggests thatstress and genetic vulnerability may interact. Perhapsthe condition of premorbid schizophrenia, with its psy-chosocial and sensory data processing impairments, coulditself increase exposure and responsiveness to stress.Innocuous stimuli may be misperceived as threatening ordangerous and cognitive dysfunction may impair effec-tive coping with stressful circumstances. It is feasiblethat a vulnerability to schizophrenia may entail anincreased exposure or vulnerability to stress. Psychoticrelapse itself may be a major source of stress, since it hasbeen found to lead to PTSD symptoms.104 Conversely, arecent study found that duration of untreated psychosisin first-episode schizophrenia was not associated withstructural brain deficits or cognitive impairment, whichsuggests that the onset of illness itself may not be induc-ing stress-related changes in the brain.105

Just as schizophrenia is only one of a number of condi-tions that may be exacerbated by stress, stress is likelyonly one of many factors that contribute to schizophrenia.The importance of genetic factors in schizophrenia vul-nerability is virtually undisputed. As yet, however, nomajor “schizophrenia gene” has been identified, and it islikely that much of schizophrenia vulnerability mayresult from multiple genes of small effect that interact




with one another and with environmental exposures atparticular stages of development. Stress may be one suchrelevant environmental factor.

THE POSSIBILITIES FOR INTERVENTIONAND TREATMENTCognitive deficits are prevalent in schizophrenia andstrongly predict functional outcome106—yet they are thesymptoms that have proven most refractory to treatment.While cognitive impairments are typically viewed as afixed and early feature of illness, a sort of staticencephalopathy, more recent research demonstrates someprogression of cognitive dysfunction in schizophrenia.106,

107 If cognitive impairment is related to the stress cas-cade, then opportunities may exist for intervention inpatient subgroups with stress reactivity.

Furthermore, if hippocampal damage were immutablyfixed in early life, then interventions to directly improvehippocampal function would be limited. But if the hip-pocampus is plastic, then improvement in cognition andoutcome for patients with schizophrenia may be possible.Data suggest that dynamic changes can occur in theadult hippocampus, including the genesis of new neuronsin the dentate gyrus.37 These new cells may have animportant function in the consolidation of new memoryand may offer an antidote to stress-induced injury.

We have described animal data showing that the den-dritic branches in the pyramidal cells of the hippocampusmay regenerate when a stressor is eliminated or cortisolis reduced. In humans, stress responses may be attenuat-ed by nonpharmacologic interventions. Environmentalenrichment, which stimulates hippocampal neuronregeneration in animals,108 also reduces stress in adultswith schizophrenia. Stress management techniques pre-vent deterioration early in the course of schizophrenia,delay relapse,109, 110 and reduce anxiety.111, 112 Identifyinga subset of schizophrenia patients with cortisol dysregu-lation, small hippocampi, and poor cognition introducesthe possibility of targeting such treatment for this groupto improve cognition.

Numerous neuroactive medications have been shownto prevent stress-induced damage to the hippocampus in

animal studies. Tianeptine, an antidepressant and sero-tonin uptake enhancer, has been found to block cortisol-induced dendritic atrophy in the hippocampus andreverse maze deficits in rats, an effect not seen with flu-oxetine and desipramine.42 NMDA blockers and adrenalsteroid synthesis inhibitors reduce stress-induced dam-age, as may some benzodiazepines.

A significant body of work has shown neuroprotectiveactivity of the anticonvulsant phenytoin. Phenytoinblocks the atrophy of pyramidal cell apical dendrites inthe CA3 region of rat hippocampus that is induced bystress or glucocorticoids. The neuroprotective effect ofphenytoin is not achieved via a reduction in cortisol lev-els, as phenytoin remains protective even in the contextof high levels of cortisol; also, phenytoin administrationdoes not block the stress-induced weight gain or adrenalenlargement that result from high cortisol levels. Rather,phenytoin appears to inhibit glucocorticoid-induced api-cal dendritic atrophy of CA3 pyramidal cells by blockingcalcium influx and the release of excitatory amino acids.The mechanism may include modifying neuronal nitricoxide synthase (NOS) messenger RNA expression ininhibitory hippocampal interneurons. The role of NOS inmemory is likely mediated by its effects on long-termpotentiation (LTP).

An additional potential treatment for the cognitivedeficits of schizophrenia may be another adrenal steroid,dehydroepiandrosterone (DHEA), which, along with itssulfated ester DHEAS (together abbreviated DHEA(S)),is the most abundant steroid hormone in the body.113 Likecortisol, DHEA(S) is produced and secreted by the adre-nal cortex, but it is also synthesized in the brain, where itacts locally.114, 115 DHEA(S) is neuroprotective and mayact as an endogenous restraint against cortisol: it hasbeen proposed that the ratio of cortisol to DHEA may bea more significant correlate of neurotoxicity than the lev-els of either hormone alone.116 For example, the ratio ofevening levels of cortisol to DHEA was found to predictpersistent major depression, as well as subsequent disap-pointing life events, in 8 to 16 year olds.117 DHEA(S)blocks the neurotoxic effects of cortisol on hippocampalcells.116, 118 In vitro, it protects hippocampal neuronsagainst excitotoxicity from glutamate and NMDA118–120

and against oxidative injury.115 In rats, DHEA(S) increas-es long-term potentiation (associated with memory andlearning) in the dentate gyrus (a part of the hippocampalformation)113 and enhances activity of hippocampal cellsin the CA1 region.121 It has been found to improve mem-ory to youthful levels in old mice.122

Like cortisol, DHEA plasma levels reflect a circadianrhythm. In schizophrenia, abnormal diurnal patterns ofDHEA, but not cortisol, aldosterone, or testosterone, dif-ferentiated patients from healthy normal subjects with100% accuracy.123 The implications of a disturbed circadi-an rhythm of DHEA in schizophrenia are not clear. The



If cognitive impairment is related to thestress cascade, then opportunities mayexist for intervention in patient subgroupswith stress reactivity.


finding is not specific, as morning levels of DHEA havebeen found to be lower among depressed adolescents,adults124, 125 and depressed elderly women (but notmen).126

Treatment with DHEA has been found to be efficaciousin depression, improving mood and memory, in both open-label and placebo-controlled double-blind studies.127–129

Administration of DHEA to healthy aging individuals,however, has yielded mixed results,130 with only somestudies reporting an improvement in well-being.131 Asyet, there have not been any published reports of DHEAtreatment in schizophrenia since 1954, when case reports(unblinded and uncontrolled) claimed that DHEAimproved a range of negative symptoms. If cortisol toxic-ity proves to be an important mechanism in the emer-gence of schizophrenia symptoms, it will warrant a studyof DHEA in the treatment of the cognitive impairmentsthat are so debilitating and refractory in schizophrenia.

CONCLUSIONAlthough the role of stress as a factor in the onset andcourse of schizophrenia has been studied for decades, therelationship between stress and illness remains to be elu-cidated. This will involve a careful assessment of expo-sure to stress in patients with schizophrenia, including ahistory of prenatal exposures, obstetric events, earlytrauma, major life events, and day-to-day stress. It alsowarrants an investigation of potential associations ofstress in schizophrenia with cortisol dysregulation, hip-pocampal function, and cognitive impairment. There maybe a subset of schizophrenia patients who have abnormalcortisol indices, small hippocampi, and memory impair-ment. Characterizing this subset in terms of timing andnature of CNS exposure to stress may help elucidate theprocess by which abnormal neurodevelopment leads tothe expression of schizophrenia.

Animal studies have demonstrated that both stressand cortisol are toxic to the brain, especially to the hip-pocampus, and lead to impairments in hippocampus-dependent cognition. This toxicity is mediated throughexcessive glutamate, which has been hypothesized to playa role in several neuropsychiatric disorders, includingschizophrenia.132 In humans, there is extensive and con-sistent research that links cortisol, hippocampal volumes,and hippocampus-dependent memory across many condi-tions, including Cushing’s disease, depression, PTSD, andage-related cognitive impairment. In light of these dataand the well-replicated findings of reduced hippocampalvolume and impaired cognition in schizophrenia, it isimportant to examine these associations in patients withschizophrenia.

There are many challenges in understanding the mech-anisms by which stress might play a role in schizophre-nia. It is a heterogeneous disorder, so it is possible thatstress may be a significant etiological factor in some cases

of schizophrenia but less important or irrelevant in oth-ers. This would certainly impede our attempts to under-stand its relationship to this disease as a whole. Anotherchallenge is that the relationship between stress andschizophrenia is likely to be complex and bidirectional,unfolding over the course of development and interactingwith other factors, such as genetic vulnerability. Yet,despite these obstacles, understanding how stress mayaffect the onset and course of schizophrenia has impor-tant implications for the development of novel treat-ments, both pharmacologic and nonpharmacolgic, for thedevastating and so far relatively untreatable cognitiveimpairments distinctive to this illness.

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