Download The Stress Cascade and Schizophrenia

The Stress Cascade and Schizophrenia:
Etiology and Onset
By Cheryl Corcoran, Elaine Walker, Rebecca Huot, Vijay Mittal,
Kevin Tessner, Lisa Kestler, and Dolores ^Aalaspina
Abstract
Psychosocial stress is included in most etiologic models
of schizophrenia, frequently as a precipitating factor
for psychosis in vulnerable individuals. Nonetheless,
the stress-diathesis model has not been tested prospectively in prodromal patients as a predictor of psychosis. The biological effects of stress are mediated by
the hypothalamic-pituitary-adrenal (HPA) axis, which
governs the release of steroids, including cortisol. The
past few decades have witnessed an increased understanding of the neural effects of stress and cortisol,
including both normal and abnormal diatheses. As few
biological markers have been evaluated as risk factors
for psychosis in prodromal patients, the HPA axis and
its interaction with intervening life events are apt candidates for study. In this article, we review the HPA
axis and its neural effects, present a model for how
stress might precipitate psychosis in vulnerable individuals, review the empirical evidence of a link
between stress and schizophrenia symptoms, and propose a research design and appropriate statistical
models to test the stress-diathesis model for psychosis
onset in prodromal patients.
Keywords: Schizophrenia, psychosis, prodrome,
stress, cortisol.
Schizophrenia Bulletin, 29(4):671-692,2003.
The past decade has witnessed major developments in the
prediction of psychosis among individuals with subclinical positive symptoms. Measures have been developed to
assess "prodromal" symptoms and identify "prodromal"
individuals, of whom 40 to 50 percent become overtly
psychotic within 1 to 2 years (McGorry et al. 2001; Miller
et al. 2001). However, no clear biological markers of risk
for psychosis have been established within a prodromal
population. Variables identified thus far as having predictive value for psychosis among prodromal individuals
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have been mostly symptoms and clinical characteristics:
that is, Brief Psychiatric Rating Scale scores (total and
psychotic), symptoms of depression and anxiety, low
global functioning, and duration of symptoms (McGorry
et al. 2001). With the exception of maternal age, developmental variables (e.g., retrospective assessments of obstetric complications, developmental milestones, childhood
behaviors, premorbid adjustment) have also failed to predict psychosis in prodromal individuals (McGorry et al.
2001). Neuropsychological domains of premorbid intelligence, executive functioning, and memory are also not
predictive (McGorry et al. 2001), although new evidence
suggests that poor olfactory identification may predict the
development of schizophrenia spectrum disorders among
prodromal patients (Brewer et al. 2003). Some researchers
have found that prodromal individuals who later become
psychotic have a higher baseline ratio of left hippocampal
volume to whole brain volume than do prodromal patients
who do not become psychotic, an unexpected and paradoxical finding that requires further investigation
(McGorry et al. 2001; Phillips et al. 2002).
To date, other than brain volumes, few biological
markers have been evaluated, either as baseline predictors
or as dynamic mediating variables for the emergence of
psychosis, in individuals identified as at risk for psychosis.
Such studies are important in this high-risk group, as they
can shed light on the pathophysiology of the onset of psychosis in vulnerable individuals, which in rum can lead to
the development of new treatment and prevention strategies. A reasonable candidate system to evaluate is the
stress cascade, including the HPA axis, as stress has been
theorized to precipitate a first onset of psychosis in schizophrenia. In fact, preliminary evidence suggests that intolerance to normal stress, a dimension in prodromal scales,
may be predictive of outcome (Yung et al. 2003). It has
Send reprint requests to Dr. C. Corcoran, New York State Psychiatric
Institute, Unit 2, 1051 Riverside Drive, New York, NY 10032; e-mail:
cc788 @ columbia.edu.
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
C. Corcoran et al.
long been assumed that stress is relevant to the course of
schizophrenia, and stress has been included as a "triggering" element in the dominant etiologic models of the disorder. In particular, diathesis-stress models originated in
the field of schizophrenia and were subsequently applied
to other forms of psychopathology. Although the earliest
incarnations of the diathesis-stress model of schizophrenia
were primarily focused on the interaction between psychosocial stress exposure and genetic vulnerability, more
recent models have encompassed a neurobiological level
of analysis (Walker and Diforio 1997). Several of these
recent approaches have addressed the biological aspects of
the stress response, including elements of the HPA axis,
such as cortisol. The HPA axis is an appropriate candidate
neural system to study as a risk factor and marker for onset
of psychosis and schizophrenia, as cortisol dysregulation
characterizes a subset of schizophrenia patients and cortisol levels have been associated with psychosis, cognitive
deficits, and schizophrenia-like brain changes across a
host of disorders.
There is now evidence that HPA function may be pertinent to the question of psychosis risk in prodromal individuals. Baseline cortisol levels in adolescents with
schizotypal symptoms, who may be at risk for psychosis,
predict severity of their schizotypal symptoms 1 and 2
years later (Walker et al. 2001) and their risk for conversion to Axis I psychotic disorders (Walker and Walder
2002). These results are consistent with the notion that the
HPA axis moderates the expression of psychotic symptoms. This is also parallel to what has been found in other
at-risk adolescent samples, as baseline morning cortisol is
associated with a 7-fold increase in risk for the onset of
major depression within a year in adolescents identified as
at high risk for depression (Goodyer et al. 2000). In adolescents with depression, evening cortisol levels have been
found to predict chronic depression (Goodyer et al. 2001),
recurrence of depression (Rao et al. 1996), and future suicide attempts (Mathew et al. 2003).
The notion that stress is a precipitating factor for psychosis in vulnerable individuals has face validity and resonates for patients and their families. The stress-vulnerability model currently provides the foundation for what is
considered state-of-the-art psychological treatment for
prodromal patients in clinics worldwide. However,
although stressful life events are implicated in psychosis
relapse, die contribution of stress to psychosis onset has
not yet been studied prospectively (Nuechterlein et al.
1992). However, in a cross-sectional study of young adults
who are identified as being at high risk for schizophrenia
on the basis of having at least one affected first degree relative, current psychotic symptoms were related in crosssection to recent life events in a dose-dependent relationship, with an estimated effect size of 2.0 (Miller et al.
2001). Prospective studies in adolescents at risk for
depression demonstrate the importance of psychosocial
stress. Among adolescents at risk for depression, major
disappointments and permanent losses predicted the onset
of major depression in the ensuing month, with odds ratios
of 58.9 (7.0-495.5) and 8.8 (2.02-38.6), respectively
(Goodyer et al. 2000).
The stress cascade and its corresponding neurobiology, in terms of activation of the HPA axis and consequent
neurological effects, are reasonable to explore as both a
risk factor for and a marker of evolving psychosis.
Namely, how might stress and the HPA axis influence vulnerability to schizophrenia? And how might stress and
HPA activity trigger episodes in vulnerable individuals? In
this article, we will (1) review the effects of stress and the
HPA axis on the brain in both animals and humans, (2)
describe how neurodevelopmental pathology might lead to
an enhanced vulnerability to psychosis in the context of
stress, and (3) describe methodological and statistical
approaches to research on stress and the HPA axis in prodromal patients.
The Stress Cascade and Its Effects on
the Brain
Review of the HPA Axis. The HPA axis is one of the
main neural systems mediating the stress response in
mammals. It involves three chemical messengers: corticotropin-releasing hormone (CRH), adrenocorticotropic
hormone (ACTH), and glucocorticoids (figure 1). In
response to stress, cells in the periventricular nucleus of
the hypothalamus release CRH, which stimulates the pituitary to secrete ACTH. In turn, ACTH stimulates the
adrenal cortex to release glucocorticoids, specifically cortisol in primates and corticosterone in rats. Of note, CRH
is not only a component of the HPA axis diat stimulates
pituitary release of ACTH but also a neuropeptide for
which receptors are located diroughout the cortex. CRH
has direct effects on the brain, including the locus
coeruleus, the periventricular nucleus of the hypothalamus, the bed nucleus stria terminalis (BNST), and the
central nucleus of the amygdala (Koob and Heinrichs
1999). Interaction of CRH with the noradrenergic system
in these four sites can lead to a feed-forward activation
that can result in significant alterations to homeostasis—
that is, "allostasis" and possibly psychopathology.
Stress leads to glucocorticoid secretion in both animals and humans. In rats, stressors such as restraint, aversive noise, and separation from conspecifics result in a rise
in corticosterone secretion (Sanchez et al. 2001). Similarly, in humans, cortisol release is linked with stress exposure across the life span, from infancy through adulthood
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deficit in negative feedback. Physiological challenges,
such as glucose tolerance tests, determine the extent to
which the HPA axis responds to provocation and can identify individuals who have a hyperresponsive HPA axis,
with sustained increases in cortisol.
Figure 1. The HPA axis and the brain1
:
HypO*hfllarniis-Pituitary-ArirMnal
Effects of Stress and the HPA Axis on the Brain.
Chronic stress and persistent elevation of glucocorticoids
lead to neural changes and "sensitization" to stress, which
may result from feed-forward systems as described above,
and/or from changes in the negative feedback system that
dampens HPA axis activation, such as neurotoxicity to the
hippocampus and a subsequent reduction in GC receptors
(Sapolsky et al. 1985; Sapolsky et al. 1990; Sapolsky
1992; Stein-Behrens et al. 1994). Stress has been shown
to have a number of effects on the GC receptor-rich hippocampus, including not only cell death (Uno et al. 1989)
but also potentially reversible processes, such as atrophy
of dendrites on excitatory pyramidal neurons (McEwen
and Magarinos 1997), decrease in the generation of new
neurons (Gould and Tanapat 1999), reduced expression of
neurotrophic factors such as brain derived neurotrophic
factor (BDNF) (Vaidya et al. 1999), and suppression of
long-term potentiation (Diamond et al. 1994), the biological underpinning of memory. Thus, it is not surprising that
rodents exposed to high levels of corticosterone manifest
deficits in hippocampal-dependent spatial memory (Luine
1994). The degree of impairment in new spatial learning
in rats is correlated with cell loss in the CA3 region of the
hippocampus (Arbel et al. 1994).
There is evidence in humans that chronic stress and
glucocorticoid elevation may also be toxic to the brain,
specifically the hippocampus, as there are interrelationships among stress, cortisol function, hippocampal volume, and hippocampus-dependent cognition in stressrelated disorders. In post-traumatic stress disorder
(PTSD), which by definition involves a significant stressor, there is prominent reduction in hippocampal volume
(Bremner et al. 1997) that is accompanied by deficits in
hippocampus-dependent explicit memory. Similarly, in
depression, there is hippocampal volume reduction (Bremner et al. 2000), and there are memory deficits that are
associated with duration of illness (Sheline et al. 1999).
The role of glucocorticoids in these deficits is suggested
by found associations between urinary cortisol and cognitive impairments (Rubinow et al. 1984) and between cortisol dysregulation and hippocampus volume reduction
(Axelson et al. 1993). However, the causal relationships
among these variables cannot be determined by cross-sectional studies, and it has been suggested that a smaller hippocampus could be a marker or risk factor for PTSD or
chronic depression, and not itself an effect of stress and
glucocorticoid exposure.
STRESS
(e.g. threat)
Adrcnb
Kidney
V M
1
Reprinted with permission from Erno Vreugdenhil, Ph.D.
(Medical Pharmacology/Leiden Amsterdam Centre for Drug
Research), University of Leiden, the Netherlands.
(Kirschbaum et al. 1992). Stressors have consistently been
linked over minutes to hours to increases in human salivary cortisol in both naturalistic studies (Smyth et al.
1998; van Eck et al. 1996) and in the laboratory (Hubert
and de Jong-Meyer 1989; Wittling and Pfluger 1990;
Kirschbaum et al. 1993; McCleery et al. 2000). Of note,
laboratory stressors include imagined bereavement, public
speaking, and the viewing of disturbing popular movies,
such as The Shining.
Glucocorticoids have effects throughout the body, and
they are critical to the physiological changes that accompany stress exposure. Furthermore, glucocorticoids are
known to affect the brain. Glucocorticoid (GC) receptors
are located in various regions throughout the brain, and
they provide feedback for regulating the activity of the
HPA axis. The hippocampus contains GC receptors, and it
is postulated to be the main part of a negative feedback
system modulating HPA activation (Sapolsky et al. 1990;
Lupien et al. 1998). GC receptors have also been found in
the medial prefrontal cortex (Diorio et al. 1993), and 40 to
75 percent of midbrain dopaminergic neurons have GC
receptors (Harfstrand et al. 1986).
Glucocorticoids can be measured in cerebrospinal
fluid (CSF), urine, plasma, and saliva. The responsivity of
the HPA axis can be probed through challenge, through
either induced stressors or pharmacological challenge. For
example, dexamethasone, a steroid, normally provides
negative feedback to the HPA axis, leading to a suppression of cortisol secretion. Failure to suppress cortisol constitutes an abnormal dexamethasone test and indexes a
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C. Corcoran et al.
More solid evidence that cortisol may mediate neurotoxicity in humans comes from studies in individuals who
have high cortisol levels, from either endogenous (Cushing's disease) or exogenous (pharmacological corticosteroids) sources. In Cushing's disease, hippocampal volumes are inversely correlated with plasma cortisol levels
(r = -0.73, p < 0.05) (Starkman et al. 1992) and positively
associated with verbal memory scores corrected for IQ. Of
note, these memory deficits (Mauri et al. 1993) and hippocampal volume reductions (Starkman et al. 1999) are
both reversible with treatment and normalization of cortisol levels, suggesting that cortisol may have direct and
reversible effects on hippocampal volumes and hippocampus-dependent memory in humans. Further, exogenous
glucocorticoids have reversible effects on cognition,
specifically memory (Wolkowitz et al. 1990; Newcomer et
al. 1994; Kirschbaum et al. 1996).
(Ganguli et al. 2002), a regionally specific response that
the authors suggest may be evidence of an abnormal brain
activation pattern in schizophrenia patients in response to
stress. Postmortem studies demonstrate reduced cell size
in the hippocampus, as well as abnormal apical dendrites
on pyramidal cells in the subiculum (Rosoklija et al.
2000), findings that could be consistent with the known
effects of stress and cortisol on apical dendrites in the hippocampus (McEwen and Magarinos 1997). Postmortem
studies also show a decrease in GC receptor message in
several brain regions in schizophrenia patients compared
with normal controls (Webster et al. 2002), including not
only layers HI to VI of the frontal cortex and layer IV of
the inferior temporal cortex but also the dentate gyrus,
CA(4), CA(3), and CA(1) regions of the hippocampus.
This decrease in GC receptors is consistent with
decreased feedback of the HPA axis, resulting in heightened glucocorticoid secretion, as well as differences in
cortisol-induced brain activity.
HPA Axis and the Brain in Schizophrenia. Evidence of
HPA dysfunction also exists in schizophrenia and includes
pathology in the neural target of glucocorticoids, the hippocampus, and associated memory deficits. These may be
a consequence of the abnormal neurodevelopmental
processes that lead to schizophrenia pathophysiology (i.e.,
an abnormal hippocampus leads to poor memory and
impaired feedback of the HPA axis). We hypothesize that
abnormality in the hippocampus may be one feature of the
neural diathesis in prodromal patients that puts them at
risk of developing psychosis in the context of stress. An
impaired hippocampus that results from genetic liability
or early environmental exposures could lead to an unrestrained HPA axis response to stress, as the hippocampus
is rich in GC receptors that are integral to the negative
feedback of the HPA axis. Further stress around the time
of onset of first psychosis may affect the hippocampus,
but that is not an integral part of our model.
HPA axis. Two meta-analyses have demonstrated a
significantly higher rate of dexamethasone nonsuppression of cortisol in schizophrenia (Sharma et al. 1988;
Yeragani 1990), and dexamethasone nonsuppression has
been associated with both negative and cognitive symptoms (Newcomer et al. 1991). There is elevated cortisol
secretion in early sleep (van Cauter et al. 1991) and at 4
p.m. in unmedicated schizophrenia patients when compared with controls (Thakore et al. 2002).
Hippocampus. Meta-analysis has demonstrated hippocampal volume reduction in schizophrenia (Wright et
al. 2000). Other evidence of hippocampal abnormality in
schizophrenia comes from spectroscopic (Deicken et al.
1999) and functional imaging (Heckers et al. 1998;
Malaspina et al. 1998) studies. In fact, regional blood flow
in the hippocampus is increased in response to exogenous
cortisol in schizophrenia patients compared with controls
Hippocampus-dependent explicit memory.
Cognitive deficits exist in many domains in schizophrenia, including attention, executive function, and working
memory. However, a meta-analysis of 70 studies that
examined cognition in schizophrenia showed the largest
effect sizes across studies for explicit memory, both verbal and nonverbal and both immediate and delayed
(Aleman et al. 1999). Cognitive function, specifically hippocampus-dependent verbal memory, is a strong predictor
of functional outcome in schizophrenia (Green 1996) and
is inversely associated with cortisol levels. Verbal memory deficits exist during the prodrome (Hawkins et al.
2001) and may either be a marker of liability (hippocampal abnormality) or a risk factor itself for psychosis.
However, studies by McGorry et al. (2001) have not
found verbal memory deficits to be more marked in prodromal patients who will convert to psychosis.
Possible explanations for the associations of these
elements in schizophrenia. As in several other clinical
disorders, hippocampal, cognitive, and HPA axis measures are interrelated in schizophrenia. However, the
questions of timing and causality remain unanswered.
Abnormality in the hippocampus could occur primarily
early in life and represent a marker or risk factor for the
eventual development of psychosis and schizophrenia.
Another possibility is that there are structural changes in
the hippocampus later in life that reflect evolution of
symptoms and possibly stress during the prodromal
period. In support of this idea, there have been reports of
progressive cognitive deficits, including deficits in
explicit memory (Hawkins et al. 2001), and hippocampal
volume reduction (Pantelis et al. 2000) in the transition
from the prodrome to psychosis. Also, high-risk patients
have hippocampal volumes intermediate between those of
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normal controls and those of schizophrenia patients
(Lawrie et al. 2001), and as mentioned above, one
research group reported the counterintuitive finding that
larger left hippocampal volume predicted conversion to
psychosis among prodromal patients (Phillips et al. 2002).
Therefore, it is not clear whether the structural effects
of stress and cortisol on the hippocampus might play a role
in the early development of symptoms in schizophrenia,
including both the onset of psychosis and cognitive
deficits. A model for such effects would involve synaptic
reorganization, a process that is increased in adolescence,
the period when vulnerable individuals begin to manifest
prodromal signs. The synaptic pruning hypothesis is one
of the leading models for the development of symptoms in
schizophrenia (Feinberg 1982) and is supported by computer modeling (Ruppin et al. 1995; McGlashan and Hoffman 2000), spectroscopic studies (Keshavan et al. 2003),
and postmortem studies (reviewed in Harrison 1999).
Synaptic pathology could arise in vulnerable adolescents
by virtue of an abnormal substrate, resulting from genetic
liability or early exposures, and/or an abnormal neuromaturational process, which could be augmented by environmental factors, such as stress. Stress and glucocorticoids
can lead to reversible neuroplastic changes (Fuchs and
Flugge 1995), such as atrophy of excitatory apical dendrites on pyramidal cells in the hippocampus, and can perturb N-methyl-D-aspartate (NMDA)-dependent synaptic
plasticity in the hippocampus (Petrie et al. 2000). Glucocorticoid administration reorganizes dendritic arborization
in the medial prefrontal cortex as well (Wellman 2001).
Dendritic pathology consistent with stress-induced
changes has been found in schizophrenia in both the hippocampal formation (Rosoklija et al. 2000) and the prefrontal cortex (Glantz and Lewis 2001). Such neuroplastic
changes could putatively fluctuate with psychotic symptoms, as basal cortisol levels have been observed to do
(Sacharetal. 1970).
Nonetheless, although stress may precipitate structural changes in the hippocampus and consequently
worsen cognitive deficits during the prodrome, this is not
a key element of our model. In our model, we suggest that
hippocampal impairment may be part of the abnormal
neural substrate in schizophrenia that confers increased
likelihood to develop psychosis in response to stress.
Many exposures associated with increased schizophrenia
risk are particularly injurious to the hippocampus, including obstetric complications (McNeil et al. 2000), head
injury (Bigler et al. 2002), and both prenatal and postnatal
stress (Avishai-Eliner et al. 2002). Hippocampal abnormality may augment the effects of hypofrontality
described below through contributing to decreased feedback of the HPA axis. In a rodent model of schizophrenia,
rats with neonatal excitotoxic hippocampal damage show
greatly increased mesolimbic release of dopamine in
response to stress (Lipska et al. 1993). Stimulation of the
prefrontal cortex in nonhuman primates who have a
neonatal medial temporal lobe lesion also leads to a phasic increase in subcortical dopamine (Saunders et al.
1998).
Model of the Stress Cascade and
Psychosis in Schizophrenia
In addition to structural effects on the brain, there are neurochemical effects of glucocorticoids and stress, and these
may be the key to the onset of psychosis in prodromal
patients. Stress exposure affects neurotransmitter systems
and brain regions that have been implicated in psychosis.
Walker and Diforio (1997) proposed that stress exposure
may trigger or exacerbate psychotic symptoms by augmenting dopamine activity, particularly in the subcortical
region of the limbic circuitry. This idea is supported by
animal research that shows that stress can increase
dopamine activity via the effects of glucocorticoids. In
rodents, stress leads to an increased locomotor response to
amphetamine, an animal model for psychosis (Deroche et
al. 1992). Adrenalectomy in rodents has the same effect as
antipsychotics, leading to a decrease in basal dopamine
release in the nucleus accumbens and a reduction in apomorphine-induced locomotor activity (Piazza et al. 1996a,
1996Z>).
The neural diathesis of schizophrenia may entail a
special vulnerability to develop psychosis in the context of
stress. Abnormal functioning of the prefrontal cortex may
lead to a hyperresponsivity to stress by subcortical
dopaminergic neurons that do not have normal inhibition
from the prefrontal cortex. Moghaddam (2002) writes: "A
primary dysregulation in executive functioning of the PFC
can lead to abnormal regulation of stress-related circuitry
in regions downstream from the PFC, such as in the amygdala, ventral striatum or hippocampus, and produce an
altered response to stress that elicits behavioral disruptions
that are mechanistically distinct from those seen during
normal conditions (p. 776)."
One model of psychosis in schizophrenia suggests
that cortical dopaminergic dysfunction leads to a disinhibition of excitatory glutamatergic projections to subcortical
dopaminergic neurons, specifically in the nucleus accumbens (ventral striatum) (Finlay and Zigmond 1997; Krystal
et al. 1999). Dopamine neurons coming in to the prefrontal
cortex hold projection glutamatergic pyramidal neurons
under tonic inhibition. If these inhibitory dopaminergic
afferents are disabled, heightened glutamatergic activity
renders the nucleus accumbens hyperresponsive to stressful experiences (Deutch et al. 1990). The nucleus accum-
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C. Corcoran et al.
bens is posited to be relevant to the attribution of incentive
salience; Heinz (2002) has theorized that "stress-induced
or chaotic activation of dopamine release may attribute
incentive salience to otherwise irrelevant stimuli and thus
be involved in the pathogenesis of delusional mood and
other positive symptoms (p. 13)." Further, King et al.
(1997) speculate that "a disruption in the interaction
between these mesocortical dopaminergic neurons and
dopaminergic neurons projecting to the nucleus accumbens shell is involved in those symptoms of schizophrenia
that are influenced by stress (p. 141)." Support for this
model comes from animal studies: the depletion of
dopamine in the medial prefrontal cortex leads in rodents
to increased basal and stress-induced dopamine efflux in
the nucleus accumbens (Deutch et al. 1990; King et al.
1997).
As for prodromal or clinically at-risk patients, we
hypothesize that hypofrontality, as reflected in negative
symptoms and deficits in executive function, can set the
stage for increased susceptibility to developing psychosis
in the context of stress. As mentioned, this diathesis may
be augmented by abnormality in the hippocampus, such
that there are fewer GC receptors, disrupted feedback to
the HPA axis, and prolonged cortisol secretion in response
to stress. As in other disorders, disturbance of baseline
diurnal cortisol in schizophrenia is assumed to reflect both
cumulative effects of stress and trait characteristics, and
may therefore predict conversion to psychosis in prodromal patients. Furthermore, it is likely that psychosocial
stress interacts with the neural diathesis over time to produce surges in cortisol secretion that will trigger or exacerbate psychotic symptoms.
tibility gene and reactivity to psychosocial stress, there is
evidence that earlier stress exposure might increase
stress vulnerability.
Postnatal Stress. Sensitivity to stress and consequent
behavioral changes may result from stress early in development (Levine 1993; Plotsky and Meaney 1993;
Coplan et al. 2001). Rodent and primate models of early
adverse experience demonstrate long-term changes in
neuroendocrine responses to stress, cognition, brain
morphology, and emotional and behavioral regulation
(Sanchez et al. 2001). Further, early stress in rodents can
reprogram the brain to have increased stress-induced
dopamine release in the nucleus accumbens (Cabib et al.
2002), a model for psychosis. In fact, adrenalectomy in
the rat leads to decrease of dopamine in the nucleus
accumbens shell, both at baseline and in response to
mild stress, an effect reversed by corticosterone (Barrot
et al. 2000).
Experience of earlier trauma may predispose individuals to develop psychosis. Although the effect of early
trauma as a risk factor for psychosis has not yet been
studied in prodromal patients per se, general population
surveys show that a history of childhood abuse predicts
development of psychotic disorders in individuals who
endorse any psychotic symptoms at baseline, controlling
for potential confounds, and that this relationship is dose
dependent (Janssen et al. 2002). Of interest, PTSD
involves rates of psychosis as high as 30 to 40 percent
(David et al. 1999; Hamner et al. 1999), and the psychosis
in PTSD can resemble that of schizophrenia (Mueser and
Butler 1987; Butler et al. 19%). In one study, at least 75
percent of veterans with PTSD and psychosis had some
hallucinations and delusions that were not combat related
(Hamner et al. 1999). Also, as compared with schizophrenia patients, combat veterans with PTSD and psychosis
have similar global Positive and Negative Syndrome
Scale (PANSS) ratings (Hamner et al. 1999) and PANSS
negative symptoms (Hamner et al. 2000), hallucinations,
and suspiciousness, although not delusions and conceptual disorganization (Hamner et al. 2000). Further, combat veterans with PTSD score high on the "schizophrenia"
subscale of the Minnesota Multiphasic Personality Inventory (Fairbank et al. 1983; Frueh et al. 1996). These findings suggest that trauma can be related to schizophrenialike psychosis.
There is evidence of more early trauma exposure in
schizophrenia patients than in controls (Mueser et al.
1998; Neria et al. 2002), and early trauma is related to the
severity of positive symptoms (Ross et al. 1994). Studies
of genetic high-risk populations show that childhood
stress further increases the risk for schizophrenia; highrisk children who are raised in institutional settings
What May Constitute Stress
Vulnerability in Schizophrenia?
Persons with schizophrenia do not appear to experience
more stressful life events than normal controls, but they
do report greater subjective stress (Norman and Malla
1993; Walker and Diforio 1997). Stress vulnerability is
enhanced in patients with schizophrenia, such that they
respond with more negative emotions to everyday stressors than do controls (Myin-Germeys et al. 2001). Of
interest, family members of these schizophrenia patients
demonstrate a stress sensitivity lower than that of
patients but higher than that of controls (Myin-Germeys
et al. 2001). This suggests that stress reactivity may be
associated with liability for psychotic disorder as well as
the expression of the illness. This liability may very well
have a genetic component, as it is at least partially shared
by family members. Although there is no established
association between any purported schizophrenia suscep-
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(Walker et al. 1981) or by adoptive families that are "dysfunctional" (Tienari et al. 1994) or show "communication
deviance" (Wahlberg et al. 1997) are more likely to succumb to schizophrenia. Early adversity may, therefore,
interact with genetic liability to lead to schizophrenia.
A caveat is that this relationship between early trauma
and liability to psychosis may not be causal. Childhood
behavioral problems are a common precursor of schizophrenia and could contribute to the occurrence of early trauma.
Also, genetic factors may account for this relationship, such
that families with a history of mental illness may be characterized by less stability, lower socioeconomic status, and
higher rates of abuse, as well as more offspring with psychiatric disorders. Therefore, early trauma could be a marker of
risk for psychosis, not a risk factor in and of itself. Also, any
causal relationship might not be direct (e.g., early trauma
could lead to an increase in behaviors, such as drug use, that
can increase risk for psychosis).
Why Adolescence?
Although the vulnerability to schizophrenia likely originates during fetal development, it is not until adolescence
and early adulthood that the prodromal phase and first
episode of psychosis typically emerge (Bunney and Bunney 1999). Many neuromaturational processes take place
following the onset of puberty, and one or more of these
may be related to the emergence of the prodromal phase of
schizophrenia and the subsequent onset of psychosis.
Normal adolescents have a progressive decrease in
gray matter, which may reflect synaptic reorganization,
and an increase in white matter, which is consistent with
myelination of cortical fiber pathways (Giedd et al. 1999).
In addition, neuromaturation is apparent in functional
activity, with evidence of enhanced activity in the frontal
cortex (Thatcher et al. 1987; Anokhin et al. 2000), as well
as decreases in metabolic demand (Chugani et al. 1987).
Taken together, these lines of evidence support the idea of
greater cortical organization and functional efficiency with
development. Furthermore, puberty is marked by hormonal surges and increased activation of the hypothalamic-pituitary-gonadal and HPA axes (Walker et al. 2001).
These neural and hormonal changes may unmask a latent
vulnerability to psychosis and schizophrenia. Myelination
could lead to greater excitatory inputs that are unrestrained
because of GABAergic dysfunction (Benes 2000). Also,
cortisol may be neurotoxic to inhibitory GABAergic cells
in the hippocampal formation, which may already be compromised from abnormal developmental processes.
Prenatal Stress. In rodents, prenatal stress is associated
in the adult offspring with behavioral changes, persistent
elevations in HPA axis activity, and changes in GC receptor density (Takahashi et al. 1992; Henry et al. 1994;
Lordi et al. 2000; Szuran et al. 2000). Maternal stress or
corticosterone administration also increases amphetamine-induced locomotor behavior in the adult offspring, a
rodent model for psychosis (Diaz et al. 1995; Henry et al.
1995; Koenig et al. 2001). In nonhuman primates, prenatal stress leads to impaired attention, neuromotor abnormalities, decreased locomotion, and hyperreactivity to
stress in the adult offspring (Schneider et al. 2002).
Prenatal stress in primates also leads in offspring to
increased levels of dihydroxyphenylacetic acid (DOPAC),
a dopamine metabolite, in the CSF, suggesting increased
dopamine activity.
In longitudinal research on humans, schizophrenia has
been linked with exposure to several forms of prenatal
maternal stress, including the death of the father during
pregnancy (Huttunen and Niskanen 1978), unwanted pregnancy (controlling for maternal depression) (Myhrman et
al. 1996), and exposure to war and disasters, such as the
1940 invasion of Holland (van Os and Selten 1998), the
nuclear attack on Nagasaki, and tornadoes (reviewed in
Koenig et al. 2002). Elevated rates of schizophrenia are
also related to maternal depression during pregnancy
(Jones et al. 1998) and maternal malnutrition, obesity, and
infections (influenza, rubella). It is noteworthy that these
maternal conditions are known to be associated with hypercortisolemia (Walker and Diforio 1997; Koenig et al.
2002). It has been hypothesized that a potential mechanism
by which these exposures increase schizophrenia risk is
through modification of the HPA axis and hence an
increased responsivity to stress.
Baseline Cortisol as a Risk Factor for
Psychosis in Prodromal Patients
There is a diurnal rhythm to cortisol secretion, with a surge
around the time of waking and then a steady decrease
throughout the day (figure 2). Abnormality in the diurnal
rhythm can consist of either elevated cortisol levels at any
time of day or persistence in secretion, resulting in a less pronounced slope of decline and hence elevated cortisols later in
the day. Studies have explored the associations of these disturbances with demographic and behavioral characteristics.
Baseline Cortisol and Psychosocial Stress in Children.
Evidence suggests that, in children, relatively higher baseline cortisol values, especially in the morning, seem to be
related to lower socioeconomic status (Lupien et al. 2000)
as well as to disturbance in living situation. In a 9-year
study in the Caribbean (Flinn and England 1997), mean
cortisol levels were higher for children who lived with
only their mother or lived with either half-siblings or
more distant relatives. This could reflect chronic stress,
the accumulation of more frequent acute stressors, or poor
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C. Corcoran et al.
Figure 2. Serum cortisol profiles for boys and
girls during pubertal development1
elevated rates of baseline cortisol. In a large study of adolescents (Klimes-Dougan et al. 2001), internalizing problems in teens were associated with a more gradual decline
in cortisol over the course of a day. In the Flinn and
England study cited above, chronically high average cortisol levels, derived from multiple measures within individuals in the morning and afternoon, were associated with
anxiety and withdrawal behavior.
Likewise, in adults, baseline cortisol levels have been
associated with trait anxiety (van Eck et al. 1996) and
impairment in social functioning. Mason et al. (2002)
found that among PTSD patients undergoing intensive
exposure therapy, urinary cortisol sampled monthly for 90
days had individual stability unrelated to the exposure to
treatment but highly related to social functioning. Similarly, in treated depressed patients, urinary cortisol is associated with social functioning as measured by the Social
Adjustment Scale but not with depression severity (Rothschild et al. 1993). Twin studies of morning cortisol levels
not only demonstrate some heritability (r = 0.4) but also
reveal a relationship with reports of social stress and lack
of social recognition (Wust et al. 2002).
Baseline diurnal cortisol has marked intraindividual
stability in normal children over an average of 1 year, consistent with a traitlike feature (Knutsson et al. 1997) that is
independent of age, weight, height, and pubertal stage. The
free cortisol response to awakening involves a mean cortisol
increase of about 50 percent within the first 30 minutes after
awakening (Wust et al. 2000). This free cortisol response
also has remarkably high intraindividual stability over time,
with correlations up to 0.63, and appears to be unrelated to
age, use of oral contraceptives, smoking, time of awakening, sleep duration, or even use of an alarm clock.
OB
Clock time (h)
'Values shown are mean ± standard error of the mean. The areas
under the curve (AUCs) for the girts were 4,383 ± 199; 4,642 ±
393; 3.694 ± 234; 3,809 ± 274; and 4,058 ± 375 at pubertal
stages 1-5, respectively. The AUCs for the boys were 4,201 ±
110; 3,715 ± 123; 3,561 ± 219; 3,037 ± 219; and 3,662 ± 171 at
pubertal stages 1-5, respectively. There was a significant difference (p < 0.05) between boys and girls at pubertal stage 2 (by
Mann-Whitney U test). Reprinted with permission from Knutsson
etal. (1997).
Cortisol and Psychosis
Cross-Sectional Associations. HPA axis function has
been linked to the expression of psychotic symptoms in
psychiatric disorders. Among depressive disorders, psychotic depression is associated with a higher rate of dexamethasone nonsuppression than is depression in the
absence of psychosis (Nelson and Davis 1997; Duval et
al. 2000), and higher levels of baseline cortisol
(Schatzberg et al. 1983). Among patients with PTSD,
those with psychotic symptoms have higher levels of corticotropin releasing factor (CRF) in CSF than do those
without psychotic symptoms, again suggesting that psychotic symptoms may be associated with heightened
activity of the HPA axis (Sautter et al., in press). In
patients with schizophrenia and other psychotic disorders,
cortisol levels are positively correlated with ratings of
positive, disorganized, and overall symptom severity
(Walder et al. 2000).
coping skills. Furthermore, in the Caribbean study, mean
cortisol levels in children were associated with frequency
of illness (primarily upper respiratory infections) during 11
months of direct observation. These findings suggest that
elevated cortisol could mediate the relationship between
psychosocial adversity and psychosis. These findings are
also relevant for McEwen's concept of allostasis, the
notion that chronic stress is associated with disturbances in
the HPA axis, and consequent illness outcomes.
Baseline Cortisol and Anxiety, Behavioral Inhibition,
and Social Functioning. Baseline cortisol levels are
related to trait characteristics, such as anxiety, behavioral
inhibition, and social discomfort. Kagan et al. (1988)
found that in young children, shyness was associated with
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Schizophrenia Bulletin, Vol. 29, No. 4, 2003
HPA function may also be related to psychosis expression among individuals with equivalent genetic liability
for psychosis. In a recently published study, concordance
for neurohormones such as epinephrine, norepinephrine,
and several dopamine metabolites was examined in
monozygotic (MZ) twins discordant for psychosis (Walker
et al. 2002). In healthy MZ twin pairs, these tend to be
concordant, but in discordant MZ twin pairs, there was no
concordance for epinephrine, norepinephrine, or cortisol.
This finding suggests that the expression of psychotic disorders (as opposed to simple liability) is associated with
functional changes in the noradrenergic systems and HPA
axis.
Psychosocial Stress as a Trigger for
Psychosis
Stress is associated with relapse or exacerbation of a number of medical illnesses, such as asthma, ulcerative colitis,
and multiple sclerosis (reviewed in Corcoran et al. 2001).
It is associated with outcome in myocardial infarction,
melanoma, and breast cancer (reviewed in Leserman et al.
1999). Of interest, in a prospective study, cumulative
mean life events (and cumulative mean cortisol) were
associated with conversion to AIDS among HIV-positive
men, with an increase of 4 points on a life events scale
reflecting a doubling of risk for AIDS (Leserman et al.
2000). Correspondingly, the risk for AIDS was doubled for
every 5 microgram/deciliter increase in cortisol. The relationships between stress and cortisol with the onset of
AIDS persisted even when controlling for a host of relevant factors, including baseline CD4 count and viral load,
antiviral medication exposure, and health habits.
Stress can worsen symptoms and precipitate relapse
across a wide range of psychiatric conditions, including
postpartum psychosis, affective illness, and alcohol dependence (reviewed in Corcoran et al. 2001). Although the
role of stress in psychosis onset has not yet been examined
in prodromal patients, several studies have found a relationship between stress and relapse of psychosis.
Longitudinal Associations. Increases in endogenous and
exogenous cortisol in humans are associated with heightened risk for psychosis. Psychosis can be the presenting
symptom in Cushing's disease (Saad et al. 1984; Gerson
and Miclat 1985; Hirsch et al. 2000), and case reports
indicate that there is a remission of psychosis in
Cushing's disease with correction of the endogenous
hypercortisolemia (Johnson 1975; van der Lely et al.
1991; Chu et al. 2001). Steroid treatment may also lead to
psychosis (Brown and Suppes 2000; Patten and Neutel
2000), which remits with lowering of the dose (Lee et al.
2001).
Longitudinal studies show a relationship between
temporal fluctuations in cortisol and symptoms in psychotic patients. Sachar et al. (1970) measured daily urinary cortisol in four young adult patients over a 2- to 3month period and found that cortisol levels were
significantly higher (250%) immediately preceding psychotic episodes when compared with periods of recovery.
Levels during episodes fell midway between the preepisode and recovery periods. Similarly, Franzen (1971)
withdrew medication from ten schizophrenia patients for 5
weeks and found that increases in cortisol release were
associated with subsequent increases in psychotic symptoms. Cortisol levels are decreased with the successful
treatment of psychosis with clozapine (Hatzimanolis et al.
1998; Markianos et al. 1999).
Life Events and Relapse. Stress exposure, specifically
life events, increases in the weeks to months leading up to
relapse (Malla et al. 1990; Hultman et al. 1997). When
patients are their own controls (relapse vs. baseline), or
when "relapsing" patients are compared with "nonrelapsing" patients, an association of life events and relapse is
observed (Ventura et al. 1989; Malla et al. 1990; Hultman
et al. 1997). Schizophrenia patients have significantly
more stressful life events during the 3 weeks preceding a
relapse than they do during other time periods (Brown
and Birley 1968; Day et al. 1987). This has been confirmed in prospective studies (Ventura et al. 1989). In a 1year followup of schizophrenia patients, a proportional
hazards regression model showed that life events made a
significant cumulative contribution over time to the risk of
relapse (Hirsch et al. 1996): 23 percent to 41 percent of
the relapse risk could be attributed to life events, depending on the extent of exposure. Prospective studies reduce
the problem of recall bias, although causality remains an
issue, as symptoms may begin to exacerbate prior to
relapse and may lead a patient to incur more life events
(Ventura et al. 1989). Also, worsening symptoms may be
a great source of stress, as psychotic and other symptoms
can be frightening and interfere with functioning (Walker
and Diforio 1997).
Could Elevated Cortisol in Psychosis Reflect
Psychosocial Stress? Of interest, in a sample of inpatients admitted for an acute episode of psychosis, pretreatment plasma cortisol levels were correlated with the
severity of recent stressors, even when controlling for
demographic and clinical factors, such as age, sex, marital
status, diagnosis, age of onset, and duration of psychotic
symptoms. This finding suggests that the relationship
between HPA function and psychotic symptoms could be
initiated by experience of psychosocial stress (Mazure et
al. 1997).
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C. Corcoran et al.
Coping and Antipsychotics. Coping strategies and
antipsychotic medications may protect against stressinduced psychosis relapse in schizophrenia. In a
prospective study, relapse was correlated with fewer
cognitive resources and less coping ability only in the
absence of major life events (Pallanti et al. 1997).
Effective coping may act as a buffer between stressors
and relapse (Hultman et al. 1997). As neuroleptics can
lower HPA activity, it is expected that antipsychotic
medications may protect against the psychotogenic
effects of stress. In fact, among patients who relapsed in
one study, those on medication experienced a significantly greater number of stressful life events prior to
relapse than did those who were not on medication
(Nuechterlein et al. 1992, 1994). These results suggest
that neuroleptics may raise the threshold for psychosis,
so that more stress is required to trigger relapse
(Nuechterlein et al. 1994).
greater triggering potential for the first episode of psychosis than for relapse. Laruelle (2000) has proposed a
model of sensitization of subcortical dopaminergic
pathways in schizophrenia, which suggests a progressive enhancement of dopamine response under repeated
stress exposure, such that provocation of the dopaminergic system by stress may be different in early schizophrenia. Laruelle (2000) theorizes that sensitization
drives the prodromal and initial phases of illness in
schizophrenia, with increases in subcortical dopamine
activity culminating in the expression of psychosis.
This sensitization is self-perpetuating and eventually
becomes independent of the environmental factors
responsible for its initiation. Sensitization is under maturational, genetic, and environmental influences—that
is, perinatal anoxia and prenatal stress (reviewed in
Lamelle 2000). Of note, in animals, sensitization is
heterogeneous and state dependent, which is consistent
for a process that may underlie psychotic symptoms in
schizophrenia. An example of exogenous sensitization
in humans is the stress-induced psychotic symptoms
seen in individuals with a history of methamphetamine
psychosis (Yui et al. 1999).
Daily Hassles and Expressed Emotion. In addition to
life events, there are more subtle everyday factors that
might be associated with illness, such as daily stressors
or hassles (Fowles 1992; Norman and Malla 1993).
Also, expressed emotion (EE), which refers to family
members' negative emotional reactions to patients, may
be relevant as a stressor in psychosis relapse in schizophrenia (Nuechterlein et al. 1992). Schizophrenia
patients returning to families with high criticism and
emotional involvement levels have about a 50 percent
chance of relapse, compared with 15 percent in patients
returning to low-EE families (Vaughn and Leff 1976;
Butzlaff and Hooley 1998). Family interventions
designed to minimize EE are effective in preventing
relapse (Leff et al. 1982; Leff 1994), and low EE can
buffer the effects of stressful events (Nuechterlein et al.
1994). As with life events and psychosis, the direction of
causality cannot be assumed as a patient's symptoms and
behavior likely affect the behavior of the family toward
the patient (Fowles 1992). In fact, the bidirectionality of
the patient/family interaction is now assumed
(Barrowclough and Parle 1997).
How to Study the HPA Axis
Glucocorticoids can be measured in CSF, urine, plasma,
and saliva. Each of these measures has advantages and disadvantages. Plasma and serum samples can be assayed for
CRH and ACTH, as well as cortisol, so that all levels of the
HPA axis can be probed As yet, this is not true for saliva,
in that saliva assays for CRH and ACTH are not available.
However, serum samples are highly labile and require
immediate freezing, unlike salivary cortisol, which is more
stable (Kirschbaum and Hellhammer 1994; Clements and
Parker 1998). Plasma and serum samples may also be distorted by the HPA axis response to venipuncture. Serum
sampling is not the method of choice in longitudinal studies, especially for children and adolescents, as studies show
significant sample attrition for repeat phlebotomies, and the
more impaired teens are more likely to decline further participation (Susman et al. 1997). Cortisol can also be measured in 24-hour collections of urine. However, many individuals are reluctant to collect urine over the period of a
day, and it is difficult for researchers to assess whether all
urine was in fact collected.
Is the Connection Between Life Events and
Psychosis Stronger Earlier in the Dlness? Stressful
events may be more relevant for the onset of psychosis
than for relapse in schizophrenia patients, similar to
what has been found in major depression (Ghaziuddin
et al. 1990) and bipolar disorder (Post 1992). In a
cross-sectional study of 32 male schizophrenia inpatients, those with fewer than four episodes had significantly more recent life events than did those with more
episodes (Castine et al. 1998). There is a neurobiological basis for expecting that external stressors may have
HPA activity can be measured under baseline or
stress-induced conditions, as well as repeatedly over time
to index changes. It should be kept in mind, however, that
samples collected in the laboratory or the clinic do not
necessarily represent "baseline" levels in the natural environment. This is especially true of the samples collected
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immediately following the individual's arrival in the
research setting, as novelty augments HPA activity. It is
therefore advisable to obtain multiple measures, including
fluid samples collected after the research participant is
acclimated to the setting.
Functional properties of the HPA axis can be tested by
administering CRH or ACTH to detennine the responsivity
of the pituitary and adrenal glands, respectively. Sensitivity
to GC-mediated negative feedback can also be tested using
the synthetic glucocorticoid dexamethasone in the dexamethasone suppression test Dexamethasone should suppress
the HPA axis in normal individuals through negative feedback action. Individuals with impaired feedback will demonstrate no suppression, or an early release from suppression.
Salivary Cortisol Assessment Among the simplest and
most reliable ways to measure baseline and stress-induced
HPA activity is through salivary cortisol assay, using
radioimmunoassay, which has been employed as an index
of the HPA axis in more than 400 studies (Silver et al.
1983; Schwartz et al. 1998; Netjek 2002. Saliva samples
are typically obtained in specimen tubes, and a common
method is to instruct subjects to place a cotton roll in their
mouth on the order of minutes, until it is saturated. This is
nonintrusive and generally well tolerated.
Salivary cortisol is a reliable indicator of free cortisol
in plasma, which is considered to be the biologically
active hormone. Salivary and serum cortisols have been
correlated in both children and adults (Burke et al. 1985;
Bober et al. 1988; Woodside et al. 1991). Saliva cortisols
are also significantly correlated with 24-hour urine cortisols, as was demonstrated in a patient with Cushing's disease who had daily salivary cortisol assessment and 24hour urine samples for 725 days (Hermus et al. 1993).
Further, salivary cortisol levels are unaffected by salivary flow rate (Netjek 2002), and it appears that smoking,
eating, consuming caffeine, consuming alcohol, and exercising strenuously have only short-term and very modest
effects on salivary cortisol levels (Smyth et al. 1998). Salivary cortisol is responsive to stress exposure and demonstrates the expected circadian rhythm .
The time frame of the response of salivary cortisol
secretion to stressors ranges from minutes to hours. Activation of hypothalamic paraventricular neurons leads to
ACTH secretion by the anterior pituitary within 10 minutes. Then it takes 15 to 20 minutes after the onset of
ACTH release for cortisol secreted by the adrenal cortex
to reach the acinar cells of the parotid gland. Peak poststimulus salivary cortisol has been observed to occur
about 20 to 30 minutes after stress onset (Kirschbaum and
Hellhammer 2000). Salivary cortisol has a half-life of
approximately 1 hour (van Eck et al. 1996), and cortisol
levels return to baseline within 1 to 2 hours after the termination of a stressor.
681
Because activity of the HPA axis shows a diurnal
rhythm, it is critical to consider time of day in collection of
samples for assay (Halbreich et. al. 1985a, 1985fc), and
efforts should be made to standardize time of collection
across subjects. Cortisol is highest in the morning and then
gradually declines over the course of a day, with a brief
postprandial small peak after lunchtime. Multiple sampling throughout the day can illustrate the diurnal pattern.
Psychopathology is often associated with a less steep
decline and hence elevated cortisol values in the afternoon
and evening. Although traditionally it has been recommended that baseline diurnal cortisol rhythm be assessed
over a few days, high interreliability of cortisol levels
across 3 days was demonstrated in a study of normal children and children with PTSD, suggesting that 1 day of
assessment may be sufficient (Carrion et al. 2002).
There are several variables that can influence cortisol
secretion, and efforts should be made to document or standardize them in research protocols, including age, gender,
season, phase of menstrual cycle, sleep-wake cycle patterns and eating, activity, caffeine use, and cigarette smoking. Salivary cortisol levels should be obtained while in a
sitting position, as postural changes can alter measures.
Research Design and Statistical
Approaches
Survival Analysis. A prospective cohort study can be
conducted of prodromal patients, with the sample stratified into above-median and below-median baseline levels
of cortisol. This can be a proxy for exposure, and rates of
"failure" (conversion to psychosis) can be estimated for
the two groups. The data for subjects who either drop out
of the study or complete the study without conversion to
psychosis would be considered "censored." Kaplan-Meier
curves could be compared for the two groups (low-cortisol and high-cortisol) and log rank tests would be used to
determine whether they had significantly different risks
for psychosis. The hypothesis that intervening life events
are associated with the onset of psychosis also can be
addressed through survival analysis techniques, specifically through the use of Cox proportional hazards models.
Survival analyses can include intermediate measurements
of life event exposure and cortisol measures. These can be
entered into the model as cumulative means, as in a study
of stress and cortisol in HTV+ patients (Lesennan et al.
2000), if it is hypothesized that cumulative exposure is
relevant to psychosis risk, which is consistent with
McEwen's concept of allostasis. Alternatively, if major
life events are seen as triggers, the occurrence of any
major life events at a current or previous time point could
be entered into the model as a potential variable of
import. Using survival analyses and Cox proportional
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
C. Corcoran et al.
hazards models, potential confounds such as drug use and
medication exposure can be incorporated into statistical
models.
by the positive correlation observed by two independent
variables that both happen to have upward, parallel temporal trends.
Effect sizes can be derived for the relationship
between two variables in a time series. The within-person
effect sizes would typically be standardized regression
coefficients from time series regression equations. The
effect sizes can then be subjected to further analyses to test
for differences among individuals or groups. Researchers
have employed concomitant time series procedures to
study individual differences in relations among variables
that are hypothesized to be causally interrelated. In prodromal subjects, this procedure would allow researchers to
identify individuals who seem to be more stress-sensitive,
such that they show a stronger association between stressful events and positive symptoms. Similarly, this strategy
would allow the investigator to answer questions about
group or individual differences in the strength of the relation between psychosocial stress and positive symptoms—
that is, are prodromal patients with more elevated baseline
cortisol levels more likely to develop psychotic symptoms
after stress exposure?
Biological processes occur in real time, and behavioral effects are not expected to be immediate. Cross-correlational techniques are often used in conjunction with
time series analysis to explore delayed effects. The crosscorrelation coefficient indexes the strength of the simple
linear relationship (if any) between successively timelagged measurements in two paired and equally spaced
time series (Veldhuis et al. 1994). This allows the investigator to answer questions about the temporally lagged
effects of one factor on another. For example, increases in
cortisol may be associated with the emergence of psychosis. If the increase in cortisol precedes the worsening
of symptoms leading to psychosis onset, it may be causal.
However, if cortisol increases follow the worsening of
symptoms leading to psychosis, it may reflect the stress of
having psychotic symptoms. Likewise, testing cross-correlations among time-lagged measures of life events and
symptoms can help determine whether more life events
precede (and then may trigger) psychotic symptoms, or if
increased rates of life events follow the worsening of psychotic symptoms.
Cross-correlation is performed for paired variables
considered simultaneously (zero time lag) and at various
time lags between the sampling intervals. Imagine a study
in which the researchers measure levels of cortisol and
psychotic symptoms weekly, over a period of 3 months. In
the data analysis, cortisol levels in time series A can be
correlated pairwise with psychotic symptoms (series B)
measured simultaneously (zero lag), later (positive lag), or
earlier (negative lag). Error estimates for the cross-correlation coefficients can be derived from the pooled intrasam-
Time Series Analysis and Special Statistical Methods
for Longitudinal Data. Although survival analysis is
very useful for studying predictors of outcome in a cohort,
it cannot be used to analyze dynamic processes and interplay among multiple factors over time. In the following
paragraphs, we will briefly describe analytic procedures
that are ideally suited for studying biobehavioral
processes in the prodrome, such as those involving psychosocial stress exposure, HPA axis activity, and the
development of psychotic symptoms. These procedures
fall under the general rubric of time series analysis, which
is used to test hypotheses based on temporal data involving measurement of the same variable(s) at multiple time
points (Boker et al. 2002). Time series analysis can be
applied to research designs involving one or more variables, and with single subjects or multiple subjects.
When applied to single variables, time series analysis
can address questions about temporal trends in the data,
including linear and nonlinear aspects. When applied to
multiple variables, the concomitant time series approach
answers questions about the relationships among variables
measured simultaneously, or at successive time points.
When data from multiple subjects are available, moderating variables can be incorporated to test for the effects of
individual differences, demographics, or clinical factors.
In this article, we have repeatedly noted that in cross-sectional and even longitudinal studies, it can be difficult to
discern causal relationships among variables. As causal
relationships can be inferred through the evaluation of
temporal sequence, time series analysis is a useful way to
begin to address this question.
To examine relationships of HPA activity, psychosocial stress, and the development of psychotic symptoms
in the prodrome, concomitant time series analysis offers
major advantages. It can provide information about the
interrelations among variables while taking into consideration linear and nonlinear trends that can obscure the
true relation between two factors over time. Concomitant time-series methods correct for serial dependencies
in time series data, such as autocorrelation and linear
trending, which spuriously inflate the cross-series association and bias standard errors for significance tests.
Autocorrelation refers to the fact that, in repeated measures within individuals, observations are more similar
to one another than would occur by chance. If autocorrelation is not accounted for, there would be an artificial
deflation in error variance, an increase in the test statistic, and hence an increase in the probability of making a
type I error. As for linear trending, this is demonstrated
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pie variances, based on the total series length (n) and the
number of lag units (k) considered. The statistical significance of a coefficient at any given lag time can be tested
against the null hypothesis that the z score distribution of
coefficient values is normal with a mean of zero and a
standard deviation of one with a statistic, such as the Kolmogorov-Smimov.
As with any statistical procedure, the required number
of subjects and observations will depend upon the nature of
the data and the hypotheses to be tested. For some time
series applications, there is only a single subject. This
would be the case if the researcher is interested in testing
predictions about the temporal trends in a particular variable (e.g., symptoms), or the relation among variables (e.g.,
symptoms and stress) over time. The number of observations required depends upon the reliability of the measure
and the nature of the expected temporal trends. For variables that can be measured with a fairly high level of reliability (i.e., low error variance), fewer observations are
needed. For example, biological variables from assays may
be more reliable than self-report measures of symptoms or
stress. The predicted temporal pattern will also play a role
in determining the number of observations. As a case in
point, if a variable of interest is expected to show a
monthly cycle of fluctuation, daily sampling for at least 30
days would be necessary. In one study of a single subject,
we detected significant lagged relations between symptoms
and stress with only 30 observations. Of course, the more
observations available, the greater the statistical power for
detecting temporal patterns and lagged relationships.
When the investigator is interested in applying time
series analysis to the study of group or individual differences, the required number of subjects can be determined
by a power analysis. Again, as with other parametric procedures, the sample size needed for time series will be
largely determined by the reliability of the dependent variable and the frequency with which it is measured.
the only medications that have been systematically tested
in prodromal patients. In one published double-blind
placebo-controlled study, olanzapine led to improvement
of subclinical positive symptoms over 6 to 8 weeks but was
also associated with a mean weight gain of ten pounds
(Woods et al. 2003). Clearly, there is a need for consideration of medications that may have fewer side effects. In the
future, for example, CRH receptor antagonists, such as
R121919 (Heinrichs and Tache 2001), may be candidate
treatments in the schizophrenia prodrome.
At the same time, it is important that research on the
biobehavioral course of the prodromal process be
expanded. In particular, there is a need for longitudinal
studies that combine neurohormonal and behavioral measures, so that the biobehavioral and interactional processes
can be charted. There is strong empirical evidence to support the notion that the biological response to stress, especially activation of the HPA axis, is capable of triggering a
downstream cascade of neurochemical events that can precipitate or exacerbate psychosis. If researchers are able to
shed greater light on this chain of events, it may be possible
to develop effective strategies for preventive intervention.
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Our conceptualization of the diathesis-stress model of
schizophrenia has been transformed by the revolution in
behavioral neuroscience. Experimental research on animals
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The Authors
Cheryl Corcoran, M.D., is Assistant Professor of Clinical
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University, New York, NY. Elaine Walker, Ph.D., is
Samuel Candler Dobbs Professor of Psychology and Neuroscience; Rebecca Huot, Ph.D., is Postdoctoral Fellow;
Vijay Mittal, B.A., is graduate student; Kevin Tessner,
B.A., is graduate student; and Lisa Kestler, M.A., is graduate student; Emory University, Atlanta, GA. Dolores
Malaspina, M.D., Ms. PH. is Professor of Clinical Psychiatry at New York State Psychiatric Institute/Columbia
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