COMT Val158Met-stress interaction in psychosis: role of background psychosis risk.

Abstract

The interplay between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and environmental stress may have etiological relevance for psychosis, but differential effects have been reported in healthy control and patient groups, suggesting that COMT Val158Met interactions with stress may be conditional on background genetic risk for psychotic disorder.
Patients with a nonaffective psychotic disorder (n = 86) and control participants (n = 109) were studied with the experience sampling method (a structured diary technique) in order to assess stress, negative affect and momentary psychotic symptoms in the flow of daily life.
Multilevel analyses revealed significant three-way interactions between group status (patient or control), COMT genotype and stress in the model of negative affect (χ(2)(2) = 13.26, P < 0.01) as well as in the model of momentary psychotic symptoms (χ(2)(2) = 6.92, P < 0.05). Exploration of the three-way interaction revealed that in patients, COMT genotype moderated the association between stress and negative affect (χ(2)(4) = 11.50, P < 0.005), as well as the association between stress and momentary psychosis (χ(2)(4) = 12.79, P < 0.005). Met/Met genotype patients showed significantly increased psychotic and affective reactivity to stress in comparison to the Val/Met and Val/Val genotypes. In contrast, healthy controls did not display large or significant COMT Val158Met X stress interactions.
Important differences exist in the effect of COMT Val158Met on stress reactivity, which may depend on background risk for psychotic disorder. Differential sensitivity to environmental stress occasioned by COMT Val158Met may be contingent on higher order interactions with genetic variation underlying psychotic disorder.

Full text

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Interactions in Psychosis
Linking environment, brain and genes

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© Dina Collip, Maastricht 2011
Cover Design | Sven Homes
Layout | Dina Collip & Sven Homes
Print | Wöhrmann Print Service
ISBN | 978-90-8570-841-4

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Interactions in Psychosis
Linking environment, brain and genes
PROEFSCHRIFT
Ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van
de Rector Magnificus, Prof. Mr. G.P.M.F. Mols, volgens het besluit van het College van
Decanen, in het openbaar te verdedigen op woensdag 14 september 2011 op 12:00
door
Dina Collip
Geboren op 27 augustus 1981 te Aachen

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Promotores
Prof. dr. I. Myin-Germeys
Prof. dr. J. van Os
Beoordelingscommissie
Prof. dr. M.W. deVries (voorzitter)
Prof. dr. R. Bentall (University of Liverpool)
Prof. Alison Yung (University of Melbourne)
Dr. Machteld Marcelis
Dr. Marieke Wichers
South Limburg Mental Health and Teaching Network PhD Series
The research presented in this thesis was conducted at the School for Mental Health and
Neuroscience, Departement of Psychiatry and Neuropsychology of Maastricht University, Maastricht
University Medical Centre and Mondriaan Zorggroep.
Publication of this thesis was financially supported by: Lundbeck B.V.

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FÜR MEINE ELTERN


I am! Yet what I am who cares or knows?
My friends forsake me like a memory lost.
I am the self-consumer of my woes;
They rise and vanish, an oblivious host,
Shadows of life, whose very soul is lost.
And yet I am - I live - though I am toss’d
into the nothingness of scorn and noise,
Into the living sea of waking dream,
Where there is neither sense of life, nor joys,
But the huge shipwreck of my own esteem
And all that is dear. Even those I loved the best
Are strange - nay, they are stranger than the rest.
I long for scenes where man has never trod -
For scenes where a woman never smiled or wept -
There to abide with my creator, God,
And sleep as I in childhood sweetly slept,
Full of high thoughts, unborn. So let me lie -
The grass below; above, the vaulted sky.
John Clare (1793 -1864)

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Paranimfen
Margreet Oorschot
Johan Lataster

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CONTENTS
Chapter 1 Introduction......................................................................................... p. 9
Chapter 2 Does the concept of “sensitization” provide a plausible
mechanism for the putative link between the environment
and schizophrenia?.............................................................................. p. 23
Chapter 3 Dynamic association between interpersonal functioning
& positive symptom dimensions of psychosis over time:
a longitudinal study of healthy adolescents....................................... p. 37
Chapter 4 Social world interactions: how company connects to paranoia.......... p. 51
Chapter 5 Daily cortisol, stress reactivity and psychotic experiences in
individuals at above average genetic risk for psychosis...................... p. 71
Chapter 6 Hippocampal volume as marker of daily life emotional and
cortisol stress sensitivity in psychosis................................................ p.91
Chapter 7 COMT Val158Met–stress interaction in psychosis:
role of background psychosis risk...................................................... p. 111
Chapter 8 Epilogue............................................................................................. p. 131
Summary............................................................................................ p. 143
Samenvatting..................................................................................... p. 148
Acknowledgements........................................................................... p. 153
Curriculum Vitae................................................................................ p. 159
List of publications............................................................................. p. 16� List of publications............................................................................. p. 16�

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1
Introduction

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10
Introduction
Phenomenology of psychosis
Psychotic disorders, including schizophrenia and other non-affective psychoses, are characterized by
severe problems to recognize and understand reality. Among the core symptoms are positive symptoms,
e.g. delusions and hallucinations, and negative symptoms, e.g. flat affect and anhedonia [see 1 for
detailed description]. Besides positive and negative symptoms, alterations in functioning, including
cognitive and social functioning, are a common characteristic of patients with schizophrenia or a first
episode of psychotic illness [2, 3].
Schizophrenia, with a life time prevalence of �.5-1% [4], is probably the most severe form of psychotic
disorders, which affect about 2-3% of the population [5]. It is a disorder of marked heterogeneity.
The heterogeneity of the illness has traditionally been divided into two main forms [6-9], the positive
syndrome, or non-deficit, type I schizophrenia and the negative syndrome, or deficit, type II schizophrenia.
The first is characterized by sudden onset, an episodic course, a good outcome, a good response to anti-
psychotic treatment, and high levels of positive symptoms, while the latter is characterized by a gradual
onset, chronic course, poor outcome, resistance to drug treatment, high levels of negative symptoms
and cognitive impairments [6-9].
In addition to this marked heterogeneity [1�], psychotic experiences are thought to exist at levels
below clinical expression, as subclinical psychotic experiences are commonly reported in the general
population [11], particularly during adolescence, when expression of psychosis proneness peaks
[12-14]. Therefore, the psychosis phenotype may be better understood as an extended psychosis
phenotype. Subclinical psychotic experiences are mostly transient in nature [15-17], but in some
individuals, psychotic experiences may be predictive of the development of psychotic disorder [16, 18].
According to the psychosis proneness – persistence – impairment model [19] the path from incidental
psychotic experiences to clinical psychosis is mediated by the persistence of these experiences.
Even though most subclinical psychotic experiences are transitory [2�, 21], a familial and etiological
continuity between subclinical psychotic experiences and psychotic disorders has been suggested.
Etiological continuity refers to the notion that environmental factors implicated in clinical psychosis
might be also important in eliciting subtle psychotic phenomena at preclinical stages of the psychosis
continuum. Familial continuity indicates that the families of individuals with clinical psychotic disorder
have higher rates of subclinical psychotic experiences and/or schizotypy, the milder and non-clinical
form of psychosis at the level of personality structure [22]. Therefore,investigatingpsychoticsymptoms Therefore, investigating psychotic symptoms
in non-clinical populations with a higher than average risk of developing the disorder (psychometrically
identified individuals with high schizotypy scores or first-degree relatives of patients with psychotic
disorder) may help to increase the understanding of underlying mechanisms of psychotic symptoms
and endophenotypes (e.g. increased stress sensitivity), without the problem of, for instance, potential
confounding by antipsychotic treatment or effects of chronicity of psychotic illness.

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Chapter 1
However, besides evidence supporting a psychosis continuum, the exact nature of this continuum still
remains to be elucidated [23], including the identification of mechanisms and processes of transition
over that continuum. While some studies suggest quantitative differences along the continuum, there
might also be qualitative differences between those with subclinical symptomatology and those with
established psychotic disorder, suggesting that studying mechanisms at different levels of psychosis risk
may be valuable.
Clinical as well as subclinical psychotic experiences comprise broad concepts and have been divided
into several symptom dimensions. Besides the possible classification into positive, negative, manic,
depressive and disorganized symptoms and developmental cognitive alterations [24], there are
several specific dimensions of positive psychotic symptoms such as hallucinations and delusions.
Similarly, subclinical symptom dimensions have been identified, including persecutory ideation, bizarre persecutory ideation, bizarre
experiences, perceptual abnormalities and magical thinking [13]. BentallandFernyhoughhaveproposedBentall and Fernyhough have proposed
that environmental influences impacting on psychotic experiences may display degrees of dimensional
specificity [25], emphasizing the need to differentiate between symptom dimensions when studying
underlying mechanisms. Therefore, one focus of this thesis was to differentially study positive symptom
dimensions in association to environmental and genetic factors (Chapter 3, 4 & 5).
Affective pathway to psychosis
In line with the idea of different subtypes of schizophrenia are the results of recent studies, which, in
search of causal mechanisms and endophenotypes, investigated aberrations in sensitivity to stress as
underlying vulnerability for psychotic disorders. In the face of everyday stress, patients with a psychotic
disorder and their unaffected first-degree relatives have been found to display elevated emotional and
behavioral responses [26].Itissuggestedthatthisphenomenon,describedasincreasedstresssensitivity,[26]. It is suggested that this phenomenon, described as increased stress sensitivity,
might be a sign of genetic and/or environmental liability to psychotic disorder [27]. Subsequent studies
have shown that increased stress sensitivity clusters within families and might indeed be a vulnerability
marker for psychosis [28, 29]. Moreover, studies revealed that increased stress reactivity is independent
from cognitive impairments and might even be a mutually exclusive mechanism or pathway to psychotic
disorder [3�-32]. While cognitive impairments seem to be predominantly associated with negative
symptoms, increased stress reactivity has been found to be associated with positive psychotic symptoms
[32]. Importantly, a genetic correlation between increased stress reactivity and the positive dimension
of psychosis has been reported for clinical [29] as well as for subclinical psychotic experiences [28]. In
addition, there is some evidence that part of the elevations in stress sensitivity can be explained by
prior environmental exposures as life events [33] and childhood trauma [34]. Interestingly,thesestudiesInterestingly, these studies
suggest that increased stress sensitivity characterizes a certain subgroup of patients that experience
predominately positive psychotic symptoms.

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12
Introduction
In conclusion, these studies provide evidence that increased sensitivity to stress is an endophenotype
for psychosis. The underlying biological and genetic mechanisms of this increased stress sensitivity,
however, have not satisfactorily been identified. Therefore, a main goal of the current thesis was to
examine biological and genetic correlates of elevated stress sensitivity in psychosis (chapter 5, 6 & 7).
(Social) Environment and psychosis
At present, there is overwhelming epidemiological evidence supporting the importance of environmental
stress exposure in the developmental trajectory towards psychotic disorders [35] as well as for
psychotic experiences in the general population [36]. Many of those factors, e.g. growing up in an urban
environment [37, 38], experiencing discrimination [39] or childhood trauma [4�] can be considered
as indicators of social stress. Stress is thus an important factor in the etiology of psychosis, but many
questions remain unanswered. None of the factors, for example, seems a necessary or sufficient cause
to predict psychosis and it is unlikely that the diversity of environmental influences can be linked to as
many different underlying mechanisms.
One possible approach to clarify the findings of epidemiological research may be to zoom into the
microenvironment [41]. An excellent tool to study mechanisms at the microenvironment of everyday life
is the Experience Sampling Method (ESM), as this enables the study of moment-to-moment changes of
symptomatology in association with various contextual factors [42]. ESM isastructuredself-assessmentis a structured self-assessment
diary technique that is used to assess momentary context, thoughts, mood, and symptoms in the flow
of daily life. Studies have demonstrated the feasibility, validity, and reliability of ESM in general and
patient populations [42, 43]. In chapter 4, we present a study in which we used ESM to investigate
whether social contextual variables are predictive of momentary increases in the intensity of paranoid
thinking in a sample of participants ranging across the psychometric paranoia continuum.
Besides the external social environmental factors, there is also evidence for more internal trait-like
problems, including alterations in social and interpersonal functioning. Clinical improvement in patients
is often independent of improvements in social functioning, suggesting that alterations in social
functioning may be a continuation of poor premorbid functioning [44]. This is in line with evidence of
alterations in premorbid social development in childhood [45-47] and adolescence [48] in individuals
who later develop non-affective psychotic disorder. Individuals at UHR who make the transition to an
overt psychotic outcome also show alterations in social functioning compared to individuals who do
not develop clinical psychotic states [49-52]. Furthermore, at the level of the general population, the
persistence of subclinical psychotic experiences is similarly associated with poorer social functioning
[16]. Together, these findings suggest that alterations in social functioning may impact on development
of psychotic illness in those at risk. However, several issues remain. For instance, most studies only
addressed one direction -social functioning predicting psychosis rather than the other way round- or used

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Chapter 1
a cross-sectional design, which precludes observing how the variables are related over time. Moreover,
most studies have looked at overall psychotic symptomatology or psychotic illness as outcome, but not
at separate dimensions of symptoms. Most importantly, the majority of studies were conducted in UHR
or patient populations. In individuals further along the extended psychosis continuum, it may be more
difficult to draw conclusions, because the very presence of clinical psychotic experiences may color the
interpretation of (neutral) social stimuli. In chapter 3 a study is presented, in which we extend results of
the association between social functioning and psychotic symptoms in at-risk and patient populations
to a general adolescent sample, considering differences between different symptom dimensions in the
association with interpersonal functioning.
Biological underpinnings
The biological substrates underlying the phenomenon of increased stress sensitivity or the link between
stress and psychotic experiences remain largely unknown, and vulnerability markers need to be identified.
Results of experimental studies suggest that increased psychotic reactivity to stress may reflect increased
dopamine reactivity [53, 54]. In addition, several lines of evidence indicate that dysregulation of the
hypothalamic-pituitary-adrenocortical (HPA) axis may play a role in the relationship between stress and
psychotic experiences [55, 56]. In individuals with a psychotic disorder, abnormalities have been found
at various levels of the HPA axis, including functional and structural changes in the hypothalamus [57], ,
the pituitary [58], and the hippocampus [59]. Morespecifically,patientswithpsychoticdisorderdisplayMore specifically, patientswithpsychoticdisorderdisplayatients with psychotic disorder display
reduced hippocampal size [6�-63]. Recent studies have shown that similar alterations in hippocampal
volume (HV) are present in first-degree relatives of patients with schizophrenia [64, 65], suggesting
that HV changes constitute part of the liability to psychosis. The hippocampus plays a pivotal role in
regulating emotional responses to stressful stimuli and in the negative feedback mechanism on HPA
axis activity [66-7�], and is therefore an interesting candidate in search for biological underpinnings of
increased stress sensitivity.
Similarly, diurnal cortisol levels and cortisol reactivity to stress may be disturbed in patients with psychotic
disorder [71-79], although results are inconsistent. Moreover, patient status and use of medication, although results are inconsistent. Moreover, patient status and use of medicationMoreover, patient status and use of medication
introduce difficulties for the interpretation of the results: are cortisol alterations a state marker, a
trait marker or a result of antipsychotic medication? Therefore, studies in individuals at increased
psychometric risk for psychotic disorder were conducted. Schizotypal adolescents, for example, were
found to have higher cortisol levels than controls [8�], and heightened cortisol secretion in another
sample of schizotypal adolescents was associated with schizotypal symptomatology at 2-year follow-up
[81]. The potential predictive value of cortisol alterations is further supported by findings in a sample of
young people at increased risk of psychotic disorder; Walker et al. (2�1�) recently reported that higher
cortisol levels predicted higher risk of conversion to psychotic disorder in an at-risk sample studied

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14
Introduction
longitudinally. However, cortisol reactivity to daily life stress in a sample at heightened genetic risk for
psychosis has never been investigated.
Together these findings add support to the hypothesis that HPA axis abnormalities may underlie
vulnerability to psychotic disorder and potentially also to heightened stress reactivity. Consequently,Consequently,
we examined daily life cortisol patterns in siblings of patients with a psychotic disorder compared to
healthy controls. Besides examinationofthediurnalslopeandcortisolreactivityinresponsetonaturallyexamination of the diurnal slope and cortisol reactivity in response to naturally
occurring stressors, we investigated the association between momentary psychotic experiences and
momentary cortisol secretion. Results of this study are presented in chapter 5. Moreover, the study Moreover, the study
presented in chapter 6 investigated the association between hippocampal volume and emotional
and cortisol reactivity to daily life stress in a sample of individuals with different degrees of psychosis
liability.
Gene-environment interactions
Heterogeneity in behavioral and biological responses to environmental stressors can best be understood
in the framework of the vulnerability-stress model [82]. According to the vulnerability-stress model,
sensitivity to environmental stressors depends on the genetic liability of an individual. This approach
has led to a series of studies investigating gene-environment interactions in the search for mechanisms
of stress sensitivity and the development of positive psychotic symptoms [e.g. 83].
Moffitt et al. (2��5) recommended a prospective collection of cumulative, repeated measures of
proximal rather than distal environmental risk factors to optimize the environmental risk measurement
in gene–environment research [84]. ESM has therefore been proposed as an excellent tool to study
gene-environment interactions [42]. This is confirmed by a few studies of our group that used ESM to
study gene-environment interactions in psychopathology [85-87].
In individuals at increased genetic risk for psychosis, augmented stress sensitivity in daily life has been
associated with an augmented dopamine response to a physiological stressor [88]. Therefore, genetic
variation in the Val158Met functional polymorphism of the catechol-O-methyltransferase (COMT) gene
is an obvious candidate to study genetic moderation of environmental stress in psychosis. The COMT
gene encodes an enzyme that is critical in the breakdown of dopamine, especially in the prefrontal
cortex, and brain COMT enzyme activity in individuals with the Val/Val genotype is about 4�% higher
than in individuals with Met/Met genotype [89].
While the Val-allele carriers have been found to be more sensitive to the psychotogenic effects of
cannabis [87], results of some COMT-stress interaction studies point towards exaggerated sensitivity
to stress in Met-carriers [9�, 91]. The first ESM study in patients with psychotic disorder showed that

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Chapter 1
patients with the Met/Met genotype reported the largest increase in psychotic symptoms and negative
emotions in response to daily stressors, thus providing evidence for gene-environment interaction
mechanisms in the formation of psychotic symptoms [86]. Interestingly, this effect was not found in the
healthy control group and a second study in a general population sample found opposite results, with
Val/Val carriers displaying more feelings of paranoia in response to stress [92]. Thus, COMT Val158Met
interactions with stress may be contingent on background genetic risk for psychotic disorder, revealing
the need for replication studies. Consequently, in chapter 7, such a replication study is presented
including patients with a psychotic disorder as well as healthy controls allowing the examination of
disease specific effects.
Aims of this thesis
The overall aim of this thesis was to further explore potential mechanisms underlying clinical and
subclinical positive psychotic symptoms as well as the mechanisms underlying increased stress
sensitivity, including contextual effects (social factors), biological markers and genetic underpinnings in
the form of gene-environment interactions.
This led to the following research:
In chapter 2, literature is reviewed about environmental effects on psychosis. We propose the concept
of sensitization as a possible link between environment and psychosis and discuss potential biological
correlates of sensitization processes. As epidemiological studies suggest that social factors may be
important risk factors for psychosis, we investigated the bi-directional, longitudinal association between
interpersonal functioning and different positive psychotic symptom dimensions in a general population
adolescent sample (chapter 3). In chapter 4, we zoomed in into the microenvironment of daily life in
order to understand effects of social context on momentary paranoia at different levels of the paranoia
phenotype.
A further aim was to investigate biological correlates of the association between stress and psychosis and
of increased stress sensitivity. In chapter 5, cortisol patterns in the context of daily life were examined
in siblings of patients with a psychotic disorder compared to healthy controls. This included, among
others, examination of the diurnal slope, cortisol reactivity in response to naturally occurring stressors, examination of the diurnal slope, cortisol reactivity in response to naturally occurring stressors,
and the association between momentary psychotic experiences and momentary cortisol. In In chapter
6, we investigated the role of hippocampal volume in association with levels of emotional and cortisol
reactivity to daily life stress and the hypothesis whether this association was different between groups
with different degrees of risk for psychotic disorder.
Genetic variation might act synergistically with environmental stress in eliciting psychotic symptoms. In
chapter 7, we aimed to replicate the association between the COMT gene and stress sensitivity and to
clarify whether it might be moderated by psychosis liability.