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EXPLORING THE PATHOPHYSIOLOGY OF
CHRONIC DEPRESSION: THE INTERPLAY
BETWEEN DEPRESSION, CORTISOL
RESPONSES, AND PERSONALITY
By
Kevin Kumar Chopra
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy
Institute of Medical Sciences
University of Toronto
© Copyright by Kevin Kumar Chopra 2013
ii
Exploring the Pathophysiology of Chronic Depression: The Interplay Between
Depression, Cortisol Responses, and Personality
Doctor of Philosophy
Kevin Kumar Chopra
Institute of Medical Science
University of Toronto
2013
ABSTRACT
Chronic major depressive disorder (CMDD) is a common and debilitating illness. Its
pathophysiology needs further elucidation, before more effective targeted treatments can
be developed for this condition. To gain a better understanding of the psychobiology of
CMDD, three interconnected studies were conducted that examined the interplay between
chronic depression, cortisol responses, and personality.
Study 1 examined cortisol responses to the Trier Social Stress Test (TSST) in
CMDD participants (n=29) as compared to healthy controls (n=28). It was hypothesized
that cortisol responses would be greater in the CMDD population. Results indicated that
females with CMDD had increased cortisol output compared to female controls, a pattern
consistent with the hypothesis. However, males with CMDD had decreased cortisol
responses compared to male controls. These results suggest that cortisol responses to
social stress are altered in those with CMDD; however, females and males experience
fundamentally different changes.
iii
Study 2 examined moderating effects of personality on cortisol responses to the
TSST in those with CMDD (n=51) as compared to healthy controls (n=57). It was
hypothesized that higher neuroticism and/or lower extraversion would be associated with
increased cortisol responses in CMDD participants. As hypothesized, lower extraversion
was associated with increased cortisol reactivity in those with CMDD but not in healthy
controls. However, no association was found between neuroticism and cortisol responses.
These findings could support the notion that lower extraversion is a vulnerability marker
for chronic depression and thus a possible target for treatment.
Study 3, evaluated the cortisol awakening response (CAR) in CMDD participants
(n=27) compared to healthy controls (n=30). It was hypothesized that such awakening
responses would be more pronounced in the depressed population compared to controls.
Contrary to expectation, no differences were found between the groups. However, lower
extraversion was associated with a lower CAR in both CMDD and healthy controls, a
finding that was not anticipated a priori.
These interconnected studies suggest that examining relationships between
depression, cortisol responses, and personality, can assist with identifying distinct
psychobiological profiles in those with chronic depression. It is proposed that this
strategy will improve the likelihood of developing more targeted treatments for this
population.
iv
ACKNOWLEDGEMENTS AND
CONTRIBUTIONS
First and foremost, I would like to thank Robert Levitan, who has been a formidable
mentor. His enthusiasm for research is infectious and his scientific rigour has ensured a
high quality training experience. A special thanks to Arun Ravindran, who has provided
valuable guidance in my research and academic career. I am grateful for having such an
esteemed graduate committee: Stephen Matthews, Sidney Kennedy, Neil Rector, and
Michael Bagby, have generously provided their expertise to shape this PhD project.
I would also like to thank Dr. Hymie Anisman who generously conducted the
cortisol analyses and Tamara Arenovich who provided statistical consultations for this
project. I am very appreciative of all the research coordinators and graduate students who
helped conduct this research project including Jessica Grummitt, Barbara Wendland,
Martha McKay, and Bronwyn Mackenzie. I am indebted to a number of volunteers who
assisted with running the social stress paradigm as well as with data entry. Funding for
this project was gratefully received from the Canadian Institute of Health Research
(CIHR) (CIHR/Wyeth and CIHR/Rx&D-CPRF awards) and the Government of Ontario
(Gregory M. Brown Scholarship).
My PhD would not have happened without the tremendous support from my family.
Words cannot describe my gratitude to my parents and in-laws. My wonderful wife,
Sumeeta, has been my backbone, and has provided endless love and support. During the
process of my PhD, I was blessed with the births of my children. My daughter, Mila, and
my son, Shalin, are the greatest joys of my life, and have given me balance and
perspective during this project.
v
TABLE OF CONTENTS
ABSTRACT ..................................................................................................................................... ii
ACKNOWLEDGEMENTS AND CONTRIBUTIONS ............................................................. iv
TABLE OF CONTENTS ................................................................................................................ v
LIST OF FIGURES AND TABLES ............................................................................................ viii
LIST OF ABBREVIATIONS .......................................................................................................... x
Chapter 1 ......................................................................................................................................... 1
Introduction ..................................................................................................................................... 1
1.1. Overview of Major Depressive Disorder (MDD) ................................................................... 2
1.1.1. Definition, Epidemiology, and Economic Costs ............................................................. 2
1.1.2. Pathophysiology ............................................................................................................ 4
1.1.3. Treatment ...................................................................................................................... 7
1.2. Chronic Major Depressive Disorder (CMDD) ...................................................................... 10
1.2.1. Definition and Epidemiology ....................................................................................... 10
1.2.2. Clinical Features and Morbidity ................................................................................... 10
1.2.3. CMDD versus Other Forms of Chronic Depression ..................................................... 14
1.2.4. Etiology and Pathophysiology ..................................................................................... 15
1.3. Hypothalamic-Pituitary-Adrenal (HPA) Function and Depression ..................................... 17
1.3.1. Introduction ................................................................................................................. 17
1.3.2. The HPA Axis and Depression ...................................................................................... 21
1.3.3. The HPA Axis and Chronic Depression ........................................................................ 23
1.4. Social Stress Paradigms as a Method to Examine Cortisol Responses in Depression ........ 25
1.4.1. Overview ...................................................................................................................... 25
1.4.2. The Trier Social Stress Test (TSST) ............................................................................... 26
1.4.3. Studies using the TSST in Depressed Populations ....................................................... 30
1.5. Personality, Cortisol Responses, and Depression ............................................................... 32
1.5.1. Personality Pathology and Depressive Illness ............................................................. 32
vi
1.5.2. Neuroticism, Extraversion, and Depression: Literature Review .................................. 36
1.5.3. Neuroticism, Extraversion, and HPA Function: Literature Review .............................. 38
1.6. The Cortisol Awakening Response (CAR)............................................................................ 40
1.6.1. Introduction ................................................................................................................. 40
1.6.2. Overview of the CAR .................................................................................................... 40
1.6.3. The CAR and Depression ............................................................................................. 43
Chapter 2 ....................................................................................................................................... 45
Rationale and Study Design ........................................................................................................... 45
2.1. Rationale and Study Design ................................................................................................ 46
2.2. Conceptual Model for Thesis .............................................................................................. 48
2.3. Study Aims and Major Hypotheses .................................................................................... 50
2.4. Study Implications .............................................................................................................. 51
Chapter 3 ....................................................................................................................................... 53
Study 1: Evaluating Cortisol Responses to a Social Challenge in CMDD ....................................... 53
3.1. Introduction and Hypothesis .............................................................................................. 54
3.2. Methods ............................................................................................................................. 55
3.3. Results ................................................................................................................................ 59
3.4. Discussion ........................................................................................................................... 65
Chapter 4 ....................................................................................................................................... 69
Study 2: Does Neuroticism and/or Extraversion Moderate Cortisol Responses in CMDD? ......... 69
4.1. Introduction and Hypothesis .............................................................................................. 70
4.2. Methods ............................................................................................................................. 71
4.3. Results ................................................................................................................................ 73
4.4. Discussion ........................................................................................................................... 81
Chapter 5 ....................................................................................................................................... 85
Study 3: The Cortisol Awakening Response (CAR) in CMDD ......................................................... 85
5.1. Introduction and Hypotheses ............................................................................................. 86
5.2. Methods ............................................................................................................................. 87
5.3. Results ................................................................................................................................ 89
5.4. Discussion ........................................................................................................................... 96
vii
CHAPTER 6 ..................................................................................................................................... 99
A Closer Examination of Clinical and Social Factors that may be linked to Cortisol Responses in
CMDD ............................................................................................................................................ 99
6.1. Introduction ...................................................................................................................... 100
6.2. Is a History of Childhood Abuse Associated with Cortisol Responses to Social Stress in
CMDD? ..................................................................................................................................... 101
6.3. Are the Cortisol Responses to Social Stress Different for those with CMDD who are on
SSRIs from those who are Unmedicated? ............................................................................... 107
6.4. Is PTSD Comorbidity Associated with Individual Differences in Cortisol Stress Responses to
Social Stress in CMDD? ............................................................................................................ 115
6.5. Do Cortisol Responses to Social Stress Differ Between Atypical and Melancholic Forms of
Depression? ............................................................................................................................. 117
6.6. Overall Summary .............................................................................................................. 124
Chapter 7 ..................................................................................................................................... 126
General Discussion of Thesis ....................................................................................................... 126
7.1. Introduction ...................................................................................................................... 127
7.2. Relevance of Study Findings ............................................................................................. 131
7.3. Study Limitations .............................................................................................................. 135
7.4. Future Directions .............................................................................................................. 139
7.4.1. Overview .................................................................................................................... 139
7.4.2. Future Research Direction (Short term): The CAR and the Prediction of Treatment
Response and Relapse in Depressive Illness ....................................................................... 140
7.4.3. Future Research Direction (Medium term): Identification of Biomarkers in Depressive
Illness: HPA Axis and Beyond ............................................................................................... 141
7.4.4. Future Research Direction (Long term): Personalized Medicine .............................. 147
7.5. Final Summary .................................................................................................................. 150
APPENDIX 1: Additional Analyses and Interpretations of Study 1 Results .................................. 153
REFERENCES ................................................................................................................................ 157
viii
LIST OF FIGURES AND TABLES Figure 1: The Hypothalamic-Pituitary-Adrenal Axis
Figure 2: Trier Social Stress Test
Figure 3: Diurnal Cortisol Rhythm
Figure 4: The Cortisol Awakening Response
Figure 5: Conceptual Model for Thesis: the interplay between CMDD, cortisol
responses, and personality
Figure 6: Mean (± SEM) Cortisol Responses to the TSST in CMDD Subjects vs.
Healthy Controls Grouped by Condition and Sex
Figure 7: Comparison of Sex Differences in AUC and Peak Percentage Change in
Cortisol in CMDD Subjects vs. Healthy Controls
Figure 8: Association between Extraversion and Cortisol Reactivity in CMDD Subjects
and Healthy Controls
Figure 9: Association between Extraversion and Subjective Stress Ratings of the TSST
in CMDD Subjects and Healthy Controls
Figure 10: Mean (± SEM) CAR in CMDD Subjects vs. Healthy Controls
Figure 11: Mean (± SEM) AUCg and AUCi Cortisol at Awakening in CMDD Subjects
vs. Healthy Controls
Figure 12: Association between Extraversion and AUCi Cortisol at Awakening in
CMDD Subjects and Healthy Controls
Figure 13: Association between Neuroticism and AUCi Cortisol at Awakening in
CMDD Subjects and Healthy Controls
Figure 14: Conceptual Model for Thesis: the interplay between CMDD, cortisol
responses, and personality
Table 1: Association between Demographic and Clinical Variables to Cortisol
Measures in CMDD Subjects
ix
Table 2: Results of Hierarchical Linear Regressions Evaluating Associations between
Neuroticism and Extraversion and Cortisol Responses in CMDD Subjects vs.
Healthy Controls
Table 3: Mean Values for Awakening, 30 min., and 60 min. Post-Awakening Cortisol
Measures in CMDD Subjects and Healthy Controls
Table 4: Cutoff scores for Childhood Abuse Subscales of the CTQ
Table 5: Mean Childhood Abuse Scores in CMDD Participants
Table 6: Correlation of Cortisol Responses to the TSST with Mean CTQ scores and
Mean CTQ subscale scores in CMDD
Table 7: Psychotropic Medication Usage in CMDD Subjects
Table 8: Comparison of AUCg Cortisol during the TSST in CMDD Subjects Treated
with SSRI/SNRIs with those not on Psychotropic Medications
Table 9: Comparison of AUCi Cortisol during the TSST in CMDD Subjects Treated
with SSRI/SNRIs with those not on Psychotropic Medications
Table 10: Frequency of Depressive Subtypes in CMDD
Table 11: Comparison of AUCg Cortisol during the TSST in Atypical, Melancholic and
Neither Subtype in CMDD
Table 12: Comparison of AUCi Cortisol during the TSST in Atypical, Melancholic and
Neither Subtype in CMDD
x
LIST OF ABBREVIATIONS ACTH: adrenocorticotropic releasing hormone
AUC: area under the curve
AUCg: area under the curve with respect to ground
AUCi: area under the curve with respect to increase
BDNF: brain-derived neurotrophic factor
BMI: body mass index
CAMH: Centre for Addiction and Mental Health
CAR: cortisol awakening response
CBASP: Cognitive Behavioral Analysis System of Psychotherapy
CBG: corticosteroid-binding globulin
CBT: cognitive behavioural therapy
CMDD: chronic major depressive disorder
CNS: central nervous system
GR: glucocorticoid receptor
CRF: corticotropin-releasing factor
CRH: corticotropin-releasing hormone
CSF: cerebrospinal fluid
DD: double depression
Dex: dexamethasone
DSM: Diagnostic and Statistical Manual of Mental Disorders
DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,
Text Revision
DST: dexamethasone suppression test
ECT: electroconvulsive therapy
FFM: Five-Factor Model
HDRS: Hamilton Depression Rating Scale
HPA: hypothalamic pituitary adrenal
IPT: interpersonal therapy
MDD: major depressive disorder
MDE: major depressive episode
MAOI: monoamine oxidase inhibitor
MR: mineralocorticoid receptor
NEO PI-R: Revised NEO Personality Inventory
NIMH: National Institute for Mental Health
NOS: not otherwise specified
PTSD: post-traumatic stress disorder
PVN: paraventricular nucleus
RANOVA: repeated measures analysis of variance
RIA: radioimmunoassay
SCID-I/P: Structure Clinical Interview for DSM-IV-TR Axis I Disorders
SSRIs: selective serotonin reuptake inhibitors
SNRIs: serotonin-norepinephrine reuptake inhibitors
STAR*D: Sequenced Treatment Alternatives to Relieve Depression
xi
TCA: tricyclic antidepressant
TMS: transcranial magnetic stimulation
TSST: Trier Social Stress Test
1
CHAPTER 1
INTRODUCTION
2
1.1. Overview of Major Depressive Disorder (MDD)
1.1.1. Definition, Epidemiology, and Economic Costs
Depression affects more than 121 million people worldwide, and is among the
leading causes of disability in the world (www.who.int). Strikingly, the World Health
Organization predicts that by the year 2030, depression will become the leading cause of
ill health globally, overtaking even heart disease (Lepine and Briley, 2011).
The diagnosis of depression, as defined by the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) (American Psychiatric
Association, 2000), requires that a person experience two weeks of clinically significant
dysphoria or anhedonia and five of the following nine symptoms:
1) depressed mood most of the day
2) marked diminished interest or pleasure
3) significant changes in appetite (either increased or decreased)
4) insomnia or hypersomnia
5) psychomotor agitation or retardation
6) fatigue
7) feelings of worthlessness or excessive guilt
8) diminished concentration
9) suicidal ideation
3
These symptoms result in functional impairment that cannot be explained by another
psychiatric or medical illness.
About 20 percent of the population will develop depression at some point in their
lives (Lewinsohn et al., 1991, Kessler et al., 1994). Twice as many women as men suffer
from depression (Kessler et al., 2003). There are enormous economic costs associated
with depressive illness. Greenberg et al. (2003) estimated the economic costs of
depression to be $81.1 billion in 2000. The World Health Organization Global Burden of
Disease Study ranked depression as the single most burdensome illness in terms of total
disability-adjusted life years among middle-aged people (Murray and Lopez, 1996).
The economic costs associated with depressive illness are due to a combination of
factors including its associated high lifetime prevalence, early age of onset (median age
of onset is in the mid-twenties), high chronicity, and high functional impairment. The
Collaborative Depression Study, a large naturalistic study evaluating the course of
depression, revealed that the rate of depressive recurrence is 25 to 40 percent in the first
two years but increases to 60 percent at five years (Lavori et al., 1994). Angst (1992)
found that 75 percent of individuals who had a history of depression had a recurrence in a
ten-year follow up study. About 20 percent of those who develop depression will have a
chronic course of the illness (Keller and Hanks, 1994, Gilmer et al., 2005).
There is high rate of mortality associated with depression. The estimated lifetime risk
of suicide has varied across studies, but has been found to be as high as 15 percent in
more severely depressed patients. Studies suggest that more men commit suicide than
women (CDC, 2007), but more women attempt suicide than men (Brockington, 2001).
4
The current project will focus on chronic depression, the subgroup of depressed
individuals with the highest rates of morbidity and mortality.
1.1.2. Pathophysiology
Biological Factors
A number of biological mechanisms have been associated with depressive illness
(for review, see Thase, 2009). Twin studies suggest that genes account for about 40 to 50
percent of the risk of depression in the population (reviewed in Sullivan et al., 2000).
However, the genetic underpinnings of depression remain largely unknown. One
landmark study by Caspi and colleagues (2003) reported that individuals with one or two
copies of the short allele of the serotonin transporter gene promoter polymorphism are
more susceptible to developing depression after major life events. It is likely that a
number of genes interact to increase an individual’s susceptibility to depression (Moldin
et al., 1991). Furthermore, the genetic effect on depression risk is probably also related to
specific gene-environment interactions (Kendler et al., 2004).
Altered monoamine function (in particular serotonin and norepinephrine), has been
one of the most significant neurobiological findings in depression research. It is believed
that the therapeutic efficacy of many of the current antidepressant medications is via their
effects on serotonin and norepinephrine neurons (Duman et al., 1997, Nemeroff, 1998).
There is also a well-established link between the stress hormone cortisol and depressive
illness. This biological pathway is the primary focus of this project, and will be discussed
in depth in this thesis. Other biological abnormalities found to characterize depression
5
include REM sleep dysfunction (Thase, 2006) and EEG rhythm abnormalities (Davidson,
1998). Brain imaging has led to important insights into our understanding of the
pathophysiology of depression. Structural imaging studies have found smaller volumes in
some brain areas including the hippocampus (Sheline et al., 1996, Sheline, 2000,
Bremner et al., 2000). Functional imaging studies have suggested different patterns of
brain activation in depressive illness. The amygdala, prefrontal cortex, and anterior
cingulate gyrus play significant roles in causing emotional dysregulation that
characterizes depressive illness (Drevets et al., 1997, Strakowski et al., 1999, Pizzagalli
et al., 2003).
Psychological and Social Factors
Aaron Beck’s (1976) cognitive theory of depression proposed that negative cognitive
schemas were a psychological mechanism underlying depression. In general, individuals
who are depressed have more negative views of themselves, the future, and the world
around them (Ingram et al., 1998). There is evidence that negative cognitions are not just
a state of depression, but also promote vulnerability to future depression. In a
longitudinal study by Alloy et al. (2006), non-depressed individuals who had higher
dysfunctional attitudes and negative attribution styles were more likely to experience
depression. Negative cognitions also increase the risk of relapse in depression. In a study
by Segal et al. (2006), remitted depressed individuals with greater levels of dysfunctional
cognitions in response to a sad mood provocation were more likely to have a recurrence.
One of the most effective treatments for depression is cognitive behavioural therapy, a
6
treatment that focuses on correcting negative cognitive appraisals that influence one’s
behaviour and emotions (Beck, 1976).
The social environment also plays a key role in understanding mechanisms
underlying depression. Early adverse experiences, such as early parental loss, are
associated with an increased risk for developing depression (Cerel et al., 2006).
Childhood abuse is also a risk factor for depression, and may promote the risk of
depression through changes in the HPA axis (Heim et al., 2000). As well, inadequate
parenting (e.g., neglectful, harsh, and inconsistent) can lead to insecure attachment
relationships which can promote an elevated risk for depressive illness (Cummings and
Cicchetti, 1990).
Major life stressors are associated with more severe forms of depression (Monroe et
al., 2001). Low socioeconomic status has been associated with an increased risk of
developing depression and is also associated with a more persistent depressive illness
(Lorant et al., 2003).
In summary, there are a number of biological, psychological, and social pathways
leading to depressive illness. One common thread appears to be stress, as mechanisms
underlying depression are linked to stressful life events or are related to how an
individual responds and/or copes with stress. In the current study, examination of the
interplay between depression, cortisol responses (to social stress), and personality is in
keeping with the biopsychosocial model of depression.
7
1.1.3. Treatment
Given the complexity of the etiological pathways for depression, not surprisingly,
there are many avenues of treatment that are currently being used, including biological
and psychosocial remedies.
Biological therapies
Over the past several decades there has been a dramatic increase in the number of
antidepressant medications available for use. More than two dozen pharmacological
agents are available to treat depression (Mignon and Stahl, 2010). The most commonly
used drugs are selective serotonin reuptake inhibitors (SSRIs) and serotonin-
norepinephrine reuptake inhibitors (SNRIs) which have a more favourable side effect
profile than older antidepressants, such as tricyclic antidepressants (TCAs) and
monamine oxidase inhibitors (MAOIs). All commonly used antidepressants work on
enhancing monoaminergic function and are similar in efficacy. Currently, there are no
biological markers to aid in the choice of antidepressant medication. Side effect profile,
family history of antidepressant response, cost, and physician preferences are factors that
may be taken into account when choosing a specific antidepressant agent.
In randomized controlled studies, about 60 percent of individuals will respond to an
antidepressant agent as compared to placebo (Klein et al., 1980, Gartlehner et al., 2011).
Antidepressant medication response is often delayed by two or more weeks, with
continuing improvement experienced over subsequent weeks (Posternak and
Zimmerman, 2005). In the Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) trial, the largest naturalistic treatment study of depression to date, many
8
patients did not achieve full remission until eight to fourteen weeks of active medication
treatment (Trivedi et al., 2006).
Several brain stimulation therapies are now used in the treatment of depression.
Electroconvulsive therapy (ECT) is a well-established and highly effective treatment
(Husain et al., 2004, Petrides et al., 2011), but is generally reserved for more treatment-
resistant cases. ECT is a procedure in which an electrical current is passed through the
brain to induce a brief seizure. The mechanism of action of ECT remains unknown. Other
more novel brain stimulation treatments for depression include repetitive transcranial
magnetic stimulation (TMS), vagal nerve stimulation, and deep brain stimulation (Cusin
and Dougherty, 2012).
Psychotherapy
Research has demonstrated efficacy of several forms of therapy for acute depression
including individual, group, and marital therapy (Dobson, 1989, Leff et al., 2000,
Huntley et al., 2012). Within these forms of therapy, many psychotherapeutic approaches
can be taken. The two most empirically studied approaches are cognitive behavioural
therapy (CBT) and interpersonal therapy (IPT). Randomized controlled trials have found
that these are effective treatments for mild to moderate forms of depression (Dobson,
1989, Weissman, 1994, Parikh et al., 2009). In CBT, the therapist addresses negative
cognitions and maladaptive thinking that promote and/or maintain depressive illness. IPT
focuses on assisting patients with coping strategies to improve feelings, thoughts, and
behaviours that occur in difficult interpersonal relationships. In mild to moderate
depression, there is evidence that psychotherapy can be as effective as medication in
9
some individuals, although a combination of the two is generally accepted as the gold
standard.
In summary, both medication and psychotherapy are effective treatment approaches
for depressive illness. However, up to one third of patients will not respond to treatment
and will have a chronic course of illness. At present, it is unknown what mechanism
underlies lack of response and chronicity of depressive illness. One of the primary goals
of the current project was to improve the understanding of the pathophysiology of
CMDD.
10
1.2. Chronic Major Depressive Disorder (CMDD)
1.2.1. Definition and Epidemiology
The presence of chronic forms of depression has been noted for many decades
(Kraepelin, 1921, Robins and Guze, 1970), although specific research in this population
did not occur until the 1970’s and 1980’s (Weissman and Klerman, 1977, Akiskal et al.,
1980, Keller and Shapiro, 1982). It was not until the DSM–III-R (American Psychiatric
Association, 1987) that chronic depression was distinguished as a category. In the current
version of this text, the DSM-IV-TR, (American Psychiatric Association, 2000), CMDD
is defined as a major depressive episode (MDE) that persists for a minimum of two years.
In the general population, it is estimated that the lifetime prevalence of chronic
depression is over 6 percent (Kessler et al., 1994). It occurs in up to 20 percent of
depressed individuals (Keller and Hanks, 1994, Gilmer et al., 2005), but constitutes the
most common presentation of major depressive disorders (MDDs) in many specialized
clinical settings including at the Centre for Addiction and Mental Health (CAMH) in
Toronto, Canada.
1.2.2. Clinical Features and Morbidity
While some aspects of CMDD naturally overlap with those of acute depression,
several clinical features distinguish these two groups. Compared to acute depression,
CMDD is associated with greater comorbidity, particularly with anxiety, substance abuse,
and personality disorders (Keller et al., 1998, Russell et al., 2003). In a large multicentre
treatment study of chronic depression, almost a quarter of subjects had a lifetime history
11
of an anxiety disorder and over a third reported a lifetime history of a substance abuse or
dependence disorder (Keller et al., 1998). Furthermore, over half of the patients in this
study were diagnosed with a personality disorder, with avoidant (25.3 percent) and
obsessive-compulsive (18.1 percent) personalities being the most frequently diagnosed. It
should be noted that these high rates of comorbidity occurred despite strict exclusion
criteria, and therefore underestimate the actual rates of comorbidity in naturalistic
chronically depressed populations. There is controversy regarding the high rates of
comorbidity, with many believing that the comorbidity observed in depression is merely
an artifact of the current DSM diagnostic system which uses a categorical approach to
define distinct disorders. Whether comorbidities between illnesses, such as depression
and anxiety, are variants of a single disorder or represent qualitatively different disorders
still remains to be determined.
In addition to seeing high rates of personality disorders among those suffering from
CMDD, more recent studies focusing on dimensional measures of personality have found
higher levels of neuroticism and lower levels of extraversion in CMDD individuals
compared to those with acute depression (Wiersma et al., 2011, Klein et al., 2011). The
association between CMDD, cortisol responses, and both neuroticism and extraversion
forms an integral part of this thesis (see Chapter 4). Other features differentiating CMDD
from acute depression include increased rates of attempted suicide (Gilmer et al., 2005),
higher rates of childhood adversity, (Brown and Moran, 1994, Zlotnick et al., 1997, Riso
et al., 2002), and more of the “atypical” symptoms of depression (e.g., over-eating,
hypersomnia, leaden paralysis, and rejection sensitivity) (Horwath et al., 1992, Stewart et
al., 1993, Matza et al., 2003).
12
Treatment response also differs in those with CMDD and acute depression in that
CMDD is associated with poorer treatment outcomes with conventional antidepressant
use (Kocsis et al., 1988, Akiskal et al., 1997, Riso et al., 2002, McGrath et al., 2006).
Moreover, those with CMDD exhibit lower placebo response rates in comparison to those
with acute depression (Khan et al., 1991, Brown et al., 1992) which is suggestive of a
greater severity of illness.
The first large investigation of treatment response in CMDD was a double blind,
randomized, multicentre study that evaluated treatment response to sertraline versus
imipramine in 635 outpatients with chronic major depression and/or double depression
(major depressive episode superimposed on dysthymic disorder) (Keller et al., 1998).
Key findings included gender differences in both the response and tolerability of SSRIs
versus tricyclic antidepressants. Premenopausal females had a significantly greater
response to sertraline and were less likely to withdraw from sertraline than imipramine in
comparison to males. In contrast, males on imipramine responded better and were less
likely to drop out of the study than those on sertraline. There were no differences in
treatment response between postmenopausal females and older males. When interpreting
these findings, the authors suggested that the serotonergic potency of sertraline might be
an important factor in the treatment of chronic depression in young females. Other
studies, but not all, have also found gender differences in treatment response among those
with chronic forms of depression. A study of subjects with atypical depression and
associated panic attacks, a group known to have high rates of chronicity, found that
females had a greater response to MAOIs, whereas males had a greater response to TCAs
(Davidson and Pelton, 1986). In a study by Haykal and Akiskal (1999), females with
13
dysthymia had a greater response to fluoxetine compared to males. Taken as a whole, it is
clear that it is important to consider sex differences in the study of CMDD. Whether
differences in treatment response reflect differences in the underlying biology of chronic
depression in males versus females is an intriguing question.
A specialized form of psychotherapy, Cognitive Behavioral Analysis System of
Psychotherapy (CBASP), was developed to treat chronic forms of depression. This type
of therapy aims to assist patients with interpersonal, cognitive-emotional, and
maturational deficits that stem from early maltreatment by focusing on the therapeutic
relationship. In a study by McCullough et al. (2000), CBASP in combination with
antidepressant treatment was more effective than medication or therapy alone in chronic
depression. In this same study population, CBASP was found to be particularly effective
with or without additional medication in the subgroup of chronic depressives with early
childhood adversity (Nemeroff et al., 2003). However, subsequent studies have
questioned whether CBASP augmentation is more effective than antidepressant treatment
alone and whether CBASP is more effective than other psychotherapies (Kocsis et al.,
2009, Schramm et al., 2011).
Individual and Societal Costs
CMDD has a major impact on psychosocial functioning and is associated with
significant individual and societal costs (Miller et al., 1998, Howland, 1993, Riso et al.,
2002). CMDD is associated with significant impairments in numerous psychosocial
domains including relationships, family functioning, and work performance (Miller et al.,
2004). Greenberg et al. (2003) estimated the economic cost of depression in 2000 in the
14
United States to be $81.1 billion. As would be expected, chronic forms of depression are
associated with significantly greater economic costs than acute depression (Greenberg et
al., 2004). Several factors that contribute to this finding include greater impairments in
work performance, increased health care utilization, and more frequent hospitalizations.
In a study by Keller et al. (1998), individuals with chronic depression had a rate of
unemployment of 20.6 percent which was considerably higher than the national average
of 5 to 6 percent at the time of their study. Among the patients that were employed, about
a third had been in a job that was below their educational level and training. In the recent
STAR*D study, those with chronic depression had less education, lower income, higher
rates of unemployment, and a higher burden of medical illness than non-chronically
depressed individuals (Gilmer et al., 2005).
Whether psychosocial impairments associated with chronic depression are
antecedents to or the result of the illness is a difficult question. Impairments in one or
more psychosocial domains could be a risk factor for depression or could perpetuate the
illness. Furthermore, as depressive illness does impact overall functioning, it would seem
logical that the longer the depressive episode, the greater the impact on psychosocial
functioning. It has been speculated that psychosocial impairments are, in fact, both
antecedents to and the result of chronic depressive illness, although few studies have
examined this directly (Miller et al., 2004).
1.2.3. CMDD versus Other Forms of Chronic Depression
There has been much debate over what constitutes chronic depression, with several
studies attempting to subcategorize this illness. As stated above, CMDD is defined as a
15
MDE that has continued for at least two years. Dysthymic disorder has been identified as
a milder form of chronic depression lasting two years. Double depression has been
defined as a major depressive episode (MDE) superimposed on dysthymic disorder.
MDE, recurrent, without full inter-episode recovery, is yet another putative subtype.
Determining whether these diagnostic distinctions are meaningful for chronic forms
of depression was the focus of two large out-patient studies by McCullough et al. (2000,
2003). In these studies, various forms of chronic depression including CMDD, double
depression, recurrent depression without inter-episode recovery, and CMDD
superimposed on antecedent dysthymic disorder were compared for symptomatology,
clinical characteristics, family history, natural course, and treatment outcome.
Interestingly, few differences between the chronically depressed groups were found,
echoing results of previous studies in this area (McCullough et al., 1994, Donaldson et
al., 1997). The authors concluded that the similarities between various forms of chronic
depression outweighed the differences, thereby supporting a broad category of chronic
depression rather than distinguishing between its multiple forms. If so, the findings from
this project, which focuses on CMDD, are likely to be generalized to other forms of
chronic depression.
1.2.4. Etiology and Pathophysiology
To date, there have been few prospective studies examining the antecedents of
chronic depression, as most of the information known about chronic depression has been
based on cross-sectional studies.
16
The most comprehensive review of the etiology and pathophysiology of chronic
depression was by Riso et al. (2002). The goal of this review was to improve preventative
strategies and management of chronic forms of depression through a greater
understanding of their underlying causes. Riso et al. examined several areas including
developmental factors, personality, psychosocial stressors, comorbid disorders, biological
factors, and cognitive variables. Of all factors studied, childhood adversity, personality
features associated with increased stress reactivity (e.g., high neuroticism), and chronic
environmental stress were suggested as possible determinants of chronic depression.
Although several important findings emerged from this study, three are most relevant to
this thesis, namely the following: 1) there was some evidence that the hypothalamic-
pituitary-adrenal (HPA) axis and immunological function are altered in dysthymia; 2)
neuroticism was strongly associated with chronic depression in both cross-sectional and
prospective research; and 3) there was a limited understanding of the pathophysiology of
CMDD because of the dearth of research in this area. Despite this observation, only a
small number of biological studies on CMDD have been undertaken since the Riso et al.
report. As will be discussed below, some of these studies suggest that HPA activity may
be different in CMDD as compared to acute forms of depression. These various findings
provide a rationale to examine the interplay between CMDD, cortisol responses, and
personality in this thesis.
17
1.3. Hypothalamic-Pituitary-Adrenal (HPA) Function
and Depression
1.3.1. Introduction
This section provides an overview of cortisol responses and the HPA axis, and its
association with various forms of depression.
Definition of Stress
There are a number of definitions of stress and the term “stress” can have different
meanings for different people depending on the context. One of the pioneers in the field
of stress, Hans Selye, sometimes referred to as the “father of stress,” defined stress in a
generic fashion: a non-specific response of the body to any demand (Selye, 1956). This
sparked controversy, as later researchers determined that characteristics of a stressor
(namely cognitive, psychological, and biological variants), were shown to impact an
individual’s unique response to stress. Others define stress as a behavioural response to
the perception of threat that results in anxiety and tension. Sociologists might define
stress as the result of social disequilibrium. To engineers, stress is simply the effect of an
external force on a material, causing strain. Biologists might explain stress in purely
neuroendocrinological terms, as any stimulus that provokes the release of
adrenocorticotropic releasing hormone (ACTH) and adrenal glucocorticoids. Finally,
many believe that there is no one overarching definition of stress that is sufficiently
comprehensive in meaning, though most would agree that it is a universally recognized
18
condition that causes problems in human life deserving consideration from many vantage
points. This project focuses on the psychoneuroendocrinology of stress.
The HPA Axis
The HPA axis is an integral part of the neuroendocrine system that controls one’s
physiological reactions to stress. This axis also regulates many body processes including
digestion, the immune system, energy storage and expenditure, and mood. Focusing on
stress reactivity, the HPA axis mediates cortisol release as follows: when an individual
experiences stress, either biological or psychological, the HPA axis is activated. Stress
triggers the release of corticotropin-releasing hormone (CRH) from the hypothalamus and
extra-hypothalamic regions. CRH is synthesized in the hypothalamus, primarily in the
parvocellular neurons of the paraventricular nucleus (PVN). CRH-containing neurons
within the hypothalamus project to the median eminence which is the bridge between the
hypothalamus and the anterior pituitary. CRH then acts on specific receptors on the
pituitary to stimulate the release of ACTH which, in turn, stimulates the adrenal gland to
release cortisol (see Figure 1 below).
19
Figure 1: The Hypothalamic-Pituitary-Adrenal Axis. Stress results in the release of CRH
from the hypothalamus. This triggers the release of ACTH from the pituitary which then
stimulates the release of cortisol from the adrenal gland. Cortisol has negative feedback effects
at the level of the pituitary and hypothalamus (image online, available at
www.montana.edu/wwwai/imsd/alcohol/Vanessa/vwhpa.htm, accessed November 12, 2012).
20
As shown above, the HPA axis is regulated by a cortisol-mediated negative feedback
mechanism which controls its activity during the course of the day and during periods of
stress. Cortisol acts on mineralocorticoid (MR) and glucocorticoid (GR) receptors. The
MR is a high affinity receptor abundant in limbic areas of the brain. The GR differs from
the MR in that it is a low affinity receptor which is widespread in the brain and is
distributed throughout the body. There is a particularly high concentration of GRs in the
hippocampus and hypothalamus. The GR is generally believed to be the central agent
involved in the regulation of cortisol and is particularly important in the regulation of the
response to stress when levels of glucocorticoids are high, such as in acute depression.
However, more recent work has also lent support to the role of MRs in the response to
stress. In fact, it may be that the synergy of both receptors may be important in mediating
glucocorticoid negative feedback (Pariante and Lightman, 2008).
Measurement of Cortisol
Cortisol represents the most commonly measured stress hormone, and levels can be
obtained through salivary or plasma sampling. About 90 to 95 percent of cortisol is
bound to cortisosteroid-binding globulin (CBG) and other carrier molecules (e.g.,
albumin). Only free cortisol (unbound) penetrates cell membranes and activates MR and
GR receptors and it is therefore believed to be the biological active form of cortisol.
Salivary cortisol is a measure of unbound cortisol, whereas plasma measurements include
both unbound and bound cortisol. Despite this difference, studies have shown a high
correlation between plasma and salivary cortisol levels (Kirschbaum and Hellhammer,
1989). In the current study, salivary samples were used to measure cortisol, both because
21
saliva provides a measure of free (or biologically active) cortisol, and because it is less
invasive to collect study participants’ saliva than to obtain their plasma samples.
1.3.2. The HPA Axis and Depression
Initial studies of HPA dysfunction in acute depression were published in the 1960s.
A landmark study by Carroll and his colleagues (1976) reported non-suppression to the
dexamethasone suppression test (DST) in about 50 percent of depressed individuals. In
addition, elevated cortisol levels were observed in individuals with depression. These
findings were subsequently replicated (reviewed by Carroll, 1982) and suggested
dysregulation of cortisol feedback mechanisms in depression resulting in higher levels of
cortisol secretion.
Later studies suggested that the abnormalities in the HPA axis seen in depression
likely stem from central brain regions and are related to hypersecretion of CRH
(Nemeroff et al., 1984, Nemeroff, 1988). Supporting this theory were the following
findings: 1) the cerebrospinal fluid (CSF) of depressed individuals had higher levels of
corticotropin releasing factor (CRF) peptide; 2) ACTH release was blunted in depressed
individuals following exogenous systemic administration of CRF (Gold et al., 1984,
Holsboer et al., 1984a, Holsboer et al., 1984b); 3) in post-mortem studies, CRF receptor-
binding sites were significantly decreased in suicide victims suggesting that elevated
levels of CRF resulted in downregulation of CRF receptors (Nemeroff, 1988, Merali et
al., 2004); and 4) central administration of CRF and over-expression of CRF in
transgenic mice led to symptoms consistent with a depressive syndrome (Britton et al.,
22
1986, Pepin et al., 1992, Strohle et al., 1998). Overall, the above findings point to an
overactive stress system in depression.
Implications of HPA Activity in Individuals with Depression
The link between an overactive stress system and depressive illness has significant
medical implications, as prolonged exposure to glucocorticoids has been linked to various
adverse medical outcomes. Past studies have suggested an association between long-term
exposure to glucocorticoids and atrophy of the hippocampus, which could result in
impaired memory function and a reduced ability of the body to appropriately respond to
stress (MacQueen and Frodl, 2011). Higher glucocorticoid levels also contribute to an
increased allostatic load, thus promoting risk to various illness processes including
cardiovascular disease (Seeman et al., 2001).
The finding of altered HPA activity in depression also presents an opportunity to
create novel antidepressants that target this biological pathway. There has been
significant research and funding geared towards developing such medications that
downregulate the HPA axis, such as CRH antagonists (Zoumakis et al., 2006). In fact,
there is evidence that one CRH antagonist in particular, mifepristone, is effective in
treating psychotic forms of depression (Flores et al., 2006, Blasey et al., 2011).
Challenges in the Field
Despite all of the positive implications noted above, there are several challenges that
remain. First, whether HPA dysfunction represents a state effect of depression, is evident
prior to depression, or is a later consequence of ongoing depressive illness continues to
23
be a point of controversy (Pariante and Lightman, 2008). Second, although there was
initial promise that the DST may be a biological marker of depression, only about half of
those with depression show this abnormality. It is possible that the DST should be
reserved for certain subtypes of depression, for example melancholic or psychotic forms,
which are more likely to show this abnormality (Stetler and Miller, 2011). This raises
important questions about whether other measures of HPA activity (for example the CAR
and cortisol responses to the TSST as used in this study) could be useful biological
markers for other subtypes of depression (e.g., chronic depression).
1.3.3. The HPA Axis and Chronic Depression
The few studies conducted in this area suggest that HPA function may be distinct in
individuals with CMDD as compared to those with acute MDD. Watson et al. (2002)
were one of the first to conduct a study that specifically focused on HPA function in
CMDD. In this study, twenty-nine individuals with CMDD and twenty-eight matched
controls were administered both the DST and the Dex/CRH (the combined
dexamethasone/CRH) challenge. Results revealed no significant differences in either the
DST or Dex/CRH responses in those with CMDD as compared to the control group. In
addition, illness characteristics and demographic variables did not predict baseline levels
or response to challenge tests in CMDD. The majority of those with CMDD in this study
were on psychotropic medications, although the medication regime did not predict
cortisol response. Overall, this study did not show alterations in HPA activity in those
with CMDD as compared to healthy controls, which contrasts previous studies of acute
depression that point to heightened cortisol reactivity and decreased cortisol-mediated
24
feedback. In an effort to understand the unexpected negative findings, the authors
speculated on the following possibilities: 1) normalization of the HPA axis in CMDD
may be explained by chronic antidepressant use; 2) HPA patterns of activity change over
time during the course of a depressive illness; and 3) normal HPA function in depression
could be a vulnerability marker that predicts chronicity.
Other studies support the notion that HPA function may be different in chronic
versus acute forms of depression. For example, chronic depression was associated with
low basal cortisol levels in a geriatric population (Oldehinkel et al., 2001), a finding that
is opposite to what is seen in acute depression. In another study, O’Keane et al., (2005)
found increased ACTH responses to the CRH challenge test in CMDD, in contrast to
studies on acute depression that have generally reported decreased ACTH responses to
this challenge. Taken as a whole, studies on chronic depression point to either blunted or
normal HPA activity in marked contrast to findings in acute melancholic depression
(Nemeroff et al., 1984). Whether these findings reflect basic etiological differences in
HPA activity in chronic and acute depression or possibly a normalization of the HPA axis
in the transition from acute to chronic depression is unknown as of yet.
25
1.4. Social Stress Paradigms as a Method to Examine
Cortisol Responses in Depression
1.4.1. Overview
Social stress paradigms may improve our understanding of stress reactivity and
cortisol output by tapping into higher order emotional and cognitive processes that input
into the HPA system. Thus, social stressors may provide a more naturalistic assessment
of how individuals react to day-to-day stressors. Understanding the influence of cognitive
processes on HPA function may be particularly important in chronic depression, as
negative cognitive appraisals have been linked to both the etiology and maintenance of
depressive episodes (Scher et al., 2005). Furthermore, animal studies suggest that
physiological challenges may not elicit the same responses from limbic areas of the brain
as do psychological stressors (Herman and Cullinan, 1997).
Hans Selye (1956), a pioneer in demonstrating critical links between social stress,
physiology, and health, hypothesized that the characteristics of external stressors, either
physical or psychological, were of little importance in determining the physiological
stress response. However, recent reviews suggest that specific characteristics of a given
stressor can, in fact, influence cortisol output. In a key paper, Dickerson and Kemeny
(2004) reviewed 208 social stress studies and concluded that social stressors induce a
significant cortisol stress response with an overall effect size of about .31. The authors
also found that the effect size was greater with certain defined stressors, such as public
speaking and cognitive tasks. Based on their review, Dickerson and Kemeny further
concluded that stressors encompassing both social evaluation and uncontrollability
26
induced the greatest cortisol stress response. The TSST (Kirschbaum et al., 1993)
includes both of these elements, and many consider it to be the gold standard of social
stress paradigms.
1.4.2. The Trier Social Stress Test (TSST)
The TSST is the primary method used in this project to examine cortisol responses
in CMDD. This paradigm includes a five-minute public speaking task followed by a five-
minute mathematical challenge done in front of a live evaluating committee. As shown
below in Figure 2, there are various props, such as a video camera and microphone, to
further add to the stressful nature of this paradigm. TSST studies have been conducted in
both healthy and clinical populations.
27
Figure 2: Trier Social Stress Test. This paradigm consists of a five-minute public speaking task followed
by a five-minute mathematical challenge done in front of a live evaluating committee. After a preparatory
phase, participants are led into a room that mirrors a standard interview room with various props including
a video camera, microphone, and stand, and an “expert committee” of three people dressed in lab coats
sitting behind a table. Participants are told they have ten minutes to prepare a five-minute speech for the
expert committee as if they are at a job interview, after which the committee would assign them a second
task, which will also be five minutes in duration. The participants prepare their speeches in a separate
room. After participants complete the public speaking task, they complete a difficult mathematical problem
that consists of serially subtracting 13 from 1022. Once the stress challenge is completed, there is a
recovery phase in a separate room.
28
A number of demographic, psychosocial, and clinical factors contribute to individual
differences in cortisol responses to the TSST. As reviewed by Kudielka and colleagues
(2009), one of the most important variables to consider is sex differences. In healthy
populations, males have more robust cortisol responses to the TSST than do females.
While reasons for this are unknown, the type of social stressor may be one important
factor accounting for sex differences. For example, a study by Stroud and colleagues
(2002) found that males have a more robust cortisol response to achievement stressors,
whereas females have a greater cortisol response to interpersonal stressors. This
difference in response may reflect unique social roles of males and females.
Given the importance of sex differences in cortisol responses to social stress, this
variable will be controlled for in the statistical analyses in Studies 1 and 2. Other
demographic variables that may be relevant to cortisol responses to social stress include
age, body mass index, and smoking status, all of which will also be examined in this
project.
Psychosocial factors including personality and childhood adversity have also been
associated with altered cortisol responses to the TSST. Whether or not personality
dimensions of extraversion and neuroticism are associated with cortisol responses in
CMDD is a major focus on this project and will be reviewed in detail in Chapter 4.
Biological factors, such as medication (e.g., steroid and psychotropic medications),
and genetic factors have been found to contribute to individual differences in cortisol
responses to social stress. Twin studies and candidate gene studies have found that
polymorphisms in HPA axis genes (e.g., glucocorticoid) influence salivary responses to
acute challenges including TSST responses (reviewed by Wust et al., 2004).
29
The TSST has been studied in those suffering from various clinical conditions
including acute depression, anxiety disorders, post-traumatic stress disorder (PTSD),
fibromyalgia, pain disorders, and asthma. While results of past studies have been
somewhat mixed, researchers have found that differences in cortisol responses between
clinical populations and healthy controls are more evident when a system is challenged,
such as during the TSST. The studies examining TSST responses in acute depression are
discussed below. This project will be the first to examine cortisol responses to the TSST
in CMDD.
In summary, a number of demographic, clinical, and biological factors have been
associated with cortisol responses to social stress. This presents a somewhat challenging
situation, as it is not possible to account for countless potential covariates in a given
study. However, careful defining of exclusion criteria, controlling for sex differences, and
conducting social challenge tests in the afternoon have been suggested as possible
approaches to improve validity of TSST studies (Kuldieka et al., 2009) and constitutes
the approach used in this project. For completeness, Chapter 6 is dedicated to evaluating
whether other pertinent variables that are not the primary focus of the project (e.g.,
childhood adversity, SSRI medication use, PTSD, and depressive subtype), are associated
with cortisol responses in CMDD.
30
1.4.3. Studies using the TSST in Depressed Populations
More recent work has begun to examine social stress reactivity in clinically
depressed populations (Burke et al., 2005), including several studies using the TSST.
Young et al., (2000) compared TSST responses in ten acutely depressed individuals and
ten healthy controls. Depressed individuals were untreated and had no history of
childhood abuse, trauma, or PTSD. Results indicated that despite higher baseline cortisol
levels in the depressed group, the cortisol stress response was similar in depressed
individuals and healthy controls. However, those who were depressed did have a blunted
B-endorphin (derived from the same precursor as ACTH) response compared to healthy
controls. Although small, this study provided some preliminary evidence that social stress
reactivity may be altered in acute forms of depression.
In a follow up study by this same group, Young et al., (2004) examined the influence
of comorbid anxiety on TSST responses in depression. Results indicated an increased
ACTH response to the TSST in depressed individuals as compared to healthy controls;
however, this exaggerated ACTH response was exclusively in those who had both
depression and an anxiety disorder. The authors concluded that increased ACTH
reactivity following social stress may be a unique characteristic of the group suffering
from comorbid depression and anxiety disorders.
While these preliminary studies by Young et al., provided modest evidence for
altered social stress reactivity in acute depression, their findings should be interpreted in
light of the particular TSST methodology used. Participants in the studies by Young et al.
(2000, 2004) were informed at the time of recruitment that they would be performing a
public speaking task. This differs from the original protocol where participants were not
31
made aware of the nature of the task until the day of the stressor (Kirschbaum et al.,
1993). This difference in methodology likely decreased the novelty and unpredictability
of the stressor, thus limiting the intensity of the cortisol stress response.
Another study using the TSST in an acutely depressed population was published by
Heim et al., (2000b) and evaluated the role of childhood abuse on cortisol and ACTH
responses in depressed and healthy populations. Overall, the study suggested that
childhood abuse, and to a greater extent the combination of childhood abuse and
depression, were significant determinants of increased cortisol reactivity to a social
stressor in females. Therefore, the study by Heim et al., along with those by Young et
al., support the theory that social stress responses are altered in acutely depressed
populations. This work also suggests that in many cases, cortisol output in response to
social stressors may be driven by comorbidities and/or adversities, such as anxiety and/or
childhood abuse. The high prevalence of these factors in CMDD suggests that cortisol
responses to social stress may be altered in this population.
32
1.5. Personality, Cortisol Responses, and Depression
While the cortisol responses to social stress may be impacted by several
demographic, clinical, and biological factors, this project will focus on personality for
two main reasons. First, personality pathology has been strongly linked with chronic
depression. Second, the same personality factors that associate with chronic depression
have been linked to stress reactivity and HPA activity. Thus, the second major goal of
this project is to examine whether personality factors (specifically neuroticism and
extraversion) have moderating effects on cortisol responses in CMDD.
The following sections will provide an overview of: 1) personality pathology in
depressive illness; 2) associations between neuroticism and extraversion, and depressive
illness; and 3) associations between neuroticism and extraversion and HPA activity.
1.5.1. Personality Pathology and Depressive Illness
Introduction
Associations between personality pathology and depressive illness have long been
recognized. Kraepelin (1921) observed that similar personality profiles could be
identified in individuals with affective disorder and in their relatives. Sneider (1958) also
described certain personality characteristics in individuals with affective disorders.
Akiskal proposed that mood and personality combined to result in “subaffective
personalities” (Akiskal et al., 2005). This concept of subaffective personality disorders
suggests that personality pathology and mood disorders exist on a spectrum. For example,
33
depressive personality disorder (a subaffective personality disorder currently in the
appendix of DSM-IV-TR), may be the early onset, persistent trait-like variant of
depressive disorders.
Depression and Personality Disorders
Personality disorders were introduced as part of the multi-axial diagnostic system in
DSM-III (APA, 1980). The DSM-IV-TR categorizes ten different personality disorders in
three overarching clusters. Cluster A disorders characterize odd and eccentric
personalities (e.g., schizotypal, schizoid, and paranoid). Cluster B personality disorders
describe traits such as impulsivity, emotional dysregulation, and aggression (e.g.,
borderline, histrionic, and narcissistic). Cluster C personality disorders are typified by
obsessive, avoidant, and dependent traits.
There is significant comorbidity between personality disorders and depressive illness
(Bagby et al., 2008). The rates of personality disorders in depressed populations have
varied, but several studies suggested rates over 50 percent in both inpatient and outpatient
settings (Charney et al., 1981, Shea et al., 1990, Fava et al., 2002). In general, cluster C
personality disorders appear to be the most common in depressed outpatients (Shea et al.,
1987) and Cluster B personality disorders being the most common amongst depressed
inpatients (Black et al., 1999). Higher rates of personality disorders have been reported
in more chronic forms of depression (Keller et al., 1998, Russell et al., 2003).
Certain personality disorders, such as depressive personality disorder (in appendix of
DSM-IV-TR), have been found to be predictive of chronic depression. Depressive
personality disorder includes characteristics such as gloominess, feelings of inadequacy,
34
self-blame, brooding, and pessimism. Kwon et al. (2000) found that young women with
depressive personality disorder had an increased risk of developing dysthymic disorder
over the course of a three-year follow up study. Depressive personality disorder has also
been associated with poor treatment outcome in depression (Laptook et al., 2006, Ryder
et al., 2010). Klein et al. (1999) reported that in family studies of MDD, those with
chronic forms of depression had higher rates of depressive personality than their first
degree relatives.
Dimensional Models of Depression
Recent research has suggested that there are a number of challenges when studying
associations between categorical DSM-IV personality disorders and depressive illness
including: 1) low inter-rater reliability in the diagnosis of personality disorders in
depressed patients; 2) difficultly in differentiating personality traits from personality
disorders in depressed individuals; and 3) the fact that there can be overlap in the
diagnostic criteria between certain personality disorders and Axis I disorders (e.g.,
depressive personality disorder and dysthymic disorder). Based on the above limitations,
dimensional models of personality have been proposed as a better approach to
understanding personality pathology in depressive illness (Bagby et al., 2008) and will be
the approach used in this project. It is noteworthy, that adding dimensional measures of
personality is one of the major changes proposed for DSM-5.
35
The Five-Factor Model (FFM) of Personality
There are several dimensional models of personality that have been studied in
psychiatric populations including Costa and McCrae’s (1992) Five-Factor Model (FFM)
of personality, Cloninger’s Seven-Factor Psychobiological Model of Temperament and
Character (Cloninger et al., 1993), and Livesley’s eighteen-factor model of personality
pathology (Livesley and Jackson, 2002). The FFM represents one of the most commonly
used dimensional models and was therefore the chosen model in this current project.
In the FFM, personality is organized hierarchically, with five major dimensions,
namely neuroticism, extraversion, openness to experience, conscientiousness, and
agreeableness. Each of these dimensions is made up of six narrower traits or facets. The
dimensions of personality initially emerged through factor analyses of adjectives used in
different languages in non-psychiatric populations. This type of inquiry, referred to as the
lexical-semantic hypothesis, theorizes that the most salient personality characteristics are
present in language.
Costa and McCrae’s five-factor personality inventory (NEO PI-R) that measures the
above five personality dimensions was initially developed in non-clinical populations.
However, studies have demonstrated that extremes in personality traits are related to
psychopathology. A meta-analysis has demonstrated that there are meaningful
correlations between personality traits of the FFM of personality and DSM-IV
personality disorders (Saulsman and Page, 2004).
Neuroticism and extraversion are the two most studied personality dimensions in
depression and will be the focus of this project.
36
1.5.2. Neuroticism, Extraversion, and Depression: Literature Review
Neuroticism and extraversion are both heritable and stable traits that describe a
variety of moods and behaviours (Clark and Watson, 1991, Kirk et al., 2000).
Neuroticism describes an individual’s sensitivity to experience negative emotions
(Tellegen, 1985, Clark et al., 1994). These negative moods can include fear, anxiety,
sadness, guilt, and self-dissatisfaction (Watson and Clark, 1984). Furthermore,
neuroticism is also associated with negative cognitions (Clark et al., 1990), negative
appraisals of others (Gara et al., 1993), and overall work, social, and life dissatisfaction.
Extraversion on the other hand, includes characteristics such as positive emotionality,
sociability, talkativeness, and dominance. Other characteristics associated with
extraversion include high energy, friendliness, and assertiveness (Clark and Watson,
1991, Clark et al., 1994, Viken et al., 1994).
The relationship between neuroticism and/or extraversion and depressive illness has
been studied over many decades, with several reviews having been published on this
topic (Clark et al., 1994, Enns and Cox, 1997, Bagby et al., 2008, Klein et al., 2011)
suggesting that:
1) There is a robust association between higher levels of neuroticism and/or lower
levels of extraversion and depression (Clark et al., 1994, Enns and Cox, 1997,
Clark and Watson, 1999, Kotov et al., 2010, Klein et al., 2011);
2) Higher neuroticism and/or lower extraversion have been associated with a
chronic course of depressive illness, which is of significance for this project
37
(Weissman et al., 1978, Hirschfeld et al., 1986, Duggan et al., 1990, Enns and
Cox, 1997, Kotov et al., 2010, Wiersma et al., 2011);
3) In general, higher neuroticism and lower extraversion are associated with a
poor prognosis in depression (Clark et al., 1994, Enns and Cox, 1997, Ormel et
al., 2001, Quilty et al., 2008, Klein et al., 2011); and
4) Valid measures of neuroticism and extraversion personality “traits” can be
obtained in depressed individuals. While it is true that being depressed can result
in elevated neuroticism, and to a lesser extent, lower extraversion scores,
prospective studies have shown that these personality traits remain extant even in
the recovered state (Morey et al., 2010, Klein et al., 2011).
Recent research has also tried to evaluate whether personality dimensions, such as
neuroticism and/or extraversion, can help guide treatment of depressive disorders. In a
study by Bagby et al. (2006), individuals with higher neuroticism were found to
preferentially respond to medications over psychotherapy. While these results may
initially appear counterintuitive, the authors hypothesized that higher levels of
neuroticism may make it challenging for individuals to adequately use psychotherapeutic
approaches. In another paper, Quilty et al. (2008) found that depressed individuals who
responded to both psychotherapy and medications had personality characteristics that
included lower neuroticism and higher extraversion. In summary, these studies point to
the usefulness of understanding personality pathology when evaluating treatment
responses in depressed populations.
38
Whether there is a biological link between specific personality traits and depression
is an intriguing question. As reviewed by Foster and MacQueen (2008), several of the
neurobiological mechanisms believed to be associated with depressive illness
(neuroendocrine, molecular, genetic, and neuroanatomical) have also been linked with
personality traits that confer risk to depression (e.g., neuroticism). Foster and MacQueen
highlighted that more integrative research is needed to better understand the complex
relationship between personality, depression, and biological markers. This is the
approach that will be used in this thesis. One of the major areas of study in this project
and the focus of Study 2 is whether or not neuroticism and/or extraversion moderate
cortisol responses to social stress in chronic depression.
In summary, there is an extensive body of work examining associations between
neuroticism and extraversion and depressive illness. Neuroticism and extraversion have
been linked to the onset of depression, chronicity of depressive illness, and treatment
outcomes. At this point, an understanding of the biological links between personality
dimensions and depressive illness is still limited, although biological pathways such as
the HPA axis (as will be discussed in the next section) are promising avenues for future
research.
1.5.3. Neuroticism, Extraversion, and HPA Function: Literature Review
In healthy populations, there has been some support for the association between
neuroticism and/or extraversion and HPA function, although study results have varied.
Higher neuroticism has been associated with various measures of increased HPA activity
including higher cortisol awakening response (CAR) (Portella et al., 2005) and higher
39
daily cortisol levels (Nater et al., 2010). Higher neuroticism has also been associated with
increased cortisol reactivity following the Dex/CRH test (Zobel et al., 2004) and
naloxone administration (Mangold and Wand, 2006). However, some studies have linked
higher neuroticism and/or lower extraversion with decreased HPA activity (McCleery
and Goodwin, 2001, LeBlanc and Ducharme, 2005, Phillips et al., 2005, Oswald et al.,
2006), while others have found no relationship between neuroticism and/or extraversion
and altered HPA function (Kirschbaum et al., 1992a, Schommer et al., 1999).
Only one study conducted in a healthy population specifically evaluated the role of
personality dimensions (including neuroticism and extraversion) in cortisol responses to
the TSST (Oswald et al., 2006). In this study, sixty-eight healthy adults completed the
Revised NEO Personality Assessment and underwent the TSST. Cortisol responses to the
TSST were influenced by personality dimensions in a sex-specific manner. Blunted
cortisol responses were associated with higher neuroticism in females and with lower
extraversion in males. Overall, this study supports sex-specific associations between
neuroticism and extraversion and low cortisol reactivity. Specifically, it suggests that
personality traits associated with greater psychopathology are associated with blunted
social stress reactivity.
In summary, studies to date provide preliminary evidence that neuroticism and
extraversion are associated with HPA activity, including cortisol responses to social
stress. As individuals with CMDD have higher levels of neuroticism and lower levels of
extraversion compared to healthy and acute MDD populations, it is possible that these
personality dimensions may strongly contribute to individual differences in cortisol
responses in CMDD.
40
1.6. The Cortisol Awakening Response (CAR)
It has been suggested that one function of the CAR is to mobilize energy at awakening
to prepare an individual for the demands of the day.
Clow et al., 2004, Pruessner et al., 2007, Kudielka and Wüst, 2010
1.6.1. Introduction
The cortisol awakening response is a novel measure of HPA activity which has
generated increasing interest among those studying depression. While a number of
studies have found altered CAR responses in acute forms of depression, there have been
no published studies of the CAR in chronic depression. Therefore, another major goal of
this project was to evaluate the CAR in CMDD for the first time. Advantages of the
CAR test include its ease of administration and potential utility in longitudinal work in
both clinical and research settings.
The following sections provide a summary of the CAR and a review of studies
examining it in various depressed populations.
1.6.2. Overview of the CAR
Cortisol has a twenty-four-hour circadian rhythm with the highest levels occurring
after awakening and lowest levels occurring between approximately 0200 to 0300 hrs.
(see Figure 3 below).
41
Figure 3: Diurnal Cortisol Rhythm. Cortisol is released in a 24hr rhythm with the
highest levels occurring just after awakening and the lowest levels between 0200 to 0300
hrs. (image online, available at www.wardelab.com/20_3.html, accessed November 12,
2012).
As shown in Figure 3, cortisol levels rise in the early hours before awakening. The
CAR describes the spike in cortisol that occurs during the first thirty to forty-five minutes
after awakening, during which time levels can increase about 50 to 100 percent (see
Figure 4 below) (Pruessner et al., 1995, Pruessner et al., 1997, Wust et al., 2000b,
Wilhelm et al., 2007).
42
Figure 4: The Cortisol Awakening Response. Cortisol levels spike at about 30 to 45
min. post-awakening. This rise is termed the CAR which can be measured by having
individuals collect salivary cortisol levels at awakening, 30min. and 60 min. post-
awakening (image online, available at www.salimetrics.com/spit-report/archives/june-
2010, accessed November 12, 2012).
The CAR can be detected in about 75 percent of individuals, is reasonably stable
over time (r = .63 for AUC on day 1 and 2) (Wüst et al., 2000), and has moderate
heritability (Wüst et al., 2000, Clow et al., 2004). These characteristics suggest that the
CAR might be a useful trait marker of HPA function.
The exact mechanism underlying the CAR is unknown. While the CAR amplitude is
partly determined by circadian factors, it has been found to be distinct from the circadian
rise in cortisol in the morning hours (Wilhelm et al., 2007). Psychological processes may
also be important in determining the CAR. For example, social stress, loneliness, and
Cortisol level
Time after awakening (min.)
43
work overload have all been associated with an altered CAR (Wust et al., 2000a,
Kudielka and Kirschbaum, 2003, Schlotz et al., 2004).
1.6.3. The CAR and Depression
Several studies suggest that the CAR is altered in depressive illness. One of the
largest such studies examined the CAR in actively depressed individuals (n=701),
remitted depressed individuals (n=579), and controls (n=308) (Vreeburg et al., 2009). In
this study, individuals with either active or remitted depression had higher total cortisol
output (AUCg) and cortisol reactivity (AUCi) at awakening compared to healthy
controls. There was no significant difference in the CARs between active and remitted
depressed individuals. These findings are consistent with other studies that have also
reported higher CARs in depression (Bhagwagar et al., 2005), in remitted depression
(Bhagwagar et al., 2003, Aubry et al., 2010), in individuals with greater depressive
symptomatology (Pruessner et al., 2003b), in unmedicated individuals with a history of
depression, (Bhagwager et al., 2003), and in asymptomatic individuals with a familial
risk of depression (Mannie et al., 2007, Vreeburg et al., 2010). In summary, studies have
found that both the overall cortisol secretion (AUCg) and cortisol reactivity (AUCi) are
greater in depressed than in healthy populations, although some conflicting results have
also been reported (Huber et al., 2006). Given that CAR abnormalities have been found
in both remitted and currently depressed individuals, it would appear that the CAR may
represent a trait rather than a state marker of depression. However, as mentioned
previously, there is evidence to suggest that the biology of CMDD, particularly as it
44
pertains to the HPA axis, may be different than that of acute depression. Study 3 will be
the first to examine the CAR in those with CMDD versus healthy controls.
45
CHAPTER 2
RATIONALE AND STUDY DESIGN
46
2.1. Rationale and Study Design
This project was borne out of a need to improve the understanding and management
of CMDD, a common and highly disabling illness. At present, clinicians have limited
guidance in determining which medications and/or therapy are best suited for individual
patients with this condition. In order to improve its management and develop more
targeted treatments for CMDD, a greater understanding of its pathophysiology is needed.
As reviewed in Chapter 1, prior research has demonstrated that a multitude of
biopsychosocial factors contribute to the etiology of CMDD. Cortisol was chosen as the
primary biological measure based on an established link between this hormone and
depressive illness. The TSST and the CAR were the two research methods chosen to
examine salivary cortisol responses. From a social perspective, it is a well-observed
finding that individuals with chronic forms of depression are highly sensitive to
interpersonal stressors. This supported the use of a social stress paradigm, that being the
TSST, as the main method to examine cortisol responses. This paradigm would capture
cortisol fluctuations that occur in the context of higher order cognitive and emotional
processes. Finally, from a psychological standpoint, literature suggests that the effect of
social stressors on cortisol responses may be moderated by factors such as personality
(e.g., neuroticism and extraversion). Therefore, whether or not neuroticism and/or
extraversion moderated cortisol responses in CMDD was also evaluated.
In Study 1, discussed in Chapter 3, cortisol responses to social stress were compared
in CMDD versus healthy controls. Given the links between higher levels of neuroticism
and lower levels of extraversion and both chronic depressive illness and cortisol
47
responses, the moderating effects of these personality dimensions on cortisol responses in
CMDD were evaluated in Study 2 as described in Chapter 4. There has been increasing
interest in the CAR given the associations found between this measure of cortisol and
depressive illness, although no studies have been reported specifically on CMDD. One
advantage of the CAR test is that it is relatively easy to administer and it would be a
simple and cost-effective test to use longitudinally in a clinical or research setting. In
Study 3, described in Chapter 5, the CAR was examined for the first time in CMDD.
Given the number of factors that could impact cortisol responses to social stress (for
review, see Kudielka et al., 2009) it is difficult to control for every potential covariate.
Several key covariates including demographic variables (e.g., sex, age, and BMI) and
clinical variables (e.g., anxiety comorbidity and psychiatric medication use) were
examined in this project. For completeness and to help guide future research in this area,
Chapter 6 explores how other pertinent clinical and social factors impact cortisol
responses to social stress in those with CMDD. Out of the many variables found to be
associated with cortisol responses, four stood out as having particular relevance to
CMDD: childhood abuse, SSRI medication use, PTSD comorbidity, and depression
subtype (atypical versus melancholic). The associations amongst these four variables and
cortisol responses in CMDD participants were examined.
48
2.2. Conceptual Model for Thesis
The Conceptual Model of this thesis, illustrated below in Figure 5, proposes a
tripartite relationship between chronic depression, cortisol responses, and the personality
dimensions of neuroticism and extraversion. It also highlights the major study questions
that have been derived from this model. In this tripartite model, the various relationships
between the key variables were depicted as bidirectional in nature for two main reasons.
First, it acknowledges that the true causal relationships between these variables are
unknown due to the fact that most studies to date have been cross-sectional in nature.
Second, the bidirectionality further addresses the possibility that CMDD is both caused
by and causal of altered cortisol responses and/or personality. If so, this might explain
why CMDD tends to worsen and persist over time. In other words, the state of having
CMDD might further strengthen the very processes that caused it in the first place.
49
Figure 5: Conceptual Model for Thesis: the interplay between CMDD, cortisol
responses, and personality. The current project first examines associations between
cortisol responses and CMDD. The second major focus of the study is to determine
whether personality dimensions of neuroticism and extraversion moderate this
association. The arrows are depicted as bidirectional, as most studies to date have been
cross-sectional. Therefore, conclusions about causality are limited.
CHRONIC MAJOR
DEPRESSIVE DISORDER
CORTISOL RESPONSES
HIGH NEUROTICISM
LOW EXTRAVERSION
Question 1
Question 2
50
2.3. Study Aims and Major Hypotheses
This project is comprised of three inter-related investigations as outlined below:
Study 1: This study examined cortisol responses to the TSST in those with CMDD
compared to healthy controls.
Hypothesis: Given that individuals with chronic forms of depression are highly sensitive
to interpersonal stressors, it was hypothesized that CMDD participants would have
greater cortisol stress responses to the TSST than would healthy controls.
Study 2: This study examined whether higher levels of neuroticism and/or lower levels
of extraversion moderated the association between cortisol responses and CMDD.
Hypothesis: Higher levels of neuroticism and/or lower levels of extraversion are often
associated with greater interpersonal stress sensitivity. It was therefore hypothesized that
these personality dimensions would be associated with increased cortisol responses to the
TSST in individuals with CMDD as compared to healthy controls.
Study 3: This study examined the CAR in those with CMDD compared to healthy
controls.
Hypothesis: Based on prior findings that the CAR is increased in acute and remitted
depression, it was hypothesized that the CAR would be elevated in CMDD compared to
healthy controls.
51
2.4. Study Implications
Leading national and international institutions, such as the National Institute of
Mental Health (NIMH), have highlighted the need to conduct naturalistic studies on
individuals with complex psychiatric disorders. In the recent, large, and NIMH-funded
Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, treatment
response was lower in a naturalistic, depressed sample, as compared to prior reports in
narrowly-defined and less heterogeneous depressed populations (Gaynes et al., 2009). In
the STAR*D study, comorbidity in depressive disorders was the norm and the authors
emphasized the need to study “real life” patients. In particular, it was noted that there is a
dearth of knowledge on chronic and treatment-resistant forms of depression (Gaynes et
al., 2009). This project begins to tackle CMDD from a biological standpoint which is
aligned with the needs highlighted by the STAR*D study and the NIMH. If the
hypotheses of this project prove correct, it would validate the notion that biological
research can be conducted in complex populations, such as those with CMDD, and can
stimulate future work of this kind.
While there has been a well-established link between cortisol and depressive illness,
it is unknown whether cortisol patterns observed in more acute depressed populations are
also evident in CMDD populations. It is also unclear how cortisol patterns in depression
differ based on the research method used, namely the TSST and the CAR, and whether
one method is more reliable or informative than the other. The findings of this project
will help shed light on these key questions.
At present, there is no reliable method by which clinicians can choose one treatment
strategy over another in CMDD patients or predict how patients will respond to any given
52
treatment. The “one size fits all” approach to depression treatment involves trial and error
until an appropriate treatment is found. A major goal of this project is to determine
whether novel psychobiological markers in CMDD can be identified. It is hoped that
these profiles could, in turn, lead to more targeted management strategies for this
highly disabling illness.
53
CHAPTER 3
STUDY 1: EVALUATING CORTISOL
RESPONSES TO A SOCIAL CHALLENGE IN
CMDD
This study has been published by:
Chopra, K.K., Ravindran, A., Kennedy, S.H., Mackenzie, B., Matthews S., Anisman, H., Bagby,
R.M., Farvolden, P., Levitan, R.D. (2009) Sex differences in hormonal responses to a social stressor
in chronic major depression. Psychoneuroendocrinology, 34(8), 1235-41. Contents of this chapter
have been reprinted with permission from Elsevier.
54
3.1. Introduction and Hypothesis
CMDD is a debilitating illness, affecting about 20 percent of depressed populations.
Surprisingly few studies have examined its pathophysiology, although this is an essential
step to developing targeted treatments for this population. It has been well established in
the literature that associations exist between acute depression and increased HPA activity.
Whether these same alterations are present in CMDD is unknown. As cortisol is the most
commonly studied stress hormone within this axis, cortisol responses was chosen as the
biological marker in the study of CMDD in this project.
Individuals with chronic forms of depression are highly sensitive to interpersonal
stressors. Based on this clinical feature, the TSST, a social stress paradigm, was chosen to
study cortisol responses. This paradigm captures cortisol fluctuations that occur in the
context of higher order cognitive and emotional processes.
Hypothesis: Given that individuals with chronic forms of depression are highly sensitive
to interpersonal stressors, it was hypothesized that CMDD participants would have
greater cortisol stress responses to the TSST compared to healthy controls.
55
3.2. Methods
a) Participants
CMDD:
The CMDD group was recruited via posters and through the mood disorders clinic at
CAMH. For clinic patients, only those who had signed global research consent were
contacted regarding the study. All participants met criteria for CMDD (DSM-IV-TR),
defined as a MDE without remission for a minimum of two years. Each participant also
scored 18 or higher on the 29-item version of the Hamilton Depression Rating Scale
(HDRS-29) (Williams et al., 1988).1 This version of the HDRS was used to capture the
atypical symptoms of depression, including hypersomnia and hyperphagia, which are
common in the CMDD population (Horwath et al., 1992, Stewart et al., 1993).
Exclusion criteria for all participants included significant conditions likely to
confound cortisol levels including: ischemic heart disease; heart arrhythmias; current
steroid treatment; acute substance abuse; pregnancy; bipolar disorder; acute suicidal
ideation; and a history of psychotic symptoms.
Menstrual phase was documented for all participants and was defined as menstrual
phase 0 to 5, follicular phase 5 to 14, and luteal phase 15 to menses. Smoking history was
also documented.
1 Similar to Watson, et al. (2002), it was concluded a priori that a drug-free study would be desirable but
impractical in this population. However, subjects were required to be on stable doses of psychotropic
medications for a minimum of one month before study entry to limit the effect of acute medication changes
on the study results.
56
Controls:
The control group was recruited via posters and newspaper advertisements. Absence of
psychiatric history was confirmed based on the Structured Clinical Interview for DSM-
IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P) (First et al.,
1995). Only controls with a score of 7 or less on the HDRS-29 were included in the
study. The study received ethics approval from the institutional research ethics board. All
potential study participants were screened using a brief, semi-structured phone interview
to assess inclusion and exclusion criteria. Eligible participants then met with a research
assistant and provided written informed consent.
b) Procedures
Clinical Assessment (Visit 1)
Participants were administered the Structured Clinical Interview for DSM-IV (First et al.,
1995) and the HDRS-29 (Williams et al., 1988) by a trained research assistant.
The TSST (Visit 2)
A script of the protocol was followed as detailed on the following website:
http://www.macses.ucsf.edu/Research/Allostatic/notebook/challenge.html. Trained
undergraduate student volunteers, research assistants, and physicians conducted various
components of the social stress paradigm.
After a preparatory phase, participants were led into a room that mirrored a standard
interview room with various props including a video camera, microphone, and stand, and
an “expert committee” of three people dressed in lab coats sitting behind a table.
57
Participants were told they had ten minutes to prepare a five-minute speech for the expert
committee as if they were at a job interview, after which the committee would assign
them a second task, which would also be five minutes in duration. The participants
prepared their speeches in a separate room. After participants completed the public
speaking task, they completed a difficult mathematical problem during a five-minute
period that consisted of serially subtracting 13 from 1022. Protocols to deal with silences
or errors during these tasks were established a priori and followed the scripts on the
website noted above. Once the stress challenge was completed, there was a recovery
phase in a separate room. Salivary cortisol samples were taken pre-stressor (–35 min. and
–20 min.) just prior to entering the room to complete the public speaking and
mathematical challenge (0 min.), and post-stressor (+20 min., + 40 min., +60 min., and
+80 min.). All participants were administered the TSST between 1400–1830 hours to
control for circadian effects on cortisol secretion. Salivary samples were obtained by
having participants lightly chew on cotton wool salivettes (Sarstedt, Montreal, Quebec).
Cortisol levels were determined in duplicate in saliva by RIA using radioimmunoassay
kits (ICN Biomedical Inc., Costa Mesa, CA.). The intra- and extra-assay variability was
less than 10 percent. Saliva samples were stored until analysis at a minimum of –20oC.
Subjective appraisals of the TSST
To determine whether those with CMDD and healthy controls differentially
appraised the TSST, participants completed a questionnaire post-challenge that evaluated
how stressful they found the TSST. This questionnaire included the following six
questions: 1) How stressful was the experiment overall? 2) How stressful was the public-
58
speaking task? 3) How stressful was the mathematical problem? 4) Did you feel
especially anxious or tense in front of the committee? 5) Did you experience physical
signs of stress (e.g., sweating, trembling, voice cracking, increased heart rate) in front of
the committee? 6) How stressed do you think you appeared in front of the committee?
The questions were assessed using a five-point Likert scale and a total score was
calculated for each participant.
c) Statistical Analyses
Repeated measures analysis of variance (RANOVA) was conducted using the
SAS System v. 9.1.3 to assess changes in cortisol over time during the social stressor,
using both condition and sex as between group measures. Sex was included as a between
group measure as this variable may be important in determining cortisol stress reactivity
(for a review see Kajantie and Phillips, 2006) and may influence the presentation and
treatment response of chronic depression (Kornstein et al., 2000). Other standard
measures of the cortisol stress response including area under the curve (AUC) using the
trapezoid method and peak percentage change in cortisol [(maximum post-stressor
cortisol measure - T0 cortisol)/ T0 cortisol] *100 were also computed.
Pearson correlations were used to evaluate whether demographic variables, such as
age and body mass index (BMI), were correlated with the cortisol measures. In addition,
unpaired t tests were used to examine the potential effects of smoking status, medication
status, menstrual phase, PTSD diagnosis, or other anxiety disorder comorbidity on these
measures.
59
3.3. Results
Sample Characteristics
Twenty-six CMDD participants (twelve females and fourteen males) and twenty-
eight controls (fourteen females and fourteen males) completed the study. The CMDD
participants were statistically older than controls (43.3 +/- 5.7 years versus 39.4 +/- 6.0
years respectively; t (52) = -2.48, p= .016). There was no difference in mean BMI
between those with CMDD and controls (27.3 +/- 5.4 kg/m2
versus 25.0 +/- 4.4 kg/m
2, t
(45) = -1.64, p= .11), but there were significantly more smokers in the CMDD group than
in the control group (11/26 versus 3/26 respectively; χ2 = 7.01, df =1, p=.008).
Eighteen out of twenty-six CMDD participants were on one or more psychotropic
medication(s) including sixteen on antidepressants, one on a mood stabilizer (valproic
acid), four on benzodiazepines, and two on antipsychotics. Thirteen out of twenty-six had
a comorbid anxiety disorder, including six with PTSD, five with social phobia, one with
specific phobia, and one with anxiety disorder not otherwise specified (NOS). Nine had a
lifetime history of substance abuse and five had a lifetime history of an eating disorder
(either anorexia nervosa or bulimia nervosa).
Cortisol Responses to the TSST
The analysis of cortisol levels revealed a significant time by sex interaction (F=3.03;
df=4, 202; p=.02) and a significant sex by condition (control versus CMDD) interaction
(F=5.01; df= 1, 52; p=.03) (see Figure 6 below).
60
Figure 6: Mean (± SEM) Cortisol Responses to the TSST in CMDD Subjects vs.
Healthy Controls Grouped by Condition and Sex
Males
Time (minutes)
-35 -20 0 20 40 60 80
Sal
ivar
y C
orti
sol,
µg/
dl
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
CMDD
Control
Females
Time (minutes)
-35 -20 0 20 40 60 80
Sal
ivar
y C
orti
sol,
µg/
dl
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
CMDD
Control
TSST
TSST
61
Summaries of the results for AUC and peak percentage change in cortisol are graphed
in Figure 7. Females with CMDD had a significantly greater mean AUC (2.5 +/- 0.8
µg/dl) than controls (1.7 +/- 1.0 µg/dl, t (24) = -2.35, p= .027), but did not differ with
respect to mean peak percentage change in cortisol (54.4 +/- 88.2 versus 63.0 +/- 107.8
µg/dl respectively, t (24) = 0.22, p=.83). A different pattern emerged in males, with no
difference in mean AUC (CMDD = 2.1 +/- 0.6 versus controls = 2.2 +/- 0.9 µg/dl, t (25)
=.52, p = .61), but with a significant difference in mean peak percentage change (CMDD
versus controls: 48.6 +/- 66.4 versus 123.2 +/- 106.5 µg/dl; t (26) = 2.2, p= .035).
To examine whether the group differences in post-challenge cortisol levels might also
be reflected in pre-challenge cortisol levels, possible group differences in the two pre-
challenge cortisol samples taken at –35 min. and –20 min. before the TSST were
evaluated. An initial analysis revealed that these two measures were highly correlated (r=
.85, n =54, p<.001). Based on these results, a single pre-challenge cortisol level was
calculated based on the mean of the –35 min. and –20 min. samples. A univariate
ANOVA was then calculated using this pre-challenge cortisol level as the dependent
measure and both condition and sex as between-group variables. Results of this ANOVA
revealed no significant interaction or main effects of diagnosis or sex on pre-challenge
cortisol levels.
The exploratory examination of how relevant demographic and clinical characteristics
of those with CMDD were associated with the primary cortisol measures is summarized
in Table 1.
62
Figure 7: Comparison of Sex Differences in AUC and Peak Percentage Change in
Cortisol in CMDD Subjects vs. Healthy Controls
Peak
Percentage
Change in
Cortisol
AUC
(µg/dl)
Control CMDD Control CMDD
Control
CMDD Control CMDD
Male
Female Male
Female
*
*
Mean (±SEM) for AUC and Peak Percentage Change in
Cortisol in CMDD vs. respective Controls. * p < .05.
Control
63
Table 1: Association between Demographic and Clinical Variables to Cortisol
Measures in CMDD Subjects
Mean (SD) Peak%
Change
AUC Pre-
challenge
cortisol
Age (yrs.)
43.3 (5.7)
r a
.06
r a
-.10
r a
-.21
Body Mass Index
(kg/m2)
27.3 (5.4)
.01
.04
.11
Age of onset of depression
(year)
16.1 (10.0) .24 -.42* -.38
Current Duration (yrs.) 19.7 (12.0) -.10 .02 -.08
HDRS-29
HDRS-17
36.3 (9.3)
22.2 (5.1)
.11
-.06
.09
.03
.15
.05
PTSD or Other Anxiety
Disorder (Yes/No)
On Psychotropic
Medication (Yes/No)
Smoking Status (Yes/No)
n
13/13
18/8
11/26
t-statistic b
.08
.58
.54
t-statisticb
.13
1.0
-1.0
t-statisticb
.50
-.07
-.34
* p < .05, a
r= correlation coefficient, b df = 24
64
As shown above in Table 1, the only significant association was a negative
correlation between age of onset of depression and AUC post-challenge, that being, those
CMDD participants reporting an earlier age of onset had greater cortisol AUC. When
these analyses were repeated in the two sexes considered separately, a negative
correlation was found between age of onset and mean pre-challenge cortisol levels in
females with CMDD, but not in males (r = - .66, p = .019). No other correlations reached
statistical significance.
Importantly, there was no difference in AUC, peak percentage change in cortisol, or
mean pre-challenge cortisol based on the presence or absence of psychotropic
medications, a PTSD diagnosis, or other anxiety disorder diagnosis. In healthy controls,
age and BMI were not significantly associated with AUC, peak percentage change, or
mean pre-challenge cortisol measures. Across all study participants, and within the two
diagnostic groups and sexes considered separately, those who were smokers (n = 14) did
not differ significantly from non-smokers (n = 40) on these measures. Amongst the
females, AUC, peak percentage change and mean pre-challenge cortisol levels did not
differ based on menstrual phase.
Subjective Appraisals of the TSST
A univariate ANOVA using the total score from the subjective appraisal
questionnaire as the dependent measure and both condition and sex as grouping variables
revealed no significant interaction or main effects of sex. However, there was a trend for
those with CMDD to appraise the TSST as more stressful than healthy controls (mean
CMDD = 22.5 (4.8), mean control = 19.9 (5.0); F=3.78, df 1, 46, p=.058). Further
65
analysis revealed no significant correlation between subjective appraisal of the TSST and
key cortisol outcome measures in the entire sample and in each group and sex considered
separately.
3.4. Discussion
Based on the clinical observation that CMDD is often associated with marked
sensitivity to interpersonal stress, the working hypothesis for this study is that those with
CMDD would exhibit greater cortisol responses to the TSST than would healthy controls.
The overall pattern of results suggests that females with CMDD do, in fact, secrete more
cortisol in response to the TSST than do female controls, pointing to sensitization at one
or more levels of the (social) stress system. A novel and unexpected finding was that in
males, CMDD was associated with significantly decreased peak percentage change in
cortisol in response to the TSST. None of these results were readily attributable to basic
demographic and clinical variables or differences in subjective experiences during the
social challenge. Taken as a whole, these findings suggest that the nature of CMDD, at
least as it relates to social stress responsivity, might be fundamentally different in the two
sexes.
To date, few studies have evaluated HPA axis activity in chronically depressed
populations. One study reported that the cortisol stress response to the DST and
Dex/CRH challenge in CMDD participants was comparable to that of controls (Watson et
al., 2002), however, sex was not included here as a grouping variable. The discrepancy in
the results between the Watson et al. study and the current project may also reflect
66
methodological differences in evaluating the HPA axis, namely Dex/CRH versus TSST,
and/or the different populations studied. Of note is the fact that those who partook in this
project had an earlier onset of depression and a greater severity of depressive illness than
did those assessed by Watson et al. As the current study found that age of onset of
depression was associated with AUC in CMDD subjects as a whole and with mean pre-
challenge cortisol levels in females, this clinical factor may be an important consideration
in future cortisol studies in this population. Furthermore, it should not be assumed that
HPA changes that stem from pharmacological and psychosocial challenges engage the
same processes. In fact, it has been reported that amongst females with early life
traumatic experiences, challenges involving CRH administration versus the TSST
provoked very different outcomes (Nemeroff, 2004). It might similarly be the case that
pharmacological and psychosocial challenges might have different effects amongst
chronically depressed individuals.
Sex differences in HPA axis function have previously been reported in mixed
samples of acute and chronically depressed individuals. Young and Ribeiro (2006)
reported increased CRH drive in depressed females, but decreased CRH drive in
depressed males relative to controls using a twenty-four-hour metyrapone challenge, a
finding paralleling the current results. In addition, Young et al. (2007) found sex
differences in ACTH pulsatility following metyrapone blockade in MDD. Furthermore, a
treatment study of CMDD by Kornstein et al., (2000) found that females had a
significantly greater response to sertraline compared to imipramine whereas the reverse
pattern was seen in males. If one considers these studies together with the current results,
one can reasonably hypothesize that there may be sex-specific interactions between
67
cortisol stress reactivity and treatment response in CMDD that merit future investigation.
With respect to the mechanisms underlying the current findings, given the nature of
the TSST protocol, both higher order cognitive-emotional processes and differences in
HPA function ought to be examined. Specifically, it is known that interpersonal rejection
sensitivity and social anxiety are particularly common in females with chronic forms of
depression (Matza et al., 2003, Novick et al., 2005) and that this elevated reactivity could
account for increased cortisol responses to the TSST. However, this explanation does not
account for the blunted response seen in males following the TSST. While the reason for
this is as yet unknown, previous literature suggests that early life adversity, common in
this population, may differentially influence HPA axis function in males and females. For
example, in a study by Lingas and Matthews (2001), maternal nutrient restriction in late
gestation in guinea pigs resulted in sex-specific, long-term effects on HPA function.
Interestingly, restricted nutrient intake during pregnancy resulted in reduced basal
pituitary-adrenal activity in male offspring, but increased basal pituitary-adrenal function
in female offspring, findings that are similar to the current results. In another study, lower
birth weight was associated with salivary cortisol stress responses to social stress in
eight-to ten-year-old males but not females (Jones et al., 2006). Further work needs to be
done to examine how early adversity variables may differentially impact HPA function in
females and males with CMDD.
There were a number of limitations of the current study. For example, those with
CMDD on psychotropic medications were included in the current project for ethical and
pragmatic reasons, although ultimately, medication status was not associated with cortisol
stress reactivity and could not account for the group by sex interaction. One explanation
68
for the lack of effect of medication status on cortisol measures, as suggested by Watson et
al. (2002), is that over time, antidepressant use may have less of an impact on HPA
function. However, the current findings should be interpreted cautiously, as the role of
chronic psychotropic medication use on HPA activity in CMDD requires further study.
Another potential limitation of the current study is its modest sample size even though it
is consistent with other similar studies. As well, in the present study, only cortisol stress
reactivity to a social stressor was examined. Other hormonal measures, such as ACTH or
other indices of HPA activity (e.g., diurnal cortisol, Dex/CRH), might have provided a
greater depth to the findings indicating the need for further research.
Despite the study limitations, though, this is the first time cortisol responses to a
social stressor in the CMDD population has been studied. Whether current results reflect
a fundamental difference in the pathophysiology of CMDD in females and males is also a
matter in need of further research.
ADDENDUM: There were additional questions relating to the above manuscript that
arose after its publication. An Appendix (pg 154) was added to respond to these questions
in lieu of altering the content of the published manuscript. One specific question that is
addressed is whether females with CMDD have greater cortisol responses compared to
female controls or are the differences driven primarily by baseline differences in cortisol
levels. As detailed in Appendix 1, differences in AUCg between females with CMDD
and female controls need to be considered in light of baseline differences. Therefore, it
can be more accurately concluded that females with CMDD had greater cortisol output
during the TSST vs. having a heightened or sensitized response to this challenge.
69
CHAPTER 4
STUDY 2: DOES NEUROTICISM AND/OR
EXTRAVERSION MODERATE CORTISOL
RESPONSES IN CMDD?
70
4.1. Introduction and Hypothesis
In an attempt to understand the cortisol response patterns in CMDD, Study 1,
described above, demonstrated the presence of sex differences to social stress in those
with CMDD compared to healthy controls. This finding helps address question 1 of the
Conceptual Model (see Figure 5, page 49). Yet, there are obviously many other factors
that could contribute to individual differences beyond sex. Hence, in an effort to further
narrow in on the psychobiology of the CMDD population, Study 2 focused on the
personality dimensions of neuroticism and extraversion. Neuroticism and extraversion
were the dimensions selected for two reasons, those being that they are strongly
associated with CMDD and that there has been evidence linking them to cortisol
responses. It was postulated that higher levels of neuroticism and/or lower levels of
extraversion would moderate associations between cortisol responses and CMDD (see
question 2 of the Conceptual Model). If this is the case, identifying distinct
psychobiological profiles of CMDD based on cortisol responses and personality
dimensions could lead to the development of more targeted management strategies for
this difficult-to-treat population.
Hypothesis: Higher levels of neuroticism and lower levels of extraversion are often
associated with greater interpersonal stress sensitivity. It was therefore hypothesized that
these personality dimensions would be associated with increased cortisol responses to the
TSST in individuals with CMDD as compared to healthy controls.
71
4.2. Methods
The methods, including recruitment, inclusion and exclusion criteria, and the
procedure for the TSST have been detailed above for Study 1. Study 2 included both
Study 1’s participants as well as additional participants recruited to increase the statistical
power of this study. On visit 1, participants were administered the SCID-I/P and the
HDRS-29 by a trained research assistant. Participants also completed the Revised NEO
Personality Inventory (NEO PI-R) (Costa and McCrae, 1992). On visit 2, participants
completed the TSST.
Revised NEO Personality Inventory (NEO PI-R)
Participants were administered the NEO PI-R which generates data based on the Five
Factor Model (FFM) of personality (Costa and McCrae, 1992). The FFM evaluates
individuals on personality domains of neuroticism, extraversion, openness to experience,
agreeableness, and conscientiousness. The NEO PI-R consists of 240 self-report items
answered on a five-point Likert scale, with separate scales for each of the five domains.
Each personality dimension consists of six correlated facets or subscales. A factor
analytic study revealed that the same five factors and the thirty facets captured in
community samples are also represented in psychiatric samples (Bagby et al., 1999).
Stability estimates for the domains and facets are substantial in both community (Costa
and McCrae, 1992) and psychiatric samples (Trull and Goodwin, 1993, Santor et al.,
1997, Costa et al., 2005).
72
Statistical Analyses
Cortisol responses during the TSST were measured using the following: 1) area
under the curve ground (AUCg) (using the trapezoid method), in order to measure of total
cortisol output; and 2) area under the curve increase (AUCi), in order to measure stress
reactivity (Pruessner et al., 2003a). Using the formulas described in Pruessner et al.,
2003a, the following was used to calculate: a) AUCg = ((Time (T) 20min. + T0min.) / 2)
+ ((T40min. + T20min.) / 2) + ((T60min. + T40min.) / 2) + ((T80min. + T60min.) / 2),
and b) AUCi = AUCg -4 * T0min. An illustrative comparison of AUCg and AUCi is
provided in Appendix 1 pg. 155. For ease and economy, the units for AUCg and AUCi
have been summarized in units of concentration (µg/dl) throughout this thesis vs.
concentration x time (i.e. µg/dl x min.). Cortisol measures that were not normally
distributed were log transformed.
Separate hierarchical linear regressions were used to assess associations between
neuroticism and extraversion and key outcome measures. In both instances, depression
severity (using HDRS scores) and sex were entered as covariates in the first step of the
regression. These factors were controlled for, given that severity of depression can
influence personality measures (Kendler et al., 1993), and sex differences in cortisol
responses have been found in both healthy and CMDD populations (Kajantie and
Phillips, 2006, Chopra et al., 2009). At step 2, respective personality scores (neuroticism
or extraversion), group classification (CMDD participants versus healthy controls), and
the respective personality by group interaction were entered as predictor variables.
Regressions were run separately for the two dependent measures, AUCg and AUCi.
73
4.3. Results
Participant Characteristics
Fifty-one CMDD individuals (twenty-nine females and twenty-two males) and fifty-
seven healthy controls (twenty-nine females and twenty-eight males) completed the
study. CMDD participants were older than the healthy controls (41.6 ±1.9 yrs. versus
36.9 ± 7.7 yrs., respectively). As expected, the CMDD participants had significantly
higher mean neuroticism scores (70.1 ± 11.0 versus 46.5± 10.1, t= 11.6, df=106, p
<.0001) and significantly lower extraversion scores (38.0 ± 11.2 versus 51.8 ± 9.5, t= -
6.9, df = 106, p < .0001) than did the healthy controls.
For CMDD participants, the mean HDRS-29 and HDRS-17 scores were 33.7 ± 8.9
and 20.6 ± 4.6, respectively, suggesting a moderate severity of depression. As described
in Study 1 (Chopra et al., 2009), there was a high degree of psychiatric comorbidity,
particularly anxiety disorders, in the CMDD participants which is consistent with prior
literature (Kessler et al., 2003). A large proportion of participants (36/51) were on one or
more psychotropic medication(s) with the majority being on SSRIs or venlafaxine
(30/36).
Associations between Neuroticism and Cortisol Responses during the TSST in
Participants with CMDD and in Healthy Controls
As shown below in Table 2, a) and b), no significant associations between
neuroticism and cortisol responses (either AUCg or AUCi) were found in either the
CMDD or control group.
74
Table 2: Results of Hierarchical Linear Regressions Evaluating Associations
between Neuroticism and Extraversion and Cortisol Responses in CMDD Subjects
vs. Healthy Controls
a) Neuroticism and AUCi
Beta t p
Sex
-0.15
-1.55
ns
HDRS-17
-0.22
-0.69
ns
Neuroticism x Group
-0.37
-0.99
ns
Neuroticism
0.26
0.56
ns
Group
0.32
0.55
ns
b) Neuroticism and AUCg
Beta t p
Sex
-0.15
-1.55
ns
HDRS-17 0.04 0.13 ns
Neuroticism x Group
-0.55
-1.49
ns
Neuroticism
0.40
0.86
ns
Group
0.51
0.88
ns
75
Table 2: Results of Hierarchical Linear Regressions Evaluating Associations
between Neuroticism and Extraversion and Cortisol Responses in CMDD Subjects
vs. Healthy Controls (cont’d.)
c) Extraversion and AUCi
d) Extraversion and AUCg
Beta t p
Sex
-0.11
-1.13
ns
HDRS-17
-0.05
-0.16
ns
Extraversion x Group
-0.84
1.20
ns
Extraversion
-0.30
-0.81
ns
Group
-0.78
-1.40
ns
Beta t p
Sex -0.20 -2.03 .045
HDRS- 17
-0.50
-1.70
.091
Extraversion x Group
1.80
2.67
<.01
Extraversion
-1.08
-3.02
<.01
Group
-1.38
-2.58
<.05
76
Associations between Extraversion and Cortisol Responses during TSST in CMDD
Participants and Healthy Controls
For extraversion, the overall model significantly predicted AUCi (F=2.90, df = 5,
102, p < .05). Results revealed a significant association, shown above in Table 2 c),
between the extraversion by group interaction and cortisol reactivity as measured by
AUCi. Further analyses revealed that, as is shown in Figure 8 below, in those with
CMDD but not in healthy controls, a negative correlation was found such that lower
extraversion scores were associated with increased AUCi (r = 0.34, p< .05 versus r=-.12,
p = ns, respectively). When the regression was repeated for AUCg, a measure of total
cortisol output, no significant associations were found in either group, as shown in Table
2d) above.
77
Figure 8: Association between Extraversion and Cortisol Reactivity in CMDD
Subjects and Healthy Controls
1. CMDD
2. Healthy Controls
AUCi
µg/dl
(log transformed)
AUCi
µg/dl
(log transformed)
Extraversion
Extraversion
r2 = .12
p < .05
r2 = .01
p = ns
78
Subjective Appraisals of the TSST
Based on the cortisol findings, it was further examined whether participants with
higher levels of neuroticism and/or lower levels of extraversion appraised the TSST
differently, and if so, whether differences in appraisal were associated with cortisol stress
responses. Each participant completed a post-challenge questionnaire that evaluated how
stressful they found the TSST. The details of the questionnaire are described above in
Section 3.2.
In the CMDD group only, lower extraversion was associated with increased
subjective appraisals of stress during the TSST (r (46) = -.31, p < .05) (see Figure 9
below). There was no association between subjective appraisals of the TSST and
neuroticism in either the CMDD or healthy control participants. Of note is the finding
that subjective appraisals of the social challenge were not associated with cortisol
responses, as measured by AUCg and AUCi, in either the CMDD participants or the
healthy controls.
In summary, in CMDD participants, lower levels of extraversion were associated with
both increased subjective stress and increased cortisol reactivity during the TSST,
suggestive of both high psychological and physiological reactivity. However, these two
types of reactivity were not correlated with one another, meaning that increased
subjective appraisal of stress did not predict increased cortisol reactivity. A similar
disconnect between subjective distress and cortisol reactivity has been reported in prior
research (Dickerson and Kemeny, 2004).
79
Figure 9: Association between Extraversion and Subjective Stress Ratings of the
TSST in CMDD Subjects and Healthy Controls
1. CMDD
2. Healthy Controls
Extraversion
Extraversion
r2 = .10
p < .05
r2 = .03
p = ns
Subjective Stress
Ratings of TSST
Subjective Stress
Ratings of TSST
80
Pre-Challenge Cortisol Levels
To explore the possible role of anticipatory stress on the current results, associations
between neuroticism and extraversion and pre-TSST cortisol levels were examined next.
As the two pre-challenge cortisol levels (-35min. and -20min.) were significantly
correlated, r (106) = .77, p < .001), a single mean pre-challenge cortisol measure was
computed. Results indicated no significant association between mean pre-challenge
cortisol measures and neuroticism or extraversion in the entire sample as a whole and in
the CMDD and healthy control populations individually. This suggests that the
relationship between low extraversion and increased cortisol reactivity in CMDD
participants was independent of pre-challenge cortisol measures.
Evaluation of Other Potential Covariates
As a final step, several potential covariates were examined. Age, BMI, and smoking
status (yes/no) were not associated with cortisol reactivity. There was a trend for CMDD
subjects who were on psychotropic medications to have lower total cortisol output
(AUCg) (0.67 ± 0.42 µg/dl) as compared to CMDD subjects who were not taking
psychotropic medications (0.91 ± 0.28 µg/dl, t = 0.71, df =49, p = .06). However,
psychotropic medication use (yes/no) was not associated with cortisol reactivity (AUCi)
(0.81µg/dl ± .25 versus 0.87 ± 0.30, µg/dl t =2.0, df =49, p = ns, respectively). When
psychotropic medication use (yes/no) was controlled for in the regression model, the
association between the extraversion by group interaction and AUCi remained
significant, further suggesting that the results were not related to the effects of
psychotropic medications.
81
4.4. Discussion
Study 2 is the first study to evaluate the association between dimensional personality
traits and cortisol responses to the TSST in chronically depressed individuals. The main
finding was that lower levels of extraversion were associated with increased cortisol
responses during the social stressor in CMDD participants but not in healthy controls.
Furthermore, CMDD participants with low levels of extraversion appraised the TSST as
more stressful, although appraisal ratings were not correlated with cortisol reactivity.
Interestingly, neuroticism was not associated with cortisol responses or subjective stress
ratings in either group. These findings could not be attributed to clinical or demographic
variables, medication status, or pre-challenge cortisol levels.
The current findings add to the growing literature highlighting the important
relationship between personality factors and chronic depressive illness. In a recent study
by Wiersma et al. (2011), multiple psychological characteristics including personality,
cognitive reactivity, and external locus of control were evaluated in 690 non-chronic and
312 chronically depressed individuals. Chronicity of depression was associated with
neuroticism, hopelessness, risk aversion, rumination, and external locus of control, as
well as with lower levels of extraversion, agreeableness, and conscientiousness.
However, multivariate analyses revealed that only low extraversion, rumination, and
external locus of control remained significantly associated with chronicity when
controlling for other psychological factors. In combination with Study 2’s results, this
suggests that lower levels of extraversion may have unique relevance in CMDD that is
distinct from other psychological factors including neuroticism.
82
The association between lower extraversion and increased cortisol reactivity in
CMDD participants is intriguing and presents two possible interpretations of this finding.
First, an increased cortisol response could suggest a pathological process. This
interpretation is consistent with a study by Heim et al. (2000b) which reported increased
cortisol reactivity to the TSST in women with depression and a history of childhood
abuse. However, it is important to note that robust cortisol responses have also been
found to be normal or adaptive in certain populations such as healthy males (Kirschbaum
et al., 1992b), while blunted responses have been associated with psychopathology (Heim
et al., 2000a). At this time, until normal parameters for cortisol responses to social stress
can be defined, determining whether an increased cortisol response is pathological or
adaptive remains a key challenge for the field.
Nevertheless, from a clinical standpoint it appears plausible that the association
between lower extraversion and increased cortisol responses to social stress represents an
alteration in HPA activity in those with CMDD. If future work supports this hypothesis
this could have important theoretical and clinical implications for this difficult-to-treat
population. Recent research has highlighted the need to identify distinct intermediate
phenotypes within heterogeneous depressed populations that can provide more tangible
targets for both neurobiological research and tailored treatment approaches (Klein et al.,
2011). Could the current findings suggest that those with CMDD who have low levels of
extraversion may be in need of treatments that can moderate cortisol reactivity to social
stress? It is already known that increased social connections, development of
relationships, and engagement in activities are proven psychological treatment strategies
for CMDD (Keller et al., 2000, Bhagwagar et al., 2003, Schramm et al., 2008). However,
83
it would be valuable to determine whether CMDD patients who have lower extraversion
scores have the greatest benefit from this treatment approach, both symptomatically and
in terms of cortisol reactivity. Alternatively stated, does treatment that targets lower
levels of extraversion improve outcomes for this subgroup of CMDD individuals and is
this effect mediated through cortisol reactivity?
There are several limitations that merit consideration. To begin with, the study is
cross-sectional. Therefore, the degree to which the personality scores represent
longstanding personality traits versus those influenced by the state of depression cannot
be determined. However, previous studies have suggested that meaningful measures of
personality can be conducted in the depressed state (Trull and Goodwin, 1993; Santor et
al., 1997, Costa et al., 2005). Furthermore, studies have found that extraversion, in
particular, is a personality dimension that is less affected by the state of depression than
are other personality measures, such as neuroticism (Morey et al., 2010, Klein et al.,
2011). Other limitations of this study include the modest sample size and the fact that
most CMDD participants were on psychotropic medications. Importantly though,
controlling for medication status did not influence the primary findings of the study. As
well, despite the fact that clinical and demographic variables were non-significant
predictors of the cortisol stress response, it is possible that potential covariates were not
sufficiently accounted for.
In summary, Study 2 suggests that lower levels of extraversion are associated with
increased cortisol reactivity to a social challenge in CMDD participants but not in healthy
controls. The negative effects of long-term cortisol exposure on mood regulation and
84
brain pathology indicate the possible role of extraversion as a clinical target in CMDD
treatment and merits further research.
85
CHAPTER 5
STUDY 3: THE CORTISOL AWAKENING
RESPONSE (CAR) IN CMDD
86
5.1. Introduction and Hypotheses
The cortisol awakening response (CAR) is a unique measure of HPA activity
describing the sharp rise in cortisol during the first thirty to forty-five minutes after
awakening. Interestingly, a number of studies have found a higher CAR in acute and
remitted depression, although this has yet to be studied in the CMDD population. It was
particularly appealing to investigate the CAR due its ease of measurement relative to the
TSST. If proven to be a useful biological marker in CMDD, it would be a simple and
cost-effective test to administer longitudinally in a clinical or research setting. The goal
of Study 3, the final study of this project, was to evaluate the CAR in those with CMDD.
Hypotheses:
1) Based on prior findings that the CAR is increased in acute and remitted depression, it
was hypothesized that the CAR would be elevated in CMDD as compared to healthy
controls.
2) Given the association between lower levels of extraversion and higher cortisol
response to the TSST in those with CMDD (as seen in Study 2), it was expected that
lower levels of extraversion would also predict a higher CAR in those with CMDD
as compared to healthy controls.
3) Given the lack of association between higher levels of neuroticism and cortisol
responses to the TSST in both CMDD and healthy participants (as seen in Study 2), it
87
was similarly expected that no association would exist between neuroticism and the
CAR.
5.2. Methods
A subgroup of study participants comprising of twenty-seven CMDD participants
and thirty healthy controls were administered both the CAR test and the TSST. Each
participant completed the TSST (Kirschbaum et al., 1993) during a weekday between
1400 and 1800 hrs. The TSST methodology is described above in Section 3.2. Two
consecutive days of awakening salivary samples were collected by participants at home
to determine the CAR. In most cases, the CAR tests and TSST were completed between
24hrs and one week apart. For logistical reasons, five participants had the CAR and TSST
completed more than a week apart, with the maximum length between the two tests being
thirty-five days. Salivary samples were obtained by having participants lightly chew on
cotton wool salivettes (Sarstedt, Montreal, Quebec). Cortisol levels were determined in
saliva by RIA using radioimmunoassay kits (ICN Biomedical Inc., Costa Mesa, CA.).
The intra- and extra-assay variability was less than 10 percent. Saliva samples were
stored until analysis at –20oC. Smoking history was documented for each participant.
Menstrual phase was also documented for all female participants and defined as
menstrual phase 0 to 5, follicular phase 5 to 14, and luteal phase 15 to menses.
CAR Collection
Each participant collected salivary samples at home upon awakening, as well as at
thirty and sixty minutes post-awakening on each of two consecutive days. Participants
88
were given verbal and written instructions regarding proper collection of cortisol samples
and were to refrain from eating or brushing their teeth until after the three morning
salivary samples were collected. Samples were to be refrigerated up until they were
returned to the study coordinator, at which time they were stored at a minimum of –20oC
until analyses were done.
Statistical Analyses
Repeated measures analysis of variance (RANOVA) was used to assess changes in
cortisol over time during the first hour of awakening (awakening, +30 min., and + 60
min.) using both condition and sex as between group measures. Other standard measures
of the CAR were examined, including the AUCg and AUCi (Pruessner et al., 2003).
Cortisol measures that were not normally distributed were log transformed.
Four separate step-wise linear regressions were used to examine associations
between extraversion and neuroticism and either AUCg or AUCi. In each model,
depression severity (HDRS scores) and sex were entered in the first step of the
regression. At step 2, respective personality scores (extraversion or neuroticism), group
classification (CMDD participants versus healthy controls), and the respective personality
by group interaction were entered as predictor variables.
89
5.3. Results
Sample Characteristics
Twenty-seven CMDD participants (nineteen females and eight males) and thirty
controls (fifteen females and fifteen males) completed the study. The CMDD participants
were older than the control group at a trend level (40.0 +/-9.8 years versus 35.3 +/- 8.9
years respectively; t (55) = 1.9, p= .07). There was no difference in mean BMI between
CMDD participants and controls (27.4 +/- 5.5 kg/m2
versus
25.5 +/- 4.7 kg/m2,
respectively; t (49) = 1.3, p= 0.2).
Twenty out of the twenty-seven CMDD participants were on one or more
psychotropic medications including seventeen on antidepressants, four on
benzodiazepines, and one on an antipsychotic. Eighteen out of the twenty-seven CMDD
participants had one or more comorbid anxiety disorder(s), including ten with generalized
anxiety disorder, six with PTSD, seven with social phobia, and one with specific phobia.
CAR Analyses
Prior to completing the full analyses of CAR data, correlations between awakening
cortisol measures on Day 1 and Day 2 were examined. The awakening, 30 min., and 60
min. post-awakening cortisol measures were significantly correlated across Day 1 and
Day 2 (at awakening: r (55)=.55, p< .0001; 30 min. post awakening: r (55) =.68, p<
.0001; 60 min. post awakening: r (54) =.60, p <.0001). Similar findings were found when
correlations were repeated in depressed and healthy participants considered separately.
Based on these results, mean values were determined for each participant using the data
90
from both days, as shown in Table 3 below, and these values were used for computation
of the AUCg and AUCi for each participant.
Table 3: Mean Values for Awakening, 30 min., and 60 min. Post-Awakening
Cortisol Measures in CMDD Subjects and Healthy Controls
Awakening
µg/dl
30 min.
Post-awakening
µg/dl
60 min.
Post-awakening
µg/dl
CMDD
.79 ± .33
.91 ± .42
.84 ± .41
CONTROLS
.65 ± .36 .85 ± .37 .76 ± .33
Examining the CAR in CMDD Participants Compared to Healthy Controls
RANOVA revealed a significant change in cortisol during the first hour post-
awakening (F=8.5, df 2, 51, p = .001). As shown in Figure 10 below, cortisol levels
increased from awakening to the 30 min. time point in both groups and then declined
toward the 60 min. time point. However, there was no significant time by group (F=.34;
df=2, 51; p=.71), time by sex (F=1.0; df=2, 51; p=.37), or time by sex by group
interaction (F=.005; df= 2, 51; p=.995). The main effects of group and sex were also not
significant.
91
Figure 10: Mean (± SEM) CAR in CMDD Subjects vs. Healthy Controls
0.5
0.6
0.7
0.8
0.9
1
1.1
Awakening 30 min 60 min
Time
Co
rti
so
l (u
g/d
l)
CMDD
Healthy
Group comparisons of cortisol AUCg and AUCi at awakening are illustrated in
Figure 11 below. There was no significant difference in AUCg in individuals with
CMDD (1.7 +/- 0.7 µg/dl) versus healthy controls (1.6 +/- .6 µg/dl, t (55) = .87, p= .39).
There was also no difference in AUCi in CMDD versus healthy controls (.15 +/-.39
versus .27 +/- .46 µg/dl respectively, t (55) = -1.1, p= .29).
92
Figure 11: Mean (± SEM) AUCg and AUCi Cortisol at Awakening in CMDD
Subjects vs. Healthy Controls
0
0.5
1
1.5
2
AUCg AUCi
Co
rtis
ol
(ug
/dl)
CMDD
Healthy
Conclusion 1:
There were no group differences in the CAR in those with CMDD compared to healthy
controls.
93
Associations between Extraversion and Neuroticism and the CAR in CMDD
Participants Compared to Healthy Controls
As would be expected, the CMDD participants had significantly lower extraversion
scores (37.8 ± 8.9 versus 50.0 ± 10.5, t=-4.6, df=53, p<.000) and significantly higher
mean neuroticism scores (68.7 ± 9.8 versus 49.4 ± 11.4, t=6.7, df=53, p<.000) than did
the healthy controls. As noted previously, separate, stepwise linear regression analyses
were conducted to determine whether extraversion and/or neuroticism were associated
with the CAR. In each model, Step 1 included sex and HDRS scores, while Step 2
included personality (extraversion or neuroticism), group classification (CMDD
participants versus healthy controls), and the respective personality by group interaction.
Interestingly, extraversion was significantly associated with AUCi (β = .286, t 2.2,
p = .034), while none of the other variables (sex, HDRS, or extraversion by group)
contributed significantly to the model. As is shown in Figure 12 below, there was a
significant association between lower levels of extraversion and cortisol reactivity at
awakening (AUCi) in both groups, but in the opposite direction of what was expected.
Specifically, lower levels of extraversion were associated with lower cortisol reactivity
upon awakening. There was no association between lower extraversion and AUCg.
94
Figure 12: Association between Extraversion and AUCi Cortisol at Awakening in
CMDD Subjects and Healthy Controls
70.0060.0050.0040.0030.0020.0010.00
1.50
1.00
0.50
0.00
-0.50
-1.00
Fit line for Total
control
depressed
Group
AUCi
µg/dl
Extraversion
CMDD and Controls:
r2 = .08, p < .05
95
Consistent with Hypothesis #3, step-wise linear regressions revealed no significant
association between neuroticism or the neuroticism by group interaction and the CAR
(AUCg and AUCi). Figure 13, shown below, illustrates the lack of association between
neuroticism and AUCi in both those with CMDD and healthy controls.
Figure 13: Association between Neuroticism and AUCi Cortisol at Awakening in
CMDD Subjects and Healthy Controls
AUCi
µg/dl
Neuroticism
CMDD and Controls:
r2 = .038, p = .16
96
Conclusion 2:
Unexpectedly, lower levels of extraversion were associated with decreased CARs
(AUCi) in both the CMDD and control groups. As hypothesized, there was no
significant association between neuroticism and the CAR in either those with CMDD
or healthy controls.
5.4. Discussion
Study 3 examined group differences in the CAR in CMDD participants compared to
healthy controls and the potential role of personality (e.g., extraversion and neuroticism)
in shaping the CAR.
Contrary to Hypothesis #1, no significant difference was found in the CAR in
participants with CMDD compared to healthy controls. This was an unexpected finding
in light of literature that links elevated CARs to acute depression (Bhagwager et al.,
2005, Vreeburg et al., 2009, 2010). In another study of CMDD, Watson et al. (2002)
reported no difference in cortisol responses following either the DST or the Dex/CRH
challenge in those with CMDD compared to healthy controls. Taking these various
findings into consideration, it is concluded that basic physiological measures of the HPA
axis are not elevated in CMDD, which contrasts most work in acute depression.
However, sex differences in cortisol responses are evident in this population during a
social stress challenge (Chopra et al., 2009 (Study 1)). This highlights the unique value of
using social stress paradigms to assess cortisol responses in psychiatric populations. More
specifically, the TSST may be better able to capture higher order central nervous system
97
(CNS) processes that impact the HPA axis. It is well established that negative cognitions
and emotions are fundamental to the etiology and maintenance of depressive episodes.
Contrary to Hypothesis #2, lower levels of extraversion were associated with
decreased cortisol reactivity to awakening in both those with CMDD and healthy
controls, even after controlling for depression severity and sex. Higher cortisol reactivity
upon awakening was expected based on findings in acutely depressed populations and the
central dogma that higher cortisol levels are associated with psychopathology. However,
there is a growing body of literature that links blunted cortisol responses, even upon
awakening, with psychopathology such as PTSD, fibromyalgia, and chronic stress
(Gaynes et al., 2009, Wessa et al., 2006, Chida and Steptoe, 2009). As one function of
the CAR is believed to be the mobilization of energy to prepare an individual for the
demands of the day (Clow et al., 2004, Pruessner et al. 1997, Kudielka and Wüst, 2010),
a blunted CAR could suggest malfunction of this otherwise adaptive process.
Several limitations of this study merit consideration. To begin with the study had a
modest sample size although it is consistent with several past studies in the field. A type
II error cannot be ruled out, particularly if the differences between the two groups are
subtle in nature. Another limitation was that data on waking time and sleep quality was
incomplete. Although participants were provided with both verbal and written
instructions, similar to prior studies of this kind, full compliance at home is never
guaranteed. Any inconsistencies, however, are mitigated by the fact that there was
consistency between awakening cortisol measures on Days 1 and 2. Electronic devices
have been used in a few previous studies in an effort to track when participants removed
the lid to access the cotton swab for cortisol sampling. However, these devices do not
98
assure the accuracy of the time of the first awakening sample, and indicate only that the
subsequent samples were taken at the correct intervals.
99
CHAPTER 6
A CLOSER EXAMINATION OF CLINICAL
AND SOCIAL FACTORS THAT MAY BE
LINKED TO CORTISOL RESPONSES IN CMDD
100
6.1. Introduction
The first two studies of this project revealed that cortisol responses to social stress
was different in those with CMDD as compared to healthy participants, and highlighted
the important role of sex and personality (namely, lower extraversion) in moderating
these effects. In both studies, several potential covariates including demographic
variables (sex, age, and BMI) and key clinical variables (anxiety comorbidity and
psychiatric medication use) were examined. It was found that none of these factors
impacted the main study findings.
Given the number of factors that could impact cortisol responses to social stress (for
review, see Kudielka et al., 2009) it was difficult to control for every potential covariate.
However, to help guide future research in this area, this chapter explores how other
pertinent clinical and social factors might impact cortisol responses to social stress in
CMDD. Of the many variables found to be associated with cortisol responses in prior
research, four stood out as having particular relevance to CMDD, those being childhood
abuse, SSRI medication use, PTSD comorbidity, and depression subtype (atypical versus
melancholic). The potential roles of these four variables in shaping cortisol responses in
CMDD are described in the following sections.
101
6.2. Is a History of Childhood Abuse Associated with
Cortisol Responses to Social Stress in CMDD?
A history of childhood abuse is a risk factor for depression and predisposes
individuals to a chronic course of the illness (Brown and Moran, 1994). In addition, a
history of childhood abuse has been associated with alterations in the HPA axis in both
healthy and acutely depressed populations (Heim et al., 2000b, Newport et al., 2004). For
example, Heim and colleagues (2000) compared responses to the TSST in women with
and without a history of MDD and/or childhood abuse. They found that women with a
history of childhood abuse exhibited increased pituitary and autonomic responses to the
TSST compared to normal controls. This effect was particularly robust in women
experiencing current symptoms of depression. This study suggests that acute depression
and a history of trauma can have a synergistic effect in enhancing HPA reactivity and
arousal mechanisms in MDD.
However, whether a history of childhood abuse is associated with cortisol responses
in CMDD is unknown. As childhood abuse is highly prevalent in CMDD (Hovens et al.,
2012), can individual differences in cortisol responses based on this variable be
determined?
Research question:
Does a history of childhood abuse contribute to individual differences in cortisol
responses in CMDD?
Hypothesis:
Childhood abuse measures will be associated with higher cortisol responses to the TSST.
102
Method:
Participants completed the Childhood Trauma Questionnaire (CTQ), a validated and
reliable measure of childhood abuse (Bernstein et al., 1994). The CTQ is a 28-item
inventory that assesses self-reported experiences of abuse and neglect before age eighteen
(Bernstein et al, 1994). Items on the CTQ begin with the phrase: "When I was growing
up," and are rated on a 5-point Likert scale. Individuals are determined to have none, low
to moderate, moderate to severe, or severe to extreme levels of childhood abuse based on
the cutoff scores summarized in Table 4 below.
Table 4: Cutoff Scores for Childhood Abuse Subscales of the CTQ
None Low to
Moderate
Moderate to
Severe
Severe to
Extreme
Sexual abuse
0–5
6,7
8–12
≥ 13
Physical abuse
0–7
8,9
10–12
≥ 13
Physical neglect
0–7
8,9
10–12
≥ 13
Emotional abuse
0–8
9–12
13–15
≥16
Emotional neglect
0–9
10–14
15–17
≥ 18
103
Statistical Analyses:
Pearson correlations were computed to examine associations between the mean CTQ
scores and mean CTQ subscale scores and cortisol responses (AUCg and AUCi) during
the TSST in CMDD.
Results:
a) Childhood Abuse Scores in the CMDD Group
In total, out of forty-eight participants who completed the CTQ, forty-three suffered
at least mild to moderate abuse as a child. Furthermore, thirty-four of the participants
suffered from abuse that was of moderate or greater severity. As summarized below in
Table 5, the mean scores for CMDD participants indicated at least low to moderate
degrees of childhood abuse on each of the subscales. CMDD participants scored the
highest on the emotional abuse and emotional neglect scales, with moderate to severe
levels of abuse on these subscales.
104
Table 5: Mean Childhood Abuse Scores in CMDD Participants
CMDD
(n=48)
(mean ± SD)
Females
(n= 26)
(mean ± SD)
Males
(n=22)
(mean ± SD)
CTQ*
60.7 ± 16.9
(n=45)
58.7 ± 16.6
(n=23)
62.8 ± 17.4
(n=22)
Sexual Abuse
7.8 ± 4.8
(n=46)
8.7 ± 5.6
(n=24)
6.8 ± 3.6
(n=22)
Physical Abuse
9.7 ± 5.1
(n=48)
8.9 ± 4.4
(n=26)
10.6 ± 5.7
(n=22)
Physical Neglect
8.5 ± 3.7
(n=48)
8.0 ± 3.3
(n=26)
9.2 ± 4.1
(n=22)
Emotional Abuse
12.8 ± 5.6
(48)
11.5 ± 4.9
(n=26)
14.2 ± 6.0
(n=22)
Emotional Neglect
14.8 ± 5.3
(n=47)
13.5 ± 4.9
(n=25)
16.2 ± 5.5
(n=22)
* 3 subjects (3/51) were missing complete CTQ data resulting in n=48. In addition, two participants were
missing data for the sexual abuse subscales and one participant did not complete the emotional neglect
subscale. One subject was not included in the analyses based on outlying scores.
105
b) Correlations between Childhood Abuse Scores and Cortisol Responses during the
TSST
Table 6, shown below, summarizes correlations between the CTQ scores and cortisol
responses to the TSST in CMDD subjects. There was no significant correlation between
cortisol responses (AUCg and AUCi) and mean CTQ scores. There was also no
correlation between cortisol responses and the mean CTQ subscales scores (e.g., sexual
abuse, physical abuse, physical neglect, emotional abuse, and emotional neglect
subscales). Further, there was no association between mean CTQ scores and cortisol
responses (AUCg and AUCi) in female and male CMDD participants considered
separately.
106
AU
Ci (µ
g/d
l) r (lo
g tran
sform
ed) n
AU
Cg
(µg/d
l) r (lo
g tran
sform
ed) n
*
-.09
(45)
-.18
(45)
CT
Q
(mean
)
-.19
(46)
-.23
(46)
Sex
ual
Abuse
(mean
)
-.12
(48)
-.13
(48)
Physical
Abuse
(mean
)
-.04
(48)
-.04
(48)
Physical
Neg
lect (m
ean)
-.09
(48)
-.20
(48)
Em
otio
nal
Abuse
(mean
)
.01
(47)
-.02
(47)
Em
otio
nal
Neg
lect (m
ean)
Tab
le 6: C
orrelatio
n o
f Cortiso
l Resp
onses to
the T
SS
T w
ith M
ean C
TQ
scores an
d
Mean
CT
Q su
bscale sco
res in C
MD
D
* d
ifferences in
nu
mb
er (n) reflect m
issing
data
107
Discussion:
Unexpectedly, childhood abuse was not associated with cortisol responses to social
stress. In interpreting this negative finding, it is noteworthy that 90 percent of CMDD
participants had experienced at least a mild form of childhood abuse while 71 percent had
experienced moderate to severe childhood abuse. It may be that these very high rates of
childhood abuse in CMDD make it difficult to statistically determine the independent
effects of this factor on cortisol responses. A study comparing cortisol responses in
CMDD participants with and without childhood abuse may be needed; however, it would
be a challenge to find a CMDD group without childhood abuse. Longitudinal studies,
ideally beginning in childhood, would also assist in examining the interplay between
childhood abuse, cortisol responses, and depressive illness.
6.3. Are the Cortisol Responses to Social Stress
Different for those with CMDD who are on SSRIs from
those who are Unmedicated?
The monoamine hypothesis of depression attributes depressive symptomatology to a
lack of monoamines in various brain regions. SSRI medications are believed to exert their
therapeutic effects by increasing levels and synaptic effects of monoamines, particularly
serotonin.
Antidepressant effects may also arise from normalization of the HPA axis (Holsboer,
2000, Pariante and Miller, 2001, Barden et al., 2005). Studies have found that
antidepressant medications enhance the expression and function of the glucocorticoid
receptor (GR), a key regulator of the negative feedback of the HPA axis (Holsboer, 2000,
108
Pariante and Miller, 2001, Pariante et al., 2004). The precise mechanism underlying
improved negative feedback is unknown. However, molecular mechanisms such as
antidepressant-induced GR activation and translocation from the cytoplasm to the nucleus
have been implicated (Funato et al., 2006, Pariante et al., 2012). This section specifically
examined the association between SSRIs and cortisol responses, given that different
antidepressant classes may have specific effects on GR receptor function and HPA
activity (Funato et al., 2006).
Research question:
Do cortisol responses to the TSST differ in CMDD individuals treated with SSRIs from
those not on psychotropic medications?
Hypothesis:
Given that SSRI treatment has been found to increase GR negative feedback, it was
hypothesized that SSRI treatment will be associated with lower cortisol responses to the
TSST in CMDD.
109
Method:
CMDD participants on psychotropic medications had to be on stable doses for at
least one month before entering the study to limit the potential effects of dose changes on
cortisol responses. T tests were computed to compare cortisol responses in CMDD
participants receiving SSRI treatment (either alone or in combination with another
psychotropic medication) with CMDD participants not on psychotropic medications.
Results:
a) SSRIs and Psychotropic Medication Usage in CMDD Participants
Table 7, below, summarizes psychotropic medication usage in CMDD participants. As
shown in the table, thirty-six out of fifty-one CMDD participants were on one or more
antidepressant medications. Eighteen participants were taking an SSRI either alone
(12/18) or in combination with another psychotropic medication (three were on
benzodiazepines, two were on Welbutrin, and one was on trazodone).
110
Table 7: Psychotropic Medication Usage in CMDD Subjects
CMDD
n
Psychotropic Medications
(yes/total)
36/51
SSRIs (yes/total)
18/51
SNRIs (yes/total)
12/51
Bupropion (yes/total)
5/51
Atypical Antipsychotics (yes/total)
4/51
Benzodiazepines (yes/total)
7/51
Trazodone (yes/total)
1/51
b) SSRI Medication Usage (yes/no) and Cortisol Responses to the TSST
As reported previously in this project (see results of Study 1 and 2), there were no
significant differences in cortisol responses to the TSST in CMDD participants on
psychotropic medications compared to those not on medications.
The current analyses focused on whether SSRI medication use (alone or in
combination with another psychotropic medication) was associated with cortisol
responses. As summarized below in Table 8, CMDD participants on SSRIs had a
significantly lower AUCg than those not on psychotropic medications. Table 9, below,
illustrates that there was no significant difference in AUCi in SSRI-treated CMDD
111
participants compared to those not on psychotropic medications. The analyses were
repeated excluding the six out of the eighteen participants on SSRIs who were taking
other psychotropic medications. A similar pattern of results were found. CMDD
participants who were only on SSRI medication had reduced AUCg cortisol compared to
those not on psychotropic medications (.66 ± .31µg/dl versus .91 ± .28µg/dl, t= - 2.1,
df=25, p<.05, respectively). There remained no association between AUCi cortisol and
SSRI medication usage in CMDD participants who were on SSRIs only compared to
those not on psychotropic medications.
As SNRI medications overlap in mechanism with SSRIs, a final analysis was
conducted to determine whether cortisol responses differed in CMDD participants on
either SSRIs or SNRIs (alone or in combination with other psychotropic medications)
compared to those not on medications. A similar pattern emerged with CMDD
participants on either SSRIs or SNRIs having a significantly lower AUCg cortisol
compared to unmedicated CMDD participants (see Table 8). There was no significant
difference in AUCi in CMDD individuals on SSRIs or SNRIs compared to those not on
medications (see Table 9).
112
SS
RI
or
SN
RI-treated
vs.
unm
edicated
CM
DD
particip
ants
SS
RI-treated
vs.
unm
edicated
CM
DD
particip
ants
.67 ±
.38
vs. .9
1 ±
.28
.66 ±
.32 v
s. .91 ±
.28
AU
Cg (µ
g/d
l)
mean
± S
D
(log tran
sform
ed)
2.1
2.3
t
43
31
df
.04
.03
p
Tab
le 8: C
om
pariso
n o
f AU
Cg C
ortiso
l du
ring th
e TS
ST
in C
MD
D S
ub
jects Trea
ted
with
SS
RI/S
NR
Is with
those n
ot o
n P
sych
otro
pic M
edica
tion
s
113
SS
RI
or
SN
RI-treated
vs.
unm
edicated
CM
DD
particip
ants
SS
RI-treated
vs.
unm
edicated
CM
DD
particip
ants
.82 ±
.24 v
s. .87 ±
.30
.75 ±
.25 v
s. .87 ±
.30
AU
Ci (µ
g/d
l)
mean
± S
D
(log tran
sform
ed)
.63
1.3
t
43
31
df
.53
.21
p
Tab
le 9: C
om
pariso
n o
f AU
Ci C
ortiso
l du
ring th
e TS
ST
in C
MD
D S
ub
jects Trea
ted
with
SS
RI/S
NR
Is with
tho
se not o
n P
sych
otro
pic M
edica
tion
s
114
Discussion:
As hypothesized, CMDD participants on SSRI medications had significantly lower
AUCg cortisol during the TSST compared to those not on psychotropic medications.
However, SSRI treatment in CMDD was not associated with AUCi cortisol.
It is believed that antidepressant-induced change in HPA activity is one mechanism
through which therapeutic effects is mediated. In CMDD, SSRIs/SNRIs are inducing the
expected decrease in overall HPA activity as defined by AUCg cortisol. However, this
change is not associated with treatment response. Could this point to a unique biology in
CMDD as compared to more acute forms of depression? Might alternative treatment
strategies be needed for individuals with CMDD (e.g., medication strategies that do not
target GR)?
Based on the association between SSRI/SNRI medication usage and decreased
AUCg cortisol during the TSST, a re-analysis of AUCg cortisol findings was conducted
for Studies 1 and 2. In the subsample of Study 1, after controlling for SSRI/SNRI
medication use (yes/no), the sex by condition interaction remained significant in
predicting cortisol responses during the TSST. Furthermore, females with CMDD
continued to have a greater AUCg cortisol during the TSST as compared to female
controls. In Study 2, after controlling for SSRI/SNRI medication usage (yes/no), there
remained no significant association between neuroticism and extraversion and AUCg
cortisol in CMDD participants compared to healthy controls. Therefore, while
SSRI/SNRI usage did significantly decrease AUCg in CMDD participants, it did not have
a major impact on AUCg findings reported in Study 1 and 2 of this project.
115
6.4. Is PTSD Comorbidity Associated with Individual
Differences in Cortisol Stress Responses to Social Stress
in CMDD?
PTSD is a severe and disabling illness and a common comorbidity in CMDD.
Individuals suffering from PTSD experience three distinct, but co-occurring symptom
clusters. First, patients with PTSD have re-experiencing symptoms, such as flashbacks
and nightmares of the traumatic event. The second feature of PTSD is severe avoidance
of any reminders (persons, places, or things) of the traumatic event. The third feature is
hyperarousal symptoms, such as anxiety and an increased startle response. In the DSM-
IV-TR, these symptoms must be associated with functional impairment and continue for
at least one month following the trauma to meet criteria for PTSD.
Research has revealed that the HPA profiles are different in PTSD than in depressed
populations (for review, see Yehuda, 2009). In general, PTSD has been associated with
lowered urinary and plasma cortisol as compared to the higher levels usually reported in
depression. Furthermore, PTSD is associated with increased suppression to
dexamethasone which also differs from findings in depression.
Research question:
Is PTSD comorbidity in CMDD associated with individual differences in cortisol
responses to the TSST?
116
Hypothesis:
Given findings of decreased cortisol levels in PTSD, it was hypothesized that CMDD
participants with comorbid PTSD will have a blunted cortisol stress response to the
TSST.
Method:
PTSD was diagnosed using the SCID-I/P (First et al., 1995). A series of t tests were
computed to determine differences in cortisol responses to the TSST in CMDD subjects
with or without comorbid PTSD.
Results:
Eleven out of fifty CMDD participants had comorbid PTSD. T test revealed no
significant difference in AUCg cortisol in CMDD participants with or without PTSD
comorbidity (.83 ± .27µg/dl versus .72 ± .43µg/dl, t = -.81, df = 48, p = .42, respectively).
Similarly, there was no difference in AUCi cortisol in CMDD participants with PTSD
compared to those without PTSD (.85 ± .26µg/dl versus .77 ± .29µg/dl, t = 0.9, df = 48, p
= .37, respectively).
Discussion:
Contrary to our hypothesis, PTSD comorbidity was not associated with blunted
cortisol responses to the TSST in CMDD. In general, lower cortisol levels have been
associated with PTSD, although less is known about cortisol responses to social stress in
117
these populations. In a review by Yehuda et al. (2009), it was noted that the presence of
lower baseline cortisol levels in PTSD does not necessarily imply that these individuals
will have blunted neuroendocrine responses to psychosocial challenges. In fact, in PTSD
higher neuroendocrine responses to psychosocial challenges have been reported
(Liberzon et al., 1999, Elzinga et al., 2003). Therefore, it may be that individuals with
PTSD have blunted basal levels as compared to depressed populations but have similar
cortisol responses to social stress. It may also be that cortisol responses differ in pure
PTSD versus PTSD comorbid with chronic depressive illness, but this has not been
explored to date.
6.5. Do Cortisol Responses to Social Stress Differ
Between Atypical and Melancholic Forms of
Depression?
The DSM-IV-TR defines two major depressive subtypes, namely atypical and
melancholic depression. Atypical depression is characterized by rejection sensitivity,
leaden paralyses, and reversed vegetative symptoms (e.g., overeating and oversleeping).
In contrast, melancholic depression is typified by decreased sleep, diminished appetite,
and a profound lack of interest and enjoyment in daily activities. Twenty-five to 30
percent of depressed patients present with melancholic depression and 15 to 30 percent
present with atypical depression (Gold and Chrousos, 2002). However, in chronic forms
of depression, there are much higher rates of atypical than melancholic depression
(Stewart et al., 1993, Matza et al., 2003).
118
Research has demonstrated that cortisol responses and HPA activity differ in atypical
and melancholic forms of depression. Most studies of melancholic depression support the
hypothesis that HPA activity is increased (Lightman, 2008, Stetler and Miller, 2011,
O'Keane et al., 2012). In atypical depression, a unique pattern of decreased HPA activity
has been found. For example, O’Keane et al. (2005) found that chronically depressed
individuals with atypical features had increased ACTH responses to the CRH challenge.
Levitan et al. (2002), found that individuals with atypical depression had increased
cortisol suppression to the low dose DST compared to healthy controls. The findings by
O’Keene et al. and Levitan et al. are indicative of decreased HPA activity and are in
contrast to prior work in melancholic depression (Stetler and Miller, 2011). The unique
HPA profiles in melancholic and atypical depression are believed to be central in origin.
Higher CRF levels centrally in melancholic depression result in higher cortisol release
from the adrenal gland, whereas CRF deficiency in atypical depression leads to the
opposite pattern (Gold and Chrousos, 2002).
Research question:
Does the depressive subtype (namely, atypical and melancholic depression) contribute to
individual differences in cortisol responses in CMDD?
Hypothesis:
As atypical depression has been associated with decreased HPA activity, it was
hypothesized that among individuals with CMDD, those with atypical depression will
have lower cortisol responses to the TSST than those with melancholic depression.
119
Method:
Atypical and melancholic depression were diagnosed using the SCID-I/P (First et al.,
1995). A series of t tests were computed to determine differences in cortisol responses to
the TSST in individuals with atypical depression as compared to melancholic depression.
Results:
a) Rates of Depressive Subtype in CMDD
Table 10 summarizes the frequencies of melancholic, atypical, and the neither subtype
(that is, criteria for melancholic or atypical depression were not met) in CMDD. As
expected, there were much higher rates of atypical depression than melancholic
depression in CMDD, consistent with prior literature (Stewart et al., 1993, Matza et al.,
2003).
120
Table 10: Frequency of Depressive Subtypes in CMDD
Frequency
Percent
Atypical Depression
28
54.9
Melancholic Depression
9
17.6
Neither Subtype *
11
21.6
Missing data
3
5.9
Total
51
100
* criteria for atypical or melancholic depression not met
b) Cortisol responses in Atypical, Melancholic, and Neither Subtypes in CMDD
Tables 11 and 12 summarize cortisol AUCg and AUCi during the TSST in the atypical,
melancholic, and neither subtype groups in CMDD. As shown, there was no significant
difference in cortisol AUCg and AUCi during the TSST among the three groups.
121
Melan
cholic v
s. Neith
er Subty
pe
Aty
pical v
s. Neith
er Subty
pe
Aty
pical v
s. Melan
cholic
.80 ±
.40 v
s. .69 ±
.55
.73 ±
.36 v
s. .69 ±
.55
.73 ±
.36 v
s. .80 ±
.40
AU
Cg
(µg/d
l)
mean
± S
D
(log tran
sform
ed)
.49
.23
.50
t
18
37
35
df
.63
.82
.62
p
Tab
le 11: C
om
pariso
n o
f AU
Cg C
ortiso
l du
ring th
e TS
ST
in A
typical, M
elanch
olic, an
d
Neith
er Subty
pe in
CM
DD
122
Melan
cholic v
s. Neith
er Subty
pe
Aty
pical v
s. Neith
er Subty
pe
Aty
pical v
s. Melan
cholic
.89 ±
.34 v
s. .85 ±
.28
.79 ±
.27 v
s. .85 ±
.28
.79 ±
.27 v
s. .89 ±
.24
AU
Ci (µ
g/d
l)
mean
± S
D
(log tran
sform
ed)
.3
-.58
.92
t
18
37
35
df
.77
.56
.62
p
Tab
le 12: C
om
pariso
n o
f AU
Ci C
ortiso
l du
ring th
e TS
ST
in A
typical, M
elanch
olic,
and N
either S
ubty
pe in
CM
DD
123
Discussion:
There were higher rates of atypical (28/51) versus melancholic depression (9/51) in
the CMDD group, which is consistent with past literature. Contrary to the hypothesis,
there was no significant difference in cortisol responses to the TSST between the two
depressive subtypes. There was also no difference in cortisol response between CMDD
participants with atypical and melancholic depression and those who did not meet criteria
for either subtype.
If these preliminary findings are replicated, what are the potential explanations? One
explanation (similar to that mentioned for PTSD above) is that differences in cortisol
responses between these two depressive subtypes might be dependent on the
methodology used. In other words, while differences in diurnal cortisol levels and cortisol
responses to the DST have been demonstrated in atypical versus melancholic depression
(Gold and Chrousos, 2002), these differences may not be relevant when using social
stress paradigms. Alternatively, it may be that differences in cortisol responses in atypical
versus melancholic depression are less pronounced in more chronic forms of depression.
In summary, depressive subtype was not associated with cortisol responses to social
stress in CMDD. Given the high rates of atypical depression in CMDD and the prior
association found between atypical depression and lowered HPA activity, it would be
important to re-examine this negative finding in the CMDD population in larger studies.
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6.6. Overall Summary
There are numerous variables that could potentially be associated with cortisol
responses in any given population. Out of the many variables, four stood out as having
particular relevance to CMDD. This chapter was an exploratory examination of how a
history of childhood abuse, SSRI treatment, PTSD comorbidity, and depressive subtype
(namely, atypical and melancholic depression) were associated with cortisol responses to
social stress in CMDD. The goal was that findings from this examination could inform
future work in CMDD.
Several important findings were revealed, some surprising. As expected, SSRI usage
in CMDD was found to be associated with decreased AUCg cortisol. This suggests that
although SSRIs are able to lower total cortisol output, this effect does not result in
treatment response in CMDD, hence these individuals remain symptomatic. Future
studies are needed to better understand whether therapeutic mechanisms of SSRIs differ
in acute and chronic depression. A second finding was the extremely high rate of
childhood abuse in CMDD, consistent with the literature. This finding in conjunction
with the high rate of PTSD, points to trauma being a primary feature of CMDD.
However, neither childhood abuse nor PTSD was associated with cortisol responses in
the CMDD group. It may be that these very high rates of childhood abuse in CMDD
make it difficult to statistically determine the independent effects of this factor on cortisol
responses. Finally, contrary to expectations, there was no difference in cortisol responses
to the TSST in atypical compared to melancholic depression.
* Differences in N across variables are due to missing data ** r
values are for total samples i.e. males and females
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In conclusion, the work described in this chapter added another dimension to the
understanding of cortisol responses to social stress in CMDD. Based on these results, it is
apparent that cortisol findings in the general depression literature are not indicative of
cortisol findings in CMDD. Furthermore, cortisol responses using a social stress
challenge appear to differ from prior findings using other measures of HPA function
(e.g., diurnal and DST).
There was a general lack of association between the variables examined in this
chapter and cortisol responses. Given the number of covariates examined in this chapter
and in Studies 1 and 2, the main findings of this project appear to be highly significant.
Taken as a whole, sex differences and lower levels of extraversion appear to be two key
drivers of cortisol responses to social stress in CMDD.
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CHAPTER 7
GENERAL DISCUSSION OF THESIS
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7.1. Introduction
CMDD is a common and debilitating psychiatric illness, with a lifetime prevalence
of over 6 percent (Howland, 1993, Kessler et al., 1994, Keller et al., 1998, Gilmer et al.,
2005). Despite the significant morbidity and mortality associated with CMDD, few
studies have examined its biological underpinnings, an essential step to developing
targeted treatment regimens for those who suffer from this illness.
There is robust evidence linking stress and depressive illness. Stressful life events
can precipitate depressive episodes (Hammen, 2005). Seventy percent of initial
depressive episodes are preceded by a stressor (Monroe and Harkness, 2005). Alterations
in stress physiology, specifically HPA activity, are well documented in depression. As
cortisol is the most commonly studied stress hormone within this axis, cortisol responses
was chosen as the biological marker in this study of CMDD.
Personality dimensions, such as higher levels of neuroticism and lower levels of
extraversion, are associated with chronic depressive illness and have been linked to
altered cortisol responses. It follows that these personality dimensions may then have
moderating effects on the relationship between chronic depression and cortisol responses.
To gain a better understanding of the underlying psychobiology of CMDD, three
studies were conducted that examined the interplay between chronic depression, cortisol
responses, and the personality dimensions of neuroticism and extraversion. This interplay
is illustrated below in Figure 14 in the Conceptual Model (this figure is the same as
Figure 5 on page 49, but has been included again here for the benefit of the reader).
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Figure 14: Conceptual Model for Thesis: the interplay between CMDD, cortisol
responses, and personality
CHRONIC MAJOR
DEPRESSIVE DISORDER
CORTISOL RESPONSES
HIGH NEUROTICISM
LOW EXTRAVERSION
Question 1
Question 2
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Summary of Major Findings:
a) Study 1:
In Study 1, cortisol responses to the TSST were examined in CMDD participants
compared to healthy controls. It was hypothesized that individuals with CMDD would
have greater cortisol responses to the TSST. Overall, the results support the notion that an
association exists between CMDD and cortisol responses, as represented by Question 1
of the Conceptual Model shown above. Consistent with the hypothesis, females with
CMDD had greater cortisol output during the TSST as compared to female controls.
However, males with CMDD had decreased cortisol stress responses compared to male
controls. These results suggest that cortisol responses to social stress are altered in
CMDD but with fundamentally different changes in each sex.
b) Study 2:
Many factors besides sex can contribute to individual differences in cortisol responses
in CMDD. In an effort to further understand cortisol responses in CMDD, and to identify
distinct cortisol response profiles in this heterogeneous population, focus was placed on
the effects of the personality dimensions of neuroticism and extraversion. These
dimensions were selected for two reasons, namely that they are strongly associated with
CMDD and that there has been evidence linking them to cortisol responses. It was
hypothesized that higher levels of neuroticism and/or lower levels of extraversion would
contribute to greater cortisol responses to the TSST in those with CMDD compared to
healthy controls.
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Contrary to this hypothesis, no association between neuroticism and cortisol responses
was found. However, as postulated, comparatively lower levels of extraversion were
associated with increased cortisol reactivity in those with CMDD but were not so in
healthy controls. These findings address Question 2 of the Conceptual Model shown
above, suggesting that lower extraversion does moderate the relationship between CMDD
and cortisol responses. These results also raise the possibility that lower extraversion is a
unique vulnerability marker and potential treatment target in CMDD.
c) Study 3:
Study 3 examined the CAR in CMDD. Based on the fact that acute depression has
been associated with an increased CAR, it was hypothesized that the CAR would be
greater in those with CMDD than in healthy controls.
Contrary to this hypothesis, no significant difference was found in the CAR between
CMDD participants and healthy controls. In light of Study 1 results demonstrating an
association between cortisol responses to the TSST and CMDD, one might postulate that
a social stress paradigm taps into the psychobiology of CMDD to a greater extent than do
other measures of cortisol.
Given the association between lower levels of extraversion and higher cortisol
responses to the TSST in CMDD participants found in Study 2, it was also hypothesized
that lower levels of extraversion would predict a higher CAR in those with CMDD.
Surprisingly, while extraversion did significantly associate with cortisol reactivity, the
direction of this relationship was opposite to expectations. Specifically, lower
extraversion predicted a lower CAR across both the CMDD population and healthy
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controls. Going back to the Conceptual Model shown above, there was no unique
relationship between CMDD and cortisol responses as measured by the CAR.
Furthermore, although lower extraversion is associated with the CAR, it does not
moderate the relationship between the CAR and CMDD, as the association is the same
across CMDD and healthy control groups.
7.2. Relevance of Study Findings
The current findings may have relevance to future biological and treatment studies in
CMDD as follows:
1. Biological studies, specifically those related to cortisol responses, can be
conducted in CMDD
The inherent complexity and heterogeneity of CMDD explain why few biological
studies have been conducted to date. However, leading national and international
institutions, such as the NIMH, have highlighted the need to conduct naturalistic studies
on individuals with complex psychiatric disorders. In the recent, large, NIMH-funded
STAR*D trial, treatment response was lower in a naturalistic, depressed sample
compared to those reported in narrowly defined, less heterogeneous depressed
populations (Gaynes et al., 2009). In the STAR*D study, comorbidity in depressive
disorders was the norm and the authors emphasized the need to study “real life” patients.
In particular, it was noted that there is a dearth of knowledge on chronic and treatment-
resistant forms of depression (Gaynes et al., 2009).
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In keeping with the needs stated above, this project begins to tackle this complex and
heterogeneous population using a naturalistic sample. Despite the challenges inherent to
this approach, sex differences were observed in cortisol responses in those with CMDD
compared to healthy controls. Furthermore, strong links were found between extraversion
and cortisol reactivity. These findings offer strong initial support that biological
research can be conducted in this population. More specifically, the results support the
use of cortisol responses in the context of a social stressor, as well as dimensional
measures of personality, as one means to define biologically distinct profiles in CMDD.
2. The choice of test to measure cortisol responses matters
While there may be several tests to measure cortisol responses, the results of this
project suggest that using a social challenge may uncover differences in cortisol
responses in CMDD that are not evident when using other tests. Study 1 revealed sex
differences in cortisol responses to the TSST in those with CMDD compared to healthy
controls. In contrast to this, a previous study by Watson et al. (2000) using
pharmacological challenges (namely, the DST and Dex/CRH tests) did not find
alterations in cortisol reactivity in those with CMDD compared to healthy controls. It
would appear that the TSST taps into higher order emotional and cognitive pathways that
may underlie the deficits in interpersonal functioning so characteristic of those suffering
from CMDD. These same pathways may not be directly assessed by other measures of
HPA function. It can therefore be concluded that social stress reactivity is a valuable
measure of HPA function, particularly where emotional and cognitive processes are
believed to play a key role in the etiology and maintenance of the illness.
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While the TSST is highly useful in research settings, it is not practical for use in
daily clinical practice. Furthermore, longitudinal studies may be problematic when using
the TSST given the critical role of novelty in eliciting cortisol release. Previous studies
have demonstrated that the cortisol responses to the TSST decreases with repeated
administration (Kirschbaum et al., 1995, Wust et al., 2005). Given the limitations of the
TSST, another goal of this project was to assess the utility and practicality of the CAR in
CMDD with a view to use this measure in future longitudinal studies.
Though highly preliminary and based on a modest sample size, the results of this
project, described in Study 3, suggest that assessing cortisol responses using the CAR can
be informative given the significant association found between lower extraversion and a
blunted CAR across all study participants. Whether the CAR can demonstrate unique
vulnerabilities in the CMDD population will require further study of a larger population.
3. Both increased and blunted cortisol responses should be considered when
studying the interplay between chronic depression, cortisol responses, and
personality.
Although the central dogma in the literature is that depression is associated with
higher levels of cortisol, findings of both blunted and increased cortisol responses were
found in CMDD as compared to healthy controls in this project. Study 1 showed that
while females with CMDD had greater cortisol output during the TSST, consistent with
the current dogma, males with CMDD unexpectedly demonstrated blunted cortisol
responses to the TSST. In Study 2, lower levels of extraversion in the CMDD population
were associated with increased cortisol responses to the TSST. This suggests that the
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relationship between cortisol responses and CMDD should include both heightened and
blunted cortisol responses as potential biological markers.
The finding of blunted cortisol responses in males during the TSST in Study 1 is in
keeping with a growing body of literature that has found associations between blunted
cortisol responses and psychopathology (Heim et al., 2000a, Wessa et al., 2006, Chida
and Steptoe, 2009). One theory is that cortisol responses changes from being sensitized to
hypoactive in the transition from acute to chronic illness (Miller et al., 2007). Another
possibility is that blunted cortisol responses are a vulnerability factor for the development
of stress-related illnesses.
4. Identification of psychobiological markers in CMDD may assist in the
development of targeted management strategies for this difficult-to-treat
population
In examining the interplay of CMDD, cortisol responses, and personality, the
following unique psychobiological profiles within a heterogeneous CMDD population
were identified:
1) Males with CMDD had blunted cortisol reactivity to a social stressor.
2) Females with CMDD had greater cortisol output during the social stressor.
3) CMDD individuals with lower levels of extraversion had increased cortisol reactivity
to a social stressor.
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Defining novel and empirically defined psychobiological profiles raises the prospects
of developing more targeted management strategies in this difficult-to-treat population.
For example, Study 2 found that CMDD individuals with lower levels of extraversion had
greater cortisol reactivity. It is known that increased social connections, development of
relationships, and engagement in activities are proven psychological treatment strategies
for CMDD (Keller et al., 2000, Browne et al., 2002, Schramm et al., 2008). Based on this
knowledge, it would be valuable to progress to the next level and determine whether the
CMDD individuals with lower extraversion scores derive greater benefit from specific
treatment approaches. For example, does psychological treatment approaches geared at
increasing aspects of extraversion (e.g., increased social connections and increased
activity level) improve outcomes in CMDD individuals with lower levels of
extraversion? Furthermore, could this beneficial effect be mediated through changes in
cortisol responses?
7.3. Study Limitations
a) Cross-Sectional Study:
There are several limitations of this project that merit consideration. First, the cross-
sectional nature of this study limits the ability to establish causal relationships. It is not
known whether findings in this project (e.g., blunted cortisol responses in males with
CMDD) are evident in these individuals prior to the onset of illness and represent a
vulnerability factor for chronic depression. Second, it is plausible that cortisol responses
changes from being sensitized to hypoactive in the transition from acute to chronic
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depression. Ultimately, studies comparing acute and chronic depression directly are
needed, as well as longitudinal studies examining how the relationships between
personality (e.g., lower levels of extraversion), cortisol responses, and depression evolve
over time.
b) Psychotropic Medication Use:
Another important limitation of this project was the inability to study a drug-free
CMDD population. Antidepressant medications can influence HPA function and
normalize the HPA changes found in acutely depressed individuals (Nickel et al., 2003).
Ideally, it would be preferable to study a drug-free population, but for practical and
ethical reasons this was not possible. As well, consideration was given to the possibility
that the actual process itself of discontinuing long-term medications in CMDD
participants could have a major effect on cortisol responses that would confound study
results. Furthermore, this study aimed to better understand the psychobiology of a
naturalistic CMDD population, given the need for studies of this kind. Studying a drug-
free CMDD population would not be as “naturalistic,” as most CMDD patients are
treated with psychotropic medications.
In the total sample, CMDD participants on SSRI or SNRI medications had lower
AUCg compared to those not on psychotropic medications. Nevertheless, there are
reasons to conclude that medication use did not have a major impact on the main findings
of this project. First, medication usage was controlled for in the statistical analyses.
Second, medication usage, including SSRI usage, was not a significant predictor of
cortisol AUCi (cortisol reactivity) to the TSST or to the CAR test. Nevertheless, the
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mechanism by which psychotropic medications impact cortisol responses and how this
relates to treatment response in CMDD and acute depression requires further elucidation.
c) Comorbidity and Heterogeneity:
As expected, there was significant heterogeneity and comorbidity in this project’s
naturalistic study population, which is often mentioned as a reason to avoid biological
studies in complex patients. CMDD, as compared to acute forms of depression, has high
rates of comorbidity with other psychiatric illnesses, such as anxiety disorders (including
PTSD), personality disorders, and substance use disorders. High rates of comorbidity lead
to many methodological and research challenges. One of the known limitations of the
DSM is that the diagnoses are not etiologically based, rather have been developed based
on clusters of symptoms. Due to the overlap of these symptom clusters in psychiatric
illness, multiple diagnoses become inevitable. This limitation raises two issues. First, it
can be difficult to determine what the primary diagnosis in these complex individuals is.
Second, it is probable that diagnoses with overlapping symptom profiles, as defined in
the DSM, (e.g., MDD and generalized anxiety disorder) may, in fact, have similar
biological underpinnings.
Another challenge is that the comorbid disorders in CMDD have also been
independently associated with alterations in the HPA axis. For example, PTSD is
associated with decreased baseline cortisol and hypersuppression to the TSST (Yehuda,
2009). This is contrary to findings of increased baseline cortisol levels and non-
suppression to the TSST that is commonly reported in depressed populations. In this
project, PTSD comorbidity was not associated with cortisol responses to the TSST. It is
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possible that the sample was not large enough to independently assess the role of this
comorbidity on HPA function in CMDD.
In summary, comorbid conditions are commonly found in CMDD and can present
methodological challenges. However, as multiple comorbidities amongst chronically
depressed patients are the norm rather than the exception, it may be reasonable to expect
to see biological patterns in CMDD despite it being a complex population.
d) Generalizability:
This project examined cortisol responses in a highly complex population of CMDD. It
should be noted that the majority of participants were recruited from the Centre for
Addiction and Mental Health, a tertiary care centre in Toronto, Canada. It is possible that
this population is more severe than chronically depressed patients treated in community
settings. Also, information about treatment resistance was not obtained from participants
in this study, although it is likely that many were treatment resistant given the nature of
patients seen at this centre. Whether the results of this project generalize to community or
treatment resistant populations needs further elucidation.
Understanding the generalizability of this project’s results would also be enhanced by
examining cortisol responses in other depressed populations. This will be the approach
used in the Alternative Inpatient Milieu (AIM) study (discussed in 7.4.2.) which will
examine the cortisol awakening response in both unipolar and bipolar depression, as well
as acute and chronic depression.
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7.4. Future Directions
7.4.1. Overview
The goal of this project was to define novel psychobiological profiles within a
heterogeneous CMDD population which could, in turn, lead to more targeted
management for this highly disabling illness. It is likely that the mechanisms underlying
CMDD and depression involve a complex interplay among a host of biopsychosocial
factors, including altered cortisol responses and personality. Moving forward, how can
the current understanding of mechanisms underlying CMDD be built upon to ultimately
improve treatment for this disabling illness?
In answer to this question, one must look at future research directions. In the short-
term (ongoing and to be completed within three years), the author is investigating how
changes in the CAR over time may assist in understanding patterns of response to and
relapse after a novel inpatient treatment program for depression. This study will be
discussed in the next section. In the medium term (three to five years), the author plans
to engage in research that will move towards identification of more reliable biomarkers
(cortisol and beyond) in CMDD and other depressive subtypes. As will be reviewed,
using multiple HPA markers, evaluating both HPA and other biological measures in
combination with one another, and incorporating imaging techniques are all approaches
that may lead to the identification of a reliable biomarker in CMDD. In the long term
(five to ten years), the author plans to focus his research on personalized medicine by
incorporating the information about patients’ psychobiological profiles in determining
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specific treatment choices. An overview of what personalized medicine entails and what
it could mean for the management of depression is discussed below in Section 7.4.4.
7.4.2. Future Research Direction (Short term): The CAR and the
Prediction of Treatment Response and Relapse in Depressive Illness
One major challenge in treating inpatients with depression is the high rate of relapse
post-discharge. As it stands, there is very little empirical research to guide individualized
approaches to treatment and discharge planning. The general goal of this ongoing project
is to determine whether psychobiological profiling can assist in this process. There is a
evidence demonstrating that persistent dysregulation of the HPA axis after depression
remits is associated with a higher risk of recurrence (Zobel et al., 2001, Lok et al., 2012).
This ongoing project combines elements of these studies with the findings of this thesis
work in order to accomplish this goal.
More specifically, this ongoing study investigates whether longitudinal changes in
the CAR over a four-week hospital stay and post-discharge can predict response and
relapse in depressed patients. The study will investigate whether patterns of the CAR
predict relapse one and four months post-treatment. This study is being done at the
Alternative Inpatient Milieu (AIM), a novel in-patient unit at CAMH for the treatment of
severe and chronic mood disorders. Novel aspects of AIM include the development of
coping and stress management skills and the promotion of patient autonomy within a
“home-like,” in-patient environment. The treatment team is multidisciplinary, including
psychiatrists, nurses, psychologists, occupational therapists, and social workers, in
keeping with the complex nature of depressive illness and in an effort to target
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biopsychosocial mechanisms inherent to depression. It is highly plausible that many
improve while on the AIM unit through changes in stress reactivity. Based on the
research findings described in this thesis, the examination of the role of depression
chronicity, sex, and the personality dimension of extraversion in shaping CAR patterns
will be an important component of the AIM study. One working hypothesis of the study
is that those with CMDD with lower levels of extraversion will show a different pattern
of CAR changes over the four-week hospital stay than will those with higher levels of
extraversion. It also predicted that this psychobiological profile, defined by extraversion
and the CAR over time, will be associated with patterns of relapse. Additional goals of
the study are to determine whether psychosocial therapies that focus on aspects of
extraversion (e.g., increased social connectedness and activity level) impact on pre- and
post-therapy cortisol levels and whether this, in turn, impacts on remission and relapse
rates.
7.4.3. Future Research Direction (Medium term): Identification of
Biomarkers in Depressive Illness: HPA Axis and Beyond
“A biomarker is defined as a characteristic that can be objectively measured and
evaluated as a measure of a normal biological process, pathogenic process or a
pharmacological response to a therapeutic intervention.”
(Jain, 2009b)
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A reliable biological marker could have several functions including: 1) being a
sensitive and specific measure of a disease state; 2) being a target for drug development;
3) assisting in predicting response; 4) being an indicator of prognosis; and 5) reducing
the financial and safety risks associated with clinical trials (Feuerstein and Chavez,
2009).
The identification of biomarkers is a major goal of both medical and psychiatric
research. While several biomarkers have been identified for medical illnesses (e.g.,
cholesterol measures and blood pressure), no such markers have been identified for
complex psychiatric disorders including depression. One of the most studied areas of
psychiatric research, as it pertains to biomarkers, has focused on cortisol and the HPA
axis. Despite significant research in this area, no single marker of HPA activity has been
shown to have sufficient sensitivity and specificity to have widespread clinical utility.
Going forward, how can research improve this state of affairs?
As will be discussed below, a profiling approach that uses multiple HPA measures in
tandem and/or HPA measures in combination with other biological measures, while
incorporating imaging studies to assess the higher order mechanisms tied to HPA
function, may be needed to address this challenge.
a) Using Multiple HPA Measures may be Necessary to Identify a Reliable Biomarker of
Depression
There are a number of methods to examine HPA activity including diurnal measures,
pharmacological challenges, and social stress responses. As highlighted previously, each
test is distinct and examines a different component of the HPA axis. For example, a
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diurnal measure, such as the CAR, provides insights into basal cortisol secretion, whereas
pharmacological challenges, such as the DST, provide a measure of glucocorticoid
receptor activity, a critical component of HPA regulation. Social stressors, such as the
TSST, help assess how higher level CNS processes impact cortisol responses. In
reviewing this literature, one limitation of work to date has been the tendency to focus on
only one component of the HPA axis at a time. Assessing multiple measures would
provide a comprehensive assessment of HPA activity. This is the approach used when
assessing biological markers in other fields of medicine. For example, when examining
cholesterol levels, treatment is not based on a single cholesterol marker but is based on a
number of markers as well as ratios between these markers. It might be necessary for
future studies to go beyond a single measure of HPA axis activity and instead examine
HPA profiles in depressed populations. Whether an HPA profile or a single HPA measure
is more meaningful in depressed populations needs to be examined directly in future
studies.
b) Evaluating Both HPA and Other Biological Measures in Combination
It was suggested above that a HPA profile that includes several measures of HPA
function may be a more useful biological marker of depression than a single HPA
measure. Similarly, it may be that multiple biological marker profiles of different
biological systems could be even more informative in assisting with diagnosis and
management in various depressed populations. Again, this is an approach that has been
used in other fields of medicine. For example, multiple biological markers such as
cholesterol levels, blood pressure, and blood glucose determine an individual’s
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cardiovascular risk and, in turn, guide management of cardiovascular disease. Could the
assessment of multiple biological systems in depression assist in a similar manner?
Schmidt et al. (2011) argued that a biomarker panel that aims to profile multiple
biological markers (e.g., growth, immune and endocrine) may be needed to stratify
depressed patients into more distinct subpopulations. Possibly, a panel of biomarkers
would aid in subdividing a heterogeneous depressive illness that presents with a similar
phenotype. This may, in turn, lead to more effective, etiologically based treatments for
subgroups of patients with depression.
There are a number of potential biological markers that have been linked to
depression. In reviewing the literature, growth factors and cytokine and inflammatory
markers are measures other than cortisol that appear particularly promising and that will
be strongly considered by the author in future work.
Growth Factors:
One growth factor that has received significant attention is the brain-derived
neurotrophic factor (BDNF). This growth factor is involved in regulating synaptic
plasticity in neuronal networks associated with depression (Pittenger and Duman, 2008).
A number of clinical studies suggest that BDNF levels are lower in depressed patients
and levels increase after antidepressant treatment (Gervasoni et al., 2005, Aydemir et al.,
2006, Brunoni et al., 2008). These findings support the notion that serum BDNF levels
could be a useful biomarker and may assist in our understanding of the pathophysiology
and treatment response in depression. Other growth factors that may also have relevance
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as biological markers include insulin-like growth factor-1 and vascular endothelial
growth factor (Schmidt et al., 2011).
Cytokines and Inflammatory Markers:
There is a growing body of work suggesting alterations in cytokines and
inflammatory markers in depressive illness (Miller et al., 2009). For example, higher
levels of TNF-α and IL-6 have been found in depressed patients (Dowlati et al., 2010).
As well, there is evidence that antidepressant treatment can normalize elevations in
cytokines and that persistent elevation of cytokines may be associated with treatment
resistance (Maes et al., 1997, Steptoe et al., 2007). Another inflammatory marker of
interest in depression is high-sensitivity C-reactive protein, which has been positively
associated with depressive illness (Howren et al., 2009).
There is a dynamic relationship between cytokines and inflammatory markers and the
HPA axis (Zunszain et al., 2011). Therefore, understanding both inflammatory, cytokine,
and HPA systems simultaneously in depression may be more useful than examining each
system on its own.
c) The Role of Imaging Studies in Identifying an HPA Axis Biomarker in Depression
As reviewed by Dedovic et al. (1998), amygdala, hippocampal, and prefrontal
regions of the brain play regulatory roles in response to social stressors in humans. In
addition, research has shown that repeated and chronic stress can change brain structure,
morphology, and function in these regions (Bremner et al., 2000, Ingram et al., 1998).
Functional imaging studies done following social stress challenges, with a particular
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focus on the hippocampal, amygdala, and prefrontal cortex regions, may provide new
insights regarding the mechanism underlying altered cortisol stress responses in
CMDD and how this critical circuitry might differ in CMDD and more acute forms of
depression. Potentially, TSST responses in conjunction with imaging findings may lead
to a more reliable biomarker of CMDD.
Studies incorporating both imaging studies and HPA activity are starting to be done.
For example, Aihara et al. (2007) found that hypometabolism in the right medial
prefrontal cortices discriminated Dex/CRH non-suppressors from suppressors in un-
medicated MDD. In another study by Drevets et al. (2002), left amygdala metabolism
was positively correlated with plasma cortisol levels in MDD and bipolar depressed
groups.
An exciting developing field is imaging genetics which examines how genetic
variations can influence brain structure and function in various illnesses such as
depression. For example, gene variants of the serotonin transporter gene (LALA versus S
or LG alleles) have been associated with enhanced amygdala activation to fearful faces in
patients with depressive or anxiety disorders (Lau et al., 2009). Interestingly, this gene
has also been linked with alterations in HPA activity (Miller et al., 2012). Taken as a
whole, imaging genetics may provide an important added dimension in understanding the
mechanisms (both genetic and brain function/circuitry) underlying altered cortisol
responses to social stress in CMDD, and may prove to be a powerful technique for
identifying biomarkers in depressed populations.
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d) Next Steps in Biomarker Research
To date, a number of putative markers of depression have been identified, but as of
yet, no one marker has been found to be a sensitive or reliable marker of depressive
illness. It is likely that a number of biological processes are involved in depression and
therefore, examining multiple biological systems may be a logical approach in future
studies. Studies of this nature will involve a large investment of resources and
infrastructure, though, and much larger samples of depressed patients will need to be
studied. Even so, research along these lines is starting to be done. For example, Dunlop
and colleagues (2012) are examining how multiple clinical, biological, genetic, and
psychological factors moderate response to treatment in patients with MDD who have
never received treatment before. Biological measures in this study include fMRI, immune
markers, genetic markers, and the Dex/CRH test. This is an intriguing study and
hopefully will provide insights into which biomarkers are most relevant in depressive
illness. This work may also provide clues to treatment resistance and possible markers of
chronicity in depression.
7.4.4. Future Research Direction (Long term): Personalized Medicine
“Prescription of specific treatment and therapeutics best suited for an individual taking
into consideration of both genetic and environmental factors that influence response to
therapy.” (Jain, 2009a)
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Personalized medicine is one of the strategic objectives of the NIMH in the hope that
more specific treatments will be developed for illnesses such as depression. However, at
present, there is no reliable method for clinicians to choose one antidepressant over
another and predict patient response to a given treatment. The “one size fits all” approach
to depression treatment usually does not work and instead, there must be a great deal of
trial and error until an appropriate treatment is found. The goal of personalized medicine
is to choose and/or design the right treatment for the right patient based on the individual
characteristics of the patient. Designing such an approach is particularly important in
depression. By not having personalized treatment strategies for depression, a disservice is
being done to patients given the lag time in treatment response, which can be up to six
weeks, and the increased risk of treatment resistance the longer a patient is symptomatic.
The current project was a step towards personalized medicine, by identifying unique
psychobiological profiles in chronic depression. Over the long-term, the author plans to
focus his research on personalized medicine by incorporating information about patients’
psychobiological profiles when determining specific treatment choices.
One area that appears particularly promising in personalized medicine is the field of
pharmacogenomics (Lin et al., 2010), defined as the study of how variations in genes
affect the response to medications. For example, almost all antidepressants are
metabolized by cytochrome P450 enzymes (CYPs) in the liver. Studies suggest that
polymorphisms in these enzymes can provide valuable information on medication dose
and the emergence of its side effects (Luo et al., 2005, Yin et al., 2006). There is
intriguing research examining how polymorphisms of genes encoding monoamines, the
targets for current antidepressants, influence treatment response. Several studies have
149
found that polymorphisms of the serotonin transporter gene may assist in determining
treatment response and the emergent of side effects (Lin et al., 2010).
So what could personalized medicine look like in depression treatment in the
future? Ultimately, personalized medicine for depression would include a comprehensive
biopsychosocial profile of the patient, one of which is pharmacogenomics. Physicians
would be able to use information from this profile to determine more effective and
targeted management strategies for patients with depression. Practically speaking, the
steps towards instituting a personalized approach to treatment of CMDD may be as
follows:
Upon entering the clinic, patients would provide a blood sample and using a
biomarker panel, several vulnerability markers would be immediately assessed
(e.g., HPA axis, immune and inflammatory markers, and growth factors).
An imaging study would be done to examine brain function and/or structure.
A genetic panel would be completed that could assist with diagnosis and
treatment decisions. For example, a genetic profile could assist with determining
pharmacokinetic and pharmodynamic profiles of patients which would aid in
determining the dose and choice of antidepressant.
Comprehensive psychological (e.g., personality) and social assessments (e.g.,
childhood adversity) would be done.
All of the information collected would be entered into a computer program
(possibly using a hand-held device) which would provide the clinician with
information that would augment the clinical interview.
150
The clinician would then be able to use this comprehensive assessment to
determine the most effective treatment strategy for the patient.
Although, personalized medicine may be in its infancy with respect to depressive
treatment, it is the way of the future. It is anticipated that over the coming years,
knowledge of a patient’s psychobiology will assist in providing a more effective and
individualized approach to treatment.
7.5. Final Summary
This project was developed out of a need to improve the management of CMDD, a
common and highly disabling illness. At present, clinicians are often at a loss when faced
with these patients and have limited guidance in determining which medications and/or
therapy would be best suited for them. In order to improve management and develop
more targeted treatments for CMDD, a greater understanding of its underlying
pathophysiology is needed.
The author’s graduate work has led to several important findings related to cortisol
responses in a naturalistic and highly complex sample of CMDD individuals. Various
unique psychobiological profiles were identified in chronic depression that merits further
investigation. Study 1 demonstrated that cortisol responses are different in those with
CMDD than in healthy controls, but only when sex differences are considered. Females
with CMDD had greater cortisol output following the social challenge relative to healthy
controls. In contrast, males with CMDD have blunted cortisol reactivity under the same
151
challenge compared to male controls. This suggests the existence of opposite stress
response mechanisms in females and males. The cortisol-mediated over-arousal by
females and under-arousal by males in the face of social stress could be reflective of sex-
specific defence and coping mechanisms. This finding could present interesting
possibilities for psychological therapies that cater to the unique defense style of each sex.
Studies 2 and 3 demonstrated that psychobiological profiles of CMDD based on the
personality dimension of extraversion may also have great utility in future work. CMDD
individuals with lower levels of extraversion secrete more cortisol when socially
challenged than do those with higher levels of extraversion. These findings suggest that
CMDD individuals with lower levels of extraversion may, in fact, represent a distinct
phenotype. In addition, these findings suggest that those with CMDD who have low
levels of extraversion may be in need of treatments that can moderate cortisol reactivity
to social stress. It is already known that increased social connections, development of
relationships, and engagement in activities (all of which are features of extraversion) are
proven psychological treatment strategies for CMDD (Keller et al., 2000, Bhagwagar et
al., 2003, Schramm et al., 2008). However, it would be valuable to determine whether
CMDD patients who have lower extraversion scores have the greatest benefit from this
treatment approach both symptomatically and in terms of cortisol reactivity. Alternatively
stated, does a treatment targeting lower level of extraversion improve outcomes for
CMDD individuals who score lower on this personality dimension, and is this effect
mediated through cortisol reactivity?
The results of the project point to several interesting questions that may eventually
lead to improved management of CMDD, including the following:
152
1) Should unique treatment approaches be considered for females and males with
CMDD?
2) Are lower levels of extraversion a target for treatment or a predictor of relapse in
CMDD?
3) Will alterations in cortisol responses be a quantifiable biological marker to measure
response or risk of relapse, much like assessment scales used in clinical practice?
4) Should unique treatment approaches be considered for individuals with CMDD
compared to those with acute depression?
The author is currently involved in a study that will start addressing some of these
questions. The AIM study is an ongoing study that examines whether patterns of the
CAR can assist in predicting response and relapse in depressive illness. Based on the
research findings described in this project, examination of the role of depression
chronicity, sex, and the personality dimension of extraversion on the CAR will be an
important component of the AIM study.
Over the long term, the author plans to examine biomarkers above and beyond
cortisol, for example immune, inflammatory, and growth factors. Imaging studies would
also be an interesting future direction that would allow for the examination of brain
circuitry and how this may be related to altered cortisol responses and treatment response
in CMDD. It is anticipated that over the next several years, research of this kind will start
identifying new targets for treatment that reflect a more personalized approach for
managing individuals with CMDD.
153
APPENDIX 1
Additional Analyses and Interpretations of Study 1 Results
There were additional questions pertaining to Study 1 that arose after this study was
published. Chapter 3 includes the published manuscript i.e. Chopra et al., 2009. An
appendix was added to the thesis to address the following questions:
1. Do females with CMDD have greater cortisol responses to the TSST than
female controls or are the differences mainly due to baseline differences in
cortisol levels given that 1) pre-challenge levels are higher in female
depressed as compared to female controls and 2) there were only differences
in AUCg (a measure of total cortisol output) and no difference in peak
percentage change in cortisol in females with CMDD compared to female
controls.
2. Are the results of Study 1 replicated in the larger study sample that was
recruited to examine moderating effects of personality on cortisol responses?
Response to Question 1:
In Study 1, it was found that females with CMDD had greater AUCg compared to
females controls (page 61 first paragraph; figure 7, page 62). As illustrated below,
AUCg is a measure of total cortisol output that includes both baseline (AUCB) levels
and cortisol changes over time or cortisol reactivity (AUCi).
154
Therefore, it is important to consider differences in baseline cortisol levels when
interpreting AUCg findings. The degree to which higher AUCg cortisol following the
TSST in female depressed as compared to female controls is determined by higher pre-
challenge cortisol levels remains an open question. However, it should be noted that
Time 0 cortisol levels (figure 6, pg 60) obtained just prior to the TSST were not
significantly different between females with CMDD and female healthy controls. This
suggests that the TSST also contributed to the differences found between these two
groups. A more parsimonious interpretation of Study 1 findings is that females with
CMDD had greater cortisol output vs. a heightened or sensitized cortisol response
during this challenge.
Time
AUCg Cortisol
AUCi
AUCB
Comparison of AUCg, AUCi and AUCB. Adapted from
Fekedulegn et al., 2007).
155
Response to Question 2:
Additional participants were recruited for Study 2 to increase the statistical power so
that moderating effects of personality on cortisol responses could be examined. Whether
the finding of sex differences in cortisol responses in those with CMDD as compared to
healthy controls in Study 1 was replicated in the larger sample was examined to ensure
the robustness of Study 1 findings.
A linear mixed model was conducted using The SAS System v.9.1.3 in order to
assess changes in cortisol associated with sex and group (CMDD vs. healthy controls)
over the course of the TSST in the larger sample. As with the initial model in Study 1, all
possible interactions between sex, condition, and time were included in the model. Model
diagnostics found that cortisol values for two subjects were unusually high and had an
undue influence on the estimation of model parameters. The cortisol value for one
participant at 60 minutes was replaced with a missing value and another participant was
excluded from the analysis altogether. Diagnostics for the model based on the reduced
sample found that that the underlying model assumptions were reasonably well met. The
results of this model are summarized in the following table:
Mixed model analysis results
Predictor F, df Statistical Significance
Time F=14.84, df=4,418 p<0.0001
Sex F=1.55, df=1,105 p=0.2165
Condition F=1.86, df=1,105 p=0.1754
Time*Gender F=2.45, df=4,418 p=0.0457
Time*Condition F=0.54, df=4,418 p=0.7053
Sex*Condition F=2.76, df=1,105 p=0.0993
Time*Sex*Condition F=1.99, df=4,418 p=0.0947
156
As shown in the above table, the results in the larger sample are consistent with those
in Study 1. There remained a significant main effect of time and the interaction between
sex and condition trends towards significance. It is important to note that in the larger
sample, the sex distribution between male CMDD participants (n= 22) and male controls
(n=28) was not evenly matched which might be one reason for the decreased level of
significance in the larger sample.
Taken as a whole, the pattern of results in the larger sample were consistent with those
in Study 1 which supports the finding that there are sex differences in cortisol responses
in CMDD participants as compared to healthy controls.
157
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