Final Paper - C Vannelli 0532292 - The Physiology of Stress in Depression and Anxiety

Running head: THE PHYSIOLOGY OF STRESS IN DEPRESSION AND ANXIETY
The Physiology of Stress in Depression and Anxiety:
Causes, Implications for Health, and Treatment
Christina Vannelli
Nipissing University
THE PHYSIOLOGY OF STRESS IN DEPRESSION AND ANXIETY 2
Abstract
This project investigates the physiology of stress in depressed and anxious adults. Sources of
stress are explored through dimensions of life stress. Sources of depression and anxiety are
reviewed in terms of biology (short allele for the serotonin transporter gene), and common traits
such as dysfunctional cognition, worry and rumination, self-conscious emotions or negative self-
view, neuroticism, and exaggerated threat perception. Physiological dysregulation was explored
in the immune, endocrine and neurological systems, with emphasis on the effects of stress in the
hippocampus. Lastly, contemporary pharmacological and alternative treatments that address
these aspects of dysregulation were reviewed. Findings among depressed and anxious groups
include high levels of interpersonal stress and health problems, dysregulation of cortisol, pro-
inflammatory cytokines, immunosuppression, and hippocampal atrophy. Treatments to
ameliorate both cognitive and physiological dysfunction are discussed. This paper emphasizes
consideration of biological and cognitive etiology of depression and anxiety in order to better
understand the physiology of stress in these disorders and their subtypes.

Acknowledgements
I would like to express gratitude to those who have provided me with support and
encouragement in completing this project. I am very appreciative for the guidance of my course
instructors, Anna-Liisa and Nancy. I have learned a great deal about integrity in research and the
value of a critical perspective. I will remember and strive for these qualities in all of my research
endeavors in the future.
I am tremendously indebted to my family and close friends K., P., and A. for their kind
words of support when I have been difficult or discouraged. Special thanks to my family for
providing me with the opportunity to attend school. I sincerely hope that I have and will
continue to make them proud.
I especially thank all of these individuals for their willingness and ardor to engage with
me in understanding of my research topic, which has in turn taught me a great deal about myself.
The Physiology of Stress in Depression and Anxiety: Causes, Implications for Health, and
Treatment
Foundations in the Study of Stress and Mental Health
Twenty four centuries ago, Hippocrates (460 BC 370 BC), known as the Father of
Medicine, established that sickness is not only suffering, or pathos, but also toil, or pnos that
is, the fight of the body to restore itself (Grammaticos & Diamantis, 2008). Cannon (1932), a
Harvard physiologist, named this ability homeostasis. For this process of homeostasis to occur,
the human body must maintain balance and communication between its highly complex systems
(Cannon, 1932). This is supported by the nervous system, the endocrine system, and the immune
system. When an individual experiences stress or tension physically or psychologically, the
brain and body must respond accordingly in order to survive. Lovallo and Thomas (2000)
emphasize that physical stressors have the direct ability to damage tissues, and psychological
stressors challenge homeostasis because of their perceived potential to cause harm. Both types
of stressors result in physiological and behavioural changes in order to maintain homeostasis.
Selye (1956) redefined the notion of stress into its modern physiological definition. In
his book The Stress of Life (1956), Selye discusses stress as the non-specific response of the
body (Selye, 1956, p. 74). As a medical student, Selye studied the development of cancer in
laboratory rats and it was during this time that he noticed the prominent triad of symptoms,
which he referred to as a syndrome: adrenocortical stimulation, thymicolymphomatic activity,
and intestinal ulcers (Selye, 1956). That is to say, he discovered that many of the rats had
swelling of the adrenal cortex above the kidneys, atrophy (or deterioration) in the thymus, and
duodenal and gastric ulcers. These symptoms occurred in the rats that were exposed to the
chronic stress of Selyes experiments chasing them around the room and repeatedly missing
injection sites; the rats injected by his more skilled colleague did not develop any of these three
symptoms.
The triad of symptoms in rats is also present in humans when exposed to chronic stress
through prolonged activation of the hypothalamic pituitary adrenocortical (HPA) axis and stress
response. While Selye was concerned primarily with physiological symptoms and consequences
of stress, Mason (1975), a Yale physiologist, expanded upon these ideas to account for the
powerful cognitive and emotive capacities of humans. Mason argued that HPA axis responses
and the stressfulness of a stimulus each result from cognitive and emotional reactions (Mason,
1975). According to Shiota and Kalat (2011), this can also be referred to as cognitive appraisal.
Furthermore, Mason contended that certain stimuli are more likely to produce HPA responses,
and individuals differ in their reactivity to such stimuli or events. Thus, physiological and
psychological responses to stress represent both a traditional learned stimulus-response pattern
and also individual differences in response (Lovallo & Thomas, 2000).
Anxiety and Depression
Differences in response to stress and the effects of stress are readily visible in those who
suffer from anxiety or depression. Individuals who suffer from one or both of these disorders
appear to demonstrate distinctive physiological and psychological changes and dysregulation in
their endocrine system, immune system, and neurochemistry. Stress can be measured through
physiological means, such as salivary cortisol, heart rate, blood pressure, pupil dilation, or
psychological means such as subjective thoughts and feelings (Lieberman, Kellogg, Kramer,
Bathalon, & Lesher, 2012; Qin, Hermans, Marle, & Fernandez, 2012).
Anxiety disorders present themselves in several different ways. This paper will examine
stress physiology in generalized anxiety disorder (GAD), panic disorder, post-traumatic stress
disorder (PTSD), and obsessive compulsive disorder (OCD). The prevalence of GAD rests at
approximately 5% of individuals over their lifetimes. Rosenberg and Kosslyn (2011) estimate
that in the United States, PTSD will occur in 8% of adults. Panic disorder is estimated to occur
in roughly 3% of people worldwide, with an estimated 30% of people experiencing at least one
panic attack in their lives. Similarly, social phobia is also projected at a 3% prevalence rate.
Regarding OCD, Rosenberg & Kosslyn (2011) estimate that 2 3% of Americans will develop
this disorder at some point in their lives.
Anxiety disorders have a tendency to be comorbid with a depressive disorder. Depressive
disorders discussed in this paper include major depressive disorder (MDD) and chronic
depression. According to Rosenberg and Kosslyn (2011), around 10 25% of females and 5
12% of males will develop MDD over their lifetime.
Comorbidity between depression and anxiety is extremely common, with about 50% of
those suffering from an anxiety disorder also suffering from depression (Rosenberg & Kosslyn,
2011). It is important to distinguish between each disorder and its subtypes, as they possess
physiological and cognitive traits that may be unique to each subtype. Furthermore, they may
also possess a unique physiological profile.
This paper shall discuss how biological and cognitive sources of stress, depression, and
anxiety contribute to dysregulation in the endocrine, immune, and neurology of individuals with
depressive and anxious disorders. Specifically, this paper shall first explore dimensions of life
stress in the independent, dependent, interpersonal, and non-interpersonal domains, and their
relationship with biological and cognitive sources of depression and anxiety. Next, this paper
shall address the dysregulation that occurs in the three main systems involved in the stress
response: the endocrine system, the immune system, and neurological structures of interest.
Third, this paper shall discuss contemporary pharmacological and alternative treatments for
depressive and anxious disorders, while focusing on addressing some of the problems that occur
in sources of stress, immune, endocrine, and neurological dysregulation. Finally, this paper shall
discuss implications of these findings for the health and treatment of those who suffer from
anxiety and depression.
Limitations
This paper shall examine scientific writings that draw samples from various populations
in terms of age, gender, ethnicity, and location. The focus of the paper is human physiology,
which draws from multidisciplinary sources relevant to people of all ages and ethnicities, such as
psychology, biology and genetics, chemistry, neuroscience, and the humanities. Therefore, it is
not within the scope of this paper to address major differences in gender, ethnicity, and age. This
paper focuses largely on the adult population.
Additionally, this paper seeks to explore the differences in the physiology of stress in the
specific populations of those who suffer from anxiety disorders, depression, or both. It is
important to note that these disorders are highly comorbid and not all scientific and clinical
studies distinguish between subtypes when measuring depressive and anxious symptoms.
Furthermore, depressive and anxious disorders often have overlapping symptoms. Also, it is not
within the scope of the paper to discuss all subtypes or other comorbidities (e.g. substance use),
and therefore there is a focus on social phobia, generalized anxiety disorder, post-traumatic stress
disorder, and major depression.
This paper shall examine the function and dysregulation that can occur in many different
biological systems within the human body, such as the endocrine system, immune system,
cardiovascular system, and nervous system, and their relationships to stress, depression, and
anxiety. This paper is limited in this way, as it would not be feasible to include all systems of the
body.
Furthermore, the author notes that there are many other biological markers that may
potentially play a major role in the physiological response to stress in depression and anxiety.
Human physiology and neurochemistry is both fascinating and complex. For instance, substance
P, brain-derived neurotrophic factor, tumor necrosis factors, endorphins, serotonin and other
neurotransmitters, growth and sexual hormones are only some of those factors which will not be
discussed in the interest of brevity. The structure of the paper shall follow the order of its three
research questions.
Research Questions
This paper seeks to address the following questions: What are biological, psychological,
and environmental sources of stress that contribute to anxiety and depression?; How do sufferers
of depression and anxiety experience endocrine, immune, and neurochemical dysregulation?; and
additionally, what are the treatments for depression and anxiety? These questions will be
explored by examining scientific readings in psychology, neuroscience, biology, and health. By
understanding the sources of stress, depression, and anxiety, one can gain insight into the
dysregulation that can occur within the body under these conditions. These findings will be
further evaluated under the final question regarding the treatment of these conditions. Efficacy
of treatments for anxiety disorders and depression will be reviewed from a physiological
perspective. How and why do these treatments work at the level of the endocrine, immune, and
nervous systems?
The study of stress reveals the complete integration of hormonal outflow with thoughts
and feelings, and makes this field of study ideal for psychological research. Adrenal secretions
are more than simply an output of the organisms interaction with the environment: it reflects
interconnections between metabolic regulation, emotions, and cognition (Lovallo & Thomas,
2000). One might even consider anxiety or depression a whole-body disorder as opposed to
solely a mental disorder, for stress can have profound effects on the body and the brain,
especially in vulnerable populations. Individuals suffering from anxiety or depression present an
interesting case of endocrine, immune, and neurochemical dysregulation that is exacerbated by
the effects of chronic stress.

Sources of Stress, Depression, and Anxiety
This section explores sources of stress, depression, and anxiety, as well as the
interconnection between these variables. Individuals with depression and anxiety share a
common genetic predisposition for the development of anxious and depressive disorders. Also
shared between these groups is the common personality/cognitive trait of neuroticism. They also
tend to develop maladaptive behaviours (i.e. cognitive appraisals of threat, or negative emotion-
focused coping style). Maladaptive behaviours and cognition discussed in this section are: the
tendency to perceive life events as threatening or having a high negative impact, self-conscious
emotions or negative view of self, and a tendency to worry or ruminate. Though individuals with
depression and anxiety do not necessarily experience more fateful life stressors, stress generation
theory suggests that cognitive style and other factors leave individuals with depression and/or
anxiety vulnerable to more interpersonal stress and health problems.
Sources of Stress
How do we define stress? Researchers have very different definitions of this term
especially in the context of chronic stress ranging from several weeks to enduring events with
an undetermined on or offset (Liu & Alloy, 2010, p. 585). There are many different sources of
stress with roots in interpersonal domains, family or home life, occupation, school or education.
Additionally, life stress can occur more suddenly in the form of a natural disaster, accident, or
physical/mental illness. Moreover, just as past depression [and anxiety] consistently has been
found to be a strong predictor of future depression [or anxiety], so may past stress, in like
manner, predict future stress (Liu & Alloy, 2010, p. 585). In order to gain a better
understanding of the physiology of stress, this paper shall explore how individuals with
depression and anxiety experience stress in different domains.

Dimensions of Life Stress. Research shows that major stressful life events can be used to
predict severity and onset of a depressive or anxious episode (Uliaszek et al., 2012, p. 4). This
theory of stress generation identifies four different dimensions of life stress as independent,
dependent, interpersonal, and non-interpersonal. Independent life stress occurs out of ones
control. Dependent life stress describes events that occur, at least in part, due to the individuals
actions. Interpersonal life stress manifests as difficulties with family, peers, or romantic partners.
Non-interpersonal stress describes occupational, educational, and health problems (Uliaszek et
al., 2012). A meta-analysis by Liu & Alloy (2010) in the Department of Psychology of Temple
University, Philadelphia, assessed the relationship between dimensions of life stress and
depression. This analysis found that depression was predictive of interpersonal stress, but was
not predictive of independent or fateful events (such as loss or accidents) that cause distress.
High levels of individual differences present challenges in measuring psychological and
emotional stress as not all people find the same events stressful. Hobson (1998) surveyed over
300 people on stressful life events in their past 12 months to determine which events were the
most stressful. A series of minor stressors did not necessarily represent more stress than one
major stressor. The most highly rated stressful life event was the death of a spouse/mate,
followed by the death of a close family member, and then injury or illness to oneself. Various
other stressors involved work, school, caring for dependents, etc. Many of these stressors
reported by participants followed the classification of independent-dependent, interpersonal-non-
interpersonal, which shall be further examined.
Independent. Independent life stress events (also called fateful events) are events
that occur out of the control of the individual (Uliaszek et al., 2012, p. 5). Individuals with
depression and anxiety do not necessarily experience more independent life stress than healthy
people or people with other disorders. However, certain independent life stress events can
facilitate the development of a depressive or anxious disorder. For example, interpersonal loss
events (e.g. death or separation) may be more strongly related to depression whereas
danger/threat events (e.g. accidents or assaults) may be more strongly linked to the development
of an anxiety disorder (Sandin, Chorot, Santed, & Valiente, 2004), a good example of which is
post-traumatic stress disorder.
Interpersonal events and dependent events seem to be more predictive of depression than
independent or fateful events (Liu & Alloy, 2010, p. 583). However, independent stressful life
events can contribute to the development of depression or anxiety. For example, early loss or
separation of a parent (Slavich, Monroe, & Gotlib, 2011, p. 1149), or low socioeconomic status
(Wang, Schmitz, & Dewa, 2010) may also contribute to depression. Assault (Creighton & Jones,
2012) and political strife and war (Almedom, 2004) may contribute to anxiety.
Dependent. These life stressors are, at least in part, a result of the individuals
own actions (Uliaszek et al, p. 5). Examples of this type of stressor include financial, marital, or
academic difficulties, though under different circumstances, they might be classified as
independent events. According to Liu & Alloy (2010), the stress generation model of depression
and anxiety dictates that depression and anxious prone individuals are not passively responding
to stressful life events, but are actively involved in the generation/creation of life stressors. In
other words, individuals who are predisposed to depression (whether it is due to cognitive or
genetic predisposition), when compared to individuals without this vulnerability, are more likely
to experience a higher rate of dependent life stressors. In particular, they are likely to experience
it interpersonally; these dependent events are partially influenced by maladaptive behaviours

(e.g. coping style) (Liu & Alloy, 2010, p. 583) which can overflow into the interpersonal
domain.
Interpersonal. Interpersonal stress in depression is characterized by negative
inferential style, the tendency to ruminate, higher self-criticism, hopelessness, neuroticism, and
maladaptive coping (Liu & Alloy, 2010). A history of depression tends to be related to higher
levels of interpersonal life stress (Uliaszek et al., 2012). This type of stressful event is defined as
difficulties with family, peers, or significant others (Uliaszek et al., p. 5). According to the stress
generation model (Uliaszek et al., 2012; Liu & Alloy, 2010), individuals with depression and
anxiety contribute to stressful events in their lives through their thoughts, feelings, and
behaviours. For instance, a tendency toward self-conscious emotions such as shame and guilt is
linked to the way an individual approaches social interactions. Shame-prone individuals tend to
have more problems with relationships, as they experience more hostility and social anxiety
(Shiota & Kalat, p. 262).
Research on self-conscious emotions has demonstrated that individuals who suffer from
depression and anxiety may be self-conscious and have low self-esteem (Sowislo & Orth, 2013).
Self-esteem has positive interpersonal value, fostering a sense of belonging, social support and
inclusion, and a sense of mastery and control (Sowislo & Orth, 2013, p. 215). Naturally, a sense
of low self-esteem might lead to feelings of depression, loneliness, anxiousness, and self-
consciousness. These feelings are likely to be exacerbated by the effects of both severe and non-
severe life stressors, especially if they are interpersonal. Individuals who feel confident
about themselves in social situations do not become embarrassed often, and handle their
embarrassment well when they do (Shiota and Kalat, 2011, p. 260). Those who are highly
neurotic experience more self-conscious emotions, such as anxiety, fear, guilt, self-disgust, and
shame (Penley & Tomaka, 2002, p. 1222).
It is interesting to consider these self-conscious emotions in the context of stress and the
activation of the sympathetic nervous system (also known as the fight-or-flight response).
Individuals with greater activity of their parasympathetic nervous system report more positive
affect in their daily lives (Shiota & Kalat, 2011, p. 107). Correspondingly, individuals with
greater activation in the sympathetic nervous system will experience more stress.
High levels of interpersonal stress in depression might be due to the style of interaction
with others. Interpersonal style in depression is fixated on negativity, higher self-criticism,
hopelessness, neuroticism, and maladaptive coping that is emotion-focused instead of problem-
focused (Liu & Alloy, 2010). Research in psychology and the health sciences is becoming
interested in the relationship between stress, depression or anxiety, and health or disease.
Non-Interpersonal. This type of stress refers to occupational, educational, and
health problems (Uliaszek et al., 2012. p. 5). The study of stress physiology is important
because anxiety and depressive disorders place individuals at a much greater risk for developing
an array of diseases and illnesses, which can be exacerbated by the immunosuppressive effects of
stress. Common medical conditions associated with anxiety and depression include Cushings
syndrome (Pereira, Tiemensma, & Romijn, 2010), cardiovascular illness (Kunert, 2011), acne
vulgaris (Atkan, Ozmen, & Sanli, 2000), migraine and headache (Wacogne et al., 2003;
Peroutka, Price, Wilhoit, & Jones, 1998), sleep disorders such as insomnia (Edinger et al., 2000),
periodontal conditions such as gingivitis (Johannsen, 2006), and chronic conditions such diabetes
type II (Ryan, Sheu, Critchley, & Gianaros, 2012).

Certain disorders may be related to problematic health behaviours. For example, a study
of individuals with post-traumatic stress disorder (PTSD) found that this condition is associated
with a higher incidence of poor health habits. PTSD was found to be associated with an 80%
higher chance of poor medication adherence (forgetting or skipping medications). It was also
found that PTSD was correlated with an increased likelihood of being a current or former
smoker, with a more extensive history of tobacco use. Lastly, PTSD with comorbid depression
was associated with low physical activity (Zen, Whooley, Zhao, & Cohen, 2012). Other research
shows that sufferers of PTSD have higher rates of substance abuse (Bremner, 2005).
Conclusion. Examining the sources of stress has shed light on how individuals cope with
problems. Certainly, there are individual differences in both perceptions of stressful life events
and also with coping style. Evidence indicates that those with depression and anxiety are not
more likely to experience independent life stress than other groups, but are experiencing higher
levels of stress in dependent, interpersonal, and non-interpersonal domains. Elevated levels of
dependent and interpersonal life stress in individuals with depression and anxiety seem to be
influenced by the symptoms of the disorders themselves. More specifically, perceiving events as
having very high negative impact, high levels of self-conscious emotions, or even poor health
behaviours may be contributing to dependent and interpersonal stress. Furthermore, the
physiology of these mental disorders is also implicated in non-interpersonal stress in the form of
many different diseases and conditions. There may be underlying factors, such as biology or
cognitive and social styles common to these disorders that foster an elevated level of overall
stress, which shall be addressed next.

Sources of Depression
This paper emphasizes the importance of considering biological and cognitive etiology of
depression and anxiety in order to better understand the physiology of stress in these disorders
and their subtypes.
Biological. The use of genetics in understanding depression or anxiety in the context of
stress becomes imperative as genetics contain information passed on to us from our parents that
provide a blueprint for how we will grow and develop (Bremner, 2005, p. 63). Evidence
suggests that there is a genetic influence in the development of depression. The risk of
depression is highest for individuals whose relatives became depressed early in life, especially
for those with depressed female relatives compared to those with depressed male relatives
(Shiota & Kalat, 2011, p. 338). Incidence of maternal depression tends to play a role in the
development of depressive disorders (Espejo et al., 2012; Liu & Alloy, 2010, p. 584). The
heritability of depression is not yet fully understood, though the mechanism by which this occurs
might be in the serotonin transporter gene; individuals with certain variations of this gene are
more likely to develop major depression after a stressful life event (Bukh, Bock, Vinberg,
Werger, Gether, & Kessing, 2009). The serotonin transporter gene (5-HTTLPR) is also
implicated in anxiety disorders and will be further elaborated upon later.
Cognitive and Social
Neuroticism. A trait commonly considered to be characteristic of neuroticism is
the tendency to react negatively to stressors (Espejo, Hammen, & Brennan, 2012, p. 304).
Individuals who score high on neuroticism on personality trait questionnaires tend to use
maladaptive means for coping with problems and have stronger negative reactions to stress.
Furthermore, they are more sensitive to social and interpersonal stress (Funder, 2010, p. 247).
Accordingly, the tendency to cognitively appraise life events as having an intense negative
impact is predictive of subsequent onset of both depressive and anxious disorders, even when
controlling for covariates like exposure to stressful life events, current symptoms of depression,
and the presence of other disorders. Additionally, depression that is comorbid with anxiety is
strongly associated with cognitive appraisals of high negative impact of stressors (Espejo et al.,
2012, p. 311). It seems that a feature of neuroticism, depression, and anxiety is a tendency to
react negatively to life stressors, and view these events as very threatening. Stressful life events
may not actually be threatening or realistic, but they seem to be psychologically distressing and
real.
Researchers Penley & Tomaka (2002) conducted an experimental study with 97 male and
female undergraduate students and the associations between neuroticism, cognitive appraisals,
and responses to the stress of a public speaking task. It was found that individuals who scored
high on measures of neuroticism experienced greater levels of self-conscious emotions (i.e. fear,
anxiety, guilt, and shame). These individuals also demonstrated a tendency to cognitively
appraise the public speaking task as a threat and not a challenge. Neuroticism was also
negatively associated with participants self-reports of coping and ability perceived performance,
even though it was uncorrelated with observers ratings of task performance. Neurotic subjects
reported that they coped or performed poorly, but these reports did not correspond to the actual
performance as rated by observers. Participants who displayed high levels of neuroticism also
reported use of emotion-focused strategies to cope with the stress of the task. That is, defensive
coping in the form of disengagement and denial, and emotional awareness/regulation in the form
of trying to control negative thoughts and feelings (Penley & Tomaka, 2002, p. 1222).
Overall, neuroticism is associated with depression and negative life outcomes (i.e.
interpersonal, family, and occupational difficulties) (Funder, 2010, p. 247). It is unfavourable, as
findings seem to indicate that the type of individuals to experience more interpersonal life stress
are the same individuals who are particularly sensitive to it. Likewise, they may also have a
tendency to ruminate about these events.
Rumination. Rumination, a type of thought pattern studied across a variety of
disorders, has been defined as maladaptive, repetitive negative thinking that is relatively
uncontrolled (McLaughlin & Nolen-Hoeksema, 2011, p. 186). It is a manner of responding to
stress in which an individual persistently thinks about his or her upsetting symptoms and the
consequences of those symptoms (McLaughlin & Nolen-Hoeksema, 2011; Hong, 2007). This
type of thought pattern is harmful because the individual fails to consider problem-solving that
might change his or her view or resolve the cause of distress. Furthermore, this type of thinking
can yield more depressed or anxious feelings, and is related to hopelessness and aggression
(Seldenrijk et al., 2013).
Rumination leads to more negative thinking, less effective generation of solutions to
problems, uncertainty or hesitation in the application of solutions to problems, less willingness to
engage in distracting or mood-lifting activities, less social support and more social conflict, and
being viewed less favorably by others (McLaughlin & Nolen-Hoeksema, 2011, p. 187).
Ruminators are less confident about their problem-solving skills, less eager to follow through
with their solution, and are more likely to give up or disengage from stressful life events (Hong,
2007). The act of rumination prolongs depressive moods by increasing pessimistic or negative
thoughts (e.g. self-criticism) and interferes with problem-solving (Hong, 2007, p. 279).
A study by McLaughlin & Nolen-Hoeksema (2011) sampled a group of adolescents aged
11-14 years and a group of adults aged 25-75 years on symptoms of anxiety or depression and
rumination on three occasions across a span of 7 months. Rumination was measured with
Response Style Questionnaires, which assess the extent to which an individual responds to
feelings of sadness with rumination. In this study, rumination was defined as self-focused
thoughts about the causes and consequences of depressive mood, and unwillingness to engage in
problem solving or mood-lifting activity. Sample items of self-focused responses are thinking
about a situation and wishing it had gone better, or why do I react this way? An example of a
symptom-focused item was I think about how hard it is to concentrate. Lastly, an example of
an item about thoughts on consequences of ones negative mood is I think I wont be able to do
my job if I dont snap out of this. It is important to understand the symptom of rumination
because it provides information on how and why individuals may become cognitively and
emotionally imprisoned by their depression.
Results of this study showed that rumination mediated the comorbidity of depression and
anxious symptoms in adolescents and adults over time, though the relationship was stronger for
adolescents (McLaughlin & Nolen-Hoeksema, 2011, p. 189). Implications of this study are that
rumination may be common to both anxiety and depression, especially in adolescent years.
Researchers noted that cognitive behavioural therapy might best address this problem, and
although this therapy does not necessarily target rumination, perhaps it should (McLaughlin &
Nolen-Hoeksema, 2011, p. 190).

In a similar study by Michl, McLaughlin, Shepard, & Nolen-Hoeksema (2013), a group
of adolescents and a group of adults were recruited to participate in a longitudinal investigation
on stressful life events, rumination, and coping style. Participants completed measures of self-
reported life stress and questionnaires to determine susceptibility to rumination. This study also
found that rumination was predictive of depression and anxiety. However, this study highlighted
the impact of negative life events insofar as they are often uncontrollable and chronic.
Researchers identified rumination as a mechanism behind stress and the onset of internalizing
psychopathology (i.e. depression and anxiety) (Michl et al., 2013, p. 340). Experiences of
interpersonal stress, especially social rejection, activate the brain region that is involved in self-
reflection and emotion regulation (Eisenberger, Lieberman, & Williams, 2003; Michl et al.,
2013). This particular brain region is called the anterior cingulate cortex, and will be discussed
under the next subheading, Anxiety and Threat Perception.
Conclusion. Depression appears to have some level of heritability, as evidenced by
research on the serotonin transporter gene and the role of maternal or female-relative depression.
This disorder presents a highly negative cognitive style, characterized by neuroticism and
rumination. Rumination is common to both depression and anxiety, but findings seem to indicate
that it is more characteristic to depressive disorders. Interpersonal stress seems to weigh heavily
on those who suffer from depression. Future research should attempt to clarify whether or not
specific types of life events are correlated respectively to depression versus anxiety (Espejo et
al., 2012, p. 312).
Sources of Anxiety
Biological. Differences in genetics and physiology contribute to the likelihood that an
individual may develop an anxiety disorder. The individual differences in genes, brain
chemistry, and subsequent behaviour may be consistent for years, decades, or a lifetime (Shiota
& Kalat, 2011, p. 172). For example, adults who display extreme shyness and nervousness as
children will exhibit stronger amygdala responses to photographs of faces, especially if they are
unfamiliar (Shiota & Kalat, 2011, p. 172). Individuals with social phobia show especially strong
amygdala responses to the sight of an angry or contemptuous face (Stein, Goldin, Sareen, Zorilla,
& Brown, 2002). The amygdala is implicated in emotional processing such as fear and panic
(Rosenberg & Kosslyn, 2011), and evidence seems to show that it plays a role in anxiety
disorders.
It is also possible that anxiety disorders are heritable to some degree; panic and phobic
disorders are more common among individuals who have relatives with similar disorders, which
suggest that there is a genetic influence (Shiota & Kalat, 2011, p. 172). Disorders themselves
may be heritable, or it may be that the propensity to have a certain brain chemistry is heritable.
Neurotransmission of serotonin varies among individuals with anxiety disorders. The
neurotransmitter serotonin is strongly associated with mood (Rosenberg & Kosslyn, 2011; Shiota
& Kalat, 2011). After a neuron releases serotonin to communicate with another neuron, it
attaches to the receptor, stimulates it, and then becomes detached, returning to the original
neuron. A protein on the membrane of the presynaptic neuron absorbs most of the serotonin,
recycling it to use again. This protein is called the serotonin transporter protein, and there is
much variation in the gene for this transporter in humans (Shiota & Kalat, 2011, p. 172). The
gene that controls for the serotonin transporter (5-HTTLPR) occurs in humans in two alleles: the
short allele (s), which leads to less production of the serotonin transporter; and the long allele (l),
which leads to greater production. The short allele for the 5-HTTLPR gene has been implicated
in the cause of depressive and anxious disorders alike (Zannas et al., 2013), though there seems
to be mixed results. The role of serotonin in the treatment of depression and anxiety is later
discussed in the final section on selective serotonin reuptake inhibitors (SSRIs).
Cognitive and Social. Biological sources of anxiety disorders are important in
understanding the development of this condition. However, it is equally important to consider
cognitive, social, and environmental factors.
Neuroticism. A meta-analysis by Kotov, Gamez, Schmidt, & Watson (2010)
reviewed 175 studies from the years 1980 to 2007 to explore whether or not personality traits
(i.e. the Big Five: neuroticism, extraversion, disinhibition, conscientiousness, and agreeableness)
were associated with depression or anxiety. It was found that both depressive and anxious
individuals scored high on neuroticism (Kotov et al., 2010). These findings are congruent with
other research that show neuroticism as an underlying factor in depression and anxiety (Uliaszek
et al., 2012; Funder, 2010; Penley & Tomaka, 2002)
A longitudinal study by Uliaszek et al. (2012) gathered data from 627 adolescents and
young adults to explore whether or not neuroticism and extraversion could account for stress
generation in anxious and depressive disorders. Participants completed a personality test and
structural clinical interview to determine incidence of neuroticism, major depressive disorder, or
anxiety subtypes. Next, chronic and episodic life stress was determined by the Life Stress
Interview, with the subscales of interpersonal (e.g. friendship, romantic relationships, family),
and non-interpersonal (e.g. school, work, finances, personal or family member health). Results
showed that neuroticism was risk factor for episodic and interpersonal life stress one year later
(Uliaszek et al., 2012). Researchers proposed that increases in stress over time may be related to
specific characteristics or behaviours of those high in neuroticism (Uliaszek et al., 2012).

Those who are high in neuroticism may experience self-conscious emotions (guilt,
shame, embarrassment). In the meta-analysis by Kotov et al. (2010), an unanticipated finding
was a strong association between low conscientiousness and internalizing conditions (i.e.
anxiety disorder). Individuals with generalized anxiety disorder, often viewed as an extreme
form of neuroticism, scored particularly low on personality measures of conscientiousness
(Kotov et al., 2010, p. 808). This personality trait is related to success, achievement, and drive
(Funder, 2010; Penley & Tomaka, 2002). Individuals who score low in the trait of
conscientiousness are susceptible to poor coping styles, which can contribute to the development
of disorder. Furthermore, negative self-perceptions common in internalizing behaviours may
have led to a low score in conscientiousness, as this personality trait involves self-efficacy and
goal striving. Researchers also noted that the association between low conscientiousness and
anxiety is not generally observed in the literature, and there is little conceptual framework for
interpreting this result (Kotov et al., 2010, p. 809). Due to the lack of available research on this
particular matter, it is difficult to make conclusions. However, one might reasonably presume
that anxiety, which by nature involves internalization and nervousness, is related to self-
conscious emotions, worry, and coping style, which shall be explored next.
Self-Conscious Emotions. Embarrassment, shame, and guilt arise when we have
done something morally wrong, hurt someone, or become the focus of peoples attention due to
an understandable mistake, an accident, or even a positive event (Shiota & Kalat, 2011, p.
256). Scores on questionnaires that evaluate subjective experiences of embarrassment are highly
correlated to scores on neuroticism questionnaires; neuroticism is characterized by a tendency
towards experiencing negative emotions such as fear, sadness, and embarrassment. Additionally,
embarrassment is also highly related to social anxiety, shyness, and loneliness (Shiota & Kalat, p.
260). Dysfunctional cognitions are thought to play a role in the development and maintenance of
depression, through negative views of oneself and ones life circumstances, and also to anxiety,
through an overestimation of danger/risk (Seldenrijk et al., 2013, p. 126).
Individuals with social phobia, a condition characterized by avoidance of people and
social situations, are particularly fearful of public embarrassment, and often misperceive or
overstate the frequency of embarrassing behaviours (Shiota & Kalat, 2011, p. 260).
Anxiety typically involves a high level of physiological arousal with rapid heartbeat,
shortness of breath, trembling, etc. These physiological sensations, accompanied by an
exaggerated sense of self-consciousness, might be mutually reinforcing sensing oneself as
having acted inappropriately, feeling embarrassment, guilt, or shame, and subsequently
experiencing physiological sensations of panic.
Social threats to the self tend to occur alongside self-conscious emotions (Denson,
Spanovic, & Miller, 2009, p. 828). Individuals who are self-conscious or have low self-esteem
tend to be very sensitive to criticism and social rejection (Sowislo & Orth, 2013, p. 216) and may
be prone to trait perfectionism. To investigate the relationship between perfectionism,
depression, and anxiety, 155 undergraduate students were recruited to complete questionnaires
on trait perfectionism, rumination, and measures of depressive and anxious symptoms.
Individuals who were high on self-presentation of perfectionism tended to have a highly negative
self-view, be socially anxious, and also report high levels of negative social feedback and
rumination following negative interpersonal events (Nepon, Flett, Hewitt, & Molnar, 2011, p.
297). It is possible the self-reported negative social feedback was not real, but perceived,
making it psychologically real. Social rejection (real or perceived) may trigger the onset of
depressive or anxious feelings. This may be the case among those with perfectionism (Nepon et
al., 2011, p. 298), which is prevalent among those with obsessive compulsive disorder (Clark &
Beck, 2010, p. 117).
It seems reasonable to conclude that individuals with depression and/or (but especially)
anxiety are prone to neuroticism, self-consciousness, and perfectionism. It seems to be that these
individuals have a cognitive style fixated on maintaining control of the self and situation,
demonstrated by a tendency toward negative self-view, self-conscious emotions and social
anxiety. Anxiety appears to be characterized by uneasiness and worry about oneself, ones
behaviours, and life stressors.
Worry. Symptoms of worry and rumination are very similar cognitive processes
that share the attribute of repetitive thought (Hong, 2007, p. 278). Worriers are able to produce
solutions to problems, and even engage in positive coping behaviours, but it seems they lack
confidence in their own solutions, or might procrastinate making a choice; worrying leads to
dissatisfaction with coping efforts (Hong, 2007, p. 279; Penley & Tomaka, 2002). Worrying
seems to be a way of maintaining control; something that anxious people tend to struggle with is
losing control (Gould & Edelstein, 2010). It becomes problematic because many stressful life
events are independent, and thus not controllable. Thinking about a stressor may be a way for
individuals to maintain control, albeit falsely. Changing ones cognitive appraisal or method of
coping is perhaps considered a way of letting it go, which is a choice that this type of individual
might be unwilling to make. The tendency of an anxious individual to require control and
predictability is appropriately referred to as intolerance of uncertainty (Clark & Beck, 2010, p.
117). Cognitive behavioural therapy might best address this problem. Without treatment,
however, anxious individuals will continue to think persistently about problems that may or may
not be realistic.
It makes sense to presume that worry is typically associated with anxiety about future
events and rumination tends to be related to depression over past events (Hong, 2007, p. 278);
however, it is important to note that depressed and anxious individuals alike can experience both
rumination and worry. A meta-analysis by Hong (2007) sought to challenge the assumptions that
worry correlates only to anxiety and rumination only to depressive disorders.
In his experiment, Hong (2007) recruited 248 undergraduate students (mean age 20 years
old) to assess the relationship between worry, rumination, symptoms of anxiety or depression,
and coping behaviour. Participants completed questionnaires to determine their tendency to
engage in worrisome and ruminative thoughts in two sessions, one month apart. During the
second session, participants completed the same questionnaire and then were asked to recall a
major stressful life event that occurred during the one month interval and discuss their coping
strategies for style and perceived effectiveness. To assess coping style, the COPE Scale
questionnaire was used, measuring three different subscales: problem solving, social support
seeking, and disengagement. Problem solving was defined by active planning. Social support
consisted of instrumental social support seeking, (e.g. I ask people who have had similar
experiences and what they did) and emotional support seeking (e.g. I talk about my feelings
with someone). Disengagement was described as behavioural or mental disengagement, with
items such as I admit to myself I cannot deal with it and quit trying, or I watch movies or TV
to think about it less.
Regression analyses were run to explore the dynamic relationships between worry,
rumination, depression or anxiety, and the three coping styles. Results showed worry correlated
uniquely with symptoms of both anxiety and depression, while rumination was correlated only
with depression (Hong, 2007, p. 285). Individuals who exhibited symptoms of anxiety were
more likely to demonstrate low levels of perceived coping effectiveness (Hong, 2007, p. 286).
Threat Perception. Research on emotion seems to direct attention towards
exaggerated threat perception in anxiety disorders. Anxious individuals may overestimate
situations as being threatening, frightening, or evocative of their specific anxiety state (Clark &
Beck, 2010, p. 77). Additionally, Clark & Beck (2010) contend that there are five criteria that
distinguish clinical anxiety from normal anxiousness: dysfunctional cognition in the form of
beliefs about threat and fear; impaired functioning in the form of effective and adaptive coping;
persistence, as anxiety prompts a future-oriented perspective that involves anticipation of threat
or danger (Clark & Beck, 2010, p. 7); false alarms in the form of fear and panic in situations
that may not call for it; and lastly, stimulus hypersensitivity, or general fear and phobia (Clark &
Beck, 2010, p. 7). Anxious individuals may be more likely to develop learned fears or phobias,
be more automatically evaluate stressors as threatening, and overestimate the proximity and
impending nature of such an event (Clark & Beck, 2010, p. 74). This cognitive error, also
called catastrophizing, is seen in both anxiety and depression, and the role it plays in the persist
activation of fear and stress is not fully understood (Clark & Beck, 2010, p. 75).
Furthermore, it is worth noting that anxiety is self-perpetuating (Clark & Beck, 2010, p.
40; Seldenrijk et al., 2013, p. 130). Attention is turned inward to both the physiological
sensations and of anxiety and the cognitive awareness of these thoughts and behaviours. This
heightened arousal may interfere with the individuals ability to complete a task and may
reinforce more feelings of anxiety (Clark & Beck, 2010, p. 40-41). The cognitive model of
anxiety demonstrates that internal and external cues can trigger an exaggerated perception of
threat. The types of situations that trigger anxiety often differ according to subtype, for example,
social situations are triggers for social phobia, memories of past trauma to PTSD, apprehension
to a stressful event in panic disorder (Clark & Beck, 2010, p. 42), and intrusive thoughts of dirt,
contamination, doubt, or injury to others in obsessive compulsive disorder (Clark & Beck, 2010,
p. 77). The excessive sensitivity to threat, fear, and stress in anxiety disorders has been attributed
to an overactivated amygdala (Britton et al., 2011; Shiota & Kalat, 2011; Deckersbach,
Dougherty, & Raunch, 2006).
Conclusion. In summary, some research shows that anxiety shares a common genetic
basis with depression of a short allele on the serotonin transporter gene, though more research is
needed to clarify this relationship. Evidence does seem to indicate a genetic predisposition to
develop anxiety disorders, such as panic disorder. This may be through the serotonin transporter
gene, an over-active amygdala, or through personality traits like neuroticism.
Personality traits, heritable or not (Funder, 2010), certainly play a role in the cognitive
and social sources of anxiety. From this perspective, neuroticism and a tendency toward self-
conscious emotions are seen as a source of interpersonal life stress. Lastly, worry, rumination,
and an exaggerated threat perception are other sources of stress in anxiety.
Discussion
This section has reviewed sources of stress, depression, and anxiety. Findings on sources
of stress, explored through dimensions of life stress, point to interpersonal, dependent, and non-
interpersonal (health) dimensions as presenting the greatest challenges for individuals with
depression and anxiety. These disorders are highly internalizing in nature.
After exploring biological and cognitive /social sources of depression and anxiety,
evidence for the theory of stress generation highlights the cognitive and social styles of
individuals with these disorders as major contributing factors to the interpersonal and dependent
stress domains, and consequently health problems in non-interpersonal domains.
Both depression and anxiety seem to present some degree of heritability, though it is not clear if
this is necessarily the case. More research is needed to identify genetic links between these
disorders.
Interestingly, despite the potential for sharing some genetic basis, each disorder seems to
present its own cognitive/social profile, though there certainly can be overlap of these traits from
one disorder and its subtypes into the other. For example, depression is largely characterized by
low affect, highly negative style, and rumination. Anxiety, on the other hand, presents higher
degrees of self-conscious emotions, worry, and exaggerated threat perception. Common to both
disorders are personality traits such as neuroticism and emotion-focused coping style, as opposed
to problem-focused. It is likely that the mechanisms of rumination and worry may play a role in
preventing the individual from generating problem-solving or mood-uplifting strategies to cope
with stress.
Dysregulation in Endocrine, Immune, and Neurological Systems
This section explores the dysregulation that occurs in the endocrine, immune, and
neurological systems in individuals suffering from depression and anxiety. First, the physiology
of the stress response is explored by the endocrine systems role in the activation of the
hypothalamic-pituitary-adrenal axis (HPA axis). Next, this section will discuss how this system
becomes over-activated in depressive and anxious disorders, leading to pronounced levels of
cortisol. Second, the negative effects of endocrine dysfunction that carry over to the immune
system are examined through research on immunosuppression and pro-inflammatory cytokines.
Lastly, damage/dysfunction that occurs in the neurological domain is shown through research on
hippocampal and white matter atrophy facilitated by pro-inflammatory cytokines. An important
theme in this section is negative spill-over effects; dysfunction that occurs in one system carries
over into the others.
Dysregulation in the Endocrine System
The functions of the autonomic nervous system depend on neurons that allow the brain to
communicate with specific organs (Shiota & Kalat, p. 88). The functions of various systems and
cells within the human body are controlled by hormones and proteins, which are chemicals
assembled by glands in one part of your body, and carried through the bloodstream to
communicate with organs in other areas (Shiota & Kalat, p. 88). This is the foundation of the
endocrine system, which becomes especially important during periods of stress, as it allows the
organism to survive. The endocrine system affects numerous physiological functions through
release and circulation of hormones, including metabolism and the stress response. For example,
epinephrine (adrenaline), norepinephrine (noradrenaline), and cortisol are the hormones involved
in the stress response.

HPA Axis. The stress response involves activation of a branch of the autonomic nervous
system, which is called the sympathetic nervous system. More specifically, the stress response
activates the hypothalamic-pituitary-adrenocortical axis, or the HPA axis. As implied by its
name, this axis involves the hypothalamus, pituitary gland, and adrenal cortex. The activation of
the HPA axis allows the body to respond to acute or prolonged stress. When an individual
encounters a stressor, the amygdala1 becomes activated and releases corticotropin-releasing
hormone (CRH) to the hypothalamus. CRH stimulates the pituitary gland to produce
adrenocorticotropin hormone (ACTH), which travels through the bloodstream where it reaches
the adrenal cortex by the kidneys. The adrenal cortex is responsible for the release of cortisol
(commonly known as the stress hormone), and the catecholamines epinephrine and
norepinephrine (known as adrenaline and noradrenaline) (Gunnar, Herrera, & Hostinar, 2009).
The attenuation of the stress response depends heavily on a negative feedback system in which
cortisol, after its release in the bloodstream, makes its way back to the brain through systemic
circulation (Lovallo & Thomas, 2000). In a manner of speaking, the negative feedback system
turns off the stress response by telling the brain to stop releasing CRH and ACTH, while
instructing the adrenal cortex to stop releasing cortisol. If any aspect of the HPA axis is
impaired, it becomes difficult for the brain and body to communicate, resulting in overproduction
of cortisol and catecholamines, which have potent effects on an individuals health (Qin et al.,
2012).
1
The amygdala is an important structure known to be associated with emotional responses, such
as the fight-or-flight response, vigilance, and fear (Gunnar, Herrera, & Hostinar, 2009; Bremner,
2005, p. 47).
Cortisol. Mainly, cortisol has two main functions: to suppress inflammatory and immune
responses; and to alter the metabolism of glucose, fat, and proteins (Kunert, 2011). This means
that cortisol serves to summon the bodys stored energy and suppress immune activity that is not
immediately necessary. Often, this is called the fight or flight response. Cortisol, a steroid
hormone, belongs to the family of glucocorticoids and has pronounced effects on the body.
Virtually every nucleated cell in the body contains receptors for cortisol. This hormone crosses
the cell membrane to combine with its receptors in the cytoplasm and then enters the cell
nucleus, where its primary action is to induce or inhibit expression of a wide range of regulatory
genes (Lovallo & Thomas, 2000, p. 343). For example, in the hypothalamus, CRH gene
expression is inhibited by cortisol, which allows the brain to mediate the rate at which the
pituitary gland releases ACTH pulses (Lovallo & Thomas, 2000, p. 345).
Interestingly, the pulses of ACTH that regulate the cortisol response operate during
wakefulness and sleep. In fact, humans display a distinct pattern of cortisol secretion with
specific peaks throughout a 24-hour period, which is largely influenced by circadian rhythms, or
the sleep-wake cycle. This diurnal (daily) pattern can be easily disrupted by sleep deprivation
and changes in sleep patterns (Lovallo & Thomas, 2000, p. 344), both of which are common in
depression and anxiety (Edinger et al., 2000). Cortisol peaks just before awakening, with a low
point in the evening and early morning, and shows additional rises during the day related to meal
times (Lovallo & Thomas, 2000, p. 344).

Dysfunction of cortisol secretion has been observed in individuals with anxiety and
depression. In an experiment by Yoon & Joorman (2012), participants with social anxiety
disorder demonstrated heightened cortisol reactivity, and participants with anxiety and comorbid
depression exhibited blunted or dampened cortisol response. In this experiment, participants
with anxiety, anxiety with comorbid depression, and controls completed affect ratings, providing
a saliva sample each time. Participants were informed they would be given five minutes to
prepare a five minute speech arguing for or against capital punishment. They were also informed
that the speech would be videotaped and subsequently rated by experts for clarity and quality.
Participants were given pencils and paper to prepare notes, though they were not permitted to use
the notes when delivering the speech. The experimenter left them to prepare their argument, and
returned after five minutes with a video camera on a tripod.
Repeated-measures ANOVA compared salivary cortisol levels in the three groups over
time. It was found that the socially anxious individuals had the highest salivary cortisol, and that
those with comorbid depression did not differ significantly from controls. When scores from the
socially anxious group and comorbid depression were combined in a separate ANOVA to create
one group, the interaction was no longer significant. Researchers noted that this indicates that
ignoring participants comorbidity status could have interfered with their ability to have found
that heightened cortisol reactivity was associated with social anxiety in the first place (Yoon &
Joorman, 2012).
An intriguing trait which is characteristic of social anxiety patients is an excessive fear of
situations in which one might be evaluated or observed by others. Socially anxious individuals
often avoid social situations for this reason (Yoon & Joorman, 2012). In a study of cortisol
secretion in anxiety subtypes, Vreeberg and colleagues (2010) assessed salivary cortisol seven
times throughout the day for nine days in the following subtypes: social phobia, panic disorder,
panic disorder with agoraphobia, and generalized anxiety disorder. These anxiety subtypes were
further divided into categories of comorbid depression. Researchers found that the participants
with panic disorder had the highest morning cortisol and it was even higher in panic disorder
with agoraphobia and comorbid depression. Morning cortisol was higher in this group than any
other anxiety subtype even when those subtypes had comorbid depression. Depression and
PTSD exhibit particularly low levels of cortisol (Vreeberg et al., 2010). In other studies, it was
found that the lower the levels of cortisol in depression and PTSD, the greater the impairment in
concentration and memory capacities (Bremner, 2005), which shall be discussed further.
Conclusion. Panic disorder seems to show high levels of morning cortisol. This is
interesting because it seems to reflect anticipatory stress that they experienced even before
waking. In terms of cortisol, depressed patients and PTSD patients tended to exhibit cortisol
secretion that was either the same as or less than controls. One researcher proposed that this is
because people with depression have a low amount of cortisol but sensitive receptors, and people
with anxiety have lots of cortisol but not very sensitive receptors (Kunert, 2011). Another study
by Vreeberg et al. (2009) found that morning salivary cortisol was high in individuals with
major depression, though only when it was comorbid with anxiety.
Dysregulation of the Immune System
The present section will explore the effects of immunosuppression which are brought on
by the endocrine system when the stress response becomes activated. Next, pro-inflammatory
cytokines and associated health risks are discussed.
Immunosuppression. Negative emotions such as feelings of anxiety and depression are
important risk factors in the development of illnesses with an inflammatory etiology, and
furthermore, inflammation itself may be an important mediator of emotion-disease relationships
(OConnor, OHalloran, & Shanahan., 2000, p. 1074). Cortisol is supposed to suppress
inflammation and the immune response of the body, but chronic inflammation caused by stress
keeps cortisol levels high, which severely impacts the immune system because it is
immunosuppressive in nature. Clinical and subclinical anxiety or depression can directly
influence immune dysregulation and may lead to maladaptive changes in the endocrine and
immune systems (Kiecolt-Glaser & Glaser, 2002). Furthermore, stress and symptoms of
depression and anxiety can influence changes in cellular responses. For instance, individuals
with depression will show alterations in response to the physical challenge of a vaccine (Kiecolt-
Glaser & Glaser, 2002). Even individuals who are healthy but under stress tend to produce
weaker immune responses (Cohen et al., 2012, p. 5996). As a consequence, immune responses
to pathogens are slowed, which places individuals with chronic stress and depression or anxiety
at a greater risk for more illnesses.
In an experiment by Cohen et al. (2012), 276 healthy male and female adults were
exposed to the common cold virus and were monitored for symptoms of infection or sickness.
The individuals who had experienced a prolonged stressful life event were more likely to
develop colds. The symptoms of the common cold, researchers note, are not caused by the virus
itself, but are instead side effects of the inflammatory response as the body fights the infection;
the greater the response, the more likely one is to experience cold symptoms. Researchers
concluded that the participants who experienced a stressful life event (e.g. occupational,
financial, relationships) had immune cells that were unresponsive to hormonal control through
cortisol, and subsequently, produced levels of inflammation that incited illness (p. 5996).
For individuals with depression and anxiety, stress seems to be experienced in a way that
is much more pronounced, and perhaps this is due to the fact that more events are perceived as
being stressful. For example, in healthy individuals, shopping for groceries is a normal task,
though for individuals with anxiety or depression, this can be extremely challenging. Individuals
who are anxious may not feel comfortable in crowded public spaces, and individuals with
depression may find this task exhausting. Cognitive biases, such as a bias towards threatening
information, or a bias towards negative affect, prolongs the activation of the HPA axis and stress
response.
According to Cohen et al. (2012), chronic psychological stress is a main contributor to
the bodys loss of ability to regulate the inflammatory response. As stated before, every
nucleated cell has receptors for cortisol, and immune cells fall into this category. When the HPA
axis is activated for a long period of time, the immune cells become over-saturated with cortisol
and no longer respond to its immunosuppressive effects. Thus, the body cannot regulate the
process of inflammation, which is likely the mechanism by which individuals with depression
and anxiety come to accumulate large amounts of pro-inflammatory cytokines and the risk of
diseases with inflammatory etiology.
Cohen et al. (2012) proposed that it is not necessarily the elevated levels of circulating
cortisol that place individuals at risk of disease, but more specifically the response of target
tissues to cortisol (p. 5995). However, these researchers also emphasize the role of stress
especially chronic stress in risk for development of disease.
Pro-Inflammatory Cytokines. Exaggerated and sustained threat perception may result
in chronic activation of the HPA axis, leading to increased inflammatory activity. Research
indicates that depression and anxiety may influence production of pro-inflammatory cytokines,
such as interleukin-6 (IL-6) (ODonovan et al., 2010).
A review of literature by Kiecolt-Glaser and Glaser (2002) of Ohio State College of
Medicine evaluated the function and dysregulation of pro-inflammatory cytokines, particularly
IL-6, in individuals with depression and anxiety. The purpose of inflammation in the immune
response is to attract immune cells to the site of infection or injury, and prime them to respond.
Immune cells, such as macrophages and microglia, communicate with each other by secreting
cytokines. In general, cytokines provide inter-cellular signals necessary for the function of the
immune system (Kiecolt-Glaser & Glaser, 2002).
In their review, Kiecolt-Glaser and Glaser (2002) discuss how cytokines have strong
effects on the central nervous system (CNS), including intensification of negative moods,
physical symptoms such as lethargy and fatigue, and a range of behaviours associated with
illness, such as loss of appetite. Curiously, not only do these symptoms resemble those of
depression, but depression enhances the production of IL-6, and following pharmaceutical
treatment of this disorder, elevated IL-6 levels also decline (Kiecolt-Glaser & Glaser, 2002). An
overproduction of pro-inflammatory cytokines can lead to malfunctioning in the immune system.
For example, IL-6, which is pro-inflammatory, is a powerful stimulator of the stress hormone
cortisol. Elevated cortisol can perpetuate and aggravate symptoms of depression, such as
anxiety, insomnia, and poor memory, as well as feelings of illness, because cortisol suppresses
the immune system. In this way, there is a bi-directional relationship: negative emotions that
dysregulate IL-6 secretion can also facilitate neuroendocrine changes (Kiecolt-Glaser & Glaser,
2002), and IL-6 is directly influenced by the bodys neural and hormonal responses to stress
(ODonovan et al., 2010, p. 1076).

IL-6 is an important factor in the development of cardiovascular disease (CVD) (Straub,
2011; Kiecolt-Glaser & Glaser, 2002). In the review of literature by Kiecolt-Glaser & Glaser
(2002), the relationship of IL-6 with CVD is partially due to the role of IL-6 in stimulating the
production of C-reactive protein (CRP), which is a risk factor for heart attack. The purpose of
CRP is to bind to the outside of dead or dying cells so that they can be disposed of by immune
cells (Straub, 2011); however, elevated levels of IL-6 and consequently CRP can be dangerous.
CRP is associated with the development and rupture of atheromatous plaques2, which places an
individual at risk of heart attack or stroke (Ridker & Silvertown, 2008, p. 1548). In addition to
CVD, inflammation is also linked to a variety of other conditions, including osteoporosis,
arthritis, type II diabetes, cancer, Alzheimers disease, and periodontal disease. It has been
suggested that chronic inflammation plays a major role in the decline of physical functions in
older adults which leads to frailty, disability, and death. Pro-inflammatory cytokines (such as IL-
6) may slow muscle repair and accelerate muscle atrophy, or wasting/deterioration (Kiecolt-
Glaser & Glaser, 2002).
Higher plasma IL-6 and CRP levels are associated with negative health behaviours such
as smoking, lower physical activity, and higher BMI. Individuals who experience a large amount
of stress are more likely to have health behaviours which place them at a greater risk for
developing illness. Some of these behaviours consist of poorer sleep, susceptibility to substance
abuse, poorer nutrition, and less exercise (Kiecolt-Glaser & Glaser, 2002; Straub, 2011). These
have cardiovascular, immunological, and endocrinological consequences (Kiecolt-Glaser &
Glaser, 2002) especially in individuals with clinical depression and/or anxiety.
A large number of studies have examined relationships of inflammation and depression,
while many questions remain unanswered about the link between inflammation and anxiety. It is
possible that anxiety may present an even stronger risk factor for inflammatory diseases than
depression (ODonovan et al., 2010, p. 1074). Anxiety and depression are highly comorbid with
one another, and anxiety appears to confer increased risk for CVD independent of a comorbid
depressive disorder (ODonovan et al., 2010, p. 1074).
2
Atheromatous plaques occur in atherombosis and atherosclerosis. These conditions,
characterized by fat and cholesterol deposits (plaques), and lesions or hardened arteries
(atherosclerosis) have harmful consequences for the heart and circulatory system. (For more
information see Straub 2011, and Ridker & Silvertown, 2008).
An experiment by ODonovan et al. (2010) explored the possibility that clinically
anxious participants would have higher levels of inflammatory markers (IL-6 and CRP)
compared to non-anxious participants, independent of comorbid depressive symptoms and
neuroticism. In this experiment, 56 male and female participants from Dublin, Ireland, provided
samples of blood and salivary cortisol and completed the Hospital Anxiety and Depression scale
(HADS). The HADS is a widely used and validated questionnaire that assesses 7 items for
anxiety and 7 items for depression. Compared to the non-anxious group, clinically anxious
participants did not differ in levels of CRP, had lower levels of cortisol, and significantly higher
levels of IL-6. Even after controlling for depression as a covariate, anxious participants
continued to exhibit higher levels of IL-6.
Results of both the review of literature by Kiecolt-Glaser and Glaser (2002) and the
experiment by ODonovan et al. (2010) suggest that depression and/or anxiety is related to
elevated levels of cytokines like IL-6 and cardiovascular illness. However, a difference between
these two pieces of research is that findings in the review of literature lean towards depressed
patients having the highest levels of IL-6, whereas the experiment demonstrates that anxious
patients have greater IL-6 in circulation. A major limitation of the review of literature is that the
authors did not necessarily reference studies in which depression and anxiety were understood as
covariates. This is a strong limitation as there is a very high rate of comorbidity between the two
disorders, and when they are not distinguished as two distinct conditions, results may be
reflecting the comorbidity and not one condition or the other. The experiment, however,
controlled for depression as a covariate, and found that anxious participants were displaying the
most strongly elevated IL-6 levels independent of depression.
Furthermore, as research seems to point to the link between IL-6 and CVD (Straub, 2011;
ODonovan et al., 2010; Kiecolt-Glaser & Glaser, 2002) and it is known that anxiety is more
strongly related to CVD than depression, one might conclude that it is anxiety, and arguably not
depression, that presents the greatest risk for elevated levels of IL-6. Anxiety is more closely
related to intense and sustained activation of the stress response and heightened HPA activity
which stimulates the release of interleukin-6. On the other hand, the role of inflammation in
anxiety has largely not been studied and more research is needed to clarify this association. At
present, these findings on cytokines such as IL-6 seem to indicate that individuals with
depression and anxiety experience dysregulation of the HPA axis and stress response.
Conclusion. The stress response is designed to be acute and short; when the stress
response is prolonged, it becomes immunosuppressive which has detrimental consequences for
the body, especially in individuals with depression or anxiety. The mechanism by which this
occurs seems to be through chronic activation of the HPA axis primarily the secretion of
cortisol which overwhelms immune cells, causing them to become unresponsive. The result is
a weaker immune response (immunosuppression), overabundance of glucocorticoids (cortisol)

and pro-inflammatory cytokines (IL-6, CRP), and excess inflammation. Individuals with
depression and anxiety exhibit an interesting physiological stress profile.
Dysregulation of Neurological System.
The hippocampus, the primary point of negative feedback regulation of cortisol during
both normal and pronounced stress, has more corticosteroid receptors than any other region
(Lovallo & Thomas, p. 345). This particular area of the brain, then, must endure the battering
effects of chronic stress as it is quite sensitive to cortisol. Moreover, because of its close
anatomical proximity to the amygdala (known for its role in emotional processing and fear
response), cortisol secretion is enhanced by input from the amygdala during periods of
psychological distress. The hippocampus is an extremely important area for memory and mood
(Straub, 2011; Rosenberg & Kosslyn, 2011; Shiota & Kalat, 2011). It is perhaps not
coincidental that the principal site for negative feedback regulation of glucocorticoid secretion is
the hippocampus. This suggests intimate connection between emotions, endocrine regulation,
and cognition. (Munck, Guyre, & Holbrook, 1984, p 348).
Hippocampal Volume. In depression, there is often an over-activation of microglia
which secrete pro-inflammatory cytokines such as tumor necrosis factor (TNF-) and
interleukin-6 (IL-6). This process interferes with neural progenitor cells (replace lost neural
cells) directly impeding neurogenesis of the hippocampus (Dowlati et al., 2009, p. 450). If
progenitor cells are distressed, the hippocampus will lose the ability to replace cells when they
are lost due to normal attrition and also due to stress. Past research has shown that stress may
affect hippocampal volume in a negative way, causing it to shrink. Animal studies often show
decreases in neurogenesis as well as accelerated apoptosis (cell death) in the hippocampus with
both acute and chronic stress (Lucassen et al., 2006, as cited by Zannas et al., 2013, p. 833).
Researchers at Duke University in North Carolina (Zannas et al., 2013) examined the
relationship between stress and hippocampal volume in older adults (65 years or more) with and
without depression, and whether or not there is a genetic basis for their findings on the 5-
HTTLPR gene for serotonin transportation. Participants in this study were homozygous for the
long allele (L/L), homozygous for the short allele (S/S), or heterozygous (L/S). The long allele
(L) has been discovered as the more active producer of serotonin transporter, and other research
seems to indicate that there is an imbalance in serotonin levels that may be related to depression.
In order to measure stress, participants completed the self-report Life Stress questionnaire, which
assessed a variety of stressful life events (or SLE) each item specifying whether events were
interpreted as negative, positive, or neutral. Severity of stress was also indicated on a 1-10 scale.
Some of the items on this questionnaire included illness and injury, marriage or divorce, family,
work, and finances. In order to measure hippocampal volume, a whole-body MRI system was
used, where images were processed to examine cerebral and ventricle volume in both brain
hemispheres. Genomic DNA for 5-HTTLPR alleles was extracted using a blood sample. These
assessments were performed once every three months for two years, with the exception of DNA
sequencing as this remains unchanged over time. Researchers found that greater nSLE (negative
life events) was a predictor of hippocampal volume. Furthermore, 5-HTTLPR genotype and
genotype-stress interaction was significant, but only for L/L homozygotes. The interaction
between genotype and changes in perceived stress over time was not significant for carriers of
the short allele, that is, S/S and L/S. As life stress increased, hippocampal volume decreased,
and as life stress decreased, hippocampal volume increased. This suggests that the phenomenon
of hippocampal atrophy in stress and depression might be reversible. Other research seems to
support this notion as well (OConnor, OHalloran, & Shanahan, 2000, p. 329).
The hippocampus is densely packed with white matter, some loss of this volume over
time is normal with aging but can become abnormal with acute stress (Bremner, 2005). White
matter of the brain appears white because of the myelin, the fatty, protective layer that envelops
neurons (Bremner, 2005, p. 43). New research seems to indicate that major depressive disorder
might be associated with an abnormal loss of myelin, especially in the frontal lobes of the brain
(Walther et al., 2012, p. 15, Tham et al., 2011, p. 27), and the process behind this loss will be
explored in the next section on oligodendrocytes.
Neurotransmission. The communication between brain cells depends largely on
myelination of neurons. Myelin consists of tightly compacted membranes that form an
insulating sheath around neurons (Saher, Quintes, & Nave, 2011, p. 79). Myelin, rich in
cholesterol and lipids (Saher, Quintes, & Nave, 2011, p. 80), contributes to efficient connectivity
and helps maintain both the structural and functional integrity of neurons (Saab, Tzvetanova, &
Nave, 2013, p. 1065). White matter in the brain is packed with glial (immune) cells like
microglia. It is also full of myelinated neurons, which give white matter its white appearance
(Tham et al., 2011).
Oligodendrocytes. There is new evidence that major depressive disorder involves a loss
of oligodendrocytes, which are glial cells that produce and envelop neurons with myelin (Tham
et al., 2011; Mosebach et al., 2013). Myelin is a waxy substance made of fats that speeds up the
process of neurotransmission, or the communication between brain cells (Saab, Tzvetanova, &
Nave, 2013, p. 1065). A common view in the study of psychology is that depression is a disorder
caused by low serotonin levels, but it is interesting to note that oligodendrocytes show high
levels of dopa decarboxylase, a serotonin synthetic enzyme (Barres, 2008, p. 436). This means
that a loss of oligodendrocytes would lead to not only a loss in myelination of neurons, but also a
loss of serotonin, as oligodendrocytes are involved in the synthesis/production of serotonin.
Furthermore, Barres (2008) notes that if the rate of new generation of oligodendrocytes is even
slightly lessened, for instance by stress, this could lead over time to substantial loss in myelin,
and if this is the case, that oligodendrocytes might be an important drug target (Barres, 2008, p.
436) because of their ability to restore myelin to neurons.
Recalling earlier discussion that microglia secrete pro-inflammatory cytokines such as
TNF-, it becomes important to consider that TNF- contributes to demyelination by interfering
with oligodendrocytes (Saab, Tzvetanova, & Nave, 2013, p. 1066; Barres, 2008, p. 436).
Elevated levels of TNF- in depression might be the mechanism by which loss of white matter
and demyelination in depression occurs (see Dowlati et al., 2009; Binder & Scharfman 2008).
TNF- is a cytokine, which means it is a secreted as a form of communication between cells. It
is called tumor necrosis factor because it is supposed to kill cells that are mutated, which could
cause cancer.
In depression, chronic activation of the HPA axis leads to a high level of cortisol. This
causes immune cells like microglia to become unresponsive to its commands to suppress
immune activity. In turn, microglia are secreting pro-inflammatory cytokines at a rate which
becomes harmful to the brain and body. This is directly observed in the demyelination and loss
of white matter seen in depression. Unfortunately, the available literature at present does not
seem to explore whether or not this is the case in anxiety disorders. Future studies should
explore this question. As such, it is appropriate to at least briefly discuss the implications of a
loss of myelin due to stress and depression.
It becomes curious that a common symptom of depression is psychomotor retardation
(Rosenberg & Kosslyn, 2011) which is defined as a slowing of thought and movement, with
difficulties carrying out normal/simple physical tasks. Recall that myelin (and white matter) is
important in speedy neurotransmission, and that depressed patients seem to show a loss of white
matter in their frontal lobes (Walther et al., 2012, p. 15; Tham et al., 2011, p. 27). A loss of white
matter may underlie cognitive impairment in processing speed, memory, and executive
functioning in major depressive disorder (Tham et al., 2011, p. 33). Deficits in white matter may
also be associated with more severe depressive symptoms and a lower quality of life (Tham et
al., 2011, p. 34).
Conclusion. This section has reviewed structural damage and dysregulation in
neurotransmission that is common in depression and anxiety, and the mechanisms behind which
they occur. Dysregulation of the neurological system is principally observed in loss of
hippocampal volume and white matter. The underlying mechanism behind this seems to be in
the negative spill-over effects of the dysfunction in the immune system. Mainly, this seems to be
due to overproduction of overactive immune cells (e.g. microglia) pro-inflammatory cytokines
IL-6, TNF-alpha, and the stress hormone cortisol. This hormone and these proteins are
contributing factors to the loss of oligodendrocytes, which myelinate neurons that comprise
white matter in the brain. A loss of white matter is known to lead to cognitive impairment, but
might also be involved in some of the problematic symptoms of depression (i.e. psychomotor
retardation) (see Walther et al., 2012). More research is needed on the subject of demyelination
in depressive disorders to clarify this relationship, and to explore whether or not it occurs in
anxious disorders as well.
Discussion
Findings of this section are that dysregulation is experienced in the endocrine system
through over-activation of the HPA axis in both anxiety and depression. This results in an
overproduction of glucocorticoids and catecholamines (stress hormones and adrenaline) (Qin et
al., 2012). Overproduction of cortisol is particularly pronounced in panic disorder, demonstrated
by high levels of morning cortisol. PTSD and major depression, however, exhibit particularly
low levels of cortisol. Notably, these two disorders share the common trait of difficulty
concentrating and poor memory. An interesting finding from this section is that the hippocampus
(implicated in memory) is an important structure in the negative feedback system of cortisol.
PTSD patients often have problems with concentration and memory. Furthermore, research
seems to indicate that high levels of cortisol in depression only become excessive if this disorder
is comorbid with anxiety. This makes sense because anxiety, characterized by exaggerated threat
perception, activates the stress response frequently and for a long time. Because the stress
response is considered designed to be quick and short, it suppresses the immune system, as this
system is generally not needed for immediate survival. Consequently, when the stress response
is chronically active, the immune system is chronically suppressed. Cortisol is supposed to work
through a negative feedback system to communicate with immune cells like macrophages and
microglia to stop the release of pro-inflammatory cytokines (IL-6, or TNF-). Unfortunately,
immune cells, overstimulated by cortisol, are no longer responsive to its demands to suppress the
immune system, causing dysfunction of the endocrine system to overflow into the immune
system.
Findings about dysregulation in the immune system are largely characterized by
immunosuppression and over-secretion of pro-inflammatory cytokines. In both depression and
anxiety, it seems as though the body has lost its ability to properly regulate its stress response.
Pro-inflammatory cytokines become excessive and increase inflammation, which places these
groups at risk of cardiovascular disease and many other conditions especially those with
anxiety. Health conditions with inflammatory etiology are especially risky for older adults, who,
if chronically stressed (or depressed/anxious), have likely accumulated a much greater amount of
damage because they have lived longer. Higher levels of pro-inflammatory cytokines such as IL-
6, CRP, and TNF- are damaging to the immune system, cardiovascular system, and neurological
structures like the hippocampus.
The literature seems to indicate that the hippocampus suffers the harshest consequences
of both acute and chronic stress, especially in depression and anxiety. Progenitor cells, tasked
with the replacement of dead neurons, and oligodendrocytes, targeted to protect them (through
myelination), are damaged or inhibited by cortisol and pro-inflammatory cytokines. This may be
what leads to a loss of white matter and hippocampal volume observed in depression and PTSD.
There also may be an underlying genetic influence, as there is a correlation between
hippocampal volume and the serotonin transporter gene 5-HTTLPR in depression. Loss of
hippocampal volume seems to be reversible, though, and this will be discussed in the following
section of treatment with SSRIs. Reversibility of damage makes it important to consider
oligodendrocytes as drug targets.

Treatment of Depression and Anxiety
Given the prevalence of anxiety and depression, it is important to study methods of
treatment and how they work. Mental illness can be treated pharmacologically (with
medication), individual therapy, or alternative methods. This section explores several different
medications for depression and anxiety, such as tricyclics, SSRIs, SNRIs, and anxiolytics,. Next,
alternative methods of treatment such as MDMA assisted psychotherapy, cognitive behavioural
therapy, and aerobic exercise will be presented. This paper places focus on how these treatments
will address some of the dysregulation in the endocrine, immune, and neurological systems as
previously mentioned. Lastly, this paper will discuss, in the context of stress and dysfunction of
systems, the importance of diagnosis and implications for treatment.
Pharmacological/Medical
Tricyclic. Tricyclic antidepressants work by inhibiting activity of pro-inflammatory
cytokines such as interleukin-6 (IL-6) (Hestad, Aukrust, Tonseth, & Reitan, 2009). This finding
is important because pro-inflammatory cytokines seem to influence the development of
depressive symptoms and have detrimental effects on mood (Dowlati et al., 2009, p. 450). A
relatively new development in development of tricyclic medications is a corticotropin-releasing
hormone receptor antagonist.
CRH1 Receptor Antagonists. At the Max Planck Institute of Psychiatry in Munich,
Germany, researchers Ising & Holsboer (2007) explored the hypothesis that CRH1 receptor
antagonists may be appropriate for the pharmaceutical treatment of depression and anxiety. This
question arose because preliminary research seems to indicate that corticotropin-releasing
hormone (CRH) levels are often elevated in acute depression, and CRH has a tendency to bind to
CRH1 receptors with a higher affinity (more frequently) than CRH2 receptors (Ising & Holsboer,
2007). As discussed in the previous section, CRH facilitates the release of adrenocorticotropin
hormone (ACTH), cortisol, and adrenaline (Gunnar, Herrera, & Hostinar, 2009). Therefore,
CRH1 receptor antagonists are considered prospective drug targets.
An antagonist drug is one that blocks or dampens the effects of neurotransmitters or
nerve receptors (Shiota & Kalat, 2011). Based on studies in mice, Ising & Holsboer (2007)
hypothesized that selective CRH receptor antagonists would reduce stress-induced anxiety
without interfering with the functioning of the HPA axis. It is important that the HPA axis is still
in working order, because it is necessary for survival (Selye, 1956; Gunnar, Herrera, & Hostinar,
2009). In clinical experiments by Ising & Holsboer (2007), the compounds used were not actual
drugs on the market, but are presently in development.
In Study 1, researchers administered the first test/clinical trial of NB-30775/RS121919
(also known as Compound 2). Twenty drug-free inpatients suffering from major depressive
disorder (MDD) were divided into either the low-dose condition or the high-dose condition
where they received medication for 30 days. Inpatients were closely monitored, having anxiety
or depression symptoms, and sleep electroencephalogram (EEG) assessments regularly. Results
showed that in the low-dose condition, half (5 out of 10) responded to treatment, and 3 out of 5
achieved remission. In the high dose, 8 out of 10 met criteria for a treatment response, 6 of
which were remitted. Depression symptoms dropped distinctly in both doses, with greater
effects shown in the high-dose condition. Furthermore, sleep EEG recordings showed increased
slow wave/deep sleep in both low- and high-dose patients before and after treatment with
Compound 2. REM density decreased in high-dose participants but not in the low-dose,
indicating a better-quality nights sleep (Ising & Holsboer, 2007).

This type of drug might appeal to the large portion of individuals with depression and
anxiety who are suffering from insomnia (Edinger et al., 2000). Furthermore, the blocking of
CRH circulation would also block, to some extent, the over-activation of the stress response
network.
SSRI. Selective serotonin reuptake inhibitors (SSRIs) are commonly used in the
treatment of depression and anxiety. Research seems to indicate that depression and anxiety
share the common trait of a short allele for the 5-HTTPLR serotonin transporter gene, leading to
less production of serotonin (Zannas et al., 2013). SSRI medication interferes with the reuptake
or recycling that would normally occur in the synapse of neurons. Mainly, SSRIs keep
serotonin in the synapse for a longer period of time, which increases stimulation of serotonin
receptors (Shiota & Kalat, 2012, p. 131). Furthermore, SSRIs have the potential to address some
of the dysregulation that occurs in the endocrine and immune systems, and neurological
structures like the hippocampus. The complex relationship between SSRIs and improvement in
neurogenesis will be discussed next.
It has been established that depression and anxiety are associated with immune
dysregulation through cognitive biases towards negative and threatening information. This
exaggerated threat perception or negative cognitive appraisal informs the brain that it should
activate the HPA axis, commencing the stress response. Chronic psychological stress leads to
chronic activation of this system and elevated cortisol levels. When cortisol is in circulation, one
of its primary functions is to suppress immune activity. However, with chronic and exaggerated
circulation of cortisol, immune cells such as microglia (that protect the brain and spinal cord)
become unresponsive and continue to release pro-inflammatory cytokines (to communicate and
promote inflammation). This is the proposed mechanism behind the overproduction of pro-
inflammatory cytokines such as IL-6 that is observed in depressive and anxious patients
(ODonovan et al., 2010). In depression, there is an over activation of microglia (Dowlati et al.,
2010, p. 450). This is problematic because there is not necessarily any actual infection or trauma
only psychological distress. Progenitor cells that maintain growth and development of neurons
(neurogenesis) in the hippocampus have IL-6 receptors that can be damaged through
overstimulation (Dowalti et al., 2009, p. 450). Hippocampal neurogenesis is important because,
as discussed in section 2, it seems that major depression and posttraumatic stress disorder are
associated with hippocampal atrophy which has potential negative repercussions for memory and
concentration. This is likely due to the fact that progenitor cells, damaged by the overstimulation
of IL-6, cannot grow and maintain neurons. The role of SSRI medication in neurogenesis is
through the up-regulation of brain-derived neurotrophic factor (BDNF) which promotes the
health of neurons in the hippocampus (Binder & Scharfman, 2008, p. 3). The role of SSRI
medication in improving dysregulation is through increasing serotonin (Shiota & Kalat, 2012, p.
131) while simultaneously attenuating IL-6 (Hestad et al., 2009).
Therefore, SSRI medications are able to address dysregulation and negative symptoms of
depression and/or anxiety through neurogenesis in the hippocampus and also by increasing the
amount of serotonin stimulation in the synapse during neurotransmission. Vermetten et al.
(2003) showed beneficial effects of SSRIs on hippocampal volume. After one year of
administering Paxil, an SSRI, researchers observed a 5% increase in hippocampal volume and a
20% increase in declarative memory function in PTSD patients.
SNRI. Selective norepinephrine (or noradrenaline) reuptake inhibitors (SNRIs) are
similar in function to SSRIs, in that, by definition, they reduce or inhibit reuptake of
norepinephrine in the synapse (Rosenberg & Kosslyn, 2011). In humans, norepinephrine

increases breathing, blood pressure, and subjective sensations of anxiety (Bremner, 2005, p. 87).
In general, this type of medication is provided to individuals who suffer from major depressive
disorder (Rosenberg & Kosslyn, 2011), likely because norepinephrine may underlie some of the
symptoms of anxiety.
Noradrenergic functioning is elevated in patients with posttraumatic stress disorder
(PTSD), and contributes to flashbacks, excessive arousal, hypervigilence, and increased startle
response (Bremner, 2005, p. 88). It has also been implicated in the development of substance
abuse, which tends to be prevalent among PTSD patients. Bremner (2005) noted that many of
his subjects who suffered PTSD also faced addiction to benzodiazepines, heroin, and alcohol.
Withdrawal from these types of drugs often worsened symptoms of PTSD because these drugs
act by decreasing activity of the norepinephrine neurons in the locus coeruleus. Furthermore,
Bremner (2005) highlighted that his patients felt these substances, especially heroine, reduced
symptoms of hyperarousal, startling, and intrusive memories. In addition, patients tended to
begin using these types of drugs after the onset of the disorder, and as PTSD symptoms
increased, so did drug abuse (Bremner, 2005, p. 85).
Generally, then, SNRIs are likely more ideal for those experiencing extremely low affect,
as in the case of major depressive disorder and least ideal for those who suffer from PTSD.
However, a new alternative for PTSD treatment has been proposed and will be discussed later.
Anxiolytics
The most common types of anxiolytics are known as benzodiazepines, such as diazepam
(Valium), chlordiazepoxide (Librium), and alprazolam (Xanax) (Shiota & Kalat, 2011, p. 171).
Anxiolytics function by facilitating the effectiveness of the neurotransmitter gamma-
aminobutyric acid (GABA), which is an inhibitory neurotransmitter that acts on the amygdala.
In doing so, these medications suppress fear and reduce anxiety. However, GABA is involved in
inhibition throughout the brain, and the effects of anxiolytics are not limited to acting on the
amygdala alone; a risk or side effect is drowsiness and memory impairment (Shiota & Kalat,
2011, p. 171).
Anxiolytics and benzodiazepines are likely best suited for anxiety disorders because of
their recognized ability to increase the efficacy of GABA and inhibit some of the fear that results
from over activation in the amygdala.
Alternative Treatments
Often, patients are unable or do not desire to take pharmacological medication, in which
case, it may be appropriate to suggest alternative methods of treatment.
MDMA supplemented psychotherapy. MDMA. 3,4-
methylenedioxymethamphetamine is also known as ecstasy. Cahart-Harris et al. (2013a) from
London, UK, hypothesize that MDMA would reduce subjects responses to negative memories.
These researchers believed that administration of MDMA would facilitate a positive emotional
bias to recollection of personal memories through increased serotonin functioning. Preliminary
work for this study supported the potential of MDMA as part of psychotherapy for the treatment
of posttraumatic stress disorder, but the mechanisms by which it would function are not yet fully
understood. This study used fMRI to examine autobiographical memory recollection in healthy
participants (aged 29.4 7.4) under the influence of MDMA. Participants were presented with
personalized autobiographical memory cues to evoke six of their favorite and six of their worst
memories after oral administration of either a placebo (100mg ascorbic acid) or 100 mg of
MDMA-hydrochloride. Subjective experiences were recorded on continuous scales.

The autobiographical memory cues referred to 12 separate, emotionally salient, personal
memories. Participants were instructed to write down brief cues for these memories (one
sentence or less) and to refer to specific life events rather than prolonged periods of time in their
lives; the researchers are interested in supporting MDMA as part of treatment for PTSD, which is
characterized by traumatic life events. The cues were encouraged to be highly personalized by
the participant and encrypted so that they could not be understood by others (e.g. Remember
X). This strategy was used to ensure that participants would not be afraid of social judgement.
Not all participants chose to encrypt their memories. Examples of some of the cues are
remember the waterfall (favorite), and remember being told my friend was dead (worst).
Participants were asked to lie still in the fMRI, close their eyes, and recall their memories as
vividly as possible after the memory cue. Additionally, participants gave subjective ratings
regarding vividness, and also for strength of positive or negative emotions felt for each of their
memories.
Participants reported intensification of their best memories, and similarly reported
experiencing their worst memories as less negative under MDMA. The attenuation of negative
affect during the recall of worst memories reflects a new positive-biased in the emotional
processing that is consistent with the researchers hypothesis of increased serotonergic
functioning caused by MDMA. Researchers observed reduced activation to worst memories in
the left anterior temporal pole. A significant positive correlation was also found between
temporal pole activity and ratings of negative emotions. The temporal pole is closely connected
with the amygdala, which is commonly known for its association with affective processing of
fear and anger. The findings of this study support the perception that the temporal pole is likely
involved in memory-evoked negative emotion.

A second study by Cahart-Harris et al. (2013b) investigated the mechanisms by which
MDMAs characteristic effects of euphoria and openness could be used in the treatment plan for
individuals with anxiety specifically PTSD. All participants were healthy adults (age 34 11
years) and were randomly assigned into placebo and treatment conditions. Participants
underwent fMRI imaging and also completed a 29-item questionnaire which measured the
subjective experience of MDMA. Some examples of items included are: I felt entirely normal,
the experience had a dreamlike quality, or my imagination was extremely vivid. The item I
felt amazing was most highly rated under the influence of MDMA, and likewise, I felt entirely
normal was the highest rated under placebo. Researchers were interested in the relationship
between subjective effects of MDMA and changes in cerebral blood flow.
Results of the fMRI showed decreased cerebral blood blow in the right hippocampus and
right amygdala. Furthermore, the greater the decrease in activity in the amygdalae and
hippocampi, the more intense the drugs effects were, as reflected by the participants responses
about their subjective experiences (Cahart-Harris et al., 2013b). This result is of particular
interest because MDMA is known for its serotonergic effects stimulating the release of
serotonin, dopamine, and norepinephrine all of which are implicated in positive mood
(Rosenberg & Kosslyn, 2011; Shiota & Kalat, 2011).
These results have interesting implications for psychotherapy for individuals with
posttraumatic stress disorder (PTSD), because the nature of the disorder is largely influenced by
the trauma they have experienced. Part of the difficulty of treatment for this disorder is that it
requires discussion, recollection or reliving of the traumatic event. However, if it were possible,
through administration of a small dose of MDMA, to evoke a reduction in negative feelings, it
may be easier for subjects to open up about their experiences. The pro-serotonergic effects of
MDMA distinguish it from other amphetamines, and it is often referred to as an empathogen
because it promotes social interaction, positive emotion, and openness (Cahart-Harris et al.,
2013a). The major limitations of these studies, however, are that participants were healthy
individuals (without PTSD), and the researchers did not look for dose-dependent effects by
dividing the participants into smaller or larger dosage conditions.
Aerobic Exercise. It is well known that exercise is beneficial for good health (Straub,
2011). Research is investigating the hypothesis that exercise might have special benefits for
those with depression and anxiety. The evidence is mixed on whether or not exercise actually
improves symptoms of depression and anxiety (Salmon, 2001). Typically, it seems that the anti-
depressant and anxiolytic effects of exercise are attributed to noradrenergic and opioid activity
within the body (Salmon, 2001, p. 49). Initially, it may seem counter-intuitive to increase
activity of noradrenaline, especially for individuals prone to depression, anxiety, and the negative
effects of stress. However, it has been proposed that individuals who suffer from depressive and
anxious disorders may suffer from a phenomenon called anxiety-sensitivity (Seldenrijk et al.,
2013; Broman-Fulks, Berman, Rabian, & Webster, 2004) which may be reduced through
physical exercise.
Anxiety-sensitivity refers to the degree to which an individual feels concerned about their
symptoms of anxiousness, that is, all of the cognitive and bodily sensations of anxiety
(Seldenrijk et al., 2013). Researchers Broman-Fulks and colleagues (2004) recruited 54 male
and female volunteers age 18 to 51 to participate in a study on aerobic exercise and anxiety-
sensitivity. In this experiment, volunteers with high levels of anxiety completed six 20-minute
aerobic treadmill exercises at either a high-intensity (running) or a low-intensity (walking) across
the span of two weeks. Self-ratings of anxiety-sensitivity, fear of physiological sensations

associated with anxiety, and generalized anxiety measures were taken pre- and post-treatment,
and again at the one week follow-up. Results of this study showed that both groups had reduced
scores of anxiety-sensitivity, with the largest effect sizes observed in the high-intensity group.
Additionally, only the group in high-intensity saw reductions in scores of fear of anxiety-related
bodily sensations (Broman-Fulks et al., 2004). These results are promising for the reduction of
anxiety and depressive symptoms, and furthermore, for health benefits that offset the tendency of
these groups to develop cardiovascular disease. Depression and especially anxiety are strongly
related to atherosclerosis and cardiovascular disease (Seldenrijk et al., 2013), the risk of which
can be reduced through exercise (Straub, 2011).
The rationale behind aerobic exercise as a form of treatment is that it may extinguish the
fear response and change how feelings of anxiety-sensitivity are interpreted (Broman-Fulks,
2004, p. 126). High-intensity exercise elicits many of the same bodily sensations that often
evoke anxiety or panic, such as increased breathing, heart rate, and perspiration. By eliciting
these symptoms in a healthy and safe way, aerobic exercise functions similarly to cognitive
behavioural therapy in changing the way an individual thinks and therefore feels.
Cognitive Behavioural Therapy. This type of therapy holds the objective of cognitive
restructuring (also called cognitive reappraisal), which refers to changing the emotional response
to how one thinks about an event or stimulus (Shiota & Kalat, 2011, p. 145). Cognitive
behavioural therapy has been shown to increase positive affect and lower negative affect,
increase life satisfaction, increase friendships and sharing of emotions with others, and lower
ones risk of developing depression (Gross & John, 2003). Cognitive restructuring does not
mean that one becomes optimistic necessarily, but rather becomes more realistic about their
thoughts and how they interact with others.

For example, as discussed earlier, individuals with depression and anxiety may be prone
to a negative view of self or self-conscious emotions. Instead of reacting to unpleasant
comments or interactions as finding evidence for the notion that people dont like me,
cognitive restructuring helps individuals learn to think Oh well, that person is just hard to
please, or is in a bad mood today, (Shiota & Kalat, 2011, p. 145). A form of cognitive
behavioural therapy, called acceptance-based behavioural therapy, targets similar specific
behaviours in generalized anxiety disorder. Acceptance-based therapy helps clients adopt an
expanded, compassionate, and centered awareness, as opposed to threat-focused, judgemental
stance (Hayes-Skelton, Roemer, & Orsillo, 2013, p. 762). This treatment option may also help
anxious individuals with issues of control, intolerance of uncertainty, and self-conscious
emotions, as per discussion in the previous section.
Cognitive behavioural and acceptance-based therapies may be an ideal technique of
helping improve self-esteem, reducing elevated threat perception, and decreasing rumination and
worry. What's more, it may also help reduce some of the high levels of interpersonal stress
experienced by those with depression or anxiety. These therapies can surely be tailored to fit the
unique cognitive profiles of disorders and their subtypes, or individual clients.
Conclusion. This section has discussed three contemporary methods of treatment for
depressive and anxious disorders. MDMA supplemented psychotherapy, aerobic exercise, and
cognitive behavioural therapy.
MDMA supplemented psychotherapy is aimed to treat individuals with posttraumatic
stress disorder. Unfortunately, research in this area is limited as it is a relatively new concept.
The concept of drug-assisting psychotherapy may also lay precedent for other types of
medications that may aid in psychotherapy sessions. Preliminary work with healthy patients
shows that it may be a potential drug target in the future, at least for patients who suffer from
posttraumatic stress disorder.
Unlike MDMA supplemented psychotherapy, which targets one specific subtype, aerobic
exercise presents many benefits for both depression and anxiety and all their subtypes. First,
exercise is a distraction from the sources of stress (e.g. independent, dependent, interpersonal,
non-interpersonal). Secondly, it improves overall health and would help reduce the risk of
cardiovascular disease (Straub, 2011), which these groups are particularly prone to. This is
important because, as discussed in the previous section, by nature of their physiological response
to stress, individuals with depression and anxiety are prone to diseases with inflammatory
etiology (OConnor, OHalloran, & Shanahan., 2000, p. 1074). Exercise reduces the risk of
developing these conditions (Straub, 2011). Additionally, exercise increases noradrenergic and
opioid activities, which act directly on an individuals physiological response to stressful events.
Physiological and cognitive responses to stressful events can be altered further through
treatment with cognitive behavioural or acceptance-based therapies that target the dysfunctional
cognition that occurs in depression and anxiety. These dysfunctional cognitions are worry,
exaggerated threat perception, self-conscious emotions and anxiety-sensitivity, rumination,
negative self-view and poor self-esteem. Reductions in maladaptive cognitions may also
improve interpersonal relationships. As previously discussed; interpersonal stress seems to be a
recurring problem among those with depression and anxiety. Dysfunctional cognitions are not
necessarily specific to subtype, and dynamic therapies that involve cognitive restructuring can be
personalized to fit the needs of each client. By restructuring the reaction to and appraisal of
events perceived as stressful, individuals can become freed of their symptoms of depression and
anxiety which have constrained them.

Discussion
By reviewing some examples of pharmacological and alternative treatments for
depression and anxiety, it becomes clear that treatment must be specialized for each individual,
because each disorder and its subtypes present different problems both physiologically and
psychologically/cognitively. For example, if a patient is exhibiting high levels of CRH, ACTH,
and cortisol, or have disrupted sleep, it may be appropriate to treat them with CRH receptor
antagonists. If they present particularly low levels of serotonin or have high levels of IL-6,
treatment with SSRIs may ameliorate their symptoms of anxiety, depression, and also may
improve memory and concentration through its ability to contribute to restoration of neurons in
the hippocampus. If a patient presents particularly low motivation, low affect, and symptoms of
major depressive disorder, treatment with SNRIs may be of interest. However, this draws
attention to the importance to distinguish comorbidities and subtype, as increasing noradrenergic
activity in patients with a subclinical PTSD may be counterproductive. Anxiolytics, such as
benzodiazepines, may not be ideal for PTSD patients either, as researchers noted high levels of
comorbid substance use in this subtype. Anxiolytics, which promote the efficacy of GABA, act
by suppressing amygdala activity, which, as discussed in previous sections, appears to be
overactive in anxious individuals.
Alternative treatments, such as MDMA supplemented psychotherapy may be ideal for
patients with PTSD. Research here is preliminary only, and requires more work on
understanding the serotonergic properties of MDMA, and whether or not it would be appropriate
for use in PTSD. Other alternative treatments, such as aerobic exercise, may be feasible because
it is relatively inexpensive, and there is a lot of research evidence that indicates it is good for
overall health (mental and physical). Additionally, aerobic exercise may be less exclusive, as it
seems to be beneficial to a broader range of anxious and depressed subtypes. Another therapy
that is highly inclusive is cognitive behavioural therapy, or acceptance-based behaviour therapy,
which offers patients a means of changing their thought patterns and subsequently, their feelings.
This type of therapy may be especially important in treating patients with mental disorder who
also experience high levels of stress because of the role of cognitive appraisal in the stress
response. That is, if an event or stimulus is no longer perceived as threatening (i.e. exaggerated
threat perception in anxiety), or having a high negative impact (i.e. hopeless in depression), it is
therefore less stressful to the individual.

Final Discussion
Our understanding of the physiology of stress is vastly improving over time. The Father
of Medicine, Hippocrates, was one of the first to formally document his thoughts on the
relationship between psychological and physiological distress (Grammaticos & Diamantis,
2008). Much later in time, Cannon (1932), Selye (1956), and Mason (1975), emphasized a more
clinical study of stress and physiology. Researchers such as Kalat & Shiota (2011) and Lovallo &
Thomas (2000) highlighted the importance of emotional and cognitive processing in the stress
response, that is, cognitive appraisal, and individual differences in response to stressors.
These differences make the study of stress physiology interesting in the context of mental
disorder. Certain individuals may experience, cognitively appraise and perceive stressful life
events differently. This paper has explored the physiology of stress in depression and anxiety
subtypes, focusing on major depressive disorder, generalized anxiety disorder (GAD), panic
disorder, posttraumatic stress disorder (PTSD), and others. It is important to note that many of
these conditions are highly comorbid and have similar or overlapping symptoms.
First, this paper has examined sources of stress, depression, and anxiety. By reviewing
dimensions of life stress, evidence points to interpersonal and non-interpersonal life stress as
major challenges for those with depression and anxiety (Uliaszek et al., 2012; Liu & Alloy,
2010). That is, difficulties in social relationships, and problems with ones health, respectively.
After exploring sources of depression and anxiety, research seems to indicate a biological/genetic
component (i.e. short alleles for the serotonin transporter gene). However, as evidence is mixed
on whether or not this is truly a cause, the first question what are sources of stress, depression,
and anxiety, is perhaps best answered in this paper by cognitive and social factors. The main
finding here is that elevated levels of interpersonal and health problems were perhaps due to the
symptoms of the conditions themselves. For example, high levels of negativity, negative self-
view, rumination, neuroticism and low conscientiousness, and other traits of depression may be
contributing factors to both social and health problems. Similarly, in anxiety, neuroticism, self-
conscious emotions, worry, and elevated threat perception may be important factors. It was also
interesting that symptoms of anxiety and depression are often overlapping but also self-
perpetuating.
This paper proposes these dysfunctional cognitions that occur in the mind will contribute
to dysregulation that occurs in the body. Specifically, findings indicate that structures involved in
the physiology of the stress response the immune, endocrine, and neurological systems are
negatively impacted by the effects of stress, depression, and anxiety.
In the endocrine system, it seems to be that depression and anxiety are associated with
overproduction of cortisol, especially in panic disorder. Depression and PTSD presented a unique
profile, in which cortisol levels were very low. Though, after conducting research on the
physiology of stress, it is highly suspect that cortisol levels were once high but the adrenal glands
have become exhausted. Cortisol seems to exert the most destructive effects (as opposed to the
catecholamines, epinephrine and norepinephrine). The available literature focused largely on
cortisol, and rightfully so, as it has strong immunosuppressive effects.
It has been discussed that cells of the immune system (e.g. macrophages and microglia),
which communicate via cyotkines (e.g. Interleukin-6, C-reactive protein, tumor necrosis factor)
are disrupted by surplus cortisol. It seems that these immune cells have become unresponsive
and continue to secrete pro-inflammatory cytokines to the extent that it becomes excessive,
which causes inflammation and contributes to the development of many health problems.
Primarily, cardiovascular illness seems to present a major risk to depressive and anxious patients.
The hippocampus, a neurological structure implicated in memory and in the stress
response, can become damaged by the harsh effects of cortisol especially in depression and
PTSD. Evidence indicated these groups also tend to present disturbances in memory and
concentration, and correspondingly, loss of white matter, especially in the hippocampus. On a
positive note, however, research on its etiology and treatment also highlight that these effects are
likely reversible, even in adulthood. Potential drug targets for neurogenesis in the hippocampus
are oligodendrocytes, serotonin, and brain-derived neurotrophic hormone. More research is
needed on whether or not these are possible.
Many treatments discussed in this paper, such as anxiolytics, selective serotonin reuptake
inhibitors, selective norepinephrine reuptake inhibitors, and tricyclics, are commonly known
medications for depression and anxiety that are generally effective in combatting some of the
dysregulation that occurs in depression and anxiety.
New treatments were also discussed, such as CRH1 receptor antagonists that attenuate the
stress response or MDMA which promotes openness. Additional treatments such as exercise and
cognitive behavioural therapy seem to present a more encompassing alternative, as these
therapies seem to be applicable to diverse depressive and anxious subtypes, and their
combinations.
Implications of these findings on physiology and cognition highlight the importance in
distinguishing between disorders and their subtypes. Furthermore, studying the physiology of
stress and systemic dysregulation in depression and anxiety should become important in the
diagnosis and etiology of these disorders. Each disorder and its subtype seems to present a
unique physiological profile, which has significant implications for treatment. Hypothetically,
clarifying and establishing the physiological profiles of disorders could supplement psychiatric
diagnosis, therefore making it more reliable. In other words, if mental disorders could be
identified by their physiological/biological markers (e.g. cortisol, lipids, hormones, etc.), these
measures could supplement psychiatric diagnosis conducted by interview or questionnaire.
Furthermore, by identifying the important physiological structures involved in stress, depression,
and anxiety, target treatments can be identified and made more effective to fit each profile. It
would also be optimistic to extend these implications to other mental disorders.
Major limitations in the research are heterogeneity in diagnoses of depression and
anxiety. Many studies did not distinguish between subtypes, which makes it challenging to
disentangle depression from anxiety as many symptoms are overlapping. However, the three
research questions have been, for the most part, answered, though many questions remain about
the specific physiology of stress on a micro level.
The main finding of this paper is that stress seems to exert its effects in a cumulative
manner on many of the bodys systems, and is largely exacerbated by stress and anxiety, which
underlines the importance of treatment intervention and prevention.

References
Aktan, S., Ozmen, E., & Sanli, B. (2000). Anxiety, depression, and nature of acne vulgaris in
adolescents. International journal of dermatology, 39(1), 354-357. doi:10.1046/j.1365-
4362.2000.00907.x.
Almedom, A. M. (2004). Factors that mitigate war-induced anxiety and mental distress. Journal
of Biosocial Science, 36(4). doi:10.1017/S0021932004006637
Barres, B. A. (2008). The mystery and magic and glia: A perspective on their roles in health and
disease. Neuron, 60(3), 430-440. doi:10.1016/j.neuron.2008.10.013
Binder, D. K., & Scharfman, H. E. (2008). Brain-derived neurotrophic factor. Growth Factors,
22(3), 123-131. doi:10.1080/08977190410001723308
Bremner, J. D. (2005). Does stress damage the brain? Understanding trauma-related disorders
from a mind-body perspective. New York, NY: W. W. Norton & Company, Inc.
Britton, J. C., Lissek, S., Grillon, C., Norcross, M. A., & Pine, D. S. (2010). Depression and
Anxiety, 28(1), 5-17. doi:10.1002/da.20733
Broman-Fulks, J. J., Berman, M. E., Rabian, B. A., & Webster, M. J. (2004). Effects of aerobic
exercise on anxiety-sensitivity. Behaviour Research and Therapy, 42, 125-136.
doi:10.1016/S0005-7967(03)00103-7
Bukh, D., Bock, C., Vinberg, M., Werge, T., Gether, U., & Videl-Kessing, L. (2009). Interaction
between genetic polymorphisms and stressful life events in first episode depression.
Journal of Affective Disorders, 119(1-3), 107-115. doi:10.1016/j.jad.2009.02.023
Cannon, W. B. (1932). The wisdom of the body. New York, New York: W. W. Norton &
Company Inc.
Cahart-Harris, R. L., Wall, M. B., Erritzoe, D., Kaelen, M., Ferguson, B., De Meer, I., Tanner,
M., . . . Nutt, D. J.(2013). The effect of acutely administered MDMA on subjective
BOLD-fMRI responses to favourite and worst autobiographical memories. International
Journal of Neuropsychopharmacology. Advance online publication.
doi:10.1017/S14611457130011405
Cahart-Harris, R. L., Murphy, K., Leech, R., Erritzoe, D., Wall, M. B., Ferguson, B., Williams,
L. T., . . . Nutt, D. J. (2013). The effects of acutely administered 3,4
Methylenedioxymethamphetamine with arterial spin labelling and blood oxygen level
dependent resting-state functional connectivity. Biological Psychiatry. Advance online
publication. doi:10.1016/j.biopsych.2013.12.015
Clark, D. A. & Beck, A. T. (2010). Cognitive therapy of anxiety disorders: Science and practice.
New York, NY: The Guilford Press.
Cohen, S., Janicki-Deverts, D., Doyle, W. J., Miller, G. E., Frank, E., Rabin, B. S., & Turner, R.
B. (2012). Chronic stress, glucocorticoid receptor resistance, inflammation, and disease
risk. PNAS, 109(16), 5995-5999. doi:10.1073/pnas.1118355109
Creighton, C. D. & Jones, A. C. (2012). Psychological profiles of adult sexual assault victims.
Journal of Forensic and Legal Medicine, 19(1), 35-39. doi:10.1016/j.jflm.2011.10.007
Deckersbach, T., Dougherty, D. D., & Raunch, S. L. (2006). Functional imaging of mood and
anxiety disorders. Journal of Neuroimaging, 16(1), 1-10.
doi:10.1177/1051228405001474
Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E. K., Lanctt, K. L.
(2009). A meta-analysis of cytokines in major depression. Biological Psychiatry, 67(5),
446-457. doi:10.1016/j.biopsych.2009.09.033
Edinger, J. D., Fins, A. I., Glenn, D. M., Sullivan, R. J., Bastian, L. A., Marsh, G. R., . . . Vasilas,
D. (2000). Insomnia and the eye of the beholder: Are there clinical markers of objective
sleep disturbances among adults with and without insomnia complaints?. Journal of
Consulting and Clinical Psychology, 68(4), 586-593. doi:10.1037/0022-006X.68.4.586.
Eisenberger, N. I., Lieberman, M. D., & Williams, K. D. (2003). Does rejection hurt? An fMRI
study of social exclusion. Science, 302, 290-292. doi:10.1126/science.1089134
Espejo, E. P., Hammen, C., & Brennan, P. A. (2012). Elevated appraisals of the negative impact
of naturally occurring life events: A risk factor for depressive and anxiety disorders.
Journal of Abnormal Child Psychology, 40(2), 303-315. doi:10.1007/s10802-011-9552-0
Funder, D. C. (2010). The personality puzzle (5th ed). New York, NY: W. W. Norton &
Company.
Gould, C. E. & Edelstein, B. A. Worry, emotion control, and anxiety control in older and young
adults. Journal of Anxiety Disorders, 24(7), 759-766. doi:10.1016/j.janxdis.2010.05.009
Grammaticos, P. C., & Diamantis, A. (2008). Useful known and unknown views of the father of
modern medicine, Hippocrates and his teacher Democritus. Hellenic Society of Nuclear
Medicine, 11(1), 2-4. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18392218
Gross, J. J. & John, O. P. (2003). Individual differences in two emotion regulation processes:
Implications for affect, relationships, and well-being. Journal of Personality and Social
Psychology, 85(2), 348-362. doi:10.1037/0022-3514.85.2.348
Gunnar, M. R., Herrera, A., & Hostinar, C. E. (2009). Stress and early brain development. In:
Tremblay, R. E., Barr, R. G., Peters, R., Boivin, M. (Eds). Encyclopedia on early
childhood development. Montreal, Quebec, Centre of Excellence for Early Childhood

Development, 1-8. Retrieved from http://www.ccl-
cca.ca/pdfs/ECLKC/encyclopedia/Enc09_Gunnar-Herrera-Hostinar_brain_en.pdf
Hayes-Skelton, S. A., Roemer, L., & Orisillo, S. M. (2013). A randomized clinical trial
comparing an acceptance-based behavior therapy to applied relaxation for generalized
anxiety disorder. Journal of Consulting and Clinical Psychology, 81(5), 761-773.
doi:10.10137/a0032871
Hestad, K. A., Aukrust, P., Tonseth, S., & Reitan, S. K. (2009). Depression has a strong
relationship to alterations in the immune, endocrine, and neural system. Current
Psychiatry Reviews, 5(4), 287-297. doi:10.2174/157340009789542105
Hong, R. Y. (2007). Worry and rumination: Differential associations with anxious and
depressive symptoms and coping behaviour. Behaviour and Research Therapy, 45(2),
277-290. doi:10.1016/j.brat.2006.03.006
Ising, M., & Holsboer, F. (2007). CRH receptor antagonists for the treatment of depression and
anxiety. Experimental and clinical psychopharmacology. 15(6), 519-528.
doi:10.1037/1064-1297.15.6.519
Johannsen, A. (2006). Anxiety, exhaustion and depression in relation to periodontal diseases
(Doctoral dissertation, Karolinska Institutet). Retrieved from
http://publications.ki.se/xmlui/handle/10616/38188
Kotov, R., Gamez, W., Schmidt, F., & Watson, D. (2010). Linking big personality traits to
anxiety, depressive, and substance use disorders: A meta-analysis. Psychological Bulletin,
136(5), 768-821. doi:10.1037/a0020327

Kunert, M. P. (2011). Stress and adaptation. In Porth, C. (Ed.), Essentials of pathophysiology:
Concepts of altered health states, 3rd ed. Philadelphia, PA: Lippincott Williams &
Wilkins, pp. 209-220.
Qin, S., Hermans, E.J., van Marle, H.J., & Fernandez, G. (2012). Understanding low reliability
of memories for neutral information encoded under stress: Alterations in memory-related
activation in the hippocampus and midbrain. Journal of Neuroscience. 32(12), 4032-
4041. doi:10.1523/JNEUROSCI.3101-11.2012
Lenze, E.J., Rogers, J. C., Martire, L. M., Mulsant, B. H., Rollman, B. L., Dew, . . . Reynolds, C.
F. (2001). The association of late-life depression and anxiety with physical disability: A
review of literature and prospectus for future research. American Journal of Geriatric
Psychiatry, 9(2), 113-135.
Lieberman, H. R., Kellogg, M. D., Kramer, M. F., Bathalon, G. P. & Lesher, L. L. (2012). Lipid
and other plasma markers are associated with anxiety, depression, and fatigue. Health
Psychology, 31(2), 210-216. doi: 10.1037/ac0026499
Liu, R. T. & Alloy, L. B. (2010). Stress generation in depression: A systematic review of the
empirical literature and recommendations for future study. Clinical Psychology, 30(5),
582-593. doi:10.1016/j.cpr.2010.04.010
Lovallo, W. R., & Thomas, T. L. (2000). Stress hormones in psychophysiological research:
Emotional, behavioral, and cognitive implications. In Cacioppo, J. T., Tassinary, L. S. &
Berntson, G. G. (Eds.), Handbook of Psychophysiology (pp. 342-367). Cambridge:
Cambridge University Press.
Mason, J. W. (1975). A historical view of the stress field. Journal of Human Srress, 1(1), 6-12.
doi:10.1080/0097840X.1975.9940405
McLaughlin, K. A. & Nolen-Hoeksema, S. (2011). Rumination as a transdiagnostic factor in
depression and anxiety. Behaviour Research and Therapy, 49(3), 186-193.
doi:10.1016/j.brat.2010.12.006
Mosebach, J., Keilhoff, G., Gos, T., Schiltz, K., Schoeneck, L, Dobrowolny, H., . . . Steiner, J.
(2013). Increased nuclear Olig1-expression in the pregenual anterior cingulate white
matter of patients with major depression: A regenerative attempt to compensate
oligodendrocyte loss? Journal of Psychiatric Research, 47(8), 1069-1079.
doi:10.1016/j.jpsychires.2013.03.018
Munck, A., Guyre, P. M., & Holbrook, N. J. (1984). Physiological functions of glucocorticoids
in stress and their relationship to pharmacological actions. Endocrine Reviews, 5(1),
19841. doi:http://dx.doi.org/10.1210/edrv-5-1-25
Nepon, T., Flett, G. L., Hewitt, P. L., & Molnar, D. S. (2011). Perfectionism, negative social
feedback, and interpersonal rumination in depression and social anxiety. Canadian
Journal of Behavioural Science, 43(4), 297-308. doi:10.1037/a0025032
OConnor, T. M., OHalloran, D. J., & Shanahan, F. (2000). The stress response and the
hypothalamic-pituitary-adrenal axis: From molecule to melancholia. QJM, 93(6), 323-
333. doi:10.1093/qjmed/93.6.323
ODonovan, A., Hughes, B. M., Slavich, G. M., Lynch, L., Cronin, M. T., OFarrelly, C., &
Malone, K. M. (2010). Clinical anxiety, cortisol and interleukin-6: Evidence for
specificity in emotion-biology relationships. Brain, Behavior, and Immunity, 24(7), 1074-
1077. doi:10.1016/j.bbi.2010.03.003
Penley, J. A. & Tomaka, J. (2002). Associations among the Big Five, emotional responses, and
coping with acute stress. Personality and Individual Differences, 32, 1215-1288.
Pereira, A. M., Tiemensma, J., & Romijn, J. A. (2010). Neuropsychiatric disorders in cushings
syndrome. Neuroendocrinology, 92(1), 65-70. doi:10.1159/000314317.
Peroutka, S. J., Price, S. C., Wilhoit, T. L., & Jones, K. W. (1998) Comorbid migraine with aura,
anxiety, and depression is associated with dopamine D2 receptor (DRD2) ncoi alleles.
Molecular Medicine, 4(1), 14-21. doi:10.1007/s10048-009-0176-2.
Publication Manual of the American Psychological Association (6th ed.) (2010). Washington,
DC: American Psychological Association.
Ridker, P. M., & Silvertown, J. D. (2008). Inflammation, C-reactive protein, and
atherothrombosis. Journal of Periodontology, 79(8), 1544-1551.
doi:10.1902/jop.2008.080249
Rosenberg, R. S., Kosslyn, S. M. (2011). Abnormal psychology. New York, NY: Worth
Publishers.
Ryan, J. P., Sheu, L. K., Critchley, H. D., & Gianaros, P. J. (2012). A neural circuitry linking
insulin resistance to depressed mood. Psychosomatic Medicine, 74(5), 476-482.
doi:10.1097/PSY.0b013e31824d0865.
Saab, A. S., Tzvetanova, I. D., & Nave, K. A. (2013). The role of myelin and oligodendrocytes
in axonal energy metabolism. Current Opinion in Neurobiology, 23(6), 1065-1072.
doi:10.1016/j.conb.2013.09.008
Saher, G., Quintes, S., & Nave, K. A. (2011). Cholesterol: A novel regulatory role in myelin
formation. The Neuroscientist, 17(1), 79-93. doi:10.1177/1073858410373835
Salmon, P. (2001). Effects of physical exercise on anxiety, depression, and sensitivity to stress:
A unifying theory. Clinical Psychology Review, 21(1), 33-61. doi:10.1016/S0272-
7358(99)00032-X
Sandin, B., Chorot, P., Santed, M. A., & Valiente, R. M. (2004). Differences in negative life
events between patients with anxiety disorders, depression and hypochondriasis. Anxiety,
Stress & Coping: An International Journal, 17(1), 37-47.
Seldenrijk, A., van Hout, H. P., van Marwijk, H. W., de Groot, E., Rustemeijer, C., . . . Penninx,
W. J. (2013). Sensitivity to depression or anxiety and subclinical cardiovascular disease.
Journal of Affective Disorders, 146, 126-131. doi:10.1016/j.2012.06.026
Selye, H. (1956). The stress of life. New York, New York: McGraw-Hill Book Company.
doi:10.1080/10615800310001637134
Shiota, M. N., & Kalat, J. W. (2011). Emotion (2nd ed.). Belmont, CA: Wadsworth Cengage
Learning.
Slavich, G. M., Monroe, S. M., & Gotlib, I. H. (2011). Early parental loss and depression history:
Associations with recent life stress in major depressive disorder. Journal of Psychiatric
Research, 45(9), 1146-1152. doi:10.1016/j.jpsychires.2011.03.004
Sowislo, J. F. & Orth, U. (2013). Does low self-esteem predict depression and anxiety? A meta-
analysis of longitudinal studies. Psychological Bulletin, 139(1), 213-240.
doi:10.1037/a0028931
Stein, M. B., Goldin, P. R., Sareen, J., Zorilla, L. T., & Brown, G. G. (2002). Increased amygdala
activation to angry and contemptuous faces in general social phobia. Archives of General
Psychiatry, 59(11), 1027-1034. doi:10.1001/archpsyc.59.11.1027
Straub, R. O. (2011). Cardiovascular disease and diabetes. In Feyen, K. (Ed.). Health
psychology: A biopsychosocial approach (pp. 285-316). New York, NY: Worth
Publishers.
Tham, M. W., Woon, P. S., Sum, M. I., Lee, T. S., & Sim, K. (2011). White matter abnormalities
in major depression: Evidence from post-mortem, neuroimaging and genetic studies.
Journal of Affective Disorders, 132(1), 26-36. doi:10.1016/j.jad.2010.09.013
Uliaszek, A. A., Zinbarg, R. E., Mineka, S., Craske, M. G., Griffith, J. W., Sutton, J. M., . . . &
Hammen, C. (2012). A longitudinal examination of stress generation in depressive and
anxiety disorders. Journal of Abnormal Psychology, 121(1), 4-15. doi:10.1037/a0025835
Vermetten, E., Vythillingam, M., Southwick, S. M., Charney, D. S., & Bremner, J. D. (2003).
Long-term treatment with paroxetine increases verbal declarative memory and
hippocampal volume in posttraumatic stress disorder. Biological Psychiatry, 54(7), 693-
702. doi:10.1016/S0006-3223(03)00634-6
Vreeberg, S. A., Hoogendijk, W. J., van Pelt, J., DeRijk, R.H., Verhagen, C. M., van Dyck, R.,
Smit, . . . Penninx, B. J. (2009). Major depressive disorder with hypothalamic-pituitary-
adrenal axis activity: Results from a large cohort study. Archives of General Psychiatry,
66(6), 617-626. doi:10.1001/archgenpsychiatry.2009.50
Wacogne, C., Lacoste, J. P., Guillibert, E., Hugues, F. C., & Le Jeunne, C. (2003). Stress,
anxiety, depression and migraine. Cephalalgia, 23(6), 451-455. doi:10.1046/j.1468-
2982.2003.00550.x
Walther, S., Hgil, S., Hfle, O., Federspiel, A., Horn, H., Bracht, T., . . . Mller, T. J. (2012).
Frontal white matter integrity is related to psychomotor retardation in major depression.
Neurobiology of Disease, 47(1), 13-19. doi:10.1016/j.nbd.2012.03.019
Wang, J. L., Schmitz, N., & Dewa, C. S. (2010). Socioeconomic status and the risk of major
depression: The Canadian national population health survey. Journal of Epidemiology &
Community Health, 64(5). doi:10.1136/jech.2009.090910

Yoon, K.L. & Joorman, J. (2012). Stress reactivity in social anxiety disorder with and without
comorbid depression. Journal of Abnormal Psychology, 121(1), 250-255.
doi:10.1037/a0025079
Zannas, A.S., McQuoid, D.R., Payne, M.E., Steffens, D.C., MacFall, J.R., Ashley-Koch, A. &
Taylor, M.D. (2013) Negative life stress and longitudinal hippocampal volume changes in
older adults with and without depression. Journal of Psychiatric Research, 47(6). 829-
834. doi:10.1016/j.psychires.2013.008
Zen, A. L., Whooley, M. A., Zhao, S., & Cohen, B. E. (2012). Post-traumatic stress disorder is
associated with poor health behaviors: findings from the heart and soul study. Health
Psychology, 31(2), 194-201. doi:10.1037/a0025989

Final Paper - C Vannelli 0532292 - The Physiology of Stress in Depression and Anxiety

Încărcat de

Informații document

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Final Paper - C Vannelli 0532292 - The Physiology of Stress in Depression and Anxiety

Încărcat de

Drepturi de autor:

Formate disponibile

Running head: THE PHYSIOLOGY OF STRESS IN DEPRESSION AND ANXIETY

The Physiology of Stress in Depression and Anxiety:

Causes, Implications for Health, and Treatment

hippocampus. Lastly, contemporary pharmacological and alternative treatments that address

inflammatory cytokines, immunosuppression, and hippocampal atrophy. Treatments to

understand the physiology of stress in these disorders and their subtypes.

endeavors in the future.

continue to make them proud.

Foundations in the Study of Stress and Mental Health

system. When an individual experiences stress or tension physically or psychologically, the

of stressors result in physiological and behavioural changes in order to maintain homeostasis.

which he referred to as a syndrome: adrenocortical stimulation, thymicolymphomatic activity,

psychological responses to stress represent both a traditional learned stimulus-response pattern

and also individual differences in response (Lovallo & Thomas, 2000).

Anxiety and Depression

appear to demonstrate distinctive physiological and psychological changes and dysregulation in

this disorder at some point in their lives.

Anxiety disorders have a tendency to be comorbid with a depressive disorder. Depressive

12% of males will develop MDD over their lifetime.

also possess a unique physiological profile.

anxiety and depression.

paper focuses largely on the adult population.

disorder, and major depression.

explored by examining scientific readings in psychology, neuroscience, biology, and health. By

especially in vulnerable populations. Individuals suffering from anxiety or depression present an

interesting case of endocrine, immune, and neurochemical dysregulation that is exacerbated by

the effects of chronic stress.

Sources of Stress, Depression, and Anxiety

anxiety vulnerable to more interpersonal stress and health problems.

depression and anxiety experience stress in different domains.

Non-interpersonal stress describes occupational, educational, and health problems (Uliaszek et

High levels of individual differences present challenges in measuring psychological and

reported by participants followed the classification of independent-dependent, interpersonal-non-

interpersonal, which shall be further examined.

post-traumatic stress disorder.

academic difficulties, though under different circumstances, they might be classified as

it interpersonally; these dependent events are partially influenced by maladaptive behaviours

Interpersonal. Interpersonal stress in depression is characterized by negative

(Shiota & Kalat, p. 262).

shame (Penley & Tomaka, 2002, p. 1222).

with others. Interpersonal style in depression is fixated on negativity, higher self-criticism,

hopelessness, neuroticism, and maladaptive coping that is emotion-focused instead of problem-

Non-Interpersonal. This type of stress refers to occupational, educational, and

type II (Ryan, Sheu, Critchley, & Gianaros, 2012).

levels of stress in dependent, interpersonal, and non-interpersonal domains. Elevated levels of

behaviours may be contributing to dependent and interpersonal stress. Furthermore, the

stress, which shall be addressed next.

and their subtypes.

Biological. The use of genetics in understanding depression or anxiety in the context of

implicated in anxiety disorders and will be further elaborated upon later.

Cognitive and Social

Neuroticism. A trait commonly considered to be characteristic of neuroticism is

interpersonal, family, and occupational difficulties) (Funder, 2010, p. 247). It is unfavourable, as

tendency to ruminate about these events.

Rumination. Rumination, a type of thought pattern studied across a variety of

uncontrolled (McLaughlin & Nolen-Hoeksema, 2011, p. 186). It is a manner of responding to

(Seldenrijk et al., 2013).

Rumination leads to more negative thinking, less effective generation of solutions to

problems, uncertainty or hesitation in the application of solutions to problems, less willingness to

A study by McLaughlin & Nolen-Hoeksema (2011) sampled a group of adolescents aged

emotionally imprisoned by their depression.

Nolen-Hoeksema, 2011, p. 190).

In a similar study by Michl, McLaughlin, Shepard, & Nolen-Hoeksema (2013), a group

of adolescents and a group of adults were recruited to participate in a longitudinal investigation