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DECLARATION

This work is the result of my own investigations, except where otherwise stated. This work has not previously been
accepted in substance for any degree and is not being concurrently submitted in candidature for any degree.

Signed (Candidate)

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Abstract

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Introduction

Evidence support that depression is the most prevalent mental disorder (Kessler et.al,
1994; Sinyor, Rezmovitz & Zaretsky, 2016), thus perceived as a serious threat to global health.
Smith (2014) noted that over 300 million people worldwide deal with depression, a disorder
indicated by the World Health Organization (WHO) as the number one factor conducing to
global disability. Worth mentioning is also the existing uncertainty regarding the complexity of
its pathogenesis. However, it is well established that cultural, psychological and biological
factors contribute significantly in the manifestation of depression (Gross,2014, Menard et al.,
2016). One of the most alarming findings is related to adolescents and the fact that they are 30
times more likely to commit suicide (Stringaris, 2017). The prevalence of suicide attempts
among adult population ranges at about 10%, while for adolescents appears to be the 3rd major
cause of mortality, following car accidents and homicides (Johnson et al., 2014).
Adding to this, reports of suicide rates indicate that 90% of the people who died by
suicide had a comorbid mental disorder. More specifically, 60% of those had a diagnosis of
depression (Farmer et al., 2001; Gramaglia et al., 2016; Kessler et al., 2005; Weitz et al., 2014).
This behaviour varies in the degree of intensity. For instance, in mild suicidal ideation the person
feels that life is not worth living, in moderate it is expected that someone is experiencing
thoughts of ending their life, in acts of self-harm (with dubious intent to die) and lastly the actual
successful attempt (Weitz et al., 2014). Despite the co-occurrence of suicidal ideation and
depression at approximately 47-69%, the current literature is indecisive regarding whether
depression treatments can effectively diminish suicidal behavior (Asnis, et al., 1993, Bronisch &
Wittchen, 1994, Sokero, et al, 2003).
There is a considerable body of research which suggests several therapeutic approaches
that work effectively on the treatment of depression. Namely, cognitive behavioural therapy
(CBT; Churchill et al., 2002; Butler et al., 2006), interpersonal therapy (IPT; Cuijpers, et al.,
2011), behavioural activation therapy (Ekers, et al., 2008), problem-solving therapy (Malouff et
al., 2007), supportive counselling (Cuijpers, 2012b) and psychodynamic (Driessen, et al., 2010)
are the most prominent. Besides the effectiveness of such practices on depression, these
approaches are also utilized to treat suicidal ideation according to the suggestions of treatment

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guidelines. However, significant uncertainty characterizes the utilization of these approaches on

whether this strategy for treating suicidal ideation is appropriate (Weitz et al., 2014). On the
other hand, critically important also are evidence supporting that lithium restrains suicidal
behaviour in bipolar and unipolar depression. This seems to be promising, even though the
information is inadequate regarding the effectiveness of antidepressant medication on suicidal
ideation (Baldessarini & Taldo, 2008). However, the possible effectiveness of psychotherapy or
pharmacotherapy in treating suicide and depression remains ambiguous.

Symptomatology of Major Depressive Disorder

The diagnostic features of a major depressive episode rely on the presence of five or
more symptoms observed as changes in behaviour for at least two weeks. Besides duration, the
first criterion also requires the presence of depressed mood nearly every day or the loss of
interest or pleasure in almost all activities. The overall clinical presence might include symptoms
such as; daily sleep disturbances (insomnia or hypersomnia), changes in regular weight (more or
less than 5% without dieting), psychomotor agitation or being slower than usual, diminished
energy or fatigue without physical effort, feelings of worthlessness or guilt throughout the day,
impaired ability to concentrate and make decisions and lastly suicidal thoughts and behaviours.
The second criterion underlines the impact of this symptomatology as the cause of significant
distress in several aspects of functioning such as; occupational, social and interpersonal. Finally,
the third criterion highlights the importance of detecting if the presented symptomatology results
from a medical condition or substance abuse (APA, 2013).

Symptomatology of Persistent Depressive Disorder (Dysthymia)

Different from depression, the diagnosis of dysthymia takes far more time to specify. It is
characterized by a stable depressive state of mood for at least two years. The depressed mood
must be accompanied by two or more of the following behaviours; significant deviances in
appetite ranging from overeating to inadequate eating, sleep disturbances (insomnia or
hypersomnia), decreased energy levels or exhaustion, low self-esteem, impairments in decision
making and concentration, and feelings of being hopeless. Meanwhile, within the two years, the
individual must not experience remission of symptoms for more than two months.

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Biological and genetic factors of depression and suicide

Derived from the above, it is obvious that depressive symptomatology affects several
aspects of human behavior. A significant contribution to what is currently known about the
condition is offered by studies of biological and genetic perspective. Strong evidence about the
influence of genetic factors on the risk of the development of depression is provided by twin
studies. A meta-analysis confirms that heritability chance for depression reaches 37%, coupled
with family studies which support a two-to threefold likelihood risk for developing depression in
first-degree relatives of depressed individuals (Sullivan et al., 2000; Shadrina et al.,2018).
However, the tremendous influences of depression are not only explained from a heredity
perspective, as its complex nature implies the existence of a biochemical background.
The monoamine hypothesis proposed by Joseph Schildkraut in the 1960s’ (Kraft et al.,
2005), posits that the manifestation of depression arises from the inadequacy of monoamine
neuromodulators (serotonin, dopamine, norepinephrine) in specific structures of the central
nervous system (CNS) (Shadrina et al.,2018). The important role of balance and sufficiency of
these neuromediators in depression has been verified both from the extensive analysis of their
mechanism of action and from the subsequent composition of tricyclic antidepressants and
reuptake inhibitors of monoamines (Leonard, 2000; Manji et al., 2001; Nutt, 2002; Ressler et al.,
2004). Of particular importance are evidence obtained from suicide victims who suffered from
major depression. It was found that they exhibited increased binding of an agonist of inhibitory
action to serotonin-1A receptors in the human dorsal raphe nucleus. Thus, is justified the
hypothesis that decreased activity of serotonin neurons is a risk factor both for depression and
suicide (Stockmeier et al., 1998; Mann, 2013).
An equally significant aspect of the factors who contribute to the development of
depression is the hyperactivity of the hypothalamic-pituitary-adrenal axis since it represents one
of the most consistent findings as a neuroendocrine abnormality (Holsboer, 1999). Notably,
excessive concentrations of cortisol in the plasma, urine and cerebrospinal fluid (CSF), as well
as, redundant cortisol response to adrenocorticotropic hormone (ACTH) have been found in
patients with MDD (Nemeroffm 1996; Holsboer & Barden, 1996; Holsboer, 2000). According to
this, the corticosteroid hypothesis has been proposed regarding the pathogenesis of MDD which
emphasizes on the impairment of the dependent receptor's signalling which results to diminished
feedback of cortisol, enhanced production of corticotropin-releasing hormone (CRH), as well as,

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hypercortisolism (Holsboer, 2000).

It is worth mentioning that the serotonin system (5-HT) is also affected by cortisol
and CRH (Holsboer & Barden, 1996; Nemeroff, 1996; De Kloet et al., 1998). Throughout stress
response occurs stimulation of all the features of 5-HT transmission by glucocorticoids (GCs)
(Meijer & de Kloet, 1998). This stimulation dysregulates 5-HT and noradrenergic transmission.
As a result, the hippocampus is suppressed due to chronic psychosocial stress and
hypercortisolism, which resembles the pattern of events during the depression (Wolkowitz et al.,
1993). This HPA axis dysregulation is claimed as a genetic trait that conduces to depression
development as a risk factor (Lee & Kim, 2013). Indeed, this pattern is found also in both
depressed individuals and healthy ones who are also at a high risk due to heredity. Therefore,
HPA axis should be considered as an endophenotype for mood disorders (Holsboer, 1995;
Modell et al., 1998).

Theories of causes

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According to American Psychiatric Association (APA) it is defined as a disorder that has

a significantly negative impact in several aspects of people’s lives such as; thinking, feeling and
acting (APA,2013). It floods people with sadness and feelings of worthlessness or guilt, it
dysregulates sleeping patterns, leads to fatigue, limits concentrating capacity and makes the
person indifferent to previous interests or even pleasure (Lu et al., 2014). Depending on the
magnitude of the influence, depression is a risk factor for suicide (Large, 2016; Choo, Diederich,
Song & Ho, 2014), unavoidably associated with increased mortality rates (Cujipers & Smit,
2002).

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