Pathophysiology of Depression: Anatomy, Physiology, Mechanism, Prevention and Treatment

This essay discusses the underlying anatomical and pathological changes emerging in depression and possible preventive and treatment practices for enhance management. It covers anatomy, physiology, mechanism, prevention and treatment of depression.

Running head: PATHOPHYSIOLOGY OF DEPRESSION
PATHOPHYSIOLOGY OF DEPRESSION
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1PATHOPHYSIOLOGY OF DEPRESSION
Introduction
Depression is known as a chronic psychological mood disorder which is characterized by
detrimental changes in an individual’s regulation of moods, emotions, thoughts and attitudes
towards daily life (Miller & Raison, 2016). Taking insights from the Diagnostic and Statistical
Manual of Mental Disorders, symptomatic effects of depression are characterized by the
occurrence of dysphoria or depressed mood, coupled with a loss of desire to engage in previously
enjoyable tasks (Fried et al., 2016). According to the World Health Organization, depression
affects over 450 million of the global population (Kessler et al., 2015). At present, the defects in
the neurotransmission and signaling of dopamine has been associated as the primary
pathophyiosology underlying depression. Such disruptive changes can be attributed to the
reductions in the number of receptors, decreases in the release of dopamine from presynaptic
neurons, alterations in signal processing at the cellular level and impairments in the transduction
of nervous signals (Salamone et al., 2016). The following essay attempts to discuss on the
underlying anatomical and pathological changes emerging in depression and possible preventive
and treatment practices for enhance management.
Normal Anatomy of Affected Body System
One of the key body systems affected by depression is the dopamine system of the
cerebral cortex. The normal anatomy of the dopamine system consists of a group of neurons,
with their originations from the mid-section of the brain. The axons of the neurons associated
with the dopamine system possess extensions towards the forebrain, and consists of three neural
branches performing essential functions which will be discussed in the succeeding sections
(Seitz, Paloutzian & Angel, 2018). Of the three branches, one branch extends to the frontal

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cortex, another branch possesses extensions to the striatum while the third branch, protrudes into
the limbic system of the brain. The limbic system of the brain, alternatively known as the center
of for rewards and perceptions of pleasure, comprise of the primary section affected by the
pathophysiology of depression (Popova et al., 2015).
Normal Physiology of Affected Body System
The mesolimbic dopamine system is of major concern in the pathophysiology of
depression and is associated with neural connections from the midbrain dopamine system to the
cerebral limbic and nucleus accumbens areas. These core cerebal areas of the limbic system are
one of the oldest sections of the brain to have emerged and survived since the evolution of
mankind and are associated with neural structures responsible for determining our mood,
emotions and environmental perceptions in response to stimuli and rewards (Riccelli et al.,
2016). The harbingers of the limbic system considering emotional regulation are the amygdale,
located in the temporal lobe and the hippocampus situation adjacently. These regions are the
primary cerebral centers for housing prolonged memories and thought processes and are highly
receptive to situations of stress, agitation, threat or anxiety. Hence, in the presence of challenging
or demanding situations, activation of the hippocampus results in activation of the hypothalamus
and the resultant stimulation of the hypothalamus-pituitary-adrenal (HPA) axis (Rajagopalan et
al., 2017). Stimulation of the HPA axis results in an endocrinal cascade characterized by
pituitary activation directed by the hypothalamus, further leading to activation of the adenal
glands. Hence, as a normal physiological process, in response to stress, challenging or depressive
life events, such stimulation encourages adrenal secretion of cortisol (Radley et al., 2016).
Cortisol, a steroid hormone, prepares the body for responding to challenging situations through
physiological changes in the form of increased alertness, enhanced blood sugar levels and

3PATHOPHYSIOLOGY OF DEPRESSION
metabolic regulation. Hence, it is through the HPA axis and cortisol secretion functioning that
the human body attempts to maintain physiological and psychological homeostasis in a situation
of stressful life events (Seo et al., 2019).
Mechanism of Pathophysiology
According to Keller et al., (2017), the pathophysiology of depression has been associated
with changes in the HPA axis in situations of excessive and chronic stress, which is a
characteristic resultant of traumatic life events. Exposure to chronic stress in the form of
challenging or traumatic life events, has been associated hyperactivity of the HPA axis. Such
hyper functioning results in continuous elevations in the adrenal secretion of cortisols and
corticosteroids. Steroidal hormones such as corticosteroids pose direct associations with the
pathology of depression, where high levels of the same have been shown to result in reductions
in the secretion of neurotransmitter dopamine as well as decreases in the size of the
hippocampus. The hippocampus is the primary regulator of the HPA axis and hence, it plays a
key role in exerting inhibition upon this axis (Du & Pang, 2015). Hence, as researched by
Dwivedi et al., (2015), stress and corticosteroid induced hippocampul reduction results in lack of
regulation of the HPA axis, further leading to uncontrolled secretion of corticosteroids.
Excessive corticosteroids have been implicated to yield depression like symptoms and alterations
in emotion and further has been associated with reducing the size of the amygdala, the primary
limbic center associated with memory, mood and reward perceptions. Hence, as researched by
Grace (2015), hindrances to the dopamine system, exerted by corticosteroids results in alterations
of the ventral tegmental area and nucleus accumbens - cerebral amygdala areas concerned with
perception of reward responses – leading to reductions in the sensation of pleasure and
malfunctioning brain reward circuit. Indeed, such structural alterations in response to traumatic

4PATHOPHYSIOLOGY OF DEPRESSION
event or chronic stress induced hypercortisolemia can be justified in the observed decreases in
glial density and volume of grey matter of the hippocampus and prefrontal cortex cerebral areas
in post mortem, neuro-imaging reports of animal based research models (Kraus et al., 2017).
As systematically reviewed by Black et al., (2015), an additional pathophyisiology underlying
depression is the observed alterations in genes controlling endogenous antioxidant enzymatic
function as a result of chronic stress and excessive corticosteroid secretion. Such alterations have
been implicated to result in loss of functioning of essential enzymes such as glutathione
reductase, gluatathione peroxidase, superoxide dismutase, catalase and NADPH oxidase. Such
losses in enzymatic functioning results in increased oxidative stress due to inflammatory
responses induced by free radicals like reactive oxygen species (ROS), which have implicated to
yield symptoms associated with depression (Bakunina, Pariante & Zunszain, 2015).
Hence, considering the above pathological processes, depression emerges due to a loss of
neurotransmitter and adrenal homeostasis resulting in inhibited HPA hippocampus and elevated
amygdala functioning further leading increased perceptions of negativity and brooding over past
memories (Belzung, Willner & Philippot, 2015).
Prevention
As observed from the above pathologies, mechanisms of chronic stress have been
implicated to be a key regulator in the emergence of depression. Hence, adoption of stress coping
mechanisms may prove to be beneficial in improving one’s response to stress and the resultant
hypercortisolemia associated malfunctioning in the brain dopamine system and the HPA axis
(Song & Lindquist, 2015). Likewise, adherence to physical activity such as exercise has been
associated with depression prevention due to secretion of mood-elevating hormones such as

5PATHOPHYSIOLOGY OF DEPRESSION
endorphins and enhanced secretion of serotonin and dopamine (Schuch et al., 2016). Likewise,
considering the association of oxidative stress and depression pathologies, adherence to a diet
rich in antioxidants such as Vitamins C, E and A, along with Omega 3 fatty acids may prove to
be beneficial in reducing the effect of free radicals on the emergence of depressive symptoms
(Gangwisch et al., 2015).
Treatment
Considering the pathophysiology of hampered HPA axis and dopamine secretion in
depression, current medications target the disturbed neurotransmission of monoamines
associated with this disease. Hence, the aim of these drugs lies in enhancing the concentration of
synaptic monoamines such as dopamine, serotonin and norepinephrine in the human body. Such
drugs aim to achieve this by reversibly or irreversibly, inhibiting the enzymatic activity of
monamine oxidase, whose primary function lies in degradation of monoamines (Kumar, Mantha
& Kumar, 2016). An alternative mechanism undertaken by such antidepressant drugs include
binding to the concerned transporter of the neurotransmitter resulting in blockages in the
reuptake of monoamines by the presynaptic neuron (Luethi et al., 2018). Considering the
observed alterations in the structural components of the brain associated with depression,
additional treatments include electroconvulsive therapy and transcranial magnetic stimulation,
which involves transmission of weak electric currents to specific regions of the brain
(Livingston, Anandan & Moukaddam, 2016).
Clinical Relevance
Existing treatments of depression are aimed at usage of psychotherapeutic or behavioral
counseling techniques which target the detrimental thought processes and perceptions underlying

6PATHOPHYSIOLOGY OF DEPRESSION
depression. Likewise, such therapies aim to regulate and modify the characteristic pessimistic
and negative thoughts and attitudes in depressive people into positive ones especially in the
response to specific stimuli. Despite the considerable successes associated with these techniques,
relapses are prevalent in a significant number of patients suffering from depression (Weitz et al.,
2017). Hence, such individuals may need alternative therapeutic interventions targeting the
intrinsic monoamine and hormonal pathologies underlying depression. The observed benefits
currently associated with medications targeting monoamine concentrations provide key insights
into the dopamine and malfunctioning HPA axis associated origins of major depressive disorders
(Chung et al., 2018). Hence, alternative treatments employing a pathophysiological approach to
depression may prove to be beneficial for depressive patients unresponsive to traditional
psychotherapeutic procedures. This, such treatment possibilities enhance the clinical relevance of
studying the pathophysiology underlying depression (Cuijpers, 2018).
Conclusion
At present, the pathophysiology of depression has been associated with losses in the
neurotransmission of monoamines such as dopamine and hindrances in the functioning of the
HPA axis. Continued exposure to chronic stress results in excessive cortisol secretions further
resulting in malfunctioning HPA axis and reductions in the sizes of mood regulating cerebral
areas like the hippocampus and the amygdale. Adherence to stress coping mechanism, exercise
and an antioxidant rich diet can be considered beneficial in the prevention of depression.
Antidepressant drugs targeting dopamine concentrations are the primary treatment mechanism
formulated considering the above mentioned pathologies. Hence, to conclude, adoption of
depression treatment approach targeting pathophysiology mechanisms can be of relevance in the

7PATHOPHYSIOLOGY OF DEPRESSION
management of depressive in individuals unresponsive to traditional psychotherapeutic
treatments.
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