A Comprehensive Study on the Biological Aspects of Major Depressive Disorder

Alcantara, Mikaela M.

Casas, Nicole Shaine D.

Macatangay, Ma. Frances M.

Mendoza, Marianne G.

National University Lipa-Bachelor of Science in Psychology

Y1T2PSYCH04X Biological Psychology

Balantac, Salve Deinne E.

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February 16, 2024

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 A Comprehensive Study on the Biological Aspects of Major Depressive Disorder

Depression, otherwise known as Major Depressive Disorder, based on the fifth edition

of the Diagnostic and Statistical Manual of Mental Health Disorders (DSM-5), is “a period of

at least two weeks when a person experienced a depressed mood or loss of interest or

pleasure in daily activities, and had a majority of specified symptoms, such as problems with

sleep, eating, energy, concentration, or self-worth.” This definition excludes grief after

mourning. Aside from the emotional problems caused by depression, individuals can also

present with a physical symptom such as chronic pain or digestive issues. The social

symptoms of depression also include avoiding contact with friends and taking part in fewer

social activities, neglecting your hobbies and interests, and having difficulties in your home,

work or family life that causes deviance, danger, dysfunction and distress. To be diagnosed

with depression, symptoms must be present for at least two weeks.

The DSM-5 outlines the following criterion to make a diagnosis of depression. The

individual must be experiencing five or more symptoms during the same 2-week period and

at least one of the symptoms should be either (1) depressed mood or (2) loss of interest or

pleasure.

 Depressed mood most of the day, nearly every day.

 Markedly diminished interest or pleasure in all, or almost all, activities most of the

day, nearly every day.

 Significant weight loss when not dieting or weight gain or decrease or increase in

appetite nearly every day.

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  A slowing down of thought and a reduction of physical movement (observable by

others, not merely subjective feelings of restlessness or being slowed down).

 Fatigue or loss of energy nearly every day.

 Feelings of worthlessness or excessive or inappropriate guilt nearly every day.

 Diminished ability to think or concentrate, or indecisiveness, nearly every day.

 Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a

suicide attempt or a specific plan for committing suicide.

To receive a diagnosis of depression, these symptoms must cause the individual clinically

significant distress or impairment in social, occupational, or other important areas of

functioning. The symptoms must also not be a result of substance abuse or another medical

condition. The latest edition of the Diagnostic and Statistical Manual of Mental Disorders

(DSM), the DSM-5, added two specifiers to further classify diagnoses:

 With Mixed Features – This specifier allows for the presence of manic symptoms as part

of the depression diagnosis in patients who do not meet the full criteria for a manic

episode.

 With Anxious Distress – The presence of anxiety in patients may affect prognosis,

treatment options, and the patient’s response to them. Clinicians will need to assess

whether or not the individual experiencing depression also presents with anxious

distress.

The earliest written accounts of what is now known as depression appeared in the

second millennium B.C.E. in Mesopotamia. In these writings, depression was discussed as a

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spiritual rather than a physical condition. Like other mental illnesses, it was believed to be

caused by demonic possession. As such, it was dealt with by priests rather than physicians.

Because of this belief, it was often treated with methods such as beatings, physical restraint,

and starvation in an attempt to drive the demons out.

During the common era, many barbaric and primitive treatments for depression

continued to be the norm. Cornelius Celsus (25 BCE to 50 CE) reportedly recommended the

very harsh treatments of starvation, shackles, and beating in cases of mental illness. A Persian

doctor named Rhazes (865–925 CE), however, did see mental illness as arising from the brain.

He recommended such treatments as baths and a very early form of behavior therapy which

involved positive rewards for appropriate behavior.

During the Middle Ages, religion, especially Christianity, dominated European

thinking on mental illness, with people again attributing it to the devil, demons, or witches.

Exorcisms, drowning, and burning were popular treatments of the time. Many people were

locked up in so-called "lunatic asylums."

During the Renaissance, which began in 14th century Italy and spread throughout

Europe during the 16th and 17th centuries, witch hunts and executions of the mentally ill were

still quite common; however, some doctors were revisiting the idea of mental illness having a

natural rather than a supernatural cause. In the year 1621, Robert Burton published "Anatomy

of Melancholy," in which he outlined the social and psychological causes of depression (such

as poverty, fear, and loneliness). In this book, he made recommendations like diet, exercise,

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travel, purgatives (to clear toxins from the body), bloodletting, herbs, and music therapy in the

treatment of depression.

During the 18th and 19th centuries, also called the Age of Enlightenment, depression

came to be viewed as a weakness in temperament that was inherited and could not be changed.

The result of these beliefs was that people with this condition should be shunned or locked up.

During the latter part of the Age of Enlightenment, doctors began to suggest the idea that

aggression was at the root of the condition. Treatments during this period included water

immersion (staying underwater for long as possible without drowning) and using a spinning

stool to put the brain contents back into their correct positions. Additional treatments included:

Diet changes, Enemas, Horseback riding and Vomiting. Benjamin Franklin is also reported to

have developed an early form of electroshock therapy during this time.

Today’s understanding of depression involves a depressed mood or loss of pleasure or

interest in activities for long periods of time. Depression is different from regular mood

changes and feelings about everyday life. It can affect all aspects of life, including relationships

with family, friends and community. With mental health theories abounding from the end of

the 19th Century, it became necessary to reach a working consensus on how to identify, group

and treat mental health conditions based on statistical field data. Thus, a number of attempts

were made to create a comprehensive mental health classification system. Eventually, two main

systems emerged: the International Statistical Classification of Diseases, Injuries and Causes of

Death (ICD) in 1949, and the Diagnostic and Statistical Manual of Mental Disorders (DSM) in

1952. While the ICD examines both physical and mental ailments and is used across the globe,

the DSM specifically examines mental disorders and is primarily used in the US. Both are

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periodically updated to reflect the changing times and their shifting approaches to mental

health.

As times changed, so did the ICD and DSM’s definitions of depression, with the

various symptoms that go into the diagnosis reflecting up-to-date field data. As an example of

this change, the DSM-IV, which was published in 1994, excluded instances of depression that

can be better explained by bereavement. DSM-V, which was published in 2013, added a

“mixed features” sub-diagnosis of depression that includes manic episodes, in addition to an

“anxious distress” sub-diagnosis that is defined by having at least two of the following

symptoms: tension, restlessness, difficulty concentrating due to worrying, fear that something

awful might happen, and feeling a loss of control. Be it through deep psychoanalytic treatment,

a more existential approach, exploring scientifically proven treatment options like Deep TMS,

incorporating medication into your healthcare regimen or taking a look at the detrimental set of

beliefs that define it, individuals battling depression today are able to benefit from those who

came before them. The philosophy, research and cultural shifts that continue to this day have

resulted in a multitude of perspectives, a range of available treatment options, and the

somewhat comforting knowledge that our passion to gain a better understanding of depression

has already progressed us as a society toward a fuller, broader and more compassionate view of

this complex condition.

The general statement or purpose of this paper is typically to deepen our understanding

of the causes, risk factors, symptoms, and effective treatments for Major Depressive Disorder

(MDD). This comprehensive study serves the purpose of advancing our knowledge about the

condition’s underlying mechanisms, it’s impact on individuals and society, and how the

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concept of depression evolved over time. This research aims to contribute valuable insights that

can enhance diagnosis, interventions, public awareness and support for individuals affected by

this mental health condition to ultimately enhance their overall well-being and foster improved

diagnostic criteria.

Biochemistry and Brain Structure

The concept of chemical imbalances in depression refers to disruptions in the

normal levels of neurotransmitters, such as serotonin, dopamine, and norepinephrine.

Studies have shown that in people with depression, there may be a decrease in the amount

of these neurotransmitters available, which can cause symptoms like loss of interest or

pleasure in activities, changes in appetite or sleep, and feelings of anxiety. Norepinephrine,

a neurotransmitter, plays a crucial role in modulating the stress response, influencing

energy levels, and enhancing focus. Research suggests that norepinephrine contributes to

increased alertness and arousal during stress, as well as promoting attention and

concentration (Moriguchi et al., 2017). Another line of research has investigated linkages

between the stress response, hormones, depression, and norepinephrine. Norepinephrine

helps our bodies to recognize and respond to stressful situations. Researchers suggest that

people who are vulnerable to depression may have a norepinephrinergic system that doesn't

handle the effects of stress very efficiently. The neurotransmitter dopamine is also linked to

depression. Dopamine plays an important role in regulating our drive to seek out rewards,

as well as our ability to obtain a sense of pleasure. Low dopamine levels may in part

explain why many depressed patients or people don't derive the same sense of pleasure out

of activities or people that they did before becoming depressed (España et al., 2016).

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 The neurotransmitter serotonin is involved in regulating many important

physiological (body-oriented) functions, including sleep, aggression, eating, sexual

behavior, and mood. Serotonin is produced by serotonergic neurons. Current research

suggests that a decrease in the production of serotonin by these neurons can cause

depression in some people, other mood disorders, and more specifically, a mood state that

can cause some people to feel suicidal (Blier & Mansari, 2013). Other neurotransmitters

may also be involved in the development of and susceptibility to depression. This includes

glutamate that plays a role in how easily neurons can strengthen their connections.

Glutamate dysregulation has been linked to depressive symptoms. Also, Acetylcholine,

involved in cognitive functions and has been associated with mood regulations. Disruptions

in acetylcholine signaling has been found in people with depression (Duman et al., 2019).

A. Magnetic Resonance Imaging (MRI)

One of the most difficult problems in tackling depression has been the absence of

scans or lack of tests in diagnosing the condition. Scientists however have found out a way

to identify MDDs easily by using radio waves and magnetic waves to investigate the

internal organs of the body. Scanning is done in different angles in cross-sections and slices

to acquire attenuated images. These images are sent to the computer and a software

program puts these cross-sections and slices together to obtain a picture of the organ

(Pilmeyer et al., 2022). Three main areas where MRI reports have conveyed evident major

differences in depressed brains are:

1. Blood-brain barrier (BBB)

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 BBB is the barrier between the brain tissue and the blood vessels. In recent research

by Dr. Wengler (n.d.), connections between BBB and MDD using MRI method called as

IDEALS (intrinsic diffusivity encoding of arterial labelled spins) i.e., 3D MRI which gives

an understanding of brain-water permeability was studied. This study showed how the

water movement from blood vessels into brain tissue through BBB took place. This

confirmed the disturbances in BBB, particularly in the amygdala (responsible for emotions)

and the hippocampus (Medina‐Rodriguez & Beurel, 2022).

2. Connectome

The connectome is known as the network of complex connections. The deformities

of the connectome using MRI (shows slight changes in blood flow in the brain) were

studied by Dr. Goushi and his team from Chicago by observing 66 adults with MDD and 66

healthy people. Decreased level of excitation and inhibition in the cortex (responsible for

cognitive control) and amygdala were observed in the MDD patients. Reduced levels of

excitation and inhibition were noted in the dorsal lateral prefrontal cortex in MDD patients.

Furthermore, the elevation in the amygdala was observed which contributed to anxiety and

negative moods (Chai et al., 2023).

3. Machine learning algorithm

A different study was done, where the brain patterns in depressed patients were

identified. The occurrence of such similar patterns was searched in other patients to see if

they were suffering from depression too. Many brain regions are involved in the network

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identified in depressed people. It can involve the four lobes of the brain namely, the frontal,

parietal, temporal and occipital lobes (Aleem et al., 2022).

Variations in grey and white matter density were found in patients with depression

and are shown in Fig. 1. These enlarge from prefrontal to parietal lobes and include

occipital and cerebellar regions. These same patterns were matched with other people who

were also suffering from depression. It was observed that the same pattern of regions was

found to underlie in depressed individuals, making it the true biological marker of

depression (Qiu & Li, 2018).

Fig.1. Grey matter patterns in

depression

B. Positron Emission Tomography (PET)

PET is different from other imaging procedures as it is based on the molecular

processes that occur in the living organisms. The positron-emitting nuclide, usually short-

lived is used in PET imaging. The organ of interest is scanned after injection. PET imaging

is majorly used for studying the brain, the neuro molecular processes in humans and as well

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as in animals. Comparison of the brain with depression and normal brain can be done with

PET scan. As shown in Fig. 2, an increase in green and blue areas along with a decrease in

yellow and white colors show reduced brain functioning because of depression (Savitz &

Drevets, 2013).

Fig. 2. PET image of a depressed vs. normal brain

Numerous studies that focused on gray and white matter have found significant

brain region alterations in major depressive disorder patients, such as in the frontal lobe,

hippocampus, temporal lobe, thalamus, striatum, and amygdala. The results are inconsistent

and controversial because of the different demographic and clinical characteristics.

However, some regions overlapped; thus, we think that there may be a “hub” in MDD and

that an impairment in these regions contributes to disease severity. Brain connections

contain both structural connections and functional connections, which reflect disease from a

different view and support that MDD may be caused by the interaction of multiple brain

regions (Smith & Jakobsen, 2013). According to previous reports, significant circuits

include the frontal‐subcortical circuit, the suicide circuit, and the reward circuit. As has

been recognized, the pathophysiology of major depressive disorder is complex and

changeable. The current review focuses on the significant alterations in the gray and white

matter of patients with the depressive disorder to generate a better understanding of the

circuits. Moreover, identifying the nuances of depressive disorder and finding a biomarker

will make a significant contribution to the guidance of clinical diagnosis and treatment

(Zhang et al., 2018).

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 The brain can be divided into the prefrontal neocortex (involved in higher cognitive

processes as well as regulation of emotions by their connections to the limbic region), the

limbic or mammalian brain (involved in emotions which guide self-preservation and

procreation of species) and the reptilian complex composed of the basal ganglia and brain

stem structures (involved in routine motor function/reflexes as well as social

communication such as territorial and courtship displays). Regional brain imaging studies

have investigated abnormalities in each of these brain subdivisions to investigate the

location of depression in the brain. A decreased metabolism in the prefrontal cortex,

especially dorsolateral and dorsoventral brain regions, is a frequently replicated finding in

MDD. Furthermore, deficient prefrontal perfusion in these regions, coupled with a

reduction in problem-solving abilities and higher propensity to act on negative emotions,

has been implicated in suicidal behavior (Su et al., 2014).

The insula particularly its anterior subdivision has been implicated in experience of

emotions such as disgust, self-reflection and assessment of internal visceral states, and

response to stimuli of taste and smell. In depression, insular activation has been reported to

be increased in response to disgust inducing stimuli and negative pictures and insular

volume has been noted to correlate with depression scores. One study on the other hand

reported increased insular activation in response to negative stimuli after antidepressant

treatment. Overall, these findings suggest increased sensitivity of the insula to internal

visceral and cognitive processes during depression (Mutschler et al., 2019). The main

subcortical limbic brain regions implicated in depression are the amygdala, hippocampus,

and the dorsomedial thalamus. Both structural and functional abnormalities in these areas

have been found in depression. Decreased hippocampal volumes have been noted in

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subjects with depression. Subjects who remit with treatment have even been shown to have

larger pre-treatment hippocampal volumes while those with smaller hippocampal volumes

were reported to be more prone to relapse. Decreased amygdala core volume has been

reported in depression. The exact significance of these volumetric abnormalities is not

known. In the case of loss of hippocampal volume, a definite pathophysiology related to

hypercortisolemia related neurotoxicity has been postulated (Nolan et al., 2020). In

summary, various cortical, subcortical and brain stem regions have been shown to have

abnormal activation or metabolism in brain imaging studies.

Genetics

Research suggests that genetics plays a role in Major Depressive Disorder (MDD).

While no specific "depression gene" has been identified, there is evidence that certain genetic

factors contribute to susceptibility. The serotonin transporter gene (SLC6A4), for instance,

has been studied extensively. Variations in this gene may affect serotonin reuptake,

influencing mood regulation. Additionally, the serotonin receptor gene (HTR2A) and the

brain-derived neurotrophic factor (BDNF) gene have been associated with MDD. A serious

mental illness “Major Depressive Disorder” has several hypotheses to explain its

pathophysiology. However, low levels of serotonin in the central nervous system are one of

the hypotheses most supported by the scientific community, despite the need for clarification

(Cowen & Browning, 2015). This disease is a complex condition characterized by numerous

molecular and cellular features. While serotonin has long been associated with depression, it

is important to acknowledge that there are various other factors at play, such as

neuroinflammation and dysregulation in diverse neurotransmitters, such as gamma-

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aminobutyric acid (GABA) and glutamate (Otte et al., 2016). These genes are involved in

neurotransmitter function and synaptic plasticity, critical for mood regulation. Moreover,

several studies have also found that reduced levels of BDNF are associated with an increased

frequency of depressive symptoms. Indeed, it is known that BDNF levels can be restored

with antidepressant therapy. Thus, BDNF appears to play an important role in the underlying

mechanisms of depression, according to several studies (Arosio et al., 2021).

Variants in brain-derived neurotrophic factor (BDNF), crucial for neuronal growth

and survival, may impact the brain's response to stress, a factor linked to depression. Genetic

research methods such as twin studies, family studies, and genome-wide association studies

(GWAS) have been pivotal in identifying these associations. Understanding the genetic basis

of MDD can guide personalized treatment approaches and contribute to the development of

targeted therapies. A genome-wide association (GWA) meta-analysis based on 135,458 cases

and 344,901 controls, we identified 44 independent and significant loci. The genetic findings

were associated with clinical features of major depression, and implicated brain regions

exhibiting anatomical differences in cases. Targets of antidepressant medications and genes

involved in gene splicing were enriched for smaller association signals. We found important

relations of genetic risk for major depression with educational attainment, body mass, and

schizophrenia: lower educational attainment and higher body mass were putatively causal

whereas major depression and schizophrenia reflected a partly shared biological etiology. All

humans carry lesser or greater numbers of genetic risk factors for major depression. These

findings help refine and define the basis of major depression and imply a continuous measure

of risk underlies the clinical phenotype (Wray et al., 2018).

Treatment Approaches

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Pharmacological Intervention

Antipsychotic drugs are primarily designed to treat conditions like schizophrenia and

bipolar disorder, and they are not typically the first-line treatment for Major Depressive

Disorder (MDD). However, they may be prescribed in certain cases, particularly when

depressive symptoms are severe or accompanied by psychotic features. The most notable

changes in the DSM-5 were the recognition of the possibility of mixed symptoms in major

depression and related disorders (MDD). While MDD and bipolar and related disorders are

now represented by 2 distinct chapters, the addition of a mixed features specifier to MDD

represents a structural bridge between bipolar and major depression disorders, and formally

recognizes the possibility of a mix of hypomania and depressive symptoms in someone who

has never experienced discrete episodes of hypomania or mania (Suppes & Ostacher, 2017).

Nonetheless, antipsychotics generally work by affecting neurotransmitters, particularly

dopamine and serotonin, in the brain. They can help regulate these neurotransmitters,

influencing mood and behavior.

In MDD, the atypical antipsychotics, such as quetiapine and aripiprazole, are

sometimes used as adjuncts to traditional antidepressants. Advantages include their potential

to address severe symptoms and improve overall treatment response. However, drawbacks

include the risk of side effects, which can range from metabolic issues (weight gain, diabetes

risk) to movement disorders (tardive dyskinesia). It's crucial for healthcare providers to weigh

the benefits against potential side effects when considering antipsychotics for MDD, and their

use is generally reserved for specific situations. Regular monitoring and communication with

healthcare professionals are essential to manage potential risks. Comorbid posttraumatic

stress disorder and diabetes were significantly associated with aripiprazole augmentation in

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our primary and post-hoc binary logistic regression analyses. Furthermore, we identified an

association between aripiprazole co-administration and the presence of additional psychotic

features, higher rates of AD combination treatment, and a longer duration of psychiatric

hospitalizations during the lifetime, which, however, lost significance after correcting for

multiple comparisons. Regarding treatment outcome, we found a trend of higher response

rates and greater reductions in severity of depressive symptoms in MDD patients dispensed

quetiapine (Bartova et al., 2021).

Adjacent Treatment

Major depressive disorder (MDD) is a complex mental health issue that affects

millions of people around the world. Traditional therapies have limitations, necessitating a

transition to innovative options. This study dives into adjacent treatment, investigating

strategies to supplement existing procedures. After decades of slow progress, scientists

unexpectedly discovered the antidepressant benefits of intravenous ketamine, a dissociative

anesthetic, and N-methyl-d-aspartate (NMDA) receptor antagonist. Beyond "proving the

concept" that a drug that directly addressed glutamatergic signaling could treat MDD, the

discovery of ketamine's antidepressant effects prompted the search for related newer

medications, such as S-ketamine (esketamine), which was developed for intranasal

administration and approved by the US Food and Drug Administration (FDA) as an

adjunctive strategy for treatment-resistant depression in 2019 (Thase, 2023).

In 2019, the FDA authorized two new antidepressants: Esketamine for refractory

depression and Bresanolone for postpartum depression. The FDA approved Esmolamine, a

derivative of the anesthetic medication ketamine, for the treatment of resistant depression

after many preliminary clinical investigations. Although several potential drugs have yet to

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be approved by the FDA, they are significant milestones in the development of

antidepressants that could be modified and used clinically in the future, such as compounds

containing dextromethorphan (a non-selective NMDAR antagonist), sarcosine (N-methyl

glycine, a glycine reuptake inhibitor), AMPAR modulators, and mGluR modulators (Li et al.,

2021).

Psychotherapeutic techniques are commonly utilized to treat and prevent most

psychiatric diseases. Such therapies are frequently used in cases of depression, psychological

issues, interpersonal problems, and intrapsychic conflicts (Karrouri et al., 2021). As we

examine complementary therapies for Major Depressive Disorder (MDD), we look at

therapeutic modalities that provide special ways to deal with and manage the symptoms of

this widespread depression. Every strategy, from problem-solving methods to cognitive and

behavioral therapies to psychoeducation, is essential to boosting mental health and raising the

standard of living for people with major depressive disorder.

 Cognitive and behavioral therapies

CBT is a well-documented method of treating depression, focusing on changing

dysfunctional behaviors and thoughts. It challenges and refutes the irrational beliefs of

depressed patients and has been shown to be effective in the treatment of major depressive

disorder (MDD). The patient's success depends on his ability to monitor and change beliefs,

which are addressed through techniques such as behavioral activation, the integration of

pleasurable activities to promote positive interaction (Nakao et al., 2021).

 Problem-solving therapy (PST)

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 Combines cognitive and interpersonal skills with a focus on negative situational

appraisals and effective problem-solving strategies. Despite the small effect, PST is

comparable to other forms of depression treatment in various settings, such as prevention of

depression in the elderly and treatment of mild depressive symptoms, especially in primary

care settings (Kirkham et al., 2015).

 Marital and family therapy (MFT)

Effectively treats some aspects of depression. It has been shown to be useful in

severe depression associated with medication and hospitalization. MFT recognizes that

marital and family problems increase vulnerability to depression and seeks to address these

issues. In relationship therapy, both partners are involved, taking into account the

interpersonal dynamics of depression. Goals include improving communication, resolving

marital conflict, and applying similar principles to involve all family members in treating

depression in the context of family dynamics (Waraan et al., 2022).

 Psychodynamic therapy

Psychodynamic therapy includes a variety of short- and long-term psychological

approaches based on psychoanalytic theories. It focuses on internal conflicts related to shame,

repressed impulses and early childhood problems with emotional caregivers that affect self-

esteem and emotional regulation. In the treatment of the acute phase of major depressive

disorder (MDD), psychodynamic therapy has been shown to be effective compared to other

psychotherapies (Ribeiro et al., 2017).

 Group therapy

The use of group therapy (GT) in major depressive disorder (MDD) is limited. Some

data indicate the effectiveness of CBT and IPT-inspired types of GT. Group CBT is useful for

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post-symptomatic depression, but its effectiveness diminishes at follow-up. Supportive GT

and group CBT help reduce depressive symptoms, especially in patients with common

comorbidities. However, research in this area is still scarce (Radfar et al., 2022).

 Psycho-education:

This intervention educates depressed patients and their consenting family members

about the symptoms and treatment of depression. Information should be shared in a way that

the patient understands, and misconceptions about medications, duration of therapy, risk of

relapse and early signs of depression should be addressed. In addition, patients are

encouraged to maintain healthy lifestyles and improve social skills to prevent depression and

improve overall mental health. Many studies highlight the positive effects of psychoeducation

on clinical outcome, adherence and psychosocial functioning in depressed patients (Freher et

al., 2022).

Research and Critical Analysis

Major depressive disorder is a highly prevalent psychiatric disorder. It has a lifetime

prevalence of about 5 to 17 percent, with the average being 12 percent. The prevalence rate is

almost double in women than in men. This difference has been considered to be due to the

hormonal differences, childbirth effects, different psychosocial stressors in men and women,

and behavioral model of learned helplessness. Though the mean age of onset is about 40

years, recent surveys show trends of increasing incidence in younger population due to the

use of alcohol and other drugs of abuse. MDD is more common in people without close

interpersonal relationships, and who are divorced or separated, or widowed. No difference in

the prevalence of MDD has been found among races and socioeconomic status. Individuals

with MDD often have comorbid disorders such as substance use disorders, panic disorder,

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social anxiety disorder, and obsessive-compulsive disorder. Depression is found to be more

prevalent in rural areas than in urban areas (Malhi & Mann, 2018).

An estimated 3.8% of the population experience depression, including 5% of adults

(4% among men and 6% among women), and 5.7% of adults older than 60 years.

Approximately 280 million people in the world have depression. Depression is about 50%

more common among women than among men. Worldwide, more than 10% of pregnant

women and women who have just given birth experience depression. More than 700 000

people die due to suicide every year. Suicide is the fourth leading cause of death in 15–29

year-olds (WHO, 2023).

As per the World Health Organization (WHO) report, it is estimated that 3.3 million

people are affected by depression in the Philippines. Reports show that the Philippines has

the highest number of depressed people in Southeast Asia and the National Statistics Office

reported that mental illness is the third most common form of disability in the country

(Maravilla & Tan, 2021). Clearly, existing reports on the rates of depression in the

Philippines varies widely from one report to the other. Likewise, the proportion of the

estimated 100 million individuals who suffer from anxiety and distress in rural areas,

especially from lower-income communities living in the Philippines. It is likely that the

issues associated with depression and its consequences are even greater in the young adult

Filipino population since depression has been reported elsewhere to have the highest

prevalence among individuals who are between the ages of 15 to 25 (Puyat et al., 2021).

Han et al. (2020) examines the complex link between major depressive disorder

(MDD) and brain aging using data from the ENIGMA major depressive disorder working

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group that includes data from 45 MDD study cohorts from 14 countries across six continents.

With an improved understanding of the influence of MDD on brain structure and function,

this study intends to provide useful insights into the neurobiological elements of depression.

The primary goal of the study is to look at brain aging trends in people with MDD. The

researchers use a collaborative strategy, relying on the ENIGMA consortium's various

datasets and modern neuroimaging techniques, particularly structural magnetic resonance

imaging (MRI). The study involves a large sample size gathered from several groups around

the world, ensuring a broad representation of people with major depressive disorder.

The study uses modern neuroimaging techniques, including structural magnetic

resonance imaging (MRI), to evaluate brain regions and uncover probable structural changes

linked with major depressive disorder. Previous studies have revealed a relationship between

major depressive disorder and hippocampal changes. The study most likely investigates

whether there are any differences in hippocampus volume between people with MDD and

healthy controls. The study investigates changes in cortical thickness and surface area, which

could provide information on the structural integrity of the cerebral cortex in people with

major depressive disorder. The variations in imaging methods among distinct populations

have the potential to generate methodological differences, which could have an impact on the

findings' consistency. A standard approach to all imaging procedures would improve the

internal validity of the research. All possible confounding factors, including differences in

treatment modalities, duration of illness, and complications, might not have been fully taken

into consideration in this study. These variables may affect brain structure apart from MDD.

The investigations’s limitations addresses a critical gap in the literature, marked by a

limited number of studies on the intersection of brain aging and major depressive disorder

(MDD), often constrained by small sample sizes (fewer than 211 patients). The study's

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strength lies in its inclusion of a substantial and diverse cohort, encompassing over 6900

individuals from the ENIGMA MDD consortium, spanning 19 cohorts across 8 countries

worldwide, and capturing an extensive age range (18–75 years). However, this expansive

scope introduces potential variability and heterogeneity, urging researchers to exercise

caution when extrapolating findings to broader populations due to the inherent diversity

within the study cohort. The characteristics of the participants included may also limit the

generalizability of the study's findings. Notably, the reliance on cross-sectional designs in

many neuroimaging studies, including those on brain aging and MDD, hinders concluding

causality or the direction of observed effects. Additionally, the field's reliance on diverse

techniques and protocols in neuroimaging studies, coupled with differences in data

acquisition, preprocessing, and analysis methods across research centers, introduces

variability that can impact the reliability and reproducibility of results. Another consideration

is the potential bias in the literature, where studies with statistically significant results are

more likely to be published, potentially leading to an overemphasis on specific findings and

skewing the overall understanding of the topic. This comprehensive assessment underscores

the need for cautious interpretation and further research to refine and expand our

understanding of the intricate relationship between brain aging and MDD.

Recommendations include further research into certain brain regions would be helpful

to improve the study's findings. It would also be important to determine whether the aging

effects that have been observed are consistent with various types of severe depressive

disorders. Furthermore, combining cognitive tests with brain imaging may offer a more

thorough comprehension of the influence on cognitive processes. Comparing people on

medication with those who are not might be a useful way to investigate how drugs can affect

brain aging. Gaining knowledge on how lifestyle choices like food, exercise, and sleep affect

23
the aging of the brain in major depressive disorder patients could be useful. Additionally,

examining subgroups within major depressive disorder—such as those with differing duration

or severity of symptoms—and combining genetic and epigenetic analyses may offer a more

complex picture of the connection between depression and brain aging.

The findings, which point to possible structural alterations in MDD patients' brains,

have important implications for clinicians. Comprehending these neurological facets may

facilitate the development of focused therapies and therapeutic methodologies. The findings

provide a way for deeper study into the mechanisms behind brain aging in MDD. Further

investigations may examine the effects of treatment approaches, lifestyle choices, and

additional variables on the anatomy of the brain. The research adds to the increasing amount

of data supporting a comprehensive strategy for mental health. It highlights how crucial it is

to take biological factors into account when creating regulations and treatments for

depression.

Conclusion

In conclusion, this comprehensive investigation into major depressive disorder

examined the diagnosis, standards, historical interventions, and the evolving understanding of

the condition over time. The DSM-5 defines depression as a complex set of symptoms that

affect various aspects of life and must be present for at least two weeks to be diagnosed. The

historical journey revealed the attitudes in Mesopotamia, the mistreatment throughout history,

the shift towards humanity with Rhazes, and the various methods used during the Middle

Ages and Renaissance. The Age of Enlightenment brought misguided ideas that led to harsh

treatments and rejected practices, such as Benjamin Franklin's early electroshock therapy.

24
Consensus on recognizing, classifying, and treating mental health disorders gave rise to

categorization systems like the DSM and ICD in the 20th century.

The changing nature of our understanding is evident in the evolution of depression

classifications in the DSM and ICD, which reflect current evidence in the field. Key changes,

such as the exclusion of bereavement-related depression in the DSM-IV and the addition of

sub-diagnoses like "mixed features" and "anxious distress" in the DSM-V, demonstrate

ongoing refinement. Looking at treatment options showcases the advancements in depression

treatment, ranging from psychoanalysis to Deep TMS. Perspectives and available treatments

have expanded due to research, philosophy, and cultural changes coming together. How can

we maintain this momentum in understanding and treating depression, ensuring that new

knowledge leads to more empathetic and effective support networks? How does the changing

definition of depression contribute to reducing stigma and promoting understanding? These

questions highlight the ongoing pursuit of a comprehensive understanding of major

depressive disorder and emphasize the importance of continued research and raising public

awareness for better mental health outcomes.

Upon reflection, it becomes apparent that understanding the biological components of

depression is crucial, as this knowledge plays a vital role in developing effective therapies.

What lessons from the past can we apply to create more compassionate and scientifically

supported depression treatments today? How does the use of categorization systems like the

DSM contribute to a shared understanding of mental health? The significance of developing

new strategies to support individuals with major depressive disorder is underscored by these

questions, which encourage ongoing contemplation on the diagnosis and treatment of the

illness.

25
 In the article, the chemical imbalance concept of depression was explored, with a

focus on neurotransmitters like serotonin, dopamine, and norepinephrine. Imbalances in these

neurotransmitters have been linked to depression symptoms, including mood, sleep, appetite,

and pleasure. Other neurotransmitters like glutamate and acetylcholine have also been

identified as potential factors in depression susceptibility. The role of MRI in understanding

depression was discussed, highlighting its ability to reveal significant differences in the

depressed brain. The study also examined blood-brain barrier disruption, connectivity

distortions, and the use of machine learning algorithms to identify depression-related brain

patterns.

Understanding the biological aspects of depression through neurotransmitter

dysregulation and improved imaging techniques is crucial for enhancing diagnosis and

treatment. How might insights from MRI change how we approach depression diagnosis and

interventions? How can an understanding of neurotransmitter functions lead to more targeted

and effective treatments for individuals with major depression? These questions prompt

reflection on the transformative potential of biological understanding in improving mental

health outcomes for those with depression.

The paper also explored the biological aspects of depression, focusing on imaging

techniques like MRI and PET to understand differences in gray and white matter. Specific

brain regions, including the frontal lobe, hippocampus, temporal lobe, thalamus, striatum,

amygdala, and insula, were studied for their role in depression. MRI revealed patterns of gray

matter density that serve as biological markers of depression, while PET scans visualized the

decline in brain function in depressed individuals, providing insights into molecular

processes. Regional brain imaging studies highlighted abnormalities in the prefrontal

26
neocortex, limbic brain, and reptilian complex, shedding light on the complex network

involved in depression.

Reflecting on the importance of understanding the biological aspects of depression, it

becomes evident that these insights contribute to a nuanced understanding of the condition.

How can the identification of specific brain regions associated with depression inform

targeted interventions and treatment approaches? In what ways can imaging techniques

revolutionize our diagnostic capabilities and enhance personalized treatment plans for

individuals with major depressive disorder? These questions encourage deeper reflection on

the transformative potential of biological understanding in advancing mental healthcare for

those affected by depression.

Furthermore, the paper explored the genetic basis of major depressive disorder

(MDD), emphasizing the role of genes like SLC6A4, HTR2A, and BDNF in influencing

susceptibility and neurotransmitter function. Genome-wide association studies provided

insights into the genetic risk factors associated with MDD, shedding light on the complex

causes of the condition. Considering the genetic aspects of depression, it is clear that a deeper

understanding of molecular and cellular features, including neuroinflammation and

neurotransmitter dysregulation, is crucial. How can this genetic knowledge be used to

develop personalized treatment approaches based on individuals' unique genetic profiles?

What ethical considerations should be addressed when applying genetic information to

depression treatment? These questions prompt further contemplation on the intersection of

genetics and mental health.

The paper also discussed treatment approaches, including pharmacological

interventions like antipsychotics and innovative methods like ketamine for treatment-resistant

depression. Psychotherapeutic techniques, such as Cognitive-Behavioral Therapy (CBT),

27
Problem-Solving Therapy (PST), Marital and Family Therapy (MFT), Psychodynamic

Therapy, Group Therapy, and Psychoeducation, were explored for their roles in managing

and preventing depressive symptoms. Understanding the biological aspects of depression not

only provides insights into the condition's origin but also guides diverse and personalized

treatment strategies.

As we navigate these complexities, how can a holistic approach that integrates genetic

understanding and various therapeutic modalities enhance the well-being of individuals with

major depressive disorder? How might the intersection of genetics and psychotherapeutic

approaches redefine the landscape of depression treatment in the future? These questions

encourage exploration of the evolving dynamics of mental health interventions and their

profound impact on individuals' lives.

In summary, this paper examined the prevalence and impact of major depressive

disorder (MDD) globally, highlighting regional variations, gender differences, and

socioeconomic implications. The study particularly focused on the alarming rates of

depression in the Philippines, emphasizing the urgent need for mental health awareness and

support in the country. By exploring the complex relationship between MDD and brain aging,

the study shed light on structural changes associated with depression using modern

neuroimaging techniques. The focus on brain regions, especially the hippocampus, provided

valuable insights into the neurobiological aspects of depression.

A thought-provoking question arises: How can the findings on structural alterations in

the brains of MDD patients guide the development of targeted therapies and treatment

approaches? Understanding the potential impacts of treatment approaches, lifestyle choices,

and other variables on brain anatomy prompts deeper reflection on the holistic nature of

mental healthcare. As we consider the importance of understanding the biological aspects of

28
depression, we may ask: How can a holistic and personalized approach that considers both

biological and environmental factors enhance the effectiveness of depression prevention and

treatment strategies? This question emphasizes the need for a nuanced understanding of

depression that goes beyond biological markers, incorporating diverse elements for a

comprehensive mental healthcare approach.

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