🧠 Overview — Overview of Major Depressive Disorder (MDD)
Major Depressive Disorder (MDD), or “major depressive disorder,” is one of the mood disorders that most deeply affects the brain, mind, and behavior in human beings.It is not just a “sad mood” that will fade away on its own over time, but rather a state in which the brain systems that regulate mood and motivation fall out of balance, until the sense of “wanting to live” and “seeing value in oneself” gradually fades away without the person even realizing it.
People with MDD often describe their feelings as if they are “trapped in a dark hole” — the outside world looks the same, but the brain can no longer register or feel happiness.
Even when good things happen around them — such as friends inviting them out, or receiving compliments from a loved one — they still “feel nothing,” as if their emotions have been cut off from the world (emotional numbness).
A key point of MDD is that symptoms must continue for at least 2 weeks or more,
and it is not just a period of “feeling tired” or “temporary burnout” from daily life stress.
In many cases, symptoms may persist for months or recur in episodes throughout a lifetime, with each episode often being severe enough to disrupt functioning in all areas of life.
MDD is classified as a type of “Unipolar Depression,” which is different from bipolar disorder where there are periods of abnormally elevated mood (mania/hypomania) alternating with depressive episodes.
Patients with MDD have only depressive episodes, without episodes of abnormally elevated mood.
The World Health Organization (WHO) estimates that depression is one of the leading causes of loss of work capacity and overall functioning worldwide,
with more than 280 million people living with depression globally, and the number is rising every year — especially in adolescents and working-age adults who face high levels of pressure.
In some countries, MDD has become one of the key factors underlying suicide and social dysfunction, to the point where governments must intervene at the policy level.
What makes MDD particularly complex is that it frequently occurs together with other conditions (comorbidities) such as anxiety disorders, burnout, insomnia, ADHD, or even chronic physical illnesses like diabetes and heart disease.
When these occur together, the depressive symptoms become even more “deeply hidden,” and the person may not realize they are suffering from depression, instead thinking they are “just tired from work” or “just being lazy for a while.”
From a brain-based perspective, MDD arises from dysfunction in multiple systems at the same time — including neurotransmitters (serotonin, dopamine, norepinephrine), the HPA axis (stress system), and brain circuits between the prefrontal cortex and the amygdala that regulate mood and motivation.
When these brain areas fail to coordinate properly, the person feels as if they have completely lost control over their own emotions.
This disorder can occur in all genders, all ages, and across all occupational levels.
Even people who appear “successful” in the eyes of others can be affected, without anyone noticing, because they often hide their symptoms behind a smile (often referred to as “Smiling Depression”).
Most importantly, understanding that MDD is not a sign of personal weakness is crucial.
It is a “brain disorder” that can be treated and improved, just like other physical illnesses, if appropriate care is received early on.
Clinically, MDD may occur as only one episode in a lifetime (single episode),
or it may appear recurrently in multiple episodes (recurrent depression), which often requires long-term, ongoing treatment to prevent relapse.
Ultimately, the goal of understanding MDD is not just to know “what depression is,”
but to recognize that sadness that goes beyond normal limits is a signal from the brain asking for help,
and once we understand this, we can help ourselves or the people around us in more accurate and compassionate ways.
🧩 2. Core Symptoms — Core Symptoms of Major Depressive Disorder (MDD)
The symptoms of MDD are not limited to “feeling sad” or “crying.”Instead, it is a disturbance that operates simultaneously at the levels of emotion, cognition, brain function, and the body,
which together cause the entire life system to stall — as if the brain has switched from the mode of “wanting to live” to merely “existing day by day.”
Neuropsychologists often divide the core symptoms of MDD into four major dimensions,
each of which reflects and reinforces the others over time, as follows:
2.1 Emotion (Affective Symptoms)
Symptoms in this dimension are the “heart of the disorder” —
a state of persistent, deep sadness that is not proportionate to, or directly explained by, current life events.
Patients often describe themselves as “not knowing why they feel sad” or “waking up already feeling like they have no energy or will to live.”
A pervasive sense of hopelessness, emptiness, or meaninglessness steadily takes over the mind.
The joy and excitement they once felt completely disappear — even for things they used to love, such as music, hobbies, or time with loved ones.
There is often emotional flattening: a blank or flat facial expression, a soft or monotonous voice, as if they “don’t feel anything” at all.
In some cases — especially in men or adolescents — the emotion may present more as anger or irritability rather than obvious sadness (irritable depression).
There is a tendency to interpret even small daily events as personal failures, for example:
“He didn’t reply to my chat, which must mean no one wants me anymore.”
Key terms:
Depressed mood, Hopelessness, Worthlessness, Anhedonia (loss of pleasure), Guilt
2.2 Cognition and Perception (Cognitive Symptoms)
The brain’s information-processing system (cognitive system) becomes impaired in almost every domain.
Repetitive negative thinking (Negative Automatic Thoughts):
The brain gets “stuck in a loop” of thoughts such as “I’m a failure / I’m worthless / nothing will ever get better.”
These thoughts arise automatically and are very difficult to control.
Emotional bias: The brain selectively remembers only negative events and filters out positive ones.
Executive dysfunction: Planning, organizing time, and making decisions become extremely difficult tasks.
Attention & Memory Impairment: Reduced concentration, forgetfulness, slowed thinking — like having “thick fog in the head” (brain fog).
Pessimistic future orientation: Inability to see a positive future, with a belief that “no matter what I do, nothing will improve.”
Suicidal ideation: Some individuals begin to have thoughts of wanting to disappear from the world — ranging from passive wishes to die to actively planning or attempting suicide.
Clinicians often find that the prefrontal cortex and anterior cingulate cortex function at reduced levels during this phase.
This leads to the brain becoming “locked in a mode of negative self-evaluation,” unable to shut down that cycle on its own.
2.3 Body and Biology (Somatic / Neurovegetative Symptoms)
MDD is a disorder that is clearly reflected in the body,
even when there is no underlying physical illness. The brain, hormones, and autonomic nervous system malfunction in such a way that physical symptoms appear as if there were a bodily disease.
Sleep: Difficulty falling asleep or frequent nighttime awakenings (insomnia),
or, in some cases, the opposite — excessive sleeping (hypersomnia) while still feeling tired.
Appetite: Appetite may decrease to the point of significant weight loss, or increase due to using food to regulate emotion (emotional eating).
Energy: Easily fatigued, feeling drained, and lacking energy even for small daily tasks such as getting out of bed or taking a shower.
Psychomotor changes: Some individuals become abnormally slow (psychomotor retardation) —
walking slowly, speaking slowly, as if their body is extremely heavy.
Others show the opposite pattern, becoming restless (psychomotor agitation) — pacing, nail-biting, or constantly fidgeting.
Pain and discomfort: Commonly reported symptoms include headaches, back pain, stomach pain, and other aches without a clear physical cause.
Other biological systems: The sleep–wake cycle (circadian rhythm) and cortisol secretion patterns become dysregulated.
This weakens the immune system and leads the brain to misinterpret the body as being “sick” even when no clear physical illness is present.
2.4 Behavior and Daily Functioning (Behavioral / Functional Symptoms)
When emotion, cognition, and the body all deteriorate simultaneously, day-to-day behavior inevitably changes in noticeable ways.
Withdrawal: Pulling away from friends, family, and all social activities.
Reduced self-care: Not showering, skipping meals, or letting the room become messy because they “don’t have the energy to care.”
Productivity drop: A clear decline in work performance, academic performance, or ability to meet responsibilities.
Avoidance: Avoiding facing problems — for example, not opening emails, not answering phone calls.
Emotional burnout: Feeling completely burned out, not wanting to start anything new, and not wanting to plan for the future.
Loss of motivation: Even when they know what needs to be done, they cannot “move” themselves to begin.
From the outside, this may look like “laziness,” but in reality, this reflects reduced functioning in the brain’s motivation circuit (fronto–striatal network),
which can be clearly seen in brain imaging studies.
🔹 Summary of Core Symptom Dimensions in MDD
| Dimension | Main Brain Mechanisms Involved | Example Key Symptoms |
|---|---|---|
| Emotion (Affective) | Amygdala, Insula, vmPFC | Sadness, despair, hopelessness |
| Cognition (Cognitive) | DLPFC, ACC, Hippocampus | Rumination, poor concentration, negative view of the future |
| Body (Somatic) | HPA Axis, Circadian System | Insomnia, fatigue, loss of appetite |
| Behavior (Behavioral) | Striatum, Dopaminergic Pathway | Social withdrawal, absenteeism, lack of self-care |
📋 3. Diagnostic Criteria — Diagnostic Criteria (DSM-5 / DSM-5-TR)
The diagnosis of MDD is based on the psychiatric manual of the American Psychiatric Association (APA),using the criteria for a Major Depressive Episode (MDE) as the foundation.
If a patient has had at least one MDE and has never had a manic or hypomanic episode → they are diagnosed with MDD.
3.1 Basic Conditions
1️⃣ The person has at least 5 out of 9 core symptoms listed below.
2️⃣ Symptoms occur nearly every day, for most of the day.
3️⃣ Symptoms persist for at least 2 consecutive weeks.
4️⃣ At least 1 of the first 2 symptoms must be present:
(1) Depressed mood
(2) Loss of interest or pleasure (Anhedonia)
3.2 The 9 DSM-5 Criteria
| Order | Core Symptom | Clinical Description |
|---|---|---|
| (1) | Depressed mood | Feeling sad, empty, or hopeless almost every day; in children and adolescents this may present as irritability. |
| (2) | Loss of interest or pleasure (Anhedonia) | Markedly diminished interest or pleasure in activities previously enjoyed; reduced desire for social interaction. |
| (3) | Appetite or weight change | Significant weight loss or gain (more than 5% within one month), or marked changes in appetite. |
| (4) | Sleep disturbance | Insomnia (trouble falling or staying asleep) or hypersomnia (sleeping excessively). |
| (5) | Psychomotor changes | Observable psychomotor agitation or retardation — either restlessness or slowed movements/speech noticeable to others. |
| (6) | Fatigue or loss of energy | Feeling tired or having a lack of energy almost every day; difficulty carrying out usual activities. |
| (7) | Feelings of worthlessness or guilt | Excessive or inappropriate guilt, or feelings of worthlessness, even over minor issues. |
| (8) | Cognitive impairment | Diminished ability to think, concentrate, or make decisions. |
| (9) | Suicidal ideation | Recurrent thoughts of death, suicidal ideation, plans, or attempts. |
3.3 Additional DSM-5 Requirements
The symptoms must cause clinically significant distress
or impairment in social, occupational, or academic functioning in at least one major area of life.
These symptoms must not be attributable to the physiological effects of a substance or another medical condition —
for example, medications, alcohol, or thyroid disorders.
There must be no history of mania or hypomania
(if such a history exists, bipolar disorder must be considered instead).
3.4 Levels of Severity (Severity)
DSM-5 divides the severity of MDD into three broad levels to help guide treatment planning:
- Mild Depression — Symptoms meet the minimum of 5 criteria, but the person is still able to function to some degree.
- Moderate Depression — Symptoms clearly interfere with daily life and functioning.
- Severe Depression — Marked impairment in all areas of functioning and/or the presence of suicidal thoughts or behaviors.
3.5 Types of Episode (Course Specifiers)
- Single Episode: Only one depressive episode occurs over the lifespan.
- Recurrent: Multiple episodes (at least 2 episodes), with each episode separated by at least ≥ 2 months of full remission.
- Chronic Depression: Depressive symptoms persist for ≥ 2 years (may overlap with Persistent Depressive Disorder).
3.6 Key Clinical Red Flags
- Insomnia combined with suicidal ideation = a high-risk warning sign.
- Marked appetite loss and significant weight loss → evaluation for thyroid issues and other chronic illnesses is recommended.
- If there are periods of “abnormally elevated mood” or “talking very fast, being excessively driven” during what appears to be a depressive episode → screening for bipolar disorder is necessary.
3.7 Additional Assessment
Clinically, psychiatrists or clinical psychologists often use additional assessment tools such as:
- PHQ-9 (Patient Health Questionnaire-9):
A brief screening tool that aligns with the 9 DSM-5 criteria. - HAM-D / MADRS:
Scales used in research and clinical practice to rate the severity of depression. - Suicidal Risk Assessment:
Structured assessment of suicidal thoughts, intent, plans, and access to means.
🧠 In-depth Note
Although DSM-5 primarily uses behavioral criteria,modern research shows that neurocircuit dysfunction is the fundamental root of all these symptoms.
Therefore, the treatment of MDD should be approached as a “whole-brain” problem,
rather than just an attempt to “fix sadness” on the surface.
4. Subtypes or Specifiers — Subtypes / Specifiers of MDD
DSM-5 / DSM-5-TR uses the term “specifiers” to describe additional specific characteristics of each depressive episode, such as severity, course, and distinctive symptom patterns, etc. Wiley Online Library+2Wikipedia+2The commonly seen groups include:
4.1 By Severity & Course — Based on Severity and Course
- Mild / Moderate / Severe — Classified by the number of symptoms, their intensity, and the impact on functioning.
- With Psychotic Features — Presence of delusions and/or hallucinations (which may be mood-congruent or mood-incongruent).
- In Partial / Full Remission — Indicates whether the person is partially improved or has fully recovered from a previous episode.
- Single Episode / Recurrent — Whether a depressive episode has occurred only once, or if multiple episodes have occurred over time.
4.2 Symptom Pattern Specifiers — Distinct Symptom Patterns
- Loss of almost all capacity for pleasure; mood does not improve in response to positive events.
- Symptoms are worse in the morning; early morning awakening; poor appetite and weight loss; marked psychomotor retardation.
- Mood can still react to positive events to some extent.
- Increased appetite and weight gain; hypersomnia; heavy, leaden feeling in the limbs (leaden paralysis).
- Marked sensitivity to interpersonal rejection.
- Prominent anxiety, tension, and fear of losing control or “going crazy” accompanying depression.
- Associated with a higher risk of suicide and somewhat different treatment response patterns. PMC
- Some opposite-pole (hypomanic/manic-like) symptoms appear within the depressive episode,
such as increased energy, talkativeness, or racing thoughts.
- Presence of motor abnormalities such as stupor, mutism, rigidity, or repetitive, purposeless movements.
4.3 Time & Trigger Related Specifiers — Linked to Time / Triggers
- With Seasonal Pattern — Depression occurs in a seasonal pattern (e.g., worsening during winter).
- With Peripartum Onset — Onset during pregnancy or within a specified period after childbirth.
These specifiers help clinicians:
- Understand the underlying brain and hormonal mechanisms that differ between each pattern.
- Choose treatment strategies and estimate prognosis with greater precision.
🧠 5. Brain & Neurobiology — Brain and Neurobiology of Major Depressive Disorder (MDD)
MDD is not merely “sadness” or “negative emotions.”It is a network-level dysfunction of the brain
that affects emotion, cognition, perception, and the physiological functioning of the body.
In other words, MDD is a “whole-brain disorder” that involves four key axes:
1️⃣ The neurotransmitter system (Monoamine System)
2️⃣ The stress and endocrine system (HPA Axis)
3️⃣ Functional brain networks (Neurocircuitry Networks)
4️⃣ Inflammation and brain repair (Neuroinflammation & Neuroplasticity)
5.1 Monoamine Hypothesis — The Neurotransmitter Hypothesis
This classical hypothesis proposes that MDD arises from an imbalance of brain chemicals, specifically:
Serotonin, Norepinephrine, and Dopamine.
Serotonin (5-HT):
Involved in regulating mood, sleep, appetite, and feelings of calm.
When serotonin levels decrease → feelings of sadness, apathy, and anxiety arise.
Norepinephrine (NE):
Involved in arousal, attention, and motivation.
A lack of NE leads to lethargy, poor concentration, and reduced drive to start new activities.
Dopamine (DA):
The neurotransmitter of “reward and motivation” (reward & motivation system).
Reduced dopamine results in loss of interest in previously enjoyable activities (anhedonia),
and is linked to a reduction in reward-seeking behaviors.
These findings led to the development of many antidepressant classes such as SSRIs, SNRIs, TCAs, and MAOIs,
which help “restore neurotransmitter balance.” However, later research found that this is not the full story of the disorder,
since some patients with normal serotonin levels still experience depression.
Thus, modern neuroscience views neurotransmitter abnormalities as downstream effects of deeper structural and circuit-level changes in the brain.
5.2 HPA Axis & Stress System — The Body’s Stress Axis
The Hypothalamic–Pituitary–Adrenal (HPA) axis is the system connecting the brain and adrenal glands,
regulating the stress response through the hormone cortisol.
In patients with MDD, this system is often in a state of chronic hyperactivation.
- Exposure to stress → the hypothalamus secretes CRH.
- CRH stimulates the pituitary gland to secrete ACTH.
- ACTH stimulates the adrenal glands to secrete cortisol.
- Cortisol should then feed back to shut down further release (negative feedback) once the situation resolves.
However, in MDD this feedback mechanism is disrupted → resulting in persistently elevated cortisol levels throughout the day,
which leads to shrinking of the hippocampus (responsible for memory and inhibiting the stress response),
and increased inflammation within the brain.
The result is a self-perpetuating loop of “stress–cortisol–depressed mood”,
causing the brain to adopt a new neural baseline of sadness as its default state.
5.3 Neurocircuitry Dysfunction — Abnormal Brain Circuits
The brains of individuals with MDD show dysfunctional activity across multiple major networks:
(A) Limbic System — Emotional Circuit
- Amygdala: Overreacts to emotional stimuli, particularly fear and social rejection.
→ Causes the brain to interpret окружаing events in a negative light.
- Hippocampus: Responsible for memory and linking experiences with emotion.
→ Often “shrinks” and functions less efficiently in MDD due to chronic elevated cortisol.
(B) Prefrontal Cortex — Reasoning and Emotional Control Circuit
- Dorsolateral Prefrontal Cortex (DLPFC):
Used for rational thought, planning, and cognitive control, but functions below normal in MDD.
→ As a result, “reasoning can’t overpower sadness.” - Ventromedial / Orbitofrontal Cortex:
Involved in evaluating reward value and emotional decision-making.
→ When dysfunctional, everything is perceived as “worthless” or “not worth the effort.”
(C) Default Mode Network (DMN)
- A network that becomes active when the brain is “at rest” or engaged in self-referential thinking.
- In MDD, this network becomes overconnected, leading to rumination —
(D) Reward Network (Mesolimbic Pathway)
- Composed of the Ventral Tegmental Area (VTA) and Nucleus Accumbens (NAc),
which regulate dopamine release and feelings of reward and pleasure. - In MDD, connectivity between these regions is reduced → patients no longer “feel good” from things they used to enjoy.
5.4 Neuroinflammation & Immune System — Brain-level Inflammation
New research suggests that MDD is associated with chronic low-grade inflammation,
which leads the brain to produce inflammatory molecules called cytokines such as IL-6, TNF-α, and CRP.
These substances can cross the blood–brain barrier
and activate microglia — the brain’s immune cells — into an overactivated state.
This leads to ongoing changes:
- Reduced production of serotonin.
- Increased breakdown of tryptophan into kynurenine → which can generate neurotoxic metabolites.
- Neurons maintain a pro-inflammatory signaling state over time.
There is also evidence that
chronic systemic inflammation — for example, from obesity, chronic allergies, or heart disease —
can increase the risk of developing MDD, because the immune system and brain are directly linked via the vagus nerve (Vagus Nerve).
5.5 Neuroplasticity — Brain Repair and Recovery
In the past, it was believed that the adult brain “stops growing.”
However, it is now known that the brain can form new connections (synaptic plasticity),
especially in areas like the hippocampus and prefrontal cortex.
In MDD, neurogenesis (creation of new neurons) is reduced,
and synaptic connections between neurons are weakened.
Many antidepressants, such as SSRIs or ketamine, have been shown to increase levels of BDNF (Brain-Derived Neurotrophic Factor),
a protein that helps neurons grow, survive, and form stronger connections.
This supports the brain in restoring emotional balance over the long term.
🔹 Summary of Brain Changes in MDD
| System | Finding in MDD | Impact on Mood |
|---|---|---|
| Serotonin / NE / DA | Decreased | Reduced pleasure and motivation |
| HPA Axis | Elevated cortisol | Chronic stress, poor sleep |
| Amygdala | Hyper-responsive | Heightened sensitivity to criticism, fear of rejection |
| Prefrontal Cortex | Underactive | Reasoning cannot override sadness |
| Hippocampus | Atrophied | Impaired memory, repetitive negative thinking |
| Reward Circuit | Impaired | No pleasure from previously enjoyable activities |
| Inflammation | Increased | Low-grade brain inflammation |
| BDNF | Decreased | Slower brain repair and plasticity |
🌍 6. Causes & Risk Factors — Causes and Risk Factors of MDD
MDD does not have a single cause.It usually arises from the convergence of multiple factors — biological, psychological, and social,
which in psychiatry are referred to collectively as the Biopsychosocial Model of Depression.
6.1 Biological Factors
1️⃣ Genetics
- Twin studies show that the heritability of depression is around 30–40%.
- Relevant genes include SLC6A4 (serotonin transporter), BDNF, COMT, 5-HTTLPR, etc.
- Having a first-degree relative with depression increases one’s risk by 2–3 times.
2️⃣ Hormones and Endocrine System
- Dysregulation of the HPA axis, thyroid hormones, and female sex hormones directly affects mood.
- In women, fluctuations in estrogen levels before menstruation or after childbirth are significant triggers.
3️⃣ Brain Structure and Neuroanatomy (Neurostructure)
- Patients with MDD often have smaller hippocampal and prefrontal cortex volumes compared to healthy individuals.
- Connectivity within the limbic–frontal network is imbalanced.
4️⃣ Chronic Physical Illnesses
- Conditions such as diabetes, hypertension, heart disease, Parkinson’s disease, or autoimmune disorders all increase the risk of depression.
- One reason is that chronic inflammation directly affects brain chemistry.
5️⃣ Medications and Substances
- Certain drugs — such as corticosteroids, interferon, isotretinoin, as well as alcohol, nicotine, and some sleeping pills —
can trigger or exacerbate depressive symptoms.
6.2 Psychological and Developmental Factors
1️⃣ Childhood Trauma
- Abuse, neglect, or lack of love and emotional safety during childhood makes the brain build a “hypervigilant threat circuit.”
- This leads to an amygdala that is easily triggered and an HPA axis that is hyper-responsive throughout life.
2️⃣ Negative Cognitive Schemas
- According to Aaron Beck’s theory, depressed individuals have a “negative cognitive triad” —
they view themselves, the world, and the future in a pessimistic, distorted manner. - The brain preferentially encodes negative information and filters out positive experiences without awareness.
3️⃣ Personality Traits
- Those with perfectionism, high neuroticism, or strong self-criticism are at greater risk for MDD.
- “Caretaker” personalities, who constantly shoulder others’ emotions, are also particularly vulnerable.
4️⃣ Major Losses or Life Transitions
- Events such as divorce, job loss, or the death of a loved one
5️⃣ Learned Helplessness
- Repeated exposure to failure or uncontrollable negative situations teaches the brain that “nothing I do makes a difference,”
eventually resulting in a chronic state of psychological paralysis.
6.3 Social and Environmental Factors
1️⃣ Social Isolation
- Lack of meaningful connection with others is a major risk factor for MDD.
- The human brain needs interaction and “mirror neuron” feedback to maintain emotional balance.
2️⃣ Socioeconomic Stress
- Work-related stress, financial strain, debt, or job insecurity
can chronically activate the HPA axis, driving the system toward depression.
3️⃣ Bullying and Stigma
- Especially in adolescence, being bullied or stigmatized triggers brain responses similar to physical injury,
because the brain treats social rejection as a real threat.
4️⃣ Family Climate
- Families characterized by violence, negative communication, or lack of emotional safety
teach children to internalize schemas like “I am not worthy of love.”
5️⃣ Culture and Society (Cultural Factors)
- In some cultures, sadness and vulnerability are labeled as “abnormal” or “weak,”
resulting in people being unwilling to seek help. - Achievement-oriented cultures, which place strong emphasis on success and productivity,
tend to have higher rates of MDD than cultures that prioritize family and togetherness.
6.4 Emerging Risk Domains in Modern Research
Gut–Brain Axis:
- Imbalance in gut microbiota (microbiota dysbiosis) affects serotonin production and brain inflammation.
Epigenetics:
- Stress can alter gene expression via methylation and other epigenetic mechanisms, without changing the underlying DNA sequence.
Digital Stress:
- Excessive consumption of online media — especially social comparison on social networks —
increases the prevalence of MDD in adolescents and young adults.
🔹 Summary of Risk Factors for MDD
| Factor Group | Examples | Resulting Effects |
|---|---|---|
| Biological | Genes, hormones, brain, physical illness | Increased sensitivity to stress |
| Psychological | Trauma, cognitive bias, personality | Formation of entrenched negative thinking patterns |
| Social | Isolation, pressure, culture | Reduced emotional and social support |
| Modern | Gut–brain axis, epigenetics, online stress | Triggers inflammation and neurotransmitter dysregulation |
7. Treatment & Management — Treatment and Management Strategies
Mainstream treatment for MDD typically involves a combination of multiple approaches: psychotherapy, antidepressant medication, physical health and lifestyle interventions, and in some cases advanced biological treatments such as ECT or rTMS, according to international clinical guidelines. PMC+4AAFP+4Ministry of Health Malaysia+4Very important: The choice of treatment must be evaluated by a physician/psychiatrist.
One should never start or stop medication on their own.
7.1 Initial Assessment
- Evaluate severity: mild / moderate / severe.
- Screen for suicidal risk in detail.
- Conduct physical examinations and blood tests to rule out medical conditions that may be related (e.g., thyroid problems).
- Assess for comorbid disorders such as anxiety disorders, bipolar disorder, substance use disorders, ADHD, ASD, etc.
7.2 Psychotherapy — Psychological Treatments
Well-supported approaches include:
Cognitive Behavioral Therapy (CBT)
- Focuses on identifying and restructuring distorted negative thoughts.
- Includes behavioral activation, encouraging patients to re-engage with meaningful activities.
Interpersonal Therapy (IPT)
- Focuses on relationships, social roles, loss, and interpersonal conflict.
Other formats include psychodynamic psychotherapy, mindfulness-based therapies, etc.
Many international guidelines recommend using psychotherapy alone or in combination with medication,
particularly in cases of mild–moderate depression. American Psychological Association+2ACP Journals+2
7.3 Pharmacotherapy — Antidepressant Medications
Main classes include:
- SSRIs (e.g., sertraline, fluoxetine, escitalopram)
- SNRIs (venlafaxine, duloxetine)
- Atypical antidepressants (bupropion, mirtazapine, etc.)
- Older drugs such as TCAs and MAOIs are used in specific cases under specialist supervision.
Key principles:
- Medications must be taken continuously for several weeks before clear benefits are seen.
- After improvement, treatment usually needs to continue to prevent relapse (maintenance phase).
- Side effects may occur and must be monitored in collaboration with a physician.
- If there is inadequate response, clinicians may adjust the dose, switch medications, or use combination therapy in accordance with guidelines.
7.4 Neurostimulation & Other Biological Treatments
Used in cases that are very severe / high suicide risk / treatment-resistant:
Electroconvulsive Therapy (ECT)
- Has strong evidence for severe MDD, especially when psychotic features are present or risk is high.
Repetitive Transcranial Magnetic Stimulation (rTMS)
- Uses magnetic fields to stimulate brain areas involved in mood regulation.
Ketamine / Esketamine (in some countries)
- Rapid-acting treatments used in certain cases of treatment-resistant major depression, under close medical supervision.
7.5 Lifestyle & Psychosocial Interventions
These are not “miracle cures,” but they are the foundation of long-term recovery:
- Establish a consistent sleep–wake cycle (sleep hygiene).
- Engage in regular, moderate exercise → evidence shows it can significantly reduce depressive symptoms.
- Maintain balanced nutrition; reduce alcohol and substance use.
- Build a social support system: family, friends, peer support groups.
- Practice stress management skills (e.g., mindfulness, relaxation, breathing exercises).
8. Notes — Additional Observations
- MDD is not personal weakness, but a disorder with clear biological and psychosocial underpinnings.
- Diagnosis requires time for interviews and professional assessment; it cannot rely solely on online self-tests.
- MDD frequently co-occurs with other conditions (comorbidities) such as anxiety, PTSD, substance use, ADHD, ASD, etc., which influence treatment strategies and prognosis.
- Early treatment reduces the likelihood of chronic recurrent episodes and minimizes long-term impact on the brain.
- If there are clear suicidal thoughts, one must seek immediate help, such as contacting medical personnel or mental health hotlines in their country.
All of this content is intended for educational purposes and cannot replace professional diagnosis or individualized medical advice.
If you suspect you may have MDD, you should see a psychiatrist or clinical psychologist for a formal evaluation.
📚 References — Academic Sources
Otte, C., et al. (2016). Major depressive disorder. Nature Reviews Disease Primers, 2, 16065.
➤ A highly in-depth review of the biology, brain mechanisms, and neuro-pathophysiology of MDD.
Cui, L., et al. (2024). Major depressive disorder: hypothesis, mechanism and translational research. Signal Transduction and Targeted Therapy, 9(1), 45.
➤ Modern research on the HPA axis, inflammation, and neuroplasticity.
Li, Z., et al. (2021). Major depressive disorder: Advances in neuroscience research of the pathophysiology and treatment. Neuroscience Bulletin, 37(8), 1019–1035.
➤ Explains the connections between the limbic system, prefrontal cortex, and default mode network.
Karrouri, R., et al. (2021). Major depressive disorder: Validated treatments and future directions. Frontiers in Psychiatry, 12, 692168.
➤ A comprehensive summary of treatment and biological aspects of depression.
Duman, R. S., & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: Potential therapeutic targets. Science, 338(6103), 68–72.
➤ Describes neuroplasticity mechanisms and the role of BDNF in MDD.
Belmaker, R. H., & Agam, G. (2008). Major depressive disorder. The New England Journal of Medicine, 358(1), 55–68.
➤ A classic medical overview of the causes and brain mechanisms of MDD.
Bains, N., & Abdijadid, S. (2023). Major Depressive Disorder. StatPearls [Internet].
➤ Updated clinical summary from the StatPearls medical database.
American Psychiatric Association (APA). (2022). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR).
➤ The standard reference for MDD diagnostic criteria.
World Health Organization (WHO). (2023). Depression: Key facts.
➤ Global statistics and overview of the burden of depression.
Haroon, E., et al. (2018). Inflammation and the pathophysiology of depression. Nature Reviews Immunology, 18(11), 641–655.
➤ Shows the connection between the immune system and depression.
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