What Is Depression?
Major depressive disorder (MDD) is not the same as "feeling down for a few days." It is a psychiatric condition with a well-established neurobiological basis, defined by at least two weeks of persistent low mood or loss of interest, accompanied by changes in sleep, appetite, energy, concentration, and self-worth[1].
According to the World Health Organization, approximately 280 million people worldwide are currently affected by depression, making it the leading cause of disability globally[2]. Women have roughly twice the lifetime prevalence of men, although male depression often presents differently, manifesting as irritability, substance use, or overwork, which leads to lower rates of help-seeking[3].
Many patients walk into my clinic saying, "I don't even know what's wrong with me." They can still work, socialise, and smile, but at some point everything starts to feel as though it is happening behind glass. Nothing quite reaches them anymore. That is one of the most disorienting aspects of depression: it does not always look like crying. Sometimes it looks like feeling nothing at all.
Causes and Brain Mechanisms
Depression arises from the interaction of multiple factors. Current neuroscience highlights several key domains:
Neurotransmitter Imbalance
Three major neurotransmitter systems are implicated:
- Serotonin: Regulates mood, sleep, and appetite. Reduced serotonergic activity in the synaptic cleft is the primary target of SSRI antidepressants[4]
- Norepinephrine: Governs alertness and motivation. Deficits are associated with fatigue, poor concentration, and lack of drive
- Dopamine: Central to the reward circuit and the experience of pleasure. Low dopamine function is directly linked to anhedonia, the inability to feel enjoyment
Brain Structural and Functional Changes
Neuroimaging studies have identified structural and functional alterations in key brain regions of people with depression[5]:
Key neurobiological findings in depression
| Brain Region | Normal Function | Changes in Depression |
|---|---|---|
| Prefrontal Cortex | Decision-making, emotion regulation, planning | Reduced activity and grey matter volume, contributing to slowed thinking and indecisiveness |
| Hippocampus | Memory formation, stress regulation | Volume reduction, linked to chronically elevated cortisol under prolonged stress |
| Amygdala | Threat detection, emotional response | Hyperactivity, amplifying responses to negative stimuli while dampening responses to positive ones |
Genetic and Environmental Factors
Twin studies estimate the heritability of depression at around 37%. Having a first-degree relative with depression roughly doubles or triples your risk[3]. However, genes only set the stage. Environmental stressors, such as childhood adversity, bereavement, financial hardship, and chronic interpersonal conflict, often act as the trigger. Epigenetic research has also shown that stress experiences can alter gene expression through mechanisms like DNA methylation, further increasing vulnerability[6].
Common Symptoms
According to the DSM-5 diagnostic criteria[1], at least five of the following nine symptoms must be present during the same two-week period, and at least one must be either the first or second item:
- Depressed mood most of the day, nearly every day (feeling sad, empty, or hopeless)
- Markedly diminished interest or pleasure in nearly all activities
- Significant weight change (more than 5% in a month without dieting) or appetite disturbance
- Insomnia or hypersomnia
- Psychomotor agitation (restlessness, hand-wringing) or retardation (slowed movement and speech)
- Fatigue or loss of energy
- Feelings of worthlessness or excessive guilt
- Diminished ability to think, concentrate, or make decisions
- Recurrent thoughts of death, suicidal ideation, or a suicide plan
In my clinical experience, the symptom patients most often overlook is the second one: loss of interest. Many assume they are simply tired or overworked, without realising that things they once enjoyed no longer spark any motivation. Another commonly missed presentation is in middle-aged men, who may not say "I feel depressed" but instead visit multiple specialists for headaches, chest tightness, or gastrointestinal symptoms that never resolve.
Treatment Options
Medication
International treatment guidelines consistently recommend medication for moderate-to-severe depression[7]. First-line options are SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors). These typically take 4 to 6 weeks to reach full effect, and treatment should continue for at least 6 to 12 months to reduce relapse risk.
Commonly prescribed antidepressants
| Medication | Class | Key Features |
|---|---|---|
| Sertraline | SSRI | Relatively few side effects, often used as first choice for most patients |
| Escitalopram | SSRI | Highly selective, fewer drug interactions |
| Fluoxetine | SSRI | Long half-life, milder discontinuation symptoms, but may be activating |
| Venlafaxine | SNRI | Dual-action on serotonin and norepinephrine, effective for low-drive depression |
| Duloxetine | SNRI | Particularly useful for depression with comorbid chronic pain |
| Mirtazapine | NaSSA | Promotes appetite and sleep, good for patients with severe insomnia and weight loss |
| Bupropion | NDRI | Does not affect sexual function, advantages for anhedonia and fatigue |
These medications are not sedatives and are not addictive. They work by adjusting neurotransmitter levels in the synaptic cleft, allowing the brain's mood regulation systems to gradually recover. When it is time to stop, the dose should be tapered slowly under medical guidance to avoid discontinuation symptoms.
Psychotherapy
Psychotherapy is an essential component of depression treatment. Mild depression may be treated with therapy alone; moderate-to-severe cases are best managed with a combination of therapy and medication. The three best-supported approaches are:
- Cognitive Behavioural Therapy (CBT): Helps identify and restructure negative automatic thoughts such as "I can't do anything right" or "Things will never get better." Research shows CBT is as effective as medication, with superior relapse prevention[8]
- Interpersonal Therapy (IPT): Focuses on four core interpersonal issues: grief, role disputes, role transitions, and interpersonal deficits. Particularly effective when depression is triggered by relationship problems[9]
- Behavioural Activation: Starts by increasing engagement in positive activities, breaking the cycle of "don't want to move, less motivation, worse mood." A short-term approach with rapidly growing evidence
rTMS Treatment
Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive brain stimulation treatment that delivers magnetic pulses to the left dorsolateral prefrontal cortex (DLPFC), increasing activity in this region to improve depressive symptoms.
rTMS has received FDA clearance for treatment-resistant depression. A standard course runs 4 to 6 weeks with five sessions per week. The procedure requires no anaesthesia, and patients can resume normal activities immediately afterward. The most common side effect is mild headache at the treatment site, which typically diminishes over the first few sessions[10].
A large network meta-analysis found that rTMS achieves remission rates of approximately 30% to 35% and response rates of 50% to 55% in treatment-resistant depression[11]. For patients who cannot tolerate medication (for example, during breastfeeding or due to severe side effects) or who have not responded adequately to pharmacotherapy, rTMS is a promising treatment option worth considering.
Self-Assessment
The PHQ-9 (Patient Health Questionnaire-9) is one of the most widely used depression screening tools in the world. It covers the nine core symptoms of the DSM-5 criteria and takes about two minutes to complete. It is not a diagnostic tool, but your score can help you gauge symptom severity and decide whether to seek professional evaluation[12].
PHQ-9 scoring: 0 to 4 = minimal, 5 to 9 = mild, 10 to 14 = moderate, 15 to 19 = moderately severe, 20 to 27 = severe. If your score is 10 or above, or if you scored above zero on item 9 (thoughts of self-harm or suicide), please schedule an appointment with a psychiatrist as soon as possible.
Go to the online self-assessment tool (PHQ-9)
When to Seek Help
Consider booking a psychiatric consultation if any of the following apply to you:
- Low mood or loss of interest lasting longer than two weeks
- Significant deterioration in sleep quality (difficulty falling asleep, waking in the middle of the night, waking too early)
- Noticeable decline in work performance or social functioning
- Thoughts of "life isn't worth living" or self-harm
- Persistent physical symptoms (headaches, chest tightness, digestive issues) that do not respond to treatment from other specialists
Depression is a highly treatable condition. With early intervention, more than 70% of patients experience significant improvement during their first course of treatment[7]. The hardest step is often the first one: walking through the clinic door.
If you are in crisis right now, please call the Taiwan Suicide Prevention Hotline at 1925 (24 hours, free) or go to the nearest emergency department.
References
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). Washington, DC: APA; 2022.
- GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019. Lancet Psychiatry. 2022;9(2):137-150. DOI PubMed
- Malhi GS, Mann JJ. Depression. Lancet. 2018;392(10161):2299-2312. DOI PubMed
- Moncrieff J, Cooper RE, Stockmann T, et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2023;28(8):3243-3256. DOI PubMed
- Schmaal L, Veltman DJ, van Erp TG, et al. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group. Mol Psychiatry. 2016;21(6):806-812. DOI PubMed
- Nestler EJ, Pena CJ, Kundakovic M, et al. Epigenetic basis of mental illness. Neuroscientist. 2016;22(5):447-463. DOI PubMed
- National Institute for Health and Care Excellence (NICE). Depression in adults: treatment and management. NICE guideline [NG222]. 2022. NICE
- Cuijpers P, Berking M, Andersson G, et al. A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments. Can J Psychiatry. 2013;58(7):376-385. DOI PubMed
- Cuijpers P, Donker T, Weissman MM, et al. Interpersonal psychotherapy for mental health problems: a comprehensive meta-analysis. Am J Psychiatry. 2016;173(7):680-687. DOI PubMed
- Perera T, George MS, Grammer G, et al. The Clinical TMS Society consensus review and treatment recommendations for TMS therapy for major depressive disorder. Brain Stimul. 2016;9(3):336-346. DOI PubMed
- Brunoni AR, Chaimani A, Moffa AH, et al. Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis. JAMA Psychiatry. 2017;74(2):143-152. DOI PubMed
- Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-613. DOI PubMed
Want to book with Dr. Tam?
Attending psychiatrist at Ten-Chan General Hospital and Tien-Hsiang Hospital, Zhongli. Consultations in English, Mandarin, and Cantonese.
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