Major Depressive Disorder

• 4th leading cause of disability worldwide with approximately ~$85 billion/year loss of productivity ^[2]
• WHO ranks MDD as the single largest contributor to global disability (years lived with disability, YLD) ^[1]
• Lifetime prevalence: 10–20% globally ^[2]
• 12-month prevalence: ~7% in Western populations; varies by country

• 2.9% prevalence in Hong Kong (Hong Kong Mental Morbidity Survey, HKMMS) ^[2][4]
• This is likely an underestimate due to:
  • Stigma around mental illness in Chinese culture → under-reporting
  • Tendency to present with somatic complaints rather than mood symptoms (somatisation)
  • Under-recognition in primary care
• Increasing trend over time ^[2]

• Mean age of onset ≈ 27 years, commonest in 18–44 year age group ^[2]
• ↑ in females (2–3×), unemployed, divorced ^[2]
• Reasons for female preponderance are uncertain. Postulated reasons include ^[2]:
  1. Greater readiness of women to admit depressive symptoms
  2. Misdiagnosis as alcohol-related disorder in men (due to higher rates of comorbid alcohol abuse)
  3. Social disadvantages in women
  4. Female hormones may sensitise the brain to effects of stress
• ↑ comorbidity with other disorders, especially anxiety and substance abuse ^[2]

Depression is NOT just a "mood problem" — it has systemic medical consequences ^[2]:

• ↑ Morbidity: associated with ↓ birth weight, chronic medical illness, poor self-perceived health, functional and cognitive impairment
• ↑ Mortality: RR 1.2–4.0× non-suicide mortality ^[2]
  • Why? Behavioural risk factors (poor treatment adherence, inactivity, ↑ alcohol), biological risk factors (altered thrombogenesis, HPA axis dysregulation → cardiovascular risk), and subclinical/prevalent disease (CVS diseases) ^[2]

• Stress and trauma: long-term difficulties, recent life events (in particular events that lead to feelings of entrapment and humiliation) ^[3]
• ↑ 6× risk of adverse life events before onset of MDD ^[2]
• Especially common in losses (bereavement, breakup), entrapment, and humiliation (e.g., bullying) ^[2]
• Less important in established melancholic depression and strong family history (? ↓ threshold for spontaneous episodes) ^[2]
• Medical illnesses can act as non-specific stressors or cause depression via physiological mechanisms (e.g., Cushing's disease, puerperium, hypothyroidism) ^[2]

• Ongoing psychosocial stressors (poverty, abusive relationship, chronic pain)
• Cognitive distortions (see Cognitive Theory below)
• Substance misuse (alcohol is a depressant → vicious cycle)
• Non-adherence to treatment
• Social isolation and withdrawal (symptom becomes perpetuator)
• Comorbid medical illness

The three monoamine systems implicated in depression originate from brainstem nuclei that belong to the reticular activating system (RAS) ^[2]:

1. Serotonin (5-HT) — from dorsal raphe nuclei

   • Affects body temperature, regulates sleep and wakefulness, mood and impulse control ^[3]
   • Low levels of serotonin metabolites found in the brains of suicide decedents and spinal fluids of depressed patients ^[3]

2. Noradrenaline (NE) — from locus coeruleus

   • Regulates mood and anxiety levels ^[3]
   • Mood symptoms emerged among patients who took propranolol (beta-blocker) ^[3]

3. Dopamine (DA) — from ventral tegmental area (VTA)

   • Regulates motor and mental activity, attention and motivation ^[3]
   • Dopaminergic neurons in the mesolimbic reward pathway play an important role in motivation, reinforcement, and the pleasure response ^[3]
   • However, they are diminished in the brains of suicidal decedents with depression ^[3]

These neurones regulate global behavioural states — sleep-wake cycle, appetite, motor activity, learning and memory, emotional processes ^[2]. This is why depression disrupts so many different functions simultaneously.

Based on number of symptoms, symptom intensity, and functional impairment:

• Mild: Few, if any, symptoms beyond minimum criteria; minor functional impairment
• Moderate: Symptoms and functional impairment between mild and severe
• Severe: Most symptoms present, marked functional impairment; may have psychotic features

• Dysthymia (Persistent Depressive Disorder): Persistent depressive symptoms NOT meeting full criteria for ≥ 2 years. Usual onset in early adulthood. May be associated with superimposed major depressive episodes ("double depression") ^[2]

  • Lifetime risk ~4%, higher in women and divorced ^[2]

• Minor anxiety-depressive (affective) disorders: Very commonly seen in primary care (6.9% prevalence). Commonly present with prominent somatic symptoms. Mood symptoms (anxiety, depression, irritability) + somatic symptoms (fatigue, insomnia, bodily preoccupation) + cognitive symptoms (poor concentration) ^[2]

The clinical features of MDD are best understood through the lens of the affected neurotransmitter systems and brain regions. Every symptom has a pathophysiological basis.

• Occur in ~15–20% of severe depressive episodes
• Usually mood-congruent (content consistent with depressive themes):
  • Delusions of guilt ("I have caused terrible harm")
  • Delusions of worthlessness ("I am nothing")
  • Nihilistic delusions ("I am already dead," "my organs are rotting" — Cotard's syndrome)
  • Delusions of poverty ("I have lost everything")
  • Somatic delusions ("I have cancer/AIDS")
  • Persecutory delusions ("I deserve to be punished")
  • Auditory hallucinations (usually second-person derogatory voices — "you are worthless")
• Mood-incongruent psychotic features are possible but should raise suspicion for schizoaffective disorder

• Extremely common comorbidity (~60-70% of MDD patients have significant anxiety)
• Manifests as: worry, tension, restlessness, somatic anxiety symptoms (palpitations, sweating, GI disturbance)
• "Anxious distress" specifier in DSM-5-TR — associated with poorer prognosis and higher suicide risk
• Pathophysiology: Amygdala hyperreactivity + impaired prefrontal inhibition + noradrenergic and serotonergic dysfunction

• Commonly present with prominent somatic symptoms to healthcare ^[2]
• Especially important in Hong Kong and East Asian populations where somatisation of psychological distress is common
• Common presentations:
  • Headache, backache, generalised body aches
  • GI symptoms (abdominal pain, nausea, constipation)
  • Chest tightness, palpitations
  • Dizziness, fatigue
• Pathophysiology: Central sensitisation — serotonin and noradrenaline modulate descending pain inhibitory pathways. In depression, reduced monoaminergic activity → impaired pain inhibition → amplified somatic signals. This is why SNRIs (duloxetine) are used for both depression and chronic pain.

This is critical because treating the underlying condition may resolve the depression. The lecture slides provide a comprehensive list ^[3]:

Drug-related conditions that can cause or mimic depression ^[3]:

Clear-cut changes in affect, cognition, and neurovegetative functions ^[3]

5 or more of the following symptoms are present during the same 2-week period, representing a change from previous functioning; at least 1 of the symptoms is either (1) or (2) ^[3]:

At least 2 weeks' duration ^[3]

Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning ^[3]

Why 2 weeks? This threshold was chosen empirically to distinguish MDD from transient sadness. Normal grief and disappointment typically show improvement within days to a couple of weeks and retain emotional reactivity. The 2-week minimum captures persistent, autonomous mood disturbance.

The episode is not attributable to the physiological effects of a substance or to another medical condition ^[3]

This is why investigations (TFT, CBP, RFT, LFT, etc.) are essential — you must rule out organic mimics before diagnosing a primary mood disorder.

Not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders ^[3]

Why this criterion exists: Schizophrenia can have prominent negative symptoms (flat affect, avolition, anhedonia) that look like depression. The distinction is that in MDD, psychotic features (if present) are mood-congruent and episode-bound; in schizophrenia/schizoaffective, psychotic symptoms dominate and exist independently of mood episodes.

Absence of previous manic or a hypomanic episode ^[3]

This is the single most critical exclusion criterion. A patient with a current depressive episode + any history of mania/hypomania = bipolar disorder, not MDD. This changes management entirely (antidepressant monotherapy is contraindicated in BAD).

• Single episode vs recurrent episode ^[3] (recurrent = ≥1 previous episode with ≥2-month interval of remission between episodes)

• Mild, moderate, severe, with psychotic features, in partial remission, in full remission, unspecified ^[3]

Other specifiers without codes ^[3]:

At least 4 of the following are required for "with somatic features" (ICD-10) or "with melancholic features" (DSM-5) ^[2]:

1. Loss of interest or pleasure in usual activities
2. Lack of emotional reactivity to normally pleasurable surroundings and events
3. Early-morning waking (≥2 hours before usual time)
4. Depression worse in the morning
5. Psychomotor agitation or retardation
6. Marked loss of appetite
7. Weight loss (≥5% of body weight in last month)
8. Marked loss of libido (ICD-10 only)
9. Distinct quality of depressed mood (DSM-5 only)
10. Excessive guilt (DSM-5 only)

DSM-5 specifically requires either "loss of interest/pleasure" or "lack of emotional reactivity" to be present ^[2].

Clinical relevance of melancholic depression ^[2]:

• ↑ neurobiological abnormalities + ↑ FHx
• ↑ severity of symptomatology
• ↓ response to placebo and ↑ response to TCA than SSRI

Indication: most effective in moderate-severe depression ^[2]

The natural history numbers are important to understand drug efficacy ^[2]:

• 20% will recover without treatment (spontaneous remission)
• 30% will respond to placebo (expectation + therapeutic alliance + natural course)
• 50% will respond to antidepressants

This means the number needed to treat (NNT) for antidepressants vs placebo is approximately 5–7 for moderate-severe depression. For mild depression, the NNT is much higher (effect barely separates from placebo) — hence why we start with psychosocial interventions.

The approach to choosing a drug ^[2][3]:

Discuss choice of drug with the patient, considering: potential therapeutic effects, possible adverse effects, likelihood of discontinuation symptoms, likely time to respond, the role of therapeutic alliance in predicting response ^[2]

Choice of medication determined by clinical circumstances, particularly the patient's physical comorbidity and concomitant medications ^[3]

Marked inter-individual variation in antidepressant tolerability ^[3]

Systematic review and network meta-analysis of 21 antidepressants ^[3]:

• More effective than other antidepressants: agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine (range of ORs 1.19–1.96) ^[3]
• More tolerable than other antidepressants: agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine (range of ORs 0.43–0.77) ^[3]

The sweet spot: escitalopram and vortioxetine appear in both the "more effective" and "more tolerable" lists, making them strong first-line choices.

The approach follows a logical stepwise escalation ^[2]:

Step 1: Start antidepressant

• Titrate to a recognised therapeutic dose
• Assess efficacy after 2 weeks — explain to patient that full effect takes 2–6 weeks (because the therapeutic effect is not just about ↑ synaptic monoamines, but downstream neuroplastic changes: ↑ BDNF, hippocampal neurogenesis, receptor downregulation)

Step 2: If effective

• Continue for 6–9 months at full treatment dose ^[2]
• Consider longer-term treatment in recurrent depression

Step 3: If NOT effective after 2 weeks

• Assess weekly for a further 1–2 weeks. If still no response, consider increasing dose ^[2]

Step 4: If poorly tolerated

• Switch to a different antidepressant ^[2]
• Titrate to therapeutic dose, assess efficacy over 3–4 weeks

Step 5: If 2nd antidepressant also fails

• Consider third choice options: mirtazapine, vortioxetine, agomelatine ^[2]

Step 6: Still no effect

• Refer to refractory depression protocol (see below)

Continuation phase ^[2]:

• First episode → continue antidepressants for ≥6–9 months at the dose that induces remission ^[2]
• This prevents relapse. Stopping too early is the most common cause of "failed" antidepressant treatment

Maintenance phase ^[2]:

• ≥2 episodes + significant functional impairment → continue antidepressants for ≥2 years ^[2]
• Some guidelines recommend lifelong treatment after 3+ severe episodes

Stopping ^[2]:

• Gradual taper over ≥4 weeks to avoid discontinuation syndrome (dizziness, nausea, electric shock sensations, irritability, insomnia — especially common with paroxetine, venlafaxine)
• Never stop abruptly

"Electro" (electricity) + "convulsive" (seizure) + "therapy" — using electricity to induce a therapeutic seizure.

Electroconvulsive therapy ^[3] — induction of seizure to treat psychiatric disorders ^[2]

Mechanism of action: Unknown precisely, but several hypotheses ^[2]:

• Neuroendocrine: ↑ hormonal release by hypothalamus and pituitary (PRL, TSH, ACTH, endorphins)
• Neurotrophic: ↑ BDNF → induces neurogenesis (may explain why multiple sessions needed)
• Other: ↑ monoamine neurotransmitter release, transient ↑ BBB permeability, changes in brain connectivity

Indications ^[2]:

ECT is indicated in severe depression when:

• Rapid definitive response required (e.g., pregnancy)
• Life-threatening (persistent suicidal intent, food refusal → malnutrition/dehydration)
• Antidepressants failed or cannot be used (refractory, medical comorbidities)
• Previous good response to ECT
• Catatonia (depressive stupor)

Mnemonic: ECT = Emergency, Catatonia, Treatment-refractory ^[2]

Also indicated for ^[2]:

• Mania/mixed states (pregnant, life-threatening, treatment-resistant)
• Puerperal psychosis with prominent mood symptoms (rapid treatment to allow reuniting with baby)
• Selective treatment-resistant schizophrenia

Administration ^[2]:

• Course: 6–12 treatments, 2–3 per week
• Process: Short-acting induction agent + muscle relaxant (suxamethonium) → ensure ~5 min of GA → psychiatrist applies two electrodes to scalp → electric pulse delivered to induce a generalised tonic-clonic seizure lasting at least 15 seconds
• Unilateral vs bilateral: bilateral is more effective but may cause more cognitive impairment. Unilateral (contralateral to dominant hemisphere) is used when cognitive effects are a concern

Adverse effects ^[2]:

• Cognitive impairment: acute confusion, anterograde or retrograde amnesia → generally short-lived (days after ECT)
• General complaints: headache, nausea, muscle pain
• Mortality: 2–4 per 100,000 (~other minor surgery under GA), usually due to cardiopulmonary events

Contraindications: No absolute contraindication. Relative contraindications include ^[2]:

• Heart disease: recent MI, heart failure, ischaemic heart disease
• ↑ ICP (risk of herniation during seizure)
• Risk of ICH: hypertension, recent stroke
• Phaeochromocytoma (seizure → catecholamine surge)
• Poor anaesthetic risk

Efficacy: ECT is considered more effective than drugs in the most severe cases ^[2]. It is especially effective for depression with psychosis and/or psychomotor retardation ^[2].

Transcranial magnetic stimulation ^[3][2]:

• Procedure: Non-invasive; hand-held plastic-coated coil placed close to scalp → external magnetic field stimulates generation of action potential and firing of neurones (targeting left dorsolateral PFC to counteract its hypoactivity in depression)
• Use: Suitable for medically unwell people who cannot tolerate antidepressants or ECT ^[2]
• Side effects: Minimal, but only available in selected centres
• FDA-approved for treatment-resistant depression

Transcranial direct current stimulation ^[3][2]:

• Procedure: Non-invasive; constant, low-voltage DC via electrodes on head → anode increases cortical excitability, cathode decreases it → modulates spontaneous neuronal network activity
• Use: NOT suprathreshold (unlike TMS, ECT) → therefore limited to adjunctive use only ^[2]
• Side effects: Minimal, but only available in selected centres

This is the complication that kills. Everything you do in managing depression — every assessment, every follow-up, every medication choice — is ultimately aimed at preventing this outcome.

Depression raises suicidal risk ^[3]:

• Increase in suicide risk attributable to depression was 20-fold ^[3]
• Suicide was the cause of death in 6% of patients with an affective disorder, and the risk would be even higher in those with psychiatric co-morbidities ^[3]
• In a longitudinal study in Sweden spanning over half a century, the long-term suicide risk in subjects with depression was 6.0% after 54–64 years of follow-up ^[3]
• Senior notes cite even higher figures for severe admitted cases: > 20× risk of suicide, can approach 15% in those with severe admitted cases ^[2]

Why does depression cause suicide? The pathophysiology converges from multiple directions:

• Hopelessness (Beck's cognitive triad: "nothing will ever get better") — the single strongest cognitive predictor of suicide
• Impaired serotonergic function — 5-HT deficiency reduces impulse control, making it harder to resist self-destructive urges
• Psychomotor retardation paradox — the most severely retarded patients may be too immobilised to act on suicidal thoughts; the danger period is when they start to improve (enough energy to act, but still deeply hopeless). This is why the early weeks of antidepressant treatment are a high-risk period
• Psychotic features — command hallucinations ("kill yourself"), delusions of guilt ("you deserve to die"), nihilistic delusions (Cotard's syndrome)
• Comorbid substance abuse — disinhibition + depression is a lethal combination

Depression accounts for a significant proportion of suicides in adults in Hong Kong ^[3]:

• Using a case-control psychological autopsy method, 150 local suicide decedents aged 15–59 were compared with 150 randomly selected age- and gender-matched control participants living in the community ^[3]
• In the presence of non-disease-related social risk factors (unemployment and unmanageable debt), current major depressive disorder independently accounted for 27% of the population-attributable risk of suicide ^[3]

Depression accounts for a significant proportion of suicides in older adults in Hong Kong ^[3]:

• Using a case-control psychological autopsy method, 70 decedents aged 60 or above who had committed suicide were compared with 100 elderly controls ^[3]
• 86% of suicide subjects suffered from a psychiatric problem before committing suicide, compared with 9% of control subjects ^[3]
• Among the psychiatric problems, major depression was the commonest diagnosis ^[3]

In some tragic cases, symptoms may be masked to others until the person is found dead by suicide ^[3]

• Cutting, burning, hitting — used as maladaptive coping to regulate overwhelming emotions
• Pathophysiology: self-injury triggers endorphin release → transient relief from emotional pain. Also, physical pain can "replace" the intolerable psychological pain
• In some younger people, the first obvious sign may be self-injury ^[3]
• Self-harm is a risk factor for completed suicide even when intent is not to die

• Depression and substance abuse have a bidirectional relationship: depression drives self-medication with alcohol, cannabis, and other substances; substance use worsens depression (especially alcohol as a CNS depressant)
• In some younger people, the first obvious sign may be drug use in a previously stable adolescent ^[3]
• ↑ comorbidity with other disorders, especially anxiety and substance abuse ^[2]
• Common comorbidities in youth depression: 70% has anxiety disorder, conduct disorder, substance abuse, dysthymia ^[2]
• Pathophysiology: dopaminergic reward pathway dysfunction in depression → patient seeks exogenous sources of dopamine (alcohol initially increases dopamine release in nucleus accumbens; stimulants directly increase dopamine). This creates a vicious cycle: substance → transient relief → withdrawal → worse depression → more substance

• Psychotic features develop in ~15–20% of severe depressive episodes ^[2]
• Psychotic symptoms occur in severe depression, invariably associated with loss of insight and may predict development into bipolar disorder ^[2]
• Specific psychotic complications:
  • Cotard's syndrome (nihilistic delusions): patient believes their organs are rotting, they are dead, the world does not exist — named after Jules Cotard (1880). This is a psychiatric emergency
  • Depressive stupor: severe psychomotor retardation progressing to point of unresponsiveness, lack of voluntary movement and near or total mutism ^[2]. This is life-threatening because the patient cannot eat, drink, or care for themselves → dehydration, malnutrition, DVT/PE from immobility
• Psychotic depression also carries higher suicide risk than non-psychotic depression (command hallucinations, delusional guilt driving self-punishment)

• ~10–20% of cases become chronic unremitting ^[2]
• ~50% do not have complete symptom remission between episodes ^[2]
• Only ~25% of those with recurrent major depression achieve 5-year clinical stability with good social and occupational performance ^[2]
• Each successive episode further sensitises the brain (kindling hypothesis) — the threshold for future episodes lowers, and intervals between episodes shorten progressively ^[2]
• Chronicity leads to cumulative neurobiological damage: progressive hippocampal atrophy (cortisol-mediated), prefrontal cortex thinning, white matter changes

• ~25% of bipolar affective disorder first presents as a juvenile depression in their first episode ^[2]
• Psychotic features in depression may predict future bipolar conversion ^[2]
• This is why longitudinal follow-up and re-assessment of diagnosis is essential — a patient diagnosed with "recurrent MDD" may actually have unrecognised bipolar disorder

Depression rarely exists in isolation:

• Anxiety disorders: ~60–70% comorbidity rate; mutual reinforcement (worry → depression → more worry)
• Eating disorders: in some younger people, the first obvious sign may be bulimia ^[3]; depression drives disordered eating through body image distortion, comfort eating, or appetite loss
• Personality disorders: borderline PD and MDD frequently co-exist; borderline features predict poorer treatment response and more frequent recurrence ^[2]

Depression increases non-suicidal mortality ^[3]:

• Reviewed 61 reports; 72% demonstrated positive association for depression and non-suicide mortality ^[3]
• RR = 1.2–4.0 ^[2][3]

Possible mediators ^[3]:

1. Behavioural risk factors: poor adherence to treatment, inactivity, ↑ alcohol consumption — depression impairs motivation and executive function → patients don't take their medications, don't exercise, and may drink more
2. Biological risk factors: altered thrombogenesis — depression activates the sympathetic nervous system and HPA axis → ↑ platelet activation, ↑ inflammatory cytokines, ↑ endothelial dysfunction → prothrombotic state → ↑ cardiovascular events
3. Subclinical disease / prevalent disease: cardiovascular disease — depression and CVD share inflammatory pathways; depression may accelerate atherosclerosis progression

Depression is an independent risk factor for:

• Coronary artery disease (CAD): depressed patients have ~1.5–2× risk of developing CAD
• Post-MI mortality: depressed patients post-MI have 3–4× higher mortality
• Heart failure: depression worsens prognosis in CHF
• Stroke: bidirectional — depression increases stroke risk; post-stroke depression is common (~30%)

Mechanisms:

• HPA axis dysregulation → hypercortisolaemia → visceral obesity, insulin resistance, dyslipidaemia
• Sympathetic hyperactivation → ↑ heart rate, ↓ heart rate variability (HRV), ↑ arrhythmia risk
• Platelet hyperactivation → altered thrombogenesis
• Endothelial dysfunction → accelerated atherosclerosis
• Behavioural factors: smoking, sedentary lifestyle, poor diet, medication non-adherence

• Depression increases risk of developing type 2 diabetes by ~37% (meta-analyses)
• Bidirectional: diabetes increases depression risk; depression worsens glycaemic control
• Mechanism: cortisol excess → insulin resistance → central adiposity → metabolic syndrome. Also, anti-depressants (especially mirtazapine, TCAs, paroxetine) can cause weight gain

• Depression → ↑ pro-inflammatory cytokines (IL-1, IL-6, TNF-α) + ↓ cell-mediated immunity (↓ NK cell activity, ↓ T-cell proliferation)
• Clinical consequence: ↑ susceptibility to infections, slower wound healing, poorer vaccine responses

• Depression and chronic pain share serotonergic and noradrenergic pathways (descending pain inhibitory system)
• Depression amplifies pain perception (central sensitisation); chronic pain perpetuates depression
• This bidirectional relationship creates one of the most treatment-resistant clinical scenarios

• ↑ morbidity: associated with ↓ birth weight ^[2] — maternal depression during pregnancy → cortisol crosses placenta → fetal HPA axis programming → low birth weight, preterm delivery
• Chronic medical illness, poor self-perceived health, functional and cognitive impairment ^[2]
• Osteoporosis: hypercortisolaemia → ↓ osteoblast activity → bone loss (depression is an under-recognised risk factor for fracture)