Major Depressive Disorder
Major depressive disorder is a psychiatric condition characterized by persistent depressed mood or loss of interest (anhedonia) lasting at least two weeks, accompanied by neurovegetative symptoms such as sleep disturbance, appetite changes, fatigue, and impaired concentration, causing significant functional impairment.
Major Depressive Disorder (MDD) is a common, recurrent psychiatric illness characterised by persistent low mood, loss of interest/pleasure (anhedonia), and a constellation of cognitive, biological, and psychomotor disturbances that cause significant functional impairment [1][2].
Let's break the name down:
- "Major" – distinguishes it from minor/subthreshold depressive conditions (e.g., adjustment disorder with depressed mood, minor depression)
- "Depressive" – from Latin deprimere ("to press down") — the mood is pushed down
- "Disorder" – a clinically significant syndrome, not just transient sadness
The key conceptual distinction: MDD is NOT ordinary sadness. Normal grief and disappointment are time-limited, proportionate to context, and retain emotional reactivity. MDD is pervasive, disproportionate, autonomous (takes on a life of its own), and disrupts biological rhythms (sleep, appetite, energy, psychomotor function) [1][2].
Core Concept
Depressive disorder is caused by a combination of biological, social, and psychological factors, which disturb the brain's capacity for stress management [3]. It is never "just" a chemical imbalance or "just" a psychological problem — it is always a biopsychosocial condition.
Epidemiology
- 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]:
- Greater readiness of women to admit depressive symptoms
- Misdiagnosis as alcohol-related disorder in men (due to higher rates of comorbid alcohol abuse)
- Social disadvantages in women
- 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]
High Yield – Depression Kills Beyond Suicide
Depression independently increases cardiovascular mortality. A depressed patient post-MI has roughly 3–4× the mortality of a non-depressed patient. Always think of depression as a systemic illness, not just a "mental" one.
Risk Factors
Organised using the biopsychosocial model and the predisposing–precipitating–perpetuating (3P) framework:
| Domain | Risk Factor | Explanation |
|---|---|---|
| Genetic | Threefold increase in risk among first-degree relatives [3] | Twin studies show 37% heritability (50% MZ concordance — lower than schizophrenia/bipolar) [2]. Probably multiple genes with small individual effects and complex gene-environment interactions. Candidate gene includes serotonin transporter (5-HTTLPR variant) [2][3] |
| Personality | Neuroticism, sociotropy (strong need for approval), personality disorders (borderline, obsessive-compulsive) [2][3] | Neuroticism is associated with depression and may represent a milder form of the disease [2]. Sociotropy means the person's self-worth depends on others' approval → vulnerable to interpersonal loss |
| Early environment | Parental separation, physical and sexual abuse, non-caring or overprotective parenting styles [3] | These create insecure attachment styles and maladaptive cognitive schemas (Beck's model) that persist into adulthood |
| Social | Lack of supportive networks, poorly functioning relationships, poor social integration [3] | Chronic stressors: not having employment outside home, raising young children [2] |
| Female sex | 2–3× risk [2] | Hormonal, social, and reporting-bias factors (see above) |
- 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
Anatomy & Functional Neuroanatomy
Understanding the neuroanatomy helps you understand why specific symptoms occur:
| Region | Normal Function | Change in MDD | Clinical Consequence |
|---|---|---|---|
| Prefrontal Cortex (PFC) – Ventromedial | Emotional and social regulatory functions, valuation, decision-making | ↑ Activity [2] | ↑ Sensitivity to pain, anxiety, depressive ruminations, tension [2] |
| Prefrontal Cortex (PFC) – Dorsolateral | Executive functions (planning, working memory, attention) | ↓ Activity [2] | Psychomotor retardation, apathy, deficits in attention/working memory [2] |
| Amygdala | Threat detection, emotional memory, fear processing | ↑ Reactivity, ↑ connectivity with vmPFC | Hypervigilance to negative stimuli, negative emotional bias, anxiety |
| Anterior Cingulate Cortex (ACC) | Error monitoring, emotional regulation, conflict resolution | Altered connectivity with amygdala | Disrupted inhibitory action in emotional regulation [2] — the "brake" on negative emotions is weakened |
| Hippocampus | Memory consolidation, contextual memory, HPA axis feedback inhibition | Reduced volume [2][3] | Both a predisposing factor and a consequence of depression [2]. Smaller hippocampus → less effective HPA axis negative feedback → cortisol stays high → more hippocampal damage (vicious cycle) |
| Subgenual cortex | Mood regulation, autonomic function | Volume reduction and decreased quantity of glial cells [3] | Contributes to autonomic dysregulation and persistent low mood |
| Mesolimbic dopamine pathway (VTA → nucleus accumbens) | Reward, motivation, pleasure | ↓ Dopaminergic activity | Anhedonia, amotivation, loss of pleasure response |
The three monoamine systems implicated in depression originate from brainstem nuclei that belong to the reticular activating system (RAS) [2]:
-
Serotonin (5-HT) — from dorsal raphe nuclei
-
Noradrenaline (NE) — from locus coeruleus
-
Dopamine (DA) — from ventral tegmental area (VTA)
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.
Aetiology & Pathophysiology
Key Principle
The pathophysiology of depression remains largely unknown. Several mechanisms have been proposed [3]. No single theory explains everything — think of these as complementary layers that converge on a final common pathway of disrupted mood regulation.
1. Biological Hypotheses
Classical "serotonin hypothesis": diminished activity of serotonin pathways plays a causal role in the pathophysiology of depression [3]
Historical evidence:
- Antihypertensive drug reserpine, which depleted monoamine, produced a depressive state [3]
- Diminished monoaminergic activity was detected in the brains of decedents of suicide and the bodily fluids of people with depression (Coppen, 1967) [3]
- Drugs that increase monoamine availability (SSRIs, SNRIs, TCAs, MAOIs) improve depression
However: Evidence suggests that the cause of depression is far more complicated than a reduced level of serotonin [3]
- SSRIs increase synaptic serotonin within hours, but clinical improvement takes 2–6 weeks → suggests downstream neuroplastic changes are the real mechanism
- Direct tryptophan depletion (reducing serotonin precursor) does NOT reliably cause depression in healthy volunteers
- Monoamine deficiency is likely a contributory factor rather than the sole cause
Monoamines including serotonin, norepinephrine and dopamine are relevant to mood regulation, and play an essential role in the regulation of other bodily function [3]
Besides, abnormalities in glutamate, GABA, and substance P have been detected in patients with depression [3]
- Glutamate (excitatory): excessive glutamatergic signalling may contribute to neuronal damage; this is why ketamine (NMDA receptor antagonist) has rapid antidepressant effects
- GABA (inhibitory): reduced GABAergic tone may contribute to anxiety and agitation in depression
- Substance P: neuropeptide involved in pain and stress signalling
- A threefold increase in risk of depression among first-degree relatives compared to the general population [3]
- 37% heritability from twin studies (50% MZ concordance) [2]
- Lower than schizophrenia (~80%) and bipolar (~85%) → environment plays a larger relative role
- Probably polygenic — multiple genes with small individual effects [2]
- Key candidate: serotonin transporter gene (5-HTTLPR) — short allele associated with depression in the presence of life stress (gene × environment interaction) [2][3]
- The 5-HTTLPR variant is also associated with early-onset depression in the presence of adversities [2]
- Volume reduction and decreased quantity of glial cells in subgenual cortex [3]
- Reduced hippocampal size [3]
- Hippocampal volume reduction is both a predisposing factor and a consequence of depression [2]
- Chronic cortisol elevation → glucocorticoid-mediated neurotoxicity → hippocampal atrophy → impaired HPA negative feedback → more cortisol → vicious cycle
Hormonal changes in depression [3]:
- Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis — hypercortisolaemia is one of the most robust biological findings in MDD
- Why? Chronic stress → ↑ CRH from hypothalamus → ↑ ACTH from pituitary → ↑ cortisol from adrenals → hippocampal atrophy → impaired negative feedback → cortisol stays high
- This explains the link between Cushing's disease and depression
- Lower estradiol (in women) and testosterone (in men) — explains perimenopausal depression and depression in hypogonadal men
- Decreased triiodothyronine (T3) and thyroid-stimulating hormone (TSH) — subclinical hypothyroidism is strongly associated with depression; T3 augmentation is sometimes used in treatment-resistant depression
- Diminished BDNF (brain-derived neurotrophic factor) level — BDNF supports neuronal survival, growth, and synaptic plasticity. Low BDNF → impaired neuroplasticity → neurons cannot adapt to stress. Antidepressants and exercise both increase BDNF.
- Elevated pro-inflammatory cytokines (IL-1, IL-6, TNF-α) found in MDD
- Inflammation activates the enzyme indoleamine 2,3-dioxygenase (IDO), which shunts tryptophan away from serotonin synthesis toward kynurenine (neurotoxic) pathway
- This connects depression with chronic inflammatory conditions (rheumatoid arthritis, IBD, cardiovascular disease)
- Explains why IFN-α therapy for hepatitis C commonly causes depression
2. Psychosocial Hypotheses
Cognitive theory: cognitive distortions are prominent in depression and are targeted in CBT [2][3]:
| Cognitive Distortion | Chinese | Definition | Example |
|---|---|---|---|
| Selective abstraction | 斷章取義 | Focusing on a detail and ignoring more important features of a situation | A student gets 9/10 on an exam and fixates on the one wrong answer |
| Overgeneralisation | 以偏概全 | Drawing a general conclusion on the basis of a single incident | "I failed one test, so I'm a total failure" |
| Personalisation | 過度自責 | Relating external events to oneself in an unwarranted way | "My friend looks unhappy — it must be because of something I did" |
| Arbitrary inference | 妄下判斷 | Drawing a conclusion when there is no evidence for it and even some evidence against it | "My boss didn't say good morning — he must be planning to fire me" |
Beck's Cognitive Triad — the depressed person has negative automatic thoughts about:
- The self — "I am worthless"
- The world — "Everything is terrible"
- The future — "Nothing will ever get better" (hopelessness)
These distortions arise from negative schemas (core beliefs) formed in early life, activated by stressful events → maintain and deepen the depressive episode.
- Psychoanalytical theory: loss of an 'object', insecure attachments [3]
- Freud proposed that depression represents anger turned inward after loss of a loved one (real or symbolic)
- While the specific Freudian mechanisms are debated, the general concept that early attachment disruption predisposes to depression is well-supported
- When an organism repeatedly experiences uncontrollable adverse events, it stops trying to escape even when escape becomes possible
- Translates to the passivity, hopelessness, and "giving up" seen in depression
- Neurobiologically linked to prefrontal cortex hypoactivity and HPA axis dysregulation
Classification
| Feature | ICD-11 | DSM-5-TR |
|---|---|---|
| Single episode | Single episode depressive disorder | Major Depressive Disorder, single episode |
| Recurrent | Recurrent depressive disorder | Major Depressive Disorder, recurrent |
| Severity | Mild / Moderate / Severe | Mild / Moderate / Severe |
| With psychotic features | With psychotic symptoms | With psychotic features |
| Persistent | Dysthymic disorder | Persistent Depressive Disorder (Dysthymia) |
| Other | — | Other Specified Depressive Disorder |
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
| Subtype | Key Features | Clinical Significance |
|---|---|---|
| Melancholic ("biological" depression) | Profound anhedonia, worse in AM, early morning wakening, psychomotor disturbance, weight loss, guilt | Better response to biological treatments (antidepressants, ECT) |
| Atypical | Mood reactivity (can brighten temporarily), hypersomnia, hyperphagia/weight gain, leaden paralysis, interpersonal rejection sensitivity | Better response to MAOIs and SSRIs (historically) |
| Psychotic | Delusions and/or hallucinations (usually mood-congruent: guilt, worthlessness, nihilism, somatic) | Requires antipsychotic + antidepressant or ECT |
| Seasonal (SAD) | Recurrent onset in autumn/winter, recovery in spring/summer [2] | Postulated to be related to daylight duration → bright light therapy [2] |
| Recurrent brief | Recurrent episodes of 2–7 days occurring once a month [2] | Often missed because episodes are too short for MDD criteria |
| Peripartum onset | Onset during pregnancy or within 4 weeks postpartum | Screen all peripartum women; risk to mother and infant |
| With anxious distress | Prominent anxiety symptoms within depressive episode | Poorer prognosis, higher suicide risk |
-
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]
Exam Tip
Current DSM/ICD classification uses a combination of the above features [2]. You need to know both the categorical diagnosis AND the specifiers. A complete diagnosis reads like: "Major Depressive Disorder, recurrent, severe, with melancholic features."
Clinical Features
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.
A. Core Features (At Least One Required)
- Differs from ordinary sadness: miserable, dejected, 'down in the dumps' [2]
- Pervasive: covers most period of the day [2]
- Loss of reactivity: loss of normal ups and downs in response to circumstances [2]
- Pathophysiology: Reflects impaired serotonergic and dopaminergic modulation of emotional processing. The ventromedial PFC is hyperactive (excessive rumination, negative bias) while the dorsolateral PFC is hypoactive (cannot override negative emotion with rational thought)
- Morning dysphoria: characteristically worse in the morning (one of the "biological" symptoms) [2]
- Why morning? Cortisol normally peaks in the early morning (cortisol awakening response). In depression, the HPA axis is dysregulated with exaggerated cortisol peaks → worst mood at peak cortisol time. This improves slightly as the day progresses.
ICD-11 cardinal symptom: Depressed mood occurring most of the day, nearly every day during a period lasting at least two weeks [3]
- Anhedonia: lack of interest and enjoyment [2]
- Loss of ability to derive pleasure from activities that were formerly enjoyed [2]
- Associated with social withdrawal [2]
- Pathophysiology: Dopaminergic hypofunction in the mesolimbic reward pathway (VTA → nucleus accumbens). This pathway normally mediates the "wanting" (motivation) and "liking" (pleasure) components of reward. In depression, both are diminished → the patient cannot feel pleasure even from things they previously loved.
ICD-11 cardinal symptom: Diminished interest in activities occurring most of the day, nearly every day during a period lasting at least two weeks [3]
- Anergia: lack of energy or ↑ fatigability on minimal exertion → ↓ activity [2]
- Pathophysiology: Multifactorial — noradrenergic hypofunction (NE regulates arousal and energy), HPA axis dysregulation (chronic cortisol elevation leads to metabolic exhaustion), and reduced dopaminergic drive (motivation deficit)
B. Biological (Somatic/Melancholic) Symptoms
These are the "vegetative" symptoms — they reflect disruption of basic biological rhythms controlled by the hypothalamus and brainstem monoamine systems:
- Most classically early morning wakening (waking 2+ hours before usual time and unable to return to sleep) [2]
- Why early morning wakening specifically? The sleep-wake cycle is regulated by serotonin (dorsal raphe) and noradrenaline (locus coeruleus). In melancholic depression, there is premature activation of the arousal system. Also, cortisol peaks earlier in depressed patients → earlier awakening.
- Initial insomnia (difficulty falling asleep) — especially when comorbid anxiety
- Middle insomnia (frequent nocturnal awakenings)
- Hypersomnia (in atypical depression) — sleeping excessively but never feeling rested
- Polysomnography findings: ↓ REM latency (enter REM sleep faster), ↑ REM density, ↓ slow-wave (deep) sleep
- ↓ Appetite and weight loss (typical/melancholic) — serotonin normally stimulates appetite via hypothalamus; 5-HT dysregulation → appetite suppression
- ↑ Appetite and weight gain (atypical) — carbohydrate craving, comfort eating; may relate to insulin resistance and leptin dysregulation in the context of HPA axis dysfunction
- Clinically significant = ≥ 5% body weight change in one month
- Psychomotor retardation (more common in melancholic):
- Slowed movements, reduced gestures, soft/monotonous speech, increased response latency
- Pathophysiology: Dorsolateral PFC hypoactivity + dopaminergic hypofunction → reduced motor planning and execution
- Psychomotor agitation (more common in anxious/mixed depression):
- Restlessness, pacing, hand-wringing, inability to sit still
- Reflects noradrenergic hyperactivation ± anxiety component
- These are observable signs, not just subjective complaints
- Mood characteristically worst in the morning and improves somewhat towards evening (as described above under morning dysphoria)
- A "biological" marker of melancholic depression
- ↓ Sexual interest and function
- Pathophysiology: Both serotonergic and dopaminergic dysfunction affect sexual desire and arousal. Also, ↓ testosterone/estradiol contributes [3]
C. Cognitive Symptoms
- Difficulty concentrating [3]
- Patients describe "can't think straight," "mind goes blank," "can't make decisions"
- Pathophysiology: Dorsolateral PFC hypoactivity → executive dysfunction. Also, rumination (vmPFC hyperactivity) hijacks cognitive resources
- In elderly patients, this can be so severe as to mimic dementia → "pseudodementia" (depressive pseudodementia)
- Feelings of worthlessness or excessive or inappropriate guilt [3]
- Guilt may reach delusional proportions in severe depression ("I have committed unforgivable sins")
- Pathophysiology: Cognitive distortions (Beck) — personalisation, selective abstraction
- Hopelessness [3]
- "Nothing will ever get better" — the most dangerous cognitive feature because it is the strongest predictor of suicide
- Reflects the "future" component of Beck's cognitive triad
- Recurrent thoughts of death or suicide [3]
- Ranges from passive ("I wish I were dead," "my family would be better off without me") to active (specific plans, means, intent)
- Must be systematically assessed in every depressed patient
- Pathophysiology: Hopelessness + impaired serotonergic function (5-HT is involved in impulse control) → reduced capacity to inhibit self-destructive impulses
- 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
Psychotic Depression vs Schizophrenia
A common exam mistake: Psychotic features IN depression are mood-congruent and occur during the depressive episode only. In schizoaffective disorder, psychotic symptoms (delusions/hallucinations) are less mood-congruent and may occur outside mood episodes. In schizophrenia, mood symptoms are secondary and brief relative to the psychotic illness.
- 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.
| Symptom Cluster | Key Neurotransmitter/Region | Mechanism |
|---|---|---|
| Depressed mood, guilt, rumination | 5-HT ↓, vmPFC ↑ | Negative emotional bias, excessive self-referential processing |
| Anhedonia, amotivation | DA ↓ (mesolimbic pathway) | Impaired reward processing |
| Anergia, fatigue | NE ↓, DA ↓ | Reduced arousal and drive |
| Sleep disturbance | 5-HT ↓, NE dysregulation | Disrupted sleep-wake regulation, premature RAS activation |
| Appetite/weight change | 5-HT ↓, hypothalamic dysfunction | Disrupted feeding centres |
| Psychomotor retardation | DA ↓, dlPFC ↓ | Reduced motor planning/execution |
| Poor concentration | NE ↓, dlPFC ↓ | Executive dysfunction |
| Suicidal ideation | 5-HT ↓ (impulse control) + hopelessness | Impaired behavioural inhibition + cognitive distortion |
| Somatic symptoms | 5-HT ↓, NE ↓ | Impaired descending pain inhibition |
| MSE Domain | Findings in MDD | Pathophysiological Basis |
|---|---|---|
| Appearance & Behaviour | Poor self-care, reduced grooming, slumped posture, reduced eye contact, psychomotor retardation (or agitation), tearful | Anergia (NE/DA ↓), loss of motivation (DA ↓) |
| Speech | ↓ Rate, ↓ volume, ↓ spontaneity, increased latency, monotonous | Psychomotor retardation (dlPFC ↓, DA ↓) |
| Mood (subjective) | "Miserable," "empty," "numb," "hopeless" | 5-HT/NE/DA deficiency |
| Affect (objective) | Flat, restricted, or tearful; may be congruent with depressed mood; loss of reactivity | Impaired emotional regulation (vmPFC/amygdala circuit) |
| Thought form | Poverty of thought, slowed thinking | dlPFC hypoactivity |
| Thought content | Guilt, worthlessness, hopelessness, helplessness, suicidal ideation; ± delusions (in psychotic depression) | Cognitive distortions (Beck); in psychotic depression, limbic overdrive |
| Perception | Usually normal; auditory hallucinations in psychotic depression (derogatory second-person voices) | Mood-congruent psychotic features |
| Cognition | Impaired attention and concentration; may mimic dementia in elderly ("pseudodementia") | dlPFC hypoactivity, hippocampal dysfunction |
| Insight | Variable — some fully aware of illness, others may lack insight (especially in psychotic depression) | |
| Judgement | Impaired — especially regarding self-harm risk |
Assessment involves [3]:
-
History, including medical and medication history — especially look for:
- Secondary causes (medical conditions, medications)
- Substance use
- Past psychiatric history (previous episodes → recurrent MDD vs single episode)
- Family psychiatric history
- Suicide risk assessment (MUST do in every patient)
-
Mental state examination
-
Use of standardised instruments — e.g., PHQ-9 (Patient Health Questionnaire-9), BDI (Beck Depression Inventory), HAM-D (Hamilton Depression Rating Scale)
-
Physical examination & investigation to rule out medical conditions that may cause depressive symptoms [3]:
- Basic: CBP, R/LFT, thyroid function test
- Others: blood alcohol level, blood and urine toxicology screen, HIV test, cosyntropin (ACTH) stimulation test (for Addison disease), EEG (for epilepsy) or CT or MRI (for organic brain syndrome or hypopituitarism) should be considered if indicated by history taking and physical examination [3]
Always Exclude Organic Causes
Before diagnosing MDD, you MUST rule out: hypothyroidism (TFT), Cushing's/Addison's, anaemia (CBP), hepatic/renal failure (LFT/RFT), substance use, medication side effects (beta-blockers, steroids, interferon), and intracranial pathology. A "psychiatric" diagnosis is always a diagnosis of exclusion of organic causes.
Secondary Causes of Depression to Exclude
| Category | Examples |
|---|---|
| Neurological | Head trauma, stroke, multiple sclerosis, neurodegeneration (Parkinson's, Alzheimer's), brain tumours |
| Metabolic/Endocrine | Thyroid disease, Cushing's/Addison's, vitamin deficiency (B12, folate, D), parathyroid disorders |
| Other medical | Systemic infections, pancreatic cancer, CHF, MI, chronic pain states |
| Medications | Antihypertensives (beta-blockers, methyldopa), neurological drugs (L-dopa, benzodiazepines, antipsychotics), steroids, OCP, opiates, indomethacin, interferon |
| Substances | Alcohol, cannabis, stimulant withdrawal, opioid withdrawal |
High Yield Summary
Definition: MDD is a recurrent disorder of persistent depressed mood/anhedonia + biological/cognitive/psychomotor symptoms lasting ≥ 2 weeks causing functional impairment.
Epidemiology: 2.9% prevalence in HK; lifetime 10-20%; F:M = 2-3:1; mean onset ~27y; 4th leading cause of disability globally.
Risk Factors (3P): Predisposing — genetics (37% heritability, 5-HTTLPR), neuroticism, early adversity, female sex. Precipitating — life events (loss, entrapment, humiliation). Perpetuating — ongoing stressors, cognitive distortions, substance use, social isolation.
Pathophysiology: Biopsychosocial — monoamine deficiency (5-HT, NE, DA), HPA axis dysregulation (hypercortisolaemia), structural changes (hippocampal/subgenual volume loss), ↓ BDNF, neuroinflammation, cognitive distortions (Beck's triad), adverse early environment.
Core Features: Depressed mood (pervasive, loss of reactivity, morning dysphoria) + anhedonia + anergia.
Biological Symptoms: Early morning wakening, appetite/weight change, psychomotor retardation/agitation, diurnal variation, loss of libido.
Cognitive Symptoms: Poor concentration, worthlessness, guilt, hopelessness, suicidal ideation.
Psychotic Features (~15-20% severe): Mood-congruent delusions (guilt, nihilistic, poverty), auditory hallucinations.
Assessment: History + MSE + standardised instruments + physical exam + bloods (CBP, TFT, R/LFT minimum) to exclude organic causes.
Active Recall - Major Depressive Disorder (Definition, Epidemiology, Aetiology, Clinical Features)
[1] WHO Depression Fact Sheet (cited in lecture slides and senior notes) [2] Senior notes: ryanho-psych.md (Psychiatry chapter, sections on depressive disorders — pages 155–158, 140, 271) [3] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pages 10–13, 26) [4] Lam LC et al. Hong Kong Mental Morbidity Survey (HKMMS). Soc Psychiatry Psychiatr Epidemiol 2015;50:1379-88 (cited in lecture slides reference list)
Differential Diagnosis of Major Depressive Disorder
When a patient presents with low mood, your job is not simply to confirm MDD — it is to systematically consider and exclude conditions that can mimic, co-exist with, or underlie depressive symptoms. The differential spans three broad domains [2][3]:
- Other primary psychiatric disorders that present with depressed mood
- Depression secondary to general medical conditions (organic mood disorder)
- Depression secondary to substances/medications (substance-induced depressive disorder)
The key principle: MDD is a clinical diagnosis of inclusion (meets criteria) AND exclusion (not better explained by something else). The DSM-5 criteria explicitly state the episode must not be attributable to the physiological effects of a substance or to another medical condition and not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders [3].
Systematic Differential Diagnosis
A. Other Primary Psychiatric Disorders
This is the single most important differential to actively exclude in every patient presenting with depression. Why? Because treatment differs radically — antidepressant monotherapy in BAD can trigger mania or rapid cycling.
- A patient with a current depressive episode + ≥1 previous manic/hypomanic episode has bipolar disorder, not MDD [2]
- Hypomanic episodes are often overlooked. Patients with BP II are misdiagnosed as having major depressive disorder [5]
- Misdiagnosis is especially common — among 600 patients with bipolar disorder, 69% were initially misdiagnosed and most frequently as major depression, followed by anxiety disorders, substance or alcohol use disorder [5]
- Correct diagnosis and treatment was delayed by 5–7 years on average [5]
How to distinguish:
- Always actively ask about past episodes of elated/irritable mood, decreased need for sleep, grandiosity, pressured speech, reckless behaviour — patients rarely volunteer hypomanic symptoms because they feel good during them
- Discerning features that favour BAD over MDD [2]: psychotic features in depression, atypical features (hypersomnia, hyperphagia, leaden paralysis), early onset, many recurrent episodes, family history of BAD, post-partum onset, rapid onset/offset of episodes
- ~25% of BAD first presents as a juvenile depression [2]
Must-Know Exam Point
Hypomanic episode is often overlooked [5]. If you diagnose "recurrent MDD" without screening for past hypomania, you may be missing bipolar II disorder. Always ask: "Have you ever had a period of days where you felt unusually high, energetic, or irritable — where you needed less sleep but still felt full of energy?"
- "Adjustment" = from Latin ad- (to) + justare (to bring near) — the person is failing to adjust to a stressor
- Develops ≤3 months of an identifiable stressor [2]
- Does not meet full criteria for a depressive episode — the symptoms are subthreshold [2]
- The emotional/behavioural response is out of proportion to the stressor OR causes significant functional impairment
- Key distinction: If meeting depressive episode criteria, should be regarded as having comorbid depression rather than adjustment disorder [2]. Adjustment disorder is a "not-otherwise-qualifying" diagnosis
- In terms of precipitating stressor, adjustment disorder is diagnosed when the stressor is not deemed traumatic in nature (cf. ASD/PTSD where the stressor is traumatic) [2]
- "Dys-" (Greek: bad/difficult) + "thymia" (Greek: mood/spirit) = persistently bad mood
- Persistent depressive symptoms NOT meeting full criteria for a major depressive episode, lasting ≥2 years [2]
- Onset usually in early adulthood → may persist throughout life → sometimes called "depressive personality" [2]
- May have superimposed major depressive episodes = "double depression" [2]
- Key distinction from MDD: chronicity (≥2 years), subthreshold severity, lack of discrete episodes
- Note: under DSM-5-TR, persistent depressive disorder subsumes both chronic MDD and dysthymia
- Mania can present with irritability rather than elation — this can be mistaken for agitated depression
- Mixed features specifier: a depressive episode with concurrent manic/hypomanic features (e.g., racing thoughts, increased energy, decreased need for sleep during a depressive episode)
- Key distinction: look for concurrent features of elevated energy, grandiosity, pressured speech, decreased need for sleep — these do NOT occur in pure MDD
- Anxiety and depression have enormous overlap — ~60–70% of MDD patients have comorbid anxiety
- GAD can mimic MDD: both have insidious onset, chronic course, prominent dysphoria, somatic symptoms [2]
- How to distinguish [2]:
- Content of rumination: depressive patients tend to brood self-critically on past events; GAD patients tend to worry about possible future events
- Somatic symptoms of depression: early morning wakening, diurnal variation in mood, suicidal thoughts are uncommon in GAD
- Both can co-exist — comorbidity is the rule rather than the exception
- Simultaneous occurrence of a depressive episode and schizophrenic symptoms lasting ≥2 weeks [2]
- Delusions and hallucinations are less mood-congruent and may occur outside mood episodes (cf. severe depression with psychotic features where psychotic symptoms are mood-congruent and episode-bound) [2]
- Must have concurrent mood + psychotic symptoms at some point (cf. schizophrenia where mood symptoms are minimal) [2]
- Depression caused directly by the physiological effects of a substance
- Should resolve or significantly improve after substance cessation
- Key substances: alcohol (a CNS depressant), cannabis, opioid withdrawal, stimulant withdrawal (cocaine, amphetamines)
- Distinguished from MDD by temporal relationship to substance use, improvement with abstinence
- The depressive syndrome is judged to be a direct pathophysiological consequence of a medical condition (not just a psychological reaction to being ill)
- See medical conditions table below
| Condition | Key Differentiating Features |
|---|---|
| Schizophrenia | Negative symptoms (flat affect, avolition, alogia) can mimic depression. However, primary psychotic symptoms (bizarre delusions, thought disorder, prominent hallucinations) dominate. Mood symptoms are secondary and brief relative to psychotic illness |
| OCD | Ruminations in OCD are intrusive, ego-dystonic, and accompanied by compulsions. In depression, ruminations are mood-congruent (guilt, worthlessness) and not experienced as intrusive in the same way [2] |
| PTSD/ASD | Can present with depressed mood, anhedonia, and withdrawal. However, require a traumatic stressor and have characteristic re-experiencing, avoidance, and hyperarousal symptoms |
| Personality disorders (especially borderline) | Chronic affective instability, identity disturbance, interpersonal dysfunction. Mood shifts are rapid (hours to days), often interpersonally triggered, and lack the sustained, pervasive quality of MDD. No classic biological symptoms |
| Somatic symptom disorder | Somatisation is common in depression, but in somatic symptom disorder, the somatic concerns persist outside depressive episodes [2] |
| Dementia ("pseudodementia" vs true dementia) | Depression in elderly can mimic dementia with cognitive decline and self-care deterioration. In some older people, symptoms may mimic dementia — deterioration of cognitive functioning and self-care [3]. Differentiating features: more well-defined onset, patient complains/worries about memory (vs dementia patients have poor insight), gives less effort on testing ("don't know" answers vs wrong answers in dementia), language/motor skills are slow but not impaired [2] |
This is critical because treating the underlying condition may resolve the depression. The lecture slides provide a comprehensive list [3]:
| Category | Examples | Why They Cause Depression |
|---|---|---|
| Neurological disorders | Epilepsy, Parkinson's disease, dementia, multiple sclerosis, Huntington disease, cerebrovascular disease, migraine [3] | Direct neuronal damage to mood-regulating circuits (frontal-subcortical pathways); dopamine depletion in Parkinson's; post-stroke depression affects ~30% (especially left frontal lesions) |
| Endocrine disorders | Hypothyroidism, hyperthyroidism, Cushing's syndrome, Addison disease, prolactinomas, hyperparathyroidism [3] | Hypothyroidism → ↓ T3/T4 → slowed metabolism and monoamine synthesis; Cushing's → cortisol excess → hippocampal neurotoxicity; Addison's → cortisol deficiency → fatigue, apathy; Hyperparathyroidism → hypercalcaemia → neuropsychiatric symptoms |
| Infectious diseases | Mononucleosis, HIV infection, hepatitis C infection, Lyme disease, syphilis [3] | Neuroinflammation, cytokine-mediated serotonin depletion (IDO pathway), direct CNS invasion (HIV, neurosyphilis) |
| Neoplasias | Pancreatic cancer, paraneoplastic syndromes [3] | Pancreatic cancer is notorious for depression preceding diagnosis (possibly cytokine-mediated or paraneoplastic); any cancer causes depression via inflammation + psychological burden |
| Chronic diseases | Coronary artery disease, type II diabetes [3] | Shared inflammatory pathways; HPA axis dysregulation; behavioural factors (inactivity, poor diet) |
| Chronic pain and psychosomatic conditions | [3] | Impaired descending pain inhibitory pathways (5-HT/NE) → central sensitisation → amplified pain → depression → more pain (vicious cycle) |
| Sleep-related disorders | Obstructive sleep apnoea [3] | Chronic sleep fragmentation → daytime somnolence, fatigue, cognitive impairment mimicking depression; hypoxia may directly impair monoaminergic function |
Pancreatic Cancer & Depression
Pancreatic cancer is one of the few malignancies where depression may be the presenting symptom — sometimes months before the cancer is diagnosed. The mechanism is not fully understood but may involve paraneoplastic antibodies, cytokines, or disruption of the gut-brain axis. In an older patient with new-onset depression and unexplained weight loss, think about this.
Drug-related conditions that can cause or mimic depression [3]:
| Category | Examples | Mechanism |
|---|---|---|
| Antihypertensives | Reserpine, methyldopa [3]; beta-blockers [2] | Reserpine depletes monoamine stores (vesicular monoamine transporter inhibitor) — this is actually the historical observation that led to the monoamine hypothesis! Methyldopa inhibits DOPA decarboxylase → ↓ dopamine/NE. Beta-blockers block noradrenergic signalling |
| Smoking-cessation aids | Varenicline [3] | Partial nicotinic agonist → may affect dopaminergic reward pathways |
| Steroids | Corticosteroids [2][3] | Exogenous cortisol → HPA axis suppression, hippocampal neurotoxicity, mood lability |
| Sex hormones and medications that affect sex hormones | OCP [2], GnRH agonists, anti-androgens [3] | Hormonal fluctuations affect serotonergic and GABAergic neurotransmission |
| H2 blockers | Ranitidine, cimetidine [3] | May cross blood-brain barrier → affect histaminergic neurotransmission |
| Sedatives, muscle relaxants | Benzodiazepines [2][3] | CNS depression, GABAergic enhancement → psychomotor slowing, apathy |
| Appetite suppressants | [2][3] | May affect serotonergic/dopaminergic pathways |
| Chemotherapy agents | [3] | Cytokine release → neuroinflammation → IDO activation → serotonin depletion |
| Neurological drugs | L-dopa [2], anticonvulsants | L-dopa can paradoxically cause depression via dopamine metabolism dysregulation |
| Substance abuse | Alcohol, cocaine, amphetamines, cannabinoids, sedatives, hypnotics, narcotics [3] | Alcohol is a CNS depressant; stimulant withdrawal causes rebound anhedonia/fatigue (dopamine depletion); cannabis chronic use → amotivational syndrome |
| Others | Interferon [2], indomethacin, opiates [2] | Interferon-α activates IDO enzyme → shunts tryptophan to kynurenine pathway → ↓ serotonin + ↑ neurotoxic metabolites |
| Differential | Key Distinguishing Feature from MDD | Why It Matters |
|---|---|---|
| Bipolar disorder | ≥1 past manic/hypomanic episode; actively ask — patients don't volunteer | Antidepressant monotherapy can trigger mania |
| Adjustment disorder | Subthreshold symptoms, onset ≤3 months of stressor, non-traumatic stressor | Self-limiting; usually responds to supportive therapy alone |
| Dysthymia | Chronic (≥2 years), subthreshold, no discrete episodes | Consider "double depression" if MDD superimposed |
| GAD | Future-oriented worry (vs past-oriented rumination in MDD); less biological symptoms | Often comorbid; treatment overlaps but emphasis differs |
| Schizoaffective disorder | Psychotic symptoms less mood-congruent, occur outside mood episodes | Requires antipsychotic ± mood stabiliser |
| Psychotic depression | Mood-congruent psychotic symptoms occurring ONLY during episode | Requires antidepressant + antipsychotic or ECT |
| Organic/medical | Temporal relationship to medical condition, abnormal investigations | Treat underlying condition |
| Substance-induced | Temporal relationship to substance use/withdrawal; improves with abstinence | Remove offending agent |
| Dementia vs pseudodementia | Depression: acute onset, complains of memory loss, "don't know" answers; Dementia: insidious, poor insight, wrong answers | Treat depression first — cognition may improve |
Physical examination & investigation to rule out medical conditions that may cause depressive symptoms [3]:
| Investigation | What You're Looking For |
|---|---|
| CBP | Anaemia (fatigue mimicking depression), ↑MCV (alcoholism), ↑WBC (infection) |
| Renal function tests | Uraemia (can cause apathy, cognitive impairment); hypoNa (SIADH or antidepressant side effect) |
| Liver function tests | GGT ↑ (alcoholism); hepatic encephalopathy |
| Thyroid function tests | Hypothyroidism (classic organic mimic); hyperthyroidism (can cause agitation/anxiety mimicking agitated depression) |
| Blood glucose | Hypoglycaemia (episodic fatigue, anxiety); diabetes (chronic disease-associated depression) |
| Calcium, phosphate | Hyperparathyroidism → hypercalcaemia → "stones, bones, groans, and psychiatric moans" |
| Vitamin B12, folate | Deficiency causes fatigue, cognitive impairment, depression |
| Blood alcohol, urine drug screen | Substance-induced depression |
| HIV test | If indicated — HIV-associated neurocognitive disorder |
| Cosyntropin/ACTH stimulation test | For Addison disease [3] — if suspected |
| ECG | Baseline before starting certain medications (TCAs, lithium prolong QT) |
| EEG | For epilepsy [3] — if seizures suspected |
| CT or MRI brain | For organic brain syndrome or hypopituitarism [3] — if focal neurology, cognitive deficits, or atypical presentation |
The Minimum Bloods for Every Depressed Patient
At a bare minimum: CBP, R/LFT, TFT. These are non-negotiable. Everything else is guided by clinical suspicion from history and physical examination. You cannot diagnose MDD without first ruling out thyroid disease, anaemia, and metabolic derangement.
High Yield Summary
Differential Diagnosis of MDD — Core Points:
-
Always screen for bipolar disorder — ask about past mania/hypomania. 69% of BAD patients are initially misdiagnosed, most commonly as MDD. Correct diagnosis delayed 5–7 years on average.
-
Adjustment disorder = subthreshold symptoms, ≤3 months of non-traumatic stressor. If full MDD criteria are met, diagnose MDD (not adjustment disorder).
-
Dysthymia = chronic (≥2 years), subthreshold. Can have superimposed MDD ("double depression").
-
Psychotic depression vs schizoaffective: mood-congruent + episode-bound psychosis = psychotic MDD. Less mood-congruent + psychosis outside mood episodes = schizoaffective.
-
Medical causes: always exclude hypothyroidism (TFT), Cushing's/Addison's, anaemia (CBP), and substance use. Minimum bloods: CBP, R/LFT, TFT.
-
Drug-induced depression: beta-blockers, reserpine, methyldopa, steroids, OCP, interferon, L-dopa, benzodiazepines. Temporal relationship to drug initiation is the key clue.
-
Pseudodementia: depression in elderly mimicking dementia. Treat depression first — cognition may recover.
Active Recall - Differential Diagnosis of MDD
References
[2] Senior notes: ryanho-psych.md (Psychiatry chapter — sections 7.1.1, 7.2, pages 140, 142–143, 154–158, 165, 188, 197, 271) [3] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pages 6, 8, 14–15) [5] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (pages 10, 12)
Diagnostic Criteria for Major Depressive Disorder
Psychiatric diagnosis rests on pattern recognition — there is no blood test or scan that confirms MDD. Diagnostic criteria exist to standardise this pattern recognition across clinicians. They consist of four components [2]:
- A cluster of symptoms — core (discriminating) + associated (characteristic)
- A minimum duration — to distinguish from transient emotional states
- Functional impairment or distress — to distinguish from normal variation
- Exclusion criteria — to distinguish from other conditions that mimic MDD
Two classification systems are in use: DSM-5-TR (American Psychiatric Association, primarily used in research and clinical practice worldwide) and ICD-11 (WHO, used in most hospital coding systems). Both converge on the same essential construct but differ in structure. HKU teaches both — you need to know the DSM-5 criteria in detail and be aware of the ICD framework.
A. DSM-5 Criteria for Major Depressive Disorder
Major depressive disorder requires ALL of the following [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]:
| # | Symptom | Pathophysiological Basis | Notes |
|---|---|---|---|
| (1) | Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful) [3] | 5-HT/NE deficiency → vmPFC hyperactivity → negative emotional bias, rumination | In children and adolescents, can be irritable mood [3] |
| (2) | Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation) [3] | DA deficiency in mesolimbic reward pathway → impaired reward/pleasure processing | This is anhedonia — one of two cardinal symptoms |
| (3) | Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day [3] | Hypothalamic dysregulation (5-HT modulates feeding centres) | In children, consider failure to make expected weight gain [3] |
| (4) | Insomnia or hypersomnia nearly every day [3] | 5-HT/NE dysregulation of sleep-wake cycle; premature RAS activation (in early morning wakening) | Classical = early morning wakening; atypical = hypersomnia |
| (5) | Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) [3] | Retardation: dlPFC hypoactivity + DA ↓; Agitation: NE hyperactivation | Must be observable — subjective feeling alone is insufficient |
| (6) | Fatigue or loss of energy nearly every day [3] | NE/DA deficiency → reduced arousal and drive; HPA axis exhaustion | Anergia — one of three ICD core symptoms |
| (7) | Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) [3] | Cognitive distortions (personalisation, selective abstraction); may reach delusional intensity in psychotic depression | Guilt about being sick does NOT count |
| (8) | Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) [3] | dlPFC hypoactivity → executive dysfunction; rumination hijacks cognitive resources | In elderly, may mimic dementia (pseudodementia) |
| (9) | Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide [3] | 5-HT ↓ (impaired impulse control) + hopelessness (cognitive triad) | Ranges from passive to active; must always be assessed |
Cardinal vs Associated Symptoms
At least one of (1) depressed mood or (2) anhedonia MUST be present. You cannot diagnose MDD without one of these two cardinal symptoms — even if a patient has 7 other symptoms (fatigue, insomnia, weight loss, etc.), without depressed mood or anhedonia, this is not MDD.
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).
Bereavement Exclusion — Removed in DSM-5
Key change from DSM-IV: Removal of the "bereavement exclusion" [3]. Previously, depressive symptoms within 2 months of bereavement were excluded from MDD diagnosis. DSM-5 removed this because: (1) bereavement can trigger a genuine MDE; (2) depressive symptoms may be understandable/considered appropriate to significant loss (e.g., bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) but can still represent MDD; (3) exercise of clinical judgment based on the individual's history and the cultural norms is required [3]. The point: grief can coexist with MDD, and withholding treatment on the basis of a "bereavement exclusion" may harm patients.
ICD-11 cardinal symptoms: depressed mood or diminished interest in activities occurring most of the day, nearly every day during a period lasting at least two weeks [3]
Additional symptoms: difficulty concentrating, feelings of worthlessness or excessive or inappropriate guilt, hopelessness, recurrent thoughts of death or suicide, changes in appetite or sleep, psychomotor agitation or retardation, and reduced energy or fatigue [3]
ICD-10/11 Severity Grading System (Box 9.1)
ICD uses a two-tier structure — Section A (core symptoms) and Section B (additional symptoms) [2]:
Section A — Core Symptoms:
- Depressed mood
- Loss of interest and enjoyment (anhedonia)
- Reduced energy and decreased activity (anergia)
Section B — Additional Symptoms:
- Reduced concentration
- Reduced self-esteem and confidence
- Ideas of guilt and unworthiness
- Pessimistic thoughts
- Ideas of self-harm
- Disturbed sleep
- Diminished appetite
Severity grading [2]:
| Severity | Section A Required | Section B Required | Overall |
|---|---|---|---|
| Mild | At least 2 of 3 | At least 2 of B | Total ≥ 4 symptoms |
| Moderate | At least 2 of 3 | At least 3 of B | Total ≥ 5 symptoms |
| Severe | All 3 of A | At least 4 of B | Total ≥ 7 symptoms |
Severity of symptoms AND degree of functional impairment also guide classification [2].
DSM-5 vs ICD: Key Differences
DSM-5: 5 of 9 symptoms (at least 1 cardinal), single threshold, severity assessed by clinical judgement and specifiers. ICD: Two-tier system (A+B) with explicit numerical thresholds for mild/moderate/severe. ICD requires anergia as a core symptom; DSM-5 lists fatigue as an associated symptom. Both converge on the same clinical picture — the structure differs.
C. DSM-5 Specifiers
Specifiers for major depressive disorder [3]:
- 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]:
| Specifier | Key Features | Clinical Significance |
|---|---|---|
| With anxious distress [3] | Feeling keyed up/tense, restless, difficulty concentrating due to worry, fear of something awful happening, fear of losing control | Poorer prognosis, higher suicide risk, slower treatment response |
| With mixed features [3] | ≥3 manic/hypomanic symptoms during depressive episode (e.g., elevated mood, grandiosity, pressured speech, racing thoughts, increased energy, decreased need for sleep) | May predict future bipolar conversion; caution with antidepressant monotherapy |
| With melancholic features [3] | Near-complete absence of the capacity for pleasure [5]; loss of emotional reactivity, early morning wakening, depression worse in AM, psychomotor disturbance, weight loss, excessive guilt | Better response to biological treatments (ECT, TCA > SSRI) [2]; ↑ neurobiological abnormalities, ↑ FHx [2] |
| With atypical features [3] | Mood reactivity, weight gain, hypersomnia [5]; leaden paralysis, rejection sensitivity | Better response to MAOIs/SSRIs; poorer response to TCA [2] |
| With psychotic features — mood-congruent or mood-incongruent [3] | Delusions/hallucinations; mood-congruent = themes of guilt, worthlessness, nihilism, poverty; mood-incongruent = themes inconsistent with depression | Requires antidepressant + antipsychotic or ECT. Mood-incongruent psychosis → consider schizoaffective |
| With catatonia [3] | Stupor, mutism, negativism, posturing, stereotypy, echolalia/echopraxia | May require benzodiazepines or ECT |
| With peripartum onset [3] | Onset during pregnancy or within 4 weeks postpartum | Severe anxiety and even panic attacks. Risk of infanticide [5]. Screen all peripartum women |
| With seasonal pattern [3] | Depression begins in fall or winter and remits in spring [5] (recurrent episodes only) | Bright light therapy; melatonin-related mechanism |
At least 4 of the following are required for "with somatic features" (ICD-10) or "with melancholic features" (DSM-5) [2]:
- Loss of interest or pleasure in usual activities
- Lack of emotional reactivity to normally pleasurable surroundings and events
- Early-morning waking (≥2 hours before usual time)
- Depression worse in the morning
- Psychomotor agitation or retardation
- Marked loss of appetite
- Weight loss (≥5% of body weight in last month)
- Marked loss of libido (ICD-10 only)
- Distinct quality of depressed mood (DSM-5 only)
- 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
Key changes from DSM-IV [3]:
- Removal of the "bereavement exclusion" — discussed above
- Dysthymia → persistent depressive disorder (includes both chronic major depressive disorder and the previous dysthymic disorder) [3]
- Introduction of two new disorders [3]:
- Disruptive mood dysregulation disorder: persistent irritability and frequent episodes of extreme, out-of-control behaviour in children up to age 18 years [3] — created to reduce over-diagnosis of paediatric bipolar disorder
- Premenstrual dysphoric disorder: mood symptoms occur during the final week before the onset of menses, and improve within a few days of menses [3] — distinct from premenstrual syndrome by severity and functional impairment
The following flowchart integrates symptom assessment, exclusion criteria, severity grading, and specifiers into a single clinical pathway:
Objective measures of severity of depression [3]:
These are useful in clinical practice and research but not diagnostic and should not be used as a substitute for a clinical diagnosis made from a thorough interview [3].
| Instrument | Type | Description | Use |
|---|---|---|---|
| Hamilton Rating Scale for Depression (HAM-D) [3] | Clinician-rated | 17-item scale; scores ≥8 = mild, ≥14 = moderate, ≥19 = severe, ≥23 = very severe | Gold standard for research; tracks treatment response |
| Montgomery-Åsberg Depression Rating Scale (MADRS) [3] | Clinician-rated | 10-item scale; more sensitive to change than HAM-D; scores 0-6 = normal, 7-19 = mild, 20-34 = moderate, ≥35 = severe | Preferred in clinical trials for antidepressant efficacy |
| Patient Health Questionnaire-9 (PHQ-9) [3] | Self-rated | 9 items mapping to DSM-5 criteria; scores 5-9 = mild, 10-14 = moderate, 15-19 = moderately severe, 20-27 = severe | Most widely used screening tool in primary care |
| Beck Depression Inventory (BDI) [3] | Self-rated | 21-item scale; scores 0-13 = minimal, 14-19 = mild, 20-28 = moderate, 29-63 = severe | Commonly used in research and CBT monitoring |
| Center for Epidemiologic Studies-Depression Scale (CES-D) [3] | Self-rated | 20-item scale; cutoff ≥16 suggests significant depression | Primarily used in epidemiological research |
| Special patient groups [3]: Geriatric Depression Scale | Self-rated | Yes/No format, simpler for elderly | Screening in elderly populations |
| Cornell Scale for Depression in Dementia [3] | Clinician-rated (with informant) | Specifically designed for patients with cognitive impairment | Distinguishes depression from dementia symptoms |
| Edinburgh Postnatal Depression Scale [3] | Self-rated | 10 items, validated for peripartum use; cutoff ≥10 or ≥13 depending on protocol | Routine screening in postnatal care |
Screening Tool ≠ Diagnosis
A common mistake: using a PHQ-9 score alone to diagnose MDD. These instruments are screening and severity measurement tools, not diagnostic instruments. A high PHQ-9 score should trigger a thorough clinical interview using DSM-5/ICD-11 criteria. Conversely, a low score does not exclude depression in a patient who minimises symptoms.
G. Investigation Modalities
Investigations in MDD serve three purposes:
- Exclude organic/secondary causes of depression
- Establish baseline parameters before starting pharmacotherapy
- Screen for neglect (e.g., malnutrition, substance misuse) and comorbidities
| Investigation | What You're Looking For | Interpretation/Rationale |
|---|---|---|
| CBP [2][3] | ↓ Hb (anaemia → fatigue mimicking depression); ↑ MCV (macrocytosis → alcoholism or B12/folate deficiency); ↑ WBC (infection as organic cause) | Anaemia alone can cause fatigue, poor concentration, and low mood. Raised MCV in a depressed patient should prompt questioning about alcohol use [2] |
| Renal function tests (RFT) [2][3] | U/Cr (renal impairment → uraemia causing apathy, cognitive impairment); HypoNa (SIADH — can be caused by SSRIs/SNRIs); Ca (hypercalcaemia → "psychiatric moans" of hyperparathyroidism) | HypoNa is also an important antidepressant side effect to monitor. Calcium is essential — hypercalcaemia causes depression, confusion, constipation [2] |
| Liver function tests (LFT) [2][3] | GGT (alcoholic liver disease — elevated GGT is a sensitive marker of chronic alcohol use); transaminases (hepatitis); bilirubin | Alcoholism is both a differential diagnosis and a comorbidity. GGT is a more sensitive marker than transaminases for chronic alcohol use [2] |
| Thyroid function tests (TFT) [2][3] | TSH, fT4 (hypothyroidism is the classic organic mimic of depression); less commonly hyperthyroidism presenting with agitated depression | Hypothyroidism → ↓ T3/T4 → slowed cerebral metabolism → fatigue, psychomotor retardation, weight gain, depressed mood. This is the single most important investigation to exclude in a depressed patient [2] |
| Investigation | When to Order | Interpretation/Rationale |
|---|---|---|
| Blood alcohol level [3] | Suspected alcohol misuse | Acute intoxication or chronic use |
| Blood and urine toxicology screen [2][3] | Suspected substance use; acute presentation; adolescents; history inconsistent with symptoms | Identifies stimulant, opioid, cannabinoid, benzodiazepine use — substance-induced depression |
| Blood glucose / HbA1c | Suspected diabetes; obesity; on antipsychotics | Type 2 diabetes is comorbid with depression; some antipsychotics cause metabolic syndrome |
| Vitamin B12 and folate [2] | Elderly, poor nutrition, raised MCV, vegan/vegetarian diet, malabsorption | B12 deficiency causes depression, cognitive impairment, and megaloblastic anaemia. Folate deficiency has similar psychiatric manifestations |
| CRP/ESR [2] | Suspected infection or inflammatory disease | Neuroinflammation contributes to depression; chronic inflammatory conditions (RA, IBD) have high rates of comorbid depression |
| HIV test [3] | Risk factors present; unexplained weight loss; young patient with atypical depression | HIV-associated neurocognitive disorder can present as depression |
| Cosyntropin (ACTH) stimulation test [3] | Suspected Addison disease — hyperpigmentation, hypotension, electrolyte abnormalities, unexplained fatigue | Adrenal insufficiency → cortisol deficiency → fatigue, depression, weight loss |
| Dexamethasone suppression test | Suspected Cushing's syndrome — moon face, central obesity, striae, proximal myopathy | Cortisol excess → hippocampal neurotoxicity → depression. Failure to suppress cortisol after dexamethasone = hypercortisolism |
| Calcium, phosphate, PTH | Suspected hyperparathyroidism — bone pain, constipation, renal stones, depression | Hypercalcaemia → neuropsychiatric symptoms ("stones, bones, groans, psychiatric moans") |
| Syphilis serology (VDRL/RPR) | Risk factors; atypical presentation; cognitive decline | Neurosyphilis can present as depression, cognitive impairment, personality change |
| Investigation | When to Order | Interpretation/Rationale |
|---|---|---|
| CT or MRI brain [2][3] | For organic brain syndrome or hypopituitarism [3]; focal neurological signs; cognitive deficits; atypical presentation; first episode in elderly; treatment resistance | Excludes structural lesions (tumours, infarcts, demyelination), hydrocephalus, pituitary pathology |
| EEG [2][3] | For epilepsy [3]; suspected seizure disorder; episodic behavioural changes; temporal lobe epilepsy | TLE can present with interictal depression, dissociative episodes. Post-ictal depression is also recognised |
| ECG [2] | Before starting TCAs, lithium, or antipsychotics; cardiac history; elderly | TCAs and lithium prolong QT interval and may trigger arrhythmias. Baseline ECG is essential before initiating these medications [2] |
SIG E CAPS (think of prescribing "energy capsules" — SIG = prescription directions)
S = Sleep disturbance (insomnia or hypersomnia) I = Interest loss (anhedonia) ★ cardinal G = Guilt (or worthlessness) E = Energy loss (fatigue) C = Concentration impairment A = Appetite/weight change P = Psychomotor agitation or retardation S = Suicidal ideation
+ Depressed mood ★ cardinal
Need ≥5/9 for ≥2 weeks, with at least 1 cardinal (depressed mood or anhedonia)
High Yield Summary
DSM-5 MDD Criteria: ≥5 of 9 symptoms (SIG E CAPS + depressed mood) for ≥2 weeks; at least one must be depressed mood or anhedonia; causes significant distress/functional impairment; not attributable to substance/medical condition; not better explained by psychotic spectrum disorders; no history of mania/hypomania.
ICD Severity: Mild (2A + 2B), Moderate (2A + 3B), Severe (3A + 4B). ICD uniquely includes anergia as a core symptom.
Key DSM-5 Changes: Removal of bereavement exclusion; dysthymia → persistent depressive disorder; new diagnoses (disruptive mood dysregulation disorder, premenstrual dysphoric disorder).
Specifiers: anxious distress, mixed features, melancholic, atypical, psychotic (mood-congruent vs incongruent), catatonia, peripartum onset, seasonal pattern. Melancholic = better response to biological Tx (TCA > SSRI, ECT).
Assessment Tools: HAM-D, MADRS, PHQ-9, BDI, CES-D + special populations (GDS, Cornell, Edinburgh). These are screening/severity tools, NOT diagnostic substitutes.
Investigations: Tier 1 (all patients) = CBP, RFT, LFT, TFT. Tier 2 (guided) = drug screen, B12/folate, glucose, HIV, ACTH stim, calcium. Tier 3 (neuro/cardiac) = CT/MRI, EEG, ECG. TFT is the single most important investigation.
Active Recall - Diagnostic Criteria, Algorithm & Investigations
References
[2] Senior notes: ryanho-psych.md (Psychiatry chapter — sections 7.1.1, 7.2, pages 4, 33, 140–143, 155–158, 162) [3] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pages 2, 3, 5, 6, 7, 8, 9, 10, 14, 15) [5] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (pages 3, 12, 22)
Management of Major Depressive Disorder
Before diving into treatments, understand the framework. Management of MDD follows the biopsychosocial model — you never treat with drugs alone or therapy alone. Treatment is always a combination of biological, psychological, and social interventions, tailored to severity.
Though changes in monoamines constitute only part of the aetiological picture, the monoamine systems provide the most accessible treatment avenue [3].
Three phases of treatment [2]:
- Acute treatment — resolve the current episode (weeks to months)
- Continuation treatment — prevent relapse of the same episode (6–9 months after remission)
- Maintenance (prophylactic) treatment — prevent recurrence of new episodes (years, sometimes lifelong)
Key Concept: Relapse vs Recurrence
Relapse = return of symptoms of the same episode (within 6–9 months of remission) — prevented by continuation treatment. Recurrence = a new episode after full recovery — prevented by maintenance treatment. This distinction matters because premature drug cessation after apparent improvement often leads to relapse (the episode never truly ended), not recurrence.
The stepped-care model matches intensity of intervention to severity of illness [2]:
These apply to every patient regardless of severity [2]:
- Avoid alcohol and substance use — alcohol is a CNS depressant that worsens depression and impairs antidepressant efficacy; cannabis worsens amotivation; stimulant withdrawal triggers rebound depression
- Lifestyle advice on diet and sleep hygiene — regular sleep-wake schedule (supports circadian rhythm regulation), avoid caffeine in the evening, structured daily routine
- Encourage suitable activity — physical inactivity causes social withdrawal and exacerbates depression [2]. Exercise increases BDNF, endorphins, and monoamine neurotransmission — it is literally a biological antidepressant
Physical activity is listed as a distinct management modality [3]:
- Aerobic exercise (30 min, 3–5×/week) has evidence equivalent to mild antidepressant effect
- Mechanism: ↑ BDNF, ↑ endorphin release, ↑ serotonin/noradrenaline, ↑ hippocampal neurogenesis, normalises HPA axis
- Most useful as adjunct; insufficient alone for moderate-severe depression
2. Pharmacotherapy
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]
| Class | Examples | Mechanism | Key Features |
|---|---|---|---|
| Selective Serotonin Reuptake Inhibitors (SSRIs) | Fluoxetine, paroxetine, sertraline, citalopram, escitalopram, vortioxetine [3] | Block SERT → ↑ synaptic 5-HT | 1st line for most patients. Best safety profile. Vortioxetine also has multimodal 5-HT receptor activity |
| Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) | Duloxetine, venlafaxine, desvenlafaxine [3] | Block SERT + NET → ↑ synaptic 5-HT and NE | Useful for depression with chronic pain (duloxetine); venlafaxine at low dose is essentially an SSRI, only becomes dual at higher doses |
| Non-selective Monoamine Reuptake Inhibitors (TCAs) | Amitriptyline, imipramine, nortriptyline, clomipramine, dothiepin, trimipramine, desipramine [3] | Block SERT + NET (+ varying degrees of DRT) | Older antidepressants associated with significant adverse events and drug-drug interactions [3]. More effective in melancholic depression but dangerous in overdose (cardiac toxicity) |
| Tetracyclic antidepressants | Mianserin [3] | α2-adrenergic antagonist → ↑ NE release; also antihistaminic | Sedating; less commonly used now |
| Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs) | Bupropion [3] | Block NET + DRT → ↑ synaptic NE and DA | Activating; no sexual dysfunction; also used for smoking cessation. CI in seizure disorders and eating disorders |
| Monoamine Oxidase Inhibitors (MAOIs) and Reversible Inhibitors of MAO-A (RIMAs) | Tranylcypromine, phenelzine, isocarboxazid, selegiline (irreversible); moclobemide (reversible) [3] | Inhibit MAO enzyme → ↓ monoamine breakdown → ↑ synaptic 5-HT, NE, DA | Effective for atypical depression. Irreversible MAOIs require strict tyramine-free diet (risk of hypertensive crisis). Moclobemide is safer (reversible) |
| Melatonergic antidepressants | Agomelatine [3] | MT1/MT2 melatonin receptor agonist + 5-HT2C antagonist | Resynchronises circadian rhythm; few sexual side effects; requires LFT monitoring (hepatotoxicity) |
| Others | Trazodone, mirtazapine [3] | Trazodone: SARI (5-HT2 antagonist + weak SERT inhibitor); Mirtazapine: NaSSA (α2 antagonist + 5-HT2/3 antagonist + H1 antagonist) | Mirtazapine: strongly sedating (H1 blockade), appetite stimulating → useful when insomnia and weight loss are prominent. Trazodone: mainly used for insomnia at low doses |
First-Line = SSRI (or Mirtazapine if Sedation Needed)
The approach from the flowchart [2]: suggest an SSRI or mirtazapine if sedation is required. SSRIs are first-line because of their favourable safety-to-efficacy ratio. The choice between specific SSRIs is guided by side-effect profile, drug interactions, and patient preference.
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
| Class | Common Side Effects | Serious Risks | Contraindications |
|---|---|---|---|
| SSRIs | GI upset (nausea, diarrhoea), headache, sexual dysfunction, insomnia/agitation (initially), weight gain (long-term) | Serotonin syndrome (if combined with MAOIs), hyponatraemia (SIADH, especially elderly), ↑ suicidal ideation in < 25y (initial weeks), GI bleeding (esp with NSAIDs) | Concurrent MAOI use (≥2 week washout; 5 weeks for fluoxetine due to long half-life) |
| SNRIs | Similar to SSRIs + sweating, dry mouth; venlafaxine: dose-dependent ↑ BP | Serotonin syndrome, hyponatraemia, ↑ BP (venlafaxine) | Concurrent MAOI; uncontrolled HTN (venlafaxine) |
| TCAs | Anticholinergic (dry mouth, constipation, urinary retention, blurred vision), sedation, orthostatic hypotension, weight gain, sexual dysfunction | Lethal in overdose (QT prolongation → ventricular arrhythmias → cardiac arrest; seizures) | Recent MI, heart block, arrhythmias, severe liver disease, acute angle-closure glaucoma, urinary retention. Avoid in suicidal patients (OD risk) |
| MAOIs (irreversible) | Orthostatic hypotension, weight gain, insomnia, sexual dysfunction | Hypertensive crisis with tyramine-rich foods (aged cheese, red wine, fermented foods, broad beans); serotonin syndrome with serotonergic drugs | Concurrent serotonergic drugs (SSRIs, SNRIs, TCAs, pethidine, tramadol); phaeochromocytoma; hepatic impairment |
| Mirtazapine | Sedation (H1), weight gain (H1 + 5-HT2C), dry mouth | Rare: agranulocytosis | Concurrent MAOI |
| Bupropion | Insomnia, dry mouth, agitation, headache | Seizures (dose-dependent; risk ~0.4% at therapeutic doses) | Seizure disorder, bulimia/anorexia (↑ seizure risk), concurrent MAOI |
| Agomelatine | Nausea, dizziness, headache, fatigue | Hepatotoxicity — requires LFT monitoring at baseline, 3w, 6w, 12w, 24w | Pre-existing hepatic impairment; concurrent potent CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) |
TCAs + Suicidal Patient = Dangerous Combination
TCAs are lethal in overdose — as few as 10 days' supply can be fatal. The mechanism: sodium channel blockade → QRS widening → ventricular arrhythmias. This is why TCAs are avoided in patients with suicidal risk. SSRIs are far safer in overdose (very rarely fatal). If a TCA must be used, dispense limited quantities and consider supervised administration.
STAR*D Trial — What Happens When Drugs Fail?
The landmark STAR*D trial (Sequenced Treatment Alternatives to Relieve Depression) [2] showed cumulative remission rates across 4 treatment steps:
- Step 1: Citalopram → 28% remission
- Step 2: Switch or augment → additional ~20–25% remission
- Step 3: Switch or augment again → additional ~12–20% remission
- Step 4: Tranylcypromine or mirtazapine + venlafaxine → additional ~7–14% remission
Key lesson: With persistent, systematic treatment, ~60–70% of patients eventually remit — but each successive step has diminishing returns. Early, aggressive, optimised treatment matters.
Psychosocial treatment is a core management modality [3].
The main psychotherapies for depression [2]:
| Therapy | Basis | Format | Mechanism | Best For |
|---|---|---|---|---|
| Cognitive-Behavioural Therapy (CBT) | Beck's cognitive model — depression is maintained by negative automatic thoughts and cognitive distortions | Structured, 12–20 sessions, homework-based | Identifies and challenges negative thoughts (cognitive restructuring) + behavioural experiments + behavioural activation | Mild-moderate depression (monotherapy); moderate-severe (combined with medication); relapse prevention |
| Mindfulness-Based Cognitive Therapy (MBCT) | Combines CBT with mindfulness meditation | Group format, 8 weeks | Teaches patients to observe thoughts non-judgementally rather than react to them → breaks rumination cycle | Relapse prevention in recurrent depression (≥3 episodes); NICE recommended |
| Interpersonal Therapy (IPT) | Problems with interpersonal life contribute to psychopathology | Brief (12–16 sessions), focused on current problems | Focus areas: grief over loss, interpersonal disputes, role transitions, interpersonal skill deficits → improve social functioning | Depression linked to interpersonal difficulties; equivalent efficacy to CBT |
| Psychodynamic therapy | Unconscious conflicts and early relational patterns shape current emotional experience | Longer-term (months to years) | Explore unconscious patterns, defence mechanisms, transference | Chronic/recurrent depression with personality factors; patients interested in deeper self-understanding |
| Behavioural activation | Withdrawal and inactivity perpetuate depression | Structured, brief | Scheduling of valued activities to counteract avoidance and withdrawal → increases positive reinforcement from environment | Mild-moderate; can be delivered by non-specialist |
| Group therapy | Various theoretical orientations | ~5–10 patients, weekly for 1h | Observation of psychological/behavioural responses to group members in a "safe" social setting | Adjunctive; social skills building; cost-effective |
Efficacy and choice depends on patient features and type of depression [2]:
- Mild depression: psychotherapy alone may be sufficient (CBT, behavioural activation, guided self-help)
- Moderate depression: psychotherapy + medication (combined is superior to either alone)
- Severe depression: medication is essential; psychotherapy is adjunctive (patients often too impaired cognitively for full engagement in therapy until medication begins to work)
When Psychotherapy Alone Is Sufficient
For mild depression, evidence supports watchful waiting + low-intensity interventions (guided self-help, computerised CBT, behavioural activation, exercise) as first-line. Medications should be reserved for moderate-severe illness or when psychosocial interventions fail. This is the stepped-care principle.
4. Physical Treatments
"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
Healthy diet may help as part of the overall depression treatment, though no specific diet has been proven to relieve depression [3]:
- Food rich in antioxidants (e.g., blueberries, oranges, carrots, nuts) [3] — oxidative stress is implicated in depression; antioxidants may have neuroprotective effects
- Complex carbohydrates (e.g., whole grains) can have a calming effect [3] — they ↑ tryptophan transport across BBB → ↑ serotonin synthesis
- Protein-rich foods (e.g., turkey, tuna, chicken) boost alertness [3] — contain tyrosine (dopamine/NE precursor) and tryptophan (serotonin precursor)
- Mediterranean diet as a source for B vitamins [3] — B6, B12, and folate are cofactors in monoamine synthesis; deficiency → impaired serotonin/dopamine production
Omega-3 fatty acids [3]:
- Essential polyunsaturated lipids that influence cellular metabolism and function [3]
- Earlier studies linked low seafood intake (a major source of omega-3 FAs) and mood disorders, and positive results with fish oil intervention → subsequent results more diversified [3]
- EPA rather than DHA as the effective component [3] — EPA has anti-inflammatory properties (↓ pro-inflammatory cytokines → ↓ neuroinflammation)
- Monotherapy as well as adjunct therapy [3]
Defined as failure to respond adequately to ≥2 adequate trials of antidepressants from different classes.
Approach [2]:
First, reconsider the fundamentals:
- Reassess diagnosis: look for secondary causes (e.g., substance abuse, medical conditions, personality disorder, bipolar disorder)
- Assess compliance: are they actually taking the medication? At adequate dose? For adequate duration?
- Assess for ongoing psychosocial stressors: no antidepressant will overcome ongoing abuse, poverty, or entrapment
Then, therapeutic options [2]:
| Strategy | Details |
|---|---|
| Switch to another class | Usually done first, preferably of a different mechanism (e.g., SSRI → SNRI, or SSRI → mirtazapine). Beware of serotonin syndrome and discontinuation syndrome → cross-tapering [2] |
| Combination therapy | Usually 5-HT mechanism (SSRI, venlafaxine) + NE/DA mechanism (bupropion, mirtazapine) → "California rocket fuel" = venlafaxine + mirtazapine [2] |
| Augmentation with lithium | Well-established evidence. Target level 0.4 mmol/L for augmentation in unipolar depression. Monitor RFT, TFT, plasma Li [2] |
| Augmentation with antipsychotics | Low-dose atypical antipsychotic, especially if psychotic features present. Antipsychotics licensed for augmentation: quetiapine, aripiprazole [2] |
| Augmentation with T3 (tri-iodothyronine) | Even in euthyroid patients, T3 25–50 μg/day can augment antidepressant response. Mechanism: T3 enhances serotonergic neurotransmission [2] |
| ECT | Considered more effective than drugs in the most severe cases. Indications: emergency, refractory, catatonic [2] |
Options for refractory depression [2]: Optimise existing treatment → Augmentation by antipsychotics, Li or T3 → Combine with another antidepressant with another mechanism → Switch to another mechanism
Newer options (for severe treatment-resistant cases):
- Esketamine (nasal spray) — NMDA receptor antagonist; approved for treatment-resistant depression; rapid onset (hours to days vs weeks for traditional antidepressants)
- Psilocybin-assisted therapy — emerging evidence; not yet standard practice
- Deep brain stimulation (DBS) — experimental; targets subcallosal cingulate (area 25)
| Population | Key Considerations |
|---|---|
| Elderly | Start low, go slow. Increased sensitivity to anticholinergic effects (TCAs → avoid). SSRI-induced hyponatraemia more common. Use Geriatric Depression Scale for assessment [3] |
| Children and adolescents | In children and adolescents, depressed mood can be irritable mood [3]. Fluoxetine is the only SSRI with robust evidence in paediatric depression. Beware of increased suicidal ideation with SSRIs in under-25s (black box warning) — monitor closely in first weeks |
| Pregnancy | Risk-benefit analysis. Untreated severe depression carries risks (poor nutrition, substance use, suicide, impaired bonding). SSRIs generally considered acceptable (sertraline, fluoxetine have most data). Paroxetine associated with cardiac malformations — avoid. ECT is safe in pregnancy [2] |
| Peripartum | With peripartum onset — severe anxiety and even panic attacks. Risk of infanticide [5]. Edinburgh Postnatal Depression Scale for screening [3]. Breastfeeding: sertraline has lowest infant exposure |
| Psychotic depression | Antidepressant alone insufficient — requires antidepressant + antipsychotic or ECT |
| Bipolar depression | NOT identical to Tx of unipolar depression [2]. Conventional antidepressants are less effective, associated with risk of inducing mania, and risk of inducing rapid cycling [2]. First-line: quetiapine or olanzapine + fluoxetine. Antidepressants should be combined with antipsychotic or mood stabiliser [2] |
Bipolar Depression ≠ Unipolar Depression Treatment
This is a critical exam point. Conventional antidepressants are (1) less effective in treating bipolar depression, (2) associated with risk of inducing mania, (3) associated with risk of inducing rapid cycling [2]. SSRIs may be effective but may induce mania. TCAs and SNRIs have ↑↑ risk of inducing mania [2]. Always use mood stabiliser cover.
Understanding prognosis helps guide duration of treatment [2]:
- Clinical course: generally self-limiting within 6 months to 1 year [2]
- Age of onset: ~50% before age 21
- Duration: average 6 months; ~25% > 1 year; ~10–20% chronic unremitting
- Recurrence: ~80% will recur, average ~4 further episodes in 25 years [2]
- Usually associated with progressive shortening of interval between episodes
- ~50% do not have complete symptom remission between episodes
- Only ~25% of those with recurrent major depression achieve 5-year clinical stability with good social and occupational performance [2]
- Mortality: > 20× risk of suicide, can approach 15% in those with severe admitted cases [2]
Prognostic factors for relapse [2]:
- Incomplete symptomatic remission
- Early age of onset
- Poor social support
- Poor physical health
- Comorbid substance abuse
- Comorbid personality disorder
High Yield Summary
Stepped-Care Model: Mild → watchful waiting + psychosocial. Moderate → antidepressant + psychotherapy. Severe → antidepressant + psychotherapy + consider inpatient. Psychotic → antidepressant + antipsychotic or ECT. Life-threatening/catatonic → ECT first-line.
First-Line Pharmacotherapy: SSRI (or mirtazapine if sedation needed). Cipriani meta-analysis: escitalopram, vortioxetine = effective + tolerable. Older antidepressants (TCAs, MAOIs) = more side effects and dangerous in OD.
Duration: Continue ≥6–9 months at full dose after remission (first episode). ≥2 years if ≥2 episodes with functional impairment. Taper gradually (≥4 weeks).
Refractory Depression: Reassess diagnosis/compliance/stressors → switch class → combine (SSRI + mirtazapine or bupropion) → augment (Li, quetiapine/aripiprazole, T3) → ECT.
ECT Indications: Emergency (suicidal, food refusal), Catatonia, Treatment-refractory. No absolute CI. Most effective treatment for severe depression, especially with psychosis/psychomotor retardation.
Psychotherapy: CBT is most evidence-based. IPT for interpersonal issues. MBCT for relapse prevention. Combine with medication for moderate-severe.
Bipolar Depression: NOT same as unipolar Tx. Antidepressant monotherapy contraindicated (mania risk). Use quetiapine or olanzapine + fluoxetine.
Prognosis: 80% recur; average 4 episodes over 25 years; > 20× suicide risk. Prognostic factors for relapse: incomplete remission, early onset, poor social support, poor physical health, comorbid SA, comorbid PD.
Active Recall - Management of Major Depressive Disorder
References
[2] Senior notes: ryanho-psych.md (Psychiatry chapter — sections 3.1.1, 3.1.3.1, 3.2, 3.3, 7.2 Management, pages 33, 44–45, 51, 56, 62–63, 71, 140, 155–162, 165) [3] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pages 13, 14, 16, 17, 24, 25) [5] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (pages 12, 22)
Complications of Major Depressive Disorder
MDD is not a "benign" mood problem. It is a systemic illness with consequences that extend far beyond sadness. The lecture slides conclude with a clear message: Depression is associated with significant morbidity and mortality [3]. Understanding complications is essential because it drives urgency of treatment, informs the consent discussion with patients ("if we don't treat this, here is what can happen"), and frames depression as a medical emergency in its most severe forms.
Complications can be organised into:
- Psychiatric complications (direct consequences of the depressive illness itself)
- Medical/physical complications (depression's impact on the body)
- Functional and psychosocial complications (impact on life, work, relationships)
- Treatment-related complications (iatrogenic)
1. Psychiatric Complications
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]
Depression = Leading Cause of Suicide in HK
In Hong Kong, MDD is the single most important psychiatric risk factor for suicide in both younger adults and the elderly. This is a high-yield exam point. Over 700,000 people commit suicide worldwide every year, and one of the major causes of suicide is depression [3]. Every depressed patient requires systematic suicide risk assessment.
- 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]
2. Medical/Physical Complications
Depression entails a non-psychiatric impact! [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]:
- 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
- Biological risk factors: altered thrombogenesis — depression activates the sympathetic nervous system and HPA axis → ↑ platelet activation, ↑ inflammatory cytokines, ↑ endothelial dysfunction → prothrombotic state → ↑ cardiovascular events
- 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)
When enduring, depression can result in impaired function at work, at school and in the family [3]
| Domain | Complication | Mechanism |
|---|---|---|
| Occupational | ↓ Productivity, absenteeism, job loss, unemployment | Anergia, poor concentration, psychomotor retardation → cannot perform at work. ~$85 billion/year loss of productivity [2] |
| Academic | Decline in school performance [3], failure, dropout | Concentration impairment, amotivation, anhedonia |
| Social | Social withdrawal, isolation, loss of friendships | Anhedonia → loss of interest in social activities; negative cognitive style → misinterprets social cues; fatigue → avoids effort of social engagement |
| Interpersonal | Relationship breakdown, divorce, family conflict | Irritability, withdrawal, loss of libido, burden on partners/family. ↑ in divorced (both cause and consequence) [2] |
| Self-care | Neglect of hygiene, nutrition, health management | Anergia, apathy, amotivation; especially in elderly → deterioration of cognitive functioning and self-care [3] |
| Parenting | Impaired bonding, inconsistent parenting, neglect | Maternal/paternal depression → insecure attachment in children → intergenerational transmission of vulnerability |
| Financial | Debt, poverty, homelessness | Job loss + impaired decision-making + potential comorbid substance abuse |
| Legal | In severe cases with psychotic features or comorbid substance abuse | Impaired judgement; antisocial behaviour secondary to substance misuse or irritability |
Youth-Specific Complications
In some younger people, the first obvious sign may be [3]:
- Loss of interest in friends
- Decline in school performance
- Self-injury or bulimia or drug use in a previously stable adolescent
In youth depression specifically [2]:
- Behavioural problems (e.g., "one case tried to steal a bus because of frustration at home, take cannabis to lift mood due to depression") [2]
- Somatic complaints (unexplained abdominal pains, headache, anorexia, enuresis) [2]
- High comorbidity rate: 70% have anxiety disorder, conduct disorder, substance abuse, or dysthymia [2]
These are complications of the treatments themselves, which must be balanced against the risks of untreated depression:
| Treatment | Complication | Mechanism | Prevention |
|---|---|---|---|
| SSRIs | ↑ Suicidal ideation in < 25 years (first 1–2 weeks) | SSRIs may initially increase energy/activation before mood improves → patient now has the energy to act on pre-existing suicidal thoughts | Close monitoring in first 2–4 weeks; start at low dose; warn patient/family |
| SSRIs | Serotonin syndrome (if combined with MAOIs) | Excessive synaptic 5-HT → hyperthermia, rigidity, myoclonus, altered mental status, autonomic instability | Mandatory washout period between SSRIs and MAOIs (≥2 weeks; 5 weeks for fluoxetine) |
| SSRIs/SNRIs | Hyponatraemia (SIADH) | Inappropriate ADH secretion → water retention → dilutional hyponatraemia | Monitor Na especially in elderly; educate about symptoms (confusion, nausea, seizures) |
| SSRIs | GI bleeding | 5-HT stored in platelets; SSRIs deplete platelet 5-HT → impaired platelet aggregation | Avoid concurrent NSAIDs; consider PPI cover in high-risk patients |
| SSRIs/SNRIs | Sexual dysfunction | 5-HT2/3 receptor stimulation in spinal cord → inhibits sexual arousal and orgasm | Consider switching to bupropion (no sexual S/E) or mirtazapine; dose reduction |
| SSRIs/SNRIs | Discontinuation syndrome | Abrupt withdrawal → rebound reduction in synaptic 5-HT → dizziness, nausea, "electric shocks," irritability, insomnia | Gradual taper over ≥4 weeks (especially paroxetine, venlafaxine) |
| TCAs | Cardiotoxicity in overdose | Sodium channel blockade → QRS prolongation → ventricular arrhythmias → cardiac arrest | Avoid in suicidal patients; prescribe limited supply; prefer SSRIs |
| MAOIs | Hypertensive crisis ("cheese reaction") | Tyramine in food normally metabolised by gut MAO-A; when MAO inhibited, tyramine → NE surge → hypertensive emergency | Strict tyramine-free diet; patient education |
| Lithium (augmentation) | Toxicity (tremor, ataxia, confusion, seizures, renal failure); hypothyroidism; nephrogenic DI; teratogenicity | Narrow therapeutic index; accumulates in renal impairment; inhibits thyroid hormone synthesis; affects renal aquaporins; neural tube defects (Ebstein's anomaly) | Regular monitoring: plasma Li, RFT, TFT every 6 months; reliable contraception |
| Antipsychotics (augmentation) | Metabolic syndrome (weight gain, dyslipidaemia, insulin resistance); extrapyramidal side effects; QTc prolongation | Histamine H1, 5-HT2C, muscarinic receptor blockade → appetite ↑, metabolic dysregulation; D2 blockade → EPS | Monitor weight, glucose, lipids, ECG; use metabolically favourable agents (aripiprazole) |
| ECT | Cognitive impairment (acute confusion, amnesia) | Seizure-induced transient neuronal disruption; bilateral > unilateral cognitive effects | Use unilateral electrode placement when possible; inform patient; usually short-lived (days) |
The complications of MDD form vicious cycles — each complication feeds back to worsen the depression:
High Yield Summary
Complications of MDD — Core Points:
-
Suicide: 20× increased risk; 6% lifetime risk of suicide death in affective disorders (15% in severe admitted cases). MDD is the commonest psychiatric cause of suicide in HK (27% population-attributable risk in adults, commonest diagnosis in elderly suicide). 86% of elderly suicide decedents in HK had a psychiatric problem; depression was the commonest.
-
Non-suicide mortality: RR 1.2–4.0. Mediated by behavioural factors (non-adherence, inactivity, alcohol), biological factors (altered thrombogenesis, HPA dysregulation), and prevalent CVD.
-
Cardiovascular disease: Depression is an independent cardiovascular risk factor. Mechanisms: hypercortisolaemia → insulin resistance; sympathetic activation → ↓ HRV; platelet activation → thrombosis; endothelial dysfunction.
-
Chronicity: 10–20% chronic unremitting; 80% recur; only 25% achieve 5-year stability. Each episode lowers threshold for future episodes (kindling).
-
Psychotic complications: 15–20% of severe episodes. Cotard's syndrome, depressive stupor (life-threatening), command hallucinations → suicide risk.
-
Functional impairment: ~$85B/year productivity loss. Occupational, academic, social, interpersonal, self-care deterioration.
-
Substance misuse: Bidirectional relationship; very common comorbidity; worsens prognosis.
-
Bipolar conversion: ~25% of BAD first presents as juvenile depression.
-
Treatment-related: SSRIs → suicidality in youth (first weeks), serotonin syndrome, hyponatraemia; TCAs → lethal in OD; MAOIs → hypertensive crisis; lithium → toxicity, hypothyroidism.
Active Recall - Complications of MDD
References
[2] Senior notes: ryanho-psych.md (Psychiatry chapter — sections 7.2 Course and Prognosis, 7.1.1, Youth Depression, pages 140, 155–162, 271) [3] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pages 2, 4, 5, 6, 15, 25)
High Yield Summary
Definition: MDD is a recurrent disorder of persistent depressed mood/anhedonia + biological/cognitive/psychomotor symptoms lasting ≥ 2 weeks causing functional impairment.
Epidemiology: 2.9% prevalence in HK; lifetime 10-20%; F:M = 2-3:1; mean onset ~27y; 4th leading cause of disability globally.
Risk Factors (3P): Predisposing — genetics (37% heritability, 5-HTTLPR), neuroticism, early adversity, female sex. Precipitating — life events (loss, entrapment, humiliation). Perpetuating — ongoing stressors, cognitive distortions, substance use, social isolation.
Pathophysiology: Biopsychosocial — monoamine deficiency (5-HT, NE, DA), HPA axis dysregulation (hypercortisolaemia), structural changes (hippocampal/subgenual volume loss), ↓ BDNF, neuroinflammation, cognitive distortions (Beck's triad), adverse early environment.
Core Features: Depressed mood (pervasive, loss of reactivity, morning dysphoria) + anhedonia + anergia.
Biological Symptoms: Early morning wakening, appetite/weight change, psychomotor retardation/agitation, diurnal variation, loss of libido.
Cognitive Symptoms: Poor concentration, worthlessness, guilt, hopelessness, suicidal ideation.
Psychotic Features (~15-20% severe): Mood-congruent delusions (guilt, nihilistic, poverty), auditory hallucinations.
Assessment: History + MSE + standardised instruments + physical exam + bloods (CBP, TFT, R/LFT minimum) to exclude organic causes.
High Yield Summary
Differential Diagnosis of MDD — Core Points:
-
Always screen for bipolar disorder — ask about past mania/hypomania. 69% of BAD patients are initially misdiagnosed, most commonly as MDD. Correct diagnosis delayed 5–7 years on average.
-
Adjustment disorder = subthreshold symptoms, ≤3 months of non-traumatic stressor. If full MDD criteria are met, diagnose MDD (not adjustment disorder).
-
Dysthymia = chronic (≥2 years), subthreshold. Can have superimposed MDD ("double depression").
-
Psychotic depression vs schizoaffective: mood-congruent + episode-bound psychosis = psychotic MDD. Less mood-congruent + psychosis outside mood episodes = schizoaffective.
-
Medical causes: always exclude hypothyroidism (TFT), Cushing's/Addison's, anaemia (CBP), and substance use. Minimum bloods: CBP, R/LFT, TFT.
-
Drug-induced depression: beta-blockers, reserpine, methyldopa, steroids, OCP, interferon, L-dopa, benzodiazepines. Temporal relationship to drug initiation is the key clue.
-
Pseudodementia: depression in elderly mimicking dementia. Treat depression first — cognition may recover.
High Yield Summary
DSM-5 MDD Criteria: ≥5 of 9 symptoms (SIG E CAPS + depressed mood) for ≥2 weeks; at least one must be depressed mood or anhedonia; causes significant distress/functional impairment; not attributable to substance/medical condition; not better explained by psychotic spectrum disorders; no history of mania/hypomania.
ICD Severity: Mild (2A + 2B), Moderate (2A + 3B), Severe (3A + 4B). ICD uniquely includes anergia as a core symptom.
Key DSM-5 Changes: Removal of bereavement exclusion; dysthymia → persistent depressive disorder; new diagnoses (disruptive mood dysregulation disorder, premenstrual dysphoric disorder).
Specifiers: anxious distress, mixed features, melancholic, atypical, psychotic (mood-congruent vs incongruent), catatonia, peripartum onset, seasonal pattern. Melancholic = better response to biological Tx (TCA > SSRI, ECT).
Assessment Tools: HAM-D, MADRS, PHQ-9, BDI, CES-D + special populations (GDS, Cornell, Edinburgh). These are screening/severity tools, NOT diagnostic substitutes.
Investigations: Tier 1 (all patients) = CBP, RFT, LFT, TFT. Tier 2 (guided) = drug screen, B12/folate, glucose, HIV, ACTH stim, calcium. Tier 3 (neuro/cardiac) = CT/MRI, EEG, ECG. TFT is the single most important investigation.
High Yield Summary
Stepped-Care Model: Mild → watchful waiting + psychosocial. Moderate → antidepressant + psychotherapy. Severe → antidepressant + psychotherapy + consider inpatient. Psychotic → antidepressant + antipsychotic or ECT. Life-threatening/catatonic → ECT first-line.
First-Line Pharmacotherapy: SSRI (or mirtazapine if sedation needed). Cipriani meta-analysis: escitalopram, vortioxetine = effective + tolerable. Older antidepressants (TCAs, MAOIs) = more side effects and dangerous in OD.
Duration: Continue ≥6–9 months at full dose after remission (first episode). ≥2 years if ≥2 episodes with functional impairment. Taper gradually (≥4 weeks).
Refractory Depression: Reassess diagnosis/compliance/stressors → switch class → combine (SSRI + mirtazapine or bupropion) → augment (Li, quetiapine/aripiprazole, T3) → ECT.
ECT Indications: Emergency (suicidal, food refusal), Catatonia, Treatment-refractory. No absolute CI. Most effective treatment for severe depression, especially with psychosis/psychomotor retardation.
Psychotherapy: CBT is most evidence-based. IPT for interpersonal issues. MBCT for relapse prevention. Combine with medication for moderate-severe.
Bipolar Depression: NOT same as unipolar Tx. Antidepressant monotherapy contraindicated (mania risk). Use quetiapine or olanzapine + fluoxetine.
Prognosis: 80% recur; average 4 episodes over 25 years; > 20× suicide risk. Prognostic factors for relapse: incomplete remission, early onset, poor social support, poor physical health, comorbid SA, comorbid PD.
High Yield Summary
Complications of MDD — Core Points:
-
Suicide: 20× increased risk; 6% lifetime risk of suicide death in affective disorders (15% in severe admitted cases). MDD is the commonest psychiatric cause of suicide in HK (27% population-attributable risk in adults, commonest diagnosis in elderly suicide). 86% of elderly suicide decedents in HK had a psychiatric problem; depression was the commonest.
-
Non-suicide mortality: RR 1.2–4.0. Mediated by behavioural factors (non-adherence, inactivity, alcohol), biological factors (altered thrombogenesis, HPA dysregulation), and prevalent CVD.
-
Cardiovascular disease: Depression is an independent cardiovascular risk factor. Mechanisms: hypercortisolaemia → insulin resistance; sympathetic activation → ↓ HRV; platelet activation → thrombosis; endothelial dysfunction.
-
Chronicity: 10–20% chronic unremitting; 80% recur; only 25% achieve 5-year stability. Each episode lowers threshold for future episodes (kindling).
-
Psychotic complications: 15–20% of severe episodes. Cotard's syndrome, depressive stupor (life-threatening), command hallucinations → suicide risk.
-
Functional impairment: ~$85B/year productivity loss. Occupational, academic, social, interpersonal, self-care deterioration.
-
Substance misuse: Bidirectional relationship; very common comorbidity; worsens prognosis.
-
Bipolar conversion: ~25% of BAD first presents as juvenile depression.
-
Treatment-related: SSRIs → suicidality in youth (first weeks), serotonin syndrome, hyponatraemia; TCAs → lethal in OD; MAOIs → hypertensive crisis; lithium → toxicity, hypothyroidism.
Depressive Disorders
Depressive disorders are a group of mood disorders characterized by persistent sadness, loss of interest or pleasure, and associated cognitive and somatic symptoms that impair daily functioning.
Anxiety Disorders
Anxiety disorders are a group of mental health conditions characterized by excessive, persistent fear or worry that is disproportionate to the actual threat and causes significant functional impairment.