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.
Depressive disorders are a group of psychiatric conditions characterised by persistent disturbances in mood, cognition, and neurovegetative function that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The core psychopathology is a sustained lowering of mood that is qualitatively different from normal sadness — it is pervasive, persistent, and shows loss of reactivity to circumstances [1][2].
Think of it this way: everyone feels sad after a breakup. In depressive disorder, the sadness takes on a life of its own — it doesn't lift when good things happen, it colours every waking hour, and it drags the body's biology down with it (sleep, appetite, energy, concentration).
Depressive disorder is caused by a combination of biological, social and psychological factors, which disturb the brain's capacity for stress management. [1]
The term "depression" in clinical medicine is an umbrella that encompasses several diagnostic entities — the most important being Major Depressive Disorder (MDD) and Persistent Depressive Disorder (Dysthymia) — each defined by severity, duration, and pattern of symptoms.
Key Conceptual Point
Depression ≠ sadness. Normal sadness is reactive (improves with positive events), self-limiting, and does not cause the full biological syndrome (sleep, appetite, psychomotor changes). A depressive episode is a syndrome — a cluster of symptoms occurring together with a minimum duration (≥ 2 weeks) and causing functional impairment.
2. Epidemiology
- 2.9% prevalence in Hong Kong (Hong Kong Mental Morbidity Survey, HKMMS) [1][2]
- This figure likely underestimates true burden because:
- Many patients present with somatic complaints (fatigue, pain, insomnia) rather than overtly reporting mood symptoms — especially in Chinese culture where psychological symptoms may be stigmatised
- Minor anxiety-depressive disorders are VERY COMMONLY seen in primary care (6.9% prevalence) [2]
- Increasing trend over time, accelerated by urbanisation, social stressors, ageing population, and the post-pandemic mental health burden
| Factor | Detail |
|---|---|
| Mean age of onset | ~27 years [2] |
| Commonest age group | 18–44 years [2] |
| Sex | ↑ in females (2–3×) [1][2] |
| Marital status | ↑ in divorced/separated [2] |
| Employment | ↑ in unemployed [2] |
| Comorbidity | ↑ co-morbidity with other disorders, especially anxiety and substance abuse [2] |
Reasons for higher rates in women are uncertain. Postulated reasons include: [2]
- 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 sensitise the brain to effects of stress
This is a crucial teaching point that students often overlook:
- ↑ Morbidity: associated with ↓ birth weight, chronic medical illness, poor self-perceived health, functional/cognitive impairment [2]
- ↑ Mortality: RR 1.2–4.0× non-suicide mortality [2]
- This may be due to: (1) behavioural risk factors (poor treatment adherence, inactivity, ↑ alcohol consumption); (2) biological risk factors (altered thrombogenesis, HPA axis dysfunction); (3) subclinical or prevalent cardiovascular disease [2]
Depression Kills — Not Just Through Suicide
Students often think depression's mortality risk is entirely from suicide. In reality, the non-suicide mortality is also significantly elevated (RR 1.2–4.0×), primarily through cardiovascular disease. Depression is an independent risk factor for MI and stroke. Always screen depressed patients for cardiovascular risk and vice versa.
3. Risk Factors
Think of risk factors using the biopsychosocial model and the predisposing–precipitating–perpetuating framework:
3.1 Predisposing Factors
- Genetic factors: a threefold increase in risk of depression among first-degree relatives compared to the general population [1]
- 37% heritability from twin studies (50% MZ concordance — lower than schizophrenia and bipolar) [2]
- Probably multiple genes with small individual effects and complex gene-environment interactions [2]
- Candidate gene includes the serotonin transporter (5-HTTLPR variant) [1][2]
- The 5-HTTLPR short allele is associated with increased vulnerability to depression in the presence of adversity — a classic gene × environment interaction
- In youth: 5-HTTLPR variant is associated with early onset depression in the presence of adversities [2]
- Stress and trauma: long-term difficulties, recent life events [1]
- Especially common in losses (bereavement, breakup), entrapment and humiliation (bullying) [1][2]
- ↑ 6× risk of adverse life events before onset of MDD [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 social adversity
- Comorbid substance use
- Untreated anxiety
- Cognitive distortions (see below)
- Poor medication adherence
- Persistent medical illness
4. Anatomy and Function (Relevant Neuroanatomy)
Understanding the neuroanatomy helps you understand why certain symptoms occur and how treatments work.
| Region | Normal Function | Abnormality in Depression | Clinical Correlate |
|---|---|---|---|
| Subgenual prefrontal cortex | Emotional regulation, reward processing | Volume reduction and decreased quantity of glial cells [1] | Anhedonia, emotional dysregulation |
| Ventromedial prefrontal cortex (vmPFC) | Emotional/social regulatory functions | ↑ activity [2] | ↑ sensitivity to pain, anxiety, depressive ruminations, tension [2] |
| Dorsolateral prefrontal cortex (dlPFC) | Executive functions (planning, working memory) | ↓ activity [2] | Psychomotor retardation, apathy, deficits in attention/working memory [2] |
| Hippocampus | Memory consolidation, stress regulation (negative feedback on HPA axis) | Reduced size [1]; Volume ↓ — both predisposing factor and consequence of depression [2] | Cognitive impairment, inability to terminate cortisol stress response |
| Amygdala | Emotional processing, fear conditioning | ↑ activity and ↑ connectivity with cortical regions | Heightened negative emotional responses |
| Anterior cingulate cortex (ACC) | Conflict monitoring, emotional regulation | Connectivity between amygdala and ACC → ↓ inhibitory action in emotional regulation [2] | Inability to suppress negative emotions |
Neurones releasing monoamines belong to the reticular activating system (RAS) → regulates global behavioural states or functions: [2]
| Monoamine | Origin | Functions Regulated | Relevance to Depression |
|---|---|---|---|
| Serotonin (5-HT) | Raphe nuclei (brainstem) | Body temperature, sleep/wakefulness, mood, impulse control [1] | Low level of serotonin metabolites in the brains of suicide decedents and spinal fluids of depressed patients [1] |
| Norepinephrine (NE) | Locus coeruleus | Mood and anxiety levels [1] | Mood symptoms emerged among patients who took propranolol [1] |
| Dopamine (DA) | Ventral tegmental area (VTA) → mesolimbic pathway | Motor and mental activity, attention, motivation [1] | Dopaminergic neurons in the mesolimbic reward pathway play an important role in motivation, reinforcement, and the pleasure response — diminished in brains of suicidal decedents with depression [1] |
Besides monoamines, abnormalities in glutamate, GABA, and substance P have been detected in patients with depression. [1]
5. Etiology and Pathophysiology
The pathophysiology of depression remains largely unknown. Several mechanisms have been proposed. [1]
5.1 Biological Hypotheses
Classical "serotonin hypothesis": diminished activity of serotonin pathways plays a causal role in the pathophysiology of depression. [1]
Supporting evidence:
- Antihypertensive drug reserpine, which depleted monoamine, produced a depressive state [1]
- Diminished monoaminergic activity was detected in the brains of decedents of suicide and the bodily fluids of people with depression [1]
- Antidepressants that increase synaptic monoamines (SSRIs, SNRIs, TCAs, MAOIs) are clinically effective
Limitations:
- Evidence suggests that the cause of depression is far more complicated than a reduced level of serotonin [1]
- Monoamine depletion in healthy volunteers does NOT reliably produce depression
- Antidepressants increase synaptic monoamines within hours, yet clinical effect takes 2–4 weeks → there must be downstream changes (e.g., receptor sensitivity, neuroplasticity)
- Traditionally believed to be the sole underlying abnormality but now thought NOT to be able to explain entire picture of depression → likely other factors also play a role [2]
Bottom line: The monoamine hypothesis was a useful starting point — it explains why antidepressants work — but depression is much more than just "low serotonin." Think of monoamines as the initial domino in a cascade involving neuroplasticity, neuroendocrine regulation, and neural circuit dysfunction.
Volume reduction and decreased quantity of glial cells in subgenual cortex, reduced hippocampal size [1]
- Hippocampal atrophy is thought to result from chronic cortisol exposure (glucocorticoid neurotoxicity) → impairs neurogenesis in the dentate gyrus
- This creates a vicious cycle: smaller hippocampus → less negative feedback on HPA axis → more cortisol → further atrophy
- In youth: cortisol-induced atrophic changes in hippocampus → ↓ 5-HT neurotransmission [2]
Hormonal changes: dysregulation of hypothalamic-pituitary-adrenal (HPA) axis [1]
| Hormonal Abnormality | Mechanism | Clinical Relevance |
|---|---|---|
| HPA axis dysregulation | Chronic stress → ↑ CRH → ↑ ACTH → ↑ cortisol; impaired negative feedback | Hypercortisolaemia → hippocampal damage, impaired neuroplasticity |
| Lower estradiol (in women) and testosterone (in men) [1] | Gonadal hormones modulate serotonin and BDNF | Explains perimenopausal depression and sex differences |
| Decreased triiodothyronine (T3) and thyroid stimulating hormone (TSH) [1] | Thyroid hormones modulate monoamine turnover and neuronal metabolism | Subclinical hypothyroidism mimics/worsens depression; T3 augmentation in treatment-resistant depression |
| Diminished BDNF (brain-derived neurotrophic factor) level [1] | BDNF promotes neuronal survival, growth, and synaptic plasticity | Low BDNF → impaired neuroplasticity → inability to adapt to stress; antidepressants ↑ BDNF |
The Neuroplasticity Model — The Modern Understanding
The most current understanding integrates the monoamine hypothesis with a neuroplasticity model: chronic stress → HPA axis dysregulation → ↑ cortisol → ↓ BDNF → impaired hippocampal neurogenesis and synaptic plasticity → depression. Effective antidepressants (including SSRIs, ketamine) ultimately work by restoring neuroplasticity, not merely by "increasing serotonin." This explains the 2–4 week lag in SSRI effect — it takes time for downstream neuroplastic changes to occur.
5.2 Psychosocial Hypotheses
Cognitive theory: cognitive distortions are prominent in depression and are the targets of CBT [1][2]:
| Cognitive Distortion | Chinese | Definition | Example |
|---|---|---|---|
| Selective abstraction | 斷章取義 | Focusing on a detail and ignoring more important features of a situation [1] | A student gets 9/10 on an exam but fixates on the one mark lost |
| Overgeneralisation | 以偏概全 | Drawing a general conclusion on the basis of a single incident [1] | "I failed this exam, therefore I will fail everything" |
| Personalisation | 過度自責 | Relating external events to oneself in an unwarranted way [1] | "My friend didn't text back — it must be because I'm boring" |
| Arbitrary inference | 妄下判斷 | Drawing a conclusion when there is no evidence for it and even some evidence against it [1] | "My boss didn't smile at me — I'm going to be fired" |
Beck's Cognitive Triad — the depressed patient has negative views of:
- Self ("I am worthless")
- World ("Everything is terrible")
- Future ("Nothing will ever get better")
These negative schemas are formed in early life (often from adverse experiences) and are activated by stressful events, producing automatic negative thoughts → depressive symptoms.
Psychoanalytical theory: loss of an 'object', insecure attachments [1]
- Freud proposed that depression arises from ambivalent feelings towards a lost object (person, relationship), with anger turned inward against the self
- Bowlby's attachment theory: insecure attachment in childhood → vulnerability to depression upon loss
- When an individual repeatedly experiences uncontrollable negative events, they develop a belief that they cannot influence outcomes → passivity, hopelessness, depressive symptoms
- This maps onto the clinical feature of hopelessness — the strongest predictor of suicidal ideation
6. Classification
The DSM-5-TR and ICD-11 classify depressive disorders as follows:
| DSM-5-TR | ICD-11 |
|---|---|
| Major Depressive Disorder (single/recurrent) | Single episode depressive disorder / Recurrent depressive disorder |
| Persistent Depressive Disorder (Dysthymia) | Dysthymic disorder |
| Disruptive Mood Dysregulation Disorder | (No direct equivalent) |
| Premenstrual Dysphoric Disorder | Premenstrual dysphoric disorder (under reproductive) |
| Substance/Medication-Induced Depressive Disorder | Depressive disorder due to substance or medication |
| Depressive Disorder Due to Another Medical Condition | Depressive disorder due to medical condition |
| Other Specified / Unspecified Depressive Disorder | Other specified / Unspecified depressive disorder |
Depression can be characterised along multiple dimensions:
| Dimension | Subtypes | Key Features |
|---|---|---|
| Severity | Mild / Moderate / Severe / Severe with psychotic features | Defined by symptom count + functional impairment |
| Episode pattern | Single episode / Recurrent / Chronic (persistent) | Recurrent = ≥ 2 episodes with ≥ 2 months remission between |
| Symptom profile | Somatic (melancholic) / Atypical / Psychotic / Catatonic | Different biology and treatment implications |
| Timing | Seasonal pattern (SAD): onset in autumn/winter, recovery in spring/summer [2] | Related to daylight duration; light therapy is treatment |
| Recurrent brief: recurrent episodes of 2–7 days occurring once a month [2] | ||
| Peripartum onset | Within 4 weeks of delivery (DSM-5) or 6 weeks (ICD) |
ICD classification of depressive episode severity [2]:
| Severity | Section A Symptoms (Core) Required | Section B Symptoms (Additional) Required |
|---|---|---|
| Mild | At least 2 of A | At least 2 of B |
| Moderate | At least 2 of A | At least 3 of B |
| Severe | All 3 of A | At least 4 of B |
Section A (Core symptoms):
- Depressed mood
- Loss of interest and enjoyment
- Reduced energy and decreased activity
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
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. [1]
Additional symptoms (ICD-11): 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. [1]
This is a clinically important specifier:
Clinical features of depression with 'somatic' or 'melancholic' features: [2]
- Loss of interest or pleasure in usual activities
- Lack of emotional reactivity to normally pleasurable surroundings and events
- Early-morning waking (2 hours or more before usual time)
- Depression worse in the morning
- Psychomotor agitation or retardation
- Marked loss of appetite
- Weight loss (5% or more 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)
At least four of these symptoms are required to diagnose depression "with somatic features" (ICD-10) or "with melancholic features" (DSM-5). DSM-5 also specifically requires either 'loss of interest' or 'lack of emotional reactivity' to be present. [2]
Clinical relevance of melancholic depression: [2]
- ↑ neurobiological abnormalities + ↑ family history
- ↑ severity of symptomatology
- ↓ response to placebo and ↑ response to TCA than SSRI
The opposite pattern to melancholic depression:
| Feature | Description | Pathophysiology |
|---|---|---|
| Mood reactivity | Mood improves in response to positive events | Preserved hedonic capacity |
| Reversed vegetative symptoms | Hypersomnia (not insomnia), hyperphagia with weight gain | ? Altered serotonergic regulation of appetite/sleep |
| Leaden paralysis | Heavy, leaden feeling in arms/legs | ? Related to psychomotor changes |
| Rejection sensitivity | Long-standing pattern of interpersonal rejection sensitivity | Overlaps with personality features |
- More common in younger patients, earlier age of onset
- Better response to MAOIs and SSRIs than TCAs (opposite to melancholic)
- Occur in severe depression
- Delusions and hallucinations can be:
- Mood-congruent: themes of guilt, worthlessness, nihilism, disease, death, deserved punishment (e.g., Cotard's syndrome — belief that one is dead or organs are rotting)
- Mood-incongruent: persecutory, referential (less common; raises differential of schizoaffective disorder)
- Important to distinguish from schizoaffective disorder where psychotic symptoms occur outside mood episodes
- Persistent depressive symptoms NOT meeting criteria for major depressive episode, lasting ≥ 2 years
- Usual onset in early adulthood and may last throughout life → 'depressive personality'
- May be associated with superimposed major depressive episodes (double depression)
- Mild depression often co-exists with and could not be separated from anxiety disorders
- VERY COMMONLY seen in primary care (6.9% prevalence)
- Clinical features: commonly present with prominent somatic symptoms to healthcare
- Mood symptoms: anxiety, depression, irritability
- Somatic symptoms: fatigue, insomnia, somatic symptoms and bodily preoccupation
- Cognitive symptoms: poor concentration
- May be associated with disabling difficulties in personal and occupational function
7. Clinical Features
The clinical features of depression can be organised into the mnemonic SIG E CAPS (think of it as a doctor writing a prescription — "Sig: Energy Capsules" — for a depressed patient who has no energy):
- Sleep disturbance
- Interest loss (anhedonia)
- Guilt / worthlessness
- Energy loss
- Concentration impairment
- Appetite / weight change
- Psychomotor changes
- Suicidality
But let's organise more systematically:
7.1 Core Symptoms (Section A — ICD)
Depressed mood: [2]
- Differs from ordinary sadness: miserable, dejected, 'down in the dumps'
- Pervasive: covers most period of the day
- Loss of reactivity: loss of normal ups and downs in response to circumstances
- Morning dysphoria: characteristically worse in the morning (one of the 'biologic'/melancholic symptoms)
Pathophysiology: ↓ serotonin and norepinephrine in limbic circuits (especially vmPFC and amygdala) → inability to generate positive emotional states and inability to suppress negative emotional processing. The morning worsening correlates with the cortisol awakening response — in depression, the HPA axis is dysregulated with abnormal diurnal cortisol patterns, and cortisol peaks more sharply in the morning.
In children: may manifest as irritable mood rather than sadness [2]
Anhedonia: lack of interest and enjoyment [2]
- Loss of ability to derive pleasure from activities that were formerly enjoyed
- Associated with social withdrawal
Pathophysiology: Dopaminergic neurons in the mesolimbic reward pathway play an important role in motivation, reinforcement, and the pleasure response. However, they are diminished in the brains of suicidal decedents with depression [1]. The mesolimbic pathway (VTA → nucleus accumbens) is the brain's reward circuit. When this circuit is hypoactive, the patient cannot experience pleasure — "anhedonia" literally means "an" (without) + "hedone" (pleasure).
Anergia: lack of energy or ↑ fatigability on minimal exertion → ↓ activity [2]
Pathophysiology: Norepinephrine is the primary neurotransmitter for arousal and energy. ↓ NE in the dlPFC and general cortical projections → reduced drive and stamina. ↓ Dopamine in the mesolimbic pathway also contributes to reduced motivation and initiation of activity. Additionally, chronic HPA axis activation with elevated cortisol leads to catabolic states and perceived fatigue.
7.2 Biological (Somatic / Melancholic) Symptoms (Section B and Beyond)
Sleep disturbances: [2]
- Most classically early morning wakening (waking ≥ 2 hours before usual time and unable to get back to sleep — a hallmark of melancholic depression)
- Initial insomnia (difficulty falling asleep — more common when anxiety is comorbid)
- Middle insomnia (frequent nocturnal awakenings)
- Hypersomnia (in atypical depression)
Pathophysiology: Serotonin is the precursor to melatonin (5-HT → N-acetyl-5-HT → melatonin via the pineal gland). Serotonin affects body temperature, and regulates sleep and wakefulness [1]. ↓ 5-HT disrupts sleep architecture. Depressed patients show:
- ↓ Slow-wave sleep (deep, restorative sleep)
- ↓ REM latency (entering REM too quickly — within ~45 min instead of ~90 min)
- ↑ REM density (more intense REM periods)
Early morning wakening is thought to reflect a phase advance of circadian rhythms — the internal clock shifts earlier, so the patient's "morning" comes at 3–4 AM.
- Marked loss of appetite with weight loss (5% or more of body weight in last month) — in melancholic depression [2]
- Increased appetite with weight gain — in atypical depression (especially carbohydrate craving)
Pathophysiology: Serotonin and norepinephrine regulate hypothalamic appetite centres. 5-HT normally promotes satiety; ↓ 5-HT can paradoxically cause either appetite loss (via associated nausea/dysphoria) or appetite increase (via loss of satiety signals). In melancholic depression, the profound anhedonia extends to food — eating is no longer pleasurable. The cortisol excess also contributes to catabolic effects.
- Psychomotor retardation: slowed movements, slow speech (↑ latency to respond), reduced gestures, monotonous voice, shuffling gait
- Psychomotor agitation: restlessness, hand-wringing, pacing, inability to sit still, pulling at clothes/hair
Pathophysiology: Psychomotor retardation, apathy, deficits in attention/working memory are linked to ↓ activity in dorsolateral prefrontal cortex [2]. Dopamine deficiency in the nigrostriatal pathway also contributes to motor slowing (similar mechanism to Parkinson's disease, which is also associated with depression in ~40% of cases). Psychomotor agitation may reflect noradrenergic hyperactivity or anxiety-circuit overactivation.
Marked loss of libido [2]
Pathophysiology: Multifactorial — ↓ dopamine (pleasure/reward), ↓ testosterone/estradiol (noted in depression), and ↓ norepinephrine (arousal) all contribute. Additionally, the general anhedonia and fatigue make sexual activity undesirable.
7.3 Cognitive Symptoms
Reduced concentration and difficulty making decisions [1]
Pathophysiology: ↓ activity in dorsolateral prefrontal cortex → deficits in attention/working memory [2]. The dlPFC is the "CEO of the brain" — responsible for executive functions. When it is hypoactive, patients cannot maintain attention, process information efficiently, or make decisions. This is sometimes called "pseudodementia" in elderly patients — it looks like dementia but reverses with treatment of depression.
Reduced self-esteem and confidence [2] Ideas of guilt and unworthiness — in severe cases, may reach delusional intensity (e.g., believing they have committed unforgivable sins)
Pathophysiology: Linked to the cognitive distortions described by Beck — negative view of self. Neurobiologically, ↑ activity in ventromedial prefrontal cortex → depressive ruminations [2] — the vmPFC is overactive, generating excessive self-referential negative processing.
Pessimistic thoughts and hopelessness [1][2]
Pathophysiology: Learned helplessness model (Seligman) — repeated uncontrollable adversity leads to belief that one cannot influence outcomes. Neurobiologically, disrupted reward circuitry means the patient cannot generate positive expectancy for the future.
Clinical Pearl: Hopelessness is the single strongest predictor of suicidal behaviour. Always ask about it specifically: "Do you feel that things will never get better?"
Recurrent thoughts of death or suicide [1] Ideas of self-harm [2]
This ranges from passive death wishes ("I wish I wouldn't wake up") to active suicidal ideation with plan and intent. Always assess:
- Frequency of thoughts
- Plan (how?)
- Access to means (especially lethal means)
- Intent (do they intend to act?)
- Protective factors (reasons to live, family, religion)
Pathophysiology: Serotonin deficiency (particularly in the ventral PFC) is associated with impulsivity and aggression, including self-directed aggression. The combination of hopelessness (cognitive) + impulsivity (serotonergic) + psychic pain (emotional) creates the highest risk.
When depression reaches its most severe form, psychotic features can emerge:
- Mood-congruent delusions: nihilistic (Cotard's syndrome), guilt, poverty, somatic (believing organs are rotting), deserved punishment
- Mood-congruent hallucinations: second-person auditory hallucinations — derogatory voices ("You're worthless," "You should kill yourself")
- Less commonly: mood-incongruent psychotic features (raises concern for schizoaffective disorder)
Pathophysiology: In severe depression, the combination of extreme cortisol elevation, dopaminergic dysregulation, and profound cognitive distortions can push perceptual and interpretive processes beyond the threshold for reality testing → frank psychosis.
- Very commonly co-occurs (up to 70% comorbidity) [2]
- Generalised worry, tension, restlessness, autonomic symptoms
- The DSM-5 "anxious distress" specifier recognises this overlap
Commonly present with prominent somatic symptoms to healthcare [2]:
- Unexplained headaches, chest pain, abdominal pain, back pain
- Fatigue, dizziness
- Palpitations
- Gastrointestinal disturbance
Pathophysiology: This is partly cultural (somatisation — expressing emotional distress through physical complaints is more socially acceptable in some cultures) and partly neurobiological (the monoamine systems regulate pain perception — ↓ 5-HT and NE lower the pain threshold, making normal bodily sensations feel uncomfortable). ↑ activity in vmPFC → ↑ sensitivity to pain [2].
Youth Depression [2]
- Adolescence: tends to be in most ways similar to adults
- Childhood: may have difficulty expressing sadness and is associated with:
- Somatic complaints (unexplained abdominal pains, headache, anorexia, enuresis)
- Irritable mood and anxiety features
- Behavioural problems (e.g., one case tried to steal a bus because of frustration at home, take cannabis to lift mood)
- Common comorbidities: 70% has anxiety disorder, conduct disorder, substance abuse, dysthymia
- Cognitive features: negative cognitive style, lack of social confidence, perfectionist traits
| MSE Domain | Findings | Pathophysiological Basis |
|---|---|---|
| Appearance | Poor self-care, unkempt, weight loss, tearful, downcast gaze, psychomotor retardation or agitation | Anergia → unable to maintain grooming; anhedonia → don't care about appearance |
| Behaviour | Slow movements, reduced gestures, poor eye contact, hand-wringing (if agitated) | ↓ dlPFC activity, ↓ DA in nigrostriatal pathway |
| Speech | Slow, monotonous, low volume, ↑ latency to respond, poverty of content | ↓ NE/DA → reduced arousal and motivation |
| Mood | "Low," "depressed," "empty," "numb" (subjective) | Core symptom |
| Affect | Flat, restricted, tearful, congruently depressed | Reduced emotional range due to reward circuit dysfunction |
| Thought content | Guilt, worthlessness, hopelessness, suicidal ideation, nihilism; delusions if psychotic | Cognitive distortions; in psychotic depression → delusional intensity |
| Thought form | Slow, impoverished | Psychomotor retardation extends to thinking |
| Perception | Auditory hallucinations (derogatory) in psychotic depression | Severe dopaminergic dysregulation |
| Cognition | ↓ Concentration, ↓ attention, "pseudodementia" in elderly | ↓ dlPFC function |
| Insight | Variable — may be preserved ("I know I'm depressed") or poor in severe/psychotic cases |
| Neurotransmitter System | Associated Symptoms When Deficient |
|---|---|
| Serotonin (5-HT) | Depressed mood, anxiety, irritability, impulsivity, insomnia, appetite changes, pain sensitivity, suicidality |
| Norepinephrine (NE) | Fatigue, anergia, poor concentration, psychomotor retardation, apathy |
| Dopamine (DA) | Anhedonia, loss of motivation, psychomotor retardation, loss of libido |
This table is important because it helps you understand why different antidepressants target different symptoms: SSRIs (serotonin) for mood/anxiety/impulsivity, SNRIs (serotonin + NE) for mood + energy/concentration, Bupropion (NE + DA) for anhedonia/fatigue/motivation, TCAs (broad monoamine) for melancholic depression.
High Yield Summary
Definition: Depressive disorders = persistent mood disturbance (≥ 2 weeks) with cognitive and neurovegetative symptoms causing functional impairment; qualitatively different from normal sadness (pervasive, loss of reactivity).
Epidemiology: HK prevalence 2.9%; lifetime 10–20%; F:M = 2–3:1; mean onset ~27y; ↑ in divorced, unemployed; ↑ non-suicide mortality RR 1.2–4.0×.
Aetiology: Biopsychosocial — genetic (37% heritability, 5-HTTLPR), early adversity, cognitive distortions (Beck's triad), monoamine deficiency (5-HT, NE, DA) + HPA axis dysregulation + ↓ BDNF/neuroplasticity. Pathophysiology remains largely unknown but current model integrates monoamines → neuroplasticity → circuit dysfunction.
Key Brain Regions: ↑ vmPFC (rumination, pain sensitivity), ↓ dlPFC (psychomotor retardation, cognitive deficits), ↓ hippocampal volume (memory, HPA feedback failure), ↓ mesolimbic DA (anhedonia).
Classification: MDD (single/recurrent), Dysthymia (≥ 2y subthreshold), specifiers (melancholic vs atypical vs psychotic vs seasonal). ICD severity: Mild (2A+2B), Moderate (2A+3B), Severe (3A+4B).
Core Symptoms: Depressed mood + anhedonia + anergia. Biological symptoms: sleep disturbance (classically early morning wakening), appetite/weight change, psychomotor changes, loss of libido. Cognitive symptoms: poor concentration, worthlessness/guilt, hopelessness, suicidal ideation.
Melancholic features: loss of reactivity, early morning wakening, morning worsening, psychomotor changes, ↑ response to TCA, ↑ neurobiological basis.
In HK/Chinese populations: prominent somatic presentations. In youth: irritability > sadness, somatic complaints, behavioural problems.
Active Recall - Depressive Disorders (Definition to Clinical Features)
Differential Diagnosis of Depressive Disorders
Depression is a syndrome, not a single disease. Before you stamp "Major Depressive Disorder" on a patient, you must systematically exclude three broad categories:
- Other primary psychiatric disorders that present with low mood
- Medical conditions that cause depressive symptoms via physiological mechanisms
- Substance/medication-induced mood disturbance
The reason this matters clinically is straightforward: treating "depression" with an SSRI when the real problem is hypothyroidism, Cushing's syndrome, or an unrecognised bipolar disorder will either fail or actively harm the patient. 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. Correct diagnosis and treatment was delayed by 5–7 years on average. [3]
The Golden Rule
Every patient presenting with depressive symptoms MUST have a thorough medical history, medication history, substance use history, and screening for past manic/hypomanic episodes — before diagnosing a primary depressive disorder. Missing bipolar disorder (by not asking about hypomania) and missing secondary causes (by not checking TFTs) are the two most common exam and clinical mistakes.
Category 1: Other Psychiatric Conditions
Adjustment disorder with depressed mood [1]
| Feature | Adjustment Disorder | MDD |
|---|---|---|
| Criteria met? | Does NOT meet full criteria for depressive episode [2] | Meets full criteria |
| Stressor | Onset ≤ 3 months of an identifiable stressor [2] | Stressor not required (though often present) |
| Duration | Symptoms resolve within 6 months of stressor ending | Minimum 2 weeks; can persist for months |
| Severity | Typically milder, proportionate (though still exceeds what would be expected) | Can be mild, moderate, or severe |
Why this distinction matters: If symptoms meet full criteria for a depressive episode, you should diagnose the depressive episode as a comorbid condition, not merely an adjustment disorder. If meeting depressive episode criteria, should be regarded as having comorbid depression. [2]
This is the single most dangerous misdiagnosis. A patient in a bipolar depressive episode looks identical to MDD — the differentiating feature is a history of mania/hypomania, which you can only find by asking.
Hypomanic episodes are often overlooked. Patients with BP II are misdiagnosed as having major depressive disorder. [3]
| Feature | Unipolar Depression (MDD) | Bipolar Depression |
|---|---|---|
| Past hypomania/mania | Absent | ≥ 1 previous manic/hypomanic episode [2] |
| Age of onset | Typically later (~27y) | Earlier (late teens–early 20s) |
| Symptom profile | Insomnia, appetite loss more common | Atypical features more common: hypersomnia, hyperphagia, leaden paralysis [2] |
| Psychotic features | Less common overall | More common; may predict future bipolar conversion |
| Family history | FHx of depression | FHx of bipolar disorder |
| Treatment response | Responds to antidepressants | Antidepressants alone are less effective and may result in manic switch and cycle acceleration [2] |
| Course | Longer episodes | Shorter, more frequent episodes |
~25% of bipolar affective disorder first presents as juvenile depression in their first episode. [2] Always ask young depressed patients (and their families) about any period of unusually elevated mood, decreased need for sleep, grandiosity, or reckless behaviour.
How to Screen for Missed Hypomania
Use structured screening tools: Mood Disorder Questionnaire (MDQ), Hypomania Checklist (HCL-32) [2]. At minimum, always ask: "Has there ever been a time when you felt the opposite of depressed — unusually energetic, needing less sleep, overly confident, doing things you normally wouldn't?"
Manic episode with irritable mood or mixed episodes [1]
Why this is confusing: A manic patient can present as irritable, angry, and dysphoric rather than euphoric — mimicking an agitated depression. Mixed features (simultaneous depressive and manic symptoms) further blur the line.
Key differentiators:
- ↑ Energy and ↓ need for sleep (despite appearing distressed) — the opposite of depressive anergia
- Pressured speech, grandiosity, distractibility
- Episode is typically shorter (days to weeks) with more acute onset than MDD
| Feature | MDD | Dysthymia |
|---|---|---|
| Symptom severity | Meets full criteria for depressive episode | Symptoms NOT meeting criteria [2] |
| Duration | ≥ 2 weeks per episode | ≥ 2 years continuously [2] |
| Onset | Any age (mean ~27y) | Usually early adulthood [2] |
| Course | Episodic (episodes with remission) | Chronic, trait-like [2] |
| "Double depression" | — | May have superimposed major depressive episodes [2] |
Why the distinction matters: Dysthymia tends to respond better to combined psychotherapy + antidepressant than antidepressant alone. The chronicity means patients often believe "this is just who I am" rather than recognising it as a treatable illness.
Anxiety and depression are the most commonly confused and comorbid psychiatric conditions. Up to 70% of depressed patients have comorbid anxiety, and up to 60% of anxious patients have comorbid depression [2].
| Feature | GAD | Depression |
|---|---|---|
| Core emotion | Worry about future events | Sadness, hopelessness about past/self |
| Content of rumination | Worry about possible future events (what if…?) [2] | Brood self-critically on previous events and circumstances [2] |
| Onset | Insidious, chronic | Can be more defined |
| Somatic symptoms of depression | Absent | Early morning wakening, diurnal variation in mood, suicidal thoughts are uncommon in GAD [2] |
| Reactivity | Mood reactive to reassurance (temporarily) | Loss of reactivity |
| Sleep | Difficulty falling asleep (initial insomnia) | Early morning wakening (terminal insomnia — melancholic) |
Note that in some patients GAD + depression can co-exist. [2] In clinical practice, when both are present, treat the more severe condition first (usually depression).
The question here is about temporal relationship and the pharmacological mechanism:
- Intoxication-related: depression during active use (alcohol is a CNS depressant; cannabis can cause amotivational syndrome)
- Withdrawal-related: depression during withdrawal (stimulant "crash" after cocaine/amphetamines)
- Medication side effects: many drugs can cause secondary depression
Drug-related conditions that can cause depressive symptoms include: [1]
- Antihypertensive medications, especially reserpine and methyldopa — reserpine depletes monoamines (the original evidence for the monoamine hypothesis!)
- Smoking-cessation aids
- Steroids — exogenous glucocorticoids dysregulate the HPA axis
- Sex hormones and medications that affect sex hormones (e.g., OCP, GnRH agonists)
- H2 blockers, sedatives, muscle relaxants, appetite suppressants
- Chemotherapy agents
- Alcohol / cocaine / amphetamines / cannabinoids / sedatives / hypnotics / narcotics abuse [1]
Additional medications from senior notes [2]:
- Beta-blockers (notorious — lipophilic ones like propranolol cross the BBB and block central β-adrenergic receptors → ↓ NE signalling)
- L-dopa (dopamine fluctuations)
- Benzodiazepines (GABAergic CNS depression)
- Antipsychotics (dopamine blockade → anhedonia, akinesia mimicking depression)
- Opiates, indomethacin, interferon (interferon-α is particularly notorious for causing severe depression — up to 30% of patients on IFN-α for Hepatitis C)
Why reserpine matters historically: Reserpine was used as an antihypertensive. It irreversibly blocks VMAT2 (vesicular monoamine transporter 2), preventing storage of monoamines (5-HT, NE, DA) in synaptic vesicles → monoamine depletion → depressive state. This observation was key evidence for the monoamine hypothesis of depression. [1]
Schizoaffective disorder: [2]
- Simultaneous occurrence of depressive episode and schizophrenic symptoms lasting ≥ 2 weeks
- Delusions and hallucinations are less mood congruent and may occur outside mood episodes (cf severe depression with psychotic features)
- Must have concurrent mood + psychotic symptoms (cf schizophrenia)
| Feature | Severe Depression with Psychosis | Schizoaffective Disorder |
|---|---|---|
| Psychotic symptoms | Mood-congruent (guilt, worthlessness, nihilism) | Less mood-congruent; may have bizarre delusions, thought alienation |
| Timing of psychosis | Only during mood episodes | Psychotic symptoms also occur outside mood episodes |
| Schneider's first-rank | Rare | May be present |
| Course | Episodic with full inter-episode recovery | More chronic psychotic residua between episodes |
Negative symptoms of schizophrenia (flat affect, avolition, anhedonia, social withdrawal, poverty of speech) can closely mimic depression. Key differences:
- Schizophrenia: prominent positive symptoms (hallucinations, delusions — mood-incongruent and bizarre); formal thought disorder; onset typically late teens to 20s; chronic deteriorating course
- Depression: mood symptoms precede and dominate; psychotic features (if present) are mood-congruent; better inter-episode functioning
| Condition | Differentiating Features |
|---|---|
| OCD | Ruminations in depression are mood congruent and not necessarily experienced as intrusive or distressing. There is also no compulsion associated [2]. In OCD, obsessions are ego-dystonic (unwanted, intrusive), and compulsions are performed to reduce anxiety |
| Somatic symptom disorder | If somatic symptoms and related concerns do not occur outside of depressive episodes, then the diagnosis of somatic symptom disorder is not made [2] |
| Dementia vs. Pseudodementia | Depression is the most important mimic of dementia ("pseudodementia"), accounts for ~10% of presumed dementia [2]. In depression: onset more defined, patient complains of memory loss (insight preserved), gives "don't know" answers, attention > memory affected. In dementia: insidious onset, patient unaware/minimises deficits, tries hard but gives wrong answers, true amnesia |
| Bereavement / Normal grief | DSM-5 removed the "bereavement exclusion" [1] — grief CAN trigger a depressive episode. Normal grief: comes in waves, preserves self-esteem, may have positive memories. Depression: pervasive, constant, marked worthlessness/guilt, suicidal ideation |
DSM-5 Key Change — Bereavement Exclusion Removed
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). However, DSM-5 recognises that bereavement can trigger a genuine depressive episode. Exercise of clinical judgment based on the individual's history and the cultural norms is required [1]. Do not dismiss a grieving patient who meets full criteria — they may need treatment.
Depression can be associated with medical conditions: [1]
The mechanism can be:
- Direct physiological effect on brain function (e.g., hypothyroidism → ↓ monoamine turnover)
- Psychological reaction to illness (e.g., adjustment to cancer diagnosis)
- Shared pathophysiology (e.g., vascular depression — cerebrovascular disease and depression share endothelial dysfunction and inflammation)
| System | Conditions [1] | Mechanism (Why?) |
|---|---|---|
| Neurological | Epilepsy, Parkinson's disease, dementia, multiple sclerosis, Huntington disease, cerebrovascular disease, migraine [1]; head trauma, tumours [2] | Parkinson's: ↓ DA in mesolimbic pathway → anhedonia + motor symptoms. Stroke: direct damage to mood-regulating circuits (especially left frontal). MS: demyelination of monoaminergic tracts. Huntington's: basal ganglia degeneration → ↓ DA. Epilepsy: especially temporal lobe epilepsy affecting limbic structures |
| Endocrine | Hypothyroidism, hyperthyroidism, Cushing's syndrome, Addison disease, prolactinomas, hyperparathyroidism [1]; vitamin deficiency [2] | Hypothyroidism: ↓ T3/T4 → ↓ monoamine metabolism and neuronal energy. Cushing's: ↑ cortisol → hippocampal damage, HPA axis disruption. Addison's: ↓ cortisol → fatigue, weakness (mimics depression). Hyperparathyroidism: ↑ Ca²⁺ → "moans, groans, stones, and psychiatric overtones" — Ca²⁺ affects neuronal excitability |
| Infectious | Mononucleosis, HIV infection, hepatitis C infection, Lyme disease, syphilis [1] | HIV: direct CNS invasion + psychosocial impact. HCV: neuroinflammation + interferon treatment. Syphilis (neurosyphilis): direct CNS damage. Post-viral fatigue syndromes |
| Neoplastic | Neoplasias and paraneoplastic syndromes, e.g., pancreatic cancer [1] | Pancreatic cancer is notorious for presenting with depression even before the cancer is diagnosed — possibly via paraneoplastic antibodies or inflammatory cytokines affecting brain function |
| Chronic disease | Coronary artery disease, type II diabetes [1]; CHF, MI [2] | Shared inflammatory pathways (↑ IL-6, TNF-α, CRP); endothelial dysfunction; behavioural inactivity; chronic pain |
| Pain/Psychosomatic | Chronic pain and psychosomatic conditions [1] | ↓ 5-HT and NE → lowered pain threshold; chronic pain itself is demoralising and disabling → depression |
| Sleep | Sleep-related disorders, in particular obstructive sleep apnea [1] | OSA → chronic hypoxia + sleep fragmentation → daytime fatigue, poor concentration, irritability (mimics/causes depression) |
High Yield — Pancreatic Cancer
Pancreatic cancer can present with depression as the earliest symptom, preceding any abdominal symptoms by months. In exam scenarios: a middle-aged or older patient with new-onset depression + weight loss + vague abdominal discomfort → think pancreatic cancer and investigate (CT abdomen, CA 19-9).
Already covered above (§1.6), but here is a quick-reference table for high-yield exam content:
| Drug Class | Examples | Mechanism |
|---|---|---|
| Antihypertensives | Reserpine, methyldopa [1]; beta-blockers [2] | Reserpine: VMAT2 blockade → monoamine depletion. Methyldopa: ↓ NE synthesis. Beta-blockers: central β-blockade → ↓ NE signalling |
| Steroids | Prednisolone, dexamethasone [1] | HPA axis disruption; direct neurotoxicity at high doses |
| Hormonal | OCP, GnRH agonists [1][2] | Estradiol fluctuations affect 5-HT systems |
| Neurological drugs | L-dopa [2], antiepileptics | DA fluctuations (L-dopa); GABAergic effects (antiepileptics) |
| Sedatives | Benzodiazepines [2], barbiturates | CNS depression, GABAergic |
| Antipsychotics | All, especially high-potency typical [2] | D₂ blockade → anhedonia, akinesia |
| Substances of abuse | Alcohol, cocaine, amphetamines, cannabinoids, opiates [1] | Alcohol: CNS depressant + neurotoxic. Cocaine/amphetamine withdrawal: DA depletion → crash. Cannabis: amotivational syndrome. Opiates: ↓ DA release with chronic use |
| Others | Interferon, indomethacin, chemotherapy, H2 blockers [1][2] | Interferon-α: ↑ IDO (indoleamine 2,3-dioxygenase) → tryptophan diverted from 5-HT synthesis to kynurenine pathway → ↓ 5-HT |
Physical examination & investigation to rule out medical conditions that may cause depressive symptoms: [1]
Basic investigations: [1]
- CBP (complete blood picture) — anaemia, infection, ↑ MCV (alcoholism) [2]
- R/LFT (renal/liver function tests) — hypoNa (antidepressant side effect), Ca²⁺ (hyperparathyroidism → secondary depression), GGT/alcoholic liver disease [2]
- Thyroid function test — hypothyroidism is the most important and common secondary cause to exclude [1][2]
Other investigations if indicated by history and physical examination: [1]
- Blood alcohol level
- Blood and urine toxicology screen — substance-induced depression
- HIV test — HIV-associated depression
- Cosyntropin (ACTH) stimulation test — for Addison disease
- EEG — for epilepsy
- CT or MRI — for organic brain syndrome or hypopituitarism
- CRP/ESR — infection or inflammatory disease [2]
- Vitamin B12 and folate — nutritional deficiency [2]
- ECG — if cardiac problems (important baseline before TCAs or lithium which prolong QT) [2]
| Feature | Depression ("Pseudodementia") | Dementia |
|---|---|---|
| Onset | More defined, relatively rapid | Insidious, gradual |
| Patient's attitude | Complains/worries about poor memory; presents themselves [2] | Poor insight; brought to doctor by family [2] |
| Effort on testing | Gives less effort; "I don't know" answers [2] | Tries hard but gives incorrect answers [2] |
| Cognitive profile | Attention and concentration primarily affected [2] | True amnesia; language and visuospatial also affected |
| Motor/language skills | Slow but not impaired [2] | Impaired (apraxia, aphasia) |
| Other features | Morning dysphoria, psychomotor retardation, biological symptoms of depression [2] | Behavioural and personality changes, disorientation |
| Treatment | Treat depression first — cognition usually improves [2] | Progressive despite treatment |
| Category | Diagnoses | Key Differentiating Feature |
|---|---|---|
| Primary mood disorders | MDD (single/recurrent) | Meets criteria, ≥ 2 wk, no mania Hx |
| Bipolar depression | ≥ 1 prior manic/hypomanic episode | |
| Dysthymia | Subthreshold, ≥ 2 years | |
| Cyclothymia | Subthreshold depressive + hypomanic, ≥ 2 years | |
| Other psychiatric [1] | Adjustment disorder with depressed mood | Not meeting criteria, ≤ 3mo of stressor |
| Anxiety disorder | Worry about future; no biological features of depression | |
| Schizoaffective disorder | Psychotic symptoms outside mood episodes | |
| Schizophrenia (negative symptoms) | Prominent positive symptoms, deteriorating course | |
| OCD | Ego-dystonic obsessions + compulsions | |
| Bereavement / Normal grief | Comes in waves, self-esteem preserved | |
| Medical conditions [1] | Neurological, endocrine, infectious, neoplastic, chronic disease, sleep disorders | History, examination, and investigations identify the cause |
| Substance/medication [1] | Drug-related conditions | Temporal relationship to substance use/medication |
| Mood disorder due to another medical condition [1] | Various (see above) | Physiological mechanism identified |
High Yield DDx Points for Exams:
- Always exclude bipolar disorder by asking about past hypomania/mania — this is the most commonly missed diagnosis
- Always check TFTs — hypothyroidism is the most common medical mimic
- Review the medication list — beta-blockers, steroids, interferon are common culprits
- In elderly with "cognitive decline" → consider pseudodementia (treat depression first)
- In new-onset depression with weight loss in middle-aged/elderly → consider pancreatic cancer
- DSM-5 removed the bereavement exclusion — grief can trigger MDD
Active Recall - Differential Diagnosis of Depressive Disorders
References
[1] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p6, p8, p9, p13, p14, p15) [2] Senior notes: ryanho-psych.md (sections on DDx of low mood, depressive disorders, dysthymia, anxiety disorders, OCD, somatic symptom disorder, dementia DDx, assessment) [3] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p10, p12)
Diagnostic Criteria for Depressive Disorders
Depression is diagnosed clinically — there is no blood test, no scan, no biomarker that confirms it. The diagnostic criteria exist to ensure:
- Reliability — two different doctors examining the same patient reach the same diagnosis
- Validity — the diagnosis identifies a genuine illness (not normal sadness) that predicts course, treatment response, and prognosis
- Exclusion of mimics — the criteria explicitly require ruling out medical, substance-related, and other psychiatric causes
Two major classification systems are used: ICD-11 (WHO, used in Hong Kong public hospitals) and DSM-5-TR (APA, used widely in research and private practice). You need to know both.
A. DSM-5 Criteria for Major Depressive Disorder
Major depressive disorder [1]:
Clear-cut changes in affect, cognition, and neurovegetative functions. Five or more of the following symptoms are present during the same 2-week period and represent a change from previous functioning; at least 1 of the symptoms is either (1) or (2): [1]
| # | 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) [1] | ↓ 5-HT and NE in limbic circuits; ↑ vmPFC activity → depressive rumination | In children and adolescents, can be irritable mood [1] |
| (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) [1] | ↓ DA in mesolimbic reward pathway → cannot generate pleasure response | This is anhedonia — "an" (without) + "hedone" (pleasure) |
| (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 [1] | ↓ 5-HT → disrupted hypothalamic appetite regulation. In melancholic: anhedonia extends to food. In atypical: carbohydrate craving | In children, consider failure to make expected weight gain [1] |
| (4) | Insomnia or hypersomnia nearly every day [1] | ↓ 5-HT (precursor to melatonin) disrupts sleep architecture; early morning wakening = circadian phase advance | Melancholic → 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) [1] | Retardation: ↓ DA in nigrostriatal pathway + ↓ dlPFC activity. Agitation: NE hyperactivity, anxiety-circuit overactivation | Must be observable by others — not just the patient's subjective feeling |
| (6) | Fatigue or loss of energy nearly every day [1] | ↓ NE (arousal), ↓ DA (motivation), chronic HPA axis activation → catabolic state | |
| (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) [1] | ↑ vmPFC → excessive self-referential negative processing; Beck's negative view of self | Can reach delusional intensity in psychotic depression |
| (8) | Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) [1] | ↓ dlPFC activity → executive dysfunction | In elderly → 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 [1] | ↓ 5-HT in ventral PFC → impulsivity + aggression; hopelessness (cognitive) + psychic pain (emotional) | Ranges from passive death wishes to active plans with intent |
Minimum Requirement for Criterion A
You need ≥ 5 symptoms, but at least one MUST be either (1) depressed mood or (2) anhedonia. A patient with insomnia, weight loss, fatigue, poor concentration, and guilt — but without depressed mood or anhedonia — does NOT meet criteria for MDD. Always start by establishing the presence of at least one core symptom.
Mnemonic — SIG E CAPS (imagine prescribing "energy capsules" to a depressed patient who has none):
- Sleep disturbance
- Interest loss (anhedonia)
- Guilt / worthlessness
- Energy loss
- Concentration impairment
- Appetite / weight change
- Psychomotor changes
- Suicidality
Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. [1]
Why this criterion exists: To separate clinical depression from ordinary sadness. A person can feel sad for two weeks after a breakup — that's normal. It becomes a disorder when it impairs their ability to work, maintain relationships, or care for themselves.
The episode is not attributable to the physiological effects of a substance or to another medical condition. [1]
This is why we order investigations (TFTs, CBP, etc.) — you must rule out secondary causes before diagnosing primary MDD.
Not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. [1]
Why: In schizophrenia, patients can appear depressed (negative symptoms: flat affect, avolition, social withdrawal). But the primary pathology is a psychotic disorder, not a mood disorder. If psychotic symptoms occur only during mood episodes and are mood-congruent, it's severe depression with psychotic features. If psychotic symptoms occur independently of mood episodes, think schizoaffective disorder or schizophrenia.
Absence of previous manic or a hypomanic episode. [1]
This is the most commonly missed criterion. If there has EVER been a manic or hypomanic episode, the diagnosis is bipolar disorder (currently depressed), NOT MDD — even if the current presentation is purely depressive. Treatment differs dramatically (antidepressants alone in bipolar depression → risk of manic switch).
Specifiers for major depressive disorder: [1]
| Category | Options |
|---|---|
| Course | Single episode, recurrent episode [1] |
| Severity | Mild, moderate, severe, with psychotic features, in partial remission, in full remission, unspecified [1] |
| Other specifiers | With anxious distress, mixed features, melancholic features, atypical features, mood-congruent psychotic features, mood-incongruent psychotic features, catatonia, peripartum onset, seasonal pattern (recurrent episode only) [1] |
Key changes from DSM-IV: [1]
- Removal of the "bereavement exclusion" — 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 if criteria are met, MDD can still be diagnosed. Exercise of clinical judgment based on the individual's history and the cultural norms. [1]
- Dysthymia → persistent depressive disorder (includes both chronic major depressive disorder and the previous dysthymic disorder) [1]
- Introduction of two new disorders: [1]
- Disruptive mood dysregulation disorder: persistent irritability and frequent episodes of extreme, out-of-control behaviour in children up to age 18 years
- Premenstrual dysphoric disorder: mood symptoms occur during the final week before the onset of menses, and improve within a few days of menses
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. [1]
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. [1]
The ICD-10 system uses a two-section approach [2]:
Section A — Core Symptoms (must have ≥ 2 for mild/moderate, all 3 for severe):
- Depressed mood
- Loss of interest and enjoyment
- Reduced energy and decreased activity
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 | Minimum Total |
|---|---|---|---|
| Mild | ≥ 2 of 3 | ≥ 2 | 4 |
| Moderate | ≥ 2 of 3 | ≥ 3 | 5 |
| Severe | All 3 | ≥ 4 | 7 |
Severity of symptoms and degree of functional impairment also guide classification [2].
| Feature | DSM-5 | ICD-10 | ICD-11 |
|---|---|---|---|
| Minimum symptoms | ≥ 5 of 9 (incl. 1 core) | Variable by severity (see above) | Similar to ICD-10 with simplified structure |
| Core symptoms required | ≥ 1 of: depressed mood OR anhedonia | ≥ 2 of: depressed mood, anhedonia, anergia (for mild/moderate) | Depressed mood OR diminished interest |
| Duration | ≥ 2 weeks | ≥ 2 weeks | ≥ 2 weeks |
| Severity levels | Mild/Moderate/Severe via clinical judgment + symptom count | Formally defined by symptom count (2A+2B / 2A+3B / 3A+4B) | Mild/Moderate/Severe with more dimensional approach |
| Psychotic features | Specifier (mood-congruent/incongruent) | Separate code (F32.3) | Specifier |
| Bereavement exclusion | Removed | Never had one | Not present |
ICD-10 vs DSM-5 — The Practical Difference
The ICD-10 system recognises anergia (reduced energy) as a separate core symptom alongside depressed mood and anhedonia. DSM-5 lists fatigue only as an associated symptom (Criterion A6). This means a patient with prominent fatigue but borderline mood/interest could meet ICD-10 criteria but not DSM-5 criteria. In Hong Kong clinical practice, know both systems but ICD codes are used for hospital documentation.
Per DSM-5:
- Depressed mood for most of the day, more days than not, for ≥ 2 years (≥ 1 year in children/adolescents)
- Presence of ≥ 2 of: poor appetite or overeating, insomnia or hypersomnia, low energy, low self-esteem, poor concentration, hopelessness
- During the 2-year period, never symptom-free for > 2 consecutive months
- Criteria for MDD may be continuously present (DSM-5 consolidated chronic MDD and dysthymia into "Persistent Depressive Disorder")
- May have superimposed major depressive episodes (double depression) [2]
At least four of the following are required: [2]
- Loss of interest or pleasure in usual activities
- Lack of emotional reactivity to normally pleasurable surroundings and events
- Early-morning waking (2 hours or more before usual time)
- Depression worse in the morning
- Psychomotor agitation or retardation
- Marked loss of appetite
- Weight loss (5% or more 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 also specifically requires either 'loss of interest' or 'lack of emotional reactivity' to be present. [2]
Specifiers for mood episodes (from bipolar lecture, equally applicable) [3]:
- With anxious distress
- With mixed features
- With rapid cycling ( > 4 episodes per year)
- With melancholic features (near-complete absence of the capacity for pleasure)
- With atypical features (e.g., mood reactivity, weight gain, hypersomnia)
- With psychotic features
- With peripartum onset (severe anxiety and even panic attacks. Risk of infanticide)
- With seasonal pattern (depression begins in fall or winter and remits in spring)
Investigation Modalities
Depression is a clinical diagnosis — investigations do not confirm it. Instead, investigations serve three purposes:
- Exclude secondary causes (medical conditions, substances)
- Establish baseline before treatment (many antidepressants have metabolic/cardiac effects)
- Screen for neglect (malnourished, self-neglecting patients may have nutritional deficiencies)
A. Assessment — Clinical Tools
Assessment: [1]
- History, including medical and medication history
- Mental state examination
- Use of standardised instruments
- Physical examination & investigation to rule out medical conditions that may cause depressive symptoms
The assessment should systematically cover [2]:
| Domain | Key Elements | Why |
|---|---|---|
| Core symptoms | Depressed mood (pervasiveness, diurnal variation), anhedonia, anergia | Establish whether core criteria are met |
| Biological symptoms | Sleep (early morning wakening?), appetite/weight, libido, psychomotor changes | Distinguish melancholic vs atypical pattern; guide treatment choice |
| Cognitive symptoms | Concentration, self-esteem, guilt, hopelessness | Hopelessness = strongest predictor of suicide |
| Psychotic symptoms | Delusions (guilt, nihilistic, persecutory), hallucinations (derogatory voices) | Changes management dramatically (needs antipsychotic ± ECT) |
| Risk assessment | Suicidal ideation, plan, intent, access to means, protective factors | Safety first — determines level of care (outpatient vs inpatient) |
| Past manic/hypomanic episodes | Ever a period of unusually elevated mood, decreased need for sleep, grandiosity? | Must exclude bipolar disorder before diagnosing MDD |
| Substance use | Alcohol, cannabis, stimulants, prescription drug misuse | Substance-induced depression; maladaptive coping |
| Medical/medication Hx | Current medications, comorbid medical conditions | Secondary depression |
| Collateral history | From family/informants | Patients may underreport hypomania or overreport/underreport severity |
Objective measures of severity of depression: [1]
| Scale | Type | Details |
|---|---|---|
| Hamilton Rating Scale for Depression (HAM-D) | Clinician-rated | 17-item, gold standard in research; scores ≥ 8 mild, ≥ 14 moderate, ≥ 23 severe |
| Montgomery-Åsberg Depression Rating Scale (MADRS) | Clinician-rated | 10-item; more sensitive to change with treatment; widely used in clinical trials |
| Patient Health Questionnaire-9 (PHQ-9) | Self-report | 9 items mapping directly to DSM-5 criteria; score 5–9 mild, 10–14 moderate, 15–19 moderately severe, ≥ 20 severe. Very commonly used in primary care |
| Beck Depression Inventory (BDI) | Self-report | 21-item; well-validated; useful for monitoring |
| Center for Epidemiologic Studies-Depression Scale (CES-D) | Self-report | 20-item; designed for epidemiological research |
| Special populations | Various | Geriatric Depression Scale, Cornell Scale for Depression in Dementia, Edinburgh Postnatal Depression Scale [1] |
Rating Scales Are NOT Diagnostic
Useful in clinical practice and research but not diagnostic. Should not be used as a substitute for a clinical diagnosis made from a thorough interview. [1] A PHQ-9 score of 20 does NOT automatically mean the patient has MDD — it means their symptom burden is severe and warrants a thorough clinical assessment to confirm the diagnosis.
| System | What to Look For | Why |
|---|---|---|
| General | Nutritional status, weight, self-care, signs of self-harm (scars on wrists/forearms) | Severity indicator; screening for neglect |
| Endocrine | Thyroid (goitre, tremor, skin/hair changes, bradycardia vs tachycardia), Cushingoid features (moon face, striae, buffalo hump, central obesity), Addisonian features (hyperpigmentation, hypotension) | Most common medical mimics |
| Neurological | Focal deficits (stroke), cogwheel rigidity/tremor (Parkinson's), cognitive screening (MMSE/MoCA for pseudodementia vs dementia), fundoscopy (papilloedema in space-occupying lesions) | Neurological secondary causes |
| Cardiovascular | Signs of heart failure | Chronic disease-associated depression; baseline before medications |
Basic investigations: [1]
| Investigation | What It Screens For | Key Findings and Interpretation |
|---|---|---|
| CBP (Complete Blood Picture) [1] | Anaemia, infection, macrocytosis | ↓ Hb → anaemia (fatigue mimics depression). ↑ MCV → alcoholism (B12/folate deficiency or direct toxic effect). ↑ WBC → infection (secondary depression from systemic illness) [2] |
| R/LFT (Renal and Liver Function Tests) [1] | Electrolytes, renal function, liver disease | Hyponatraemia → important as SSRI side effect (SIADH) and baseline before treatment. ↑ Ca²⁺ → hyperparathyroidism ("moans, groans, stones, psychiatric overtones"). ↑ GGT → alcoholic liver disease. Creatinine → renal dosing for medications (esp. lithium if bipolar suspected) [2] |
| Thyroid Function Test (TFT) [1] | Hypothyroidism / hyperthyroidism | ↑ TSH + ↓ fT4 = hypothyroidism → classic medical mimic of depression (fatigue, weight gain, cognitive slowing, depressed mood). ↓ TSH + ↑ fT4 = hyperthyroidism → can cause anxiety, irritability, or depression with agitation. This is the single most important screening investigation [2] |
Other investigations if indicated by history and physical examination: [1]
| Investigation | Indication | Key Findings and Interpretation |
|---|---|---|
| Blood alcohol level [1] | Suspected alcohol use | Elevated → active intoxication; chronic use → CNS depression, B12/folate depletion |
| Blood and urine toxicology screen [1] | Suspected substance-induced depression | Identifies cannabis, amphetamines, cocaine, opioids, benzodiazepines [2] |
| HIV test [1] | Risk factors for HIV | HIV can cause depression directly (CNS invasion) or indirectly (psychosocial) |
| Cosyntropin (ACTH) stimulation test [1] | For Addison disease | Inadequate cortisol rise after synthetic ACTH → adrenal insufficiency |
| EEG [1] | For epilepsy | Epileptiform discharges; especially temporal lobe epilepsy → mood disturbance [2] |
| CT or MRI brain [1] | For organic brain syndrome or hypopituitarism | Space-occupying lesions, vascular lesions, demyelination (MS), atrophy patterns [2] |
| CRP/ESR [2] | Infection or inflammatory disease | Elevated → chronic inflammation, autoimmune conditions |
| Vitamin B12 and folate [2] | Nutritional deficiency (esp. in malnourished, alcoholic, or elderly patients) | ↓ B12/folate → megaloblastic anaemia + neuropsychiatric symptoms (depression, cognitive decline, peripheral neuropathy) |
| ECG [2] | Cardiac disease; baseline before treatment | Prolonged QTc → risk with TCAs and some antipsychotics. Arrhythmias → contraindication to certain medications [2] |
| Fasting glucose/HbA1c | Metabolic screening; antipsychotic/mood stabiliser baseline | Diabetes → chronic disease-associated depression; baseline before atypical antipsychotics |
The Minimum Investigation Panel
For every patient you diagnose with depression, at minimum order: CBP, R/LFT (including calcium), TFT. This is the exam-safe answer. Everything else is directed by clinical suspicion. The TFT is the single most important investigation — hypothyroidism is the most treatable and most commonly missed secondary cause.
The Hong Kong Hospital Authority uses a structured tool that scores [2]:
| Domain | Items Scored |
|---|---|
| Depression | Sleep disorder, anorexia/weight loss, withdrawal/loss of interest, hopelessness/helplessness, psychomotor retardation, depressed mood (0–6) |
| Hallucination | Derogatory, criticising, about death (0–3) |
| Delusion | Guilt, death, persecutory (0–3) |
| Unstable mood | Anxiety, panic, fear (0–3) |
Supervision levels based on total score:
- Normal (0–9)
- SO1 (10–18)
- SO2 (19–28)
- SO3 (29–41)
The supervision level is determined by professional judgement without following the range of score exactly [2].
| Step | Action | Purpose |
|---|---|---|
| 1 | Comprehensive psychiatric history | Establish symptoms, duration, severity, functional impact |
| 2 | Screen for past mania/hypomania | Exclude bipolar disorder |
| 3 | Mental state examination | Objective documentation of current presentation |
| 4 | Risk assessment | Safety — suicidal ideation, plan, intent |
| 5 | Standardised rating scales (PHQ-9, HAM-D) | Quantify severity (NOT diagnostic) |
| 6 | Physical examination | Screen for medical mimics |
| 7 | Basic investigations (CBP, R/LFT, TFT) | Exclude secondary causes, establish baseline |
| 8 | Directed investigations | Based on clinical suspicion |
| 9 | Apply diagnostic criteria (DSM-5 / ICD) | Formal diagnosis with specifiers |
| 10 | Formulate using biopsychosocial framework | Predisposing / Precipitating / Perpetuating |
Diagnostic criteria are necessary but not sufficient — the diagnosis of depression also requires a clinical formulation that integrates the patient's unique biological, psychological, and social factors. This is what separates a competent clinician from an algorithm.
High Yield Summary
DSM-5 MDD Criteria: ≥ 5/9 symptoms for ≥ 2 weeks, including at least depressed mood OR anhedonia. Must cause functional impairment. Must exclude substance/medical causes, psychotic disorders, and bipolarity.
ICD-10 Severity: Mild (2A+2B), Moderate (2A+3B), Severe (3A+4B). Section A = depressed mood, anhedonia, anergia. ICD uniquely recognises anergia as core symptom.
Key DSM-5 Changes: Bereavement exclusion removed. Dysthymia renamed persistent depressive disorder. New disorders: disruptive mood dysregulation disorder, premenstrual dysphoric disorder.
Specifiers to Know: Melancholic (≥ 4 biological features, must include loss of pleasure or loss of reactivity), atypical (mood reactivity, hypersomnia, weight gain, leaden paralysis), psychotic (mood-congruent vs incongruent), peripartum, seasonal.
Rating Scales: PHQ-9, HAM-D, MADRS, BDI, CES-D — useful for severity tracking but NOT diagnostic. Special populations: GDS, Cornell Scale, Edinburgh Postnatal.
Investigations: Minimum = CBP + R/LFT + TFT. Directed = urine tox, HIV, ACTH stim test, B12/folate, CT/MRI, EEG, ECG as indicated. TFT is the single most important screening investigation.
Algorithm: History → MSE → Risk assessment → Rating scales → Physical exam → Basic bloods → Rule out secondary causes → Apply criteria → Specifiers → Formulate.
Active Recall - Diagnostic Criteria and Algorithm
[1] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p2, p3, p5, p6, p7, p8, p9, p10, p13, p14, p15) [2] Senior notes: ryanho-psych.md (sections on diagnostic criteria for depressive episode, assessment, classification, clinical features, melancholic features, dysthymia, investigation workup) [3] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p3, p22)
Management of Depressive Disorders
Before we dive into specifics, understand the logic of managing depression:
- Safety first — always assess suicide risk and determine the appropriate level of care (outpatient vs. inpatient)
- Confirm the diagnosis — ensure it's primary depression, not secondary (medical/substance) or bipolar depression (which requires a fundamentally different approach)
- Severity guides treatment — mild depression may respond to psychosocial interventions alone; moderate-severe depression usually requires pharmacotherapy ± psychotherapy
- Treatment has phases — acute (remission of current episode), continuation (prevent relapse of same episode), maintenance (prevent recurrence of future episodes)
- Biopsychosocial approach — drugs alone are rarely sufficient; address psychological and social factors concurrently
Management includes: [1]
- Pharmacological treatment
- Psychosocial treatment
- Physical activity
- Physical treatment (Electroconvulsive therapy, Transcranial magnetic stimulation, Transcranial direct current stimulation)
- Diet
Approach (NICE 2009, as per Maudsley): [2]
| Phase | Severity | Strategy |
|---|---|---|
| Acute treatment | Mild depression | Watchful waiting + psychosocial intervention [2] |
| Moderate-severe depression and dysthymia | Antidepressant treatment [2] | |
| Refractory | Augmentation by lithium or antipsychotics, add 2nd antidepressant, or ECT [2] | |
| Continuation | First episode | Continue antidepressants for ≥ 6–9 months at dose that induces remission [2] |
| Maintenance | ≥ 2 episodes + significant functional impairment | Continue antidepressants for ≥ 2 years [2] |
Why continue after remission? Depression has a high relapse rate (~80% will recur). Stopping antidepressants too early dramatically increases the risk of relapse within the first 6 months. The continuation phase allows the brain to consolidate the neuroplastic changes (↑ BDNF, restored synaptic connectivity) that underlie true recovery, not just symptom suppression.
General advice: [2]
- Avoid alcohol and substance use — alcohol is a CNS depressant that worsens mood and interacts with antidepressants
- Lifestyle advice on diet and sleep hygiene
- Encourage suitable activity as ↓ activity causes social withdrawal and exacerbates depression
1. Pharmacological Treatment
Though changes in monoamines constitute only part of the aetiological picture, the monoamine systems provide the most accessible treatment avenue. [1]
This is a crucial conceptual point: we know depression is more than "low serotonin" (neuroplasticity, HPA axis, circuit dysfunction all play roles), but the monoamine system remains the entry point for pharmacological intervention. Antidepressants modulate monoamines → downstream effects include ↑ BDNF, restored neuroplasticity, normalised HPA axis — and this is what takes 2–4 weeks to manifest clinically.
Indication: most effective in moderate-severe depression [2] Efficacy: of this group, 20% will recover without treatment, 30% will respond to placebo, 50% will respond to antidepressants [2]
Translation: The NNT (number needed to treat) with antidepressants is approximately 5–7 for moderate-severe depression. Mild depression has high spontaneous remission rates, which is why watchful waiting is appropriate.
1.2 Classes of Antidepressants
Selective serotonin reuptake inhibitors: e.g. fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and vortioxetine [1]
| Property | Details |
|---|---|
| Mechanism | Selectively block SERT (serotonin reuptake transporter) → ↑ synaptic 5-HT → downstream neuroplastic changes (↑ BDNF, receptor desensitisation) |
| Why first-line | Best balance of efficacy and tolerability; much safer in overdose compared to TCAs; fewer drug interactions than MAOIs |
| Onset of action | 2–4 weeks (time for downstream neuroplastic changes; initial ↑ 5-HT actually causes some worsening before improvement) |
| Key side effects | GI (nausea, diarrhoea — 5-HT₃ receptors in gut), sexual dysfunction (↓ libido, anorgasmia — 5-HT₂ receptor stimulation), insomnia/agitation (initial), headache, hyponatraemia (SIADH — especially in elderly) |
| Serious risks | Serotonin syndrome (especially if combined with MAOIs, tramadol, triptans); ↑ suicidal ideation in first 2 weeks (especially in young adults — due to energy returning before mood improves); bleeding risk (5-HT in platelets) |
| Contraindications | Concurrent MAOI use (must have ≥ 2 week washout; ≥ 5 weeks for fluoxetine due to long half-life of active metabolite); caution in bipolar disorder (manic switch risk) |
Why Can SSRIs Worsen Suicidality Initially?
In the first 1–2 weeks of SSRI treatment, the patient's energy and motivation may improve before their mood lifts. This creates a dangerous window where a previously too apathetic-to-act suicidal patient now has the energy to carry out a plan. This is why close monitoring (weekly follow-up) is essential in the early weeks, particularly in adolescents and young adults.
Vortioxetine — classified with SSRIs but is actually a "multimodal" antidepressant: SERT inhibition + 5-HT₃/₇ antagonism + 5-HT₁ₐ agonism → additional procognitive effects. Particularly useful when cognitive symptoms (concentration, memory) are prominent.
Serotonin and norepinephrine reuptake inhibitors: e.g. duloxetine, venlafaxine, and desvenlafaxine [1]
| Property | Details |
|---|---|
| Mechanism | Block both SERT and NET (norepinephrine reuptake transporter) → ↑ synaptic 5-HT + NE. "SNRI" = dual action |
| Clinical advantage | The NE component adds energy/motivation/concentration benefits on top of serotonergic mood/anxiety effects. Also effective for chronic pain (descending NE pathways in spinal cord modulate pain signals) |
| Key side effects | Similar to SSRIs + hypertension (NE-mediated — dose-dependent, especially venlafaxine at > 225 mg/day); sweating; discontinuation syndrome (venlafaxine is notorious due to short half-life — "brain zaps," dizziness, irritability) |
| Contraindications | Uncontrolled hypertension (venlafaxine); concurrent MAOIs |
| When to use | Depression with prominent fatigue/pain/concentration deficits; depression not responding to SSRI |
Duloxetine — the name itself: "dul" doesn't have a root, but think of it as "dual" (dual action on 5-HT + NE). FDA-approved for MDD, GAD, diabetic neuropathic pain, fibromyalgia, and chronic musculoskeletal pain — highlighting the pain-modulating properties.
Non-selective monoamine reuptake inhibitors — Tricyclic antidepressants: e.g. amitriptyline, imipramine, nortriptyline, clomipramine, dothiepin, trimipramine, desipramine [1]
| Property | Details |
|---|---|
| Mechanism | Block SERT + NET (like SNRIs) but also block muscarinic (M₁), histamine (H₁), and alpha-1 adrenergic receptors → hence the side effect burden. "Tricyclic" refers to the 3-ring chemical structure |
| Efficacy | Melancholic depression: ↑ response to TCA than SSRI [2]. Among the most effective antidepressants, but limited by tolerability |
| Key side effects | Anticholinergic (M₁ blockade): dry mouth, constipation, urinary retention, blurred vision, cognitive impairment. Antihistaminergic (H₁): sedation, weight gain. Anti-alpha₁: orthostatic hypotension. Cardiac: QTc prolongation, arrhythmias (Na⁺ channel blockade) |
| Serious risks | Lethal in overdose — cardiac arrhythmias (wide QRS → VT → death). This is why TCAs are avoided in suicidal patients |
| Contraindications | Recent MI, heart block, arrhythmias; concurrent MAOIs; caution in elderly (anticholinergic burden → delirium, falls); prostatic hypertrophy, narrow-angle glaucoma |
| When to use | Severe melancholic depression; neuropathic pain (amitriptyline); treatment-resistant depression; when SSRIs/SNRIs have failed |
Clomipramine is essentially the most serotonergic TCA — it's also the gold-standard drug for OCD (at higher doses). The name: "clomi" = chlorinated, "pramine" = imipramine derivative.
Norepinephrine and dopamine reuptake inhibitors: e.g. bupropion [1]
| Property | Details |
|---|---|
| Mechanism | Blocks NET + DAT (dopamine reuptake transporter) → ↑ NE + DA. No serotonergic action |
| Clinical advantage | No sexual dysfunction (unlike SSRIs/SNRIs — because no 5-HT₂ effect); no weight gain; mildly activating. Also used for smoking cessation (Zyban) |
| Key side effects | Insomnia, agitation, dry mouth, dose-dependent seizure risk |
| Contraindications | Seizure disorders (lowers seizure threshold); eating disorders (bulimia/anorexia — seizure risk); concurrent MAOIs |
| When to use | Depression with prominent anhedonia/fatigue; patients concerned about sexual dysfunction or weight gain; smoking cessation; as combination partner with SSRI/SNRI in refractory depression |
Monoamine oxidase inhibitors and reversible inhibitors of MAO-A: e.g. tranylcypromine, phenelzine, isocarboxazid, selegiline and moclobemide [1]
| Property | Details |
|---|---|
| Mechanism | Inhibit MAO (monoamine oxidase) → ↓ breakdown of 5-HT, NE, DA in synaptic cleft → ↑ all monoamines. MAO-A preferentially metabolises 5-HT and NE; MAO-B preferentially metabolises DA |
| Types | Irreversible, non-selective (tranylcypromine, phenelzine): bind MAO permanently → takes 2 weeks for new enzyme synthesis. Reversible inhibitor of MAO-A (RIMA): moclobemide → safer, fewer dietary restrictions |
| Clinical advantage | Effective in atypical depression (better than TCAs); treatment-resistant depression |
| Key side effects | Orthostatic hypotension, insomnia, weight gain, sexual dysfunction |
| Serious risks | Hypertensive crisis ("cheese reaction"): tyramine in aged cheeses, red wine, fermented foods is normally metabolised by MAO in gut wall. With MAO inhibited → tyramine absorbed → displaces NE from vesicles → massive sympathetic discharge → hypertensive crisis → stroke. This is less of a risk with moclobemide (reversible) |
| Contraindications | Concurrent serotonergic drugs (SSRIs, SNRIs, TCAs, tramadol, triptans) → serotonin syndrome; phaeochromocytoma; hepatic impairment (moclobemide) |
The Tyramine Crisis — Why MAOIs Need Dietary Restrictions
MAO-A in the gut wall normally breaks down tyramine (an amine found in aged/fermented foods). When MAO-A is irreversibly inhibited, dietary tyramine is absorbed intact → enters sympathetic nerve terminals → displaces NE from vesicles into the synapse → massive NE release → severe hypertension → headache, palpitations, potentially stroke. Patients on irreversible MAOIs must follow a tyramine-restricted diet. Moclobemide (reversible) carries much lower risk because tyramine can still compete for the enzyme.
Others: e.g. trazodone, mirtazapine [1]
| Property | Details |
|---|---|
| Mechanism | Noradrenergic and specific serotonergic antidepressant (NaSSA): blocks α₂-adrenergic autoreceptors → ↑ NE and 5-HT release; also blocks 5-HT₂ₐ, 5-HT₂c, 5-HT₃, H₁ receptors |
| Clinical advantage | Sedating (H₁ blockade) → useful when insomnia is a major symptom. Appetite-stimulating (H₁ + 5-HT₂c blockade) → useful in depressed patients with weight loss. Anxiolytic. Fewer GI side effects and less sexual dysfunction than SSRIs (5-HT₃ blockade prevents nausea; no direct SERT blockade) |
| Key side effects | Sedation, weight gain, ↑ appetite. Rarely: agranulocytosis (rare but serious — warn patient to report sore throat/fever) |
| When to use | SSRI or mirtazapine if sedation is required [2]; depression with insomnia and/or appetite loss; elderly patients who need weight gain; as combination partner (California rocket fuel = venlafaxine + mirtazapine) |
Melatonergic antidepressants: e.g. agomelatine [1]
| Property | Details |
|---|---|
| Mechanism | MT₁/MT₂ melatonin receptor agonist + 5-HT₂c antagonist → resynchronises circadian rhythms + ↑ NE and DA release in frontal cortex |
| Clinical advantage | Improves sleep architecture without daytime sedation; no sexual dysfunction; no weight gain; no discontinuation syndrome |
| Key side effects | Hepatotoxicity (must monitor LFTs at baseline, 3, 6, 12, and 24 weeks) |
| Contraindications | Hepatic impairment; concurrent potent CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) |
Systematic review and network meta-analysis of 21 antidepressants (Cipriani et al., 2018): [1]
- Agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine are more effective than other antidepressants (range of ORs 1.19–1.96)
- Agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine are more tolerable than other antidepressants (range of ORs 0.43–0.77)
- Older antidepressants (e.g. tricyclics, MAOIs) associated with significant adverse events and drug-drug interactions
- Marked inter-individual variation in antidepressant tolerability
- Choice of medication determined by clinical circumstances, particularly the patient's physical comorbidity and concomitant medications
The Cipriani Meta-Analysis — The Most Cited Evidence
This 2018 Lancet paper is the largest network meta-analysis of antidepressants ever published. Key takeaway for exams: escitalopram and sertraline offer the best balance of efficacy + tolerability and are commonly used first-line. Amitriptyline is highly effective but poorly tolerated. Reboxetine was the least effective. All 21 antidepressants were more effective than placebo.
Approach to antidepressant treatment: [2]
| Step | Action | Details |
|---|---|---|
| 1 | Discuss choice of drug with the patient | Consider: potential therapeutic effects, possible adverse effects, likelihood of discontinuation symptoms, likely time to respond, the role of therapeutic alliance in predicting response [2]. Suggest an SSRI or mirtazapine if sedation is required [2] |
| 2 | Start antidepressant | Titrate to a recognised therapeutic dose [2] |
| 3 | Assess efficacy after 2 weeks | Some improvement should be emerging; full effect at 4–6 weeks |
| 4a | If effective → | Continue for 6–9 months at full treatment dose [2]; consider longer-term treatment in recurrent depression |
| 4b | If poorly tolerated → | Switch to a different antidepressant [2] |
| 4c | If no response → | Assess weekly for a further 1–2 weeks. If still no response, consider increasing dose [2] |
| 5 | If still no response → | Switch to a different antidepressant, titrate to therapeutic dose, assess efficacy over 3–4 weeks [2] |
| 6 | If still no response → | Consider third choice options: mirtazapine, vortioxetine, agomelatine [2] |
| 7 | If still no response → | Refer to suggested treatments for refractory depression [2] |
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial is the largest real-world effectiveness study of antidepressant treatment [2]:
| Step | Treatment | Remission Rate |
|---|---|---|
| Step 1 | Citalopram | 28% |
| Step 2 (switch) | Bupropion 21.3% vs Venlafaxine 24.8% vs Sertraline 17.6% | ~20% |
| Step 2 (augment) | Add buspirone 30.1% vs Add T3 24.7% | ~25-30% |
| Step 3 (switch) | Mirtazapine 12.3% vs Nortriptyline 19.8% | ~15% |
| Step 3 (augment) | Add lithium 15.9% | ~16% |
| Step 4 | Tranylcypromine 6.9% vs Mirtazapine + venlafaxine 13.7% | ~10% |
Key lesson: With each failed step, remission rates drop. About 2/3 of patients will eventually achieve remission if they persist through multiple adequate trials. But "first-shot" success matters — choosing the right drug first time is important.
2. Psychosocial Treatment
Main psychological treatment for depression: [2][4]
| Aspect | Details |
|---|---|
| Basis | Targets the cognitive distortions identified by Beck (selective abstraction, overgeneralisation, personalisation, arbitrary inference) and the behavioural consequences (withdrawal, inactivity) |
| Structure | Structured, time-limited (typically 12–20 sessions), collaborative, homework-based |
| Techniques | Cognitive restructuring (identifying and challenging automatic negative thoughts), behavioural activation (scheduling pleasurable activities to break the withdrawal-anhedonia cycle), graded task assignment |
| Efficacy | As effective as antidepressants for mild-moderate depression; combined CBT + antidepressant superior to either alone for moderate-severe depression; lower relapse rates after CBT discontinuation vs antidepressant discontinuation (because patients learn skills) |
| Indications | Depression [4]; particularly useful in mild-moderate depression, relapse prevention |
Mindfulness-based cognitive therapy: [4]
- Combines CBT with mindfulness meditation techniques
- Focus: becoming aware of thoughts and feelings and accepting them rather than reacting to them
- Particularly effective for relapse prevention in patients with ≥ 3 prior episodes of depression (NICE-recommended)
- 8-week group programme
Interpersonal therapy: [2]
| Aspect | Details |
|---|---|
| Basis | Problems with interpersonal life contribute to depression |
| Focus areas | Grief over loss, interpersonal disputes, role transitions, interpersonal skill deficits |
| Structure | Current-problem focused, brief (12–16 sessions) |
| Efficacy | Well-established for depression; particularly useful for depression triggered by relationship issues or role transitions |
| Approach | Description | When to Use |
|---|---|---|
| Psychoeducation [3] | Education about the illness, its course, triggers, and treatment | All patients — foundation of management |
| Counselling and supportive psychotherapy [2] | Brief, empathetic, reflective; helps patients utilise own strengths | Mild depression, stressful life events |
| Problem-solving therapy | Structured approach to identifying and solving current problems | Mild depression, primary care settings |
| Group therapy [2] | ~5–10 patients meet with therapist weekly; based on CBT or psychodynamic principles | Cost-effective; social skill building; peer support |
| Family therapy [3] | Reduces expressed emotion, educates family, addresses family dynamics | When family conflict is prominent; family or carer-focused treatment [3] |
Physical activity [1] is an evidence-based treatment for depression:
- Mechanism: ↑ endorphins, ↑ BDNF (neuroplasticity), ↑ monoamines, ↓ cortisol, improves sleep, ↑ self-efficacy
- Evidence: Meta-analyses show moderate-intensity exercise (e.g., 30 min, 3–5×/week) is as effective as antidepressants for mild-moderate depression
- Recommended: aerobic exercise (walking, jogging, swimming, cycling) or resistance training
- Barrier: anhedonia and anergia make it hard to start → behavioural activation strategies in therapy help
4. Physical (Brain Stimulation) Treatments
Electroconvulsive therapy: [1][2]
"Electro" = electric current, "convulsive" = seizure-inducing — the name tells you what it does.
| Aspect | Details |
|---|---|
| Mechanism | Unknown [2]. Postulated: ↑ hormonal release (PRL, TSH, ACTH, endorphins); ↑ neurotrophic signalling (↑ BDNF) → neurogenesis; ↑ monoamine release; transient ↑ BBB permeability; changes in brain connectivity [2] |
| Administration | Course: 6–12 treatments, 2–3/week [2]. Under short-acting GA + muscle relaxant. Electric pulse delivered via scalp electrodes to induce a generalised tonic-clonic seizure lasting at least 15 seconds [2] |
| Electrode placement | Unilateral vs bilateral: bilateral more effective but may cause more cognitive impairment [2]. Unilateral, if done, should be done contralateral to dominant hemisphere [2] |
Indications — remember the mnemonic ECT:
- Emergency — rapid definitive response required (e.g., pregnancy); life-threatening (persistent suicidal intent, food refusal, malnutrition/dehydration) [2]
- Catatonia — life-threatening, treatment resistance [2]
- Treatment-refractory — antidepressants failed or cannot be used (refractory, medical comorbidities); previous good response to ECT [2]
Also indicated for:
- Mania or mixed affective states: pregnant, life-threatening, treatment resistant [2]
- Puerperal psychosis with prominent mood symptoms (rapid treatment to allow reuniting with baby) [2]
- Selective treatment-resistant schizophrenia [2]
ECT is especially effective for those with psychosis and/or psychomotor retardation. [2]
| Adverse Effects | Details |
|---|---|
| Cognitive impairment | Acute confusion, anterograde or retrograde amnesia — generally short-lived, lasting a few days after ECT [2] |
| General complaints | Headache, nausea, muscle pain [2] |
| Mortality | 2–4/100,000 (~other minor surgery under GA), usually associated with cardiopulmonary events (e.g., MI) [2] |
Contraindications: no absolute contraindication. Relative contraindications include [2]:
- Heart disease: recent MI, heart failure, ischaemic heart disease
- ↑ ICP
- Risk of ICH, e.g., hypertension, recent stroke
- Poor anaesthetic risk
Transcranial magnetic stimulation: [1][2]
| Aspect | Details |
|---|---|
| Procedure | Non-invasive, hand-held plastic-coated coil placed close to scalp → use of external magnetic field to stimulate generation of action potential and firing of neurones [2] |
| Target | Usually left dlPFC (which is underactive in depression) → stimulation restores activity |
| Use | Suitable for medically unwell people who cannot tolerate antidepressants or ECT [2]; treatment-resistant depression |
| Side effects | Minimal, but only available in selected centres [2] |
Transcranial direct current stimulation: [1][2]
| Aspect | Details |
|---|---|
| Procedure | Non-invasive, use of constant, low voltage DC via electrodes on head to achieve neurostimulation [2] |
| Mechanism | Anode and cathode to ↑/↓ cortical activity/excitability respectively → modulates spontaneous neuronal network activity [2] |
| Use | NOT suprathreshold (cf TMS, ECT) → therefore limited to adjunctive use only [2] |
| Side effects | Minimal, but only available in selected centres [2] |
Healthy diet may help as part of the overall depression treatment though no specific diet has been proven to relieve depression: [1]
| Dietary Component | Details |
|---|---|
| Antioxidants | Food rich in antioxidants (e.g. blueberries, oranges, carrots, nuts) [1] — oxidative stress is elevated in depression; antioxidants may help counteract this |
| Complex carbohydrates | Can have a calming effect [1] — ↑ tryptophan availability → ↑ 5-HT synthesis |
| Protein-rich foods | e.g. turkey, tuna, and chicken — boost alertness [1] — contain tryptophan (5-HT precursor) and tyrosine (DA/NE precursor) |
| Mediterranean diet | As a source for B vitamins [1] — B6, B12, folate are cofactors in monoamine synthesis |
| Omega-3 fatty acids | Essential polyunsaturated lipids that influence cellular metabolism and function [1]. Earlier studies linked low seafood intake and mood disorders, and positive results with fish oil intervention → subsequent results more diversified [1]. EPA rather than DHA as the effective component. Monotherapy as well as adjunct therapy [1] |
When a patient has not responded to ≥ 2 adequate trials of different antidepressants at adequate dose and duration, consider [2]:
Considerations before escalating treatment: [2]
- Reassess diagnosis: look for secondary causes (e.g., substance abuse) and other psychiatric disorders
- Assess compliance — non-adherence is the most common reason for "treatment failure"
- Assess for ongoing psychosocial stressors
Therapeutic options: [2]
| Strategy | Options | Details |
|---|---|---|
| Switch antidepressant | Switch to another class | Usually done first, preferably of a different mechanism (beware of serotonin and discontinuation syndrome → cross-tapering) [2] |
| Combination therapy | Usually 5-HT (SSRI, venlafaxine) + NA (bupropion, mirtazapine) [2] | "California rocket fuel" = venlafaxine + mirtazapine; targets all 3 monoamines |
| Augmentation | Low-dose antipsychotic drugs, especially in those with psychotic features [2] | Antipsychotics licensed for augmentation: quetiapine, aripiprazole (Abilify) [2] |
| Lithium [2] | Augments serotonergic function; anti-suicidal properties; requires level monitoring (target 0.4 mmol/L for unipolar depression augmentation) [2] | |
| Tri-iodothyronine (T3) [2] | T3 modulates monoamine turnover; evidence from STAR*D (24.7% remission rate as augmentation) | |
| ECT | Considered more effective than drugs in the most severe cases. Indications: emergency, refractory, catatonic [2] |
Options for refractory depression: Optimise existing treatment → Augmentation by antipsychotics, Li or T3 → Combine with another antidepressant with another mechanism → Switch to another mechanism [2]
This is not the same as unipolar depression management. Including this because it's a common exam trap [2][3]:
Treatment of bipolar depression is NOT identical to treatment of unipolar depression or bipolar mania! [2]
Treatment of bipolar depressive episode: [3]
- Monotherapy: Lithium, Lamotrigine OR Quetiapine
- Combination: Add Antidepressants (SSRI OR Venlafaxine) to monotherapy OR Combine two monotherapy agents
- Reevaluate diagnosis and consider ECT (for patients with high suicidal risk)
Key principles: [3]
- Avoid antidepressants if possible; if used, limit dose and duration [3]
- 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]
- Antidepressants, when used, should be combined with antipsychotic or mood stabiliser [2]
Indication for prophylactic treatment: [3]
- Established bipolar disorder — recurrent episodes of mania or depression
- Severe single episode with suicidal attempts, psychotic episodes and significant functional impairment (to prevent future relapse)
- Recurrence rate reduces by 50% for maintenance vs. discontinuation
- Gradual discontinuation better than abrupt discontinuation
General guidelines for prophylaxis for bipolar I: [3]
- Monotherapy: Lithium or Valproate or Quetiapine
- Psychosocial (augmentation): Psychoeducation, Cognitive behavioural therapy, Interpersonal and social rhythm therapy, Family or carer-focused treatment, Peer-support, Intensive case management
- Less hostile, more supportive, better drug compliance
Lithium is still an important drug, given that it is the only mood stabiliser to reduce suicide. [3]
Clinical course: generally self-limiting within 6 months to 1 year [2]
| Feature | Details |
|---|---|
| Age of onset | ~50% before age 21 [2] |
| Duration | Average 6 months; ~25% > 1 year; ~10–20% chronic unremitting [2] |
| Recurrence | ~80% will recur; average ~4 further episodes in 25 years [2] |
| Interval | Usually associated with progressive shortening of interval between episodes [2] |
| Remission | ~50% does not have complete symptom remission between episodes [2] |
| Stability | Only ~25% of those with recurrent major depression achieve 5-year clinical stability with good social and occupational performances [2] |
| Mortality | > 20× risk of suicide; can approach 15% in those severe admitted cases [2] |
Prognosticants 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
Treatment by severity: Mild → watchful waiting + psychosocial. Moderate-severe → antidepressant + psychotherapy. Refractory → augmentation/combination/ECT.
First-line antidepressant: SSRI (escitalopram, sertraline best balance of efficacy + tolerability per Cipriani 2018). Mirtazapine if sedation/appetite stimulation needed.
Key drug classes: SSRIs (SERT blockade), SNRIs (SERT+NET), TCAs (non-selective, lethal in OD), NDRIs (bupropion — no sexual dysfunction), MAOIs (tyramine crisis), mirtazapine (NaSSA — sedating, appetite-stimulating), agomelatine (melatonergic — monitor LFTs).
Continuation phase: ≥ 6–9 months at remission dose for first episode. Maintenance: ≥ 2 years if ≥ 2 episodes with significant impairment.
Refractory depression: Reassess dx/compliance/stressors → switch class → combine (SSRI + mirtazapine/bupropion) → augment (lithium, quetiapine, aripiprazole, T3) → ECT.
ECT indications: Emergency (suicidal, food refusal), Catatonia, Treatment-refractory. No absolute contraindications. Bilateral more effective but more cognitive side effects.
Bipolar depression: NOT the same as unipolar. First-line: quetiapine, lithium, or lamotrigine. Avoid antidepressant monotherapy (manic switch risk). Lithium is the only mood stabiliser that reduces suicide.
Prognosis: 80% recurrence; average 4 episodes in 25 years; > 20× suicide risk. Poor prognosticants: incomplete remission, early onset, poor social support, comorbid SA/personality disorder.
Active Recall - Management of Depressive Disorders
[1] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p16, p17, p24, p25) [2] Senior notes: ryanho-psych.md (sections on management of depressive disorders, antidepressants, ECT, psychotherapy, refractory depression, course and prognosis, lithium) [3] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p36, p44, p46, p47, p65) [4] Senior notes: ryanho-psych.md (sections on psychotherapy indications, CBT)
Complications of Depressive Disorders
Depression is not just a "mood problem." It is a systemic illness with complications that span every domain of a patient's life — psychiatric, medical, social, and even cognitive-neurodegenerative. Understanding these complications is essential because they explain why depression carries such a high burden of disability and mortality, and why aggressive treatment matters.
Let's work through each category systematically, connecting every complication back to the underlying pathophysiology.
1. Suicide and Self-Harm — The Most Feared Complication
This is the complication that keeps psychiatrists up at night and the one you will be examined on most heavily.
Depression raises suicidal risk. Increase in suicide risk attributable to depression was 20-fold. [1]
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. [1]
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. [1]
Mortality: > 20× risk of suicide; can approach 15% in those severe admitted cases. [2]
Over 700,000 people commit suicide every year and many more attempt suicide. One of the major causes of suicide is depression. [1]
Depression accounts for a significant proportion of suicides in adults in Hong Kong: [1]
- Using a case-control psychological autopsy method, 150 local suicide decedents aged 15–59 were compared with 150 randomly selected age- and gender-matched controls
- 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
Depression accounts for a significant proportion of suicides in older adults in Hong Kong: [1]
- 70 decedents aged 60 or above who had committed suicide were compared with 100 elderly controls
- 86% of suicide subjects suffered from a psychiatric problem before committing suicide, compared with 9% of control subjects
- Among the psychiatric problems, major depression was the commonest diagnosis
The path from depression to suicide involves convergence of multiple factors:
Key mechanistic points:
- Hopelessness (Beck's cognitive triad — negative view of future) is the single strongest predictor of suicidal behaviour, even more than depression severity itself
- ↓ 5-HT in ventral PFC → impaired impulse control and increased aggression, including self-directed aggression. Post-mortem studies of suicide decedents consistently show ↓ 5-HT and ↓ 5-HIAA (serotonin metabolite) in CSF
- Psychotic features dramatically increase risk — command auditory hallucinations telling the patient to kill themselves, or nihilistic delusions (Cotard's syndrome) making the patient believe they are already dead or that their organs are rotting
- The critical "dangerous window" occurs in early antidepressant treatment (first 1–2 weeks) when energy returns before mood lifts — a previously too-apathetic patient now has the drive to act on suicidal thoughts
Suicide can be understood as a spectrum and should be approached in a gradual manner: [2]
- Depressed mood
- Negative thoughts: guilt → worthlessness → hopelessness
- Death wish: passive ("I don't care if I wake up tomorrow") → active (active suicidal means considered)
- Suicidal acts: plans and preparations → attempts
34% of suicidal ideation becomes plans; 72% of suicidal plans become attempts. Passive ideation can quickly become active. [2]
Deliberate self-harm (DSH) — e.g., cutting, burning, overdose — frequently accompanies depression but must be distinguished from suicidal behaviour:
- Self-harm may serve as emotional regulation (the pain provides temporary relief from emotional numbness/anhedonia)
- However, DSH is itself a strong risk factor for completed suicide — every episode must be taken seriously
- In some younger people, the first obvious sign may be self-injury or bulimia or drug use in a previously stable adolescent [1]
Every Depressed Patient Needs a Suicide Risk Assessment
This is non-negotiable. You MUST assess suicide risk in every depressed patient at every encounter. Ask directly — asking about suicide does NOT increase risk (this is a common misconception). Use the mnemonic: Ideation → Plan → Intent → Means → Protective factors → Previous attempts.
2. Non-Suicidal Mortality and Medical Complications
Depression increases non-suicidal mortality: [1]
- Reviewed 61 reports; 72% demonstrated positive association for depression and non-suicide mortality
- RR = 1.2–4.0
Depression is associated with significant morbidity and mortality. [1]
Possible mediators: [1]
- Behavioural risk factors (e.g. poor adherence to treatment, inactivity, ↑ alcohol consumption)
- Biological risk factors (e.g. altered thrombogenesis)
- Subclinical disease / prevalent disease (e.g. cardiovascular disease)
| Mechanism | Pathway | Clinical Consequence |
|---|---|---|
| HPA axis dysregulation | Chronic ↑ cortisol → ↑ visceral fat, insulin resistance, dyslipidaemia, hypertension | Metabolic syndrome → accelerated atherosclerosis |
| Altered thrombogenesis | ↓ Serotonin in platelets (serotonin is stored in platelets and released during clot formation); altered platelet reactivity | ↑ Risk of thrombotic events (MI, stroke) |
| Sympathetic overactivation | ↑ NE, ↓ heart rate variability | ↑ Risk of arrhythmias, sudden cardiac death |
| Inflammation | ↑ Pro-inflammatory cytokines (IL-6, TNF-α, CRP) | Endothelial dysfunction → atherosclerosis |
| Behavioural | Physical inactivity, poor diet, smoking, medication non-adherence | Multiple cardiovascular risk factors |
Depression is an independent risk factor for MI, stroke, and cardiovascular mortality. Post-MI depression worsens prognosis — hence why cardiac rehabilitation programmes now screen for depression.
- Chronic cortisol → insulin resistance → type 2 diabetes
- Atypical depression with hyperphagia → weight gain → metabolic syndrome
- Antidepressant side effects (especially mirtazapine, TCAs, some antipsychotics used as augmentation) → weight gain, dyslipidaemia
- Depression impairs self-management of existing diabetes (poor adherence to diet, medications, glucose monitoring)
- Depression is associated with ↑ pro-inflammatory cytokines and ↓ cellular immunity (↓ NK cell activity, ↓ T-cell function)
- This may partly explain the association with:
- ↑ Susceptibility to infections
- Poorer cancer prognosis (though evidence is mixed)
- Accelerated ageing at the cellular level (telomere shortening)
- Depression and chronic pain share common neurotransmitter pathways (↓ 5-HT and NE in descending pain-modulating pathways → lowered pain threshold)
- This creates a vicious cycle: pain → depression → ↓ pain threshold → more pain → worse depression
- This is why SNRIs (duloxetine) and TCAs (amitriptyline) are used for both depression and chronic pain
3. Psychiatric Comorbidity
↑ co-morbidity with other disorders, especially anxiety and substance abuse [2]
- Prevalence: Up to 70% of depressed patients have comorbid anxiety [2]
- Why: Shared neurobiology (↓ 5-HT, HPA axis dysregulation, amygdala hyperactivation), shared genetic risk factors, and shared environmental risk factors (early adversity, neuroticism)
- Impact: Comorbid anxiety worsens depression prognosis — ↑ severity, ↓ treatment response, ↑ chronicity, ↑ suicidal risk
- Examples: GAD, panic disorder, social anxiety disorder, OCD, PTSD
- Depression: most common comorbidity [with alcoholism]; alcoholism may be a way of self-medication [2]
- Depression → substance use (self-medication: alcohol to numb emotional pain, cannabis for temporary mood lift, stimulants for energy)
- Substance use → depression (alcohol is a CNS depressant; stimulant withdrawal causes DA depletion → "crash")
- Both share genetic vulnerability
- Comorbid substance use is a major risk factor for suicide, treatment non-adherence, and poor functional outcomes
Comorbid substance abuse is a prognosticant for relapse. [2]
The distress caused by untreated mood symptoms results in increased suicidality, comorbid anxiety and substance use disorders. [3]
- ~25% of bipolar affective disorder first presents as juvenile depression [2]
- Some patients initially diagnosed with MDD will later develop a manic/hypomanic episode, reclassifying them as bipolar disorder
- Predictors of bipolar conversion: early onset ( < 25y), psychotic features, family history of bipolar, atypical features (hypersomnia, hyperphagia), antidepressant-induced hypomania/mania
Depression is the 4th leading cause of disability worldwide [2] Depressive disorder is the 1st cause of disability-adjusted life years under mental, neurological, and substance use disorders [3] ~$85 billion/year loss of productivity [2]
| Domain | Impact | Mechanism |
|---|---|---|
| Occupational | Absenteeism (missing work), presenteeism (at work but unproductive), unemployment, disability claims | Anergia, poor concentration, psychomotor retardation, anhedonia → cannot perform job tasks |
| Social | Social withdrawal, relationship breakdown, isolation | Anhedonia → loss of interest in relationships; irritability → conflict; guilt/worthlessness → feels like a burden |
| Self-care | Poor hygiene, malnutrition, medical non-adherence | Anergia + anhedonia → cannot motivate to maintain basic activities of daily living |
| Academic | Decline in school performance [1] | Poor concentration (↓ dlPFC), fatigue, absenteeism |
Only ~25% of those with recurrent major depression achieve 5-year clinical stability with good social and occupational performances. [2]
This is a sobering statistic: 3 out of 4 patients with recurrent depression will NOT achieve full functional recovery. This underscores why aggressive treatment, relapse prevention, and rehabilitation are essential.
5. Cognitive Impairment
- ↓ activity in dorsolateral prefrontal cortex → psychomotor retardation, apathy, deficits in attention/working memory [2]
- Impaired executive function, processing speed, verbal memory
- In elderly: pseudodementia — cognitive impairment that mimics dementia but is reversible with treatment of depression
- Increasingly recognised that cognitive impairment persists even after mood symptoms remit
- Affects concentration, memory, decision-making → ongoing functional impairment
- ~50% does not have complete symptom remission between episodes [2] — residual cognitive symptoms are among the most persistent
This is a critical emerging concept:
Neuroprogression theory: worse prognosis with frequent relapses. Increased risk of future development of dementia. [3]
- Each depressive episode causes cumulative neurobiological damage:
- Chronic cortisol → hippocampal atrophy → memory impairment
- ↓ BDNF → impaired neuroplasticity and neurogenesis
- Chronic neuroinflammation → neuronal damage
- Meta-analyses show depression approximately doubles the risk of developing dementia (both Alzheimer's disease and vascular dementia)
- Progressive shortening of interval between episodes [2] — suggests a "kindling" effect where each episode lowers the threshold for the next one
- This provides a strong rationale for maintenance treatment and relapse prevention — you're not just preventing mood episodes, you're protecting the brain from cumulative damage
Depression as a Neurodegenerative Process
Each untreated or inadequately treated depressive episode may cause cumulative hippocampal atrophy and neuroplastic damage (via chronic cortisol, ↓ BDNF, neuroinflammation). This "neuroprogression" means that depression is not a benign, self-limiting condition — recurrent episodes worsen long-term cognitive outcomes and increase dementia risk. This is one of the strongest arguments for aggressive relapse prevention with maintenance antidepressant therapy.
Depression entails a non-psychiatric impact: [2]
- ↑ morbidity: associated with ↓ birth weight, chronic medical illness, poor self-perceived health, functional/cognitive impairment
- ↑ mortality: RR 1.2–4.0× non-suicide mortality
| Medical Complication | Mechanism |
|---|---|
| Worsened outcomes in chronic disease | Depression impairs treatment adherence, self-care, and health behaviours (diet, exercise, smoking cessation) in patients with diabetes, CHF, COPD, CKD |
| ↓ Birth weight | Maternal depression → ↑ cortisol crosses placenta → fetal growth restriction; also poor maternal nutrition and prenatal care |
| Post-operative complications | Depression → ↓ immune function, poor wound healing, medication non-adherence, longer hospital stays |
| Osteoporosis | Chronic ↑ cortisol → bone resorption; physical inactivity; poor nutrition |
7. Treatment-Related Complications
| Side Effect | Drug Class | Mechanism | Clinical Significance |
|---|---|---|---|
| Suicidal ideation (early treatment) | SSRIs (esp. in young adults) | Energy returns before mood → dangerous window | Black box warning; close monitoring in first 2 weeks |
| Serotonin syndrome | SSRIs + MAOIs / tramadol / triptans | Excessive synaptic 5-HT → autonomic instability, neuromuscular excitation, altered mental status | Medical emergency — can be fatal |
| QTc prolongation / arrhythmias | TCAs, citalopram (high dose) | Na⁺/K⁺ channel blockade | Lethal in overdose (TCAs); ECG monitoring |
| Hyponatraemia (SIADH) | SSRIs (esp. in elderly) | ↑ ADH secretion → water retention → dilutional hyponatraemia | Monitor Na⁺; can cause confusion, seizures |
| Discontinuation syndrome | Venlafaxine (short t½), paroxetine | Abrupt withdrawal → rebound monoamine changes | "Brain zaps," dizziness, irritability, insomnia; taper gradually |
| Metabolic syndrome | Mirtazapine, TCAs, atypical antipsychotics (augmentation) | H₁ blockade → weight gain; insulin resistance | Monitor weight, glucose, lipids |
| Tyramine crisis | Irreversible MAOIs | MAO-A inhibition in gut → tyramine absorption → massive NE release → hypertensive crisis | Dietary restrictions essential |
- With chronic or recurrent depression, patients may develop secondary behavioural patterns:
- Learned helplessness → passivity and dependence on others
- Sick role adoption → disability claims, avoidance of recovery
- Caregiver burnout → relationship breakdown
- Comorbid personality disorder is a prognosticant for relapse [2]
| Domain | Complication | Mechanism |
|---|---|---|
| Relationships | Marital breakdown, family conflict, social isolation | Irritability, withdrawal, emotional unavailability, burden on caregivers |
| Parenting | Impaired parenting → adverse outcomes for children | Depressed parents less responsive, less consistent; children of depressed parents have ↑ risk of developing depression themselves (genetic + environmental) |
| Employment | Job loss, reduced income, disability | Absenteeism, presenteeism, impaired performance |
| Legal | Self-neglect, capacity issues in severe depression | Psychotic depression may impair capacity to make decisions |
| Economic | ~$85B/y loss of productivity [2]; healthcare utilisation | Direct costs (treatment) + indirect costs (lost productivity, disability payments) |
Clinical course: generally self-limiting within 6 months to 1 year [2] — but:
- ~80% will recur; average ~4 further episodes in 25 years [2]
- ~25% > 1 year duration; ~10–20% chronic unremitting [2]
- ~50% does not have complete symptom remission between episodes [2]
- Usually associated with progressive shortening of interval between episodes [2]
This chronic relapsing course is itself a major complication — each episode carries risk of:
- Further neurobiological damage (neuroprogression)
- Cumulative functional decline
- Suicide
- Substance abuse
- Caregiver and family burnout
Prognosticants for relapse: [2]
- Incomplete symptomatic remission
- Early age of onset
- Poor social support
- Poor physical health
- Comorbid substance abuse
- Comorbid personality disorder
In some tragic cases, symptoms may be masked to others until the person is found dead by suicide. [1]
| Domain | Key Complications |
|---|---|
| Suicide/Self-harm | 20× risk of suicide; 6% lifetime suicide rate; 15% in severe hospitalised cases; accounts for 27% of population-attributable suicide risk in HK |
| Medical mortality | RR 1.2–4.0× non-suicide mortality; CVD, metabolic syndrome, thrombotic events |
| Psychiatric comorbidity | 70% comorbid anxiety; substance abuse (self-medication); bipolar conversion (25% of youth) |
| Cognitive | Acute deficits (pseudodementia in elderly); residual cognitive impairment; neuroprogression → ↑ dementia risk |
| Functional/Social | 4th leading cause of disability; only 25% achieve 5-year stability; relationship breakdown; impaired parenting; job loss |
| Treatment-related | SSRI-induced suicidality; serotonin syndrome; TCA overdose; SIADH; discontinuation syndrome; metabolic side effects |
| Economic | ~$85B/y productivity loss; healthcare burden |
| Chronic course | 80% recurrence; progressive interval shortening; 10–20% chronic unremitting |
High Yield Summary
Suicide: Most feared complication. 20× increased risk; 6% lifetime suicide mortality in affective disorders. In HK, MDD accounted for 27% of population-attributable suicide risk in adults and was the commonest psychiatric diagnosis among elderly suicide decedents. Hopelessness is the strongest predictor. Always assess: ideation → plan → intent → means → protective factors.
Non-suicide mortality: RR 1.2–4.0×, primarily through CVD (altered thrombogenesis, HPA axis dysregulation, inflammation, behavioural risk factors). Depression is an independent risk factor for MI and stroke.
Psychiatric comorbidity: 70% comorbid anxiety; frequent substance abuse (self-medication); 25% of youth depression converts to bipolar.
Cognitive impairment and neuroprogression: Each episode causes cumulative hippocampal atrophy and neuroplastic damage. Depression approximately doubles dementia risk. Residual cognitive deficits persist between episodes in ~50% of patients.
Functional impairment: 4th leading cause of disability worldwide. Only 25% of recurrent MDD patients achieve 5-year functional stability. Massive economic burden (~$85B/year).
Chronic relapsing course: 80% recurrence; average 4 episodes in 25 years; progressive interval shortening (kindling); 10–20% chronic unremitting. Poor prognosticants: incomplete remission, early onset, poor social support, poor physical health, comorbid SA, comorbid personality disorder.
Treatment complications: Early SSRI-induced suicidality (energy before mood); serotonin syndrome; TCA overdose lethality; SIADH; discontinuation syndrome; metabolic effects from augmentation agents.
Active Recall - Complications of Depressive Disorders
References
[1] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p4, p5, p6, p25, p26) [2] Senior notes: ryanho-psych.md (sections on course and prognosis, epidemiology, clinical features, suicide risk assessment, psychiatric comorbidity in alcoholism, prognosticants for relapse) [3] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p14, p23, p26, p34)
High Yield Summary
Definition: Depressive disorders = persistent mood disturbance (≥ 2 weeks) with cognitive and neurovegetative symptoms causing functional impairment; qualitatively different from normal sadness (pervasive, loss of reactivity).
Epidemiology: HK prevalence 2.9%; lifetime 10–20%; F:M = 2–3:1; mean onset ~27y; ↑ in divorced, unemployed; ↑ non-suicide mortality RR 1.2–4.0×.
Aetiology: Biopsychosocial — genetic (37% heritability, 5-HTTLPR), early adversity, cognitive distortions (Beck's triad), monoamine deficiency (5-HT, NE, DA) + HPA axis dysregulation + ↓ BDNF/neuroplasticity. Pathophysiology remains largely unknown but current model integrates monoamines → neuroplasticity → circuit dysfunction.
Key Brain Regions: ↑ vmPFC (rumination, pain sensitivity), ↓ dlPFC (psychomotor retardation, cognitive deficits), ↓ hippocampal volume (memory, HPA feedback failure), ↓ mesolimbic DA (anhedonia).
Classification: MDD (single/recurrent), Dysthymia (≥ 2y subthreshold), specifiers (melancholic vs atypical vs psychotic vs seasonal). ICD severity: Mild (2A+2B), Moderate (2A+3B), Severe (3A+4B).
Core Symptoms: Depressed mood + anhedonia + anergia. Biological symptoms: sleep disturbance (classically early morning wakening), appetite/weight change, psychomotor changes, loss of libido. Cognitive symptoms: poor concentration, worthlessness/guilt, hopelessness, suicidal ideation.
Melancholic features: loss of reactivity, early morning wakening, morning worsening, psychomotor changes, ↑ response to TCA, ↑ neurobiological basis.
In HK/Chinese populations: prominent somatic presentations. In youth: irritability > sadness, somatic complaints, behavioural problems.
High Yield — Pancreatic Cancer
Pancreatic cancer can present with depression as the earliest symptom, preceding any abdominal symptoms by months. In exam scenarios: a middle-aged or older patient with new-onset depression + weight loss + vague abdominal discomfort → think pancreatic cancer and investigate (CT abdomen, CA 19-9).
High Yield Summary
DSM-5 MDD Criteria: ≥ 5/9 symptoms for ≥ 2 weeks, including at least depressed mood OR anhedonia. Must cause functional impairment. Must exclude substance/medical causes, psychotic disorders, and bipolarity.
ICD-10 Severity: Mild (2A+2B), Moderate (2A+3B), Severe (3A+4B). Section A = depressed mood, anhedonia, anergia. ICD uniquely recognises anergia as core symptom.
Key DSM-5 Changes: Bereavement exclusion removed. Dysthymia renamed persistent depressive disorder. New disorders: disruptive mood dysregulation disorder, premenstrual dysphoric disorder.
Specifiers to Know: Melancholic (≥ 4 biological features, must include loss of pleasure or loss of reactivity), atypical (mood reactivity, hypersomnia, weight gain, leaden paralysis), psychotic (mood-congruent vs incongruent), peripartum, seasonal.
Rating Scales: PHQ-9, HAM-D, MADRS, BDI, CES-D — useful for severity tracking but NOT diagnostic. Special populations: GDS, Cornell Scale, Edinburgh Postnatal.
Investigations: Minimum = CBP + R/LFT + TFT. Directed = urine tox, HIV, ACTH stim test, B12/folate, CT/MRI, EEG, ECG as indicated. TFT is the single most important screening investigation.
Algorithm: History → MSE → Risk assessment → Rating scales → Physical exam → Basic bloods → Rule out secondary causes → Apply criteria → Specifiers → Formulate.
High Yield Summary
Treatment by severity: Mild → watchful waiting + psychosocial. Moderate-severe → antidepressant + psychotherapy. Refractory → augmentation/combination/ECT.
First-line antidepressant: SSRI (escitalopram, sertraline best balance of efficacy + tolerability per Cipriani 2018). Mirtazapine if sedation/appetite stimulation needed.
Key drug classes: SSRIs (SERT blockade), SNRIs (SERT+NET), TCAs (non-selective, lethal in OD), NDRIs (bupropion — no sexual dysfunction), MAOIs (tyramine crisis), mirtazapine (NaSSA — sedating, appetite-stimulating), agomelatine (melatonergic — monitor LFTs).
Continuation phase: ≥ 6–9 months at remission dose for first episode. Maintenance: ≥ 2 years if ≥ 2 episodes with significant impairment.
Refractory depression: Reassess dx/compliance/stressors → switch class → combine (SSRI + mirtazapine/bupropion) → augment (lithium, quetiapine, aripiprazole, T3) → ECT.
ECT indications: Emergency (suicidal, food refusal), Catatonia, Treatment-refractory. No absolute contraindications. Bilateral more effective but more cognitive side effects.
Bipolar depression: NOT the same as unipolar. First-line: quetiapine, lithium, or lamotrigine. Avoid antidepressant monotherapy (manic switch risk). Lithium is the only mood stabiliser that reduces suicide.
Prognosis: 80% recurrence; average 4 episodes in 25 years; > 20× suicide risk. Poor prognosticants: incomplete remission, early onset, poor social support, comorbid SA/personality disorder.
High Yield Summary
Suicide: Most feared complication. 20× increased risk; 6% lifetime suicide mortality in affective disorders. In HK, MDD accounted for 27% of population-attributable suicide risk in adults and was the commonest psychiatric diagnosis among elderly suicide decedents. Hopelessness is the strongest predictor. Always assess: ideation → plan → intent → means → protective factors.
Non-suicide mortality: RR 1.2–4.0×, primarily through CVD (altered thrombogenesis, HPA axis dysregulation, inflammation, behavioural risk factors). Depression is an independent risk factor for MI and stroke.
Psychiatric comorbidity: 70% comorbid anxiety; frequent substance abuse (self-medication); 25% of youth depression converts to bipolar.
Cognitive impairment and neuroprogression: Each episode causes cumulative hippocampal atrophy and neuroplastic damage. Depression approximately doubles dementia risk. Residual cognitive deficits persist between episodes in ~50% of patients.
Functional impairment: 4th leading cause of disability worldwide. Only 25% of recurrent MDD patients achieve 5-year functional stability. Massive economic burden (~$85B/year).
Chronic relapsing course: 80% recurrence; average 4 episodes in 25 years; progressive interval shortening (kindling); 10–20% chronic unremitting. Poor prognosticants: incomplete remission, early onset, poor social support, poor physical health, comorbid SA, comorbid personality disorder.
Treatment complications: Early SSRI-induced suicidality (energy before mood); serotonin syndrome; TCA overdose lethality; SIADH; discontinuation syndrome; metabolic effects from augmentation agents.
Bipolar Disorder
Bipolar disorder is a chronic psychiatric illness characterized by recurrent episodes of mania or hypomania alternating with depressive episodes, resulting in significant disturbances in mood, energy, and functioning.
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.