Approach To Mood Disturbances
A systematic clinical evaluation of persistent alterations in emotional state—including depression, mania, and mixed episodes—through comprehensive history, mental status examination, and differential diagnosis to identify underlying psychiatric, medical, or substance-related etiologies.
1. Definition and Core Concepts
Mood (Latin: modus = manner, way) refers to a pervasive and sustained emotional state that colours a person's perception of the world. Think of it as the "background music" of your mental life — it sets the tone for everything else.
Mood disorders are abnormal mood states with other associated features resulting in distress and functional impairment. [1]
A few critical distinctions right at the start:
| Term | Definition | Analogy |
|---|---|---|
| Mood | Sustained, pervasive internal emotional state (subjective) | The climate |
| Affect | Observable, moment-to-moment emotional expression | The weather |
| Emotion | Discrete, short-lived feeling in response to a stimulus | A single rain shower |
Normal fluctuation vs. Abnormal state — an abnormal state refers to a pervasively high or low mood that differs from the usual mood. [1]
Mood fluctuations in response to disappointment, frustration, and losses in everyday life are usually short-lived. Natural despondency can have important survival function, resulting in reorientation and maturation. [2]
So sadness after a breakup, grief after a bereavement — these are adaptive. Depression as a disorder is different because:
- Severity of symptoms is marked — e.g., DSM-5 requires "marked" diminished interest or pleasure, "significant" weight loss or gain [2]
- It impairs adaptations and is often disabling [2]
- When enduring, depression can result in impaired function at work, at school, and in the family [2]
Key Conceptual Point
The line between normal sadness and major depressive disorder is drawn by severity, duration, pervasiveness, and functional impairment — not simply by the presence of low mood. Every human experiences sadness; not every human has MDD.
2. Epidemiology
WHO estimates 5% of adults suffer from depressive disorder worldwide, approximately 280 million people. [2]
The International Consortium of Psychiatric Epidemiology (89,037 adults from 18 countries) using the Composite International Diagnostic Interview found: [2]
- Average lifetime prevalence: 14.6% (high-income countries) and 11.1% (low- to middle-income countries)
- Average 12-month prevalence: 5.5% (high-income) and 5.9% (low- to middle-income)
- Female-to-male ratio ≈ 2:1 [2]
Why is depression more common in women? Several hypotheses [3]:
- Women may be more willing to admit depressive symptoms
- Depression in men may be misdiagnosed as alcohol-related disorder (men have higher rates of comorbid alcohol abuse)
- Social disadvantages experienced by women
- Female hormones (particularly oestrogen fluctuations) may sensitise the brain to the effects of stress — this explains perimenstrual, postpartum, and perimenopausal vulnerability windows
Hong Kong context:
- Lifetime prevalence of MDD in Hong Kong has been estimated at approximately 8-10% in community surveys
- Elderly depression is a particular concern given Hong Kong's ageing population
- Significant treatment gap exists — many patients present with somatic complaints rather than mood symptoms (especially in Chinese culture where psychological distress is often "somatised")
- Lifetime risk ~4%, higher in women and divorced individuals [3]
- Usual onset in early adulthood; may last throughout life → sometimes called a "depressive personality"
- Very commonly seen in primary care (6.9% prevalence) [3]
- Commonly present with prominent somatic symptoms to healthcare providers
- Lifetime prevalence: approximately 1-2% for Bipolar I; up to 4-5% for full bipolar spectrum
- No gender and ethnic difference [1]
- Risk factors include: high-income countries (may be due to referral bias), low income, separated/divorced/widowed status [1]
- Family history of bipolar disorder and schizophrenia: monozygotic concordance 40-70%, lifetime risk in first-degree relatives 5-10% (roughly 7 times higher than general population risk) [1]
Exam Pearl
Depression has a 2:1 female-to-male ratio. Bipolar disorder has NO gender difference. This is a classic MCQ discriminator.
3. Anatomy and Function: The Neural Circuitry of Mood
Understanding mood disorders requires knowing the brain circuits involved. Think of mood regulation as a network of interconnected regions forming a "mood circuit":
| Region | Normal Function | What Goes Wrong in Depression |
|---|---|---|
| Prefrontal Cortex (PFC) | Executive function, decision-making, emotional regulation | Hypofunction (dorsolateral PFC) → psychomotor retardation, apathy, concentration deficits |
| Ventromedial PFC / Subgenual cingulate (Brodmann Area 25) | Emotional and social regulation | ↑Activity → ↑sensitivity to pain, anxiety, depressive ruminations, tension [3] |
| Dorsolateral PFC | Working memory, executive functions | ↓Activity → psychomotor retardation, apathy, deficits in attention/working memory [3] |
| Amygdala | Threat detection, emotional salience | Hyperactivity → negativity bias, excessive fear/anxiety |
| Hippocampus | Memory consolidation, stress regulation (HPA axis feedback) | Volume reduction → both predisposing factor and consequence of depression [3][4] |
| Anterior Cingulate Cortex (ACC) | Error monitoring, emotional regulation | Abnormal connectivity with amygdala → impaired inhibitory action in emotional regulation [3] |
| Subgenual Cortex | Regulation of autonomic and neuroendocrine responses | Volume reduction and decreased quantity of glial cells [4] |
| Nucleus Accumbens / Ventral Striatum | Reward processing, motivation | Reduced dopaminergic tone → anhedonia |
Monoamines including serotonin, norepinephrine, and dopamine are relevant to mood regulation, and play an essential role in the regulation of other bodily functions. [4]
| Neurotransmitter | Normal Role | Deficiency Consequence |
|---|---|---|
| Serotonin (5-HT) | Affects body temperature, regulates sleep and wakefulness, mood, and impulse control [4] | Low mood, impulsivity, sleep disturbance, suicidality |
| Norepinephrine (NE) | Regulates mood and anxiety levels [4] | Fatigue, psychomotor retardation, poor concentration |
| Dopamine (DA) | Regulates motor and mental activity, attention, and motivation; mesolimbic reward pathway plays important role in motivation, reinforcement, and the pleasure response [4] | Anhedonia, amotivation, psychomotor slowing |
Low levels of serotonin metabolites have been found in the brains of suicide decedents and spinal fluids of depressed patients. [4]
Dopaminergic neurons in the mesolimbic reward pathway are diminished in the brains of suicidal decedents with depression. [4]
Mood symptoms emerged among patients who took propranolol (a beta-blocker that blocks noradrenergic signalling). [4]
Besides monoamines, abnormalities in glutamate, GABA, and substance P have been detected in patients with depression. [4]
Hormonal changes in depression include: dysregulation of hypothalamic-pituitary-adrenal (HPA) axis, lower estradiol (in women) and testosterone (in men), decreased triiodothyronine and thyroid-stimulating hormone, and diminished BDNF (brain-derived neurotrophic factor) level. [4]
Why does HPA axis dysregulation matter?
- Chronic stress → sustained cortisol elevation → direct toxic effect on hippocampal neurons (which are rich in glucocorticoid receptors) → hippocampal atrophy → further loss of HPA negative feedback → more cortisol → vicious cycle
- This explains why early life stress can structurally predispose to depression decades later
4. Aetiology and Pathophysiology
Mood disorders arise from a biopsychosocial model — depressive disorder is caused by a combination of biological, social, and psychological factors, which disturb the brain's capacity for stress management. [4]
4A. Biological Factors
For MDD:
- 37% heritability from twin studies (MZ concordance ~50%) [3]
- This is lower than schizophrenia (~80%) and bipolar (~85%) — depression has a larger environmental component
- Probably multiple genes with small individual effects and complex gene-environment interactions
- Candidate gene: serotonin transporter gene (5-HTTLPR) — the short allele variant reduces serotonin reuptake efficiency [3]
- A threefold increase in risk of depression among first-degree relatives compared to the general population [4]
For Bipolar Disorder:
- 79% heritability [1]
- First-degree relatives are at higher risk for bipolar, MDD, and other psychiatric disorders [1]
- Shared genetic risk between bipolar, schizophrenia, and autism [1]
- Some overlap with genes involved in circadian rhythm regulation [1]
- Genes identified include those involving neuronal development, neurotransmitter metabolism, and calcium channels [3]
Genetics Comparison
Heritability ladder: Bipolar (~85%) > Schizophrenia (~80%) > MDD (~37%). This means environmental factors play a proportionally LARGER role in MDD than in bipolar disorder. If a patient has a strong family history, think bipolar before unipolar.
The classical "serotonin hypothesis" proposes that diminished activity of serotonin pathways plays a causal role in depression. [4]
Historical evidence:
- The antihypertensive drug reserpine, which depleted monoamines, produced a depressive state [4]
- Diminished monoaminergic activity was detected in the brains of decedents of suicide and bodily fluids of people with depression [4]
However: Evidence suggests that the cause of depression is far more complicated than a reduced level of serotonin. [4] The monoamine hypothesis is now viewed as an oversimplification — it explains why antidepressants work but not the full pathophysiology.
Why can't monoamines explain everything?
- SSRIs increase serotonin within hours, but clinical response takes 2-4 weeks → downstream neuroplastic changes (not just monoamine levels) must be important
- Not all drugs that increase monoamines are antidepressants (e.g., cocaine)
- The neurotrophin hypothesis (BDNF) and neuroinflammation hypothesis are gaining traction
Volume reduction and decreased quantity of glial cells in subgenual cortex, reduced hippocampal size are observed in depression. [4]
The hippocampal volume loss is both:
- A predisposing factor (smaller hippocampi → worse stress regulation) AND
- A consequence of chronic depression (cortisol-mediated neurotoxicity)
Biochemical pathways implicated include dopaminergic, second messengers, mitochondrial, HPA axis, and thyroid pathways. [1]
- Mania is hypothesized to relate to dopamine hyperactivity but direct evidence is limited [3]
- The "kindling" model suggests that early episodes are triggered by life events, but later episodes become autonomous — the brain becomes increasingly sensitised
Infective causes, e.g., Toxoplasma gondii (the associated immune response) have been linked to bipolar disorder. [1]
4B. Psychosocial Factors
Early environment risk factors include: parental separation, physical and sexual abuse, non-caring or overprotective parenting styles. [4]
For MDD specifically [3]:
- Parental deprivation (e.g., separation, loss)
- Parenting styles (e.g., non-caring, over-protective)
- Childhood adversities (e.g., neglect, physical and sexual abuse)
- Chronic stressors: poor social support, not having employment outside the home, raising young children
For Bipolar [1]:
- Low care and overprotective parents, poor attachment relationship, childhood abuse [1]
Stress and trauma, particularly long-term difficulties and recent life events — especially events that lead to feelings of entrapment and humiliation — are major precipitants. [4]
- 6× increased risk of adverse life events before onset of MDD [3]
- Especially common in losses (bereavement, breakup), entrapment, and humiliation (bullying) [3]
- Less important in established melancholic depression and strong family history (suggesting a lower threshold for disease expression in these groups) [3]
- Medical illnesses can act as non-specific stressors or cause depression via physiological mechanisms (e.g., Cushing's disease, puerperium) [3]
For Bipolar:
Cognitive distortions are prominent in depression and form the basis of Cognitive Behavioural Therapy (CBT). Key distortions include: [4]
| Cognitive Distortion | Chinese | Meaning | Example |
|---|---|---|---|
| Selective abstraction | 斷章取義 | Focusing on a detail and ignoring more important features of a situation | "My boss praised 9 things but criticised 1 — I'm terrible" |
| Overgeneralisation | 以偏概全 | Drawing a general conclusion on the basis of a single incident | "I failed this exam, so I'll fail everything" |
| Personalisation | 過度自責 | Relating external events to oneself in an unwarranted way | "It rained on the picnic — it's my fault" |
| Arbitrary inference | 妄下判斷 | Drawing a conclusion when there is no evidence for it and even some evidence against it | "She didn't text back — she must hate me" |
Psychoanalytical theory: loss of an 'object', insecure attachments also contribute to understanding depressive vulnerability. [4]
Aaron Beck's "cognitive triad" of depression describes negative views of:
- Self ("I am worthless")
- World ("Everything is terrible")
- Future ("Nothing will ever get better")
5. Classification of Mood Disorders
The current DSM-5-TR and ICD-11 classification uses a combination of aetiology, symptom pattern, and course [3]:
The old classification by presumed aetiology is now considered obsolete [3]:
- Endogenous (independent of external stress) vs. Reactive (response to external stress) — this distinction is no longer used because most depressive episodes have both endogenous and reactive elements
Current classification uses [3]:
| Dimension | Categories |
|---|---|
| Symptomatic picture | Melancholic (more biological symptoms), Psychotic (with psychotic features), Non-melancholic/Atypical |
| Course | Unipolar vs. Bipolar; Single episode vs. Recurrent; Seasonal pattern; Recurrent brief |
| Severity | Mild, Moderate, Severe (with or without psychotic features) |
Key Diagnostic Entities
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. [4]
Additional symptoms: difficulty concentrating, feelings of worthlessness or excessive/inappropriate guilt, hopelessness, recurrent thoughts of death or suicide, changes in appetite or sleep, psychomotor agitation or retardation, and reduced energy or fatigue. [4]
- Onset in autumn/winter, recovery in spring/summer [3]
- Postulated to be related to daylight duration → rationale for bright light therapy
| Feature | Bipolar I | Bipolar II |
|---|---|---|
| Mania | Present (≥ 1 manic episode) | Absent |
| Hypomania | May occur | Present (≥ 1 hypomanic episode) |
| Depression | Common but not required for Dx | Required (≥ 1 major depressive episode) |
| Psychosis | May occur during mania | Does NOT occur during hypomania |
| Hospitalisation | Often required during mania | Typically not needed for hypomania |
Common Exam Mistake
Bipolar II is NOT a "milder form" of Bipolar I. The depressive burden in Bipolar II is often MORE severe and more chronic than in Bipolar I. The distinction is about the ceiling of the elevated mood (mania vs. hypomania), not about overall illness severity.
This is a critical clinical issue [3]:
| Direction | Problem |
|---|---|
| Underdiagnosis | Overlooking hypomanic episodes → misdiagnosis as MDD; Mania with psychosis → misdiagnosed as schizophrenia |
| Overdiagnosis | Confusing mania with simple irritability — structured interviews confirm only 43% of patients with a previous diagnosis of bipolar disorder |
Consequences of misdiagnosis:
- Undertreated: increased suicidality, comorbid anxiety, substance abuse → ↓QoL, ↓functioning, ↑healthcare costs
- Overtreated: unnecessary side effects of mood stabilisers, increased sick role and disability claims
- Mistreated: antidepressants without mood stabiliser cover → less effective and risks manic switch and cycle acceleration [3]
Correct diagnosis requires history from the patient AND collateral history from informants, and structured screening tools (e.g., Mood Disorder Questionnaire [MDQ], Hypomania Checklist [HCL-32]). [3]
Correct diagnosis and treatment of bipolar disorder is often delayed by 5-7 years on average. [3]
6. Clinical Features
6A. Depressive Episode — Symptoms and Signs
1. Depressed Mood
- Differs from ordinary sadness: miserable, dejected, "down in the dumps"
- Pervasive: covers most of the day
- Loss of reactivity: loss of normal ups and downs in response to circumstances (cf. normal sadness where a funny joke might still elicit a laugh)
- Morning dysphoria: characteristically worse in the morning — this is one of the "biological" (melancholic) symptoms. Why? Because cortisol peaks in the early morning (the cortisol awakening response is exaggerated in depression), and serotonergic tone is lowest upon waking
2. Anhedonia (Greek: an- = without, hedone = pleasure)
- Loss of ability to derive pleasure from activities that were formerly enjoyed
- Associated with social withdrawal [3]
- Pathophysiology: reduced dopaminergic signalling in the mesolimbic reward pathway (nucleus accumbens) → inability to experience reward
3. Anergia (Greek: an- = without, ergon = work/energy)
- Lack of energy or increased fatigability on minimal exertion → decreased activity [3]
- Reflects noradrenergic and dopaminergic hypofunction in prefrontal circuits
4. Sleep Disturbances
- Most classically early morning wakening (waking 2-3 hours earlier than usual and unable to return to sleep) — a hallmark of melancholic depression [3]
- Also: initial insomnia (difficulty falling asleep — more suggestive of comorbid anxiety), middle insomnia (frequent awakenings)
- In atypical depression: hypersomnia (excessive sleep)
- Pathophysiology: disruption of circadian rhythm regulation via serotonergic (raphe nuclei) and noradrenergic (locus coeruleus) systems, which regulate the sleep-wake cycle as part of the reticular activating system (RAS)
5. Appetite and Weight Changes
- Typically decreased appetite and weight loss in melancholic depression
- Increased appetite and weight gain (especially carbohydrate craving) in atypical depression
- Pathophysiology: serotonin modulates hypothalamic appetite centres; 5-HT deficiency can dysregulate appetite in either direction depending on the subtype
6. Psychomotor Changes
- Psychomotor retardation: slowed thinking, speech, and movement; reduced spontaneous gestures; long pauses before answering; monotonous speech
- Psychomotor agitation: inability to sit still, hand-wringing, pacing, pulling at clothes/skin
- Pathophysiology: dorsolateral PFC and basal ganglia hypofunction (retardation) or amygdala/ACC hyperactivation (agitation)
7. Diurnal Variation
- Typically worse in the morning, improves as the day progresses
- This is considered a biological/melancholic feature
8. Loss of Libido
- Decreased sexual desire and function
- Related to serotonergic and dopaminergic changes as well as reduced testosterone/oestrogen levels
9. Poor Concentration and Indecisiveness
- Difficulty thinking, concentrating, or making decisions
- Pathophysiology: dorsolateral PFC hypofunction → executive dysfunction
10. Negative Cognitions
- Feelings of worthlessness or excessive guilt (can be delusional in severe cases)
- Hopelessness about the future
- These reflect the cognitive triad (negative view of self, world, and future)
11. Suicidal Ideation
- Recurrent thoughts of death, suicidal ideation, plans, or attempts
- Always assess in every patient with depression — the risk is highest in the early weeks of treatment (when energy returns before mood improves, giving the patient the "energy to act" on suicidal thoughts)
- Mood-congruent delusions: delusions of guilt, poverty, nihilism (Cotard's syndrome — belief that one is dead or doesn't exist), persecution (belief they deserve punishment), hypochondriacal delusions
- Mood-congruent hallucinations: auditory hallucinations of derogatory or critical voices, voices telling the patient they are worthless or should die
- These are congruent with the depressive theme — they "make sense" in the context of extreme low mood
- Many patients, especially in Chinese culture, present with prominent somatic symptoms rather than overtly reporting mood disturbance [3]
- Common somatic complaints: headache, back pain, chest tightness, gastrointestinal upset, dizziness, fatigue
- This phenomenon is sometimes called "somatisation" but is better understood as an alternative idiom of distress
The manic episode is essentially the "mirror image" of depression in many domains, though not a simple inversion:
1. Elevated, Expansive, or Irritable Mood
- The mood can be euphoric ("I feel on top of the world!") or irritable (especially when frustrated or thwarted)
- Pervasive — present most of the day, nearly every day
- Pathophysiology: dopaminergic hyperactivity in the mesolimbic pathway → excessive reward signalling
2. Increased Energy / Goal-Directed Activity
- Markedly increased energy levels, often with increased goal-directed activity (starting new projects, excessive planning)
- Or purposeless, non-goal-directed activity (psychomotor agitation)
3. Decreased Need for Sleep
- Characteristic: the patient feels rested after only 2-3 hours of sleep (contrast with insomnia in depression, where the patient wants to sleep but cannot, and feels unrested)
- Pathophysiology: overactivation of the reticular activating system and circadian disruption
4. Pressured Speech / Talkativeness
- Rapid, loud, difficult to interrupt
- Reflects racing thoughts being translated into speech
5. Flight of Ideas / Racing Thoughts
- Subjective experience of thoughts moving too fast; speech may jump from topic to topic with loose but identifiable associations
- Differs from "loosening of associations" in schizophrenia (where the connections are not identifiable)
6. Distractibility
- Attention easily drawn to unimportant or irrelevant external stimuli
7. Grandiosity / Inflated Self-Esteem
- Ranges from uncritical self-confidence to delusional grandiosity ("I am chosen by God," "I have special powers")
- Pathophysiology: excessive dopamine in reward circuits → overvaluation of self and abilities
8. Increased Risk-Taking / Pleasurable Activities with Potential for Painful Consequences
- Excessive spending sprees, sexual indiscretions, foolish business investments, reckless driving
- Reflects impaired judgment combined with increased reward-seeking behaviour
9. Psychotic Features (in Severe Mania)
- Mood-congruent delusions: grandiose delusions (believing one is a celebrity, deity, or has special powers), persecutory delusions (believing others are jealous/trying to stop them)
- Mood-congruent hallucinations: voices affirming special status
Mania with Psychosis vs. Schizophrenia
Mania with psychotic features can be misdiagnosed as schizophrenia. The key differentiator: in mania, the psychosis is mood-congruent and occurs in the context of elevated mood/energy. In schizophrenia, psychotic symptoms persist independent of mood state and are often mood-incongruent. Always check for a mood episode first before diagnosing a primary psychotic disorder.
Hypomania is a less severe form of mania:
- Same symptom profile as mania BUT:
- Shorter duration (≥ 4 days vs. ≥ 7 days for mania)
- No psychotic features
- No marked functional impairment or hospitalisation required
- May be associated with increased functioning (the patient is more productive, sociable, creative)
- The challenge: patients often do NOT recognise hypomania as pathological — it feels good! Collateral history is essential.
- Episodes with both depressive and manic/hypomanic features simultaneously (e.g., grandiose thoughts but deeply dysphoric mood, or high energy but suicidal ideation)
- These carry a particularly high suicide risk because the patient has both the despair of depression and the energy/impulsivity of mania
- DSM-5 uses "with mixed features" specifier
Since bipolar depression accounts for the majority of illness duration in bipolar disorder, distinguishing it from unipolar depression is crucial. Clinical clues suggesting bipolar depression include:
| Feature | Unipolar Depression | Bipolar Depression |
|---|---|---|
| Age of onset | Older (often > 25) | Younger (often < 25) |
| Number of episodes | Fewer | More frequent/recurrent |
| Onset | Gradual | Can be abrupt |
| Duration of episodes | Longer | Shorter |
| Atypical features | Less common | More common (hypersomnia, hyperphagia, leaden paralysis) |
| Psychomotor retardation | Variable | Prominent |
| Psychotic features | Less common | More common |
| Family history | MDD | Bipolar disorder, schizophrenia |
| Response to antidepressants | Good | Poor, or manic switch |
| Postpartum onset | Less common | More common |
~25% of bipolar disorder first presents as a juvenile depressive episode in their first episode [3]
7. Assessment
Assessment includes: history (including medical and medication history), mental state examination, use of standardised instruments, physical examination, and investigation to rule out medical conditions that may cause depressive symptoms. [4]
Basic investigations: CBP, renal/liver function tests, thyroid function test. [4]
Others to consider if indicated by history and physical examination: blood alcohol level, blood and urine toxicology screen, HIV test, cosyntropin (ACTH) stimulation test (for Addison disease), EEG (for epilepsy), or CT/MRI (for organic brain syndrome or hypopituitarism). [4]
The provided notes reference a structured suicide risk assessment tool with scoring components [3]:
- Section B: Suicidal behaviour (suicidal ideation, plan, means, attempt, final acts/notes)
- Section C: Associated symptoms:
- Depression (sleep disorder, anorexia/weight loss, withdrawal/loss of interest, hopelessness/helplessness, psychomotor retardation, depressed mood)
- Hallucinations (derogatory, criticising, about death)
- Delusions (guilt, death, persecutory)
- Unstable mood (anxiety, panic, fear)
- Supervision levels: Normal (0-9), SO1 (10-18), SO2 (19-28), SO3 (29-41)
8. Special Populations
- Much less common in childhood ( < 1%, M:F ≈ 1:1) but increases drastically after puberty (1-year prevalence 4%, F > M ≈ 2:1)
- Aetiology: 5-HTTLPR variant associated with early-onset depression; cortisol-induced hippocampal atrophy; negative cognitive style, perfectionism; adverse life events
- Clinical features differ from adults:
- Adolescence: similar to adults
- Childhood: difficulty expressing sadness; more somatic complaints (abdominal pain, headache, anorexia, enuresis), irritable mood and anxiety, behavioural problems
- Common comorbidities: 70% have anxiety disorder, conduct disorder, substance abuse, dysthymia
- Prognosis: episodic relapsing course; majority recover within 3 months but 15% last > 18 months
- ~25% of bipolar disorder first presents as juvenile depression
- Often under-recognised and undertreated
- May present with prominent cognitive symptoms (pseudodementia) — must differentiate from true dementia
- Higher rates of somatic presentation
- Associated with medical comorbidities, functional decline, bereavement, social isolation, and polypharmacy
- Higher suicide completion rates compared to younger adults (elderly men have the highest completed suicide rate of any demographic)
High Yield Summary
Definitions
- Mood disorders = abnormal mood states with associated features causing distress and functional impairment
- Normal sadness is adaptive and short-lived; MDD is defined by severity, duration, and functional impairment
Epidemiology
- MDD: lifetime prevalence ~11-15%; F:M = 2:1; 5% of adults worldwide affected
- Bipolar: ~1-2% prevalence; NO gender difference; heritability ~79-85%
- Dysthymia: lifetime risk ~4%
Pathophysiology
- Monoamine hypothesis (serotonin, norepinephrine, dopamine deficiency) — necessary but insufficient explanation
- Structural changes: reduced hippocampal volume, subgenual cortex glial cell loss
- HPA axis dysregulation → cortisol-mediated hippocampal neurotoxicity
- Cognitive distortions: selective abstraction, overgeneralisation, personalisation, arbitrary inference
Classification
- Depression: MDD, dysthymia, minor anxiety-depressive, seasonal, recurrent brief
- Bipolar: I (mania), II (hypomania + depression), cyclothymia
- Bipolar misdiagnosis is extremely common (5-7 year diagnostic delay on average)
Core Clinical Features
- Depression triad: depressed mood, anhedonia, anergia
- Melancholic features: early morning wakening, morning dysphoria, weight loss, psychomotor retardation
- Mania triad: elevated/irritable mood, increased energy, decreased need for sleep
- Always assess for suicide risk, psychotic features, and mixed features
Key Discriminators
- Depression F:M = 2:1; Bipolar no gender difference
- Bipolar heritability (~85%) > MDD heritability (~37%)
- Early onset depression → consider bipolar
- Antidepressant-induced mania = red flag for bipolar
Active Recall - Approach to Mood Disturbances
[1] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (pp. 2, 19, 28) [2] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p. 2) [3] Senior notes: ryanho-psych.md (sections 7.1, 7.2 and Bipolar Disorder aetiology) [4] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pp. 10, 11, 12, 13)
Differential Diagnosis of Mood Disturbances
The differential diagnosis of mood disturbances is best approached by considering two separate but overlapping clinical presentations: low mood and elated/irritable mood. In practice, you encounter a patient and must work through a systematic list — "Is this a primary mood disorder, another psychiatric condition mimicking a mood disorder, a secondary (medical/substance) cause, or a normal reaction?" This section walks through that logic from first principles.
Before diving into the lists, understand why we think in a hierarchy. Psychiatry has traditionally prioritised organic (medical) causes first, because they are the most dangerous to miss and the most treatable with specific interventions. Then we consider substance-induced causes (remove the substance, the "mood disorder" resolves). Only after excluding these do we land on primary psychiatric diagnoses.
A. Differential Diagnosis of Low Mood
This is the approach when a patient presents with depressed mood, anhedonia, or anergia as the chief complaint [3].
| Diagnosis | Salient Differentiating Features |
|---|---|
| Major Depressive Disorder (MDD) | Current depressive episode (meeting full criteria) lasting ≥ 2 weeks. Graded as mild, moderate, severe, or severe with psychotic features. If ≥ 1 previous episodes → recurrent depressive disorder [3] |
| Bipolar Affective Disorder (depressive phase) | Current depressive episode + ≥ 1 previous manic or hypomanic episode. Key: always ask about past elation/irritability! Clues to bipolar depression: younger onset, atypical features (hypersomnia, hyperphagia, leaden paralysis), psychotic features, family history of bipolar, poor antidepressant response [3][5] |
| Dysthymia (Persistent Depressive Disorder) | Current symptoms NOT meeting full depressive episode criteria, lasting ≥ 2 years. Insidious onset in early adulthood, persistent low mood without distinct episodes. May have superimposed depressive episodes ("double depression") — importantly, this does NOT rule out a concurrent MDD diagnosis [3] |
| Cyclothymia | Numerous minor depressive and mild elative mood episodes (neither meeting hypomanic nor depressive episode criteria), lasting ≥ 2 years. Think of it as a "low-grade" bipolar spectrum [3] |
Why Ask About Past Hypomania in Every Depressed Patient?
Approximately 10-20% of patients initially diagnosed with MDD are later reclassified as bipolar disorder. Hypomanic episodes are often missed because patients experience them as feeling "normal" or even "good" — they don't complain about feeling great! Always take collateral history and use screening tools like the Mood Disorder Questionnaire (MDQ) or Hypomania Checklist (HCL-32). Misdiagnosis leads to antidepressant monotherapy, which can trigger manic switch and accelerate cycling [3].
| Diagnosis | Why It Mimics Depression | How to Differentiate |
|---|---|---|
| Adjustment disorder with depressed mood [6] | Develops in response to an identifiable stressor; emotional or behavioural symptoms including low mood, tearfulness, hopelessness | Develops ≤ 3 months of the stressor; does not meet full criteria for MDD; symptoms are disproportionate to the stressor but resolve once the stressor (or its consequences) has terminated. The mood disturbance is clearly "disorder vs. normal reaction" but insufficient for a specific mood/anxiety disorder diagnosis [5] |
| Anxiety disorder [6] | Anxiety and depression frequently co-exist; patients with GAD can appear low in mood, fatigued, with poor concentration | In GAD, the core feature is excessive worry about future events; in depression, the patient ruminates on past failures and worthlessness. Look for: early morning wakening, diurnal variation, suicidal thoughts (uncommon in pure GAD). Note that GAD + depression can genuinely co-exist [5] |
| Schizophrenia / Schizoaffective disorder | Negative symptoms (avolition, flat affect, social withdrawal) can closely mimic depression | In schizophrenia, look for mood-incongruent psychotic symptoms persisting outside mood episodes; formal thought disorder (loosening of associations vs. psychomotor retardation); negative symptoms are typically more enduring and less episodic than depressive episodes [3] |
| Personality disorders (e.g., Borderline PD) | Chronic feelings of emptiness, mood instability, self-harm can mimic chronic depression | Mood shifts are rapid (hours to days, not weeks), often triggered by interpersonal events; identity disturbance, intense unstable relationships, fear of abandonment are present; pattern is enduring (not episodic) [5] |
| Dementia | Apathy, social withdrawal, cognitive decline can mimic depression. Conversely, depression in the elderly can present as "pseudodementia" | Depression: onset more well-defined with rapid decline, patients complain of poor memory (vs. dementia patients who lack insight and are brought by family), give less effort on cognitive testing; language and motor skills are slow but not structurally impaired. Always consider treating depression before concluding dementia [5] |
| Grief / Bereavement | Normal grief can include profound sadness, insomnia, poor appetite, weight loss | DSM-5 removed the "bereavement exclusion" — grief CAN co-exist with or trigger MDD. Normal grief: waves of sadness mixed with positive memories; self-esteem preserved; thoughts of death relate to "joining" the deceased. MDD: pervasive depressed mood; worthlessness, guilt not related to the deceased; suicidal ideation about own worthlessness [6] |
Key DSM-5 change: 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). Exercise of clinical judgment based on the individual's history and cultural norms. [6]
This is the category you must never miss. The mechanism is either:
- Direct physiological effect on the brain (e.g., hypothyroidism → reduced monoamine synthesis; Cushing's → cortisol-mediated hippocampal damage)
- Non-specific stressor (e.g., chronic pain, cancer diagnosis → psychological burden leads to depression)
Depression can be associated with medical conditions: [6]
| Category | Examples and Mechanisms |
|---|---|
| Neurological disorders | Epilepsy (interictal depression due to limbic dysfunction), Parkinson's disease (dopaminergic degeneration in mesolimbic pathway → anhedonia, amotivation), dementia (structural degeneration of mood-regulating circuits), multiple sclerosis (inflammatory demyelination disrupting prefrontal-limbic connections), Huntington disease (caudate atrophy → frontal-subcortical circuit disruption), cerebrovascular disease (especially left frontal strokes → disruption of monoaminergic pathways), migraine (shared serotonergic dysfunction) [6] |
| Endocrine disorders | Hypothyroidism (thyroid hormones potentiate monoamine activity; low T3/T4 → functional monoamine deficiency), hyperthyroidism (can paradoxically cause depression especially in elderly — "apathetic thyrotoxicosis"), Cushing's syndrome (chronic hypercortisolism → hippocampal atrophy → depression), Addison disease (cortisol deficiency → fatigue, low mood), prolactinomas (hyperprolactinaemia → dopamine suppression → anhedonia), hyperparathyroidism (hypercalcaemia → neurotoxicity → depression) [6] |
| Drug-related conditions | Antihypertensive medications esp. reserpine and methyldopa (reserpine depletes monoamines — this was the original observation supporting the monoamine hypothesis!), smoking-cessation aids, steroids, sex hormones and medications that affect sex hormones, H2 blockers, sedatives, muscle relaxants, appetite suppressants, chemotherapy agents [6] |
| Substance abuse | Alcohol / cocaine / amphetamines / cannabinoids / sedatives / hypnotics / narcotics abuse — both intoxication (especially depressants) and withdrawal (especially stimulants) can cause depressive syndromes [6] |
| Infectious disease | Mononucleosis (post-viral fatigue), HIV infection (direct CNS invasion + psychosocial burden), hepatitis C infection (neuroinflammation + interferon treatment), Lyme disease, syphilis (neurosyphilis affects frontal lobes) [6] |
| Neoplasias | Pancreatic cancer (classically associated with depression — possibly via paraneoplastic mechanisms or cytokine release even before cancer diagnosis), paraneoplastic syndromes [6] |
| Chronic diseases | Coronary artery disease, type II diabetes (shared inflammatory pathways, HPA axis dysregulation, reduced physical activity) [6] |
| Chronic pain and psychosomatic conditions | Chronic pain → sustained activation of stress response → HPA axis dysregulation → depression (and depression lowers pain threshold → vicious cycle) [6] |
| Sleep-related disorders | Obstructive sleep apnoea — chronic sleep fragmentation → daytime fatigue, cognitive impairment, low mood; hypoxia may directly affect mood-regulating centres [6] |
Must-Know Secondary Causes for Exams
In any patient presenting with depression, you MUST rule out: (1) Hypothyroidism — the single most important medical mimic (check TFT in everyone); (2) Substance use — especially alcohol; (3) Medication side effects — especially beta-blockers, steroids, reserpine; (4) Cushing's syndrome — especially if atypical features; (5) Organic brain disease — especially in new-onset depression in the elderly. The basic workup for every depressed patient includes: CBP, R/LFT, TFT. Add further investigations as indicated by history and examination.
Investigations to rule out secondary causes [3][4]:
| Investigation | What It Rules Out |
|---|---|
| CBP | Anaemia (fatigue mimics), ↑WCC (infection), ↑MCV (alcoholism/B12 deficiency) |
| Renal function tests | HypoNa (antidepressant side effect, SIADH), uraemia, Ca (hypercalcaemia → depression) |
| Liver function tests | GGT (alcoholic liver disease), hepatic encephalopathy |
| Thyroid function test | Hypothyroidism (secondary depression) — the single most important screening test |
| Vitamin B12 and folate | Nutritional deficiency (especially in elderly, alcoholism) |
| Urine drug screen | Substance-induced depression |
| Blood alcohol level | Alcohol-related depression |
| HIV test | HIV-associated depression |
| Cosyntropin (ACTH) stimulation test | Addison disease |
| ECG | Long QT (baseline before TCA or lithium) |
| EEG | Epilepsy |
| CT or MRI brain | Organic brain syndrome, hypopituitarism — especially in elderly, new-onset, or atypical presentations |
B. Differential Diagnosis of Elated or Irritable Mood
The differential diagnosis of a manic episode includes: [7]
| Diagnosis | Salient Differentiating Features |
|---|---|
| Mania / Hypomania | Episode of elated/irritable mood associated with ↑energy and activity with considerable interference with work and social activities. Further classified by: level of psychosocial impairment (considerable = hypomania; complete disruption = mania) and presence of psychotic symptoms (present = mania). Bipolar affective disorder if ≥ 1 previous mood episode [3] |
| Depressive disorder with irritability and anxious distress [7] | Recurrent depression with prominent irritability can be mistaken for bipolar. Key: hypomanic episodes can be missed or under-reported → should be actively elicited. Discerning features of bipolar depression: psychotic features, atypical features (hypersomnia, hyperphagia, leaden paralysis) [5] |
| Diagnosis | Why It Mimics Mania | How to Differentiate |
|---|---|---|
| Psychotic disorder or schizoaffective disorder [7] | Schizophrenia can present with excited, suspicious, or agitated mood (mimics mania with psychosis). Schizoaffective disorder has simultaneous mood and schizophrenic symptoms | Schizophrenia: psychotic symptoms NOT limited to periods of prominent mood disturbance; FTD more loosening of association, neologism, thought blocking (cf mania: circumstantiality, tangentiality, flight of ideas); delusions mood-incongruent, bizarre, with passivity/thought alienation; speech more hesitant/halting (mania: pressured, difficult to interrupt); less ↓need for sleep, less hyperactive; may have catatonia or negative symptoms. Schizoaffective: delusions/hallucinations less mood-congruent and may occur outside mood episodes [3][5] |
| Attention deficit and hyperactivity disorder (ADHD) [7] | Similarities: ↓attention, difficulty with task completion, ↑energy, disinhibited behaviour, talkativeness | ADHD should NOT have ↑self-esteem, grandiosity, flight of ideas, or ↓need for sleep. ADHD has a more chronic, trait-like course (present since childhood) rather than episodic onset. Symptoms are pervasive across settings in ADHD but mood-episode-limited in bipolar [5][3] |
| Personality disorder with prominent irritability [7] | Borderline PD is often associated with marked affective instability → mimics rapid-cycling bipolar. Impulsivity, temper outbursts, mood lability overlap with hypomania | BPD: no family history of bipolar; rapid shifts of mood over hours/days (not days-to-weeks as in bipolar episodes); no classic manic symptoms (↑energy, grandiosity, flight of ideas, ↓need for sleep); mood disturbances often triggered by interpersonal issues; more stable/enduring pattern vs. episodic [5][3] |
The bipolar spectrum: BP I has severe mood episodes; BP II has milder manic symptoms with a prominent depressive element and can have the same degree of long-term impairment as BP I; BP spectrum patients are bothered by frequent mood changes and can be mistaken as borderline personality disorder. [7]
| Category | Examples and Mechanisms |
|---|---|
| Organic brain lesion | Extreme social disinhibition with no gross mood disorder → think frontal lobe pathology. Consider especially in middle-aged or older patient with expansive behaviour but no past history of affective disorder. In younger patients, consider HIV infection and head injury [5] |
| Substance/medication-induced [7] | Intoxication: stimulants (amphetamines, cocaine, caffeine), corticosteroids, L-DOPA, antidepressants (especially in unrecognised bipolar → manic switch). Withdrawal: alcohol, sedatives. Should ↓ after admission/cessation; consider urine toxicology screen if appropriate [5] |
| Medical conditions [7] | Hyperthyroidism (thyroid hormones potentiate catecholamines → hyperarousal), Cushing's syndrome, systemic lupus erythematosus (CNS vasculitis), neurosyphilis, multiple sclerosis, temporal lobe epilepsy |
Schizophrenia vs. Mania — The Hardest DDx in Psychiatry
This is the single most difficult differential in acute psychiatry. Both can present with psychomotor agitation, grandiose delusions, and disordered speech. The key differentiators: (1) In mania, psychotic symptoms are mood-congruent and usually resolve with the mood episode; (2) In schizophrenia, psychosis persists independent of mood state; (3) In mania, the logical link in speech is preserved despite being rapid (flight of ideas); in schizophrenia, associations are truly loosened (loosening of associations); (4) Biological features differ — mania has genuinely decreased need for sleep (feeling rested after 2-3 hours), while schizophrenia rarely shows this pattern. When in doubt, longitudinal course is the ultimate discriminator.
Once you've identified a mood disorder, specifiers help characterise it further and guide treatment. Mood disorders are heterogeneous conditions. Specifiers are used to better understand the patient's characteristics and to select appropriate treatment: [7]
| Specifier | Key Feature | Clinical Relevance |
|---|---|---|
| With anxious distress | Prominent anxiety symptoms during mood episode | Higher suicide risk, poorer treatment response |
| With mixed features | Depressive symptoms during mania, or manic symptoms during depression | Particularly high suicide risk (despair + energy); may need mood stabiliser rather than antidepressant |
| With rapid cycling | > 4 episodes per year | Poorer prognosis, often treatment-resistant, lithium may be less effective |
| With melancholic features | Near-complete absence of the capacity for pleasure; early morning wakening, morning dysphoria, psychomotor changes, weight loss | More neurobiological basis, stronger family history, better response to TCAs/ECT than SSRIs [3] |
| With atypical features | Mood reactivity, weight gain, hypersomnia (also leaden paralysis, interpersonal rejection sensitivity) | Better response to MAOIs; think bipolar depression if atypical features are prominent |
| With psychotic features | Delusions and/or hallucinations | Must distinguish mood-congruent vs. mood-incongruent (mood-incongruent → worse prognosis, consider schizoaffective) |
| With peripartum onset | Onset during pregnancy or within 4 weeks postpartum | Severe anxiety and even panic attacks. Risk of infanticide — always assess safety of mother and baby [7] |
| With seasonal pattern | Depression begins in fall or winter and remits in spring | Consider bright light therapy; related to daylight duration [7] |
DSM-5 classification of mood disorders: [7]
| Bipolar and Related Disorders | Depressive Disorders |
|---|---|
| Bipolar I disorder | Major depressive disorder (single episode / recurrent) |
| Bipolar II disorder | Dysthymic disorder (persistent depressive disorder) |
| Cyclothymic disorder | Other depressive disorder |
| Other bipolar disorder |
Key DSM-5 changes from DSM-IV: [6]
- Dysthymia → Persistent depressive disorder (now includes both chronic MDD and previous dysthymic disorder)
- Introduction of disruptive mood dysregulation disorder: persistent irritability and frequent episodes of extreme, out-of-control behaviour in children up to age 18
- Introduction of premenstrual dysphoric disorder: mood symptoms during the final week before menses onset, improving within a few days of menses
High Yield DDx Summary
For Low Mood — Always consider:
- Secondary causes FIRST (hypothyroidism, medications, substance use, medical illness)
- Bipolar depression (ask about past hypomania — missed in 10-20% of cases)
- MDD vs. dysthymia vs. adjustment disorder (severity + duration + stressor)
- Pseudodementia vs. true dementia (especially in elderly)
- Anxiety disorder with secondary low mood
- Personality disorder (BPD — chronic emptiness, rapid mood shifts)
For Elated/Irritable Mood — Always consider:
- Secondary causes (substance intoxication, medications, medical — especially frontal lobe lesions, hyperthyroidism)
- Mania vs. hypomania (severity, psychotic features, functional impairment)
- Schizophrenia / schizoaffective disorder (most difficult DDx — check mood congruence of psychosis, longitudinal course)
- ADHD (trait-like, no grandiosity/↓need for sleep)
- Borderline PD (rapid mood shifts, interpersonal triggers, no classic manic features)
Red Flags for Bipolar in a "Depressed" Patient:
- Age of onset < 25
- Atypical depressive features (hypersomnia, hyperphagia)
- Psychotic features during depression
- Family history of bipolar disorder
- Multiple failed antidepressant trials or manic switch on antidepressants
- Postpartum onset
Active Recall - DDx of Mood Disturbances
References
[3] Senior notes: ryanho-psych.md (sections 7.1.1, 7.1.2, 7.2, Bipolar Disorder differential diagnosis) [4] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p. 13) [5] Senior notes: ryanho-psych.md (sections 6.1, 8.1.1, ADHD differential, dementia differential) [6] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pp. 9, 14, 15) [7] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (pp. 2, 3, 10, 17, 22)
Diagnostic Criteria
Understanding diagnostic criteria from first principles: psychiatric diagnoses are clinical diagnoses — there is no blood test or scan that "confirms" depression or mania. Instead, we rely on carefully defined symptom clusters, minimum durations, functional impairment thresholds, and exclusion criteria. The two major classification systems are the DSM-5-TR (American Psychiatric Association) and the ICD-11 (WHO). Both share a similar logic but differ in specific thresholds.
The general skeleton of any psychiatric diagnostic criterion is [3]:
- Core (discriminating) symptoms — present in the defined disorder but seldom in others
- Associated (characteristic) symptoms — frequent in the defined disorder but also seen in others
- Minimum duration of symptoms
- Distress or impairment in functioning
- Exclusion criteria — rule out secondary causes and other primary disorders
This is the bread-and-butter diagnosis. Learn it cold.
At least 2 weeks' duration. [6]
Clear-cut changes in affect, cognition, and neurovegetative functions. [6]
5 or more of the following symptoms are present; at least 1 of the symptoms is either (1) or (2): [6]
| # | Symptom | Pathophysiological Basis |
|---|---|---|
| (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). In children and adolescents, can be irritable mood [6] | Serotonergic and noradrenergic hypofunction in prefrontal-limbic circuits → sustained negative emotional bias |
| (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) [6] | Reduced dopaminergic signalling in the mesolimbic reward pathway (nucleus accumbens) → inability to experience reward (anhedonia) |
| (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. In children, consider failure to make expected weight gain [6] | Serotonin modulates hypothalamic appetite centres; 5-HT dysregulation alters feeding behaviour in either direction |
| (4) | Insomnia or hypersomnia nearly every day [6] | Disruption of sleep-wake regulation via serotonergic (raphe nuclei) and noradrenergic (locus coeruleus) systems in the reticular activating system |
| (5) | Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) [6] | Retardation: dorsolateral PFC and basal ganglia hypofunction; Agitation: amygdala/ACC hyperactivation |
| (6) | Fatigue or loss of energy nearly every day [6] | Noradrenergic and dopaminergic hypofunction → reduced drive and motivation |
| (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) [6] | Cognitive distortions (personalisation, overgeneralisation) amplified by ventromedial PFC hyperactivity |
| (8) | Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) [6] | Dorsolateral PFC hypofunction → executive dysfunction |
| (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 [6] | Serotonergic deficiency in prefrontal cortex → impaired impulse control; hopelessness from cognitive triad |
Additional DSM-5 criteria: [6]
- Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
- The episode is not attributable to the physiological effects of a substance or to another medical condition
- Not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders
- Absence of previous manic or a hypomanic episode (if present → bipolar disorder, not MDD)
The SIGECAPS Mnemonic for Depression
A widely used mnemonic for the 9 DSM-5 criteria:
S — Sleep disturbance (insomnia or hypersomnia) I — Interest loss (anhedonia) ← CORE G — Guilt (or worthlessness) E — Energy loss (fatigue) C — Concentration deficit A — Appetite change (± weight) P — Psychomotor agitation or retardation S — Suicidal ideation
Plus the anchor: Depressed mood ← CORE
You need ≥ 5 of these 9 symptoms, and at least one must be depressed mood OR anhedonia.
DSM-5 Specifiers for MDD
Specifiers for major depressive disorder: [6]
| Category | Options |
|---|---|
| Course | Single episode, recurrent episode |
| Severity | Mild, moderate, severe, with psychotic features, in partial remission, in full remission, unspecified |
| 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) |
Key changes from DSM-IV: [6]
- Removal of the "bereavement exclusion" — depressive symptoms may be considered appropriate to significant loss, but clinical judgment is exercised
- Dysthymia → persistent depressive disorder (now includes both chronic MDD and previous dysthymic disorder)
- Introduction of disruptive mood dysregulation disorder and premenstrual dysphoric disorder
B. Depressive Episode — ICD-10/ICD-11 Criteria
The ICD system uses a slightly different structure, splitting symptoms into Group A (core) and Group B (associated), with severity determined by how many from each group are met [3].
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. [4]
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. [4]
ICD-10 severity grading (still commonly used in Hong Kong clinical practice) [3]:
| Group A (Core) | Group B (Associated) |
|---|---|
| Depressed mood | Reduced concentration |
| Loss of interest and enjoyment | Reduced self-esteem and confidence |
| Reduced energy and decreased activity | Ideas of guilt and unworthiness |
| Pessimistic thoughts | |
| Ideas of self-harm | |
| Disturbed sleep | |
| Diminished appetite |
| Severity | Group A | Group B | Functional Impairment |
|---|---|---|---|
| Mild | At least 2 of 3 | At least 2 | Some difficulty in continuing work/social activities |
| Moderate | At least 2 of 3 | At least 3 | Considerable difficulty continuing activities |
| Severe | All 3 | At least 4 | Unable to continue activities; may have psychotic features |
The ICD-10 "with somatic features" and DSM-5 "with melancholic features" identify a biologically-driven subtype [3]:
Clinical features required (≥ 4 of the following):
- 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 specifically requires either "loss of interest" or "lack of emotional reactivity" to be present [3].
Why does this specifier matter clinically? Melancholic depression is associated with [3]:
- ↑Neurobiological abnormalities + ↑family history
- ↑Severity of symptomatology
- ↓Response to placebo and ↑response to TCA than SSRI
Characterised by [3]:
- Variable depressed mood with often preserved mood reactivity to positive events
- Overeating and oversleeping
- Extreme fatigue and leaden paralysis (heaviness in limbs)
- Pronounced anxiety
- Classically associated with rejection sensitivity
- Significance: usually poorer response to TCA but better response to MAOI
Melancholic vs. Atypical Depression
Think of these as two ends of a spectrum. Melancholic = the "classic biological" depression (worse in morning, early wakening, weight loss, psychomotor retardation, loss of reactivity). Atypical = the "reverse vegetative" pattern (mood reactivity preserved, hypersomnia, weight gain, leaden paralysis). Atypical features should raise suspicion for bipolar depression.
DSM-5 criteria for manic episode: [7]
A distinct period of elevated, expansive or irritable mood and increased goal-directed activity lasting at least 1 week. [7]
Three or more (4 if mood is only irritable) of the following: [7]
| Symptom | Mnemonic Letter | Pathophysiological Basis |
|---|---|---|
| Inflated self-esteem or grandiosity | G | Excessive dopamine in reward circuits → overvaluation of self |
| Decreased need for sleep | S | Overactivation of reticular activating system; circadian disruption |
| Pressured speech | T | Racing thoughts translated into irrepressible speech output |
| Flight of ideas / racing thoughts | F | Dopaminergic hyperactivity → accelerated associative processing |
| Distractibility | D | Impaired prefrontal top-down attentional control |
| Increased goal-directed activity (either socially, at work or school or sexually) / psychomotor agitation | A | Mesolimbic dopaminergic overactivity → excessive motivation and drive |
| Excessive pleasurable activities (buying sprees, sexual indiscretions, or foolish business investments) | I | Reward pathway hyperactivation + impaired prefrontal judgment |
DIG FAST Mnemonic for Mania
D — Distractibility I — Irresponsibility / Indiscretions (excessive pleasurable activities) G — Grandiosity
F — Flight of ideas A — Activity increase (goal-directed or psychomotor agitation) S — Sleep decreased (need for) T — Talkativeness (pressured speech)
You need ≥ 3 of these (or ≥ 4 if mood is only irritable).
Additional criteria: [7]
- Marked impairment in functioning, observable by others, to necessitate hospitalization, or there are psychotic symptoms
- Not due to alcohol, substance, or medical conditions
DSM-5 criteria for hypomanic episode: [7]
- At least 4 days of elevated, expansive, or irritable mood and increased activity or energy
- 3 or more of manic symptoms (same DIG FAST list)
- Change in functioning observable by others but not severe enough to cause marked impairment, to necessitate hospitalization, and there are no psychotic symptoms
The key differences from mania:
| Feature | Mania | Hypomania |
|---|---|---|
| Duration | ≥ 1 week | ≥ 4 days |
| Functional impairment | Marked / hospitalisation required | Observable change but NOT marked impairment |
| Psychotic features | May be present | Never present |
Often missed by patients and doctors resulted in delayed diagnosis. [7] Why? Because hypomania often feels good — the patient is more productive, sociable, and creative. They don't present complaining about feeling great. This is why collateral history from family/friends is essential.
DSM-5 criteria for bipolar I disorder: [7]
- Most cases have both manic and depressive episodes
- There is a predominant polarity; more manic or more depressive episodes
- Presence of one single manic episode already satisfies criteria for bipolar I disorder (this occurs in only 5%) [7]
This is a critical conceptual point: you do NOT need a depressive episode to diagnose Bipolar I. A single manic episode is sufficient. The logic: mania is such a specific and dramatic clinical phenomenon that its occurrence essentially defines the disorder.
DSM-5 criteria of bipolar II disorder: [7]
- At least one hypomanic episode
- At least one previous depressive episode
- Never has a manic or mixed episode
- Depressive episodes are more common in bipolar II disorder [7]
If a patient with Bipolar II ever has a full manic episode, the diagnosis is reclassified to Bipolar I.
| Entity | Core Criteria |
|---|---|
| Persistent Depressive Disorder (Dysthymia) | Depressive symptoms NOT meeting full MDD criteria for ≥ 2 years; onset usually early adulthood; may have "double depression" (superimposed MDD episodes) [3] |
| Cyclothymic Disorder | Numerous minor depressive and mild elative episodes (neither meeting hypomanic nor depressive episode criteria) for ≥ 2 years; symptom-free periods < 2 consecutive months [3][5] |
| Adjustment Disorder with Depressed Mood | Emotional/behavioural symptoms developing ≤ 3 months of an identifiable stressor; does not meet full MDD criteria; resolves within 6 months of stressor termination [3] |
The following flowchart represents the clinical thinking process when you encounter a patient with mood disturbance. The key decision points are: (1) exclude secondary causes, (2) determine polarity, (3) determine severity and duration, (4) apply specifiers.
Investigation Modalities
Investigations in mood disorders serve four purposes [3][6]:
- Rule out secondary (organic) causes — the primary reason
- Establish baseline before starting pharmacotherapy
- Guide prescribing (e.g., renal function for lithium dosing)
- Screen for self-neglect (e.g., malnutrition in severe depression)
These should be ordered for every patient presenting with a mood disturbance:
| Investigation | What You're Looking For | Interpretation / Rationale |
|---|---|---|
| CBP (Complete Blood Picture) | ↓Hb → anaemia (fatigue mimics depression); ↑WCC → occult infection; ↑MCV → macrocytosis from alcoholism or B12/folate deficiency [3] | Anaemia causes fatigue and low energy indistinguishable from depression. Macrocytosis without anaemia may be the only clue to heavy alcohol use. |
| RFT (Renal Function Tests) | HypoNa → SIADH (antidepressant S/E, especially SSRIs in elderly); U/Cr → baseline for lithium dosing; Ca → hypercalcaemia from hyperparathyroidism causes depression [3] | SSRIs cause SIADH in ~10% of elderly patients → always check baseline Na. Hypercalcaemia classically causes "bones, stones, groans, and psychiatric moans." |
| LFT (Liver Function Tests) | ↑GGT → alcoholic liver disease; baseline for hepatotoxic drugs [3] | GGT is the most sensitive marker for chronic alcohol use. Many psychotropic drugs are hepatically metabolised. |
| TFT (Thyroid Function Tests) | Hypothyroidism → secondary depression [3][6] | This is the single most important screening test in any depressed patient. Thyroid hormones potentiate monoamine activity; low T3/T4 → functional monoamine deficiency → depression. Even subclinical hypothyroidism can worsen treatment response. |
Basic investigations: CBP, R/LFT, thyroid function test. [4]
Others: blood alcohol level, blood and urine toxicology screen, HIV test, cosyntropin (ACTH) stimulation test (for Addison disease), EEG (for epilepsy) or CT or MRI (for organic brain syndrome or hypopituitarism) should be considered if indicated by history taking and physical examination. [4]
| Investigation | When to Order | What You're Looking For | Interpretation |
|---|---|---|---|
| CRP / ESR | Suspected infection or inflammatory disease | Elevated inflammatory markers | Chronic inflammation (e.g., SLE, RA) is associated with depression via cytokine-mediated neuroinflammation |
| Vitamin B12 and Folate | Elderly, suspected nutritional deficiency, macrocytosis, alcoholism [3] | Low B12 or folate | B12 deficiency → impaired methylation → reduced monoamine synthesis → depression and cognitive impairment. Folate deficiency also reduces antidepressant efficacy |
| Urine drug screen | Suspected substance use, atypical presentation, young patient [3] | Amphetamines, opioids, cannabinoids, benzodiazepines, cocaine | Substance-induced depression resolves with cessation; substance-induced mania (stimulants) should settle after admission |
| Blood alcohol level | Suspected alcohol misuse [4] | Elevated alcohol level | Alcohol is a CNS depressant; chronic use depletes monoamines; withdrawal can cause both depression and mania-like agitation |
| HIV test | Risk factors present, young patient with new-onset mania [4] | HIV seropositivity | HIV can cause depression via direct CNS infection (HIV-associated neurocognitive disorder) and psychosocial burden; mania can be first presentation of HIV encephalopathy |
| Cosyntropin (ACTH) stimulation test | Suspected Addison disease (fatigue, hypotension, hyperpigmentation, hypoNa, hyperK) [4] | Inadequate cortisol response to synthetic ACTH | Addison disease → cortisol deficiency → fatigue, weakness, mood changes; also important because glucocorticoid replacement may resolve "depression" entirely |
| ECG | Before starting TCA or lithium; cardiac history [3] | QT prolongation, arrhythmias | TCAs and lithium prolong QTc and may trigger arrhythmias. Baseline ECG is essential for medicolegal safety. Lithium also causes T-wave flattening/inversion |
| EEG | Suspected epilepsy (especially temporal lobe epilepsy) or other neurological indications [3][4] | Epileptiform activity | Temporal lobe epilepsy can present with ictal depression, ictal fear, or interictal mood disturbance. Post-ictal depression is common |
| CT or MRI brain | New-onset depression in elderly, atypical features, focal neurological signs, cognitive deficits [3][4] | Structural lesions: tumours, cerebrovascular disease, frontal lobe pathology, normal pressure hydrocephalus | Frontal lobe tumours classically cause personality change and disinhibition (mimics mania); left frontal strokes are associated with depression; white matter hyperintensities suggest vascular depression |
| Glucose | Suspected diabetes, metabolic syndrome, or for baseline before atypical antipsychotics | Hyperglycaemia or hypoglycaemia | Episodic hypoglycaemia can mimic panic/anxiety; chronic diabetes is associated with depression; atypical antipsychotics cause metabolic syndrome |
| Syphilis serology (VDRL/RPR) | Risk factors, elderly with cognitive change | Positive serology | Neurosyphilis (tertiary) can cause depression, mania, psychosis, and dementia — the "great imitator" |
These are crucial for quantifying severity, tracking treatment response, and research — but they are explicitly 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. [6]
| Scale | Type | Details | When to Use |
|---|---|---|---|
| Hamilton Rating Scale for Depression (HAM-D) | Clinician-rated, 17-21 items | Gold standard for research; assesses somatic and cognitive symptoms | Research, clinical trials, tracking response |
| Montgomery-Åsberg Depression Rating Scale (MADRS) | Clinician-rated, 10 items | More sensitive to change than HAM-D; focuses on core mood symptoms | Research, clinical trials |
| Patient Health Questionnaire-9 (PHQ-9) | Self-rated, 9 items (maps to DSM-5 criteria) | Quick, validated screening tool; scores: 0-4 minimal, 5-9 mild, 10-14 moderate, 15-19 moderately severe, 20-27 severe | Primary care screening, monitoring |
| Beck Depression Inventory (BDI) | Self-rated, 21 items | Widely used; good for cognitive symptoms of depression | Clinical and research settings |
| Center for Epidemiologic Studies-Depression Scale (CES-D) | Self-rated, 20 items | Designed for epidemiological studies | Community-based screening |
| Special population scales | Various | Geriatric Depression Scale (GDS), Cornell Scale for Depression in Dementia, Edinburgh Postnatal Depression Scale (EPDS) [6] | Elderly patients, dementia patients, postpartum women |
For bipolar disorder screening:
The comprehensive assessment follows this structure [3]:
1. History Taking — structured approach to elicit:
| Component | What to Elicit | Why |
|---|---|---|
| Core symptoms | Depressed mood (duration, pervasiveness, diurnal variation), anhedonia, anergia | Establishes whether criteria met |
| Biological symptoms | Sleep (especially early morning wakening), appetite/weight, libido, psychomotor changes | Determines melancholic vs. atypical pattern |
| Cognitive symptoms | Self-esteem, guilt, hopelessness, concentration | Guides severity grading |
| Psychotic symptoms | Delusions (persecution, guilt, nihilism), hallucinations (accusatory voices) | Determines severe with psychotic features |
| Suicidal assessment | Ideation → plans → means → intent → protective factors | Critical for safety and supervision level |
| Past manic/hypomanic episodes | "Has there ever been a period when you felt unusually high, energetic, or didn't need sleep?" | Rules out bipolar disorder — must ask in every depressed patient |
| Substance use | Alcohol, drugs (type, quantity, temporal relationship) | Rules out substance-induced mood disorder |
| Medical history and medications | Chronic illnesses, current medications | Rules out secondary depression |
2. Physical Examination — including general, neurological, and endocrine systems [3]
3. Investigations — as detailed above
The One Question You Must Never Forget
In every patient presenting with depression, you must ask about past manic or hypomanic episodes. Failure to do so is the single most common reason for misdiagnosing bipolar disorder as MDD. This leads to antidepressant monotherapy, which can trigger manic switch and accelerate cycling. Ask: "Have you ever had a period lasting several days where your mood was unusually high, you felt you didn't need sleep, and you had lots of energy and ideas?" And get collateral history from a family member — patients often don't recognise hypomania as abnormal.
| Feature | DSM-5 (MDD) | ICD-10 (Depressive Episode) |
|---|---|---|
| Core symptoms required | ≥ 1 of depressed mood OR anhedonia | ≥ 2 of depressed mood, anhedonia, OR anergia |
| Total symptoms required | ≥ 5 of 9 | Varies by severity (mild: 2A + 2B; moderate: 2A + 3B; severe: 3A + 4B) |
| Duration | ≥ 2 weeks | ≥ 2 weeks |
| Severity grading | Via specifiers (mild/moderate/severe/psychotic) | Built into the criteria structure |
| Bereavement exclusion | Removed in DSM-5 | Not explicitly present in ICD-10 |
| Bipolar I definition | 1 manic episode sufficient | ICD-10 requires ≥ 2 mood episodes (one must be manic/hypomanic); ICD-11 aligns more with DSM-5 |
When a mood episode includes psychotic features, distinguishing between mood-congruent and mood-incongruent psychosis is diagnostically important:
| Feature | Mood-Congruent | Mood-Incongruent |
|---|---|---|
| Content | Consistent with mood theme (depression: guilt, worthlessness, nihilism, disease; mania: grandiosity, special powers) | Not consistent with mood theme (e.g., persecutory delusions without guilt theme, thought insertion, thought broadcast) |
| Prognostic significance | Better prognosis | Worse prognosis; consider schizoaffective disorder |
| Treatment implication | Antidepressant/mood stabiliser + antipsychotic | Antipsychotic may be more important; longer treatment course |
In mania, psychotic symptoms indicate the diagnosis of mania with psychotic features: delusions are often mood-congruent (grandiose, persecutory linked to status); 10-20% may have first-rank symptoms but these are usually fleeting [5].
High Yield Summary — Diagnostic Criteria and Investigations
MDD (DSM-5): ≥ 5/9 SIGECAPS criteria for ≥ 2 weeks; must include depressed mood or anhedonia; functional impairment; exclude substance/medical cause and prior mania/hypomania
ICD-10 Depressive Episode: Core (A) = depressed mood, anhedonia, anergia; Associated (B) = 7 symptoms; Mild = 2A+2B, Moderate = 2A+3B, Severe = 3A+4B
Mania (DSM-5): Elevated/irritable mood + ↑energy for ≥ 1 week; ≥ 3 DIG FAST symptoms (≥ 4 if irritable only); marked impairment or psychosis; exclude substance/medical
Hypomania: Same symptoms but ≥ 4 days; observable change without marked impairment; NO psychotic features
Bipolar I: 1 manic episode sufficient (depression not required) Bipolar II: ≥ 1 hypomanic + ≥ 1 depressive episode; never manic
Mandatory Investigations: CBP, RFT (including Ca), LFT, TFT — in every patient Key Add-ons: UDS, B12/folate, ECG (before TCA/lithium), CT/MRI brain (elderly/atypical), HIV (young mania)
Rating Scales: PHQ-9 (screening), HAM-D/MADRS (severity tracking) — useful but NOT diagnostic substitutes
Active Recall - Diagnostic Criteria and Investigations
[3] Senior notes: ryanho-psych.md (sections 7.1.1, 7.1.2, 7.2, Bipolar Disorder, diagnostic hierarchy, ICD-10 criteria) [4] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pp. 10, 13) [5] Senior notes: ryanho-psych.md (sections on Bipolar Disorder differential diagnosis, cyclothymia, mania clinical features) [6] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pp. 6, 7, 8, 9, 14, 15) [7] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (pp. 3, 5, 6, 7, 8, 10, 22)
Guiding Principles
Before diving into specific treatments, understand the overarching philosophy. Management of mood disorders is structured around three phases and always integrates biopsychosocial approaches:
- Acute treatment — resolve the current episode (weeks to months)
- Continuation treatment — prevent relapse of the same episode (months)
- Maintenance / Prophylactic treatment — prevent recurrence of new episodes (years to lifelong)
The treatment differs fundamentally between unipolar depression and bipolar disorder — this is why getting the diagnosis right matters so much. Treating bipolar depression with antidepressant monotherapy is not just ineffective; it is actively harmful (manic switch, cycle acceleration) [5][7].
Fundamentals of patient management include: correct diagnosis, illness acceptance and treatment adherence, family psychoeducation, pharmacological and psychosocial treatment. [7]
A. Management Algorithm — Unipolar Depression
The approach follows a stepped-care model (NICE guidelines) [3]:
Step-by-Step Approach
- Watchful waiting + psychosocial intervention [3]
- General lifestyle advice: avoid alcohol/substance use, diet, sleep hygiene, encourage suitable physical activity (↓activity causes social withdrawal and exacerbates depression) [3]
- Physical activity: systematic review and meta-analysis of 13 studies showed pooled standardised mean difference of -0.40; inverse association between duration of intervention and magnitude of effect [6]
- Reassess in 2-4 weeks; if no improvement, escalate to pharmacotherapy
If the patient fails to respond after adequate trials:
Considerations first [3]:
- Reassess diagnosis: look for secondary causes (e.g., substance abuse, medical conditions)
- Assess compliance
- Assess for ongoing psychosocial stressors
Therapeutic options for refractory depression [3]:
| Strategy | Options | Rationale |
|---|---|---|
| Switch | Switch to another class of antidepressant (preferably different mechanism) | If the first mechanism didn't work, try a different neurotransmitter target. Beware serotonin syndrome and discontinuation syndrome → cross-tapering |
| Combine | Usually 5-HT drug (SSRI, venlafaxine) + NA drug (bupropion, mirtazapine) | Targets multiple monoamine systems simultaneously; "California rocket fuel" = venlafaxine + mirtazapine |
| Augment | Low-dose antipsychotic (esp. with psychotic features), lithium, tri-iodothyronine (T3) | Antipsychotics licensed for augmentation: quetiapine, aripiprazole [3]. Lithium augments serotonergic function. T3 enhances monoamine receptor sensitivity |
| ECT | Electroconvulsive therapy | Considered more effective than drugs in the most severe cases. Indications: emergency, refractory, catatonic [3] |
STAR*D Trial — Real-World Remission Rates
The landmark STAR*D trial tested sequential antidepressant strategies in 2,876 outpatients with MDD. Remission rates at each step: Step 1 (citalopram): 28%; Step 2 (switch or augment): 21-30%; Step 3: 12-20%; Step 4: 7-14%. The key lesson: each subsequent step has diminishing returns. Getting the first treatment right (or close to right) matters most. Most patients need more than one trial to achieve remission. [3]
- First episode: continue antidepressants for ≥ 6-9 months at the dose that induced remission [3]
- ≥ 2 episodes with significant functional impairment: continue antidepressants for ≥ 2 years [3]
- Duration of continuation prevents relapse — this is because the underlying neurobiological changes (BDNF normalization, synaptic remodeling) require sustained pharmacological support
Course and Prognosis [3]:
- Clinical course: generally self-limiting within 6 months to 1 year
- Age of onset: ~50% before age 21
- Duration: average 6 months; ~25% > 1 year; ~10-20% chronic unremitting
- Recurrence: ~80% will recur; average ~4 further episodes in 25 years
- Mortality: > 20× risk of suicide; can approach 15% in severe admitted cases
B. Management Algorithm — Bipolar Disorder
The challenge in long-term management is the prevention of relapses, subsyndromal symptoms, and functional disability. [7]
Treatment of manic episode: [7]
Step 1: Monotherapy [7]
Step 2: Combination — Lithium/Valproate plus atypical antipsychotics [7]
Step 3: Reevaluate diagnosis and consider ECT (need of rapid response, e.g., high violence risk) [7]
Hospitalisation is necessary in all but the mildest cases of mania (insight is often impaired early) [5]
Drug options for acute mania [5]:
| Drug Class | Specific Agents | Notes |
|---|---|---|
| Atypical antipsychotics | Olanzapine, risperidone, haloperidol, quetiapine, aripiprazole, ziprasidone | Best combination of efficacy and acceptability; considered first-line in NICE guidelines [5] |
| Lithium | — | Don't start if unlikely to be compliant (discontinuation can trigger rebound mania); rapid cycling, prominent depressive symptoms, and psychotic features predict poorer response [5] |
| Valproate | Sodium valproate (Epilim) | Avoid if childbearing potential (teratogenic — neural tube defects); faster onset of action compared to lithium [5] |
| Short-term benzodiazepines | Lorazepam or clonazepam | Rationale: ↓behavioural disturbance + ↑sleep → allows ↓dose of antipsychotics needed [5] |
Critical considerations [5]:
- ALWAYS avoid/stop use of antidepressants (trigger mania)
- Ensure drug compliance by therapeutic drug monitoring
- Pregnancy: prefer haloperidol (not associated with ↑risk of congenital anomalies) → risperidone, quetiapine, olanzapine
- Treatment duration: gradual ↓dose with clinical improvement; continue treatment for ≥ 6 months and ≥ 8 weeks after complete remission (↓rebound mania) [5]
Acute treatment of bipolar depressive episodes: Because of the recognised risk of switching to manic or mixed episodes and the high risk of suicide, referral to a specialist should be considered. [7]
Treatment of bipolar depressive episode: [7]
Step 1: Monotherapy — Lithium, Lamotrigine OR Quetiapine [7]
Step 2: Combination — Add Antidepressants (SSRI OR Venlafaxine) to monotherapy OR Combine two monotherapy agents [7]
Step 3: Reevaluate diagnosis and consider ECT (for patients with high suicidal risk) [7]
Treatment is NOT identical to unipolar depression [5]:
- 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 [5]
- Not all mood stabilisers are equally effective at treating mania and depression — lamotrigine, quetiapine, and lithium are more useful for bipolar depression [5]
- SSRIs may be effective but may induce mania; TCAs and SNRIs have even higher risk of inducing mania [5]
- Antidepressants, when used, should be combined with antipsychotic or mood stabiliser [5]
Avoid antidepressants if possible; if used, limit dose and duration. [7]
Why Can't You Just Give Antidepressants for Bipolar Depression?
This is one of the most important management principles in psychiatry. Antidepressant monotherapy in bipolar depression can: (1) trigger a manic switch — pushing the patient from depression into mania; (2) accelerate cycling — increasing the frequency of mood episodes; (3) induce mixed states — combining depressive and manic features, which carry the highest suicide risk. The risk is highest with TCAs and SNRIs, intermediate with SSRIs, and lowest with bupropion. Always use antidepressants in combination with a mood stabiliser or atypical antipsychotic, and limit dose and duration.
Indication for prophylactic treatment: [7]
- 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 [7]
General guidelines for prophylaxis for bipolar I: [7]
Monotherapy: Lithium or Valproate or Quetiapine [7]
Psychosocial (augmentation): [7]
- Psycho-education
- 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 [7]
How long is the prophylactic treatment? [7]
- No strict guidelines, probably lifelong
- At least a few years without relapse (cases that have no relapse for more than 10 years relapse after discontinuation of treatment)
- Absence of subsyndromal symptoms between mood episodes is a prerequisite [7]
Relative efficacy of maintenance agents [5]:
| Agent | Prevents Manic Relapse | Prevents Depressive Relapse | Key Considerations |
|---|---|---|---|
| Lithium | +++ | ++ | The only mood stabiliser to reduce suicide [7]; monitor plasma level (0.5-1.0 mmol/L), RFT, TFT every 6 months; drug interactions with diuretics, NSAIDs, CCBs, ACEIs; teratogenic (Ebstein anomaly) [5] |
| Valproate | +++ | + | Commonly used; teratogenic (neural tube defects) — avoid in women of childbearing potential [5] |
| Lamotrigine | + | +++ | Promising agent for treatment of bipolar depression due to its tolerability and wide therapeutic margin [7]; better at preventing depressive episodes, less effective for manic episodes cf lithium/valproate [5] |
| Quetiapine | ++ | ++ | Effective for both poles; limited by metabolic side effects |
| Olanzapine | ++ | + | Effective but metabolic side effects (weight gain, diabetes) |
Atypical antipsychotics look promising as mood stabilisers, but limited by metabolic side effects. [7]
Lithium is still an important drug, given that it is the only mood stabiliser to reduce suicide. [7]
C. Pharmacotherapy — Detailed Drug Classes
1. Antidepressants
Though changes in monoamines constitute only part of the aetiological picture, the monoamine systems provide the most accessible treatment avenue. [6]
Key principle: Antidepressant effect is usually delayed for ~2 weeks (with maximum effect at 6-12 weeks) [3]. Why? Because the clinical benefit comes not from immediate monoamine increase but from downstream neuroplastic changes — BDNF upregulation, synaptic remodelling, hippocampal neurogenesis, and receptor sensitivity changes. These processes take weeks to manifest.
Change in medication should only be considered after 3-4 weeks of no effect. [3]
| Class | Examples | Mechanism | Key Points |
|---|---|---|---|
| Selective Serotonin Reuptake Inhibitors (SSRIs) | Fluoxetine, paroxetine, sertraline, citalopram, escitalopram, vortioxetine [6] | Block the serotonin transporter (SERT) → ↑synaptic 5-HT | First-line for most depression due to best balance of efficacy and tolerability |
| Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) | Duloxetine, venlafaxine, desvenlafaxine [6] | Block both SERT and NET → ↑synaptic 5-HT and NE | Dual action; may be more effective in severe/melancholic depression; venlafaxine also useful in anxiety disorders |
| Tricyclic Antidepressants (TCAs) | Amitriptyline, imipramine, nortriptyline, clomipramine, dothiepin, trimipramine, desipramine [6] | Non-selective reuptake inhibition of 5-HT and NE; also block muscarinic, histamine H1, and alpha-1 adrenergic receptors | Effective but significant side effects and dangerous in overdose (cardiac toxicity — QT prolongation, arrhythmias). Reserved for refractory cases or specific indications (e.g., neuropathic pain) |
| Tetracyclic Antidepressants | Mianserin [6] | Alpha-2 antagonism → ↑NE release; also H1 antagonism | Sedating; rarely used as first-line |
| Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs) | Bupropion [6] | Blocks NET and DAT → ↑synaptic NE and DA | Good for patients with fatigue, psychomotor retardation, or sexual dysfunction from SSRIs; also used for smoking cessation; lower seizure threshold |
| Monoamine Oxidase Inhibitors (MAOIs) | Tranylcypromine, phenelzine, isocarboxazid, selegiline [6] | Irreversibly inhibit MAO-A and MAO-B → ↓monoamine breakdown → ↑5-HT, NE, DA | Effective but significant dietary restrictions (tyramine → hypertensive crisis) and dangerous drug interactions. Rarely used |
| Reversible Inhibitors of MAO-A (RIMAs) | Moclobemide [6] | Reversibly inhibit MAO-A only | Fewer dietary restrictions than irreversible MAOIs; better tolerated |
| Melatonergic Antidepressants | Agomelatine [6] | MT1/MT2 melatonin receptor agonist + 5-HT2C antagonist → resynchronises circadian rhythm + ↑NE and DA in prefrontal cortex | Novel mechanism; good tolerability; minimal discontinuation symptoms [3]; monitor LFTs (hepatotoxicity risk) |
| Others | Trazodone, mirtazapine [6] | Trazodone: 5-HT2A antagonist + weak SERT inhibitor (sedating). Mirtazapine: NaSSA — alpha-2 antagonist + 5-HT2/5-HT3 antagonist + H1 antagonist → ↑NE and 5-HT release, strongly sedating, appetite-stimulating | Mirtazapine useful when sedation/appetite stimulation is desired (e.g., insomnia, anorexia); weight gain is main limitation |
Systematic review and network meta-analysis of 21 antidepressants (Cipriani et al., 2018): [6]
- 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 [6]
| Aspect | Detail |
|---|---|
| Common side effects | GI disturbance (nausea, diarrhoea), neuropsychiatric effects (anxiety, insomnia early on), sexual dysfunction (delayed ejaculation, anorgasmia) — all serotonergic |
| ↑Suicidal risk | Probably insignificant except in young patients < 25 years. Why? Energy may return before mood improves → patient now has the "energy to act" on suicidal thoughts |
| Drug-drug interactions | MAO-I → serotonin syndrome (agitation, hyperpyrexia, rigidity, myoclonus, coma); Antipsychotics → potentiates extrapyramidal effects; NSAIDs → ↑risk of upper GI bleed (serotonin stored in platelets → SSRIs ↓platelet aggregation); Others → inhibits CYP450 enzymes (esp. fluvoxamine, fluoxetine, paroxetine) [3] |
| Discontinuation symptoms | Occur in ≥ 1/3 of patients; usually onset ≤ 5 days upon discontinuation. Due to "receptor rebound" → ↑↑previously suppressed functions. Symptoms: affective (irritability), GI (nausea), neuromotor (ataxia), vasomotor (diaphoresis), neurosensory (paraesthesia, "electric shocks"), neurological (↑dreaming). Minimal with agomelatine and vortioxetine [3] |
| Population | Preferred | Avoid | Rationale |
|---|---|---|---|
| Elderly | SSRIs (citalopram, sertraline) | TCA/MAOIs (dangerous in OD), venlafaxine (hypertension), mirtazapine (strong sedation → falls) | Elderly at higher risk of falls, overdose, cardiac complications, hyponatraemia (SIADH from SSRIs — monitor Na) |
| Cardiovascular disease | SSRIs | TCA is contraindicated (prolongs QT, pro-arrhythmic) | TCAs block cardiac sodium channels → QT prolongation → torsades de pointes |
| Pregnancy | Sertraline (safest SSRI data), consider risk-benefit | Paroxetine (cardiac malformations), valproate, lithium (1st trimester) | All antidepressants cross the placenta; neonatal withdrawal syndrome possible |
| Bipolar depression | Avoid antidepressant monotherapy | TCAs, SNRIs (highest manic switch risk) | Always combine with mood stabiliser |
| Drug | Mechanism | Key Indications | Key Side Effects / Monitoring |
|---|---|---|---|
| Lithium | Multiple: inhibits inositol monophosphatase (↓PI signalling), inhibits GSK-3β (↑neuroprotection), modulates monoamine transmission | Acute mania, bipolar depression, maintenance, augmentation in MDD, anti-suicidal | Narrow therapeutic index (0.5-1.0 mmol/L maintenance, 0.8-1.2 acute); Toxicity: coarse tremor, ataxia, confusion, seizures, renal failure. Monitor: plasma levels, RFT, TFT (hypothyroidism), Ca (hyperparathyroidism), ECG every 6 months [5]. Interactions: diuretics, NSAIDs, ACEIs ↑lithium levels. Teratogenic: Ebstein anomaly (tricuspid valve malformation) |
| Valproate (Epilim) | GABA-ergic (↑GABA by inhibiting GABA transaminase and blocking voltage-gated Na channels) | Acute mania (faster onset than Li), maintenance | Teratogenic (neural tube defects — absolutely contraindicated in women of childbearing potential unless no alternative); hepatotoxicity; pancreatitis; weight gain; thrombocytopenia; monitor LFTs, CBP [5] |
| Carbamazepine | Voltage-gated Na channel blocker; secondary effects on monoamine systems | Mixed states, rapid cycling | Auto-induces CYP3A4 (↓levels of many co-medications including OCP); aplastic anaemia (rare); DRESS/SJS (HLA-B*1502 — test before starting, especially in Han Chinese); hyponatraemia |
| Lamotrigine | Voltage-gated Na channel blocker → ↓glutamate release (excitatory amino acid) | Bipolar depression (acute and maintenance); less effective for mania | Promising agent for treatment of bipolar depression due to its tolerability and wide therapeutic margin [7]. Key risk: Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) — must titrate very slowly (over weeks). Risk increased by co-administration with valproate (inhibits lamotrigine metabolism) |
Atypical antipsychotics have a dual role: antimanic (dopamine blockade) and mood-stabilising properties.
| Drug | Role in Mood Disorders | Key Side Effects |
|---|---|---|
| Olanzapine | Acute mania (monotherapy or combination); bipolar depression (with fluoxetine); maintenance | Significant weight gain, metabolic syndrome (diabetes, dyslipidaemia); sedation |
| Quetiapine | Acute mania; bipolar depression (monotherapy); maintenance; augmentation in MDD | Sedation, metabolic effects (less than olanzapine); orthostatic hypotension |
| Risperidone | Acute mania | EPS at higher doses; hyperprolactinaemia |
| Aripiprazole | Acute mania; maintenance; augmentation in MDD | Partial D2 agonist (unique mechanism); less metabolic effects; may cause akathisia |
| Haloperidol | Acute mania (especially if antipsychotic effect needed urgently); preferred in pregnancy | Significant EPS; QT prolongation at high doses |
Psychotherapy is a form of systematic psychological treatment with well-defined objectives. [6]
Indication [3]:
- First-line in mild depression (without pharmacotherapy)
- In addition to drugs in moderate-severe depression
- As many as 85% of patients receiving both antidepressants and psychotherapy achieve remission [6]
Cognitive behavioural therapy and interpersonal therapy are highly effective in remedying mild and moderate depression. [6]
| Modality | Approach | When Especially Useful |
|---|---|---|
| Cognitive Behavioural Therapy (CBT) | Monitor, evaluate and modify negative dysfunctional thoughts and distorted perceptions and beliefs; use cognitive techniques (e.g., list pros and cons, examine evidence); increase activity scheduling [6] | Depression with prominent cognitive distortions; anxiety comorbidity; relapse prevention |
| Interpersonal Therapy (IPT) | Problems are understood in interpersonal context — e.g., facilitate grieving process, encourage role transition, explore interpersonal disputes, improve interpersonal skills [6] | Depression triggered by interpersonal loss, role transitions, social isolation |
| Problem-Solving Therapy | Improve ability to deal with specific everyday problems and life crises; identify problems, brainstorm solutions, evaluate effectiveness → best possible solution [6] | Primary care settings; patients with identifiable psychosocial stressors |
| Supportive Therapy | Facilitate expression of affect, highlight positive and successful experiences, offer empathy, impart therapeutic optimism; empathic listening, reflection, emotional processing, encouragement [6] | Adjunctive to all treatment; patients not suitable for structured therapy |
| Psychodynamic Therapy | Explores unconscious conflicts and early relational patterns | Chronic, recurrent depression with personality factors |
| Mindfulness-Based Cognitive Therapy (MBCT) | Combines CBT with mindfulness meditation to prevent depressive relapse | Relapse prevention in recurrent depression (≥ 3 episodes) |
| Family and Marital Interventions | Addresses family dynamics, communication, expressed emotion | Depression in context of relationship difficulties |
For bipolar disorder, psychotherapy plays an adjunctive role to improve and sustain recovery [5]:
- Interpersonal and social rhythm therapy: maintain sleep-activity schedules (disrupted circadian rhythms are a key trigger for bipolar episodes) [7]
- Family-focused approaches: improve family support; shown to reduce hospitalisation and symptomatology by 1/3 [5]
- Psychoeducation: individual and family; less hostile, more supportive, better drug compliance [7]
- Mood chart: helpful for patients to understand disease course and their own situation [5]
- Advanced statements: regarding social implications of poor judgment during manic states [5]
Psychosocial intervention is important for prevention of relapses and overall management of bipolar disorder. [7]
E. Physical Treatments
Where prompt action is needed, e.g., strongly suicidal. [6]
Indications [3]:
- Emergency: life-threatening depression (e.g., actively suicidal, refusing food/fluids, depressive stupor)
- Refractory: failed adequate trials of antidepressants
- Catatonia: life-threatening, treatment-resistant
- Mania: pregnant, life-threatening, persistent and treatment-resistant
- Puerperal psychosis: with prominent mood symptoms (rapid treatment to allow reuniting with baby)
- Selective treatment-resistant schizophrenia
- Previous good response to ECT
- ECT is especially effective for those with psychosis and/or psychomotor retardation [3]
Administration [3]:
- Course: 6-12 treatments, 2-3 per week
- Process: short-acting induction agent + muscle relaxant (5 min GA) → psychiatrist applies two scalp electrodes → electric pulse induces generalised tonic-clonic seizure lasting at least 15 seconds
- Unilateral vs bilateral: bilateral more effective but may cause more cognitive impairment; if unilateral, contralateral to dominant hemisphere
Side effects: headache, confusion, memory impairment. [6] Also consider need for anaesthesia, costs and inconvenience to the patient, stigma. [6]
- Cognitive impairment: acute confusion, anterograde or retrograde amnesia → generally short-lived (lasting a few days after ECT) [3]
- General: headache, nausea, muscle pain
Mortality: 2-4 per 100,000 (comparable to other minor surgery under GA); usually related to cardiopulmonary events [3]
Contraindications: no absolute contraindication; relative contraindications include [3]:
- Heart disease (recent MI, heart failure, ischaemic heart disease)
- Raised intracranial pressure
- Risk of intracranial haemorrhage (HTN, recent stroke)
- Poor anaesthetic risk
Non-invasive; hand-held, plastic-coated coil placed close to the scalp. [6]
- Non-invasive; constant, low-voltage DC via electrodes on the head [3]
- Anode and cathode ↑/↓ cortical activity respectively → modulates neuronal network activity [3]
- NOT suprathreshold (unlike TMS, ECT) → limited to adjunctive use only [3]
- Side effects: minimal, but only available in selected centres [3]
Management of bipolar disorder requires: [7]
- Early diagnosis and maintenance treatment
- Watch out for side effects and the need for alternative treatments
- Deal with stigma and poor drug compliance
- Provide psychoeducation (individual and family)
- Pay attention to stress coping, interpersonal relationship, lifestyle regularity and other risk factors of relapse
- Recognise and treat comorbidities, e.g., anxiety disorder, sleep problems, suicidal risk, substance abuse
Summary points: [7]
- Bipolar disorder is underrecognised and undertreated
- Lithium is still an important drug, given that it is the only mood stabiliser to reduce suicide
- Atypical antipsychotics look promising as mood stabilisers, but limited by metabolic side effects
- Lamotrigine is a promising agent for treatment of bipolar depression due to its tolerability and wide therapeutic margin
- Psychosocial intervention is important for prevention of relapses and overall management of bipolar disorder
High Yield Management Summary
Unipolar Depression:
- Mild → watchful waiting + psychosocial + lifestyle (exercise)
- Moderate-severe → SSRI (first-line) + psychotherapy (CBT or IPT)
- Refractory → switch class → combine (5-HT + NA) → augment (Li, antipsychotic, T3) → ECT
- Continuation: ≥ 6-9 months (first episode); ≥ 2 years (recurrent)
- Antidepressant effect delayed ~2 weeks; don't change before 3-4 weeks
Bipolar Mania:
- Monotherapy (Li / valproate / atypical antipsychotic) → combination → ECT
- ALWAYS stop antidepressants
- Hospitalise all but mildest cases
- Continue ≥ 6 months, ≥ 8 weeks after remission
Bipolar Depression:
- Monotherapy (Li / lamotrigine / quetiapine) → add antidepressant WITH mood stabiliser → ECT
- NEVER give antidepressant monotherapy (manic switch, cycle acceleration)
- TCAs/SNRIs highest switch risk; SSRIs lower risk; bupropion lowest
Maintenance:
- Li (prevents mania + suicide), valproate (mania), lamotrigine (depression), quetiapine (both)
- Probably lifelong; reduce 50% recurrence rate
- Always add psychosocial interventions
Key Drug Facts:
- Lithium: narrow therapeutic index (0.5-1.0); monitor RFT, TFT, Ca, ECG; teratogenic (Ebstein anomaly); only mood stabiliser proven to reduce suicide
- Valproate: teratogenic (NTDs) — avoid in women of childbearing potential
- Lamotrigine: risk of SJS — titrate slowly; valproate inhibits metabolism
- SSRIs: delayed effect; discontinuation syndrome; serotonin syndrome with MAOIs
Active Recall - Management of Mood Disorders
[3] Senior notes: ryanho-psych.md (sections 7.2 Management, Refractory Depression, ECT, STAR*D, Bipolar Management, Mood Stabilisers, Psychotherapy indications) [5] Senior notes: ryanho-psych.md (sections on Bipolar Disorder acute mania treatment, bipolar depression treatment, maintenance therapy, lithium monitoring, antidepressant risks) [6] Lecture slides: GC 164. I am depressed Mood disorders.pdf (pp. 16, 17, 18, 19, 21) [7] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (pp. 36, 40, 41, 44, 46, 47, 50, 64, 65)
Complications of Mood Disorders
Mood disorders are not just about feeling sad or elated. They are systemic illnesses with far-reaching consequences affecting virtually every organ system, social functioning, and survival. Thinking of complications from first principles, consider that mood disorders involve: (1) chronic neurobiological dysregulation (HPA axis, inflammation, autonomic dysfunction), (2) behavioural changes (inactivity, substance use, self-neglect, impulsivity), and (3) treatment side effects. Each of these pathways generates its own constellation of complications.
1. Suicide — The Most Important Complication
This is the complication that kills, and the one you must assess in every single patient, every single encounter.
WHO: Over 700,000 people commit suicide every year and many more attempt suicide. One of the major causes of suicide is depression. [6]
Depression raises suicidal risk — increase in suicide risk attributable to depression was 20-fold. [6]
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 comorbidities. [6]
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. [6]
From the senior notes: > 20× risk of suicide in MDD; can approach 15% in those severe admitted cases [3].
Why does depression cause suicide? The pathophysiology is multi-layered:
- Hopelessness — the cognitive triad (negative view of self, world, future) creates a perception that suffering is permanent and inescapable
- Serotonergic deficiency in the prefrontal cortex → impaired impulse control → inability to resist suicidal urges
- Psychomotor retardation paradox — severely depressed patients may be too retarded to act on suicidal thoughts; the dangerous period is when energy returns (early treatment response) before mood improves, giving the patient the "energy to act"
- Psychotic features — command auditory hallucinations, delusions of guilt/nihilism can directly drive self-harm
Suicide risk in bipolar disorder is among the highest of any psychiatric condition:
- ~8% of hospitalised males and 5% of hospitalised females die by suicide over 40 years of follow-up [5]
- Risk is highest during depressive episodes and mixed states (combination of despair and impulsive energy)
- The distress caused by untreated mood symptoms results in increased suicidality, comorbid anxiety, and substance use disorders [7]
Lithium is still an important drug, given that it is the only mood stabiliser to reduce suicide. [7] Why? Lithium's anti-suicidal effect appears to be partially independent of its mood-stabilising properties — it may directly reduce impulsivity and aggression via serotonergic modulation.
Suicide Risk Assessment — Never Skip This
Every mood disorder patient must be assessed for suicide at every visit. Use a structured approach: Ideation → Plan → Means → Intent → Protective factors. High-risk features include: male sex, older age, living alone, recent loss, comorbid substance abuse, previous attempts, psychotic features, mixed states, recent discharge from hospital, and the early weeks of antidepressant treatment.
2. Non-Suicidal Mortality — Medical Complications
Depression increases non-suicidal mortality. [6]
Reviewed 61 reports: 72% demonstrated a positive association between depression and non-suicide mortality. RR = 1.2-4.0. [6]
Possible mediators include: 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). [6]
For bipolar disorder: mortality is significantly ↑, with ↓life expectancy by ~13 years (males) and ~9 years (females) [5].
Let us break these mediators down systematically:
| Pathway | Mechanism | Clinical Consequence |
|---|---|---|
| HPA axis dysregulation | Chronic hypercortisolism → insulin resistance, visceral obesity, dyslipidaemia, hypertension | Metabolic syndrome → atherosclerosis → MI, stroke |
| Autonomic dysfunction | ↓Heart rate variability (vagal withdrawal) in depression → sympathetic predominance | ↑Risk of arrhythmias, sudden cardiac death |
| Inflammation | ↑Pro-inflammatory cytokines (IL-6, TNF-α, CRP) in depression → endothelial dysfunction | Accelerated atherosclerosis, plaque instability |
| Altered thrombogenesis | ↑Platelet activation and aggregation in depression (serotonin stored in platelets; dysregulated serotonin → platelet hyperactivity) | ↑Risk of acute coronary events and stroke |
| Behavioural | Physical inactivity, poor diet, smoking, medication non-adherence | Compounding all of the above |
This is why depression after myocardial infarction is a recognised independent risk factor for cardiac mortality — it's not just "feeling sad about being sick."
- Depression itself is associated with insulin resistance via cortisol and inflammatory pathways
- Many psychotropic medications worsen metabolic parameters:
- Atypical antipsychotics (especially olanzapine, clozapine) → significant weight gain, dyslipidaemia, hyperglycaemia, new-onset type 2 diabetes
- Mirtazapine → weight gain via H1 antagonism (stimulates appetite)
- Lithium → weight gain, hypothyroidism (both contribute to metabolic syndrome)
- Valproate → weight gain, polycystic ovary syndrome
For bipolar disorder specifically: ↑cardiovascular disease / metabolic syndrome (medication side effects, poor lifestyle) is a major contributor to the reduced life expectancy [5].
Atypical antipsychotics look promising as mood stabilisers, but limited by metabolic side effects. [7]
Substance abuse is both a complication of and contributor to mood disorders, creating a vicious cycle:
- Depression: alcoholism is the most common comorbidity (occurs in ~40% of alcoholics); depression may drive self-medication with alcohol, and chronic alcohol use depletes monoamines, worsening depression [3]
- Bipolar I: alcoholism in 60% of patients — during manic episodes, hyperexcitability and impulsivity lead to ↑alcohol intake; alcoholism aggravates bipolar disorder and is associated with ↑suicide rate [3]
- Consequences: liver disease, nutritional deficiency (Wernicke-Korsakoff), accidents, violence, social deterioration, non-adherence to psychiatric medications
3. Functional Impairment and Psychosocial Complications
- Depression is one of the leading causes of disability worldwide (WHO Global Burden of Disease)
- Cognitive symptoms (poor concentration, indecisiveness, psychomotor retardation) directly impair work performance
- Only ~25% of those with recurrent major depression achieve 5-year clinical stability with good social and occupational performance [3]
- Bipolar disorder: only < 20% achieve a 5-year period of clinical stability [5]
- Social withdrawal (driven by anhedonia and anergia) → isolation → further worsening of depression
- Mania: reckless decisions, extravagant spending, sexual indiscretions, aggressive behaviour → damaged relationships, financial ruin, legal problems
- Advanced statements are recommended for bipolar patients to address social implications of poor judgment during manic states [5]
- Caregiver burden is significant — mood disorders are chronic relapsing conditions
- High expressed emotion (criticism, hostility, over-involvement) in families predicts relapse
- Family psychoeducation is a critical intervention to reduce relapse rates [7]
- Children of depressed parents: ↑risk of developing depression themselves (genetic + environmental), attachment difficulties, behavioural problems
4. Cognitive Complications
- Acute episodes: poor concentration, indecisiveness, psychomotor slowing — these are state-dependent and typically improve with remission
- Chronic/recurrent depression: cumulative hippocampal volume loss (cortisol-mediated neurotoxicity) can lead to persistent cognitive deficits even between episodes
- In elderly patients: depressive pseudodementia can be indistinguishable from early dementia; importantly, depression in late life is a risk factor for subsequent true dementia
Staging of illness: [7]
- Stage 1: High-risk group (positive family history) or patients with subsyndromal symptoms
- Stage 2: Patients with a few episodes and optimal functioning
- Stage 3: Recurrent episodes and decline in functioning and cognition
Neuroprogression theory: worse prognosis with frequent relapses. [7]
Increased risk of future development of dementia. [7]
This is a crucial concept — bipolar disorder is increasingly recognised as a neuroprogressive illness. With each mood episode, there is accumulative neuronal damage (via excitotoxicity during mania, cortisol toxicity during depression, and neuroinflammation). This manifests as:
- Global cognitive deficits (attention, memory, executive function) that may persist even in euthymic periods [5]
- Progressive functional decline
- Increased risk of developing dementia in later life
Why do frequent relapses worsen prognosis? The "kindling" model explains that early episodes require a stressor to trigger them, but successive episodes become increasingly autonomous and easier to trigger — the brain becomes sensitised. Each episode causes further neuroplastic damage, creating a self-perpetuating cycle. This is the strongest argument for aggressive maintenance treatment and relapse prevention.
Neuroprogression — The Case for Early, Aggressive Treatment
Every mood episode matters. The neuroprogression theory teaches us that bipolar disorder is not just a series of discrete episodes — it is a progressive illness where each relapse causes cumulative brain damage. This is why the emphasis on maintenance treatment is so strong: preventing episodes is not just about quality of life in the short term, but about preserving cognitive function and preventing dementia in the long term. Start treatment early, maintain it consistently, and prevent relapses.
5. Recurrence and Chronicity
- Recurrence: ~80% will recur; average ~4 further episodes in 25 years
- Usually associated with progressively shorter intervals between episodes
- ~50% do not have complete symptom remission between episodes (residual symptoms)
- ~10-20% develop a chronic unremitting course
Prognosticants for relapse [3]:
- Incomplete symptomatic remission
- Early age of onset
- Poor social support
- Poor physical health
- Comorbid substance abuse
- Comorbid personality disorder
- Onset ~20 years; usually begins as depression with first manic episode occurring ~5 years later
- Manic episodes usually self-limited, resolving within ~6 months even if untreated
- 2-year outcome after first mania: 98% syndromal recovery, 72% symptomatic recovery, 43% functional recovery, 40% relapse
- Further mood episodes occur in ≥ 90% of manic patients; usually ~4 major episodes per 10 years
- Depressive episodes far outnumber manic episodes in both Bipolar I and II
- Patients on maintenance treatment with no relapse for many years CAN still relapse after cessation — relatives should be educated on prodromal symptoms to allow early treatment [5]
Recurrence rate in first-episode bipolar disorder: naturalistic 1-year follow-up showed high rates of recurrent mood episodes, with depressive episodes predominating. [7]
Poor prognostic factors for bipolar disorder: [7]
- Early onset
- Greater severity, mixed episodes, repeated episodes, previous hospitalisations
- Residual symptoms, cognitive impairment
- Poor insight, side effects of medications
- Comorbid substance or personality disorder
Prognosis: poor — only < 20% of bipolar patients achieve a 5-year period of clinical stability [5].
Bipolar II disorder has a relatively better prognosis than Bipolar I as a positive prognostic factor [5].
These are iatrogenic complications arising from the medications used to treat mood disorders:
| Treatment | Complication | Mechanism | Prevention/Monitoring |
|---|---|---|---|
| SSRIs | Serotonin syndrome (with MAOIs) | Excessive synaptic serotonin → autonomic instability, hyperthermia, rigidity, myoclonus | Never combine SSRIs with MAOIs; 2-week washout (5 weeks for fluoxetine due to long half-life) |
| SSRIs | ↑Suicidal risk (age < 25) | Energy returns before mood → "energy to act" on suicidal thoughts | Close monitoring in first 2-4 weeks, especially in young patients |
| SSRIs | SIADH/hyponatraemia | Stimulation of ADH release → dilutional hyponatraemia | Monitor Na in elderly; risk factors: age, female sex, low BMI, concurrent diuretics |
| SSRIs | Sexual dysfunction | Serotonin inhibits dopaminergic reward and spinal ejaculatory reflexes | Switch to bupropion or mirtazapine if problematic |
| SSRIs + NSAIDs | Upper GI bleeding | SSRIs ↓platelet serotonin → impaired aggregation; NSAIDs damage gastric mucosa | Avoid combination; add PPI if necessary |
| TCAs | Cardiac toxicity (overdose) | Sodium channel blockade → QT prolongation → torsades de pointes | Avoid in patients with cardiac disease; ECG monitoring; dangerous in overdose (hence avoid in suicidal patients) |
| Lithium | Hypothyroidism | Inhibits thyroid hormone synthesis and release | Monitor TFT every 6 months; treat with levothyroxine if needed |
| Lithium | Nephrogenic diabetes insipidus | Blocks ADH action on collecting ducts (inhibits aquaporin-2 insertion) → inability to concentrate urine | Monitor RFT, fluid balance; polyuria/polydipsia are early signs |
| Lithium | Lithium toxicity | Narrow therapeutic index; dehydration, renal impairment, drug interactions (NSAIDs, diuretics, ACEIs) ↑levels | Keep plasma level 0.5-1.0 mmol/L; regular monitoring; educate patient about dehydration risks |
| Lithium | Teratogenicity | Ebstein anomaly (downward displacement of tricuspid valve) | Avoid in first trimester if possible; folic acid supplementation |
| Valproate | Teratogenicity | Neural tube defects (spina bifida), developmental delay | Absolutely contraindicated in women of childbearing potential unless no alternative; MHRA pregnancy prevention programme |
| Valproate | Hepatotoxicity, pancreatitis | Direct hepatotoxic effect; mechanism of pancreatitis unclear | Monitor LFTs; educate about symptoms |
| Lamotrigine | Stevens-Johnson syndrome / TEN | Hypersensitivity reaction (immune-mediated keratinocyte apoptosis) | Very slow titration (over weeks); higher risk with concurrent valproate (inhibits lamotrigine metabolism) |
| Carbamazepine | DRESS/SJS | HLA-B*1502-mediated hypersensitivity (common in Han Chinese population) | HLA-B*1502 testing before starting — especially important in Hong Kong |
| Atypical antipsychotics | Metabolic syndrome | H1 and 5-HT2C antagonism → weight gain; insulin resistance → diabetes, dyslipidaemia | Regular metabolic monitoring (weight, glucose, lipids); worst with olanzapine and clozapine |
| Antidepressants in bipolar | Manic switch / cycle acceleration | Monoamine increase destabilises mood regulation in bipolar brain → tips into mania | Avoid antidepressants if possible; if used, limit dose and duration [7]; always combine with mood stabiliser |
Misdiagnosis is especially common — among 600 patients with bipolar disorder, 69% were initially misdiagnosed, most frequently as major depression, followed by anxiety disorders, substance or alcohol use disorder. [7]
Correct diagnosis and treatment was delayed by 5-7 years on average. [7]
The consequences of misdiagnosis form their own category of complication:
| Direction | Consequences |
|---|---|
| Underdiagnosis of bipolar | Untreated mood symptoms → increased suicidality, comorbid anxiety and substance use disorders; poor QoL, greater functional impairment, increased healthcare cost; antidepressant monotherapy → manic switch and cycle acceleration [7] |
| Overdiagnosis of bipolar | Unnecessary side effects of mood stabilisers; increased sick role and disability claims [7] |
- Peripartum depression: affects 10-15% of women; consequences include impaired maternal-infant bonding, developmental delays in the child, neglect
- Postpartum psychosis/mania: there is a 50% risk of postpartum mania in untreated bipolar disorder [5] — this is a psychiatric emergency with risk of infanticide and suicide
- Treatment must balance maternal mental health with fetal/neonatal safety (see management section for drug choices in pregnancy)
High Yield Complications Summary
Suicide: The #1 cause of mortality in mood disorders. MDD: 20× risk, 6-15% lifetime. Bipolar: ~8% males, ~5% females. Highest risk in depressive episodes, mixed states, early treatment phase, psychotic features.
Non-suicidal mortality: ↓Life expectancy by 9-13 years in bipolar. Cardiovascular disease is the leading cause — driven by HPA axis dysregulation, inflammation, altered thrombogenesis, metabolic syndrome (often worsened by medications), and behavioural factors.
Neuroprogression: Each mood episode causes cumulative brain damage. Bipolar disorder progresses through stages with increasing cognitive decline. Frequent relapses → increased risk of dementia. This is the strongest argument for aggressive maintenance treatment.
Recurrence: MDD ~80% recurrence; Bipolar ≥ 90%. Only 20-25% achieve sustained clinical stability. Prognostic factors include incomplete remission, early onset, comorbid substance/personality disorder.
Treatment complications: Serotonin syndrome (SSRIs + MAOIs), lithium toxicity/hypothyroidism/NDI/teratogenicity, valproate teratogenicity, lamotrigine SJS, carbamazepine DRESS (test HLA-B*1502 in Han Chinese), atypical antipsychotic metabolic syndrome, antidepressant-induced manic switch.
Misdiagnosis: 69% of bipolar patients initially misdiagnosed; average delay 5-7 years; leads to inappropriate treatment and worse outcomes.
Active Recall - Complications of Mood Disorders
References
[3] Senior notes: ryanho-psych.md (sections 7.2 Course and Prognosis, psychiatric comorbidity in alcoholism, prognosticants for relapse) [5] Senior notes: ryanho-psych.md (sections on Bipolar Disorder course and prognosis, mortality, substance abuse comorbidity, cognitive deficits) [6] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p. 4) [7] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (pp. 12, 14, 33, 34, 49, 65)
High Yield Summary
Definitions
- Mood disorders = abnormal mood states with associated features causing distress and functional impairment
- Normal sadness is adaptive and short-lived; MDD is defined by severity, duration, and functional impairment
Epidemiology
- MDD: lifetime prevalence ~11-15%; F:M = 2:1; 5% of adults worldwide affected
- Bipolar: ~1-2% prevalence; NO gender difference; heritability ~79-85%
- Dysthymia: lifetime risk ~4%
Pathophysiology
- Monoamine hypothesis (serotonin, norepinephrine, dopamine deficiency) — necessary but insufficient explanation
- Structural changes: reduced hippocampal volume, subgenual cortex glial cell loss
- HPA axis dysregulation → cortisol-mediated hippocampal neurotoxicity
- Cognitive distortions: selective abstraction, overgeneralisation, personalisation, arbitrary inference
Classification
- Depression: MDD, dysthymia, minor anxiety-depressive, seasonal, recurrent brief
- Bipolar: I (mania), II (hypomania + depression), cyclothymia
- Bipolar misdiagnosis is extremely common (5-7 year diagnostic delay on average)
Core Clinical Features
- Depression triad: depressed mood, anhedonia, anergia
- Melancholic features: early morning wakening, morning dysphoria, weight loss, psychomotor retardation
- Mania triad: elevated/irritable mood, increased energy, decreased need for sleep
- Always assess for suicide risk, psychotic features, and mixed features
Key Discriminators
- Depression F:M = 2:1; Bipolar no gender difference
- Bipolar heritability (~85%) > MDD heritability (~37%)
- Early onset depression → consider bipolar
- Antidepressant-induced mania = red flag for bipolar
High Yield DDx Summary
For Low Mood — Always consider:
- Secondary causes FIRST (hypothyroidism, medications, substance use, medical illness)
- Bipolar depression (ask about past hypomania — missed in 10-20% of cases)
- MDD vs. dysthymia vs. adjustment disorder (severity + duration + stressor)
- Pseudodementia vs. true dementia (especially in elderly)
- Anxiety disorder with secondary low mood
- Personality disorder (BPD — chronic emptiness, rapid mood shifts)
For Elated/Irritable Mood — Always consider:
- Secondary causes (substance intoxication, medications, medical — especially frontal lobe lesions, hyperthyroidism)
- Mania vs. hypomania (severity, psychotic features, functional impairment)
- Schizophrenia / schizoaffective disorder (most difficult DDx — check mood congruence of psychosis, longitudinal course)
- ADHD (trait-like, no grandiosity/↓need for sleep)
- Borderline PD (rapid mood shifts, interpersonal triggers, no classic manic features)
Red Flags for Bipolar in a "Depressed" Patient:
- Age of onset < 25
- Atypical depressive features (hypersomnia, hyperphagia)
- Psychotic features during depression
- Family history of bipolar disorder
- Multiple failed antidepressant trials or manic switch on antidepressants
- Postpartum onset
High Yield Summary — Diagnostic Criteria and Investigations
MDD (DSM-5): ≥ 5/9 SIGECAPS criteria for ≥ 2 weeks; must include depressed mood or anhedonia; functional impairment; exclude substance/medical cause and prior mania/hypomania
ICD-10 Depressive Episode: Core (A) = depressed mood, anhedonia, anergia; Associated (B) = 7 symptoms; Mild = 2A+2B, Moderate = 2A+3B, Severe = 3A+4B
Mania (DSM-5): Elevated/irritable mood + ↑energy for ≥ 1 week; ≥ 3 DIG FAST symptoms (≥ 4 if irritable only); marked impairment or psychosis; exclude substance/medical
Hypomania: Same symptoms but ≥ 4 days; observable change without marked impairment; NO psychotic features
Bipolar I: 1 manic episode sufficient (depression not required) Bipolar II: ≥ 1 hypomanic + ≥ 1 depressive episode; never manic
Mandatory Investigations: CBP, RFT (including Ca), LFT, TFT — in every patient Key Add-ons: UDS, B12/folate, ECG (before TCA/lithium), CT/MRI brain (elderly/atypical), HIV (young mania)
Rating Scales: PHQ-9 (screening), HAM-D/MADRS (severity tracking) — useful but NOT diagnostic substitutes
High Yield Management Summary
Unipolar Depression:
- Mild → watchful waiting + psychosocial + lifestyle (exercise)
- Moderate-severe → SSRI (first-line) + psychotherapy (CBT or IPT)
- Refractory → switch class → combine (5-HT + NA) → augment (Li, antipsychotic, T3) → ECT
- Continuation: ≥ 6-9 months (first episode); ≥ 2 years (recurrent)
- Antidepressant effect delayed ~2 weeks; don't change before 3-4 weeks
Bipolar Mania:
- Monotherapy (Li / valproate / atypical antipsychotic) → combination → ECT
- ALWAYS stop antidepressants
- Hospitalise all but mildest cases
- Continue ≥ 6 months, ≥ 8 weeks after remission
Bipolar Depression:
- Monotherapy (Li / lamotrigine / quetiapine) → add antidepressant WITH mood stabiliser → ECT
- NEVER give antidepressant monotherapy (manic switch, cycle acceleration)
- TCAs/SNRIs highest switch risk; SSRIs lower risk; bupropion lowest
Maintenance:
- Li (prevents mania + suicide), valproate (mania), lamotrigine (depression), quetiapine (both)
- Probably lifelong; reduce 50% recurrence rate
- Always add psychosocial interventions
Key Drug Facts:
- Lithium: narrow therapeutic index (0.5-1.0); monitor RFT, TFT, Ca, ECG; teratogenic (Ebstein anomaly); only mood stabiliser proven to reduce suicide
- Valproate: teratogenic (NTDs) — avoid in women of childbearing potential
- Lamotrigine: risk of SJS — titrate slowly; valproate inhibits metabolism
- SSRIs: delayed effect; discontinuation syndrome; serotonin syndrome with MAOIs
High Yield Complications Summary
Suicide: The #1 cause of mortality in mood disorders. MDD: 20× risk, 6-15% lifetime. Bipolar: ~8% males, ~5% females. Highest risk in depressive episodes, mixed states, early treatment phase, psychotic features.
Non-suicidal mortality: ↓Life expectancy by 9-13 years in bipolar. Cardiovascular disease is the leading cause — driven by HPA axis dysregulation, inflammation, altered thrombogenesis, metabolic syndrome (often worsened by medications), and behavioural factors.
Neuroprogression: Each mood episode causes cumulative brain damage. Bipolar disorder progresses through stages with increasing cognitive decline. Frequent relapses → increased risk of dementia. This is the strongest argument for aggressive maintenance treatment.
Recurrence: MDD ~80% recurrence; Bipolar ≥ 90%. Only 20-25% achieve sustained clinical stability. Prognostic factors include incomplete remission, early onset, comorbid substance/personality disorder.
Treatment complications: Serotonin syndrome (SSRIs + MAOIs), lithium toxicity/hypothyroidism/NDI/teratogenicity, valproate teratogenicity, lamotrigine SJS, carbamazepine DRESS (test HLA-B*1502 in Han Chinese), atypical antipsychotic metabolic syndrome, antidepressant-induced manic switch.
Misdiagnosis: 69% of bipolar patients initially misdiagnosed; average delay 5-7 years; leads to inappropriate treatment and worse outcomes.
Other Psychiatric Conditions In Child Psychiatry
Other psychiatric conditions in child psychiatry encompass a range of disorders including childhood-onset schizophrenia, selective mutism, reactive attachment disorder, stereotypic movement disorder, and elimination disorders (enuresis and encopresis) that do not fall under the more common categories of neurodevelopmental, anxiety, or mood disorders.
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.