Psychiatry SC075: I Am A Superman: Bipolar Disorder

Question 1

Mood and Mood disorder

Answer 1

Mood vs Emotion vs Affect:
Mood: More pervasive, persistent emotional state
Emotion: More immediate, reaction to environmental stimuli
Affect: Observed emotional expression

Mood and Mood disorder:
- Normal fluctuation vs Abnormal state
- Abnormal state: Pervasively high / low mood that differs from the usual mood
- Mood disorder: Abnormal mood states with other associated features resulting in distress + functional impairment (ALWAYS compare with ***Premorbid personality)

Question 2

***Classification of Mood disorder (DSM-5)

Answer 2

1. ***Bipolar disorder (Mania + Depression)
   - Bipolar 1
   - Bipolar 2
   - Cyclothymic
   - Other bipolar disorder
2. ***Depressive disorder (Depression only)
   - Major depressive disorder
   —> Single episode
   —> Recurrent
   - Dysthymic disorder
   - Other depressive disorder

Question 3

Bipolar 1 disorder vs Bipolar 2 disorder

Answer 3

Bipolar 1:
- Presence of **1 single manic **episode already satisfies criteria for bipolar 1 disorder

Bipolar 2:
- >=1 hypomanic episode
- >=1 previous depressive episode
- ***Never has a manic or mixed episode

Bipolar 1 vs 2 vs Bipolar spectrum:
- BP 1: severe mood episodes
- BP 2: milder manic symptoms, prominent depressive element, can have the same degree of long-term impairment as BP 1
- BP spectrum: bothered by frequent mood changes, can be mistaken as borderline personality disorder, need to distinguish with mood regulation problem (BP spectrum more pervasive than mood dysregulation)

Question 4

Manic episode

Answer 4

(Manic / Hypomanic: Shorter period
Depression: Longer period)

DSM-5:
1. A distinct period of **elevated, expansive, **irritable mood + **increased goal-directed activity lasting **>=1 week (炆憎, 燥底)

2. **>=3:
   - **Inflated self esteem / grandiosity (ability / identity) (自信爆棚, 超能力)
   - **Decreased need for sleep
   - **Pressured speech (over-talkative)
   - **Flight of ideas / racing thoughts (not disjointed although not meaningful vs loosening of association: Schizophrenia)
   - **Distractibility (easily change task)
   - **Increased goal-directed activity (either socially, at work or school or sexually) / psychomotor agitation
   - **Excessive pleasurable activities (buying sprees, sexual indiscretions, or foolish business investments)
3. **Marked impairment in functioning, observable by others, to necessitate hospitalization, or there are **psychotic symptoms (vs ***Hypomanic episode)
4. Not due to alcohol, substance (e.g. steroid) or medical conditions (uncommon)

Severe manic episode:
- Presence of **psychotic symptoms (mood-congruent (e.g. **Grandiose) / mood-incongruent)
- Severe overactivity
- Bizarre / Risky behavior
- Excessive spending
- Incoherent speech
- Disorganized thinking
- Mixed episode is more difficult to treat (having manic + depression on same day)

Question 5

Hypomanic episode

Answer 5

1. ***>=4 days of elevated, expansive, irritable mood + increased activity or energy
2. ***>=3 manic symptoms
3. Change in functioning observable by others but **NOT severe enough to cause marked impairment, to necessitate hospitalization, and there are **NO psychotic symptoms

Question 6

Cyclothymic disoder

Answer 6

1. **>=2 years of numerous periods with hypomanic **symptoms + depressive **symptoms that do **NOT meet criteria for a hypomanic/depressive ***episode
2. These mood periods have lasted **at least half of the time and **<2 months without symptoms
3. Causes impairment in functioning or distress
4. Exclude other medical, psychiatric and substance-related disorders

(Hypomanic episode: 4 days
Depressive episode: 2 weeks)

Question 7

Bipolar spectrum

Answer 7

Broad term describing patients with risk of developing Bipolar disorder but not full-blown

1. Short duration hypomanic episodes (***2-3 days)
2. Hypomanic episodes with insufficient symptoms (***2-4 symptoms)
3. Drug-induced hypomanic episodes with spontaneous remission
4. Morbidity and impairment are greater in MDD with bipolarity than MDD without bipolarity

Question 8

Young Mania Rating Scale (YMRS)

Answer 8

Severity, Number, Functional impairment of symptoms

Assess severity of mania and hypomania
1. Elevated mood (0-4)
2. Increased motor activity: energy
3. Sexual interest
4. Sleep
5. Irritability* (0-8)
6. Speech (rate and amount)*
7. Language: thought disorder
8. Content*
9. Disruptive-aggressive behavior*
10. Appearance
11. Insight

• Total score 0-60
• > =20 Mania; >=12 Hypomania

Question 9

Specifiers for Mood episodes

Answer 9

• Mood disorders are ***heterogenous conditions
• Specifiers are used to **better understand each patient’s characteristic and to select **specific treatment

Specifiers:
- With anxious distress
- With mixed features
- With rapid cycling (> 4 episodes per year)
- With melancholic features (near-complete absence of the capacity for pleasure, not respond to any external stimulus)
- With atypical features (e.g., mood reactivity, weight gain, hypersomnia)
- With psychotic features
- With peripartum onset (severe anxiety and even panic attacks. Risk of infanticide)
- With seasonal pattern (depression begins in fall or winter and remits in spring)

Question 10

Drugs / Medical conditions that cause Manic symptoms

Answer 10

Drugs:
- **Steroids
- **Levodopa
- Stimulants
- ***Antidepressants
- ECT (in those with bipolar spectrum disorder)

Illicit drugs:
- Cocaine
- ***Amphetamine

Medical conditions:
- Frontal lobe lesion (causing Disinhibition)
- **Hyperthyroidism (causing Anxiety)
- **Cushing’s syndrome

Question 11

Burden of Bipolar disorder

Answer 11

• BP 1: lifetime prevalence of 0.3%-1.6%
• Bipolar spectrum disorder: 3.7%
• Mean age at onset for first mood episode is about ***18 years for BP 1, but accurate diagnosis is often delayed by 5-10 years
• 83% cases >4 episodes; 43% >7 episodes
• One third of patients attempted suicide and 10%-20% died from their illness by suicide (risk factors: past suicidal attempt and prominent depressive symptoms)
• Increased risk of psychiatric and medical comorbidity
• Increased healthcare and welfare service utilization
• 9th leading cause of disability-adjusted life years under mental, neurological, and substance use disorders, as at 2010 (depressive disorder is the 1st cause)

Question 12

Comorbidity of Bipolar disorder

Answer 12

• Common
• Need to treat both Bipolar + Comorbid condition

Psychiatric comorbidity:
1. Psychotic disorder (e.g. Schizoaffective disorder)
2. **Anxiety disorder (comorbid anxiety disorders in BD is **as common as comorbid anxiety disorders in MDD)
3. **Substance use disorder (drug abuse **more common in BD than MDD)
4. Personality disorder
5. Sleep disorder
6. Eating disorder
7. ADHD

Medical comorbidity:
1. CVS disease
2. Metabolic diseases (obesity, diabetes, hypercholesterolemia)
- Due to higher alcohol and substance use, unhealthy diet, physical inactivity, social isolation, unemployment, low education and socio-economic status, stress, poor sleep and mental health, childhood abuse, **genetic overlap and side effects of pharmacotherapy, e.g. sodium valproate, atypical antipsychotics
—> **Monitor FG, Lipid every year + ***Treat as early as possible

Question 13

Risk factors for Bipolar disorder

Answer 13

1. High income countries (may be due to referral bias)
2. Low income, separated, divorced, or widowed
3. Low care and overprotective parents, poor attachment relationship, childhood abuse
4. Family history of bipolar disorder and schizophrenia (monozygotic concordance 40-70%, life-time risk in first degree relatives 5-10%, roughly 7 times higher than the general population risk)
5. No gender / ethnic difference

Question 14

Etiology of Bipolar disorder

Answer 14

Multifactorial
1. Genetic factors
- 79% heritability
- First degree relatives are of higher risk for bipolar, MDD, and other psychiatric disorders
- Shared genetic risk between bipolar, schizophrenia and autism
- Some overlap with genes involving in circadian rhythm regulation

2. Biological factors
   - Biochemical pathways: esp. dopaminergic, second messengers, mitochondrial, HPA axis, and thyroid
   - Neuroimaging findings: structural and functional abnormalities
   - Infective causes e.g., Toxoplasmosis gondii (the associated immune response)
3. Environmental factors
   - Life events and social support
   - Low care and overprotective parents
   - Poor attachment relationship
   - Childhood abuse
   - Sleep deprivation
   - Circadian and social rhythm disruption

Question 15

DDx of Manic episode

Answer 15

1. ***Psychotic disorder / Schizoaffective disorder
2. **Depressive disorder with **irritability and anxious distress
3. ***Substance / Medication-induced / Medical conditions
4. ADHD
5. Personality disorder with prominent irritability

Bipolar 2 often misdiagnosed since symptoms not obvious (i.e. only hypomanic —> overlooked often)

Question 16

Misdiagnosis, Underdiagnosis, Overdiagnosis of Bipolar disorder

Answer 16

• ***Hypomanic episode often overlooked
• Patients with BP 2 misdiagnosed as ***MDD
• Manic episode with psychotic symptoms misdiagnosed as ***Schizophrenia
• Misdiagnosis is esp. common in some early studies
  —> Major depression (most frequently)
  —> Anxiety disorders
  —> Substance or alcohol use disorder
• Correct diagnosis and treatment was delayed by 5-7 years in average

Problem:
- Distress caused by untreated mood symptoms results in increased suicidality, comorbid anxiety and substance use disorders
- Poor QOL, greater functional impairment, increased healthcare cost
- Antidepressant monotherapy is less effective and
results in manic switch and cycle acceleration

Overdiagnosis?
- Incorrect understanding of the term “manic” “躁”
- Requires informants and collateral information (e.g.
medical record) to confirm past history of mania / hypomania
- Important to follow diagnostic criteria in making psychiatric diagnosis

Problem:
- Unnecessary side effects of mood stabilizers
- Increase sick role and disability claims

Correct diagnosis:
- History from the patient
- Collateral information from informants
- Help by the use of screening tools
—> Mood Disorder Questionnaire (MDQ)
—> Hypomania Checklist (HCL-32)

Question 17

Course of Bipolar disorder

Answer 17

• Most **manic episodes recover eventually, but residual symptoms more common after **depressive episodes (e.g. fatigue, insomnia)
• Untreated manic episodes can last ***4-6 months (but eventually will subside)
• Most cases ***relapses if not on maintenance pharmacotherapy
• Most cases are ***episodic, but individual patient has a predominant polarity (i.e. more manic / more depressive episodes)
• In average, ***4 major episodes in the first 10 years, getting more frequent then stabilize, of around once per year (outcome is variable depending on drug compliance and psychosocial factors)
• 10-15% of cases are “rapid cyclers”: >=4 episodes/year
• 2-year outcome despite treatment after the first manic episode
  —> Functional recovery 43%
  —> Relapse 40%
• Outcomes for **mixed episodes and **rapid cyclers are worse
• Chance of relapse is higher in those with previous relapse
• Recognition of prodromes (e.g. ***Insomnia) and early treatment can reduce relapse

Question 18

Staging of illness

Answer 18

Stage 1:
- High-risk group (positive FH)
- 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:
Recurrent episodes can have long-term consequences (e.g. Brain impairment)
—> Increased risk of future development of dementia

Question 19

Stigma of Bipolar disorder

Answer 19

1. Self stigma
   - reduced self-worth after being labeled as “mood disorder”
2. Public stigma
   - actual / expected rejection from others
3. Stigma coping
   - avoidance and denial are most damaging

Question 20

Management of Bipolar disorder

Answer 20

Principles:
1. Correct diagnosis
2. Illness acceptance + Treatment adherence
3. Family psychoeducation
4. **Pharmacological + **Psychosocial treatment

Treatment of different ***phases:
1. Acute manic episode
2. Acute depressive episode
3. Maintenance + Prophylactic treatment
4. Treatment of comorbidity (psychiatric + medical)
5. Treatment in special situations: childbearing-age women, pregnancy, child and adolescents, elderly

Question 21

Treatment of Manic episode

Answer 21

Acute manic episode / Mixed episode:
- Referral to specialist necessary ∵ aggression, excessive spending, disinhibited behavior
- Insight and judgment are usually impaired early

CANMAT guideline:
1. **Lithium
2. **Valproate
3. Atypical antipsychotic
- ***Quetiapine
- Risperidone
- Aripiprazole
- Palliperidone (>6mg)
- Asenspine

Approach:
Monotherapy
—> Combination: Lithium / Valproate + Atypical antipsychotic
—> Re-evaluate diagnosis + consider ***ECT (electroconvulsive therapy) (if need of rapid response e.g. violence risk)

(**Lithium: better for controlling manic phase vs **Lamotrigine: better for controlling depressive phase
***Quetiapine: can be used for both Manic + Depressive episode)

Question 22

Treatment of Depressive episode

Answer 22

Referral to a specialist should be considered:
∵ recognised risk of switching to manic or mixed episodes + high risk of ***suicide

**Bipolar 1 depression:
Drugs:
1. **Lithium (0.8-1.2 mEq/L)
2. **Lamotrigine (sometimes require higher than 200mg/day)
3. **Quetiapine (aim at 300mg/day)
4. Lurasidone
5. Valproate / Lithium + Lurasidone

Approach:
Monotherapy: Lithium / Lamotrigine / Quetiapine
—> Add ***Antidepressants (SSRI / Venlafaxine) OR Combine 2 monotherapy agents
—> Re-evaluate diagnosis + consider ECT (for patients with high suicidal risk)

(**Lithium: better for controlling manic phase vs Lamotrigine: better for controlling depressive phase
**Quetiapine: can be used for both Manic + Depressive episode)

**Bipolar 2 depression:
1st line
1. **Quetiapine
2nd line
2. **Lamotrigine
3. **Lithium
4. Antidepressants, such as sertraline, venlafaxine
3rd line
5. Valproate

Question 23

Prophylactic / Maintenance treatment

Answer 23

Indications:
1. **Established bipolar disorder
2. **Recurrent episodes of mania / depression
3. ***Severe single episode with suicidal attempts, psychotic episodes and significant functional impairment (to prevent future relapse)

• Recurrence rates of 60-80% after discontinuation of lithium or antipsychotic therapy, 20-50% during ongoing therapy
• Gradual discontinuation better than abrupt discontinuation

Duration:
- No strict guidelines
- **Lifelong probably
- At least a few years without relapse
- Absence of **subsyndromal symptoms between mood episodes is a pre-requisite

Bipolar 1:
1. Monotherapy: **Lithium / Valproate / **Quetiapine
2. Psychosocial (as Augmentation)
- Psycho-education
- CBT
- Interpersonal and social rhythm therapy
- Family or carer-focused treatment
- Peer support
- Intensive case management
- Less hostile, more supportive, better drug compliance

(NB: Drugs used during acute episode will be continued. When remission is attained, gradual reduction in dosage and number of drugs)

Bipolar 2:
1st line
1. **Quetiapine / **Lithium / Lamotrigine
2nd line
2. Venlafaxine
3rd line
3. Valproate
4. Carbamazepine
5. Other antidepressants
6. Risperidone

Question 24

Poor prognostic factors

Answer 24

1. ***Early onset
2. Greater severity, ***mixed episodes, repeated episodes, previous hospitalizations
3. ***Residual mood symptoms, Cognitive impairment
4. ***Poor insight, SE of medications
5. ***Comorbid substance / Personality disorder

Question 25

Pregnancy and Lactation

Answer 25

Pregnancy:
- Most drugs belong to class C / D (FDA classification: risk cannot be ruled out / positive evidence of risk) —> Dose dependent
- Stopping drug will increase the chance of relapse
- Stopping drug abruptly even higher
- Postpartum period: high risk of relapse (restart drug if stopped during pregnancy)

1. ***Lithium (D)
   - x3 abnormalities of all types
   - x7 cardiac abnormalities
   - Ebstein anomaly (SpC Psychi PP)
   - Neonatal goitre (SpC Psychi PP)
2. ***Valproate (D)
   - congenital malformation and developmental delay
   - FDA recommendation: valproate should not be used in female children, adolescents and women of childbearing age unless alternatives are ineffective)
3. Lamotrigine (C), Topiramate (C)
   - low risk of cleft lip / palate in neonates
4. Quetiapine, Olanzapine (C)
5. SSRI (C)
6. ***BDZ (D)

Lactation:
- Safer (Level 2): Lamotrigine, Quetiapine, Risperidone, SSRI
- Moderately safe (Level 3): Aripiprazole, Clozapine
- Possibly hazardous (Level 4): **Lithium, **Valproate

Question 26

***SE of Lithium

Answer 26

Subjective:
- Nausea
- Polydipsia
- Polyuria
- Fatigue
- Mild tremor

Systemic:
- **Renal dysfunction
- **Hypothyroidism
- Poor memory
- **QT prolongation
- **Teratogenic
- Narrow therapeutic margin
- Moderate weight gain
(- ***Nephrogenic DI)

Monitor:
1. Lithium level (>=once a year)
2. RFT
3. TFT
4. ECG

Prescribing:
- Start with 250-500 mg/day
- Lithium ***0.6-1.0 mmol/L (lower maintenance level for patients with renal dysfunction)

**Lithium toxicity (Medical emergency):
- Poor motor coordination
- Ataxia
- Muscle twitching
- Slurred speech
- Confusion
—> **Stop at once + **High intake of fluid + **Osmotic diuresis by extra NaCl
—> ***Renal dialysis (severe cases)

Risk factors of Lithium toxicity (SpC Psychi PP):
1. Dehydration
2. Renal impairment
3. Drugs (e.g. NSAID, ACEI, Diuretics)
4. Na depletion (e.g. Low salt diet)

Question 27

***SE of Valproate

Answer 27

Subjective:
- Nausea
- Vomiting
- Diarrhoea
- Tremor
- Sleepiness

Systemic effects:
- **Significant weight gain (common)
- **Hepatic derangement (uncommon)
- Haematological abnormalities (uncommon)
- **Hair thinning or loss (common)
- **Polycystic ovary syndrome (PCOS) (uncommon)
- ***Teratogenic

Prescribing:
- Start with 500 mg/day
- Within therapeutic range (according to response + SE)

Question 28

***SE of Lamotrigine

Answer 28

Subjective:
- Headache
- Fatigue
- Dizziness
- Dry mouth

Systemic:
- Rash
- ***Steven-Johnson Syndrome (Box warning)

Prescribing:
- ***Very safe drug (except SJS), well-tolerated
- Start with 25 mg/day in the first 2 weeks (to avoid SJS)
- If combine with anticonvulsants, start with 12.5 mg/day
- Aim at 50-300 mg/day
- Tailor the dose according to response + SE

Question 29

***SE of Quetiapine

Answer 29

Subjective:
- Dry mouth
- Sleepiness

Systemic:
- Weight gain
- **Metabolic syndrome
- **Type 2 DM
- ***Dyslipidemia

• Treatment of bipolar disorder requires around 200-400 mg/day for mild manic cases or depression cases, but up to 800 mg for severe manic cases
• Tailor the dose according to response + SE

Question 30

***SE of Olanzapine

Answer 30

Subjective:
- Sleepiness

Systemic:
- Weight gain
- **Metabolic syndrome
- **Type 2 DM
- **Dyslipidemia
- **Highest risk among atypical antipsychotics

Prescribing:
- Start with 5 mg/day
- Aim at 10-20 mg/day
- Tailor the dose according to response + SE

Question 31

***Baseline laboratory investigations

Answer 31

1. CBP, LRFT (24 hr Cr clearance (if history of renal disease))
2. TFT
3. Fasting glucose + Lipid profile
4. Urine for toxicology (if relevant)
5. Pregnancy test (if relevant)
6. ECG (if relevant)

Question 32

Drug interaction

Answer 32

1. **Lithium (narrow therapeutic margin)
   - Diuretics
   - **NSAID
   - CCB
   - ACE-I
2. Valproate (wider margin) (***enzyme inhibition: raised levels)
   - Aspirin
   - Anticoagulants
   - Lamotrigine
   - Other anticonvulsants
3. Carbamazepine (***CYP3A4 induction: reduced levels)
   - Oral contraceptives
   - Antipsychotic
   - BDZ
   - Phenytoin
4. Lamotrigine (inhibition):
   - Anticonvulsants

Potential negligence claims:
Cases who visit GP and given NSAID for flu/pain can result in toxic level of Li

Question 33

Summary

Answer 33

• Bipolar disorder is underrecognized and undertreated
• The challenge in long term management is the prevention of relapses, subsyndromal symptoms and functional disability
• Avoid antidepressants if possible; if used, limit dose & duration
• Lithium is still an important drug, given that it is the only mood stabilizer to reduce suicide
• Atypical antipsychotics look promising as mood stabilizers, but limited by side effects
• Lamotrigine is a promising agent for treatment of bipolar depression due to its tolerability and wide therapeutic margin (except SJS)
• Psychosocial intervention is important for prevention of relapses and overall management of bipolar disorder