GC163 I Am A Superman Bipolar Disorder
Bipolar disorder is a chronic mood disorder characterized by episodic fluctuations between mania (or hypomania)—during which grandiose delusions such as believing oneself to be a superhero may occur—and depression, with intervening periods of euthymia.
Bipolar Disorder — "I Am a Superman"
The Big Idea: Bipolar disorder is an episodic mood disorder characterised by pathological mood elevations (mania/hypomania) and depressive episodes, creating substantial personal and public burden. The core clinical challenge is correct longitudinal diagnosis (both under- and overdiagnosis are harmful), phase-specific acute treatment, and maintenance care that reduces recurrence, suicide risk and functional disability. This lecture by KF Chung (HKU Psychiatry) covers classification, diagnosis, differential diagnosis, course, aetiology, pharmacotherapy, special populations and psychosocial management. [1]
Learning Objectives (inferred from slide structure):
- Distinguish normal mood fluctuation from pathological mood states.
- Classify mood disorders per DSM-5.
- Apply DSM-5 criteria for manic, hypomanic, depressive episodes and bipolar I/II.
- Recognise the bipolar spectrum and its clinical relevance.
- Formulate the differential diagnosis of mania.
- Understand under- and overdiagnosis pitfalls.
- Describe aetiology (genetic, biological, environmental).
- Outline the course and prognostic factors, and recognise that proposed “staging/neuroprogression” models are conceptual rather than diagnostic standards.
- Manage acute mania, acute bipolar depression, and prophylaxis with appropriate pharmacotherapy.
- Identify side effects, drug interactions, and lithium toxicity.
- Manage bipolar disorder in pregnancy and lactation.
- Appreciate psychosocial interventions and the importance of stigma reduction.
Mood disorders are abnormal mood states with other associated features resulting in distress and functional impairment. [1]
Why this definition matters: Everyone's mood fluctuates. The pathological state is distinguished by:
- Pervasiveness — the abnormal mood is sustained, not fleeting.
- Associated features — cognitive, biological, psychomotor symptoms cluster with the mood change.
- Distress and functional impairment — the condition disrupts daily life.
Mood disorder is episodic. [1]
This is a fundamental conceptual point. Unlike personality disorders (which are trait-based and persistent), bipolar disorder is characterised by discrete episodes separated by periods of relative wellness (euthymia). This has implications for diagnosis (you need to identify past episodes via longitudinal history) and treatment (acute vs. maintenance phases differ).
Mood trajectory over time: The episodic course can be visualised as a fluctuating line crossing through levels of mania → hypomania → euthymia → subthreshold depression → major depression, with periods of mixed state (rapid mood fluctuation crossing above and below the euthymic range). Between episodes, patients may return to euthymia or remain at subthreshold symptom levels. [1]
DSM-5 splits mood disorders into two major branches: Bipolar Disorders and Depressive Disorders. [1]
| Bipolar Disorders | Depressive Disorders |
|---|---|
| Bipolar I disorder | Major depressive disorder (single/recurrent) |
| Bipolar II disorder | Dysthymic disorder (persistent depressive disorder) |
| Cyclothymic disorder | Other depressive disorders |
| Other bipolar disorders |
A distinct period of elevated, expansive or irritable mood AND increased goal-directed activity/energy lasting at least 1 week—or any duration if hospitalisation is necessary. [1]
Three or more of the following (four if mood is only irritable):
- Inflated self-esteem or grandiosity
- Decreased need for sleep
- Pressured speech
- Flight of ideas / racing thoughts
- Distractibility
- Increased goal-directed activity (socially, at work/school, sexually) / psychomotor agitation
- Excessive involvement in pleasurable activities with high potential for painful consequences (buying sprees, sexual indiscretions, foolish business investments) [1]
Marked impairment in functioning, observable by others, to necessitate hospitalization, OR there are psychotic symptoms. [1]
Not due to alcohol, substance or medical conditions. [1]
Mnemonic for manic symptoms: DIG FAST
- Distractibility
- Indiscretion (pleasurable activities with consequences)
- Grandiosity
- Flight of ideas
- Activity increase
- Sleep decreased
- Talkativeness (pressured speech)
Why "increased goal-directed activity" is in criterion A: DSM-5 added this to the core criterion (not just mood) because some manic patients are predominantly irritable rather than euphoric. You must see the energy/activity component alongside mood change. This prevents mislabelling every irritable patient as manic.
Why psychotic features = mania, never hypomania: If psychotic symptoms are present during a mood elevation, by definition it is a manic episode, not hypomanic. This is a key diagnostic discriminator.
At least 4 days of elevated, expansive, or irritable mood AND increased activity or energy. [1]
3 or more manic symptoms (same list as mania). [1]
Change in functioning observable by others but NOT severe enough to cause marked impairment, NOT necessitating hospitalization, and NO psychotic symptoms. [1]
Often missed by patients and doctors, resulting in delayed diagnosis. [1]
Why hypomania is missed:
- Patients feel good during hypomania — they are productive, confident, sociable. They don't seek help.
- They present during depressive episodes and report only depression.
- Doctors forget to systematically ask about past episodes of elevated mood/energy.
- Result: Bipolar II gets misdiagnosed as MDD → inappropriate antidepressant monotherapy → risk of manic switch.
| Feature | Mania | Hypomania |
|---|---|---|
| Duration | ≥1 week | ≥4 days |
| Symptom threshold | ≥3 (or 4 if irritable only) | Same |
| Functional impairment | Marked | Not marked |
| Hospitalization | Often needed | Not needed |
| Psychotic symptoms | May be present | Never present |
5. DSM-5 Criteria — Bipolar I vs Bipolar II
Presence of one single manic episode already satisfies criteria for bipolar I disorder. [1]
Most cases have both manic and depressive episodes. There is a predominant polarity (more manic or more depressive episodes). [1]
The slide states that only 5% have mania without depressive episodes. Treat this as a historical cohort estimate, not a diagnostic criterion or universal prevalence. Depressive episodes are common but never required for bipolar I diagnosis.
Why a single manic episode suffices: Mania is so distinctive and disruptive that its occurrence signals a fundamentally different illness trajectory from unipolar depression. Even one episode carries a > 90% risk of future mood episodes. [1] [5]
At least one hypomanic episode + at least one major depressive episode, with no lifetime manic episode. “Mixed episode” is older terminology; DSM-5/DSM-5-TR uses a with mixed features specifier.
Depressive episodes are more common in bipolar II disorder. [1]
Clinical implication: BP II is NOT "milder bipolar." The depressive burden is often greater than in BP I, and long-term impairment can be equivalent. [1]
Exam Trap
A patient who has ever had a full manic episode cannot be diagnosed with Bipolar II — they are Bipolar I by definition, even if they currently present with depression or hypomania. If a BP II patient later develops a manic episode, the diagnosis is reclassified to BP I.
Includes: [1]
- Short duration hypomanic episodes (2–3 days)
- Hypomanic episodes with insufficient symptoms (2–4 symptoms)
- Drug-induced hypomanic episodes with spontaneous remission
Morbidity and impairment are greater in MDD with bipolarity than MDD without bipolarity. [1]
Why this matters: These subthreshold patterns prompt a more careful longitudinal history, collateral information and follow-up. “Bipolar spectrum” is not permission to diagnose bipolar disorder from ordinary mood lability or to prescribe a mood stabiliser automatically. Borderline personality disorder tends to show rapid, cue-dependent affective reactivity and a pervasive interpersonal/self-image pattern; bipolar episodes are sustained changes in mood and energy/activity with a distinct longitudinal course.
- Chronic mood instability with alternating periods of mild elation and mild depression.
- Neither the highs nor lows meet criteria for hypomania or major depression.
- Duration: ≥2 years of fluctuating mood with no symptom-free period > 2 months.
- Significant distress/functional impairment despite subthreshold episodes.
Mood disorders are heterogeneous conditions. Specifiers are used to better understand patient's characteristic and to select appropriate treatment. [1]
| Specifier | Key Features | Clinical Relevance |
|---|---|---|
| With anxious distress | Prominent anxiety symptoms | May need anxiolytic adjunct; worse prognosis |
| With mixed features | Opposite-polarity symptoms during episode | More difficult to treat; worse outcomes [1] |
| With rapid cycling | ≥4 discrete episodes in 12 months | Review antidepressants, thyroid disease, substances and adherence; select treatment by current phase and prior response rather than assuming one universally preferred drug |
| With melancholic features | Near-complete absence of capacity for pleasure | Better response to biological treatments |
| With atypical features | Mood reactivity, weight gain, hypersomnia | More common in BP II depression |
| With psychotic features | Delusions/hallucinations | Mood-congruent vs mood-incongruent |
| With peripartum onset | Episode begins during pregnancy or within 4 weeks after delivery in DSM-5/DSM-5-TR | Requires a perinatal risk and treatment plan; postpartum psychosis/mania can deteriorate rapidly and is an emergency |
| With seasonal pattern | Depression begins in fall/winter, remits in spring | Light therapy may help |
High Yield — Rapid Cycling
The slide's 10–15% figure is a lecture-era estimate. The durable exam definition is ≥4 distinct mood episodes in 12 months; ultradian mood shifts are not “rapid cycling.” Outcomes can be poorer, but claims that rapid cycling automatically means lithium resistance or mandates valproate are too categorical.
9. Differential Diagnosis of Manic Episode
Differential diagnosis includes: [1]
- Depressive disorder with irritability and anxious distress
- Psychotic disorder or schizoaffective disorder
- Substance/medication-induced or medical conditions
- Attention deficit and hyperactivity disorder
- Personality disorder with prominent irritability
| Feature | Mania with psychotic features | Schizophrenia |
|---|---|---|
| Mood | Elated or irritable, mood-congruent psychosis | Flat/incongruous affect |
| Delusions | Grandiose, persecutory (linked to grandiosity) | Bizarre, passivity, thought alienation |
| FTD | Flight of ideas (logical links preserved) | Loosening of association, neologism, thought blocking |
| Speech | Pressured, difficult to interrupt | Hesitant, halting |
| Sleep | Decreased need (not tired) | Less prominent |
| Onset | Episodic | Insidious |
| Hallucinations | Mood-congruent (voices about special powers) | Mood-incongruent, often 3rd person running commentary |
| First-rank symptoms | 10–20% may have (usually fleeting) | More prominent and persistent |
Drugs: Steroids, L-dopa, stimulants, antidepressants, ECT (in those with bipolar spectrum disorder) [1] Substances: Cocaine, amphetamine [1] Medical: Frontal lobe lesion, hyperthyroidism, Cushing's syndrome [1]
Why these cause mania:
- Steroids/L-dopa/stimulants/cocaine/amphetamine → increase dopaminergic/noradrenergic transmission → euphoria, psychomotor activation.
- Antidepressants → can "switch" a bipolar patient into mania (this is why antidepressant monotherapy is dangerous in bipolar).
- Frontal lobe lesions → disinhibition, personality change (pseudo-manic presentation).
- Hyperthyroidism → sympathetic overactivity mimicking the biological features of mania (agitation, insomnia, weight loss).
- Cushing's syndrome → cortisol excess → psychiatric manifestations including mania and psychosis.
10. Misdiagnosis: Under- and Overdiagnosis
Hypomanic episode is often overlooked. Patients with BP II are misdiagnosed as having major depressive disorder. [1]
Manic episode with psychotic symptoms misdiagnosed as schizophrenia. [1]
Among 600 patients with bipolar disorder, 69% were initially misdiagnosed and most frequently as major depression, followed by anxiety disorders, substance or alcohol use disorder. [1]
Correct diagnosis and treatment was delayed by 5–7 years on average. [1]
Consequences of underdiagnosis: [1]
- Untreated mood symptoms → 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
Due to incorrect understanding of the term "manic" "躁". [1]
Among 180 outpatients previously diagnosed with bipolar disorder, structured interview could not confirm the diagnosis in 43 (33%) of them. [1]
Only 43% of 145 patients with a previous diagnosis of bipolar disorder had the condition confirmed by structured interview. [1]
Consequences of overdiagnosis: [1]
- Unnecessary side effects of mood stabilizers
- Increased sick role and disability claims
Requires informants and collateral information (e.g., medical record) to confirm past history of mania/hypomania. [1]
It is important to follow diagnostic criteria in making psychiatric diagnosis. [1]
The MDQ is a brief self-report screening instrument with three components: [1]
- 13 lifetime symptom questions — each answered YES/NO, covering core hypomanic/manic experiences (e.g., feeling hyper, irritability, increased self-confidence, decreased need for sleep, pressured speech, racing thoughts, distractibility, increased energy/activity, hypersociality, hypersexuality, risky behaviour, spending sprees).
- Co-occurrence question — "Have several of these ever happened during the same period of time?" (YES/NO).
- Functional impact question — "How much of a problem did any of these cause you?" (No problem / Minor / Moderate / Serious problem).
A commonly used positive-screen rule is ≥7 “YES” responses to Q1, “YES” to Q2, and at least moderate impairment on Q3. Performance and cut-offs vary by setting. MDQ/HCL-32 are screens, not diagnoses; a positive result requires a clinical interview, episode duration/impairment, secondary-cause assessment and collateral history.
History from the patient + Collateral information from informants + Screening tools: [1]
- Mood Disorder Questionnaire (MDQ)
- Hypomania Checklist (HCL-32)
11 items, total score 0–60. [1] The slide gives ≥20 for mania and ≥12 for hypomania, but these are study/service cut-offs, not DSM diagnostic thresholds.
Items (starred items scored 0–8, others 0–4): [1]
- Elevated mood
- Increased motor activity/energy
- Sexual interest
- Sleep
- Irritability
- Speech (rate and amount)
- Language – thought disorder
- Content
- Disruptive-aggressive behavior
- Appearance
- Insight
Why some items are double-weighted (0–8): Irritability, speech, content, and disruptive-aggressive behaviour are given more weight because they are the features most likely to require acute management (hospitalization, risk to self/others).
YMRS administration details: [1]
- Described as the "gold standard" for measuring severity of manic symptoms.
- Designed primarily for in-patient use but can also be used in outpatient settings to assess stability and treatment response.
- Administered by a clinician (not patient self-report); takes 20–30 minutes.
- Scores are based on both patient responses and clinician observations over the preceding 48 hours.
- The scale does not measure depressive symptoms, which may coexist in bipolar illness.
YMRS is a severity instrument, not a diagnostic test
The visual form on slide 21 combines interview responses with clinician observation over the preceding 48 hours. A score tracks severity and treatment response; it cannot by itself establish episode duration, functional impairment, exclusion of substances/medical causes or a bipolar diagnosis.
The prevalence, diagnostic-delay, episode-count and disability rankings on slide 23 come from older heterogeneous datasets. Retain them as historical lecture figures, not fixed contemporary rates.
Mean age at onset for first mood episode is about 18 years for BP I, but accurate diagnosis is often delayed by 5–10 years. [1]
83% of cases have > 4 episodes; 43% have > 7 episodes. [1]
The slide's “one third attempted” and “10–20% died by suicide” figures are historical estimates and should not be applied to an individual patient. The clinical message is current: assess suicide risk directly at every depressive, mixed or rapidly changing presentation; a previous attempt, current intent/plan, agitation, substance use and prominent depressive/mixed symptoms increase concern.
9th leading cause of disability-adjusted life years under mental, neurological, and substance use disorders (depressive disorder is the 1st cause). [1]
No gender and ethnic difference. [1]
Risk Factors
Risk factors for bipolar disorder: [1]
- High income countries (may be due to referral bias)
- Low income, separated, divorced, or widowed
- Low care and overprotective parents, poor attachment relationship, childhood abuse
- Family history of bipolar disorder and schizophrenia
- Monozygotic concordance 40–70%
- Lifetime risk in first-degree relatives 5–10%, roughly 7× higher than general population
- No gender and ethnic difference
13. Psychiatric and Medical Comorbidity
Comorbidities are common. Need to treat BOTH bipolar disorder and the comorbid conditions. [1]
Sleep disorder, eating disorder, ADHD, psychotic disorder, anxiety disorder, substance use disorder, personality disorder [1]
How to read the hub diagram: bipolar disorder sits at the centre because each surrounding disorder can (a) mimic an episode, (b) precipitate relapse, (c) worsen suicide/physical-health risk, and (d) change treatment selection. It does not mean every patient has every comorbidity.
Comorbid Anxiety Disorders (vs general population): [1]
| Anxiety Disorder | OR (vs general pop.) |
|---|---|
| Panic disorder | 9.1 |
| OCD | 11.5 |
| GAD | 4.3 |
| Social phobia | 4.1 |
| PTSD | 3.9 |
Prevalence of anxiety disorders in BD is as common as in MDD. [1]
Comorbid Substance Use Disorders: [1]
- Drug abuse/dependence: OR 5.2 vs general population; OR 3.7 vs MDD
- Alcohol abuse/dependence: OR 3.4 vs general population
Drug abuse is more common in BD than in MDD. [1]
The odds-ratio tables on slides 25–26 are historical cross-study comparisons with wide confidence intervals and differing ascertainment. Use them to recognise the direction and importance of comorbidity, not as fixed contemporary probabilities for an individual.
Higher risk of cardiovascular and metabolic diseases (obesity, diabetes, hypercholesterolaemia). [1]
Risk factors include: alcohol/substance use, unhealthy diet, physical inactivity, social isolation, unemployment, stress, poor sleep, childhood abuse, side effects of pharmacotherapy (valproate, atypical antipsychotics). [1]
14. Aetiology
Multifactorial approach [1]
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]
Biochemical pathways: especially dopaminergic, second messengers, mitochondrial, HPA axis, and thyroid. [1]
Neuroimaging findings: structural and functional abnormalities. [1]
Infective causes, e.g., Toxoplasma gondii (the associated immune response). [1]
Life events and social support, low care and overprotective parents, poor attachment relationship, childhood abuse, sleep deprivation, circadian and social rhythm disruption. [1]
None of them are specific biomarkers. [1]
How to read the four-panel brain figure: the biochemical, structural-imaging, functional-imaging and connectivity/association panels show group-level research signals. None has sufficient specificity to diagnose bipolar disorder in an individual, and routine neuroimaging is for suspected secondary pathology rather than confirmation of bipolar illness.
Why circadian rhythm matters: Bipolar patients have dysregulated circadian clocks. Sleep deprivation can precipitate mania. Social rhythm disruption (jet lag, shift work, irregular daily routines) destabilises mood. This is why Interpersonal and Social Rhythm Therapy (IPSRT) is an evidence-based psychosocial treatment — it regularises daily routines and sleep-wake cycles.
15. Course of Illness
Most manic episodes recover eventually, but residual symptoms are more common after depressive episodes. [1]
Untreated manic episodes can last 4–6 months (median duration). [1]
Most cases have relapses if they are not put on maintenance pharmacotherapy. [1]
In average, 4 major episodes in the first 10 years, getting more frequent then stabilising at around once per year. [1]
First-episode bipolar — 1-year naturalistic follow-up: A survival curve analysis showed that by 12 months after a first episode, cumulative survival (i.e., remaining relapse-free) was approximately 46% for any mood episode, 59% for depression, and 75% for mania. This indicates that depressive relapse is more common than manic relapse after a first episode. [1]
Functional recovery: 43%. Relapse: 40%. [1]
Outcomes for mixed episodes and rapid cyclers are worse. [1]
Chance of relapse is higher in those with previous relapse. [1]
Recognition of prodromes and early treatment can reduce relapse. [1]
Recurrence rate reduces by 50% for maintenance vs. discontinuation. [1]
Stage 1: High-risk group (positive FH) or patients with subsyndromal symptoms [1] Stage 2: Patients with a few episodes and optimal functioning [1] Stage 3: Recurrent episodes and decline in functioning and cognition [1]
Neuroprogression theory: worse prognosis with frequent relapses; possible later cognitive risk. [1]
Staging is conceptual
Slide 34 presents a proposed high-risk → few-episode → recurrent/functional-decline model. It is not a validated DSM/ICD staging system, and association between recurrence, cognition and later dementia does not prove that every episode causes irreversible brain damage. The practical rationale for maintenance treatment is demonstrated relapse prevention and preservation of function—not a claim of guaranteed “neuroprotection.”
Outline of management: [1]
- Correct diagnosis
- Illness acceptance and treatment adherence
- Family psychoeducation
- Pharmacological and psychosocial treatment
- Acute manic episode
- Acute depressive episode
- Maintenance and prophylactic treatment
- Special situations: childbearing-age women, pregnancy, children/adolescents, elderly
- Treatment of psychiatric and medical comorbidity
18. Acute Treatment of Mania and Mixed Episodes
Referral to a specialist for in- or out-patient care is necessary because of aggression, excessive spending and disinhibited behaviour. Insight and judgment are usually impaired early. [1]
Consider hospitalization when: [1]
- Presence of psychotic symptoms (mood-congruent or mood-incongruent)
- Severe overactivity
- Bizarre behaviour
- Excessive spending
- Incoherent speech
- Disorganised thinking
- Mixed episode (more difficult to treat)
First-line monotherapy options: lithium, divalproex/valproate, quetiapine, risperidone, aripiprazole, paliperidone, asenapine, or cariprazine. Choice depends on severity, previous response, comorbidity, adverse-effect risk, reproductive potential, and the need for rapid behavioural control. [8]
Combination treatment: lithium or divalproex plus an atypical antipsychotic is appropriate when mania is severe or a single agent is insufficient. [8]
Urgent or treatment-resistant illness: re-check diagnosis, substances, adherence and medical contributors; consider ECT when a rapid response is required, including severe agitation, catatonia, dangerousness, or failure of adequate pharmacotherapy. [8]
Why atypical antipsychotics work in mania: Mania involves dopaminergic overactivity (hence grandiosity, psychomotor agitation, psychosis). Atypical antipsychotics block D2 receptors (controlling psychotic and agitation symptoms) while also modulating serotonin pathways (contributing to mood stabilisation).
A network meta-analysis in the slides compares symptom-score change against placebo. It is not a bedside ranking: indirect comparisons, trial populations, tolerability, confidence intervals and study quality all matter. The tiny tamoxifen estimate shown elsewhere in the figure is especially imprecise and does not make tamoxifen a guideline treatment. [1,8]
| Drug | SMD (95% CrI) |
|---|---|
| Risperidone | 0.65 (0.44–0.85) |
| Haloperidol | 0.54 (0.38–0.70) |
| Olanzapine | 0.48 (0.34–0.62) |
| Cariprazine | 0.47 (0.22–0.73) |
| Lithium | 0.45 (0.30–0.61) |
| Carbamazepine | 0.44 (0.15–0.71) |
| Paliperidone | 0.37 (0.08–0.66) |
| Aripiprazole | 0.37 (0.20–0.55) |
| Asenapine | 0.36 (0.08–0.63) |
| Quetiapine | 0.35 (0.14–0.56) |
| Valproate | 0.32 (0.15–0.50) |
| Lamotrigine | 0.13 (−0.16–0.44) — not significant |
| Topiramate | −0.07 (−0.28–0.15) — not significant |
The durable message is that several antipsychotics, lithium and divalproex are effective, while lamotrigine and topiramate are not acute antimanic treatments. [1,8]
Why ECT for mania? ECT has rapid onset of action and is effective for both mania and depression. In treatment-resistant or dangerous presentations (catatonia, high violence risk, refusing oral medications), ECT can be life-saving.
19. Acute Treatment of Bipolar Depression
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. [1]
Current CANMAT/ISBD first-line options include quetiapine, lithium, lamotrigine, lurasidone monotherapy, lurasidone plus lithium/divalproex, adjunctive lamotrigine, and cariprazine. Medication-specific dosing and monitoring should follow the current formulary and specialist plan rather than the slide's fixed targets. [8]
- Confirm bipolar depression, suicide risk, mixed/manic symptoms, psychosis, substances, physical illness, adherence and current medication exposure.
- Use a first-line bipolar-depression treatment and optimise adherence/dose/tolerability.
- If response is inadequate, switch or combine evidence-based bipolar treatments. Adjunctive SSRI or bupropion is a second-line option for selected pure depression, not an automatic next step.
- Consider ECT when a rapid response is needed, including severe suicidality, catatonia, psychotic depression, or inability to maintain nutrition/hydration. [8]
First line: Quetiapine [1] Second line: Lamotrigine, lithium, or—only for selected pure/non-mixed depression—sertraline or venlafaxine [8] Third line: Valproate [1]
High Yield — Antidepressants in Bipolar Depression
Do not use antidepressant monotherapy for bipolar I depression. If an antidepressant is selected, use it adjunctively, educate about switching/cycle acceleration, and stop if early mania emerges. Avoid or use particular caution with current/predominant mixed features, recent rapid cycling, or a previous antidepressant-induced switch. Sertraline or venlafaxine may be considered second-line in selected bipolar II pure depression; that exception does not make antidepressants first-line. [8]
20. Prophylactic (Maintenance) Treatment
Established bipolar disorder with recurrent episodes of mania or depression. [1] Severe single episode with suicidal attempts, psychotic episodes and significant functional impairment. [1] Recurrence rate reduces by 50% for maintenance vs. discontinuation. [1] Gradual discontinuation is better than abrupt discontinuation. [1]
The slide pools recurrence estimates from different studies and time points; it is not one cohort followed continuously. Maintenance treatment nevertheless consistently reduced recurrence: [1]
| Time | Maintenance | Discontinuation | RR (95% CI) | NNTB (95% CI) |
|---|---|---|---|---|
| 6 months | ~32% | ~53% | 0.61 (0.54–0.70) | 5 (4–6) |
| 12 months | ~42% | ~65% | 0.63 (0.55–0.72) | 4 (3–6) |
| 24 months | ~39% | ~75% | 0.49 (0.45–0.52) | 2 (2–3) |
The apparent change in NNTB must not be interpreted as a simple within-cohort time trend. Abrupt withdrawal can itself precipitate relapse, especially with lithium, so planned discontinuation should be gradual and monitored. [1,9]
Lithium is a preferred long-term treatment. Other evidence-based options include quetiapine, divalproex, lamotrigine, asenapine, selected antipsychotics/long-acting formulations, and phase-specific combinations. Lamotrigine is more useful against depressive than manic relapse; a risperidone LAI is more useful against manic than depressive relapse. Do not over-read the slide's old network plot as a universal ranking. [8,9]
Psychosocial (augmentation): [1]
- 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. [1]
Maintenance is often long term and may be lifelong after severe, recurrent, psychotic, suicidal or highly impairing illness, but duration is individualised. Discuss past course, residual symptoms, consequences of relapse, response, adverse effects, patient preference and available monitoring. If lithium is stopped, NICE recommends tapering over at least 4 weeks and preferably up to 3 months, then monitoring closely for 3 months. [9]
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. [1]
21. Pharmacotherapy — Side Effect Profiles
Side effects of Lithium: [1]
| Subjective Effects | Systemic Effects |
|---|---|
| Nausea | Renal dysfunction |
| Polydipsia | Hypothyroidism |
| Polyuria | Poor memory |
| Fatigue | QT prolongation |
| Mild tremor | Teratogenic |
| Narrow therapeutic margin | |
| Moderate weight gain |
Start with low dose long-acting Li. Li level 0.6–1.0 mmol/L (lower maintenance level for patients with renal dysfunction). [1]
Why lithium causes nephrogenic DI: Lithium reduces aquaporin-2 (AQP2) expression in renal collecting ducts → impaired water reabsorption → polyuria and polydipsia. This is a form of nephrogenic diabetes insipidus. [6]
Why lithium causes hypothyroidism: Lithium inhibits thyroid hormone release (blocks iodine uptake and thyroglobulin coupling). Monitor TFTs regularly.
Lithium and renal function: A meta-analysis of before-and-after studies found a combined mean increase in serum creatinine of 2.9 µmol/L (95% CI: −1.4 to 7.4) after lithium treatment, which was not statistically significant (p = 0.19). However, heterogeneity was substantial (I² = 68%). Among patients whose eGFR fell below 60 mL/min/1.73 m² at the time of lithium discontinuation, trajectories were heterogeneous — only 3 out of 13 patients progressed to end-stage renal disease. [1]
Lithium and suicide risk
Lithium is associated with lower suicide and self-harm risk and remains an important first-line maintenance treatment. The lecture's “only mood stabiliser proven” wording is too absolute: suicide prevention also requires direct risk assessment, treatment of the current episode, means-safety planning, psychosocial care and follow-up. [8,9]
Side effects of Valproate: [1]
| Subjective | Systemic |
|---|---|
| Nausea, vomiting, diarrhoea | Significant weight gain |
| Tremor | Hepatic derangement |
| Sleepiness | Haematological abnormalities |
| Hair thinning or loss | |
| Polycystic ovarian syndrome | |
| Teratogenic |
Start with 500 mg/day. Dose within therapeutic range according to response and side effects. [1]
Valproate and reproductive risk
Valproate has major teratogenic and neurodevelopmental risks. Under current UK/MHRA restrictions, it must not be used in women or girls able to have children unless Pregnancy Prevention Programme conditions are met; initiation in anyone younger than 55 years generally requires two specialists to agree that no effective/tolerated alternative exists or that reproductive risk does not apply. Men also require counselling about possible reproductive risk and contraception. Follow local rules. [10]
Side effects of Lamotrigine: [1]
| Subjective | Systemic |
|---|---|
| Headache, fatigue, dizziness, dry mouth | Rash |
| Steven-Johnson Syndrome (Box Warning) |
Lamotrigine must be titrated according to the exact co-medication schedule. Valproate inhibits its clearance, requiring a lower/slower regimen; enzyme-inducing antiseizure drugs require a different schedule. “Any anticonvulsant = 12.5 mg” is incorrect. Follow the product label/formulary, assess any rash urgently, and use the restart schedule after a clinically important interruption. [1]
Why the slow titration: Lamotrigine's risk of Stevens-Johnson Syndrome (SJS) is dose-dependent and related to rate of dose escalation. Starting low and going slow (25 mg/day for 2 weeks, then doubling every 2 weeks) dramatically reduces the risk. Valproate inhibits lamotrigine metabolism, so even slower titration (12.5 mg/day) is needed with co-administration.
Lamotrigine is a promising agent for treatment of bipolar depression due to its tolerability and wide therapeutic margin. [1]
| Drug | Acute Mania | Bipolar Depression | Prophylaxis | Key Side Effects | Special Concern |
|---|---|---|---|---|---|
| Lithium | 1st line | 1st line (BP I) | 1st line | Renal, thyroid, calcium, tremor; narrow TI | Associated with lower suicide risk; major interaction burden |
| Valproate | 1st line | Not a preferred bipolar-depression monotherapy | Maintenance option with restrictions | Weight gain, liver, haematological and reproductive harms | Follow stringent reproductive-risk rules |
| Lamotrigine | Not used | 1st line (BP I/II) | 1st line (BP II) | SJS (slow titration!) | Best tolerated for depression |
| Quetiapine | 1st line | 1st line (BP I/II) | 1st line | Metabolic syndrome | Versatile across all phases |
| Olanzapine | Used | Not 1st line | Less preferred | Highest metabolic risk | Monitor weight/glucose/lipids |
Monitoring is drug-specific, not a universal battery or routine 24-hour creatinine clearance:
| Treatment/context | Core checks |
|---|---|
| Lithium | Urea/electrolytes and eGFR, calcium, thyroid function, weight/BMI, pregnancy assessment where relevant; ECG for cardiac disease/risk. Check a trough lithium level after initiation/dose or interacting-drug changes and at the locally specified maintenance interval. |
| Valproate | Full blood count, liver tests, weight/BMI, pregnancy/reproductive-risk requirements; repeat according to symptoms and local guidance. |
| Antipsychotic | Weight/BMI, waist/BP, glucose or HbA1c, lipids, movement effects and ECG when indicated. |
| Diagnostic context | Toxicology only when substance exposure is plausible; assess thyroid/medical mimics according to presentation. |
The visual checklist in the slide is a prompt, not a one-size-fits-all order set. [9]
Lithium levels commonly rise with thiazide diuretics, NSAIDs, ACE inhibitors and ARBs because renal lithium clearance falls. Calcium-channel-blocker effects are variable and should not be memorised as a universal “level rises” rule. [1,9]
Potential negligence claims: doctors prescribing NSAID for flu/pain can result in toxic level of Li. [1]
Valproate inhibits lamotrigine metabolism and raises lamotrigine exposure — not the reverse. Aspirin can increase free valproate through protein-binding displacement; anticoagulants mainly compound bleeding risk rather than predictably “raising the valproate level.” [1]
Carbamazepine is a potent enzyme inducer and can reduce hormonal-contraceptive and many psychotropic drug concentrations. Its interaction with phenytoin is bidirectional and variable, so levels and clinical effect—not a one-way arrow—guide management. [1]
Lamotrigine is not usefully remembered as a general enzyme inhibitor. Valproate raises lamotrigine; enzyme inducers lower it; oestrogen-containing contraceptives can lower lamotrigine substantially. [1]
Exam Favourite — Lithium + NSAID/Diuretic/ACEI
This is a classic drug interaction question. Lithium has a very narrow therapeutic index. Anything that reduces renal blood flow or GFR (NSAIDs, ACEi, diuretics) will decrease lithium excretion → toxicity. Always check lithium levels when co-prescribing these drugs.
Medical emergency. [1] Symptoms: Poor motor coordination, ataxia, muscle twitching, slurred speech, confusion. [1]
Treatment: stop lithium, assess urgently, obtain serial lithium/electrolyte/renal measurements and ECG, give isotonic IV crystalloid when volume depleted, and involve toxicology/nephrology early. Do not use forced or “osmotic” diuresis. [11]
Interpret concentrations in context: toxicity depends on acute versus chronic exposure, time since ingestion, renal function and symptoms; a patient with chronic toxicity can be very unwell at a concentration that looks less dramatic. Progressive features include coarse tremor, ataxia, dysarthria, confusion, seizures, coma and dysrhythmia.
| Lithium Level | Clinical Significance |
|---|---|
| 0.6–1.0 mmol/L | Therapeutic maintenance range |
| Phase-specific target | Set using the current guideline/local protocol, age, response and adverse effects; obtain a correctly timed trough sample |
| > 1.5 mmol/L | Often toxic, but symptoms/exposure context are essential |
| > 2.0 mmol/L | Greater concern; not by itself a complete dialysis rule |
When to consider extracorporeal treatment
EXTRIP recommends dialysis for severe lithium poisoning, including impaired kidney function with lithium > 4.0 mmol/L, decreased consciousness, seizures, or life-threatening dysrhythmia irrespective of level; it suggests dialysis for lithium > 5.0 mmol/L, significant confusion, or when the predicted time to fall below 1.0 mmol/L exceeds 36 hours. Use toxicology/nephrology advice because rebound and repeated levels matter. [11]
25. Pregnancy and Lactation
The slide's FDA A/B/C/D/X categories are obsolete: the FDA replaced them with narrative Pregnancy and Lactation Labeling Rule sections from 2015. Risk–benefit decisions should weigh untreated bipolar illness, episode severity, previous response, gestation, dose/polypharmacy, maternal health and fetal/neonatal effects. [12]
| Drug/group | Current clinical framing |
|---|---|
| Lithium | Cardiac-malformation risk is increased but smaller than the slide's old “×7” teaching implies. It may still be the best option after individualised perinatal-specialist counselling, dose/level and renal/thyroid monitoring, and a delivery/postpartum plan. |
| Valproate | Avoid in pregnancy and follow stringent pregnancy-prevention/regulatory restrictions because of major malformation and neurodevelopmental risks. [10] |
| Lamotrigine | Often considered when depressive-predominant illness warrants it; clearance changes substantially during and after pregnancy, so clinical/level monitoring may be needed. |
| Antipsychotics | Choice is individualised by previous response and metabolic, obstetric and neonatal risks; no class-wide “safe” label. |
Topiramate is not a standard bipolar-disorder treatment and should not be substituted into a reproductive-risk hierarchy as though it were one. [8,13]
Stopping drug will increase the chance of relapse. Stopping drug abruptly even higher. [1]
Postpartum period: high risk of relapse. [1]
A potential area for medical negligence claims. [1]
Clinical approach to pregnant bipolar patient:
- Pre-conception planning is ideal — discuss risks with patient and partner.
- If medication is needed, choose the option with the best individual balance of relapse prevention and reproductive safety; there is no universal “lowest-risk” drug.
- Review lithium and urgently avoid valproate exposure where possible, but do not stop an effective drug abruptly without a specialist relapse-prevention plan.
- Use preconception folate and obstetric advice according to local guidance; folate does not eliminate valproate's neurodevelopmental risk.
- Close monitoring during pregnancy and especially postpartum (highest risk period for relapse/new onset psychosis).
The slide's “safety level” table is outdated and misleading. Decisions depend on infant gestation/health, milk transfer, dose, combination therapy and ability to monitor. [14]
- Valproate can be used cautiously during breastfeeding of a full-term healthy infant with infant monitoring; it is not automatically “possibly hazardous.”
- Lithium may occasionally be used only with extreme caution under specialist care and strict infant clinical, lithium, renal and thyroid monitoring.
- Lamotrigine and antipsychotics require drug-specific infant observation. Clozapine is generally avoided because of serious infant adverse-effect potential; aripiprazole may suppress milk supply.
- Protect maternal sleep and create an urgent relapse plan: postpartum mania/psychosis is an emergency. [13,14]
Psychosocial intervention is important for prevention of relapses and overall management of bipolar disorder. [1]
| Intervention | Mechanism / Purpose |
|---|---|
| Psychoeducation | Understanding illness, recognising prodromes, improving adherence |
| CBT | Addressing negative cognitions, relapse prevention |
| Interpersonal and social rhythm therapy | Regularising daily routines and sleep-wake cycles (circadian stabilisation) |
| Family/carer-focused treatment | Reducing expressed emotion, improving communication |
| Peer support | Shared experience, reducing isolation |
| Intensive case management | Coordinating multidisciplinary care for complex cases |
- Diagnosis is longitudinal: establish a distinct episode of mood plus energy/activity change, impairment/duration, secondary causes, and collateral history. Avoid both missed hypomania and indiscriminate “bipolar spectrum” labelling.
- Treat the current phase with evidence-based bipolar therapy; acute mania, bipolar depression and maintenance have different evidence bases.
- Do not use antidepressant monotherapy in bipolar I depression. Selected adjunctive use requires switch-risk assessment and monitoring.
- Maintenance treatment, sleep/social-rhythm stability, psychoeducation, family involvement and comorbidity care reduce recurrence and disability.
- Lithium remains a major maintenance option with evidence of lower suicide risk, but requires renal, thyroid, calcium, interaction and toxicity monitoring.
- Reproductive planning is medication-specific: old FDA letter categories and the slide's lactation hierarchy should not guide modern care.
28. Exam Intelligence
| Trap | Correct Understanding |
|---|---|
| "BP II is milder than BP I" | BP II has equivalent long-term impairment; depressive burden is greater |
| "A single manic episode = recurrent BP" | One manic episode = BP I diagnosis (no need for recurrence or depression) |
| "Hypomania can have psychotic features" | Never — psychotic features = mania by definition |
| "Antidepressants are first-line for bipolar depression" | Wrong — use a phase-specific bipolar-depression treatment; never antidepressant monotherapy in bipolar I |
| "Lithium is simply contraindicated in pregnancy" | Wrong — old FDA category D teaching is obsolete; use individualised perinatal risk–benefit planning and monitoring |
| "Valproate reproductive risk is only a pregnancy issue" | Wrong — stringent prescribing/prevention rules and counselling apply before exposure and now include male reproductive-risk advice in some jurisdictions |
| "Rapid cycling means hours of mood change" | Rapid cycling = ≥4 discrete episodes per year (not within a day) |
| "Flight of ideas = loosening of association" | Flight of ideas preserves logical links (mania); loosening of association doesn't (schizophrenia) |
| "Lithium + NSAID is fine" | NSAIDs reduce renal excretion of lithium → toxicity |
| Parameter | Value |
|---|---|
| Manic episode duration | ≥1 week |
| Hypomanic episode duration | ≥4 days |
| Rapid cycling | ≥4 episodes/year |
| Lithium therapeutic range (maintenance) | 0.6–1.0 mmol/L |
| Lithium range | Depends on phase, age, response, adverse effects and local protocol; sample as a correctly timed trough |
| Lithium toxicity | Often apparent above 1.5 mmol/L, but exposure pattern, symptoms and renal function matter more than a single cut-off |
| YMRS ≥20 / ≥12 | Lecture/study severity cut-offs, not DSM diagnostic criteria |
| Epidemiology/genetic/suicide figures | Lecture-era group estimates; do not turn them into an individual prediction |
High Yield Summary
-
Bipolar I
- = ≥1 manic episode (≥1 week, marked impairment/psychosis).
- Bipolar II = ≥1 hypomania (≥4 days, no marked impairment, NEVER psychosis) + ≥1 depressive episode.
- Hypomania is commonly missed → BP II misdiagnosed as MDD → antidepressant monotherapy → manic switch.
- Correct diagnosis requires patient history + collateral informants + screening tools (MDQ, HCL-32).
-
Acute mania
- Lithium, valproate, or atypical antipsychotics (quetiapine, risperidone, aripiprazole). Combination if insufficient. ECT for treatment-resistant/dangerous cases.
-
Acute bipolar depression
- Use an evidence-based bipolar-depression treatment such as quetiapine, lithium, lamotrigine, lurasidone-based treatment or cariprazine according to the individual. No antidepressant monotherapy in bipolar I.
-
Prophylaxis
- Continue the effective acute agent where suitable; lithium, quetiapine and other phase-specific agents have evidence. Duration is individualised and often long term. Add psychoeducation, CBT/IPSRT/family work where appropriate.
-
Lithium
- is associated with lower suicide risk and is a key maintenance treatment.
- Monitor timed levels, eGFR/electrolytes, calcium, thyroid and interactions.
- NSAIDs, ACEi/ARBs and thiazides can increase levels.
- Toxicity is an emergency: stop lithium, urgent assessment/serial tests, isotonic crystalloid if depleted, and specialist dialysis assessment—no forced diuresis.
-
Valproate
- has major reproductive risks and stringent prescribing restrictions. Lamotrigine must be titrated according to valproate/enzyme-inducer status to reduce severe-rash risk. Quetiapine/olanzapine require metabolic monitoring.
-
Pregnancy
- Old FDA letter categories are obsolete. Plan before conception with perinatal psychiatry/obstetrics, avoid valproate exposure, do not stop effective treatment abruptly, and intensify postpartum relapse prevention.
-
Neuroprogression
- The staging diagram is a conceptual research model, not a diagnostic standard or proof that every relapse causes irreversible brain damage.
Active Recall - Bipolar Disorder
[1] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (all pages) [2] Lecture slides: CFB (PSY02) Classification and Diagnosis of Psychiatric Illness.pdf (p36) [3] Lecture slides: CFB (PSY01) An introduction to Psychiatry.pdf (p18, p20) [4] Lecture slides: Seminar 2 - Psychopathology - Dr Simon SY Lui_1_9_2025.pdf (p13) [5] Senior notes: Ryan Ho Psychiatry.pdf (p51, p144, p146, p155, p163–164, p169) [6] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p5) — lithium and AQP2/nephrogenic DI [8] Yatham LN, et al. CANMAT and ISBD Guidelines for the Treatment of Bipolar Disorder: Summary and a 2023 Update of Evidence. Focus. 2023. [9] NICE. Bipolar disorder: assessment and management (CG185), current recommendations. [10] UK MHRA. Valproate: reproductive risks, updated 2025. [11] EXTRIP Workgroup. Lithium: extracorporeal treatment recommendations. [12] US FDA. Pregnancy and Lactation Labeling Final Rule. [13] NICE. Antenatal and postnatal mental health (CG192), current recommendations. [14] NHS Specialist Pharmacy Service. Treating bipolar disorder during breastfeeding.
GC161 Alcohol And The Brain From Psychiatric To Neuropsychiatric Perspectives
An integrated clinical framework examining alcohol's effects on the brain across both psychiatric manifestations (such as mood disorders, psychosis, and dependence) and neuropsychiatric consequences (including cognitive impairment, Wernicke-Korsakoff syndrome, and alcohol-related brain damage).
GC164 I Am Depressed Mood Disorders
Mood disorders are a category of mental health conditions—including major depressive disorder, persistent depressive disorder, and bipolar disorder—characterized by significant disturbances in emotional state that impair daily functioning.