Bipolar Disorder

• Lifetime risk: ~0.3–1.6% for Bipolar I; up to 3.7% for the bipolar spectrum (including Bipolar II and cyclothymia) ^[2]
• More common in high-income countries (though this may be due to referral bias — better access to psychiatric services in wealthy nations rather than a true biological difference) ^[1]
• In Hong Kong, the prevalence is broadly consistent with global figures. Bipolar disorder is an important contributor to psychiatric morbidity, with significant under-recognition in primary care settings.

• No gender difference for Bipolar I (M:F ≈ 1:1) ^[1][2]
  • However, Bipolar II may be slightly more common in women (women tend to have more depressive episodes)
  • Women are more likely to experience rapid cycling ^[2]
• No ethnic difference ^[1]
• Mean age of onset: ~18 years ^[2]
  • But accurate diagnosis is often delayed by 5–10 years, especially for Bipolar II (because hypomania is missed) ^[2]
  • Peak onset for mania: late teens to early 20s
  • Late-onset mania (> 40 years) should always prompt investigation for organic causes (e.g., brain tumour, cerebrovascular disease, substance use)

• Psychiatric morbidity: 1/3 of patients have attempted suicide; 10–20% die by suicide ^[2]
  • Suicide risk factors include: past attempts, prominent depressive symptoms, mixed episodes, comorbid substance abuse, early onset
• 9th leading cause of disability-adjusted life years (DALYs) under neuropsychiatric disorders ^[2]
• ↑ medical comorbidities: especially cardiovascular disease (CVD), metabolic syndrome, diabetes — partly related to medication side effects (e.g., lithium → hypothyroidism, atypical antipsychotics → weight gain), partly due to lifestyle factors ^[2]
• Misdiagnosis is very common → correct diagnosis and treatment often delayed by 5–7 years on average ^[2]

Bipolar disorder is highly comorbid ^[2]:

• Psychotic disorders (psychotic features occur in mania and severe depression)
• Substance abuse (up to 40-60% comorbidity; alcohol, cannabis, stimulants are most common)
• Anxiety disorders (panic disorder, GAD, social anxiety — very common)
• Sleep disorders
• Eating disorders
• ADHD (especially in younger patients; diagnostic overlap can be tricky)
• Personality disorders (especially borderline PD — differentiation is a common exam question)

In mania: The prefrontal cortex fails to adequately "brake" the amygdala and reward circuits → uninhibited emotional expression, impulsivity, reward-seeking, grandiosity

In depression: The prefrontal cortex (especially dlPFC) is hypoactive → psychomotor retardation, poor concentration, apathy; the vmPFC is hyperactive → rumination, anxiety, pain sensitivity ^[4]

• Cognitive theory (relevant mainly to the depressive pole):

  • Cognitive distortions are prominent during depressive episodes ^[3][5]:
    • Selective abstraction (斷章取義) — focusing on a detail and ignoring more important features
    • Overgeneralization (以偏概全) — drawing a general conclusion from a single incident
    • Personalization (過度自責) — relating external events to oneself in an unwarranted way
    • Arbitrary inference (妄下判斷) — drawing a conclusion without evidence or against evidence
  • These are targets for Cognitive Behavioural Therapy (CBT)

• Psychoanalytic theory: loss of an "object," insecure attachments ^[5]

Bipolar disorder is caused by a combination of biological, social, and psychological factors, which disturb the brain's capacity for stress management ^[5].

Bipolar and related disorders are classified as a separate diagnostic chapter in DSM-5 (placed between schizophrenia spectrum disorders and depressive disorders, reflecting their "bridge" position) ^[1][2].

This is the single most important distinction in bipolar classification because it determines whether the patient has Bipolar I or Bipolar II ^[1][2].

DSM-5 allows several important specifiers ^[1]:

• With anxious distress
• With mixed features — see below
• With rapid cycling — see below
• With melancholic features
• With atypical features
• With mood-congruent / mood-incongruent psychotic features
• With catatonia
• With peripartum onset
• With seasonal pattern

Hypomania shows many of the above features but to less intensity and lasts shorter (only a few days) ^[2]:

• No marked impairment in social or occupational activities ^[2]
• Does not require admission
• NEVER psychotic features ^[2]
• The patient may actually feel "better than normal" — increased productivity, creativity, sociability
• Often ego-syntonic — the patient doesn't see it as a problem, which is why it's so often missed

Why is hypomania missed?

• Patients enjoy it and don't report it
• It may look like "normal high spirits" or a good personality trait
• Family members may not recognise it unless specifically asked
• This is why collateral history is essential and screening tools like the MDQ and HCL-32 are so important ^[2]

Bipolar depression commonly occurs during the course of bipolar disorder ^[2]:

• The majority of bipolar patients present with an episode of major depression as their first mood episode ^[2]
• This is the main reason for misdiagnosis as MDD

Clinical presentation is largely similar to MDD except ^[2]:

• More psychomotor retardation (vs agitation in unipolar depression)
• More early morning wakening
• More morning dysphoria (mood worse in the morning, improves toward evening — a "diurnal variation" pattern)
• More psychotic features (mood-congruent: nihilistic delusions, somatic delusions, auditory hallucinations of derogatory voices)
• May have some hypomanic features or mixed symptomatology ^[2]
• More hypersomnia and hyperphagia (atypical features) compared to unipolar depression
• More frequent episodes, shorter duration per episode
• Younger age of onset
• Stronger family history of bipolar disorder

Pathophysiology of bipolar depression:

• Mirrors that of MDD but with additional features:
  • Serotonergic and noradrenergic deficiency → low mood, sleep/appetite disturbance
  • dlPFC hypoactivation → psychomotor retardation, apathy, poor concentration
  • vmPFC hyperactivation → rumination, guilt, anxiety
  • HPA axis dysregulation → cortisol hypersecretion → hippocampal damage
  • ↓ BDNF → impaired neuroplasticity ^[3]

Mixed episodes (now "with mixed features" specifier in DSM-5) ^[2]:

• Hypomanic/manic and depressive features occurring at the same time ^[2]
• Or rapidly alternating mania/depression (in hours) ^[2]
• Extremely distressing and dangerous — the patient has depressive hopelessness combined with manic energy and impulsivity
• Predicts better response to valproate (rather than lithium) ^[2]
• Highest suicide risk of any mood state

• Chronic episodic course — most patients have multiple episodes over a lifetime ^[2]
• Average number of episodes: ~10 over a lifetime
• Depressive episodes are more frequent and longer than manic episodes (patients spend ~3× more time depressed)
• Inter-episode periods may show subthreshold symptoms and cognitive impairment even during "euthymia"
• Rapid cycling (≥4 episodes/year) occurs in 16-17%, more in women, often with hypothyroidism ^[2]
• Kindling hypothesis: Early episodes are more likely triggered by external stressors; later episodes may arise spontaneously as the illness "sensitises" the brain circuits (similar to epilepsy kindling)

This is the most difficult differential diagnosis ^[2] — and for good reason. Florid mania with psychotic features can look almost identical to an acute episode of schizophrenia. Both can present with agitation, grandiose or persecutory delusions, hallucinations, and disorganised behaviour.

Why the confusion?

• Schizophrenic symptoms occur commonly in mania: auditory hallucinations, delusions (including delusions of reference), even first-rank symptoms occur in 10–20% of manic patients ^[2]
• Conversely, schizophrenia patients can present with an excited, suspicious, or agitated mood that looks like mania ^[2]

Key differentiating features:

Schizoaffective disorder occupies the middle ground ^[3]:

• Concurrent schizophrenic and mood symptoms are equally prominent (fulfilling a major mood episode, e.g., manic or depressive episode) ^[3]
• Delusions and hallucinations are less mood-congruent and may occur outside mood episodes ^[2]
• Think of it as: "schizophrenia + mood disorder happening together, with both being prominent"

Drugs and medical conditions that cause manic symptoms ^[1]:

How to differentiate:

• Manic symptoms should ↓ after admission (when access to substances is removed) ^[2]
• Urine toxicology screen if substance use is suspected ^[2]
• Temporal relationship: symptoms began after starting a medication or using a substance, and resolve after discontinuation
• However, note that substances can trigger a genuine bipolar episode in a predisposed individual — so resolution after drug clearance doesn't always exclude bipolar disorder. Longitudinal follow-up is needed.

Frontal lobe lesion, hyperthyroidism, Cushing's syndrome ^[1]

This is a very common diagnostic dilemma, especially in emergency settings ^[2].

Borderline PD is often associated with marked affective instability → mimics rapid cycling bipolar disorder ^[2]

Key differentiating features ^[2]:

ADHD and mania share several features ^[2][4]:

Similarities:

• ↓ attention, difficulty with task completion
• ↑ energy and disinhibited behaviour
• Distractibility, impulsivity, talkativeness ^[4]

Key differences ^[2][4]:

ADHD should NOT have ↑ self-esteem, grandiosity, flight of ideas, or ↓ need for sleep ^[2]

Important caveat: ADHD and bipolar disorder can co-exist (comorbidity is common), making the differentiation even harder. Look for the episodic pattern layered on top of the chronic baseline.

This is listed as the first differential on the lecture slides ^[1] — and it's an important clinical scenario.

Why? Because an agitated, irritable depressed patient can be mistaken for having an irritable manic episode. The key difference:

• In agitated depression: the irritability is driven by distress, anxiety, and inner tension; the patient feels terrible and is agitated because of their suffering
• In irritable mania: the irritability is driven by frustration that the world doesn't match the patient's grandiose self-concept; the patient feels great (or at least energised) and is irritable because others are "in the way"

Look for:

• Presence of other manic features (grandiosity, ↓ need for sleep, pressured speech, flight of ideas)
• If these are absent → more likely agitated depression
• Hypomanic episodes can be missed or under-reported → should be actively elicited ^[2]

This is the most common misdiagnosis ^[1]:

• Hypomanic episodes are often overlooked → patients with Bipolar II are misdiagnosed as having major depressive disorder ^[1]

How to differentiate bipolar depression from unipolar MDD ^[2]:

Discerning features suggesting bipolarity: psychotic features, atypical features (e.g., hypersomnia, hyperphagia, leaden paralysis) ^[2]

• Dysthymia (persistent depressive disorder): chronic low-grade depression lasting ≥2 years, not meeting full MDE criteria. No manic/hypomanic episodes → not bipolar ^[2]
• Cyclothymia: chronic fluctuation between subthreshold hypomanic and depressive symptoms. It sits on the bipolar spectrum and management is similar to bipolar disorder ^[2]. The key is that symptoms never meet full criteria for a manic, hypomanic, or major depressive episode.

• Concurrent schizophrenic and depressive symptoms that are equally prominent ^[3]
• Psychotic features persist outside of mood episodes (unlike bipolar depression with psychotic features, where psychosis resolves when mood normalises)

• 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 — most frequently as major depression, followed by anxiety disorders, substance or alcohol use disorder ^[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]
• In another study, only 43% of 145 patients with a previous diagnosis of bipolar disorder had the condition confirmed by structured interview ^[1] (retrospective recall can be inaccurate)
• Requires informants and collateral information (e.g., medical record) to confirm past history of mania/hypomania ^[1]

Consequences of overdiagnosis ^[1]:

• Unnecessary side effects of mood stabilizers
• Increase sick role and disability claims

• History from the patient
• Collateral information from informants
• Help by the use of screening tools: Mood Disorder Questionnaire (MDQ), Hypomania Checklist (HCL-32)
• It is important to follow diagnostic criteria in making psychiatric diagnosis ^[1]

Both of the following core symptoms must be present ^[1][2]:

1. Abnormally elevated, expansive, or irritable mood
2. Increased energy or goal-directed activity

Why BOTH? Because elevated mood alone could be a personality trait or substance effect. The DSM-5 specifically added "increased energy/activity" as a co-required core feature to improve diagnostic specificity — you need the mood disturbance AND the energy/activity change.

≥3 of the following (or ≥4 if mood is only irritable) must be present during the mood disturbance, to a significant degree, and represent a noticeable change from usual behaviour ^[2]:

Why ≥4 if irritable only? Because irritability is less specific — many psychiatric conditions feature irritability. Requiring an extra symptom raises the diagnostic bar when elation/expansiveness is absent, reducing false positives.

≥7 days (present most of the day, nearly every day), OR any duration if hospitalisation is required ^[2]

Why 7 days? This distinguishes mania from briefer mood fluctuations (e.g., BPD, substance effects). The hospitalisation exception exists because severe mania warrants the diagnosis even before the 7-day threshold is met — clinical severity overrides duration.

Marked impairment in social or occupational functioning, OR hospitalisation required to prevent harm, OR psychotic features are present ^[2]

This is the criterion that separates mania from hypomania. The presence of marked impairment or psychosis = mania. Without them = hypomania.

Not attributable to the physiological effects of a substance (drug of abuse, medication) or another medical condition ^[2]

Important: a manic episode that emerges during antidepressant treatment but persists at fully syndromal level beyond the physiological effect of the substance IS counted as a genuine manic episode (and therefore qualifies the patient for Bipolar I).

The lecture slides provide a clear list ^[1]:

Once treatment is initiated, ongoing monitoring is essential. The specifics depend on the medication:

Systematically assess every MSE domain and document findings (as detailed in the Clinical Features section of Part 1):

• Appearance, behaviour, speech, mood (subjective and objective), thought form, thought content, perception, cognition, insight, risk

Hospitalisation: necessary in all but the mildest cases of mania (insight is often impaired early → patients refuse treatment, engage in dangerous behaviour) ^[2]

**Step 1: ALWAYS stop antidepressant treatment ^[2]

• Why? Antidepressants can fuel mania, worsen mixed features, and accelerate cycling. This is the very first thing you do.

Step 2: Determine whether the patient is already on antimanic medication ^[2]

Treatment of manic episode ^[1]:

• Monotherapy (first step)
• Combination: Lithium/Valproate plus Atypical antipsychotics (if monotherapy inadequate)
• Re-evaluate diagnosis and consider ECT (need of rapid response, e.g., high violence risk) ^[1]

Detailed Flowchart (from senior notes) [2]:

If NOT already on antimanic medication:

→ If monotherapy response inadequate → Combine antipsychotic AND valproate or lithium ^[2]

→ All patients — consider adding short-term benzodiazepine (lorazepam or clonazepam) ^[2]

• Rationale: ↓ behavioural disturbance + ↑ sleep → allows ↓ dose of antipsychotics needed ^[2]

If ALREADY on antimanic medication ^[2]:

• Gradual ↓ dose with clinical improvement ^[2]
• Continue treatment for ≥6 months and ≥8 weeks after complete remission (to ↓ rebound mania) ^[2]

• Pregnancy: prefer haloperidol (not associated with ↑ risk of congenital anomalies) → risperidone, quetiapine, olanzapine (in that order of preference) ^[2]
• Ensure drug compliance by therapeutic drug monitoring ^[2]
• Note: lithium may be relatively less effective in mixed states or substance misuse ^[2]

Treatment is NOT identical to treatment of unipolar depression or bipolar mania ^[2]:

• Conventional antidepressants are: (1) less effective in treating bipolar depression, (2) associated with risk of inducing mania, (3) associated with risk of inducing rapid cycling ^[2]
• Not all mood stabilizers are equally effective at treating mania and depression. Some (e.g., lamotrigine, quetiapine, lithium) are more useful in treating bipolar depression ^[2]
• SSRIs may be effective but may induce mania. TCAs and SNRIs have ↑↑ risk of inducing mania ^[2]

• Established bipolar disorder with recurrent episodes of mania or depression
• Severe single episode with suicidal attempts, psychotic episodes, and significant functional impairment (to prevent future relapse) ^[1][2]

• No strict guidelines → at least a few years without relapse and any subsyndromal symptoms between episodes ^[2]
• Patients on maintenance treatment with no relapse for many years CAN still relapse after cessation ^[2]
• Gradual discontinuation better than abrupt discontinuation ^[1]
• Lithium should not be started unless there is a clear intention to continue for ≥3 years ^[2]

Etymology: Named after Greek "lithos" (stone) — discovered in the mineral petalite.

Mechanism of Action ^[2]:

• Modulates second messengers (cAMP, ↓ PIP₃ formation)
• Inhibits GSK-3β (glycogen synthase kinase-3 beta) and PKC (protein kinase C)
• Net effect: ↑ neuronal survival, ↑ synaptic plasticity
• Why this matters: GSK-3β normally promotes apoptosis and is involved in circadian rhythm regulation; its inhibition promotes neuronal resilience and stabilises circadian cycles

Indications ^[2]:

• Acute treatment of moderate-severe mania (less commonly used due to slow onset)
  • Efficacy: NNT = 6, but takes ≥1 week to reach effects, difficult to reach therapeutic levels rapidly ^[2]
• Prophylaxis in bipolar affective disorder (commonly used — the main indication)
  • More effective for preventing manic episodes (NNT 10 vs 14 for depression) ^[2]
  • Better response if started earlier or combined with valproate ^[2]
• Augmentation of antidepressants in refractory unipolar depression
• Reduces suicidality: ↓80% risk of attempted + completed suicide in BAD ^[2]; the only mood stabiliser to reduce suicide ^[1]

Prescribing ^[2]:

Contraindications ^[2]:

• Significant renal impairment → ↑ risk of toxicity (lithium is renally excreted)
• Sodium depletion / dehydration → ↑ reabsorption of lithium in proximal tubule → toxicity
• Significant cardiovascular disease (HF, recent MI) → risk of arrhythmia
• Psoriasis — relative C/I (exacerbated by lithium)
• Pregnancy (relative C/I — Ebstein anomaly risk, ~0.1%; use if benefits clearly outweigh risks)

Side Effects — think of lithium as a salt that distributes throughout the body ^[2]:

Drug Interactions (critically important given narrow therapeutic index) ^[2]:

• Diuretics (especially thiazides) → ↓ renal lithium clearance → toxicity
• NSAIDs → ↓ renal lithium clearance → toxicity
• ACE inhibitors, ARBs, CCBs → ↓ renal clearance
• Anything causing dehydration or sodium depletion

Lithium Toxicity — occurs at levels > 1.5 mmol/L:

• Mild (1.5–2.0): coarse tremor, GI symptoms, lethargy
• Moderate (2.0–2.5): confusion, ataxia, dysarthria, muscle twitching
• Severe ( > 2.5): seizures, coma, renal failure, cardiac arrhythmia, death
• Management: stop lithium, IV normal saline (restore sodium/hydration), haemodialysis if severe

Etymology: Valproic acid — named after valeric acid (from valerian plant) + propionic acid.

Mechanism of Action ^[2]:

• ↓ catabolism of GABA (↑ inhibitory neurotransmission)
• ↓ sensitivity of Na⁺ channels (↓ excitatory neurotransmission)
• Also acts on signal transduction cascades: GSK-3, PKC, MARCKS, ERK kinase
• Net effect: ↑ neuroprotection and long-term plasticity

Indications ^[2]:

• NEVER in patients with reproductive potential ^[2]
• Acute treatment of mania
• Acute treatment of bipolar depression (in combination with antidepressants; effect size small-medium alone)
• Prophylactic treatment of bipolar affective episodes
• Better for mixed episodes than lithium ^[2]

Prescribing ^[2]:

Contraindications:

• Women of childbearing potential — established human teratogen (neural tube defects 1–2%, craniofacial abnormalities, neurodevelopmental impairment — absolutely contraindicated in pregnancy) ^[2]
• Active liver disease
• Porphyria

Side Effects ^[2]:

• GI: nausea, vomiting, diarrhoea
• Hepatic: hepatotoxicity (can be fatal, especially in children), ↑ LFTs
• Haematological: thrombocytopaenia, platelet dysfunction
• Neurological: tremor, sedation, ataxia
• Metabolic: weight gain, hyperammonaemia (can cause encephalopathy)
• Dermatological: hair loss (curly regrowth — "valproate curls")
• Teratogenicity: neural tube defects, developmental delay — the most teratogenic mood stabiliser

Drug Interactions ^[2]:

• ↑ level of lamotrigine (may require dose reduction — important combination)
• ↑ effects of central sedatives
• Interacts with phenytoin, TCAs, other anticonvulsants

Etymology: "Lamo-" from its chemical structure (a phenyltriazine); "-trigine" = triazine derivative.

Mechanism of Action ^[2]:

• Blocks voltage-sensitive sodium channels
• ↓ glutamate release (the main excitatory neurotransmitter)
• Net effect: stabilises neuronal membranes, reducing excitatory neurotransmission

Indications ^[2]:

• More effective for bipolar depression but little anti-manic effect ^[2]
• Acute treatment of bipolar depression
• Prophylactic treatment in bipolar affective disorder, especially when picture is dominated by depression
• Lamotrigine is a promising agent for treatment of bipolar depression due to its tolerability and wide therapeutic margin ^[1]

Prescribing ^[2]:

• Must titrate slowly: 25 mg QD × 2 weeks → 50 mg QD × 2 weeks → slowly up to 50–300 mg/day
• Why so slow? To reduce risk of skin eruption and SJS/TEN — the risk is highest in the first few weeks and with rapid titration

Side Effects ^[2]:

• Relatively well-tolerated! ^[2]
• Skin eruption: 3%, especially in first few weeks → must start slowly
• Rare: SJS/TEN, angioedema (serious but rare — risk ↑ with rapid titration and concurrent valproate)
• Other common: nausea, headache, diplopia, blurred vision, dizziness, ataxia, tremor

Drug Interactions ^[2]:

• ↑ level by valproate (halve the dose when co-prescribing with valproate — very important!)
• ↓ level by enzyme inducers (e.g., carbamazepine)

Etymology: "Carba-" = carboxamide group; "-mazepine" = related to the dibenzoazepine chemical structure (similar to tricyclic antidepressants).

Mechanism of Action ^[2]:

• Blocks voltage-sensitive sodium channels
• Relationship with efficacy in bipolar disorder is unclear

Indications ^[2]:

• Less commonly used due to ↓ tolerance, ↑ drug interactions, and ↓ efficacy of other drugs when co-prescribed
• Acute treatment of mania as alternative or addition to lithium/valproate (NOT first-line)
• Acute treatment of frequent mood swings and mixed affective episodes (may be more effective than lithium)
• Prophylactic treatment when lithium and valproate are ineffective/poorly tolerated

Prescribing ^[2]:

• Pre-treatment: CBC, RFT, LFT, baseline weight, HLA-B1502* (5% risk of SJS — must be checked, especially in patients of Southeast Asian/Chinese descent — very relevant in Hong Kong)
• Start 100–200 mg BD, titrate to 400 mg BD
• Induces its own metabolism (auto-induction) → levels drop after 2–3 weeks → may need dose increase
• Plasma drug monitoring: target 4–12 mg/L

Absolute Contraindication: women of reproductive age (established human teratogen) ^[2]

Side Effects ^[2]:

• Neurological: dizziness, drowsiness, ataxia
• Renal: hyponatraemia (SIADH pattern)
• GI: nausea, hepatitis
• Haematological: leukopenia (common, first few weeks), agranulocytosis (rare: 1/10,000–125,000)
• Hypersensitivity: rash, SJS (check HLA-B*1502!)
• Cardiac conduction abnormalities

Drug Interactions — notorious, potent inducer of P450 enzymes ^[2]:

• ↑ metabolism of most antidepressants, antipsychotics, BZDs, thyroxine, OCP
• OCP may become ineffective → need ↑ dose or alternative contraception
• Should NOT be given with MAOIs (similar TCA structure)

Mechanism of Action ^[2]:

• Unknown precisely; ?related to 5-HT₂A antagonist and 5-HT₁A partial agonist properties
• ↓ glutamate hyperactivity (downstream effect)

Key Agents:

Atypical antipsychotics look promising as mood stabilisers, but limited by metabolic side effects ^[1]

Prevalence of anxiety disorders in bipolar disorder is as common as in MDD ^[1]

(* p < 0.05; ** p < 0.01) ^[1]

Why such high comorbidity?

• Shared genetic vulnerability (overlapping genetic risk factors between bipolar disorder and anxiety disorders)
• HPA axis dysregulation is common to both → chronic cortisol elevation promotes both mood instability and anxiety
• Amygdala hyperactivation (seen in bipolar disorder) is also the core neurobiological finding in anxiety disorders
• Anxiety often develops secondary to the illness experience — patients become anxious about future episodes, social consequences, stigma

Clinical impact: Comorbid anxiety worsens bipolar prognosis — more frequent episodes, poorer inter-episode recovery, higher suicide risk, reduced treatment response.

Substance use disorders are more common in bipolar disorder than in MDD ^[1]

(* p < 0.05; ** p < 0.01) ^[1]

Bipolar I disorder: alcoholism present in 60% of patients ^[3]

Why?

• Self-medication hypothesis: Patients use substances to manage intolerable mood states — alcohol to dampen manic agitation or relieve depressive pain; stimulants to combat depressive lethargy; cannabis for anxiety
• Impulsivity during mania: Disinhibition and reward-seeking behaviour during manic episodes → reckless substance use
• Shared neurobiology: Both bipolar disorder and addiction involve dopaminergic reward circuitry dysregulation
• Social disruption: Job loss, relationship breakdown, financial ruin from manic episodes → increased vulnerability to substance use

Clinical impact:

• Substance use aggravates bipolar disorder and is associated with ↑ suicide rate ^[3]
• In manic episodes, hyperexcitability and impulsivity often leads to ↑ alcohol intake ^[3]
• Alcoholism may ↑ psychotic symptoms, mood swings, cause erratic behaviour and affect treatment (↑ non-compliance, ↑ drug abuse, ↑ drug accumulation due to hepatic damage) ^[3]
• Lithium is relatively less effective in mixed states or substance misuse ^[2] — making these patients harder to treat

• Sleep disorder — Circadian rhythm disruption is both a cause and consequence of bipolar episodes
• Eating disorder — Particularly binge eating; also medication-related weight gain
• ADHD — Significant diagnostic and therapeutic overlap
• Psychotic disorder — Psychotic features during episodes
• Personality disorder — Especially borderline PD (diagnostic overlap and genuine comorbidity)

↑ CVS disease/metabolic syndrome ^[2] — this is the leading cause of non-suicidal mortality in bipolar disorder.

Why?

Two main drivers:

1. Medication side effects:

   • Atypical antipsychotics (olanzapine, quetiapine) → weight gain, insulin resistance, dyslipidaemia, type 2 diabetes
   • Lithium → weight gain, hypothyroidism (which itself promotes metabolic syndrome)
   • Valproate → weight gain, polycystic ovary syndrome (in women)

2. Lifestyle factors:

   • Poor diet and physical inactivity (during depressive episodes especially)
   • Consequences of comorbid substance abuse and smoking ^[2]
   • Disrupted sleep-wake cycles → metabolic dysregulation
   • Reduced engagement with preventive healthcare

Components of metabolic syndrome: Central obesity, hypertension, hyperglycaemia, hypertriglyceridaemia, low HDL cholesterol → all increase cardiovascular risk

This is why watching out for side effects and the need of alternative treatments ^[1] is so emphasised. Regular metabolic monitoring (fasting glucose, lipids, weight/BMI, waist circumference, blood pressure) is essential for all patients on mood stabilisers and antipsychotics.

• Manic episodes → reckless decisions (quitting jobs, inappropriate workplace behaviour, spending sprees)
• Depressive episodes → inability to work (absenteeism, presenteeism, reduced productivity)
• Inter-episode cognitive deficits → difficulty sustaining complex work even during "euthymia"
• 2-year outcome after mania: 98% syndromal recovery, 72% symptomatic recovery, but only 43% functional recovery ^[2] — illustrating that functional recovery lags far behind symptomatic recovery

• Sexual disinhibition during mania → marital infidelity → relationship breakdown
• Irritability and aggression → domestic conflict, potential violence
• Unreliability due to mood instability → erosion of trust
• Financial ruin from manic spending sprees
• Caregiver burden → family burnout

• Overspending during mania (credit card debt, foolish investments, giving away money)
• Job loss → loss of income
• Increased healthcare and welfare service utilisation ^[1]

• Disinhibited behaviour during mania can lead to criminal acts (fraud, assault, DUI, public indecency)
• Forensic implications of impaired judgment and insight

• Dealing with stigma and poor drug compliance is explicitly highlighted as a management priority ^[1]
• Stigma leads to: delayed help-seeking, non-disclosure, social isolation, self-stigma (internalised shame), reduced employment opportunities