Bipolar Disorder
Bipolar disorder is a chronic psychiatric illness characterized by recurrent episodes of mania or hypomania alternating with depressive episodes, resulting in significant disturbances in mood, energy, and functioning.
Bipolar disorder (historically known as "manic-depressive illness") is a chronic, episodic mood disorder characterised by recurrent episodes of pathologically elevated mood (mania or hypomania) and, in most cases, episodes of depression, interspersed with periods of euthymia (normal mood) [1][2].
Let's break down the name:
- "Bi-" = two; "polar" = poles → the two poles of mood: the "high" (mania) and the "low" (depression). The illness oscillates between these extremes, though patients spend much more time depressed than manic.
The key defining feature is the manic or hypomanic episode — you cannot diagnose bipolar disorder without one. A patient who has only ever had depression has Major Depressive Disorder (MDD), not bipolar disorder, even if they later "convert" (which ~10-20% of MDD patients do over time).
Core Concept
The diagnosis of bipolar disorder hinges on identifying mania or hypomania. Depression alone is not sufficient. This is why collateral history and screening tools are so critical — hypomanic episodes are often ego-syntonic (patients enjoy them) and go unreported.
Subtypes at a Glance
| Subtype | Defining Criterion |
|---|---|
| Bipolar I disorder | ≥1 episode of mania (depression not required for diagnosis, though almost always occurs) [1][2] |
| Bipolar II disorder | ≥1 episode of hypomania + ≥1 episode of major depression [1][2] |
| Cyclothymic disorder | Chronic fluctuating mood with numerous periods of hypomanic and depressive symptoms not meeting full criteria, for ≥2 years [2] |
| Bipolar disorder, other specified / unspecified | Mood episodes that don't fit neatly into the above categories |
Bipolar II is NOT "milder" Bipolar I. It has equal or greater morbidity because patients spend proportionally more time depressed, with high suicide risk and functional impairment [2].
2. Epidemiology
- 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)
High Yield - The Misdiagnosis Problem
Misdiagnosis of bipolar disorder is extremely common and has serious consequences [2]:
Underdiagnosis:
- Overlooking hypomanic episodes → misdiagnosis as MDD (the single most common diagnostic error)
- Mania with psychosis → misdiagnosed as schizophrenia
- Consequence: untreated mood symptoms lead to ↑ suicidality, comorbid anxiety, substance abuse disorders, ↓ QoL, ↓ functioning, ↑ healthcare costs
- Mis-treatment with antidepressants alone is less effective and results in manic switch and cycle acceleration
Overdiagnosis:
- Confusion of mania with simple irritability (structured interview confirms only ~43% of patients with a previous diagnosis of bipolar disorder)
- Consequences: unnecessary side effects of mood stabilizers, ↑ sick role and disability claims
Correct diagnosis relies on:
- History from the patient AND collateral history from informants (critical — patients often don't report hypomania)
- Structured screening tools, e.g., Mood Disorder Questionnaire (MDQ), Hypomania Checklist (HCL-32) [2]
3. Anatomy and Function (Neuroanatomy of Bipolar Disorder)
Understanding the neuroanatomy helps you make sense of the clinical features. Bipolar disorder involves dysfunction in cortico-limbic circuits that regulate mood, reward, and executive function.
| Region | Normal Function | Abnormality in Bipolar Disorder |
|---|---|---|
| Prefrontal cortex (PFC) — especially ventromedial PFC (vmPFC) and dorsolateral PFC (dlPFC) | vmPFC: emotional/social regulation; dlPFC: executive function, working memory, planning | Structural: volume reduction and decreased glial cells in subgenual cortex [3]. Functional: hypometabolism in depression; hypermetabolism in mania [1] |
| Amygdala | Emotional processing, fear conditioning, salience detection | Hyperactivation → exaggerated emotional responses; ↓ connectivity with anterior cingulate → impaired emotional regulation [4] |
| Anterior cingulate cortex (ACC) | Conflict monitoring, emotional regulation, error detection | Abnormal activity → failure to modulate limbic responses |
| Hippocampus | Memory consolidation, stress regulation (via HPA axis feedback) | Reduced hippocampal volume (both a predisposing factor and consequence of illness via cortisol-mediated neurotoxicity) [4] |
| Basal ganglia / Striatum | Reward processing, motor activity, motivation | Altered dopaminergic signalling → reward-seeking behaviour in mania, anhedonia in depression |
| Cerebellum | Motor coordination, but also cognitive and affective regulation | Increased cerebellar metabolism in some studies [1] |
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]
Why Mania Looks Like 'Too Much' and Depression Like 'Too Little'
Think of the PFC as the "brakes" and the limbic system (amygdala, striatum) as the "accelerator." In mania, the brakes fail → the car races out of control (impulsivity, grandiosity, hypersexuality). In depression, the accelerator fails AND the brakes are stuck on → the car barely moves (anhedonia, psychomotor retardation, apathy).
4. Aetiology and Pathophysiology
Bipolar disorder is best understood through a multifactorial biopsychosocial model [1]. No single cause is sufficient — rather, it's the interaction of genetic vulnerability, environmental triggers, and neurobiological dysregulation.
4.1 Biological and Genetic Factors
- Strikingly high heritability: ~79–85% from twin studies [1][2]
- This is the highest heritability of any major psychiatric disorder — higher than MDD (~37%) and comparable to schizophrenia (~80%)
- Shared genetic risk between bipolar disorder, schizophrenia, and autism [1]
- Also shared with MDD and schizoaffective disorder [2]
- This explains why family members of bipolar patients have elevated rates of these conditions
- Likely polygenic with small individual effects [2]
- Genes identified include:
- Neuronal development genes
- Neurotransmitter metabolism genes
- Calcium channel genes (e.g., CACNA1C — a voltage-gated calcium channel involved in neuronal signalling; this is one of the most replicated findings in bipolar GWAS)
- Some overlap with genes involved in circadian rhythm regulation [1] — this is fascinating because it connects to the clinical observation that sleep disruption is a major trigger for mania
Why Calcium Channels?
Calcium channels are fundamental to neuronal excitability, neurotransmitter release, and intracellular signalling cascades. Dysregulation of calcium signalling could explain the "kindling" phenomenon (where episodes become easier to trigger over time) and the efficacy of mood stabilizers like lithium (which modulates intracellular calcium signalling via second messengers).
| Pathway | Role in Bipolar Disorder |
|---|---|
| Dopaminergic system | Hypothesised to be related to dopamine hyperactivity in mania (→ elevated mood, psychomotor activation, psychosis) and hypoactivity in depression (→ anhedonia, psychomotor retardation) [2]. Supported by: dopamine agonists can trigger mania; antipsychotics (D2 blockers) treat mania |
| Serotonergic system (5-HT) | Deficiency implicated in depression; ↓ 5HT2A and 5HT1A receptor densities found in frontal cortex [4]. Atypical antipsychotics used in bipolar often act as 5-HT2 antagonists |
| Glutamate | ↓ glutamate in cortical layers III-IV [1]; NMDA receptor dysfunction may contribute to both manic and depressive symptoms |
| GABAergic system | ↓ glutamic acid decarboxylase (GAD) — the synthetic enzyme for GABA — found in bipolar brains [1]; GABA is the main inhibitory neurotransmitter, so its deficiency could contribute to cortical hyperexcitability |
| Second messenger systems | Dysregulation of intracellular signalling cascades (cAMP, PIP₂/IP₃, protein kinase C [PKC], GSK-3β) — these are the targets of lithium [2] |
| Mitochondrial pathways | Mitochondrial dysfunction [1] → impaired energy metabolism in neurons → may contribute to neuronal vulnerability and episodic nature of illness |
- HPA axis dysregulation with hypersecretion of cortisol [2][3]
- Chronic cortisol elevation → hippocampal atrophy → impaired stress regulation → further HPA axis dysregulation (a vicious cycle)
- Decreased BDNF (brain-derived neurotrophic factor) levels [3] → reduced neuroplasticity and neuronal survival
- Thyroid axis involvement [1]:
- Decreased T3 and TSH levels reported [3]
- Hypothyroidism is associated with rapid cycling
- Lithium can cause hypothyroidism — monitoring thyroid function is essential
-
Structural abnormalities:
- Enlarged ventricles (↑ ventricle-to-brain ratio) [1]
- ↓ hippocampal volume [1]
- Volume reduction and decreased glial cells in subgenual cortex [1][3]
- ↓ N-acetylaspartate (NAA) — a marker of neuronal integrity [1]
- ↓ reelin and ↓ GAP (growth-associated protein) in dlPFC [1]
- ↓ GFAP (glial fibrillary acidic protein) [1]
-
Functional abnormalities:
- Hypometabolism in bipolar depression (especially frontal cortex) [1]
- Hypermetabolism in mania (especially limbic structures)
- Exaggerated functional responses to positive emotional stimuli [2]
- Disordered emotional regulation and reward processing [2]
- ↓ fronto-cerebellar reciprocity/synchrony [1]
- Increased cerebellar metabolism [1]
-
None of them are specific biomarkers [1]
Exam Point
None of the neuroimaging findings are specific biomarkers for bipolar disorder [1]. The diagnosis remains clinical. Imaging is used for research and to exclude organic causes, NOT for diagnostic confirmation.
- Toxoplasma gondii — the associated immune response (not direct infection) has been linked to bipolar disorder [1]
- This is an emerging area; the mechanism likely involves neuroinflammation and immune-mediated disruption of dopaminergic signalling
4.2 Environmental Factors
- Negative life events, especially those disrupting sleep-wake activity [2]
- Why sleep? Because circadian rhythm genes are implicated in bipolar disorder, and sleep deprivation can directly trigger mania. The sleep-wake cycle is regulated by serotonergic/noradrenergic systems in the reticular activating system — the same systems implicated in mood regulation
- Childbirth (postpartum period is a high-risk time for onset/relapse of bipolar episodes) [2]
- Sleep deprivation and circadian and social rhythm disruption [1]
-
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)
- Cognitive distortions are prominent during depressive episodes [3][5]:
-
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].
5. Classification
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].
| Disorder | Key Features |
|---|---|
| Bipolar I Disorder | ≥1 manic episode (may or may not have depressive episodes) |
| Bipolar II Disorder | ≥1 hypomanic episode + ≥1 major depressive episode (never had a full manic episode) |
| Cyclothymic Disorder | Chronic (≥2 years) fluctuating mood with numerous hypomanic and depressive symptoms NOT meeting full criteria for either [2] |
| Substance/Medication-Induced Bipolar | Mania/hypomania caused by substances (e.g., corticosteroids, stimulants, antidepressants) |
| Bipolar Due to Another Medical Condition | Mania/hypomania due to medical illness (e.g., thyrotoxicosis, Cushing's, MS, brain tumour) |
| Other Specified / Unspecified Bipolar | Bipolar-like presentations not meeting full criteria |
This is the single most important distinction in bipolar classification because it determines whether the patient has Bipolar I or Bipolar II [1][2].
| Feature | Mania | Hypomania |
|---|---|---|
| Duration | ≥7 days (or any duration if hospitalisation required) | ≥4 consecutive days |
| Severity | Severe; marked impairment in social/occupational functioning | Mild to moderate; NO marked impairment in function [2] |
| Psychotic features | May be present (grandiose delusions, hallucinations) | NEVER psychotic features [2] |
| Hospitalisation | Often required | Not required |
| Diagnosis | Bipolar I | Bipolar II (with ≥1 depressive episode) |
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
5.4 Special Subtypes
- Hypomanic/manic and depressive features occurring at the same time [2]
- Rapidly alternating mania/depression (in hours) [2]
- Predicts better response to valproate [2]
- Clinically these patients are especially high-risk for suicide (they have the depressive despair combined with manic energy/impulsivity)
- Definition: ≥4 bipolar mood episodes over 12 months [2]
- With periods of remission (≥2 months) OR switch to opposite polarity [2]
- Occurs in 16–17% of bipolar patients [2]
- F > M [2]
- Often concomitant hypothyroidism [2] — always check TFTs in rapid cyclers
- May be transient phenomenon in course of illness; remits ≤2 years in most [2]
- Often poorer response to mood stabilizers [2]
- Can be induced/worsened by antidepressants
- Definition: numerous periods of hypomanic and depressive symptoms NOT meeting either full criteria [2]
- Recurs over ≥2 years in which ≥½ of the time is symptomatic and symptom-free for < 2 consecutive months [2]
- Course: usually insidious onset and chronic course similar to dysthymia [2]
- Management: similar to bipolar disorder [2]
6. Clinical Features
Now let's go through the clinical presentation systematically. I'll separate symptoms and signs, and connect everything back to the underlying pathophysiology.
6.1 Manic Episode
Core Mood Disturbance:
-
Elation / Euphoria:
- Cheerful, optimistic, often with infectious quality [2]
- But may become offensive due to disinhibition and insensitivity to needs of others [2]
- Pathophysiology: Dopamine hyperactivity in the mesolimbic reward pathway → excessive positive affect, inflated self-worth. The prefrontal cortex fails to modulate this → it "overflows" into socially inappropriate behaviour
-
Irritability:
- ↓ frustration tolerance, anger, or even delusion of persecution [2]
- Often underappreciated — irritable mania is common and can be mistaken for agitation or personality disorder
- Pathophysiology: When the environment doesn't match the patient's grandiose self-concept, frustration results. Impaired prefrontal inhibition → inability to regulate anger
-
Mood lability:
- Also common; may even be interrupted by brief episodes of depression [2]
- Pathophysiology: Reflects instability of the mood-regulating cortico-limbic circuitry; the system is oscillating rapidly and unpredictably
Increased Energy and Activity:
-
↑ Goal-directed activity:
- Especially starting many activities but leaving them unfinished [2]
- Pathophysiology: Dopaminergic drive in the striatum → motivation and goal-pursuit, but impaired PFC executive function → inability to sustain focus or evaluate plans realistically
-
↑ Impulsivity / Disinhibition:
- Sexual infidelity, one-night-stands, overfriendliness, flirtatiousness [2]
- Pathophysiology: Ventral striatum (reward circuit) is overactive → heightened reward-seeking. vmPFC (social behaviour regulation) is underactive → loss of social inhibition
-
Recklessness / Impaired judgment:
- Overspending, giving up good jobs, embarking on unrealistic plans [2]
- Pathophysiology: dlPFC (executive function, consequence-evaluation) is functionally impaired → inability to assess risk or foresee consequences. Simultaneously, reward signals are amplified.
-
May lead to exhaustion (but less common nowadays with earlier treatment) [2]
Biological Symptoms:
- ↓ Need for sleep (NOT insomnia):
- An early warning sign of mania/hypomania [2]
- Characteristically NOT associated with fatigue; wake up early feeling energetic [2]
- Pathophysiology: Circadian rhythm disruption (genes involved in circadian regulation are implicated [1]); also noradrenergic/dopaminergic hyperactivation of the ascending reticular activating system → sustained wakefulness without the normal homeostatic sleep pressure
- This is different from insomnia in depression, where patients want to sleep but can't, and feel exhausted
Sleep in Mania vs Depression
- Mania: ↓ need for sleep — feels rested after 2-3 hours; no subjective fatigue. The brain's "alertness system" is on overdrive.
- Depression: ↓ ability to sleep (insomnia) or ↑ sleep (hypersomnia), but always with fatigue. The brain's "energy system" is depleted. This distinction is clinically very useful for differentiating manic vs depressive episodes.
-
↑ Appetite (may eat ravenously but often too distracted/active to eat regularly)
-
↑ Libido — sexual drive is markedly increased, contributing to sexual disinhibition
- Pathophysiology: Dopaminergic reward pathway hyperactivity → amplification of appetitive drives
Cognitive Symptoms:
-
Grandiosity / Inflated self-esteem:
- Ranges from unrealistic overconfidence to full grandiose delusions (e.g., believing one is God, has special powers, is on a divine mission)
- Pathophysiology: Dopaminergic excess → aberrant salience (normal self-referential thoughts become infused with excessive significance)
-
Flight of ideas / Racing thoughts:
- The patient's thoughts move so quickly that speech can barely keep up
- Pathophysiology: Cortical hyperexcitability (possibly related to GABAergic deficit and glutamatergic dysregulation) → disinhibited association pathways
-
Distractibility:
- Attention constantly drawn to irrelevant stimuli
- Pathophysiology: dlPFC executive dysfunction → impaired attentional filtering
-
Poor concentration
Psychotic Symptoms (in severe mania):
-
Delusions: usually mood-congruent [2]
- Grandiose delusions (special powers, divine mission, vast wealth)
- Delusion of persecution may occur (if irritable mood predominates) [2]
- 10-20% have Schneiderian first-rank symptoms, but usually fleeting [2]
- Pathophysiology: Dopaminergic hyperactivity in the mesolimbic pathway → the same mechanism as in schizophrenia, but coloured by the underlying mood state
-
Hallucinations: usually mood-congruent [2]
Mood-Congruent vs Mood-Incongruent Psychosis
- Mood-congruent: Psychotic content matches the mood state (grandiose delusions in mania, nihilistic delusions in depression). This is more typical of bipolar disorder.
- Mood-incongruent: Psychotic content doesn't match the mood (e.g., persecutory delusions or thought insertion in mania). This is more atypical and overlaps with schizoaffective disorder.
- First-rank symptoms (thought insertion, withdrawal, broadcasting, passivity) can occur in mania (10-20%) but are usually fleeting — if persistent, consider schizoaffective disorder or schizophrenia.
| MSE Domain | Signs in Mania | Pathophysiological Basis |
|---|---|---|
| Appearance | Bright, flamboyant clothing; excessive makeup/jewellery; may be dishevelled if severely manic (too busy to care for self) | Grandiosity → desire to display; disorganisation → self-neglect |
| Behaviour | Psychomotor excitation: inability to sit still, pacing, gesticulating expansively [2]; intrusive, overfamiliar, may be aggressive if challenged | Dopaminergic/noradrenergic hyperactivation of motor circuits; impaired PFC inhibition |
| Speech | Pressure of speech (rapid, loud, difficult to interrupt); may become incoherent in severe mania | Cortical hyperexcitability; flight of ideas expressed verbally |
| Mood | Elated, expansive, OR irritable; often labile | As above |
| Thought form | Flight of ideas (rapid shifting between loosely connected topics), clang associations (words linked by sound rather than meaning), circumstantiality | Disinhibited association pathways |
| Thought content | Grandiose ideas or delusions, persecutory delusions (if irritable), ideas of reference | Mesolimbic dopamine excess |
| Perception | Mood-congruent hallucinations (auditory or visual) | As above |
| Cognition | Distractible, poor sustained attention, may appear confused if severely manic | dlPFC dysfunction |
| Insight | Typically poor or absent | PFC dysfunction → inability to monitor own mental state |
| Risk | ↑ risk to self (through reckless behaviour, exhaustion) and potentially others (through aggression, disinhibition) | Impaired judgment + increased drive |
| Letter | Feature |
|---|---|
| D | Distractibility |
| I | Irresponsibility / Impulsivity (pleasure-seeking with consequences) |
| G | Grandiosity |
| F | Flight of ideas |
| A | Activity increase (goal-directed or psychomotor agitation) |
| S | Sleep deficit (↓ need for sleep) |
| T | Talkativeness (pressure of speech) |
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)
While bipolar disorder is a clinical diagnosis, investigations are essential to exclude medical mimics and establish a baseline before treatment:
| Investigation | Rationale |
|---|---|
| CBP (Complete blood picture) | Exclude anaemia, infection |
| Renal function tests (RFT) | Baseline before lithium (lithium is nephrotoxic) |
| Liver function tests (LFT) | Baseline before valproate (hepatotoxic); exclude hepatic causes of confusion |
| Thyroid function tests (TFTs) | Exclude hyper/hypothyroidism (thyrotoxicosis mimics mania; hypothyroidism associated with rapid cycling; lithium causes hypothyroidism) [3] |
| Blood glucose / HbA1c | Baseline metabolic screening; antipsychotics → metabolic syndrome |
| Lipid profile | Baseline before atypical antipsychotics |
| Urine drug screen | Exclude substance-induced mania (stimulants, cannabis, alcohol) |
| Blood alcohol level | As above |
| ECG | Baseline; some medications prolong QTc |
| CT/MRI brain | If late-onset mania ( > 40y), neurological signs, or atypical features → exclude organic causes (tumour, CVD, MS, neurosyphilis) |
| EEG | If suspicion of epilepsy (temporal lobe epilepsy can mimic mood episodes) |
| Cosyntropin (ACTH) stimulation test | If suspected Cushing's disease / Addison's [5] |
| HIV test | HIV can cause psychiatric symptoms including mania |
High Yield Summary
Definition: Bipolar disorder = chronic episodic mood disorder with mania/hypomania ± depression. Bipolar I = ≥1 mania. Bipolar II = ≥1 hypomania + ≥1 depression.
Epidemiology: Lifetime risk ~1-4% (spectrum). M=F. Onset ~18y. Diagnosis delayed 5-10y. 1/3 attempt suicide; 10-20% die by suicide. Highly comorbid (substance abuse, anxiety, ADHD).
Aetiology (Multifactorial):
- Genetics: 79-85% heritability (highest in psychiatry). Shared risk with schizophrenia/autism. Calcium channel, circadian rhythm, neurodevelopmental genes.
- Neurobiology: Dopamine hyperactivity (mania), serotonergic/noradrenergic deficiency (depression), HPA axis dysregulation, ↓BDNF, structural/functional brain changes (none are specific biomarkers).
- Environment: Childhood abuse, poor attachment, life events disrupting sleep, childbirth, high expressed emotion (perpetuating).
Clinical Features:
- Mania (DIG FAST): Distractibility, Irresponsibility/Impulsivity, Grandiosity, Flight of ideas, Activity increase, Sleep ↓, Talkativeness. +/- mood-congruent psychosis. ≥7 days or hospitalisation.
- Hypomania: Same features but less intense, ≥4 days, NO marked impairment, NEVER psychotic.
- Bipolar depression: Like MDD but more psychomotor retardation, morning dysphoria, psychotic features, atypical features (hypersomnia, hyperphagia).
- Mixed features: Manic + depressive features simultaneously → highest suicide risk → responds to valproate.
- Rapid cycling: ≥4 episodes/12 months. F > M. Check thyroid.
Key Diagnostic Pitfalls: Hypomania missed → diagnosed as MDD → treated with antidepressants alone → manic switch + cycle acceleration. Always take collateral history. Use MDQ/HCL-32.
Active Recall - Bipolar Disorder (Definition, Epidemiology, Aetiology, Clinical Features)
[1] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p19, p28, p29) [2] Senior notes: ryanho-psych.md (sections 7.3, pp.397-402) [3] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p12) [4] Senior notes: ryanho-psych.md (sections on neurobiology, pp.336, 388) [5] Lecture slides: GC 164. I am depressed Mood disorders.pdf (p13)
Differential Diagnosis of Bipolar Disorder
The differential diagnosis of bipolar disorder is one of the most clinically important exercises in psychiatry, because misdiagnosis is extremely common — correct diagnosis and treatment is delayed by 5–7 years on average [1][2]. Getting this wrong has real consequences: treat bipolar depression with antidepressant monotherapy and you risk triggering a manic switch and cycle acceleration; label someone with personality-driven irritability as "bipolar" and you expose them to unnecessary mood stabilizer side effects [1].
The approach to differential diagnosis depends on which pole the patient is presenting with — the differentials for a manic/hypomanic presentation are different from those for a depressive presentation. Let's be systematic.
1. Differential Diagnosis of the Manic / Hypomanic Presentation
The lecture slides give a clear list of differential diagnoses of a manic episode [1]:
- Depressive disorder with irritability and anxious distress
- Psychotic disorder or schizoaffective disorder
- Substance/medication-induced / medical conditions
- Attention deficit and hyperactivity disorder
- Personality disorder with prominent irritability
Let's go through each in detail.
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:
| Feature | Bipolar Disorder (Mania) | Schizophrenia |
|---|---|---|
| Mood | Prominent mood disturbance (elation, irritability, lability) is the core feature; psychosis is secondary | Mood may be flat, incongruent, or anxious; psychosis is the core feature |
| Temporal relationship | Psychotic symptoms occur within the context of mood disturbance and seldom outlast it [2] | Psychotic symptoms occur outside of mood disturbances and persist independently [2] |
| Psychotic content | Usually mood-congruent (grandiose delusions in mania, nihilistic in depression) | Often mood-incongruent, bizarre, with delusions of passivity / thought alienation [2] |
| First-rank symptoms | Can occur but usually fleeting [2] | Persistent and prominent |
| Thought disorder | Circumstantiality, tangentiality, flight of ideas (logical link preserved when examined closely) [2] | Loosening of association, neologism, thought blocking [2] |
| Speech | Pressured, difficult to interrupt [2] | More hesitant/halting [2] |
| Biological features | Marked ↓ need for sleep, hyperactive [2] | Less ↓ need for sleep, less hyperactive [2] |
| Motor | Psychomotor excitation | May have catatonia or negative symptoms (in addition to agitation) [2] |
| Course | Episodic with good inter-episode recovery; insight often returns | More chronic deteriorating course; negative symptoms accumulate |
| Premorbid function | Often good | Often poor premorbid adjustment |
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"
The Key Question for the DDx
Ask yourself: "Do the psychotic symptoms exist independently of the mood disturbance?"
- If psychosis ONLY occurs during mood episodes → Bipolar disorder with psychotic features
- If psychosis persists AFTER mood has normalised → Consider schizoaffective disorder or schizophrenia
- If psychosis and mood symptoms are equally prominent and concurrent → Schizoaffective disorder
Drugs and medical conditions that cause manic symptoms [1]:
| Category | Examples | Mechanism |
|---|---|---|
| Prescribed medications | Steroids (corticosteroids), L-dopa, stimulants (methylphenidate), antidepressants, ECT (in those with bipolar spectrum disorder) [1] | Steroids: HPA axis dysregulation + direct effects on mood circuits. L-dopa: ↑ dopamine → mesolimbic activation. Antidepressants: serotonergic/noradrenergic push can destabilise mood in vulnerable individuals → "manic switch" |
| Recreational drugs | Cocaine, amphetamine [1] | Cocaine blocks dopamine reuptake; amphetamines cause dopamine release → massive mesolimbic dopamine surge mimicking mania |
| Other substances | Cannabis, hallucinogens, alcohol (during intoxication or withdrawal) | Variable mechanisms; cannabis can trigger psychotic mania in genetically predisposed individuals |
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]
| Condition | Why It Mimics Mania | Differentiating Clues |
|---|---|---|
| Frontal lobe lesion (tumour, trauma, stroke, MS plaque) | The frontal lobe provides top-down inhibition over limbic structures. A lesion here → extreme social disinhibition with NO gross mood disturbance [2] — the patient acts impulsively and inappropriately but isn't truly "elated" | Consider especially in middle-aged or older patients with expansive behaviour but NO past history of affective disorder [2]. In younger patients, consider HIV infection and head injury [2]. Neurological signs, cognitive deficits, neuroimaging abnormalities |
| Hyperthyroidism | Thyroid hormone excess → global metabolic activation: tachycardia, weight loss, tremor, anxiety, irritability, insomnia, psychomotor agitation — overlaps significantly with mania | Thyroid signs (goitre, lid lag, exophthalmos, warm moist skin), abnormal TFTs. Mood is more anxious/agitated than truly elated/grandiose |
| Cushing's syndrome | Cortisol excess → HPA axis disruption, direct effects on mood circuits → can cause mania, depression, or psychosis | Cushingoid features (moon face, central obesity, striae, buffalo hump), abnormal dexamethasone suppression test |
| Other | Neurosyphilis, HIV encephalopathy, temporal lobe epilepsy, cerebrovascular disease, delirium | Respective clinical features; always consider organic causes in late-onset "mania" ( > 40 years) with no prior psychiatric history |
Red Flags for Organic Mania
Always suspect an organic cause when:
- First episode of mania in a middle-aged/older patient with NO past psychiatric history [2]
- Acute onset with confusion or fluctuating consciousness (→ delirium)
- Focal neurological signs
- Recent head trauma
- Known medical illness (thyroid, Cushing's, HIV)
- Atypical features (e.g., visual hallucinations are more suggestive of organic cause)
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]:
| Feature | Bipolar Disorder | Borderline Personality Disorder |
|---|---|---|
| Family history | Often positive FHx of bipolar disorder | No FHx of bipolar disorder [2] |
| Mood shift speed | Episodes last days to weeks/months | Rapid shifts of mood (over hours and days) [2], often within the same day |
| Trigger | Episodes may arise spontaneously (especially later in illness) | Mood disturbances often triggered by interpersonal issues [2] (rejection, abandonment) |
| Manic symptoms | Classic symptoms of mania present: ↑ energy, grandiosity, flight of ideas, ↓ need for sleep | No classic symptoms of mania [2] — no true grandiosity, no flight of ideas, no genuinely ↓ need for sleep |
| Course | Episodic — distinct episodes with intervening euthymia | Stable and enduring behaviour pattern (trait-like, not episodic) [2] |
| Self-harm | Suicide attempts (often during depressive or mixed episodes) | Chronic self-harm and suicidal gestures, often impulsive, linked to interpersonal crises |
| Identity | Intact sense of self between episodes | Chronic identity disturbance ("Who am I?") |
| Relationships | May be disrupted during episodes but stable between them | Chronic pattern of intense, unstable relationships with splitting (idealisation/devaluation) |
The Practical Test
Ask: "Does this patient have discrete episodes with clear onset and offset, during which their personality and functioning fundamentally change? Or do they have a chronic pattern of emotional instability that is always present but worsens in interpersonal situations?"
Episodes with clear boundaries → think bipolar Chronic instability, always there, worsens with interpersonal triggers → think BPD
(Note: they can co-exist! ~20% of BPD patients also have bipolar disorder.)
ADHD and mania share several features [2][4]:
Similarities:
- ↓ attention, difficulty with task completion
- ↑ energy and disinhibited behaviour
- Distractibility, impulsivity, talkativeness [4]
| Feature | Bipolar Disorder | ADHD |
|---|---|---|
| Self-esteem | ↑ self-esteem, grandiosity | Normal or low self-esteem |
| Flight of ideas | Present in mania | Absent (thoughts are scattered, not "racing") |
| Sleep | ↓ need for sleep (feels rested) | Sleep difficulties (can't settle), but feels tired |
| Mood | Elated mood, euphoria, or marked irritability [4] | Frustration-based irritability, but no true elation |
| Course | Episodic — features tend to occur episodically [4] | Chronic (trait-like) — more stable and enduring behaviour pattern [2]; symptoms present since childhood and are pervasive |
| Onset | Mean onset ~18 years (though may be earlier) | By definition, onset before age 12 |
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]
2. Differential Diagnosis of the Depressive Presentation
The majority of bipolar disorder patients present with depression as their first episode [2]. This is the main source of the infamous diagnostic delay.
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]:
| Feature | Bipolar Depression | Unipolar MDD |
|---|---|---|
| Age of onset | Younger (teens to early 20s) | Often later (late 20s–30s) |
| Family history | Bipolar disorder in first-degree relatives | Depression (without mania) in relatives |
| Psychomotor features | More psychomotor retardation | More agitation |
| Sleep | More hypersomnia (atypical features) | More insomnia (typical features) |
| Appetite | More hyperphagia | More anorexia |
| Psychotic features | More common | Less common |
| Diurnal variation | Morning dysphoria (worse AM, better PM) | Can be either pattern |
| Episode frequency | More frequent, shorter episodes | Less frequent, longer episodes |
| Postpartum onset | More likely | Less likely |
| Antidepressant response | Partial or may trigger hypomania/mania | Usually full response |
| Past hypomania | Present (but may need to be actively elicited!) | Absent |
Discerning features suggesting bipolarity: psychotic features, atypical features (e.g., hypersomnia, hyperphagia, leaden paralysis) [2]
The Most Important Question in Psychiatry
When you see a patient presenting with depression, ALWAYS screen for past mania/hypomania:
"Has there ever been a time — even if it lasted just a few days — when you felt the opposite? Unusually energetic, on top of the world, needing much less sleep but not feeling tired, spending more money than usual, taking unusual risks?"
If the patient says no, ask the informant. Patients often don't report hypomania because it feels good. This single question can prevent years of misdiagnosis.
- 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)
3. The Misdiagnosis and Overdiagnosis Problem
This is emphasised heavily in the lecture slides and deserves its own section [1]:
- 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]
| Differential | Key Differentiating Features from Bipolar Disorder |
|---|---|
| Schizophrenia | Psychosis persists outside mood episodes; mood-incongruent/bizarre delusions; loosening of association (not flight of ideas); negative symptoms; chronic deteriorating course |
| Schizoaffective disorder | Concurrent and equally prominent psychotic + mood symptoms; psychosis may occur outside mood episodes |
| MDD (unipolar) | No history of mania/hypomania; less psychomotor retardation; less atypical features; antidepressants work without manic switch |
| Borderline PD | Mood shifts over hours (not days/weeks); triggered by interpersonal events; no grandiosity/flight of ideas/↓ need for sleep; chronic trait-like course; identity disturbance |
| ADHD | Chronic trait-like since childhood; no grandiosity/euphoria/↓ need for sleep; no episodic pattern |
| Substance-induced | Temporal relationship to substance use; resolves after clearance; urine tox screen positive |
| Organic/medical | Late onset, no past psychiatric Hx, focal neurological signs; specific medical features (thyroid, Cushing's, frontal lobe); abnormal investigations |
| Agitated depression | Irritability from distress (not frustration/grandiosity); no other manic features |
High Yield Summary
DDx of Manic Presentation (from lecture slides): (1) Depressive disorder with irritability/anxious distress, (2) Psychotic disorder/schizoaffective disorder, (3) Substance/medication-induced or medical conditions (steroids, L-dopa, stimulants, antidepressants, ECT; cocaine, amphetamine; frontal lobe lesion, hyperthyroidism, Cushing's), (4) ADHD, (5) Personality disorder with prominent irritability (esp. BPD).
Key Distinctions:
- Schizophrenia vs Mania: Psychosis outlasts mood in schizophrenia; mood-incongruent, bizarre delusions; FRS persistent (vs fleeting in mania); loosening of association (vs flight of ideas); chronic course.
- BPD vs Bipolar: BPD = chronic/trait-like, mood shifts in hours, interpersonal triggers, no grandiosity/↓ sleep; Bipolar = episodic, ↑ energy/grandiosity/↓ sleep.
- ADHD vs Mania: ADHD = chronic since childhood, no grandiosity/euphoria/↓ need for sleep; Mania = episodic.
- Organic mania: Always suspect if late-onset, no past Hx, neurological signs.
Misdiagnosis: 69% initially misdiagnosed. Most common error = BP II → MDD (hypomania missed). Delayed 5–7 years. Consequence: antidepressant monotherapy → manic switch + cycle acceleration.
Correct diagnosis requires: Patient history + collateral from informants + screening tools (MDQ, HCL-32) + adherence to diagnostic criteria.
Active Recall - Differential Diagnosis of Bipolar Disorder
References
[1] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p10, p11, p12, p13, p14, p15, p17, p22) [2] Senior notes: ryanho-psych.md (sections 7.3, 7.1.2, pp.357–402) [3] Lecture slides: GC 170. Schizophrenia and related psychoses.pdf (p22) [4] Senior notes: ryanho-psych.md (ADHD section, p.664)
Diagnostic Criteria for Bipolar Disorder
Getting the diagnostic criteria right is essential — as we've discussed, misdiagnosis is extremely common and correct diagnosis and treatment was delayed by 5–7 years on average [1]. The diagnosis is entirely clinical: there is no blood test, no imaging finding, no biomarker. It rests on a careful psychiatric history, mental state examination, collateral information, and rigorous application of diagnostic criteria [1].
Let's break this down systematically.
The DSM-5 separates mood disorders into two distinct chapters, reflecting the conceptual "bridge" position of bipolar disorder between psychotic and depressive disorders [1]:
2. Diagnostic Criteria: Manic Episode (DSM-5)
The manic episode is the defining episode for Bipolar I disorder. Let me walk you through the DSM-5 criteria and explain the logic behind each one.
Both of the following core symptoms must be present [1][2]:
- Abnormally elevated, expansive, or irritable mood
- 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]:
| # | Symptom | Mnemonic (DIG FAST) | Why It Occurs (Pathophysiology) |
|---|---|---|---|
| 1 | Inflated self-esteem or grandiosity | G | Dopaminergic mesolimbic hyperactivity → aberrant salience assigned to self-referential thoughts |
| 2 | Decreased need for sleep (e.g., feels rested after only 3 hours) | S | Noradrenergic/dopaminergic overactivation of ascending reticular activating system + circadian rhythm disruption |
| 3 | More talkative than usual or pressure to keep talking | T | Racing thoughts overflow into speech; cortical hyperexcitability → pressured speech |
| 4 | Flight of ideas or subjective experience of racing thoughts | F | Disinhibited cortical association pathways; GABAergic deficit → rapid, loosely connected thought chains |
| 5 | Distractibility (attention too easily drawn to unimportant stimuli) | D | dlPFC executive dysfunction → impaired attentional filtering |
| 6 | Increase in goal-directed activity (socially, at work/school, or sexually) or psychomotor agitation | A | Striatal dopaminergic drive → motivation and motor activation |
| 7 | Excessive involvement in activities with high potential for painful consequences (impulsivity/irresponsibility) — e.g., buying sprees, sexual indiscretions, foolish investments | I | Ventral striatum (reward) overactive + vmPFC (consequence evaluation) underactive → reward-seeking without risk appraisal |
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 hypomanic episode is structurally very similar to the manic episode but with three critical differences [1][2]:
| Feature | Mania | Hypomania |
|---|---|---|
| Duration | ≥7 days (or any if hospitalisation required) | ≥4 consecutive days |
| Functional impairment | Marked impairment or hospitalisation | No marked impairment — an unequivocal change in functioning that is observable by others, but NOT severe enough to cause marked impairment or require hospitalisation [2] |
| Psychotic features | May be present | NEVER present [2] — if psychosis occurs, it is by definition mania |
Criteria A & B: Same as mania (elevated/expansive/irritable mood + increased energy; ≥3 or ≥4 associated symptoms)
Criterion C: Episode is associated with an unequivocal change in functioning that is not characteristic of the individual when not symptomatic
Criterion D: The disturbance and change in functioning are observable by others — this is key, because the patient often doesn't recognise hypomania as pathological (ego-syntonic)
The Hypomania Trap
Hypomania is often missed because:
- The patient feels great and doesn't complain about it
- It may look like a "good week" or an energetic personality
- Retrospective recall can be inaccurate [1]
- Requires informants and collateral information (e.g., medical record) to confirm past history of mania/hypomania [1]
- Screening tools like the MDQ and HCL-32 can help [1] If you miss hypomania, you diagnose MDD instead of Bipolar II → treat with antidepressant monotherapy → manic switch and cycle acceleration [1].
The depressive episode criteria are the same as for MDD. Required for Bipolar II (not technically required for Bipolar I, though nearly all Bipolar I patients experience depression):
≥5 of the following 9 symptoms present during the same 2-week period, with at least one being depressed mood or loss of interest/pleasure [2]:
- Depressed mood most of the day, nearly every day
- Anhedonia — markedly diminished interest or pleasure
- Weight/appetite change (significant weight loss/gain or decrease/increase in appetite)
- Sleep disturbance (insomnia or hypersomnia)
- Psychomotor agitation or retardation (observable by others)
- Fatigue or loss of energy
- Worthlessness or excessive guilt
- Diminished concentration or indecisiveness
- Recurrent thoughts of death, suicidal ideation, or suicide attempt
| Criterion | Bipolar I | Bipolar II | Cyclothymia |
|---|---|---|---|
| Key requirement | ≥1 lifetime manic episode [1] | ≥1 hypomanic episode AND ≥1 major depressive episode [1] | Numerous periods of hypomanic and depressive symptoms NOT meeting full criteria for either, for ≥2 years [2] |
| Manic episodes | Present (defines the diagnosis) | Never a manic or mixed episode [1] | Never |
| Depressive episodes | Common (~95%) but NOT required for diagnosis | Required (≥1 MDE) | Subthreshold only |
| Psychotic features | May occur (in mania or depression) | Only in depressive episodes (never in hypomania) | No |
| Exclusion | Not better explained by any of the psychotic disorders [2] | Not better explained by any of the psychotic disorders; causes clinically significant distress or impaired functioning [2] | ≥½ time symptomatic; symptom-free < 2 consecutive months [2] |
DSM-5 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
- Presence of one single manic episode already satisfies criteria for Bipolar I disorder, which occurs in only 5% [1]
DSM-5 criteria of Bipolar II disorder: [1]
- At least one hypomanic episode
- At least one previous depressive episode
- Never has a manic or mixed episode
- Depressive episodes are more common in Bipolar II disorder [1]
Bipolar I, Bipolar II, and Bipolar spectrum: [1]
- BP I: severe mood episodes
- BP II: milder manic symptoms, prominent depressive element, can have the same degree of long-term impairment as BP I
- BP spectrum: bothered by frequent mood changes, can be mistaken as borderline personality disorder
ICD-10 vs DSM-5 Comparison
| Feature | ICD-10 | DSM-5 |
|---|---|---|
| Bipolar diagnosis requires | ≥2 episodes of mood disruption, with ≥1 hypomanic, manic, or mixed affective episode [2] | ≥1 lifetime manic episode (for Bipolar I) — a single manic episode suffices [1][2] |
| Classification codes | F31.0 (current hypomanic) through F31.7 (in remission) [2] | Bipolar I / Bipolar II, with current/most recent episode specifiers |
| Mixed episodes | Separate subtype (F31.6) | Specifier ("with mixed features") applied to any episode |
ICD-10 vs DSM-5 — The Key Difference
In ICD-10, ≥2 mood disturbances must have occurred to diagnose bipolar disorder. In DSM-5, only 1 mood disturbance episode is required for Bipolar I if the said disturbance is mania [2]. This means a patient with a single manic episode and no depression gets diagnosed as Bipolar I under DSM-5 but not under ICD-10. In practice, this rarely matters because ~95% of Bipolar I patients eventually develop depressive episodes.
Here is a systematic approach to diagnosing bipolar disorder:
Step-by-Step Clinical Approach
Step 1: Establish the current mood episode
- What is the patient presenting with right now — mania, hypomania, depression, mixed features, or euthymia?
- Use DSM-5 criteria to classify the current episode
Step 2: Take a thorough longitudinal history
- History from the patient [1]
- Collateral information from informants — absolutely critical [1]
- Map out ALL previous mood episodes on a timeline (mood chart is helpful [2])
- Specifically ask about past mania/hypomania — patients don't volunteer this
Step 3: Use screening tools
- Mood Disorder Questionnaire (MDQ) [1] — 13 yes/no items based on DSM criteria for mania/hypomania; sensitivity ~73%, specificity ~90% in clinical settings
- Hypomania Checklist (HCL-32) [1] — 32-item self-report; better sensitivity for Bipolar II/soft spectrum
Step 4: Rule out organic and substance-induced causes
- Investigations (see below)
- Drugs and medical conditions that cause manic symptoms: steroids, L-dopa, stimulants, antidepressants, ECT (in those with bipolar spectrum disorder); cocaine, amphetamine; frontal lobe lesion, hyperthyroidism, Cushing's syndrome [1]
Step 5: Classify the bipolar subtype
- Bipolar I, II, cyclothymia, or other specified
Step 6: Apply specifiers
- With mixed features, rapid cycling, psychotic features, peripartum onset, etc.
Step 7: Assess severity and risk
- Suicide risk (especially in depressive/mixed episodes)
- Risk to others (especially in mania with irritability/psychosis)
- Functional impairment
- Comorbidities
7. Investigations
Investigations in bipolar disorder serve three purposes:
- Exclude organic/substance-induced mania (differential diagnosis)
- Establish a baseline before starting mood stabilizers/antipsychotics (which have significant metabolic and organ-specific side effects)
- Screen for comorbidities and neglect
The lecture slides provide a clear list [1]:
| Investigation | Rationale and Key Findings |
|---|---|
| CBP (Complete blood picture) [1] | Exclude anaemia (fatigue mimicking depression), infection (delirium mimicking mania), ↑MCV (macrocytosis from alcohol use — comorbid substance abuse is common) |
| LRFT (Liver and renal function tests) [1] | Liver: Baseline before valproate (hepatotoxic — valproate can cause fatal hepatic failure, especially in children); GGT elevated in alcoholism. Renal: Baseline before lithium (lithium is filtered by the kidney and is nephrotoxic — can cause nephrogenic diabetes insipidus, chronic tubulointerstitial nephropathy); U/Cr for renal dosing |
| TFT (Thyroid function tests) [1] | Three reasons: (1) Hyperthyroidism mimics mania (↑ energy, irritability, insomnia, weight loss); (2) Hypothyroidism is associated with rapid cycling; (3) Lithium causes hypothyroidism (in ~5–35% of patients) by inhibiting thyroid hormone synthesis. Baseline essential before starting lithium, then monitor regularly |
| Fasting glucose and lipid profile [1] | Baseline metabolic screening before starting atypical antipsychotics (olanzapine, quetiapine → weight gain, insulin resistance, dyslipidaemia, metabolic syndrome). Also screening for pre-existing diabetes/CVD risk (bipolar patients have ↑ cardiovascular mortality) |
| 24-hour creatinine clearance (if history of renal disease) [1] | More precise assessment of renal function before lithium in patients with known/suspected renal impairment. Lithium has a narrow therapeutic index — requires normal renal clearance for safe dosing |
| Urine for toxicology (if relevant) [1] | Exclude substance-induced mania — cocaine, amphetamines, cannabis. Substance abuse comorbidity is 40–60% in bipolar disorder. Manic symptoms from substance use should ↓ after admission [2] |
| Pregnancy test (if relevant) [1] | Many mood stabilizers are teratogenic: valproate is absolutely contraindicated in pregnancy (neural tube defects, craniofacial abnormalities, neurodevelopmental impairment); lithium carries risk of Ebstein anomaly (tricuspid valve malformation); carbamazepine is also teratogenic. Must exclude pregnancy before starting these agents |
| ECG (if relevant) [1] | Baseline before medications that prolong QTc interval (some antipsychotics — especially ziprasidone, haloperidol; also lithium can cause T-wave changes, sinus node dysfunction). Also if cardiac history or older patient |
| Investigation | When to Order | Interpretation |
|---|---|---|
| CT/MRI brain | Late-onset mania ( > 40 years) with no prior psychiatric history; focal neurological signs; atypical presentation; suspected frontal lobe lesion [2] | Exclude tumour, cerebrovascular disease, demyelination, traumatic brain injury |
| EEG | Suspected temporal lobe epilepsy (ictal mood changes, automatisms, aura); episodic behavioural disturbance | Epileptiform discharges in temporal regions |
| Calcium | Screen for hyperparathyroidism (hypercalcaemia can cause psychiatric symptoms including mania and psychosis) | Elevated Ca → investigate further with PTH |
| Vitamin B12 / Folate | Suspected nutritional deficiency (especially in elderly, comorbid alcohol use) [2] | Deficiency can cause mood disturbance, cognitive impairment |
| HIV test | Young patient with new-onset mania, risk factors for HIV | HIV can cause manic symptoms via direct CNS involvement |
| Syphilis serology (VDRL/RPR) | Suspected neurosyphilis (late-onset behavioural change, cognitive decline) [2] | Neurosyphilis can present with mania-like symptoms |
| CRP/ESR | Suspected inflammatory or infectious cause | Non-specific markers of inflammation |
| Cosyntropin (ACTH) stimulation test | Suspected Cushing's or Addison's disease | Abnormal cortisol response |
| Lithium level (if already on lithium) | Therapeutic drug monitoring; suspected toxicity | Therapeutic range 0.6–1.0 mmol/L (acute mania: up to 1.2); toxicity > 1.5 |
Why These Specific Baseline Investigations?
The baseline investigations are driven by two principles:
-
What could mimic bipolar disorder? → TFTs (hyperthyroidism), urine toxicology (stimulants), CT brain (frontal lobe lesion)
-
What do I need to know before starting treatment? → RFT (for lithium), LFT (for valproate), fasting glucose + lipids (for antipsychotics), pregnancy test (teratogenicity), ECG (QTc-prolonging drugs)
Every investigation on the list has a specific therapeutic decision tied to it. This isn't a "routine screen" — it's a targeted safety evaluation.
Once treatment is initiated, ongoing monitoring is essential. The specifics depend on the medication:
| Medication | Key Monitoring | Frequency | Why |
|---|---|---|---|
| Lithium | Serum lithium level, U&E/Cr, eGFR, TFTs, calcium, weight | Li level: weekly until stable, then every 3–6 months; RFT/TFT: every 6 months | Narrow therapeutic index (0.6–1.0); nephrotoxicity; hypothyroidism; hyperparathyroidism |
| Valproate | LFTs, CBP, weight | Baseline, then at 6 months, then annually | Hepatotoxicity; thrombocytopaenia; teratogenicity (ongoing pregnancy tests in women of childbearing age) |
| Carbamazepine | CBP, LFTs, U&E, drug level | Regular, especially early | Agranulocytosis; aplastic anaemia; SIADH (hyponatraemia); hepatotoxicity |
| Atypical antipsychotics | Fasting glucose, lipid profile, weight/BMI/waist circumference, BP | Baseline, 3 months, 6 months, then annually | Metabolic syndrome; weight gain; diabetes; dyslipidaemia |
Correct diagnosis of bipolar disorder requires [1]:
- History from the patient
- Collateral information from informants
- Help by the use of screening tools
| Tool | Description | Use |
|---|---|---|
| Mood Disorder Questionnaire (MDQ) [1] | 13-item yes/no self-report screening tool based on DSM criteria for mania/hypomania. Also asks if symptoms occurred at the same time and caused moderate-to-serious problems | Screening for Bipolar I (good sensitivity); less sensitive for Bipolar II. A positive screen requires clinical confirmation |
| Hypomania Checklist (HCL-32) [1] | 32-item self-report checklist specifically designed to detect hypomania, including "softer" presentations | Better sensitivity for Bipolar II and bipolar spectrum than MDQ. Useful when you suspect bipolarity in a patient presenting with depression |
It is important to follow diagnostic criteria in making psychiatric diagnosis [1]. Screening tools assist but do not replace clinical judgment. Structured interview could not confirm the diagnosis in 33% of previously diagnosed outpatients [1] — highlighting that even experienced clinicians can overdiagnose without rigorous criteria.
9. Assessment Framework: Putting It All Together
The senior notes provide a comprehensive assessment structure [2]:
| Component | What to Elicit |
|---|---|
| Core symptoms | Elated mood, irritability, violence risk, duration, severity, sleep pattern, energy level, activity changes |
| Associated symptoms | Grandiosity, flight of ideas, distractibility, pressured speech, impulsivity, reckless behaviour, spending patterns, sexual behaviour |
| Psychotic features | Delusions (grandiose, persecutory, reference), hallucinations (auditory, visual), first-rank symptoms |
| Depressive features | Screen for concurrent/past depressive episodes (for Bipolar II diagnosis); mixed features |
| Past psychiatric history | Previous mood episodes (mania, hypomania, depression), hospitalisations, treatments tried, response |
| Collateral history | From family/friends — essential for detecting hypomania that the patient doesn't report [1] |
| Substance use history | Alcohol, cannabis, stimulants, prescribed medications |
| Family history | Bipolar disorder, schizophrenia, depression, suicide in first-degree relatives |
| Suicide risk assessment | Past attempts, current ideation, plans, access to means, protective factors |
| Premorbid personality | Baseline functioning, temperament (cyclothymic traits?) |
| Social history | Relationships, employment, living situation, forensic history (impulsive acts during mania) |
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
High Yield Summary
Diagnostic Criteria — Key Points:
Manic Episode (Bipolar I): Elevated/expansive/irritable mood + increased energy (both required) + ≥3 associated symptoms (DIG FAST; ≥4 if irritable only) + ≥7 days (or any duration if hospitalised) + marked impairment/psychosis + not substance-induced.
Hypomanic Episode (Bipolar II): Same core + associated symptoms as mania BUT ≥4 days only, NO marked impairment, NEVER psychotic. Observable change in functioning. Bipolar II also requires ≥1 MDE.
ICD-10 vs DSM-5: ICD-10 requires ≥2 mood episodes for bipolar; DSM-5 requires only 1 manic episode for Bipolar I.
Diagnostic Algorithm: History (including collateral) → Screen for past mania/hypomania (MDQ, HCL-32) → Classify current episode → Rule out organic/substance causes → Classify subtype (I/II/cyclothymia) → Apply specifiers → Assess risk.
Baseline Investigations (from lecture slides): CBP, LRFT, TFT, fasting glucose + lipids, 24h CrCl (if renal disease), urine toxicology (if relevant), pregnancy test (if relevant), ECG (if relevant). Purpose: exclude organic mimics + establish baseline before treatment.
Screening Tools: MDQ (13 items, good for BP I), HCL-32 (32 items, better for BP II). Neither replaces clinical interview + collateral history.
Active Recall - Diagnostic Criteria, Algorithm and Investigations
References
[1] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p3, p7, p8, p10, p11, p12, p13, p14, p15, p17, p22, p23, p24, p61) [2] Senior notes: ryanho-psych.md (sections 7.3, 7.1.2, pp.348–402)
Management of Bipolar Disorder
Managing bipolar disorder is fundamentally different from managing unipolar depression — and getting this wrong can be harmful. The overarching philosophy is: stabilise the mood in both directions (prevent highs AND lows), minimise harm from treatment, and sustain functional recovery over a lifetime. This is a chronic relapsing-remitting illness, so think of it like managing diabetes — acute treatment of crises, then long-term maintenance to prevent complications.
The lecture slides lay out a clear outline of management [1]:
-
Fundamentals of patient management
- Correct diagnosis
- Illness acceptance and treatment adherence
- Family psychoeducation
-
Pharmacological and psychosocial treatment
-
Treatment of different phases of bipolar illness
- Acute manic episode
- Acute depressive episode
- Maintenance and prophylactic treatment
-
Treatment in special situations: childbearing-age women, pregnancy, child and adolescents, elderly
-
Treatment of psychiatric and medical comorbidity
And the summary slide captures the key overarching goals [1]:
- Early diagnosis and maintenance treatment
- Watch out for side effects and the need of alternative treatments
- Deal with stigma and poor drug compliance
- Provide psychoeducation (individual and family)
- Pay attention to stress coping, interpersonal relationship, lifestyle regularity and other risk factors of relapse
- Recognise and treat comorbidities, e.g., anxiety disorder, sleep problem, suicidal risk, substance abuse
The Three Cardinal Rules of Bipolar Management
- Always stop/avoid antidepressant monotherapy — it triggers manic switch and cycle acceleration
- Always think long-term — acute treatment is just the beginning; maintenance prevents the next episode
- Always involve the family — psychoeducation and expressed emotion management reduce relapse
3. Phase 1: Treatment of Acute Mania / Hypomania
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:
| Option | When to Choose | Key Considerations |
|---|---|---|
| Antipsychotic | If symptoms severe or behaviour disturbed [2] | Best combination of efficacy and acceptability; considered 1st line in NICE guidelines [2]. Options: olanzapine, risperidone, haloperidol, quetiapine, aripiprazole, ziprasidone [2] |
| Valproate | Alternative first-line | Avoid in women of childbearing potential [1][2]. Faster onset of action compared to lithium [2] |
| Lithium | If future adherence likely [2] | Don't start if unlikely to be compliant (discontinuation can trigger mania) [2]. Rapid cycling, prominent depressive symptoms, and psychotic features predict poorer response [2] |
→ 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]:
| Current Medication | Action |
|---|---|
| On antipsychotic | Check compliance and dose; increase if necessary; consider adding lithium or valproate |
| On lithium | Check plasma levels; consider increasing dose to give levels 1.0–1.2 mmol/L (acute episode, not long-term); and/or add antipsychotic |
| On valproate | Check plasma levels; increase dose to give levels up to 125 mg/L if tolerated; consider adding antipsychotic |
| On lithium or valproate AND mania is severe | Check levels, add antipsychotic |
| On carbamazepine | Consider adding antipsychotic (higher doses may be needed as antipsychotic levels are reduced by carbamazepine enzyme induction) |
4. Phase 2: Treatment of Acute Bipolar Depression
This is where bipolar management diverges most sharply from unipolar depression. The lecture slides highlight this critical point [1]:
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]
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]
The Antidepressant Problem in Bipolar Disorder
Avoid antidepressants if possible; if used, limit dose and duration [1].
Why? Antidepressants push the serotonergic/noradrenergic system upward. In a bipolar brain that is already prone to oscillating between poles, this "push" can overshoot into mania ("manic switch") or destabilise the cycling pattern ("cycle acceleration"). This is why:
- Antidepressants should NEVER be used alone in bipolar disorder
- If used, they should be combined with a mood stabiliser or antipsychotic
- TCAs are the worst offenders (highest switch risk), followed by SNRIs, then SSRIs (lowest risk)
- Antidepressants, when used, should be combined with antipsychotic or mood stabilizer [2]
4.2 Treatment Options
Treatment of bipolar depressive episode [1]:
- Monotherapy: Lithium, Lamotrigine OR Quetiapine
- Combination: Add Antidepressants (SSRI OR Venlafaxine) to monotherapy OR Combine two monotherapy agents
- Re-evaluate diagnosis and consider ECT (for patients with high suicidal risk) [1]
| Agent | Details |
|---|---|
| Lithium | Target 0.8–1.2 mEq/L [1]. Moderate evidence for bipolar depression. Also has anti-suicidal properties (unique benefit) |
| Lamotrigine | Sometimes requires higher than 200 mg/day [1]. More effective for bipolar depression but little anti-manic effect [2]. Must titrate slowly (risk of SJS/TEN) |
| Quetiapine | Aim at 300 mg/day [1]. Good evidence for both depressive and manic poles. Sedation is a common side effect but can help with insomnia |
| Lurasidone | [1] Newer atypical antipsychotic with good evidence for bipolar depression. Less metabolic side effects than olanzapine/quetiapine |
| Valproate or Lithium + Lurasidone | [1] Combination option |
| Line | Agents |
|---|---|
| First line | Quetiapine |
| Second line | Lamotrigine; Lithium; Antidepressants such as sertraline, venlafaxine |
| Third line | Valproate |
- First-line:
- Olanzapine + fluoxetine OR quetiapine alone if not on mood stabiliser
- ↑ mood stabiliser dose if previously on mood stabiliser
- Other options: olanzapine alone, lamotrigine alone
- ECT: if severe, refractory, or need urgent treatment
- Not preferred: SSRI alone, other antidepressants alone [2]
5. Phase 3: Maintenance / Prophylactic Treatment
This is the most important phase for long-term outcomes. Recurrence rate reduces by 50% for maintenance vs. discontinuation [1].
- 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]
5.3 Maintenance Treatment Options
General guidelines for prophylaxis for Bipolar I [1]:
- Monotherapy: Lithium or Valproate or Quetiapine
- Psychosocial (augmentation):
- Psychoeducation
- Cognitive behavioural therapy
- Interpersonal and social rhythm therapy
- Family or carer-focused treatment
- Peer support
- Intensive case management
- Less hostile, more supportive, better drug compliance [1]
| Line | Agent | Key Points |
|---|---|---|
| First-line | Lithium | Gold standard. The only mood stabiliser proven to reduce suicide [1]. Better at preventing manic episodes (NNT 10) than depressive episodes (NNT 14) [2]. Monitor levels (0.6–1.0 mmol/L), RFT, TFT every 6 months [2] |
| First-line (alternatives) | Valproate | Also commonly used. Avoid in women of childbearing potential (teratogenic). Good for mixed episodes [2] |
| First-line (alternative) | Quetiapine | Effective for both manic and depressive poles [2] |
| Second-line | Olanzapine | Effective but limited by metabolic side effects (weight gain, diabetes) [2] |
| Third-line | Other antipsychotics, carbamazepine, lamotrigine [2] | Lamotrigine is better at preventing depressive episodes, less for manic episodes compared to lithium/valproate [2] |
| Line | Agent |
|---|---|
| First line | Quetiapine, Lithium, or Lamotrigine |
| Second line | Venlafaxine |
| Third line | Valproate; Carbamazepine; Other antidepressants; Risperidone |
| Agent | Prevents Mania | Prevents Depression | Anti-suicidal |
|---|---|---|---|
| Lithium | ✓✓✓ | ✓✓ | ✓✓✓ (unique — ↑80% ↓ risk of attempted + completed suicide) [2] |
| Valproate | ✓✓✓ | ✓ | — |
| Lamotrigine | ✓ | ✓✓✓ | — |
| Quetiapine | ✓✓ | ✓✓ | — |
| Olanzapine | ✓✓ | ✓ | — |
6. Pharmacological Agents — Detailed Profiles
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)
- 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]:
| Step | Details |
|---|---|
| Pre-treatment | RFT (eGFR), TFT ± ECG (if CVS risk factors) + reliable contraception |
| Initiation | Usually 350–500 mg/day, titrate up 300–600 mg/day every 1–5 days until therapeutic level reached (usually 900–1800 mg/day) |
| Pharmacokinetics | Rapidly absorbed from GI tract; half-life ~24 hours (takes 4–5 days to reach steady state) |
| Drug level monitoring | 12 hours after last dose (morning trough level). Targets: 0.4 mmol/L (minimum/unipolar), 0.6–1.0 mmol/L (bipolar prophylaxis), > 0.8 mmol/L (acute mania) |
| When to check levels | Every 6 months if stable; before and 7 days after any dose change |
| On-treatment monitoring | Plasma lithium, eGFR, TFT every 6 months ± plasma calcium yearly |
| Discontinuation | Gradually over ≥1 month, avoiding incremental reductions > 0.2 mmol/L. Should not be started unless clear intention to continue ≥3 years (discontinuation ↑↑ relapse risk) [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]:
| System | Side Effects | Mechanism |
|---|---|---|
| Renal | Nephrogenic diabetes insipidus (polyuria, polydipsia); chronic tubulointerstitial nephropathy | Lithium inhibits ADH action on collecting duct aquaporin-2 channels |
| Thyroid | Hypothyroidism (5–35%); goitre | Inhibits thyroid hormone synthesis and release |
| Parathyroid | Hyperparathyroidism, hypercalcaemia | Stimulates PTH secretion |
| Neurological | Fine tremor, ataxia, cognitive dulling | Direct CNS effects |
| GI | Nausea, diarrhoea, metallic taste | GI mucosal irritation |
| Cardiac | T-wave flattening/inversion, sinus node dysfunction | Direct effect on cardiac ion channels |
| Metabolic | Weight gain | Multiple mechanisms including hypothyroidism |
| Dermatological | Acne, psoriasis exacerbation, hair thinning | Unknown |
| Teratogenicity | Ebstein anomaly (tricuspid valve malformation) — risk ~0.1% | Direct effect on cardiac development |
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]:
| Step | Details |
|---|---|
| Pre-treatment | CBC, LFT, weight/BMI |
| Initiation | Can use loading dose → faster onset of action compared to lithium [2] |
| Dosing | Start 200–400 mg/day → titrate to 1–2 g/day |
| Monitoring | CBC, LFT after 6 months; BMI continuously |
| Discontinuation | Slowly over ≥1 month |
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:
| Agent | Role | Key Side Effects |
|---|---|---|
| Quetiapine | First-line for acute mania, bipolar depression, AND maintenance. 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 [1]. Tailor the dose according to response and AE [1] | Dry mouth, sleepiness (subjective) [1]; Weight gain, metabolic syndrome and type 2 diabetes, dyslipidaemia (systemic) [1] |
| Olanzapine | Acute mania, bipolar depression (especially + fluoxetine), maintenance | Significant weight gain, metabolic syndrome — limited by metabolic side effects [1] |
| Risperidone | Acute mania | Extrapyramidal side effects, hyperprolactinaemia |
| Aripiprazole | Acute mania, maintenance | Partial D₂ agonist — less metabolic side effects; akathisia |
| Lurasidone | Bipolar depression [1] | Less metabolic side effects; akathisia, nausea |
| Haloperidol | Acute mania (especially in pregnancy) | EPS, QTc prolongation |
Atypical antipsychotics look promising as mood stabilisers, but limited by metabolic side effects [1]
Etymology: "Electro-" = electrical; "convulsive" = seizure-inducing; "therapy" = treatment.
Mechanism of Action: Unknown, but hypothesised [2]:
- ↑ hormonal release by hypothalamus/pituitary (prolactin, TSH, ACTH, endorphins)
- ↑ neurotrophic signalling (e.g., ↑ BDNF) → induces neurogenesis
- ↑ monoamine neurotransmitter release
- Changes in brain connectivity
Indications in Bipolar Disorder [1][2]:
- Acute mania: need of rapid response (e.g., high violence risk) [1]; pregnant patients; life-threatening; persistent and treatment-resistant
- Bipolar depression: severe, refractory, high suicidal risk [1]; when antidepressants failed or cannot be used
- Catatonia
- Puerperal psychosis with prominent mood symptoms
Administration [2]:
- Course: 6–12 treatments, 2–3 per week
- Under brief general anaesthesia with short-acting induction agent and muscle relaxant
- Unilateral vs bilateral: bilateral more effective but may cause more cognitive impairment [2]
Adverse Effects [2]:
- Cognitive impairment: acute confusion, anterograde/retrograde amnesia (generally short-lived)
- General: headache, nausea, muscle pain
- Mortality: 2–4/100,000 (~other minor surgery under GA)
Relative Contraindications [2]:
- Recent MI, heart failure, ischaemic heart disease
- ↑ ICP (raised intracranial pressure)
- Risk of ICH (hypertension, recent stroke)
- Poor anaesthetic risk
- No absolute contraindication [2]
Psychosocial intervention is important for prevention of relapses and overall management of bipolar disorder [1]
Role: Less important than in depression (cf pharmacotherapy is the mainstay), mainly adjunctive to improve and sustain recovery [2]
| Intervention | Description | Evidence |
|---|---|---|
| Psychoeducation [1] | Teaching patient and family about the illness, early warning signs, medication adherence, lifestyle regularity | Core component; reduces relapse |
| Cognitive Behavioural Therapy (CBT) [1] | Addresses cognitive distortions during depression, improves insight and compliance | Theoretically beneficial; evidence uncertain [2] |
| Interpersonal and Social Rhythm Therapy (IPSRT) [1] | Maintain sleep-activity schedules [2]; stabilise daily routines and circadian rhythms | Reduces relapse by addressing the circadian rhythm disruption that triggers episodes |
| Family or carer-focused treatment [1] | Improve family support; reduce expressed emotion | Shown to reduce hospitalisation and symptomatology by 1/3 [2] |
| Peer support [1] | Connection with others who have the condition | Reduces isolation, improves engagement |
| Intensive case management [1] | For complex cases with multiple comorbidities | Improves continuity of care |
| Mood chart [2] | Patient tracks mood daily | Helpful in helping patient understand disease course and own situation [2] |
| Advanced statements [2] | Pre-written instructions for when the patient is manic and lacks judgment | Addresses social implications of poor judgment during manic states [2] |
Bipolar disorder is underrecognised 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 and duration
Lithium is still an important drug, given that it is the only mood stabiliser to reduce suicide
Atypical antipsychotics look promising as mood stabilisers, but limited by metabolic side effects
Lamotrigine is a promising agent for treatment of bipolar depression due to its tolerability and wide therapeutic margin
Psychosocial intervention is important for prevention of relapses and overall management of bipolar disorder
| Indication | FDA-Approved Agents |
|---|---|
| Mania | Valproate, carbamazepine CR, lithium, aripiprazole, ziprasidone, risperidone, quetiapine, chlorpromazine, olanzapine |
| Mixed | Carbamazepine CR, aripiprazole, ziprasidone, risperidone, olanzapine |
| Depression | Quetiapine, olanzapine/fluoxetine combination |
| Maintenance | Lithium, lamotrigine, aripiprazole, olanzapine |
High Yield Summary
Acute Mania: Stop antidepressants → Monotherapy (antipsychotic OR valproate OR lithium) → If inadequate, combine (lithium/valproate + antipsychotic) → If still inadequate, re-evaluate dx + ECT. Add short-term BZD for behavioural disturbance. Continue ≥6 months, ≥8 weeks post-remission. Hospitalise all but mildest cases.
Acute Bipolar Depression: Monotherapy (lithium OR lamotrigine OR quetiapine) → Add SSRI/venlafaxine to mood stabiliser if inadequate → ECT if severe/refractory/suicidal. NEVER antidepressant monotherapy. BP II: quetiapine first-line.
Maintenance: Lithium (gold standard, only drug to ↓ suicide), valproate (avoid women of childbearing potential), quetiapine. Lamotrigine for depression-predominant. Psychosocial interventions essential. Continue ≥3 years for lithium; relapse possible even after years of remission.
Key Drug Points:
- Lithium: narrow therapeutic index (0.6–1.0), monitor levels/RFT/TFT q6mo, anti-suicidal, avoid with thiazides/NSAIDs/ACEi
- Valproate: NEVER in women of reproductive potential (teratogenic), faster onset than lithium, good for mixed episodes
- Lamotrigine: good for depression pole, titrate slowly (SJS risk), well-tolerated, ↑ levels with valproate
- Carbamazepine: potent P450 inducer (drug interactions!), check HLA-B*1502 (SJS), auto-induces own metabolism
- Quetiapine: versatile (mania + depression + maintenance), metabolic side effects
- ECT: no absolute C/I, rapid response, use when pharmacotherapy fails or in emergencies
Active Recall - Management of Bipolar Disorder
References
[1] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p36, p40, p41, p42, p44, p45, p46, p47, p51, p59, p64, p65) [2] Senior notes: ryanho-psych.md (sections 3.1.3, 3.1.3.1, 3.2, 7.3 Management, pp.123–151, 403–408)
Complications of Bipolar Disorder
Bipolar disorder is not simply an illness of "mood swings." It is a systemic, chronic, progressive condition with devastating complications that span psychiatric, medical, social, cognitive, and treatment-related domains. Understanding these complications — and why they occur — is essential for holistic management.
The prognosis is sobering: only < 20% of patients achieve a 5-year period of clinical stability [2]. Life expectancy is ↓ by ~13 years (males) and ~9 years (females) [2]. The complications are what drive this excess morbidity and mortality.
This is the most feared and most important complication of bipolar disorder.
- One third of patients attempted suicide; 10–20% died from their illness by suicide [1][2]
- Risk factors: past suicidal attempt and prominent depressive symptoms [1]
- ~8% (males) and 5% (females) of hospitalised patients die by suicide over 40 years [2]
- Suicide accounts for approximately 1/3 of all mortality in bipolar disorder [2]
Why is suicide risk so high?
- Depressive episodes are the primary driver — patients experience profound hopelessness, worthlessness, and psychic pain. Bipolar patients spend far more time depressed than manic, and bipolar depression is often more severe and treatment-resistant than unipolar depression.
- Mixed features are particularly dangerous: the patient has the despair and suicidal ideation of depression combined with the energy, impulsivity, and disinhibition of mania — this removes the "psychomotor retardation" that paradoxically protects profoundly depressed patients from acting on their suicidal thoughts.
- Impulsivity during mania — even without depressive despair, the reckless judgment and disinhibition of mania can lead to dangerous behaviour.
- Comorbid substance abuse (present in 40–60%) further disinhibits and amplifies suicide risk.
- Psychotic features (command hallucinations, nihilistic delusions) can drive self-harm.
Protective factor: Lithium is the only mood stabiliser proven to reduce suicide — ↓ 80% risk of attempted and completed suicide in bipolar disorder [1][2]. This is a unique property not shared by valproate, lamotrigine, or antipsychotics, and is one of the strongest reasons to consider lithium as maintenance therapy.
Exam Point: Suicide in Bipolar Disorder
Mixed episodes carry the HIGHEST suicide risk of any mood state — higher than pure depression or pure mania. Always assess suicide risk carefully when a patient presents with mixed features. The combination of depressive hopelessness + manic energy = ability and motivation to act on suicidal impulses.
2. Psychiatric Comorbidity
Psychiatric comorbidities are common and need to be treated alongside bipolar disorder [1]. They worsen the course, reduce treatment response, and increase functional impairment.
Prevalence of anxiety disorders in bipolar disorder is as common as in MDD [1]
| Anxiety Disorder | OR vs General Population | 95% CI |
|---|---|---|
| Panic disorder | 9.1* | 3.3–24.8 |
| Agoraphobia | 3.5 | 0.7–18.3 |
| Social phobia | 4.1* | 1.1–15.5 |
| GAD | 4.3* | 1.9–10.1 |
| OCD | 11.5* | 2.3–58.5 |
| PTSD | 3.9* | 1.0–15.5 |
(* 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]
| Substance Use Disorder | OR vs General Population | OR vs MDD |
|---|---|---|
| Drug abuse/dependence | 5.2* | 3.7* |
| Alcohol abuse/dependence | 3.4* | 1.4 |
(* 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)
3. Medical Complications
Increased risk of medical comorbidity [1] is a major contributor to the ↓ life expectancy by 13 years (males) and 9 years (females) [2].
↑ CVS disease/metabolic syndrome [2] — this is the leading cause of non-suicidal mortality in bipolar disorder.
Why?
Two main drivers:
-
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)
-
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.
| Complication | Mechanism |
|---|---|
| Hypothyroidism | Lithium inhibits thyroid hormone synthesis → hypothyroidism in 5–35% of lithium-treated patients. Also associated with rapid cycling. |
| Renal impairment | Chronic lithium use → nephrogenic diabetes insipidus (polyuria, polydipsia) → chronic tubulointerstitial nephropathy → rarely, chronic kidney disease |
| Hyperparathyroidism | Lithium stimulates PTH secretion → hypercalcaemia → renal stones, bone disease |
| Hepatotoxicity | Valproate → hepatic damage, especially in children; rarely fatal |
| Haematological | Valproate → thrombocytopaenia; carbamazepine → leukopenia, rarely agranulocytosis |
| Dermatological | Lithium → psoriasis, acne; carbamazepine → SJS/TEN (check HLA-B*1502); lamotrigine → SJS/TEN (titrate slowly) |
| Teratogenicity | Valproate → neural tube defects (NEVER in women of reproductive potential); lithium → Ebstein anomaly; carbamazepine → neural tube defects |
Global cognitive deficits are present in bipolar disorder, but there is no evidence of progressive decline during the illness [2] — however, the concept of neuroprogression has gained traction.
Cognitive domains affected:
- Attention and processing speed
- Verbal memory and learning
- Executive function (planning, set-shifting, inhibition)
Why?
- Repeated mood episodes cause cumulative neuronal stress (cortisol-mediated hippocampal atrophy, oxidative stress, inflammatory cascades)
- Medication side effects (lithium → cognitive dulling; antipsychotics → sedation)
- Comorbid substance abuse
- Sleep disruption
Staging of illness [1]:
- Stage 1: High-risk group (positive FH) or patients with subsyndromal symptoms
- Stage 2: Patients with a few episodes and optimal functioning
- Stage 3: Recurrent episodes and decline in functioning and cognition
Neuroprogression theory: worse prognosis with frequent relapses [1]
- Increased risk of future development of dementia [1]
This concept has important implications: it reinforces the rationale for early and aggressive maintenance treatment to prevent episodes and limit cumulative neurobiological damage. Each episode is not just a discrete event — it leaves a "scar" that makes the next episode more likely and recovery less complete (the "kindling" model).
Why Preventing Episodes Matters
Think of each mood episode as a small "brain injury." The kindling model suggests that early episodes are triggered by external stressors, but with each subsequent episode, the threshold drops — later episodes can arise spontaneously. Meanwhile, each episode contributes to cumulative neuronal damage, cognitive decline, and functional impairment. This is why the challenge in long-term management is the prevention of relapses, subsyndromal symptoms and functional disability [1]. Every prevented episode protects the brain.
5. Functional and Social Complications
Bipolar disorder devastates social functioning, often disproportionately to the time spent acutely symptomatic.
- 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
Watch out for side effects and the need of alternative treatments [1]
| Medication | Key Complications |
|---|---|
| Lithium | Renal impairment (nephrogenic DI → CKD), hypothyroidism, hyperparathyroidism, weight gain, tremor, cardiac conduction abnormalities, teratogenicity (Ebstein anomaly), toxicity (narrow therapeutic index — interactions with diuretics, NSAIDs, ACEi) |
| Valproate | Hepatotoxicity, teratogenicity (neural tube defects — NEVER in women of reproductive potential), weight gain, thrombocytopaenia, PCOS, hyperammonaemic encephalopathy |
| Carbamazepine | SJS/TEN (check HLA-B*1502), agranulocytosis, hyponatraemia (SIADH), hepatitis, P450 induction (renders OCP and other drugs ineffective), teratogenicity |
| Lamotrigine | SJS/TEN (must titrate slowly), skin eruption (3%) |
| Atypical antipsychotics | Metabolic syndrome and type 2 diabetes, dyslipidaemia, weight gain [1]; EPS (especially risperidone, haloperidol); QTc prolongation; sedation; hyperprolactinaemia |
| Antidepressants (if misused) | Manic switch and cycle acceleration [1] — arguably the most important iatrogenic complication |
| ECT | Cognitive impairment (confusion, amnesia — usually short-lived), rare cardiovascular events |
Manic switch from antidepressants deserves special emphasis:
- Antidepressant monotherapy is less effective and results in manic switch and cycle acceleration [1]
- TCAs and SNRIs have ↑↑ risk of inducing mania; SSRIs have lower but non-zero risk [2]
- This is why avoiding antidepressants if possible; if used, limiting dose and duration is a fundamental principle [1]
Clinical course: chronic remitting-relapsing with predominant polarity [2]
| Feature | Detail |
|---|---|
| Onset | ~20 years, usually begins as depression with first manic episode occurring ~5 years later [2] |
| Episode pattern | 83% of cases have > 4 episodes; 43% have > 7 episodes [1] |
| Episode frequency | Usually ~4 major episodes per 10 years, become more frequent then stabilise [2] |
| Episode polarity | Depressive episodes >> manic episodes in both Bipolar I and II [2] |
| Manic episode duration | Usually self-limited, resolve within ~6 months (even if untreated) [2] |
| 2-year outcome | 98% syndromal recovery, 72% symptomatic recovery, 43% functional recovery, 40% relapse [2] |
| Recurrence | ≥90% of manic patients have further mood episodes [2] |
| Relapse after treatment cessation | Recurrence up to 60–80% after discontinuation of lithium/antipsychotics (vs 20–50% with ongoing treatment) [2]. Patients with many years of remission CAN still relapse after cessation [2] |
Poor prognostic factors [1][2]:
- 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
Positive prognostic factor: Bipolar II disorder (relative to Bipolar I) [2]
Underdiagnosis [1]:
- The distress caused by untreated mood symptoms results in increased suicidality, comorbid anxiety and substance use disorders
- Poor QoL, greater functional impairment and increased healthcare cost
- Antidepressant monotherapy is less effective and results in manic switch and cycle acceleration
Overdiagnosis [1]:
- Unnecessary side effects of mood stabilisers
- Increase sick role and disability claims
High Yield Summary
Suicide: 1/3 attempt, 10–20% die by suicide. Mixed episodes = highest risk. Lithium is the only mood stabiliser to reduce suicide (80% reduction).
Psychiatric comorbidity: Anxiety (OR 4–11× general population), substance use (OR 3–5×, especially drugs — more common in BD than MDD), sleep disorders, eating disorders, ADHD, personality disorders. Must treat both BD and comorbidities.
Medical complications: CVD/metabolic syndrome (leading non-suicidal cause of death — medication side effects + lifestyle), hypothyroidism (lithium), renal impairment (lithium), hepatotoxicity (valproate), teratogenicity (valproate > carbamazepine > lithium), SJS/TEN (carbamazepine, lamotrigine).
Cognitive decline: Global cognitive deficits. Neuroprogression theory — worse with frequent relapses; increased risk of future dementia. Staging: Stage 1 (high risk/subsyndromal) → Stage 2 (few episodes, good function) → Stage 3 (recurrent episodes, declining function/cognition).
Functional impairment: Functional recovery (43%) lags behind syndromal recovery (98%) — job loss, relationship breakdown, financial ruin, legal consequences, stigma.
Prognosis: Poor. < 20% achieve 5-year stability. Life expectancy ↓13y (M), ↓9y (F). ≥90% have further episodes. 40% relapse within 2 years.
Iatrogenic: Antidepressant monotherapy → manic switch + cycle acceleration (most important avoidable complication). Metabolic syndrome from antipsychotics. Lithium toxicity.
Active Recall - Complications of Bipolar Disorder
References
[1] Lecture slides: GC 163. I am a superman Bipolar disorder.pdf (p14, p23, p24, p25, p26, p34, p41, p49, p64, p65) [2] Senior notes: ryanho-psych.md (sections 7.3 Course and Prognosis, Management, pp.397–408) [3] Senior notes: ryanho-psych.md (Alcoholism and psychiatric comorbidity, p.269)
High Yield Summary
Definition: Bipolar disorder = chronic episodic mood disorder with mania/hypomania ± depression. Bipolar I = ≥1 mania. Bipolar II = ≥1 hypomania + ≥1 depression.
Epidemiology: Lifetime risk ~1-4% (spectrum). M=F. Onset ~18y. Diagnosis delayed 5-10y. 1/3 attempt suicide; 10-20% die by suicide. Highly comorbid (substance abuse, anxiety, ADHD).
Aetiology (Multifactorial):
- Genetics: 79-85% heritability (highest in psychiatry). Shared risk with schizophrenia/autism. Calcium channel, circadian rhythm, neurodevelopmental genes.
- Neurobiology: Dopamine hyperactivity (mania), serotonergic/noradrenergic deficiency (depression), HPA axis dysregulation, ↓BDNF, structural/functional brain changes (none are specific biomarkers).
- Environment: Childhood abuse, poor attachment, life events disrupting sleep, childbirth, high expressed emotion (perpetuating).
Clinical Features:
- Mania (DIG FAST): Distractibility, Irresponsibility/Impulsivity, Grandiosity, Flight of ideas, Activity increase, Sleep ↓, Talkativeness. +/- mood-congruent psychosis. ≥7 days or hospitalisation.
- Hypomania: Same features but less intense, ≥4 days, NO marked impairment, NEVER psychotic.
- Bipolar depression: Like MDD but more psychomotor retardation, morning dysphoria, psychotic features, atypical features (hypersomnia, hyperphagia).
- Mixed features: Manic + depressive features simultaneously → highest suicide risk → responds to valproate.
- Rapid cycling: ≥4 episodes/12 months. F > M. Check thyroid.
Key Diagnostic Pitfalls: Hypomania missed → diagnosed as MDD → treated with antidepressants alone → manic switch + cycle acceleration. Always take collateral history. Use MDQ/HCL-32.
High Yield Summary
DDx of Manic Presentation (from lecture slides): (1) Depressive disorder with irritability/anxious distress, (2) Psychotic disorder/schizoaffective disorder, (3) Substance/medication-induced or medical conditions (steroids, L-dopa, stimulants, antidepressants, ECT; cocaine, amphetamine; frontal lobe lesion, hyperthyroidism, Cushing's), (4) ADHD, (5) Personality disorder with prominent irritability (esp. BPD).
Key Distinctions:
- Schizophrenia vs Mania: Psychosis outlasts mood in schizophrenia; mood-incongruent, bizarre delusions; FRS persistent (vs fleeting in mania); loosening of association (vs flight of ideas); chronic course.
- BPD vs Bipolar: BPD = chronic/trait-like, mood shifts in hours, interpersonal triggers, no grandiosity/↓ sleep; Bipolar = episodic, ↑ energy/grandiosity/↓ sleep.
- ADHD vs Mania: ADHD = chronic since childhood, no grandiosity/euphoria/↓ need for sleep; Mania = episodic.
- Organic mania: Always suspect if late-onset, no past Hx, neurological signs.
Misdiagnosis: 69% initially misdiagnosed. Most common error = BP II → MDD (hypomania missed). Delayed 5–7 years. Consequence: antidepressant monotherapy → manic switch + cycle acceleration.
Correct diagnosis requires: Patient history + collateral from informants + screening tools (MDQ, HCL-32) + adherence to diagnostic criteria.
High Yield Summary
Diagnostic Criteria — Key Points:
Manic Episode (Bipolar I): Elevated/expansive/irritable mood + increased energy (both required) + ≥3 associated symptoms (DIG FAST; ≥4 if irritable only) + ≥7 days (or any duration if hospitalised) + marked impairment/psychosis + not substance-induced.
Hypomanic Episode (Bipolar II): Same core + associated symptoms as mania BUT ≥4 days only, NO marked impairment, NEVER psychotic. Observable change in functioning. Bipolar II also requires ≥1 MDE.
ICD-10 vs DSM-5: ICD-10 requires ≥2 mood episodes for bipolar; DSM-5 requires only 1 manic episode for Bipolar I.
Diagnostic Algorithm: History (including collateral) → Screen for past mania/hypomania (MDQ, HCL-32) → Classify current episode → Rule out organic/substance causes → Classify subtype (I/II/cyclothymia) → Apply specifiers → Assess risk.
Baseline Investigations (from lecture slides): CBP, LRFT, TFT, fasting glucose + lipids, 24h CrCl (if renal disease), urine toxicology (if relevant), pregnancy test (if relevant), ECG (if relevant). Purpose: exclude organic mimics + establish baseline before treatment.
Screening Tools: MDQ (13 items, good for BP I), HCL-32 (32 items, better for BP II). Neither replaces clinical interview + collateral history.
High Yield Summary
Acute Mania: Stop antidepressants → Monotherapy (antipsychotic OR valproate OR lithium) → If inadequate, combine (lithium/valproate + antipsychotic) → If still inadequate, re-evaluate dx + ECT. Add short-term BZD for behavioural disturbance. Continue ≥6 months, ≥8 weeks post-remission. Hospitalise all but mildest cases.
Acute Bipolar Depression: Monotherapy (lithium OR lamotrigine OR quetiapine) → Add SSRI/venlafaxine to mood stabiliser if inadequate → ECT if severe/refractory/suicidal. NEVER antidepressant monotherapy. BP II: quetiapine first-line.
Maintenance: Lithium (gold standard, only drug to ↓ suicide), valproate (avoid women of childbearing potential), quetiapine. Lamotrigine for depression-predominant. Psychosocial interventions essential. Continue ≥3 years for lithium; relapse possible even after years of remission.
Key Drug Points:
- Lithium: narrow therapeutic index (0.6–1.0), monitor levels/RFT/TFT q6mo, anti-suicidal, avoid with thiazides/NSAIDs/ACEi
- Valproate: NEVER in women of reproductive potential (teratogenic), faster onset than lithium, good for mixed episodes
- Lamotrigine: good for depression pole, titrate slowly (SJS risk), well-tolerated, ↑ levels with valproate
- Carbamazepine: potent P450 inducer (drug interactions!), check HLA-B*1502 (SJS), auto-induces own metabolism
- Quetiapine: versatile (mania + depression + maintenance), metabolic side effects
- ECT: no absolute C/I, rapid response, use when pharmacotherapy fails or in emergencies
High Yield Summary
Suicide: 1/3 attempt, 10–20% die by suicide. Mixed episodes = highest risk. Lithium is the only mood stabiliser to reduce suicide (80% reduction).
Psychiatric comorbidity: Anxiety (OR 4–11× general population), substance use (OR 3–5×, especially drugs — more common in BD than MDD), sleep disorders, eating disorders, ADHD, personality disorders. Must treat both BD and comorbidities.
Medical complications: CVD/metabolic syndrome (leading non-suicidal cause of death — medication side effects + lifestyle), hypothyroidism (lithium), renal impairment (lithium), hepatotoxicity (valproate), teratogenicity (valproate > carbamazepine > lithium), SJS/TEN (carbamazepine, lamotrigine).
Cognitive decline: Global cognitive deficits. Neuroprogression theory — worse with frequent relapses; increased risk of future dementia. Staging: Stage 1 (high risk/subsyndromal) → Stage 2 (few episodes, good function) → Stage 3 (recurrent episodes, declining function/cognition).
Functional impairment: Functional recovery (43%) lags behind syndromal recovery (98%) — job loss, relationship breakdown, financial ruin, legal consequences, stigma.
Prognosis: Poor. < 20% achieve 5-year stability. Life expectancy ↓13y (M), ↓9y (F). ≥90% have further episodes. 40% relapse within 2 years.
Iatrogenic: Antidepressant monotherapy → manic switch + cycle acceleration (most important avoidable complication). Metabolic syndrome from antipsychotics. Lithium toxicity.
Approach To Mood Disturbances
A systematic clinical evaluation of persistent alterations in emotional state—including depression, mania, and mixed episodes—through comprehensive history, mental status examination, and differential diagnosis to identify underlying psychiatric, medical, or substance-related etiologies.
Depressive Disorders
Depressive disorders are a group of mood disorders characterized by persistent sadness, loss of interest or pleasure, and associated cognitive and somatic symptoms that impair daily functioning.