Bipolar Disorder

Bipolar disorder is a chronic, recurrent mood disorder defined by the lifetime occurrence of at least one manic or hypomanic episode, almost always punctuated by major depressive episodes as well.^[1] It is fundamentally different from unipolar major depression — the two can look identical during a depressive episode, but need different first-line pharmacotherapy, and treating unrecognized bipolar depression with an antidepressant alone risks triggering mania, a mixed episode, or accelerated cycling. Depressive episodes and depressive symptoms dominate the overall course of bipolar illness far more than manic or hypomanic episodes do, which is a major reason bipolar disorder is so often initially misdiagnosed and treated as unipolar depression. This chapter follows the CANMAT/ISBD 2018 guideline and its 2023 evidence update as the primary pharmacotherapy framework — phase-specific (acute mania, acute depression, maintenance) hierarchical first-, second-, and third-line recommendations, ranked not only by efficacy in the phase being treated but also by efficacy across other phases and long-term tolerability, since bipolar disorder is a lifelong condition requiring lifelong treatment planning.^[2][3]

Add the modifier rapid cycling when a patient has 4 or more distinct mood episodes (manic, hypomanic, or depressive, in any combination) within a 12-month period. This is not a separate diagnosis but changes management: screen for and correct reversible drivers first — undiagnosed hypothyroidism, ongoing antidepressant use, active substance use — before escalating to third-line, specialist-directed pharmacotherapy.^[2]

• Family history of bipolar disorder or another mood disorder in a first-degree relative — the single strongest known risk factor.
• Onset of a first mood episode in adolescence or young adulthood.
• The postpartum period — a well-recognized high-risk window for a first manic, hypomanic, or severe depressive episode, including postpartum psychosis.
• Significant sleep deprivation or major circadian disruption (shift work, transmeridian travel, postpartum sleep loss).
• Comorbid substance use disorder.
• Major stressful life events.
• Starting an antidepressant, without a mood stabilizer on board, in a person with an underlying but not-yet-diagnosed bipolar diathesis — can unmask a first manic or hypomanic episode.

Distinguishing bipolar depression from unipolar major depression

A depressive episode can look identical whether or not the patient has ever had mania or hypomania, and depression dominates the course of bipolar illness — so every patient presenting with a depressive episode should be screened for a lifetime history of hypomanic or manic symptoms before an antidepressant is started. The following features should raise suspicion of underlying bipolarity in a patient presenting with depression.^[3]

History

• Ask every patient presenting with depression directly about past periods of elevated mood, decreased need for sleep, increased energy, grandiosity, or impulsive or risky behaviour — patients rarely volunteer this, and often do not recognize hypomania as pathological.
• Obtain a reliable collateral history from a family member or close friend whenever possible — this is often more diagnostically useful than the patient's own account of a manic or hypomanic episode.
• Ask specifically about family history of bipolar disorder, other mood disorders, and substance use.
• Characterize the current episode fully: polarity, duration, severity, psychotic features, suicidal ideation, and functional impairment.
• Screen for comorbidities that commonly complicate diagnosis and treatment — anxiety disorders, substance use disorder, ADHD, and personality disorder.

Screening tool: Mood Disorder Questionnaire (MDQ)

The MDQ is a brief, validated self-report screening tool for bipolar spectrum disorder, useful for flagging patients who need a more detailed clinical evaluation. It is a screening instrument, not a diagnostic one, and a validated adolescent-adapted version also exists.^[5]

A positive screen — 7 or more "yes" answers on the symptom list, AND several occurring during the same period, AND at least a moderate reported problem — warrants a full clinical evaluation for bipolar disorder. It is a prompt for further assessment, not a diagnosis on its own.^[5]

Investigations

• Baseline bloodwork for every patient starting treatment: complete blood count, electrolytes, renal function, liver function, and thyroid function.
• Beta-hCG before starting any medication that is contraindicated or requires precautions in pregnancy.
• Metabolic baseline before starting any medication with metabolic risk: weight, waist circumference, fasting glucose, and fasting lipid profile — atypical antipsychotics and some mood stabilizers carry real metabolic burden.
• Structural brain imaging (CT or MRI) is not routinely needed for a typical-presentation young adult with a classic episode pattern — reserve it for a first manic or psychotic episode presenting after age 40, new focal neurologic signs or symptoms, or an atypical presentation.

• Resolve the acute episode (mania, hypomania, or depression) safely and as completely as possible — partial response with residual symptoms is a known driver of relapse.
• Prevent recurrence of future mood episodes through maintenance pharmacotherapy and psychosocial support.
• Reduce suicide risk, which is markedly elevated across the course of bipolar illness.
• Restore functioning, cognition, and quality of life between episodes.
• Identify and manage comorbid psychiatric conditions (anxiety, substance use) and medical conditions (thyroid disease, metabolic syndrome) that complicate the course of illness.

• Psychoeducation is the best-evidenced adjunctive intervention across the illness course — structured group formats delivered over a defined number of sessions substantially reduce relapse risk and are recommended as a first-line adjunctive treatment.^[3]
• Cognitive-behavioural therapy — second-line adjunct for acute depression and for relapse prevention in maintenance.
• Family-focused therapy — second-line adjunct for acute depression and for maintenance-phase relapse prevention.
• Interpersonal and social rhythm therapy — supports regulating sleep and daily routines; third-line adjunct in maintenance.
• Peer support interventions — third-line adjunct in maintenance.
• Build a personalized "relapse drill" with every patient: help them identify their own early warning symptoms of an incipient manic or depressive episode, and agree in advance on a specific response plan — contacting the treating clinician promptly, temporary medication adjustments, and reinforcing sleep regulation.
• Protect sleep and circadian regularity — sleep loss is both a trigger for mania and an early warning sign of relapse.
• Support discontinuation of alcohol, cannabis, and stimulant use, all of which destabilize mood and interact with treatment.
• Address cognitive impairment directly where present: treat the mood episode to full remission, treat comorbid substance use, anxiety, or ADHD, review for and consider discontinuing medications with high anticholinergic burden or other cognition-impairing effects, treat subclinical thyroid disease, and encourage regular exercise and consistent sleep.
• For patients planning a pregnancy, consider building a written "pregnancy contract" with the patient in advance — a short summary of their typical manic and depressive symptoms and their preferred treatment options for each, shared with the treatment team and family as a nonbinding advance plan.

Pregnancy

Because bipolar disorder often begins early in life, many patients will be living with the illness when planning a pregnancy. Balance the risk of untreated illness — including a substantial risk of relapse and postpartum psychosis, which can itself endanger both parent and infant — against medication risk; do not simply stop treatment.^[7]

Avoid divalproex/valproic acid in anyone who could become pregnant unless every alternative has failed and the conditions of a valproate pregnancy prevention program (confirmed negative pregnancy test, effective contraception throughout treatment, at least annual specialist reassessment of ongoing need) are met — valproate carries the highest teratogenic risk of the mood stabilizers, including neural tube defects and long-term neurodevelopmental effects.

Lithium carries a smaller but real teratogenic risk (cardiac malformation, including Ebstein's anomaly) — when continued in pregnancy, add fetal echocardiography at 16-20 weeks; the risk-benefit balance still frequently favours continuing lithium in a patient who has responded well to it, given the relapse risk of stopping.

Lamotrigine has a comparatively lower teratogenic signal and is often favoured for a depression-predominant illness course in a patient planning pregnancy.

If medication is being changed before conception, taper with medical supervision rather than stopping abruptly, and use a collaborative-care model involving psychiatry, obstetrics, and family medicine.^[7]

Breastfeeding

Lithium passes into breast milk in significant amounts — if continued during breastfeeding, monitor the infant's lithium level, renal function, and thyroid function, and maintain close pediatric follow-up. Divalproex, lamotrigine, and most atypical antipsychotics are generally considered compatible with breastfeeding with infant monitoring; avoid unnecessary polypharmacy while breastfeeding when a simpler regimen is equally effective.

Children and adolescents

Diagnostic criteria are the same as in adults, but distinguishing episodic mania/hypomania from the chronic, continuous irritability of ADHD or an emerging personality disorder is essential — treat the bipolar illness first if both are present, then address ADHD once mood is stabilized.

Acute mania, 1st line lithium, risperidone, aripiprazole, asenapine, or quetiapine.

Acute depression, 1st line lurasidone is the only first-line option; use antidepressants only in combination with a mood stabilizer, and with caution.

Maintenance, 1st line aripiprazole, lithium, or divalproex.

Older adults

Acute mania, 1st line lithium or divalproex, with quetiapine as the only second-line agent.

Acute depression, 1st line lurasidone or quetiapine, with lithium and lamotrigine as second-line options.

Use reduced lithium target levels in older adults (0.4-0.8 mmol/L acute, lower end during maintenance). All second-generation antipsychotics carry a regulatory warning of increased stroke risk and mortality in elderly patients with dementia-related psychosis — weigh this carefully, though the morbidity and mortality of undertreated bipolar disorder in this population is also substantial. Complete a thorough physical and neurologic examination, with neuroimaging if there are focal signs, an abrupt late onset, or an atypical presentation.

Renal impairment

Lithium is renally cleared with a narrow therapeutic index — dose adjustment and closer level monitoring are required, and significant renal impairment may require an alternative agent in consultation with nephrology.

Hepatic impairment

Divalproex and valproic acid are contraindicated in significant hepatic disease or dysfunction.

Baseline and periodic laboratory monitoring

• Lithium: level 9-13h post-dose, checked 5 days after each dose change until stable, then at least every 3-6 months; renal function and thyroid function at baseline, 6 months, and at least annually thereafter (more often if there are risk factors or symptoms).
• Divalproex/valproic acid: liver function tests and CBC/platelets at baseline, every 3-6 months for the first year, then annually; menstrual history to screen for polycystic ovary syndrome in patients of reproductive age; check ammonia if lethargy, vomiting, or altered mental status develops, even with normal liver enzymes.
• Carbamazepine: serum sodium at least annually given hyponatremia risk; CBC given rare blood dyscrasias.
• Atypical antipsychotics: weight monthly for the first 3 months then every 3 months; fasting glucose, lipid profile, and blood pressure at 3 months then annually; regular screening for extrapyramidal symptoms and akathisia.
• Lamotrigine: patient education on rash recognition at every dose increase; no routine serum level required for most patients.

Recognizing and managing lithium toxicity

Ongoing follow-up

Assess adherence and reinforce the individualized relapse drill at every visit. Screen for early warning signs of relapse (sleep changes, mood shifts, energy changes) proactively rather than waiting for the patient to report them. Reassess suicide risk regularly, not only during acute episodes. If an antidepressant is being used adjunctively, monitor closely for any sign of a hypomanic or manic switch and discontinue it promptly if one emerges.

1. Confirm adherence and confirm the current dose has actually reached a therapeutic level or dose before declaring a trial inadequate — a minimum 2-week trial at a therapeutic dose for mania, 2-4 weeks for depression.
2. Screen for and address confounders that mimic treatment resistance: active substance use, undiagnosed thyroid dysfunction, other medical comorbidity, or concurrent antidepressant use in a patient with mania or mixed features.
3. Optimize the current first-line agent's dose to the top of its tolerated range before switching to something else.
4. Switch to or add an alternate first-line agent, following the hierarchical order, rather than jumping straight to second- or third-line options.
5. Move to second-line options once multiple first-line trials (alone and in combination, where applicable) have failed — including ECT, which should be considered earlier for severe, refractory, or psychotic presentations, or when suicide risk demands a rapid response.
6. Move to third-line, specialist-directed options and refer to a psychiatrist or mood-disorders specialist, particularly for genuine treatment resistance or rapid cycling.

• Starting or continuing an antidepressant as monotherapy for bipolar depression.
• Failing to ask every patient presenting with depression about a lifetime history of hypomanic or manic symptoms before starting an antidepressant.
• Misdiagnosing bipolar disorder as unipolar depression, borderline personality disorder, ADHD, substance use disorder, or schizophrenia — or over-diagnosing it in a patient whose symptoms actually fit one of those conditions better.
• Stopping lithium or another mood stabilizer abruptly — this carries a substantial rebound relapse risk; taper with medical supervision instead.
• Assuming a lithium level "in range" rules out toxicity — early toxicity can occur at technically therapeutic levels, especially in older adults or with dehydration or an interacting drug.
• Prescribing divalproex or valproic acid to a person who could become pregnant without contraception counselling and a documented pregnancy-prevention plan.
• Accepting residual symptoms as "good enough" rather than treating to full remission — partial response is a known driver of relapse.
• Discontinuing the antipsychotic component of a mania combination too early (before the 6-month post-remission mark) or leaving it in place indefinitely without ever reassessing whether it can be tapered.
• Skipping metabolic monitoring (weight, glucose, lipids) for patients on atypical antipsychotics.
• Missing an active comorbid substance use disorder as the real driver of apparent "treatment resistance."

How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Mood stabilizers

Atypical antipsychotics

Typical antipsychotics

Antidepressants used adjunctively (never as bipolar-depression monotherapy)

Depression-augmentation and specialist-directed adjuncts (3rd line)

Not recommended

The following are specifically flagged as ineffective or unfavourable by the CANMAT/ISBD guideline and should not be used the way listed, even though some of the individual drugs are appropriate for other conditions:

• Antidepressant monotherapy for bipolar depression of either pole.
• gabapentin or topiramate as monotherapy for acute mania — not effective as primary antimanic agents, though sometimes used off-label as adjuncts for comorbid anxiety or craving management.
• lamotrigine monotherapy for acute mania (it is not effective for mania) — and specifically, combining lamotrigine with folic acid is flagged as an ineffective combination for bipolar depression, not a beneficial one.
• oxcarbazepine and eslicarbazepine acetate monotherapy for acute mania — limited evidence relative to carbamazepine.
• perphenazine and tricyclic antidepressants for maintenance therapy.
• Adjunctive mifepristone for bipolar depression.
• Monotherapy with allopurinol, zonisamide, valnoctamide, or omega-3 fatty acids for acute mania — insufficient evidence to support use as a primary antimanic agent.