Bipolar Disorder: A Comprehensive Guide for PEBC Exam Preparation

The material on Bipolar Disorder presented here is specifically organized and tailored for those preparing for the Pharmacy Examining Board of Canada (PEBC) exams, aiming to offer a precise yet comprehensive understanding of the topic.

Algorithm: Management of Mania Episodes in Bipolar Disorder

Step 1: Initial Assessment

1. Assess safety and functionality.

2. Establish the treatment setting.

3. Discontinue antidepressants.

4. Rule out medical causes for symptoms.

5. Advise on lifestyle changes:

• Limit caffeine, alcohol, and illicit substances.

• Incorporate behavioral strategies and rhythms.

• Provide psychoeducation.

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Step 2: Determine Current Treatment

Is the patient currently on a first-line agent for acute mania?

• Adjunctive benzodiazepines (e.g., clonazepam) may be used at any stage.

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Step 3: If NOT on First-Line Therapy

Initiate first-line monotherapy:

• Consider combination therapy if symptoms are severe.

• Refer to Table 3 for specific medication recommendations.

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Step 4: Assess Response

Has there been significant symptom improvement within 2 weeks of using therapeutic doses?

• Yes: Proceed to maintenance therapy (Step 6).

• No: Adjust or switch therapy (Step 5).

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Step 5: Adjust or Switch Treatment

1. Add or switch to another first-line agent for mania.

• Refer to Table 3 for additional options.

2. Reassess improvement within 2 weeks of therapeutic doses:

• Yes: Proceed to maintenance therapy (Step 6).

• No: Replace one or both agents with alternate first-line or second-line agents.

• Consider ECT for refractory cases.

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Step 6: Evaluate Long-Term Maintenance

1. If significant improvement is achieved:

• Maintain treatment and consider dose adjustments to the lowest effective level.

• Optimize a maintenance strategy to prevent relapse.

2. If symptoms persist:

• Proceed to mood disorder specialist consultation.

• Consider third-line therapies only if first- and second-line options have failed.

Algorithm: Management of Depressive Episodes in Bipolar Disorder

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Step 1: Initial Assessment

• Evaluate Safety and Functioning:

• Assess patient safety and ability to function.

• Establish the appropriate treatment setting.

• Rule out medical causes for symptoms.

• Provide guidance to:

• Limit caffeine, alcohol, and illicit substances.

• Incorporate behavioral strategies and regular rhythms.

• Offer psychoeducation.

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Step 2: Determine Current Therapy

• Is the patient already on a first-line agent for acute depression?

• If Yes: Proceed to adherence assessment.

• If No:

• Initiate first-line monotherapy (e.g., lithium, quetiapine, lurasidone, or lamotrigine).

• Consider combination therapy if symptoms are severe.

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Step 3: Assess Adherence and Response

• Adherence:

• Assess adherence and optimize dosage if necessary.

• Response After 2–4 Weeks:

• Has there been significant symptom improvement?

• If Yes: Proceed to maintenance therapy (Step 5).

• If No: Adjust or switch therapy (Step 4).

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Step 4: Adjust or Switch Therapy

• Add or switch to another first-line agent for depression (refer to depression Table).

• Monitor for improvement over another 2–4 weeks:

• If Yes: Proceed to maintenance therapy (Step 5).

• If No:

• Replace one or both agents with alternate first- or second-line agents.

• Consider ECT or other second-line therapies for refractory cases.

• Try several first-line options before moving to second-line therapies.

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Step 5: Maintenance Therapy

• If symptoms are well-controlled:

• Maintain treatment.

• Lower the dose if clinically appropriate.

• Evaluate and optimize the maintenance strategy to prevent relapse.

• If symptoms persist:

• Consult a mood disorder specialist.

• Consider third-line options if all first- and second-line therapies fail.

Algorithm: Management of Maintenance Therapy for Bipolar Disorder

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Step 1: Initial Assessment

• Assess safety and functioning.

• Establish the treatment setting.

• Rule out medical causes for symptoms.

• Provide guidance to:

• Limit caffeine, alcohol, and illicit substances.

• Incorporate behavioral strategies and regular rhythms.

• Offer psychoeducation.

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Step 2: Is the Patient Currently on Maintenance Therapy?

1. If Yes:

• Assess adherence and optimize dosage.

2. If No:

• Initiate first-line monotherapy or combination therapy if there is a history of multiple relapses (refer to maintenance therapy table).

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Step 3: Reassess After 2 Months of Therapy

• Evaluate whether the patient has achieved remission with minimal symptoms:

• If Yes:

• Continue medications.

• For combination therapy, consider:

• Gradual dose reduction.

• Discontinuation of one agent after 6 months of stable mood.

• If No:

• Add or switch to another first-line agent for maintenance therapy (refer to Table 5).

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Step 4: Reassess Again After 2 Months

• Check if the patient has achieved remission with minimal symptoms:

• If Yes:

• Continue and optimize treatment as in Step 3.

• If No:

• Consider second-line options if multiple first-line attempts have failed.

• If still unsuccessful, consult a mood disorder specialist and explore third-line options (refer to Table 5).

Introduction

Bipolar disorder is a multifaceted and recurrent mood disorder that affects approximately 1–2% of the population. It is characterized by episodes of altered mood states, primarily involving manic episodes, hypomanic episodes, and major depressive episodes. For a diagnosis of bipolar disorder, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) emphasizes that mania or hypomania must exhibit abnormally and persistently elevated energy levels or goal-directed activity, in addition to mood changes. This guide is tailored for candidates preparing for the PEBC exams, providing a clear framework for understanding the diagnostic criteria, symptoms, and subtypes of bipolar disorder.

Core Features and Symptomatology

1. Manic Symptoms:

• Manifestations include elevated or irritable mood, heightened energy levels, reduced sleep requirements, and in some cases, psychotic features such as delusions or hallucinations.

• Behavioral changes often lead to social, occupational, or functional disruptions.

2. Depressive Symptoms:

• Common presentations include profound fatigue, oversleeping, social withdrawal, cognitive impairments, and in severe cases, suicidal ideation or psychotic symptoms.

Subtypes of Bipolar Disorder

Bipolar disorder is formally categorized into the following types:

• Bipolar I Disorder: At least one manic episode, with or without depressive episodes.

• Bipolar II Disorder: A history of one or more major depressive episodes combined with at least one hypomanic episode, without full-blown mania.

• Substance/Medication-Induced Bipolar Disorder: Symptoms induced by external agents such as drugs or medical conditions.

• Other Specified or Unspecified Bipolar Disorders: For cases that do not meet the usual criteria.

Diagnostic Challenges

Diagnosing bipolar disorder can be challenging due to its variable clinical presentation and overlap with other psychiatric or medical conditions:

• In its psychotic phases, it may resemble schizophrenia.

• During depressive episodes, it mimics unipolar depression.

• When symptoms fluctuate rapidly or are mild, it can appear similar to borderline personality disorder.

• In children, it may be misdiagnosed as attention-deficit hyperactivity disorder (ADHD).

• Comorbid conditions such as substance use disorders or personality disorders add further complexity.

Goals of Therapy

1. Symptom Control: Alleviate symptoms during acute manic or depressive episodes.

2. Prevention: Reduce the frequency and severity of recurrences.

3. Comorbidity Management: Address associated psychiatric conditions (e.g., anxiety, substance use disorders) and medical issues (e.g., metabolic or endocrine disorders).

4. Function Restoration: Enhance cognition and optimize functional capacity.

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Therapeutic Strategies

1. Nonpharmacologic Interventions

Psychoeducation and structured psychotherapy are crucial adjuncts to pharmacologic treatment:

• Psychoeducation: Provides patients with information about bipolar disorder, including episode triggers, coping mechanisms, and early warning signs.

• Example: Group sessions focused on relapse prevention reduce recurrence risk.

• Cognitive Behavioral Therapy (CBT): Aids in relapse prevention and mood stabilization.

• Family Therapy: Improves communication and support within families.

• Online Resources:

• Tools like eMoods for tracking mood patterns.

• Patient guides from the International Society for Bipolar Disorders (ISBD).

• The CREST.BD self-management toolkit.

Strategies like "relapse drills" train patients to recognize early symptoms and respond proactively by:

• Adjusting medications.

• Promptly contacting their healthcare provider.

• Modifying daily routines, such as sleep regulation.

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2. Pharmacologic Management

Pharmacologic treatment is tailored to the stage and type of episode (e.g., mania, depression, or maintenance). Since bipolar disorder treatment is lifelong, shared decision-making is essential to:

• Weigh the pros and cons of therapeutic options.

• Ensure patient engagement and adherence.

Management of Mania Episodes in Bipolar Disorder

First-Line Treatments: Recommended for moderate to severe mania. Often involves monotherapy or combination therapy with lithium, divalproex, or second-generation antipsychotics.

• Lithium: While higher lithium levels may yield greater benefits, they also increase risk, particularly in young adults. Aim for moderate blood levels and supplement with other anti-manic agents as necessary. Overall, lithium remains a strong initial choice.

• Quetiapine: Quetiapine can be rapidly titrated safely, but blood pressure should be monitored for signs of hypotension.

• Divalproex: A loading dose of Divalproex (20 mg/kg) is an option to reach therapeutic blood levels (350–800 mmol/L) more quickly.

• Asenapine: Asenapine Comes in a sublingual formulation; avoid eating or drinking for 10 minutes after taking the dose.

• Aripiprazole: Has limited use in depressive episodes; less suitable for individuals with a history of recurrent depressive episodes.

• Paliperidone (>6 mg): is available in extended-release tablets and as a long-acting intramuscular injection.

• Risperidone: Regular monitoring is advised to detect potential side effects like orthostatic hypotension and motor disturbances such as akathisia.

• Cariprazine: Effective for both manic and depressive symptoms. Higher doses are usually needed for mania, and lower doses for depression.

• Lithium or Divalproex + Quetiapine

• Lithium or Divalproex + Aripiprazole

• Lithium or Divalproex + Risperidone

• Lithium or Divalproex + Asenapine

Second-Line Treatments:

• Olanzapine: Slightly more effective than other SGAs, but far more long-term side effects.

• Carbamazepine: Watch for hepatic induction, which lowers blood levels of many medications, including key SGAs and some antidepressants.

• Lithium or Divalproex + Olanzapine: Good for severe episodes, but highest side effect burden in the long term.

• Lithium + Divalproex: Less beneficial than combinations of a mood stabilizer plus SGA.

• Ziprasidone: Limited evidence in maintenance, not effective for depression, cardiac monitoring at higher doses.

• Haloperidol: Well tolerated and highly efficacious acutely, but promotes depression relapse and tardive dyskinesia concerns in the long term.

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Not recommended: Use of some of the following agents as adjunct therapy may be appropriate when initiated prior to mania for other symptoms, e.g., using gabapentin for anxiety, topiramate for alcohol craving but they need to be implemented by a specialist:

• Monotherapy With Allopurinol, Eslicarbazepine/Licarbazepine,

• Gabapentin,

• Lamotrigine,

• Omega-3 Fatty Acids,

• Topiramate,

• Valoctamide,

• Zonisamide;

• Combination Therapy With Carbamazepine Plus Risperidone Or Olanzapine

Key Considerations for Treatment:

1. Assess Antidepressant Use: Discontinue during acute mania to avoid worsening symptoms.

2. Tailor Treatment: Adjust regimens based on the severity of symptoms and comorbidities.

3. Monitor for Side Effects:

• Antipsychotics: Risk of weight gain, dyslipidemia, and diabetes.

• Mood Stabilizers: Lithium requires renal and thyroid function monitoring.

Management of Depressive Episodes in Bipolar Disorder

Effective management of depressive episodes in bipolar disorder requires a thorough initial assessment and a strategic approach to treatment. Here's an elaborated guide to this process:

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Initial Assessment

1. Evaluate Safety Concerns:

• Assess for suicidal ideation, self-harm risk, comorbid medical conditions (e.g., diabetes, cardiovascular issues), or substance use disorders.

2. Determine Treatment Context:

• Identify whether the patient:

• Is currently on medication and experiencing a breakthrough depressive episode.

• Is medication-free and experiencing their first depressive episode.

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First-Line Treatment Options

For unmedicated patients, treatment should begin with one of the following first-line monotherapies:

1. Lithium:

• Well-established for its mood-stabilizing and anti-suicidal properties.

2. Lamotrigine:

• The most tolerable option but has a slower onset of action and may be slightly less effective than other first-line treatments.

3. Lurasidone:

• An effective atypical antipsychotic with minimal risk of weight gain or metabolic disturbances.

4. Quetiapine:

• Proven efficacy in managing depressive symptoms, particularly for patients requiring sedation.

In addition to these, cariprazine, a newer atypical antipsychotic approved in Canada in 2022, is an effective option for both bipolar depression and mania.

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Combination and Adjunctive Strategies

• Combination Therapies:

• For severe depressive episodes, initiate with two first-line agents, such as lithium plus quetiapine.

• Adjunctive Strategies:

• Combine lurasidone with lithium or divalproex.

• Add lamotrigine to an existing first-line therapy.

Lurasidone-Specific Benefits:

• Clinical trials demonstrate its efficacy in both monotherapy and combination therapy for bipolar depression.

• Common side effects include anxiety, headache, insomnia, nausea, and extrapyramidal symptoms (EPS).

• Compared to other treatments, lurasidone carries a lower risk of weight gain and metabolic issues, making it a suitable option for long-term management.

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Second-Line Treatment Options

1. Adjunctive Antidepressants:

• Options like SSRIs (e.g., sertraline) or bupropion may be effective.

• These are used cautiously due to the risk of inducing mania, particularly in:

• Mixed episodes.

• Rapid-cycling patients.

• Patients with a history of antidepressant-triggered mania.

2. Combination Therapy:

• Olanzapine + Fluoxetine:

• Effective for severe cases but requires careful monitoring for metabolic side effects.

• Two Mood Stabilizers:

• Combining lithium and divalproex can provide added stability for severe episodes.

• Divalproex Monotherapy:

• A valuable alternative for patients unable to tolerate combination regimens.

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Advanced and Experimental Treatments

1. Electroconvulsive Therapy (ECT):

• Considered for severe bipolar depression or treatment-resistant cases.

2. Intravenous (IV) Ketamine:

• Strong evidence supports its efficacy in unipolar depression, with growing support for bipolar depression.

• Administration frequency and treatment duration are not yet standardized.

3. Esketamine (Intranasal):

• Approved for unipolar depression and shows preliminary promise for bipolar depression.

4. Lumateperone:

• Approved internationally for schizophrenia and under FDA review for bipolar depression.

• Clinical trials indicate its antidepressant efficacy.

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Not Recommended

1. Adjunctive Antidepressants + Gabapentin or Ziprasidone

2. Levetiracetam

3. Lamotrigine + Folic Acid

4. Mifepristone

Key Considerations

• Treatment Adjustment Timeline:

• Reassess therapy every 2–4 weeks to evaluate progress and make necessary changes.

• Psychosocial Interventions:

• Intensive interventions provide better outcomes than minimal interventions when paired with ongoing pharmacotherapy.

• Avoiding Risks:

• Avoid antidepressants in patients with mixed features, rapid cycling, or a history of antidepressant-induced mania.

Maintenance Therapy for Bipolar Disorder

• Maintenance Phase: Begins when patients recover from an acute episode and remain well with minimal or no symptoms for at least two months.

• Risk Without Treatment:

• ~70% risk of recurrence within 1 year.

• ~95% risk of recurrence within 5 years.

• Primary Risk Factor: Nonadherence to pharmacologic treatment is the most significant predictor of recurrence.

Adherence and Collaborative Care

• Adopt a collaborative approach:

• Discuss adherence and treatment concerns non-judgmentally.

• Encourage open dialogue about attitudes toward medication and its impact on their life.

• Periodically reinforce psychoeducation, such as providing annual updates on the disorder and treatment strategies, to promote long-term adherence.

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Interventions to Prevent Relapse

1. Psychosocial Strategies:

• Psychoeducation: Teach patients about the disorder, relapse risks, and management of side effects.

• Cognitive-Behavioural Therapy (CBT): Address thought patterns that contribute to stress and symptom recurrence.

• Family Therapy: Engage family members to support the patient’s adherence and emotional well-being.

• Interpersonal and Social Rhythm Therapy:

• Establish routines for sleep, activity, and meals to stabilize mood.

• Train patients to recognize early signs of relapse.

2. Patient-Centered Care:

• Encourage patients to share the impact of the illness on their life.

• Address concerns about long-term medication effects.

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Medication-Based Maintenance Strategies

• Core Medications for Relapse Prevention:

• Lithium: Effective across manic, depressive, and mixed episodes. Provides anti-suicidal benefits.

• Divalproex: Effective for patients with rapid cycling or mixed episodes.

• Quetiapine: Approved for maintenance, particularly following acute stabilization.

• Lamotrigine: Prevents depressive relapses with limited effects on mania.

• Lurasidone: A newer option, particularly for depressive symptoms.

• Cariprazine:

• Efficacious in acute episodes and is anticipated to show benefits in maintenance phases as ongoing studies are completed.

• Combination Therapy:

• For patients at high risk of relapse:

• Combine lithium or divalproex with another first-line agent (e.g., quetiapine or lamotrigine).

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Emerging Focus: Cognitive Optimization

• Cognitive Deficits:

• Even in remission, many patients experience issues in attention, memory, and executive functioning.

• Potential Treatments:

• No pharmacologic treatments are definitively proven for cognitive deficits in bipolar disorder.

• Stimulants (e.g., for ADHD) are often used off-label in clinical settings.

• Non-pharmacologic approaches such as cognitive training and structured routines are valuable.

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Key Recommendations for Maintenance Therapy

1. Reinforce Adherence:

• Provide regular opportunities for patients to express concerns.

• Tailor therapy based on individual preferences and beliefs.

2. Relapse Prevention Plan:

• Use psychoeducation, structured therapy sessions, and appropriate pharmacologic interventions.

3. Evaluate Cognition:

• Incorporate strategies to address cognitive challenges alongside mood stabilization.

Management of Bipolar Disorder During Pregnancy and Breastfeeding

Family Planning and Pregnancy

1. Early Consideration of Bipolar Disorder in Reproductive Age:

• Bipolar disorder often begins early in life, meaning many patients may face challenges while planning a family.

2. Risk Assessment:

• Risk of Pregnancy-Induced Destabilization: Pregnancy may destabilize bipolar disorder, potentially leading to severe manic or depressive episodes.

• Risk to Mother and Child: Untreated bipolar disorder poses risks such as postpartum depression, which may include psychotic features and harm to the child.

3. Collaborative Care Approach:

• Involve a psychiatrist, obstetrician, and family physician to manage pregnancy comprehensively.

• Consult organizations like MothertoBaby for guidance on medication use during pregnancy and breastfeeding.

4. Medication Discontinuation Prior to Conception:

• If stopping medication is necessary, taper doses under medical supervision to avoid sudden withdrawal effects.

5. Pregnancy Contract:

• A patient-prepared document detailing their symptoms during manic and depressive phases and listing preferred treatments.

• Shared among healthcare providers and family to serve as an advance directive for future episodes.

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Medication Management During Pregnancy and Breastfeeding

• Complexity: Managing bipolar disorder medications during pregnancy and breastfeeding requires individualized planning.

• CANMAT Guidelines: Follow detailed recommendations outlined in the CANMAT Bipolar Guidelines for best practices.

• Specialized Resources: Use references such as Drug Use During Pregnancy and Drug Use During Breastfeeding for specific medication safety information.

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Therapeutic Tips for Managing Bipolar Disorder

Promoting Adherence

• Recurrent nonadherence is a hallmark of bipolar disorder.

• Use shared decision-making and psychoeducation to strengthen therapeutic alliances and encourage adherence to treatment.

Lithium as a Key Medication

1. Role of Lithium: Despite newer treatment options, lithium remains a cornerstone for treating bipolar disorder, particularly during the early stages of illness.

2. Patient Education:

• Maintain consistent salt and caffeine intake.

• Monitor fluid balance, especially during episodes of vomiting or diarrhea, and adjust fluid intake accordingly.

3. Dosage Adjustments in Mania:

• Higher doses may be required during acute manic episodes due to increased lithium tolerance, with reductions needed once mania resolves.

4. Addressing Side Effects:

• Cognitive Impairment: Check lithium levels and thyroid function. Switching to a slow-release formulation or reducing the dose can improve cognition.

• Tremor: Reduce dietary caffeine, lower the lithium dose, or add a beta-blocker such as propranolol or atenolol.

• Diarrhea: Patients using slow-release lithium who experience diarrhea may respond better to immediate-release formulations.

Antipsychotic Use

• Educate patients on the risk of temperature dysregulation associated with antipsychotics.

• Advise on strategies to prevent heat stroke, such as maintaining hydration and avoiding excessive sun exposure.

Lithium Maintenance Recommendations

1. Optimal Levels:

• Aim for low to medium blood levels (0.5–0.8 mmol/L) during maintenance therapy to minimize side effects.

• If stability cannot be achieved, consider switching or adding another maintenance medication instead of increasing lithium levels.

2. Regular Monitoring: Monitor lithium levels, kidney function, and thyroid function regularly to ensure safe and effective treatment.