What are the most effective treatments for bipolar disorder?

The most effective treatments for different phases and presentations of bipolar disorder

Bipolar disorder (BD), also known as bipolar affective disorder, is a leading cause of disability globally. It is characterized by recurring episodes of mania or hypomania alternating with depression and is often initially misdiagnosed. Effective treatment typically involves both pharmacotherapy and psychosocial interventions, with continuous reevaluation and treatment modification being common during long-term care. Management of co-occurring psychiatric and chronic medical conditions may also be necessary.

The current guidelines, including those from the Canadian Network for Mood and Anxiety Treatments (CANMAT), International Society for Bipolar Disorders (ISBD), British Association for Psychopharmacology (BAP), and International College of Neuro-Psychopharmacology (CINP), emphasize an interprofessional holistic team approach to achieve the best possible outcomes. This approach integrates psychiatric and medical healthcare and includes patient psychoeducation, collaborative decision-making, and the use of evidence-based treatment guidelines.

According to these guidelines, here are the most effective and recommended treatments for different phases and presentations of bipolar disorder:

Acute Manic/Hypomanic Episodes

The goal of management in mania or a mixed episode is to control aggression, agitation, and disruptiveness as quickly as possible.

Pharmacological Monotherapy:

First-line options include mood stabilizers like lithium or valproate, or antipsychotics such as aripiprazole, asenapine, cariprazine, quetiapine, or risperidone. Haloperidol and olanzapine are also considered highly effective.
Lithium is particularly preferred for classical euphoric grandiose mania with few prior episodes, a mania-depression-euthymia course, or a family history of lithium response.
Valproate is effective for both classical and dysphoric mania, and recommended for patients with multiple prior episodes, predominant irritable or dysphoric mood, comorbid substance abuse, or a history of head trauma. However, valproate should not be used for women of childbearing potential due to its unacceptable risk to the fetus (teratogenesis and impaired intellectual development).
Antidepressants should generally be tapered and discontinued during a manic phase.

Combination Therapy:

Combining lithium or valproate with a dopamine antagonist/partial agonist (e.g., aripiprazole, asenapine, olanzapine, quetiapine, or risperidone) is recommended when a faster response is needed, or for more severe manic episodes. This combination tends to work faster than monotherapy.
For patients already on lithium monotherapy who present with inadequate symptom control, adding a second drug like a dopamine antagonist/partial agonist or valproate is recommended.

Adjunctive Treatments:

Benzodiazepines can be used for short durations to manage agitation and induce sedation or sleep.
Electroconvulsive therapy (ECT) may be considered as monotherapy or part of combination therapy for patients whose mania is particularly severe, treatment-resistant, or in pregnant women with severe mania. It is also an option for delirious mania, which can be a medical emergency.

Clinical Features Influencing Treatment Choice:

Anxious distress: While no specific studies exist, divalproex, quetiapine, and olanzapine may have anxiolytic benefits, and carbamazepine may also be useful. These symptoms often improve as mood disturbance resolves.
Mixed features: Depressive symptoms co-occurring with mania indicate a more severe course. Atypical antipsychotics and divalproex are preferentially used, often requiring combination therapy. Antidepressants should be avoided in patients with mixed features.
Psychotic features: At least half of manic episodes involve psychosis. There’s no evidence of superiority among first-line monotherapies or combinations for psychotic features. However, clinical experience suggests that combining lithium or divalproex with an atypical antipsychotic is appropriate for manic patients with mood-incongruent psychotic features.
Rapid cycling: Assess and address factors like hypothyroidism, antidepressant use, and substance abuse. No single first-line treatment is superior for acute manic symptoms in rapid cycling. Combinations of mood-stabilizing drugs are often necessary. Antidepressants are not recommended as they can destabilize patients.

Acute Bipolar Depression

The primary goal is to achieve euthymia and normal functioning, while avoiding a switch to hypomania/mania.

Pharmacological Monotherapy:

First-line options include quetiapine, olanzapine, or lurasidone.
Lithium and lamotrigine are also recommended as first-line monotherapy for bipolar I depression.
Lamotrigine requires slower titration due to skin rash risk and is not ideal for rapid response.

Combination Therapy:

Olanzapine-fluoxetine combination is a first-line option.
Lurasidone plus lithium or valproate is also a first-line combination.
Lithium plus lamotrigine can also be considered.
Antidepressant medications should generally not be used as monotherapy in most bipolar patients due to lack of efficacy evidence and risk of manic switch or mood instability. They can be administered adjunctively to mood stabilizers (e.g., lithium and lamotrigine) and second-generation antipsychotics. Bupropion has been associated with the lowest risk of antidepressant-induced switch.

Adjunctive Treatments:

Cognitive Behavioral Therapy (CBT) is considered a second-line adjunctive treatment to pharmacotherapy. It should never be considered as monotherapy for acute bipolar depression due to minimal evidence.
Family-Focused Therapy (FFT) is also a second-line adjunctive treatment.
Interpersonal and Social Rhythm Therapy (IPSRT) is a third-line adjunctive treatment.
ECT may be considered for severe depression, especially with suicidality, risk of harm to others, catatonic or psychotic symptoms, or during pregnancy.

Clinical Features Influencing Treatment Choice:

Need for rapid response: Quetiapine and lurasidone show early separation from placebo (as early as week 1). ECT is also a rapid option.
Mixed features: Atypical antipsychotics (olanzapine-fluoxetine combination, asenapine, lurasidone) show efficacy. Antidepressants should be avoided.
Psychotic features: ECT and antipsychotics are highly effective, though relative efficacy among medications has not been specifically examined.
Rapid cycling: Discontinuation of antidepressants, stimulants, and drugs of abuse is imperative. Lithium, divalproex, olanzapine, and quetiapine have comparable maintenance efficacies. Lamotrigine did not show efficacy in rapid cycling maintenance.

Mixed Episodes (DSM-5 Mixed Features)

Treatment for mixed features in a manic or hypomanic episode generally follows the approach for mania. Evidence supports preferential use of atypical antipsychotics and divalproex, often requiring combination therapy. There is no indication to start or continue antidepressants in a mixed state.

Maintenance Treatment

Most patients with bipolar disorder will require long-term, possibly lifelong, maintenance treatment to prevent recurrent episodes and restore functioning.

Pharmacological Mainstays (Alone or in Combination):

Lithium is highly effective and considered a first-line monotherapy. It has substantial evidence against manic, depressive, and mixed relapse, and is associated with a decreased risk of suicide. Regular monitoring of serum lithium concentrations is standard. Once-daily nighttime dosing is recommended for adherence and potentially less renal risk.
Quetiapine, divalproex, and lamotrigine are also considered first-line monotherapies. Lamotrigine is particularly effective in preventing depressive episodes, but less so for manic ones.
Asenapine and aripiprazole (oral or long-acting injectable) are also recommended as first-line monotherapies, showing efficacy in preventing manic and depressive episodes (asenapine) or any mood/manic episode (aripiprazole).
Combination therapies such as quetiapine with lithium/divalproex and aripiprazole plus lithium/divalproex are first-line options and have demonstrated efficacy in preventing mood episodes.
Olanzapine is effective in preventing any mood, manic, or depressive episode, but is considered second-line due to metabolic side effect concerns.
Long-acting injectable risperidone is effective in preventing any mood or manic episode.
Carbamazepine is less effective than lithium for maintenance but may be used, particularly in patients not showing classical euphoric mania, and is primarily effective against manic relapse. It has considerable pharmacokinetic interactions and side effect profile.

Psychosocial Interventions:

Adjunctive psychosocial interventions are important components of maintenance treatment, shown to reduce recurrence rates and improve quality of life.
Psychoeducation (individual and group) is the only first-line psychosocial intervention for the maintenance phase and should be offered to all patients. It focuses on illness education, early warning signs, stress management, social rhythms, and medication adherence.
CBT and Family-Focused Therapy (FFT) are second-line adjunctive options.
IPSRT and peer support are third-line adjunctive options.
Functional remediation may be helpful for cognitive and functional deficits.

Clinical Factors for Maintenance Choice:

The medication that was effective during the acute phase is often continued for maintenance.
Predominant polarity can guide choice: lithium, valproate, or carbamazepine if more manic episodes; lithium, lamotrigine, or quetiapine if more depressive episodes.
For rapid cycling, discontinuation of stimulants and antidepressants, and treatment of hypothyroidism are important. Combinations of mood stabilizers may be necessary.

Special Populations and Comorbidities

Bipolar II Disorder (BD-II):

While Bipolar II Disorder is seen by most as the second of the two main types of bipolar disorder, it is seen by some as a special population. In either case, the treatments are similar to Bipolar I Disorder and many of the treatments listed above also apply to BD II.

Treatment for BD-II depression is generally similar to BD-I depression.
Quetiapine is the only first-line treatment for BD-II depression listed in any major medical guidelines.
Second-line options include lithium, lamotrigine, and the antidepressants sertraline and venlafaxine for pure (non-mixed) depression.
While antidepressants may have a more favorable risk-benefit ratio in BD-II, caution is still advised against monotherapy due to hypomania/mixed states/rapid cycling risk.

Children and Adolescents:

Pharmacological treatment data are limited.
For mania: Aripiprazole is a first-line option (licensed for adolescents >13 years); olanzapine, quetiapine, and risperidone are also efficacious. Lithium and divalproex are also first-line.
For depression: Data are scarce. Quetiapine and lurasidone are mentioned as first-line options for acute bipolar depression in youth . Open trials support lithium and lamotrigine .
Maintenance: Aripiprazole, lithium, and divalproex are preferred options. Combination therapy may be more effective for maintaining remission.

Older Adults:

Treatment follows general principles but with lower doses and careful titration due to increased susceptibility to adverse reactions, impaired clearance, and multiple medical comorbidities.
For acute mania/hypomania: Lithium or divalproex monotherapy are first-line.
For bipolar depression: Quetiapine and lurasidone monotherapy are first-line. Lithium or lamotrigine may be considered.
For maintenance: Lithium, lamotrigine, and divalproex are recommended options.

Comorbid Conditions:

Most bipolar patients have at least one comorbid psychiatric diagnosis, commonly substance use disorder, anxiety disorders, and personality disorders. Comorbidity can increase treatment resistance and suicide risk.
Anxiety Disorders: Quetiapine has shown superiority in improving anxiety symptoms in patients with comorbid generalized anxiety disorder (GAD) and/or panic disorder. Specific anxiety-focused psychological treatments may be considered adjunctive, though evidence is less robust than for mood symptoms. Regular monitoring of anxiety is important.
Substance Use Disorders: Patients with co-occurring alcohol or substance use disorders may benefit from the involvement of an addiction specialist. Effective treatment of substance use can improve compliance and bipolar outcomes. Divalproex is recommended for patients with comorbid substance abuse.

General Principles of Management

Individualized Treatment: Treatment should be tailored to individual patient needs, clinical characteristics, and preferences.
Adherence: Medication adherence is a critical component of maintenance treatment, and non-adherence leads to more frequent recurrences and hospitalizations. Psychoeducation and collaborative decision-making improve adherence.
Monitoring: Continuous reevaluation and treatment modification are required. Regular monitoring of physical health, including weight, blood pressure, lipids, and thyroid/renal function, is crucial, especially with certain medications like lithium and antipsychotics. Suicidality surveillance is critical throughout the illness course, especially during depressive episodes.
Team-Based Care: An interprofessional team, including psychiatrists, primary care providers, nurses, social workers, and pharmacists, is a mainstay in treating bipolar disorder.

References: Coming Soon

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