BPD

Pharmacotherapy of Bipolar Disorder

Presented by Michael Kotlyar, PharmD

Affiliation

  • College of Pharmacy, University of Minnesota

  • Driven to DiscoverSM

Learning Objectives

  • Describe the epidemiology and criteria for diagnosing Bipolar Disorder.

  • Describe key clinical considerations for medications used to treat Bipolar Disorder, focusing on:
      - Adverse Effects
      - Drug Interactions

Bipolar Disorder – Epidemiology

  • Lifetime Prevalence: About 4%
      - Bipolar I: Approximately 1% - 2%

  • Average Onset of First Manic Episode:
      - Early 20s
      - 70% have initial symptoms before age 25

  • History of Depression: Not necessary for diagnosis
      - Unipolar Mania: Less than 5% of patients

  • Manic Episodes: 80% of individuals have more than 4 manic episodes in their lifetime.

  • Gender Differences:
      - Women have more depressive episodes compared to manic episodes.
      - Men show a more equal distribution of manic vs. depressive episodes.

Bipolar Disorder – Etiology

  • Heredity as a Risk Factor:
      - Monozygotic Twins: 60% - 80% concordance rate
      - Dizygotic Twins: 10% - 20% concordance rate

  • Familial Link:
      - 60% - 90% of patients have a biologic relative with a mood disorder.

  • First-Degree Relatives:
      - 15% - 35% risk of developing any mood disorder.
      - 5% - 10% risk of developing bipolar disorder.

  • Secondary Mania: Important to rule out secondary causes of mania (Refer to Table 93-2).

Various Theories on Etiology

  - Neurotransmitter Theories:
    - Monoamine Hypothesis
    - Dysregulation of amino acid neurotransmitters: e.g. GABA, Glutamate
    - Cholinergic Hypothesis
  - Hypothalamic-Pituitary-Thyroid Axis Dysregulation
  - Environmental, stress, and nutritional factors.
  - Sensitization and Kindling Theories:
    - Initial triggers lead to spontaneous episodes due to increased CNS sensitivity.
  - Secondary Causes of Mania: Include medical conditions and medications (Refer to Table 93-2).

Bipolar Disorder Subtypes

Table 93-1: Subtypes

  • Bipolar I: Characterized by a manic episode.

  • Bipolar II: Involves:
      - Hypomanic episode + Major depressive episode.
      - More prevalent in women.

  • Cyclothymia:
      - Fluctuations between subsyndromal depressive and hypomanic symptoms.
      - 15% - 50% chance of developing bipolar disorder.

Manic Episode – DSM Criteria

  • Defined by:
      - A distinct period of elevated, expansive, or irritable mood and increased activity or energy lasting at least 1 week (or any duration if hospitalization is required).

  • During this period, three or more symptoms must be present (or four if mood is irritable):
      - Inflated self-esteem or grandiosity.
      - Decreased need for sleep: e.g. feels rested after 3 hours of sleep.
      - More talkative than usual or feels pressured to keep talking.
      - Flight of ideas: subjective experience of racing thoughts.
      - Distractibility: attention easily drawn to unimportant stimuli.
      - Increased goal-directed activity or psychomotor agitation.
      - Excessive involvement in high-risk activities (e.g. buying sprees, sexual indiscretions).

  • Severity: Must cause marked impairment in social or occupational functioning or necessitate hospitalization to prevent harm, or be accompanied by psychotic features.

  • Exclusion Criteria: Not attributable to the physiological effects of substances or another medical condition.

Manic Episode Symptoms

Common Symptoms

  • Decrease in sleep.

  • Euphoria.

  • Irritability.

  • Expansiveness.

Other Symptoms:

  • Psychotic Symptoms: Main manifestations include:
      - Pressured Speech.
      - Hyperverbosity.
      - Physical Hyperactivity and Agitation.
      - Decreased Need for Sleep.
      - Hypersexuality.
      - Extravagance.
      - Impaired Judgment.

Manic Episode – Presentation

  • Typically escalates over several days to a week.

  • Change in sleep pattern is often the first clue of an episode.

  • Precipitating Factors:
      - Seasonal changes, stressors, sleep deprivation, medications (Refer to Table 93-2).

  • Average Length: Untreated manic episode lasts from 4 to 13 months.

  • Attention Span: Usually very short leading to "flight of ideas."

  • Severe Stages: May resemble schizophrenia, including bizarre behavior, hallucinations, and delusions (often grandiose or paranoid).
      - Psychotic features remit upon normalization of mood; otherwise consider schizoaffective disorder.

Bipolar Depression

Features

  • Atypical Features are more common, including:
      - Hypersomnia.
      - Hyperphagia.
      - Leaden Paralysis.

  • Seasonal Patterns: More common in bipolar disorder.

Other Definitions

Hypomanic Episode

  • Similar to manic episode but requires presence for 4 days without functional impairment. May switch to manic state.

Manic/Depressive Episode with Mixed Features

  • Full criteria for either manic or hypomanic episodes with three depressive symptoms.

  • Full criteria for major depressive episodes with three manic symptoms.

  • Occurs in up to 40% of episodes. Generally have poorer prognosis and lower response to monotherapy.

Rapid Cycling

  • Defined as > four major depressive or manic episodes (manic, mixed, or hypomanic) in 12 months.

  • Lifetime Prevalence: About 25% - 40% of patients, more common in women.

  • May be linked to clinical or subclinical hypothyroidism.

Bipolar Disorder – Prognosis

  • Risk of Suicide: Untreated depressed or mixed-state patients have a 25% - 50% chance of attempting suicide at least once.

  • Age-Related Changes: With age, the interval between episodes may decrease, and the duration of episodes may increase.

  • Treatment Access Issues: Many patients do not receive adequate treatment due to:
      - Failure to recognize the disease.
      - Reluctance to acknowledge illness.
      - Non-adherence to treatment.
      - On average, an 8-year delay in initiating treatment following the first mood episode.

  • Substance Use Disorders: Co-occurrence with alcohol or substance use disorder in 40% - 50% of patients.

Goals of Treatment

Table 93-3: Treatment Goals

  • Resolution of Acute Symptoms: Achieving remission.

  • Prevention of Future Episodes.

  • Return to Complete Psychosocial Functioning.

  • Adherence with Treatment.

  • Minimize Adverse Effects.

  • Treat Comorbid Substance Abuse.

  • Avoidance of Stressors that may precipitate episodes.

Factors Affecting Adherence

  • Human Nature: Intrinsic behavioral tendencies.

  • Side Effects: Adverse effects of medications.

  • Substance Abuse: Interference with treatment adherence.

  • Missing “Highs”: Longing for manic episodes.

  • Lack of Insight: Awareness of one’s condition.

  • Complex Medication Schedules: Difficulty in following treatment regimens.

  • Lack of Psychosocial Support: Absence of support systems.

Risk Factors for Non-Adherence to Medications

Table 16: Risk Factors
Sociodemographics

  • Male, younger age, low level of education, single.

Psychological Factors

  • Poor insight, lack of disease awareness, negative attitudes toward treatment, fear of side effects, overall low life satisfaction, low cognitive functioning.

Comorbidity

  • Presence of alcohol or cannabis use, obsessive-compulsive disorder.

Social Factors

  • Lack of social activities, work impairment.

Chronology

  • Younger age of onset, current inpatient status, hospitalization or suicide attempt within the past 12 months.

Disease Characteristics

  • Mixed episodes, rapid cycling, delusions and hallucinations, greater severity of illness, BDI diagnosis, higher number of episodes.

Treatment-Related Factors

  • Side effects of medications, inadequate efficacy of medication, use of antidepressants, low treatment doses.

  • Sources: Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for managing bipolar disorder.

General Principles of Treatment

  • Mood Charting: Continuous assessment of mood changes and stressors over time.

  • Optimizing Sleep: Ensuring adequate sleep to stabilize mood.

  • Eliminating Mood Destabilizers: Identifying and removing factors that disrupt mood stability.

Medications Used to Treat Bipolar Disorder

Table 93-5: Approved Medications

  • Lithium (Eskalith, Lithobid): Approved for acute and prophylactic treatment of bipolar disorder.

  • Carbamazepine (Tegretol), Valproate (Depakote), Asenapine (Saphris), Aripiprazole (Abilify), Olanzapine (Zyprexa), Risperidone (Risperdal), Quetiapine (Seroquel), Ziprasidone (Geodon), Cariprazine (Vraylar), Milnacipran (Bysanti): Approved for treatment of acute manic or mixed episodes.

  • Olanzapine/Fluoxetine (Symbyax), Quetiapine (Seroquel), Lurasidone (Latuda), Lumateperone (Caplyta®), Cariprazine (Vraylar): FDA approved for depressive episodes associated with bipolar disorder.

  • Lithium, Lamotrigine (Lamictal), Olanzapine (Zyprexa), Aripiprazole (Abilify), Risperidone LAI (Risperdal Consta), Asenapine (Saphris): FDA approved for maintenance treatment of Bipolar I Disorder.

  • Ziprasidone (Geodon), Quetiapine (Seroquel): FDA approved for maintenance therapy of Bipolar I as adjuncts to lithium or valproate.

Treatment – Acute Episode

Acute Mania

  • Primary Treatments:
      - Lithium
      - Valproic Acid
      - Atypical Antipsychotics (SGA)
      - Carbamazepine

  • Adjunctive Agents: Benzodiazepines for symptom management.

Acute Bipolar Depression

  • Primary Treatments:
      - Lithium
      - Lamotrigine
      - Atypical Antipsychotics (SGA)

  • Caution with Antidepressants: To be used cautiously.
      - Valproic Acid
      - Carbamazepine

Conclusion

University Information

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