Bipolar Disorder

Aka: Bipolar Disorder, Bipolar Depression, Bipolar I Disorder, Bipolar II Disorder, Bipolar 1 Disorder, Bipolar 2 Disorder, Mania, Manic Depression, Manic Disorder, Hypomania, Cyclothymia, Cyclothymic Disorder

1. See Also
   1. Mania Diagnosis
   2. Hypomania Diagnosis
   3. Mania Secondary Causes
   4. Major Depression Diagnosis
2. Epidemiology
   1. Bipolar Incidence: 1% of adults (United States)
   2. Gender predisposition: Men and women equally affected
   3. Age of onset: Early adulthood to mid-40s
   4. Affective disorder Family History confers risk
      1. One parent with affective disorder: 27%
      2. Two parents with affective disorder: 50-75%
   5. Mean age onset
      1. Bipolar I: Age 18 years
      2. Bipolar II: Age 22 years
   6. Llifetime Incidence
      1. Bipolar I: 0.6%
      2. Bipolar I: 0.4%
3. Risk Factors
   1. Family History of affective disorder or Bipolar Disorder (see epidemiology as above)
   2. Stressful life events
      1. Acute stress often triggers initial episode
      2. Childhood Trauma and adverse events
   3. Family member Suicide
   4. Disrupted sleep cycle
4. Pathophysiology
   1. Related to noradrenergic system (Norepinephrine)
5. Types
   1. Bipolar I Disorder
      1. Manic or mixed episode
      2. Psychosis may be present
      3. Major Depression may be present
   2. Bipolar II Disorder
      1. Recurrent Major Depression
      2. Hypomanic episodes that do not meet criteria for Mania Diagnosis
   3. Cyclothymic Disorder (Cyclothymia)
      1. Depressive symptoms that do not meet criteria for Major Depression
      2. Hypomanic episodes that do not meet criteria for Mania Diagnosis
      3. Bipolar II Diagnosis not met
      4. Occurs for over 2 years, and with only two months or less symptom free
   4. Bipolar Disorder with Mixed Features
      1. Concurrent features of Hypomania/mania and depression
   5. Substance-Induced Mania
      1. See Substance-Induced Psychotic Disorder
      2. Examples: Methamphetamine, Cocaine, Alcohol, Corticosteroids
   6. Miscellaneous
      1. Bipolar Disorder not otherwise specified (does not meet criteria for other Bipolar Disorders)
      2. Bipolar Disorder unspecified (unconfirmed diagnosis for acute presentation)
6. History
   1. Recurrent Major Depression
      1. Typically onset by age 13 years
      2. May present as Seasonal Affective Disorder (seasonal variability to depression episodes)
      3. Failed response to at least three Antidepressants
      4. Atypical Depression
      5. Hypersomnia
      6. Pathologic guilt
      7. Labile Mood or significant irritability
   2. Attempted Suicide
   3. Manic symptoms
      1. Mania or Hypomania episodes
      2. Periods of intense goal oriented activity
      3. Decreased need for sleep
      4. Racing thoughts interfere with sleep
      5. Psychosis
      6. Agitation or mania caused by Antidepressant, Corticosteroid or other medication
      7. Episodic hypersexuality
      8. Impulsive or irrational behavior
   4. Comorbid mental health disorders (up to 75% have 3 concurrent mental health disorders)
      1. See associated conditions as below
      2. Substance Use Disorder (Drug Abuse or Alcohol Abuse)
      3. Anxiety Disorder
      4. Attention Deficit Disorder
   5. Family History
      1. Bipolar Disorder Family History
      2. Multiple relatives with Major Depression, Anxiety Disorder, Panic Disorder or Attention Deficit Disorder
      3. Multiple relatives with Suicidality, incarceration, Drug Abuse or Alcohol Abuse
   6. Impaired social functioning
      1. Multiple divorces
      2. Legal or financial problems
      3. Recurrent job loss
   7. Triggers
      1. Emotional Stressors
      2. Serious life events
      3. Hormonal fluctuations in women (pregnancy, Menopause, Menses)
      4. Sleep disruptions (see symptoms below)
      5. Seasonal pattern (25% of cases)
7. Symptoms: Adults
   1. Maintains several days with reduced sleep and without feeling tired
   2. Frequent mood swings (or mood lability) or periods of intense goal orientation
   3. Racing thoughts interfere with sleep onset
   4. Sleep disruptions trigger mania or Hypomania
      1. Seasonal changes in spring and fall
      2. Jet Lag on time zone changes
      3. Shift work or child care
   5. Associated symptoms
      1. Irritability
      2. Impulsivity
      3. Irrationality
8. Symptoms: Children
   1. Present with irritability, sadness and Insomnia (euphoria is typically absent)
9. Symptoms: Miscellaneous Features Present in Some Bipolar Patients
   1. Anxious Distress
      1. Feeling restless, Excessive Worry, loss of control
      2. Associated with increased Suicidality risk
   2. Atypical features
      1. Depression related sleeping more and eating more
   3. Catatonic State
   4. Melancholia
   5. Psychotic features
   6. Rapid Cycling (Bipolar 1 Disorder)
10. Exam
    1. Background
       1. Thorough evaluation provides baseline before medications and evaluates for secondary causes and complications
    2. Obtain full Vital Signs
       1. Body Mass Index (BMI)
       2. Blood Pressure
       3. Waist Circumference
    3. Full physical exam
    4. See Mental Status Exam
    5. See Psychosis Exam
    6. Neurologic Exam including gait
11. Differential Diagnosis
    1. See Mania Secondary Causes
    2. Personality Disorder
    3. Recurrent Major Depression
    4. Schizophrenia
    5. Obsessive-Compulsive Disorder
12. Associated Conditions
    1. Anxiety Disorder
    2. Impulse Control
    3. Attention Deficit Disorder
    4. Substance Use Disorder
    5. Cardiovascular Disease
       1. Bipolar disease patients have twice the risk of cardiovascular disease than general population
       2. Screen for Cardiovascular Risk Factors
13. Diagnosis
    1. Specific Bipolar Disorder diagnosis (see Types above) rely on diagnostic criteria for Major Depression and mania/Hypomania
    2. See Major Depression Diagnosis
    3. See Mania Diagnosis
    4. See Hypomania Diagnosis
14. Grading: Severity
    1. Mild
       1. Diagnosis criteria met
       2. Mild functional Impairment
    2. Moderate
    3. Severe
       1. Severe distress and functional Impairment
15. Labs: Consider for evaluation of secondary causes
    1. Highest yield tests
       1. Thyroid Function Tests (Thyroid Stimulating Hormone)
       2. Urine Drug Screen
       3. Urinalysis
          1. Older patients to evaluate for Urinary Tract Infection
    2. Sexually Transmitted Diseases
       1. Syphilis Serology (e.g. RPR)
       2. HIV Test
       3. Hepatitis C
    3. Uncommon to rare causes
       1. Heavy metal levels
       2. Serum Ammonia level
16. Labs: Consider for baseline labs prior to starting medications
    1. Complete Blood Count
    2. Chemistry panel with Renal Function tests
       1. Serum Sodium
       2. Serum Creatinine
       3. Serum Glucose
    3. Liver Function Tests
    4. Serum Prolactin
       1. Antipsychotics may increase Prolactin levels
       2. Consider in patients with Amenorrhea, Galactorrhea, Gynecomastia
    5. Urine Pregnancy Test
    6. Electrocardiogram (for baseline QT Interval)
       1. Many neuropsychiatric medications risk QT Prolongation
       2. Also provides baseline EKG due to Bipolar Disorder associated cardiovascular disease risk
    7. Cardiovascular Disease Risk Screening
       1. Fasting Glucose
       2. Lipid Profile
17. Diagnostics: Consider if suggested by history or examination
    1. Head MRI
    2. Electroencephalogram (EEG)
18. Management: General
    1. Continue mood stabilizers indefinately due to high relapse rate
    2. Consult psychiatry for comanagement
    3. Discuss Teratogenicity of medications with women of child bearing age
       1. Reliable Contraception is critical
    4. Do not use Antidepressants as monotherapy for mania, mixed disorder or Bipolar Disorder
       1. High risk of triggering manic episode
    5. Avoid medications that are more likely to trigger or exacerbate mania
       1. Avoid Trazodone
       2. Avoid Tricyclic Antidepressants
       3. Avoid SNRIs (e.g. Venlafaxine or Duloxetine)
    6. Patient should keep their own of medications, adverse effects and effectiveness
    7. Employ behavioral management as a first line therapy to reduce psychosocial stress
       1. Cognitive Behavioral Therapy
       2. Caregiver Support
       3. Regular Exercise
       4. Coping Strategy education
       5. Well Balanced Nutrition
       6. Intensive psychotherapy for exacerbations
    8. Manage comorbidity
       1. Alcohol Abuse
       2. Tobacco Abuse
       3. Drug Abuse
    9. Patients and their family should be aware of early warning signs of relapse and emergency features
       1. Sleep disturbance
       2. Agitation
       3. Increased goal oriented activity
       4. Disrupted routine
       5. Suicidality
       6. Homicidality
    10. Clinicians should be alert for Extrapyramidal Side Effects (and modify therapy to reduce adverse effects)
        1. Perform Abnormal Involuntary Movement Scale (AIMS) at least every 6 months while on Antipsychotic Medications
           1. https://dmh.mo.gov/media/21821/download
        2. Akathisia
           1. Motor restlessness (differentiate from worsening mania, anxiety)
           2. May increase Suicidality
        3. Parkinsonism
        4. Dystonia
        5. Dyskinesia
        6. Tardive Dyskinesia
           1. Particular caution in elderly, cardiovascular disease risk, HIV Infection, neurologic disorders
    11. Consider medication dose reduction at every visit
        1. Adverse effects (esp. Extrapyramidal Side Effects) should prompt dose reduction (or medication change)
        2. Especially consider lower dose in children, older adults, underweight and with chronic disease
        3. Dose increases are needed with exacerbations
19. Management: Acute
    1. Acute Mania
       1. Hospitalize due to high risk of self harm or Suicidality
       2. Therapy goals
          1. Adequate sleep
          2. Reduce psychotic symptoms
       3. Medication protocol
          1. Start mood stabilizer (see below)
             1. Lithium (preferred) or
             2. Valproate
          2. Start adjunctive therapy (see below)
             1. Indicated while mood stabilizer (esp. Lithium) reaches steady state over days
             2. Atypical Antipsychotic (e.g. Olanzapine, Quetiaprine) or Haloperidol
             3. Benzodiazepines (e.g. Lorazepam)
    2. Acute Hypomania
       1. Medication management is similar to acute mania
       2. Observe for major depressive episode immediately following acute Hypomania episode
       3. Assess for functional capacity
          1. Decision making
          2. Compliance with treatment
    3. Acute Major Depression
       1. Hospitalize for Suicidality or Homicidal Thoughts
       2. Psychotherapy
       3. First-line therapies (combination of mood stabilizer with Atypical Antipsychotic)
          1. Primary mood stabilizers are both effective for Major Depression
             1. Lithium (preferred)
             2. Valproate
          2. Atypical Antipsychotics effective for Major Depression
             1. Quetiapine or Seroquel (preferred)
                1. Risk of weight gain, Glucose Intolerance, and Extrapyramidal Side Effects
             2. Olanzapine (Zyprexa)
             3. Cariprazine (Vraylar)
             4. Lurasidone (Latuda)
       4. Second-line therapies
          1. Add only to first line agents if effect is incomplete
             1. Do not use standard Antidepressants without mood stabilizers
             2. These agents do not increase efficacy over mood stabilizers alone
             3. Avoid Tricyclic Antidepressants, Trazodone, or Venlafaxine which can trigger manic episodes
          2. Selective Serotonin Reuptake Inhibitors
          3. Bupropion (Wellbutrin)
          4. Anticonvulsants effective for Major Depression
             1. Lamotrigine or Lamictal (preferred)
                1. Requires 6 weeks to titrate to level (due to Steven's Johnson Syndrome risk)
             2. Carbamazepine or Tegretol
             3. Topiramate
    4. Acute Mixed Features (combined features of Major Depression and mania/Hypomania)
       1. Avoid Lithium in mixed features or rapid cycling presentation (ineffective)
       2. Avoid monotherapy with Antidepressant for mixed features presentation
       3. Atypical Antidepressants are preferred in acute mixed feature presentations
          1. Ariprazole (Abilify)
          2. Olanzapine (Zyprexa)
          3. Quetiapine (Seroquel)
          4. Risperidone (Risperdal)
          5. Ziprasidone (Geodon)
          6. Asenapine (Saphris)
          7. Cariprazine (Vraylar)
    5. Refractory Cases
       1. Consider switching mood stabilizer
       2. Consider combining 2-3 mood stabilizers
       3. Consider Electroconvulsive Therapy
          1. Older patients
          2. Refractory to medications
          3. Catatonia
          4. Acute Psychosis with Suicidality
20. Management: Mood Stabilizer Selection
    1. Mood stabilizer options
       1. First-line agents
          1. Lithium (preferred)
             1. Suicide is 3 fold less likely with Lithium than Valproate
             2. Starting dose may be up to 300 mg twice daily
             3. Titrate dose every 2-3 days as tolerated to effect and serum Lithium level of 0.6 to 1.5 mEq/L
             4. Target dose: 900 to 1800 mg orally daily
          2. Valproate
             1. Loading dose in acute mania: 15-20 mg/kg
             2. Starting dose without load: 500 to 750 mg/day in divided dosing
             3. Titrate every 2-3 days as tolerated to serum Valproic Acid level of 50 to 125 mcg/ml
             4. Target dose: 200 to 1600 mg daily
       2. Alternative mood stabilizers (consider for specific indications)
          1. Carbamazepine (Tegretol)
             1. Starting dose 200 mg twice daily
             2. Therapeutic range for biopolar: 4-12 mcg/ml
             3. Available as long acting agent (Equetro)
          2. Oxcarbazepine
             1. Consider instead of Carbamazepine
             2. Similar efficacy with fewer adverse effects
          3. Lamotrigine (Lamictal)
             1. Starting dose 25 mg daily
             2. Effective as mood stabilizer and Antidepressant
             3. No blood monitoring needed
             4. Rash develops in 10% of patients (Risk of Steven's Johnson)
                1. Requires slow titration over at least 6 weeks to effective dose
                2. Titrate Lamotrigine slowly (2 week increments)
                3. Do not exceed 100 mg when combined with Valproate
    2. Specific agent indications
       1. Classic mania or Hypomania (Euphoric mood)
          1. Lithium (preferred) or
          2. Valproate
       2. Mixed episode or rapid cycling
          1. Valproate (preferred) or
          2. Carbamazepine
    3. Combinations in refractory cases
       1. Lithium with Lamotrigine OR Valproate
       2. Valproate with Lithium OR Lamotrigine
21. Management: Adjunctive Medications
    1. Adjunctive medications: Benzodiazepine
       1. Examples: Lorazepam, Clonazepam
       2. Indications for Benzodiazepine
          1. Mania or Hypomania with Insomnia or Agitation
          2. Psychosis refractory to Antipsychotic
       3. Alternatives
          1. Consider Gabapentin for anxiety
    2. Adjunctive medications: Antipsychotics
       1. Precautions
          1. Monitor for Extrapyramidal Side Effects (e.g. Tardive Dyskinesia)
          2. Atypical Antipsychotic agents have specific lab monitoring guidelines
       2. Antipsychotic indications
          1. Psychosis
             1. Consider Electroconvulsive Therapy
          2. Mania with Insomnia or Agitation
             1. Despite Benzodiazepine
          3. Acute mania episode
             1. Antipsychotic use may increase Lithium or Valproate efficacy
       3. Agents (low doses are often effective in mania)
          1. Risperidone (Risperdal) 2-4 mg per day
          2. Olanzapine (Zyprexa) 10-15 mg per day
          3. Lurasidone (Latuda) 20 mg orally daily (may advance gradually to 60 mg daily)
          4. Quetiapine 400-800 mg per day
             1. Mood stabilizers have improved efficacy when used with Quetiapine
             2. Yatham (2009) Bipolar Disord 11(3):225-55 [PubMed]
          5. Avoid Antipsychotics with lower efficacy in Bipolar Disorder
             1. Avoid Aripiprazole (Abilify)
             2. Avoid Ziprasidone (Geodon)
    3. Adjunctive medications: Antidepressants
       1. See Acute Depression Management above
       2. First-line agents
          1. Mood Stabilizers (Lithium, Valproate)
       3. Second-line agents (used only in combination with mood stabilizers)
          1. Selective Seotonin Reuptake Inhibitors (SSRIs) or Bupropion
             1. Risk of precipitating mania (do not use as montherapy)
             2. Avoid Tricyclic Antidepressants, Trazodone, or Venlafaxine which can trigger manic episodes
             3. Avoid Paroxetine (Paxil) as it is less effective in Bipolar Disorder
             4. May taper off 6-8 weeks after full bipolar remission (restart as needed)
    4. Other adjunctive measures (insufficient evidence)
       1. Omega-3 Fatty Acid Supplements
       2. Light Therapy
22. Prognosis
    1. Relapse Rate
       1. One year: 25% with treatment (40% without treatment)
       2. Five years: 70% (regardless of treatment)
    2. Suicide Attempt: 33% lifetime risk (half of those within the last year)
       1. Higher risk with anxious stress
       2. Completed Suicide in 6-7%
       3. Within 6 weeks of hospital discharge in 26%
       4. Schaffer (2015) Aust N Z J Psychiatry 49(11): 1006-20 [PubMed]
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    2. (1997) Am Fam Physician 55(4):1447-9 [PubMed]
    3. Docherty (1996) J Clin Psychiat 57(suppl 12A):1-89 [PubMed]
    4. Marzani (2021) Am Fam Physician 103(4): 227-39 [PubMed]
    5. Manning (2010) J Clin Psychiatry 12(suppl 1): 17-22 [PubMed]
    6. McIntyre (2004) Can Fam Physician 50:388-94 [PubMed]
    7. Price (2012) Am Fam Physician 85(5): 483-93 [PubMed]
    8. Werder (1995) Am Fam Physician 51(5):1126-36 [PubMed]