Bipolar Disorder

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%

Pathophysiology

1. Related to noradrenergic system (Norepinephrine)

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

History

1. Impaired social functioning
   1. Multiple divorces
   2. Legal or financial problems
   3. Recurrent job loss
2. Recurrent Major Depression
   1. Typically onset by age 13 years
   2. May present as Seasonal Affective Disorder
   3. Failed response to at least three Antidepressants
   4. Atypical Depression
   5. Hypersomnia
   6. Pathologic guilt
3. Attempted Suicide
4. Drug Abuse or Alcohol Abuse
5. Manic symptoms
   1. Mania or Hypomania episodes
   2. Psychosis
   3. Agitation or mania caused by Antidepressant, Corticosteroid or other medication
6. Family History
   1. Bipolar Disorder
   2. Multiple relatives with Major Depression or Anxiety Disorder
   3. Multiple relatives with Suicidality, incarceration, Drug Abuse or Alcohol Abuse

Symptoms

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

Differential Diagnosis

1. See Mania Secondary Causes
2. Personality Disorder
3. Recurrent Major Depression
4. Schizophrenia
5. Obsessive-Compulsive Disorder

Diagnosis

1. See Mania Diagnosis

Labs: Consider for evaluation of secondary causes

1. Highest yield tests
   1. Thyroid Function Tests (Thyroid Stimulating Hormone)
   2. Serum or 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. Rare causes
   1. Heavy metal levels

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
5. Urine Pregnancy Test
6. Electrocardiogram (for baseline QT Interval)

Diagnostics: Consider if suggested by history or examination

1. Head MRI
2. Electroencephalogram (EEG)

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. Employ behavioral management as a first line therapy
   1. Cognitive behavioral therapy
   2. Caregiver support
7. Manage comorbidity
   1. Alcohol Abuse
   2. Tobacco abuse
   3. Drug Abuse
8. Patients and their family should be aware of early warning signs of relapse
   1. Sleep disturbance
   2. Agitation
   3. Increased goal oriented activity
   4. Disrupted routine

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
      1. Primary mood stabilizers are both effective for Major Depression
         1. Lithium (preferred)
         2. Valproate
      2. Other 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
      3. 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)
   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
4. Refractory Cases
   1. Consider switching mood stabilizer
   2. Consider combining 2-3 mood stabilizers
   3. Consider Electroconvulsive Therapy

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. 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

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 10-15 mg per day
      3. 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
3. Adjunctive medications: Antidepressants
   1. See Acute Depression Management above
   2. First-line agents
      1. Mood Stabilizers (Lithium, Valproate)
   3. Second-line agents (used in combination with mood stabilizers)
      1. Atypical Antipsychotics
      2. Selective Seotonin Reuptake Inhibitors (SSRIs)
         1. Risk of precipitating mania (do not use as montherapy)
         2. Avoid Tricyclic Antidepressants, Trazodone, or Venlafaxine which can trigger manic episodes
   4. Other adjunctive measures
      1. Omega-3 Fatty Acid Supplements