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A. Definitionsnavigator

  1. Two Main Types of Mood (Affective) Disorders
    1. Major Depression (unipolar)
    2. Bipolar Disorder (Manic-Depressive Illness)
  2. Bipolar Disorder (BPI)
    1. Disorder including both manic or hypomanic episodes with depression
    2. Formerly called manic-depressive illness (MDI)
    3. Divided into Bipolar I and II
    4. More common in creative persons and their relatives than in general population
    5. Also increased in substance abusers
    6. Male = Female
  3. Bipolar I Disorder
    1. Recurrent mood disroder
    2. One or more manic or mixed episodes OR
    3. Both manic and mixed episodes and at least one major depressive episode
    4. May also experience psychotic symptoms
  4. Bipolar II Disorder
    1. History of depression and hypomania
    2. One more episodes of major depression with at least one hypomanic episode
  5. Mania
    1. Distinct period of abnormally elevated, expansive or irritable mood
    2. Lasts at least 1 week
    3. Symptoms including grandiosity, decreased need for spleep, racing thoughts
    4. Must impair normal function (contrast with hypomania)
    5. Manic episodes occur much less frequently than depressive episodes
    6. Acute mania is a medical emergency
  6. Hypomania [12]
    1. Mood elevations that are abnormal for individual
    2. Do not seriously impair function or require hospitalization
    3. Generally treated first with psychiatric therapy (not medications)
  7. Major Depression Episode
    1. Period at least 2 weeks
    2. Either depressed mood or with loss of interest or pleasure in most activities
  8. Mixed Episode
    1. Period of at least one week in which:
    2. Criteria are met for both manic and major depressive episodes
  9. Cyclothymic Disorder
    1. Chronic (>2 years) with fluctuating mood disturbances
    2. Numerous periods of mild hypomanic and depressive symptoms
    3. Depressive symptoms do not meet criteria for major depression

B. Bipolar I Disorder (BPI) navigator

  1. Also called manic-depressive illness (MDI)
  2. Epidemiology [3]
    1. Lifetime BPI prevalence in primary care screening population ~10%
    2. No differences in age, sex, ethnicity on prevalence
    3. Most BPI patients on screening had current depression, anxiety, or substance abuse
    4. Peak onset ages 15-24
    5. Onset in >60 year olds likely due to underlying organic medical condition
    6. Risk for suicide is as high as 15% amongst untreated patients
  3. Differential Diagnosis
    1. Schizophrenia
    2. Depression with Psychosis
    3. Medical Illness which can initiate bipolar behavior (mainly in persons >60)
    4. Neuroglical: trauma, neoplasm, multiple sclerosis, epilepsy
    5. Endocrine: hypothyroidism, Cushing's Syndrome
    6. AIDS
    7. Systemic Lupus Erythematosus
  4. Anatomy and Pathophysiology [1,2,4]
    1. Abnormalities in serotonergic system well documented
    2. Disturbances in hypothalamic-pituitary-adrenal axis
    3. Magnetic resonance imaging shows periventricular T2 white matter hyperintensities
    4. Enlargement of lateral and third ventricles
    5. Genetic basis for bipolar disorder well documented
    6. Rates are 40-70% in monozygotic twins versus 10-15% in other relatives
    7. Reduction in levels of transcription factors that regulate myelination genes in oligodendrocytes in both schizophrenia and bipolar disorder [4]
    8. Schizophrenia and bipolar disorder may have similar pathophysiologies
  5. Therapy Overview
    1. Long term treatment of bipolar disorder
    2. Treatment of Bipolar Depression
    3. Treatment of acute mania
  6. Chronic MDI Therapy (in order of preference) [1,5]
    1. Valproate (Depokote®) - better tolerated but overall less effective than lithium [6,7]
    2. Lithium - mainly for manic symptoms, alternative first line treatment
    3. Carbamazepine (Equetro®) - initially 200mg bo pid, maximum 1600mg divided daily [8]
    4. Olanzapine (Zyprexa®) is also approved for use in bipolar disorder
    5. Combination of olanzapine and fluoxetine (Symbyax®) approved for bipolar depression [9]
    6. Lamotrigine (Lamictal®) has some activity as maintenance therapy in bipolar disorder
    7. Other anticonvulsants are being investigated as monotherapy or adjunctive therapy
  7. Treatment of Bipolar Depression
    1. Lithium + antidepressant or + anticonvulsant for severe disease
    2. Symbyax® (olanzapine+fluxoetine combined pill) may be reasonable alternative
    3. Lithium + psychotherapy or behavioral therapy for mild disease
    4. If mood stabilizer is being used and depression occurs, add serotonin reuptake inhibitor or second mood stabilizer
    5. Addiing paroxitine or buproprion to mood stabilizer in bipolar depression did not improve efficacy or induce an affective switch [13]
    6. Avoid antidepressants with depression in rapid cycling; use second mood stabilizer
    7. Levothyroxine can be added for rapid cycling
    8. Electroconvulvie therapy for refractory depression
  8. Valproate [6,7]
    1. As effective as lithium for symptom control, with fewer side effects
    2. Less effective than lithium for prevention of suicide attempt and death [6]
    3. For acute mania, dose is 500-1000 mg po qd in 2 to 4 divided doses (250 mg/dose)
    4. Maintenance therapy based on drug levels, usually 1000-2500 mg/day
    5. Goal is trough serum concentrations of 50-125 µg/mL
    6. Effects observed after 7-14 days
    7. Follow liver function tests q 2 weeks initially, then monthly
    8. Some women develop polycystic ovary syndrome on valproate

C. Manianavigator

  1. Symptoms
    1. Irritability, euphoria, delusions (grandiose)
    2. Rapid speech, flight of ideas, pressured speech
    3. Decreased sleep, increased appetite, increased sexual drive
    4. Increased distractability
    5. Increased activities, usually with hightened risk potential (for pain)
  2. Over 90% of patients with one manic episode will recur
  3. Acute Therapy
    1. Lithium + antipsychotics are most effective in severe disease
    2. Carbamazepine as effective as lithium and may be used instead
    3. Valproate + antipsychotics second line
    4. Antipsychotics - typical (haloperidol, Haldol®) or atypical (olanzapine, Zyprexa®)
    5. Short term treatment with olanzapine is often the preferred therapy
    6. Benzodiazepines in high dose - clonazepam (Klonopin®) or lorazepam
    7. Electroconvulsive Therapy (ECT) - only for acute refractory mania
    8. Valproate is preferred for mixed or dysphoric type of mania
  4. Maintenance Therapy (in usual order of preference) [1,5]
    1. Lithium (Eskalith®) - first line therapy, but valproate is equally effective
    2. Valproate (Depakote®, Depakene®) - alternative first line to lithium
    3. Carbamazapine (Tegretol®) - for patients intolerant or unresponsive to other agents
    4. Gabapentin or lamotrigine may also be used alone or in combination
  5. Drug Selection
    1. Valproate probably preferable over lithium for most patients
    2. Valproate cannot be give to patients with hepatic dysfunction
    3. Carbamazepine is avoided in patients with intermittent prophyria or atrioventricular block
    4. Titrate to full dose valproate within 1-2 days; efficacy in 5-7 days

D. Lithium (Eskalith®, others) [5,10]navigator

  1. Mechanism of Action [1]
    1. Not completely clear
    2. Lithium interferes with glutamate toxicity
    3. Lithium down regulates the excitotoxicity of glutamate at NMDA receptors
    4. Alters electrophysiologic response of neurons
    5. Reduces and shortens action potentials
    6. Enhances uptake-inactivation process of biogenic amines
    7. Is neuroprotective and enhances neurogenesis
    8. Increases bcl-2 protein, a neuronal pro-survival factor
    9. Lithium can also overcome carbamazepine's neurotoxic effects
  2. Clinical Response to Lithium
    1. Acutely manic patients and acute bipolar disorder - slow onset (7-10 days)
    2. Prophylactic use of lithium in affective illness ~80% initially effective
    3. Mildly effective in depression of MDI; augmentation for unipolar depression
    4. ~50% relapse rates within 1 year on lithium
    5. Addition of lithium to standard antidepressants increases response rates, particularly in refractory patients (600-800mg/d for >1 week) [7]
    6. Divalproex had 1.7-1.8X increased risk of suicide attempts and death versus lithium [6]
  3. Side Effects of Lithium
    1. Cognitive side effects, weight gain, lack of coordination are main side effects
    2. Polyuria: blocks vasopressin action (nephrogenic DI) and has direct osmolar effects
    3. Polyuria may be pronounced and can lead to dehydration
    4. Unlikely long term reduction in renal function (reduced glomerular filtration rate)
    5. Fine tremor (treat with ß-blockers) and/or ataxia, incoordination
    6. Dry skin, alopecia (may be exacerbated by hypothyroidism
    7. Diarrhea - especially while adjusting doses
    8. Thyroid disorder - usually hypothyroidism; inhibits T4 secretion (often requires treatment)
    9. Multiple drug interactions: ACE inhibitors, thiazides, NSAIDs reduce excretion (raise levels)
    10. Fetal cardiac malformations have been reported
  4. Dosage and Monitoring [11]
    1. Excreted by kidneys, so half life of ion inversely related to renal function
    2. Routine dose 300-600 mg Lithium Carbonate po tid
    3. Avoid in patients with renal dysfunction
    4. Slow release form reduces dosing frequency
    5. Optimal serum levels 0.8-1.0mEq/L, probably as low as 0.6 mEq/L
    6. InstaRead Lithium System® can reliably determine lithium levels with 1-2 drops of blood [11]
    7. Monitor serum levels, renal function and thyroid function
  5. Toxic Serum Levels
    1. Nausea, vomiting, diarrhea, coarse tremor, ataxia, dysarthria (>2 mEq/L)
    2. ECG changes, especially T waves
    3. Confusion, obtundation, coma (>3.5 mEq/L)

References navigator

  1. Belmaker RH. 2004. NEJM. 351(5):476 abstract
  2. Muller-Oerlinghausen B, Berghofer A, Bauer M. 2002. Lancet. 359(9302):241 abstract
  3. Das AK, Olfson M, Gameroff MJ, et al. 2005. JAMA. 293(8):956 abstract
  4. Tkachev D, Mimmack ML, Ryan MM, et al. 2003. Lancet. 362(9386):798 abstract
  5. Psychiatric Medications. 1997. Med Let. 39(998):33 abstract
  6. Goodwin FK, Fireman B, Simon GE, et al. 2003. JAMA. 290(11):1467 abstract
  7. Valproate for Psychiatric Illness. 2000. Med Let. 42(1094):114 abstract
  8. Carbamazepine Extended Release. 2005. Med Let. 47(1205):27 abstract
  9. Olanzapine/Fluoxetine for Bipolar Depression. 2004. Med Let. 46(1178):23 abstract
  10. Freeman MP and Freeman SA. 2006. Am J Med. 119(6):478 abstract
  11. InstaRead Lithium System. 2005. Med Let. 47(1219):82 abstract
  12. Benazzi F. 2007. Lancet. 369(9565):935 abstract
  13. Sachs GS, Nierenberg AA, Callabrese JR, et al. 2007. NEJM. 356(17):1711 abstract