Mood Disorders

Bipolar Disorder

Depression

Bipolar Disorder

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Onset usually in late adolescence or early adulthood
• Not caused by a substance or a general medical condition
• Bipolar I disorder: one or more manic or mixed episodes, often alternating with major depressive episodes
• Bipolar II disorder: recurrent major depressive episodes with hypomanic episodes
• Cyclothymic disorder: at least 2 yr of fluctuating mood disturbance involving numerous periods of hypomanic symptoms and numerous periods of depressive symptoms
• Rapid cycling bipolar disorder: ≥ 4 episodes within 1 yr
  • Typically develops late in the course of illness
  • More common in women
• Manic episode
  • Distinct period of abnormally elevated, expansive, or irritable mood lasting at least 1 wk
  • Includes ≥ 3 of these symptoms (4 if mood is only irritable):
  • Inflated self-esteem or grandiosity
  • Decreased need for sleep
  • Being more talkative than usual or feeling need to keep talking
  • Flight of ideas or sense that thoughts are racing
  • Distractibility
  • Increased goal-directed activity or psychomotor agitation
  • Excessive involvement in pleasurable activities that have a high potential for painful consequences
  • About half of manic episodes include psychotic features (e.g., grandiose delusions or auditory hallucinations)
  • About a quarter of manic patients have hallucinations
• Hypomanic episode
• Distinct period of elevated, expansive, or irritable mood lasting at least 4 days
• Includes ≥ 3 symptoms of a manic episode (4 if the mood is only irritable)
• No psychotic features are present
• Mixed episode
• Major depressive episode and manic episode simultaneously within 1 wk
• Patients are dysphoric but hyperactive, agitated, and unable to sleep
  

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Differential Diagnosis

• Other psychiatric conditions
  • Schizophrenia
  • Schizoaffective disorder
    • A primary psychotic disorder in which a major depressive episode, a manic episode, or a mixed episode occurs
    • Psychotic symptoms, however, must also be present for at least 2 wk in the absence of prominent mood symptoms
  • Personality disorders
    • Certain personality disorders are characterized by chronic and pervasive rapidly fluctuating affective lability
    • Many patients with cluster B personality disorders (e.g., borderline personality disorder) may also meet DSM-IV criteria for dysthymic disorder, bipolar II disorder, or cyclothymic disorder
  • Drug abuse
    • Alcohol
    • Amphetamines
    • Hallucinogens
    • Cocaine
    • Urine or blood toxicologic screens necessary to differentiate primary mania from a substance-induced mood disorder with manic features
      • Because comorbidity is common, a positive urine drug screen does not exclude a primary bipolar disorder
  • Delirium, dementia, and medical illnesses, especially in elderly patients

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Best Tests

• Medical history and physical examination
• Detailed substance-use history
• Thorough mental status examination findings may include the following:
  • Eccentric dress, brightly colored clothing, excessive make-up, or multiple pieces of jewelry
  • Euphoria, excitement, intrusiveness, or irritability
  • Psychomotor agitation and an increase in goal-directed activity
  • Increased rate and rhythm of speech
  • Flight of ideas/racing thoughts
  • Elevated self-worth, grandiosity, mood-congruent psychotic features
• Cognitive assessment may show the following:
• Memory impairment
• Difficulties with attention and concentration
• Risk assessment for self-care and suicidality

• Urine drug screen
• Blood chemistries
• Thyroid function studies
• Syphilis serology

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Best Therapy*

• Hospitalization for acute mania
• Drug treatment for bipolar disorder
  • Combination therapy often necessary
  • Lithium: gold standard
    • Assess renal and thyroid function before initiating
    • ECG before initiating
    • Avoid NSAIDs and diuretics
    • Maintain uniform salt intake
    • Monitor serum levels periodically
    • Measure 10–12 hr after last dose
    • Measure 4–5 days after last dosage change
    • Monitor BUN, serum creatinine, TSH every 6 mo
    • Side effects: cognitive slowing, nausea, diarrhea, polyuria, polydipsia, weight gain, tremor, metallic taste in the mouth
    • Dose: lithium carbonate
      • Initial: 300 mg t.i.d. or 450 mg b.i.d.
      • Maintenance: 900–1,800 mg/day
      • Therapeutic blood level: 0.8–1.2 mEq/L
  • Anticonvulsants
  • Valproic acid or divalproex sodium: more effective for manias that are dysphoric or mixed and for rapid cycling
  • Assess CBC and liver function before starting
  • Take with food
  • Dose: initial, 250 mg b.i.d.; maintenance, 750–2,000 mg/day
  • Therapeutic blood level: 100–125 mg/L
  • Carbamazepine: approved for mania and mixed episodes
    • Assess CBC and liver function before starting
    • Patients of Chinese ancestory should be checked for HLA-B*1502 prior to initiating (dramatically increases risk for Stevens-Johnson Rxn)
    • Monitor for drug–drug interactions and autoinduction
    • Dose: initial, 100–200 mg b.i.d.; maintenance, 400–600 mg/day
    • Therapeutic blood level: 6–10 µg/ml
  • Lamotrigine: for the maintenance treatment of adults with bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy (more robust in bipolar depression than mania)
    • Dose: 25 mg/day for 2 weeks; 50 mg/day for 2 weeks; 100 mg/day for week 5; 200 mg/day for week 6
    • Slower titrations are required for patients taking carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or valproate because of risk of severe rash
  • Atypical antipsychotics
    • Risperidone
      • Dose: initial, 1–2 mg/day; maintenance, 2–6 mg/day
    • Olanzapine
      • Dose: initial, 5–10 mg/day; maintenance, 10–20 mg/day
    • Quetiapine
      • Dose: initial, 100–200 mg/day; maintenance, 400–800 mg/day
    • Ziprasidone
      • Dose: initial, 20 mg b.i.d.; maintenance, 40–80 mg b.i.d.
    • Aripiprazole
      • Dose: initial, 5–15 mg/day; maintenance, 15–30 mg/day
    • Asenapine
      • Dose initial and target, 10 mg sublingually b.i.d.
• Drug treatment for depression associated with bipolar disorder
  • Lithium for mild depression
  • Olanzapine + Fluoxetine
  • Quetiapine
  • Fluoxetine or other antidepressant with concurrent mood stabilizing agent
  • Lamotrigine
    • Dose: 25 mg/day for 2 weeks; 50 mg/day for 2 weeks; 100 mg/day for week 5; 200 mg/day for week 6
    • Slower titrations are required for patients taking carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or valproate because of risk of severe rash
• Drug treatment for psychotic symptoms associated with a manic episode
  • Antipsychotic agents (atypical or typical antipsychotics depending on patient risk profile and preference)
• Psychotherapy: useful as adjunctive treatment to improve speed of response in depressive states, increase medication adherence, and reduce risk of relapse

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Best References

Fountoulakis KN, et al: Int J Neuropsychopharmacol 11:999, 2008 [PMID: 18752718]

Youngstrom EA, et al: Bipolar Disorders 10:194, 2008 [PMID: 18199237]

Ghaemi SN, et al: Bipolar Disorders 10:117, 2008 [PMID: 18199230]

Miklowitz DJ, et al: Bipolar Disorders 11 Suppl 2:110, 2009 [PMID: 19538690]

Goodwin GM, et al: J Psychopharmacol 23:346, 2009 [PMID: 19329543]

May 2010

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Depression

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References


Definition/Key Clinical Features

• Distinguished from normal sadness and grief by severity, pervasiveness, and duration of mood disturbance and by presence of neurovegetative abnormalities and other symptoms
• Neurovegetative abnormalities
  • Sleep disturbance (most often insomnia with early-morning awakening)
  • Change in appetite (usually anorexia)
  • Decreased energy
  • Psychomotor abnormalities (slowed thinking/movement and speech or agitation)
  • Diurnal variation in mood (typically worse in morning)
• Other symptoms
  • Depressed mood (may be irritability or loss of interest)
  • Loss of enjoyment of usual activities (e.g., eating, work, sex, hobbies, time with family and friends)
  • Loss of hope
  • Diminished self-esteem
  • Difficulty concentrating
  • Poor memory
  • Ruminations and excessive or inappropriate guilt
  • Suicidal thoughts or recurrent thoughts of death
    

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Differential Diagnosis

• Most common causes of secondary depression:
  • Alcohol abuse or dependence
  • Alzheimer’s disease
  • Substance abuse or dependence
  • Parkinson’s disease
  • Serious medical illness
  • Stroke

Red Flags

• Post-MI patients: 1-yr mortality higher with depression
• Women > 67 yr: overall mortality higher with more depressive symptoms; risk of falls and fractures greater with depression
• Elderly patients: suicide is major risk in the depressed
• Adolescents and young adults 15–24 yr old: suicide is third leading cause of death

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Best Tests

• No definitive biologic marker
• Clinical observation (DSM-IV)
• Brief questionnaires
  • Two-question test
  • Center for Epidemiologic Studies Depression Questionnaire (CES-D) (15-item self-assessment)
  • Geriatric Depression Scale (GDS) (15-item self-assessment) (for patients > 60 yr)
  • Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ) (9-item self-assessment)

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Best Therapy*

Psychotherapy

• Cognitive-behavioral therapy and interpersonal therapy are effective in acute treatment of major depression and dysthymic disorder of mild to moderate severity
• Combination of psychotherapy and medication may be more effective than either alone

Electroconvulsive Therapy

• Single most effective therapy for acute treatment of serious major depression
• Often indicated for treatment of depression associated with the following
  • Medication resistance or intolerance
  • Psychotic symptoms
  • Catatonia
  • Medical illness that contraindicates drug treatment
  • Acute mania
  • Active suicidal ideation (short-term protective effect)
• Contraindicated in presence of increased cranial pressure

Antidepressants

• Selective serotonin reuptake inhibitors
  • Citalopram: 20 mg/day initially, then typically doubled in 1 wk in cases of severe or recurrent depression; up to 60 mg/day in event of nonresponse
  • Dose: 40 mg/day (20–60 mg/day)
  • Escitalopram: 10 mg/day initially
  • Dose: 10 mg/day (10–30 mg/day)
  • Fluoxetine: 20 mg/day q.a.m. initially; reduce to 10 mg/day for patients with side effects
    • Dose: 20 mg/day (10–80 mg/day)
  • Fluvoxamine: 50 mg/day initially, with target dosage of 150–250 mg/day
    • Dose: 200 mg/day (50-300 mg/day)
  • Paroxetine: 20 mg initially in morning or evening; 10 mg/day in elderly or patients with hepatic or renal dysfunction or in patients who do not tolerate 20 mg/day dosage; increase in 10 mg increments up to 50 mg/day in healthy adults (40 mg/day in the elderly) who do not respond after 4 wk
    • Dose: 20 mg/day (10-50 mg/day)
  • Sertraline: 50 mg/day initially, with target dosage of 100–150 mg/day in healthy adults
    • Dose: 100-150 mg/day (50-200 mg/day)
• Other New Antidepressants
  • Mirtazapine (α₂ blocker, 5-HT₂ blocker, 5-HT₃ blocker)
    • Dose: 30 mg/day
  • Bupropion SR: start treatment at 100 mg b.i.d. and increase to 100 mg t.i.d. on fourth day of treatment; may increase to maximum of 450 mg/day
    • Dose: 300-400 mg/day
  • Reboxetine: not available in U.S.
    • Dose: 8-10 mg/day
  • Nefazodone
    • Dose: 150-400 mg/day
  • Trazodone
    • Dose: 150-400 mg/day
  • Venlafaxine XR
    • Dose: 75-225 mg/day
  • Desvenlafaxine
    • Dose: 50 mg/day
  • Tricyclic antidepressants and related agents: use as second- or third-line pharmacotherapy when insufficient response to SSRI or other antidepressant; increase dosage gradually (e.g., by 25–50 mg/wk) until achieving therapeutic dose
    • Amitriptyline
      • Dose (range): 150-200 mg/day (75-300 mg/day)
    • Amoxapine
      • Dose (range): 150-200 mg/day (75-300 mg/day)
    • Clomipramine
      • Dose (range): 150-200 mg/day (75-250 mg/day)
    • Desipramine
      • Dose (range): 150-200 mg/day (75-300 mg/day)
    • Doxepine
      • Dose (range): 150-200 mg/day (75-300 mg/day)
    • Imipramine
      • Dose (range): 150-200 mg/day (75-300 mg/day)
    • Maprotiline
      • Dose (range): 150-200 mg/day (75-225 mg/day)
    • Nortriptyline: more potent than other TCAs; begin at 10-25 mg/day
      • Dose (range): 75-100 mg/day (40-150 mg/day)
    • Protriptyline: more potent than other TCAs; begin at 10-25 mg/day
      • Dose (range): 30 mg/day (15-60 mg/day)
    • Trimipramine: more potent than other TCAs; begin at 10-25 mg/day
      • Dose (range): 150-200 mg/day (75-300 mg/day)
  • Monoamine oxidase inhibitors: Patients taking nonselective MAOIs must avoid foods or meds that contain tyramine or other pressor amines; interactions with SSRIs may also occur
    • Isocarboxazid
      • Dose: 30 mg/day; range, 20-60 mg/day
    • Phenelzine: If no improvement in 3-4 wk, dosage may increase to as high as 90 mg/day.
      • Dose: 60-75 mg/day; range, 60-90 mg/day
    • Tranylcypromine
      • Dose: 30 mg/day; range, 20-90 mg/day
    • Selegiline
      • Dose: 6-12 mg once daily (patch)

Treatment-Resistant Depression

• Experienced by up to 30% of patients
• If initial antidepressant drug has been given at full therapeutic dose with no improvement after 4-6 wk, change drug
• If initial antidepressant drug has caused partial response, augment with lithium, buspirone, buproprion, or T3
• If SSRIs are ineffective, consider trying other drug classes
• Consider electroconvulsive therapy early in course of treatment
• Consider other procedural interventions such as rTMS or vagal nerve stimulator for treatment refractory patients

Pregnancy and Postpartum Depression

• Many antidepressant drugs are relatively safe for pregnant woman and fetus
• Limited courses of fluoxetine or cognitive-behavioral therapy are effective in treating postpartum depression

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Best References

Adams SM, et al: Am Fam Physician 77:785, 2008 [PMID: 18386592]

Parikh SV, et al: J Affect Disorders 117 Suppl 1:S15-25, 2009 [PMID: 19682749]

Malhi GS, et al: Acta Psychiatr Scand Suppl 439:8, 2009 [PMID: 19356154]

Acknowledgements
The authors and editors gratefully acknowledge the previous authors, Michael T. Compton, M.D., M.P.H. and Charles B. Nemeroff, M.D., Ph.D., to the development and writing of this module.

Disclosures
Jair C. Soares, M.D. has been a speaker for Lilly, AstraZeneca and BMS, has received research grants from Pfizer and Repligen and has been a consultant for Organon and Shire. Hasan A. Baloch, M.D. has no disclosures of potential conflict of interest.

* To obtain additional drug information, click on the DrugInfo tab in the left column, or click on the following link: http://search.medscape.com/drug-reference-search?queryText=

May 2010

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