Best Dx/Best Rx: Bipolar Disorder and Depression

Michael T. Compton, M.D., M.P.H.

Charles B. Nemeroff, M.D., Ph.D.
Emory University School of Medicine

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):
- 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

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 and psychotic symptoms are 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

Best Tests

Thorough Medical and Psychiatric Evaluation

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

Laboratory Tests

Urine drug screen
Blood chemistries
Thyroid function studies
Syphilis serology

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
  - 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
  - Cost/mo: $38
- Anticonvulsants
Drug treatment for depression associated with bipolar disorder
Drug treatment for psychotic symptoms associated with a manic episode
Psychotherapy: useful as adjunctive treatment

Best References

American Psychiatric Association: Am J Psychiatry 159(suppl):1, 2002 [PMID 11958165]

Bearden CE, et al: Bipolar Disorders 3:106, 2001 [PMID 11465675]

Bowden CL: J Clin Psychiatry 66(suppl 1):3, 2005 [PMID 15693745]

De Leon OA: Harv Rev Psychiatry 9:209, 2001 [PMID 11553525]

January 2007

Depression

Michael T. Compton, M.D., M.P.H.
Emory University School of Medicine

Charles B. Nemeroff, M.D., Ph.D.
Emory University School of Medicine

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

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

Best Tests

No definitive biologic marker
Clinical observation (DSM-IV)
Brief questionnaires
- Two-question test
- Center for Epidemiologic Studies Depression Questionnaire (CES-D) (10-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) (nine-item self-assessment)

Best Therapy

Psychotherapy

Cognitive-behavioral therapy 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)
  - Cost/mo: $195
- Escitalopram: 10 mg/day initially
  - Dose: 10 mg/day (10–30 mg/day)
  - Cost/mo: $176
- 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)
  - Cost/mo: $92
- Fluvoxamine: 50 mg/day initially, with target dosage of 150–250 mg/day
  - Dose: 200 mg/day (50-300 mg/day)
  - Cost/mo: $176
- 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)
  - Cost/mo: $143
- 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)
  - Cost/mo: $148
Other New Antidepressants
- Mirtazapine (α₂ blocker, 5-HT₂ blocker, 5-HT₃ blocker)
  - Dose: 30 mg/day
  - Cost/mo: $43
- 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
  - Cost/mo: $214
- Reboxetine: not available in U.S.
  - Dose: 8-10 mg/day
- Nefazodone
  - Dose: 150-400 mg/day
  - Cost/mo: $46
- Trazodone
  - Dose: 150-400 mg/day
  - Cost/mo: $19
- Venlafaxine XR
  - Dose: 75-225 mg/day
  - Cost/mo: $185
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)
  - Cost/mo: $7
- Amoxapine
  - Dose (range): 150-200 mg/day (75-300 mg/day)
  - Cost/mo: $91
- Clomipramine
  - Dose (range): 150-200 mg/day (75-250 mg/day)
  - Cost/mo: $81
- Desipramine
  - Dose (range): 150-200 mg/day (75-300 mg/day)
  - Cost/mo: $44
- Doxepine
  - Dose (range): 150-200 mg/day (75-300 mg/day)
  - Cost/mo: $20
- Imipramine
  - Dose (range): 150-200 mg/day (75-300 mg/day)
  - Cost/mo: $40
- Maprotiline
  - Dose (range): 150-200 mg/day (75-225 mg/day)
  - Cost/mo: $50
- Nortriptyline: more potent than other TCAs; begin at 10-25 mg/day
  - Dose (range): 75-100 mg/day (40-150 mg/day)
  - Cost/mo: $26
- Protriptyline: more potent than other TCAs; begin at 10-25 mg/day
  - Dose (range): 30 mg/day (15-60 mg/day)
  - Cost/mo: $235
- Trimipramine: more potent than other TCAs; begin at 10-25 mg/day
  - Dose (range): 150-200 mg/day (75-300 mg/day)
  - Cost/mo: $171
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
  - Cost/mo: $128
- 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
  - Cost/mo: $210

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, 300 mg t.i.d.
If SSRIs are ineffective, alternative is to add bupropion, 150-300 mg/day, or another newer agent, or TCA
Consider electroconvulsive therapy early in course of treatment

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

Best References

Davis: Essent Psychopharmacol 2:309, 1998

Keller, et al: JAMA 280:1665, 1998

Silverstone, et al: J Clin Psychiatry 60:22, 1999

October 2004

Michael T. Compton, M.D., M.P.H, has received research grants from the Emory Medical Care Foundation and has been a consultant for AstraZeneca and Medscape. Charles B. Nemeroff, M.D., Ph.D., holds stock in Corcept Therapeutics, Inc. and Neurocrine Biosciences, Inc., and has received grants for clinical research from, served as consultant for, or been a member of the speakers’ bureaus of the following companies and organizations: Abbott Laboratories; Acadia Pharmaceuticals, Inc.; the American Foundation for Suicide Prevention; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Co.; Corcept Therapeutics, Inc.; Cypress Bioscience, Inc.; Cyberonics, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Merck & Co., Inc.; the National Alliance for Research on Schizophrenia and Depression; the National Institute of Mental Health; Neurocrine Biosciences, Inc.; Novartis Pharmaceuticals Corp.; Organon International, Inc.; Otsuka America, Ltd.; Pfizer, Inc.; Sanofi-Aventis; SCIREX; Somerset Pharmaceuticals, Inc.; Stanley Foundation/NAMI Research Institute; and Wyeth.