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A. Epidemiology [3,15]

  1. Up to 30% of the population has depressive symptoms
  2. These include unhappiness, disappointment
  3. In USA, ~14 million with major depressive disorder (MDD)
  4. Lifetime Risk of MDD
    1. Men is 5-12%
    2. Women is 10-25%
    3. 1-4% of elderly have MDD [15]
    4. UP to 10% of adults >65 years old seen in primary care have significant depression [2]
  5. Depressive Syndromes [15]
    1. Depressive symptoms: up to 30% of population; female to male 1.7:1
    2. Dysthymia: ~5% of population; female to male ~2.5:1
    3. Major Depression: 5-11% of population; female to male 2:1
    4. Bipolar Disorder: 1-4% of population; female to male 1:1
    5. Postpartum: nonpsychotic major depression 10-20% within 6 months of birth [8]

B. Symptoms [10]

  1. When symptoms become pervasive or interfere with normal function, they are pathologic
  2. Depressed mood and restricted (blunted) affect
  3. Lack of motivation
    1. Disinterest in previously enjoyable activities
    2. Psychomotor retardation or agitation
    3. Decreased Libido
  4. Decreased appetite (weight loss)
  5. Poor sleep (classically early morning awakening) or increased sleep (apathy)
  6. Severe Symptoms
    1. Paucity of speech
    2. Suicidal Ideations
    3. Attempts at suicide
    4. Identification and management of suidice risk is critical [17]

C. Risk Factors

  1. Traumatic Events
  2. Living alone
  3. History of depression
  4. Miscarriage
  5. Alcoholism
  6. Drug abuse
  7. Seasonal Affective Disorder
  8. Post-stroke [4]
  9. Post-partum (within 6 months of giving birth) [8,54]
  10. Smoking cessation can provoke a recurrence [45]
  11. Cardiovascular Disease (CVD) - both a symptom of, and contributing to CVD [26]
  12. ß-adrenergic blocker use not associated with depression [52]

D. Pathogenesis [1,14]

  1. Largely unknown
  2. Serotonin (5HT) reduction or receptor insensitivity (resistance) likely plays a role
  3. Norepinephrine (NE) underactivity also implicated
  4. Dopamine (DA) underactivity may also be involved, particularly with psychomotor slowing
  5. Alphamethylparatyrosine induced depression by depleting NE and DA [60]
  6. Deficiencies in gamma-aminobutyric acid (GABA)
  7. Hypercortisolism also implicated in depression
  8. Disordered neural circuitry in a variety of brain structures has been identified
  9. Duration of local daylight inversely related to mood in many people

E. Screening and Diagnosis [5,6]

  1. Depression screening is a critical part of primary care medicine
    1. Depression found in ~30% of typical primary care practice
    2. Screening is a standard and essential component of primary care
    3. Failure to detect depression may result in unnecessary diagnostics, treatments, suffering, and even suicide
  2. Simplified depression screening in primary care
    1. Two questions can cover depression screening about as well as more complex screens
    2. "During the past month, have you often been bothered by feeling down, depressed, or hopeless ?"
    3. During thepast month, have you been bothered by little interest or pleasure in doing things ?"
    4. This test has a fairly high false positive rate (specificity 57%)
    5. Therefore, with at least one positive answer, additional information about sleep, eating, and other aspects of life should be assessed
  3. Patient-based PRIME-MD Tool for Screening Depression [7]
    1. Primary Care Evaluation of Mental Disorders
    2. Completed by patients in primary care setting
    3. For screening depressive, anxiety, alcohol, somatoform, and eating disorders
    4. Self administered version is very effective, sensitive, and does not require clinician
    5. Based on results of PRIME-MD, clinician can focus discussion
  4. DSV-IV Criteria for Major Depression (5 or more of following for at least 2 weeks) [5]
    1. Depressed mood - most of day, every day (required)
    2. Anhedonia - markedly diminished pleasure (required)
    3. Weight Change - substantial unintended gain or loss
    4. Sleep Disturbance - insomnia or hypersomnia nearly every day
    5. Psychomotor Problems - agitation or retardation nearly every day
    6. Lack of Energy - fatigue or loss of energy nearly every day
    7. Excessive guilt - feelings of worthlessness or excessive guild nearly every day
    8. Poor Concentration - diminished ability to think or concentrate nearly every day
    9. Suicidal Ideation - recurrent thoughts of death or suicide
  5. Indications for Referral to Psychiatrist [19]
    1. Plans to commit suicide (perhaps for suicidal thoughts)
    2. Substance abuse
    3. Bipolar disorder
    4. Psychosis or psychotic features
    5. Psychotherapy needed as primary or adjunct treatment
    6. Drug-refractory: >2 failed antidepressant trials
    7. Complex medical or psychiatric comorbidities
    8. SSRI resistance in adolescents [55]
  6. Younger patients with apparent unipolar depression and psychotic features may be at very high risk for conversion to bipolar disorder [56]
  7. High prevalence in elderly, doubling after age 70-85 years, should prompt careful screen [15]

F. Differential Diagnosis

  1. Major Psychiatric Illness
    1. Psychotic Depression (for example, with schizophrenia)
    2. Bipolar Disorder - particularly when psychotic features present [56]
  2. Pseudodementia - patient may appear to have dementia simply because of depression
  3. Post-stroke depression - location of brain lesion does not affect risk of depression [4]
  4. Subcortical Dementia
  5. Anxiety Disorder with Mild Depression
  6. Dysthymia
    1. Chronic mood disorder, affects ~5% of adults
    2. Depressed mood throughout life; no specific onset
    3. Symptoms similar to, but milder than, major depression
    4. Prevalence probably incresaed in older adults
    5. Marked increased use of medical services and sedative agents
  7. Reduced libido may be due to reduced testosterone levels in men or women
  8. Post-traumatic stress disorder (PTSD)
  9. Post-partum Depression [8,54]
    1. Up to 13% of female patients following birth
    2. Occurs within 6 months of giving birth
    3. Most have history of depression or premenstrual dysphoric disorder
    4. Psychosocial stress
    5. Inadequate social support
    6. Postpartum psychosis also occurs, often with bipolar disorder

G. Treatment Overview [5,9,19,55,62]

  1. Must rule out delirium, or dementia of other cause (such as subcortical dementa)
  2. Undertreatment of depression is a major health/economic problem in USA
    1. Effects of undertreatment include increased suicide and long term suffering
    2. Interpersonal relationships suffer and occupational impairment occurs
    3. Currently available agents are safe and very effective
    4. Based on these considerations, undertreatment is malpractice
    5. Depression treatments which omit medications are less than optimally effective
    6. Combination medication and psychotherapy is probably optimal maintenance therapy
    7. Medical treatment for dysthymia in older adults provides clear benefits [12]
    8. Early intervention in elderly patients improves depression, reduces suicidal ideation [63]
  3. Types of Therapy
    1. Pharmacologic
    2. Psychotherapy
    3. Electroconvulsive Therapy (ECT)
    4. Novel therapies
    5. Nutriceuticals / Natural Products
  4. Classes of Antidepressents [13,18,66]
    1. Selective Serotonin Reuptake Inhibitors (SSRI) [61]
    2. Mixed Reuptake Inhibitors (serotonin and norepinephrine reuptake inhibitors, SNRI)
    3. Norepinephrine specific reuptake inhibitors (NRI)
    4. Atypicals (such as buproprion and buspirone)
    5. Tricyclic Antidepressants (TCA)
    6. Monoamine Oxidase Inhibitors: phenelzine (Nardil®), tranylcypromine (Parnate®)
    7. Benzodiazepines (focused on anxiety component of serious depression)
  5. First LIne Pharmacologic Treatment [9,13,66]
    1. Overall initial 60-75% response with10-25% relapsing
    2. Consistent 20-30% placebo response in most depression clinical trials
    3. Select agents by side effect profile, patient compliance, suicide risk
    4. Some increase in suicide risk within first 9 days of initiating a variety of antidepressants [64]
    5. SSRI are as effective and far better tolerated than TCAs [16,61]
    6. First Line (most patients): SSRI, SNRI, NRI
    7. Paroxetine, sertraline, fluoxetine have similar effectiveness for depression [47]
    8. In most patients, >4 weeks required for significant efficacy
    9. This delay is likely due to time for "remodelling" neuronal connections
    10. Maximal therapeutic benefit is usually achieved within 12-14 weeks on any specific agent
    11. At least 6-8 weeks should be allowed for any specific therapy before changing agent unless tolerability is major problem
  6. Considerations in Initial Drug Selection [13,16]
    1. First line therapy with SSRI, SNRI, NRI
    2. SSRIs have more rapid efficacy, fewer drug interactions, fewer side effects than TCA
    3. SSRI appear safe in lactation (sertraline, fluvoxamine preferred) [8]
    4. Increased risk of persistent pulmonary hypertension of newborn when used in pregnancy
    5. Venlafaxine (SNRI) may be more effective than SSRIs for initial therapy [57]
    6. Consider TCA for partial or non-response after TWO of these classes
    7. Patients should receive a minimum of 6 weeks prior to switching classes
    8. Paroxetine or TCA for significant sleep disturbance
    9. Bupropion is associated with least amount of sexual dysfunction
    10. If suicide is a concern, TCAs should not be given in an open setting due to overdose potential
    11. Patients who do not respond to one agent may respond to another agent within or outside of class of first agent
    12. SSRIs and TCAs had similar rates of hip fractures in elderly people
    13. Combined antidepressants with benzodiazepines for up to 2 weeks improves depression and reduces dropouts compared with antidepressants alone [46]
    14. Fluoxetine recommended in adolescents, initiated at 50% usual starting dose [33,55]
    15. Paroxetine is generally not recommended in adolescents due to concern for suicide [33,64]
    16. SSRIs and SNRIs recommended first line in elderly [15]
    17. Avoid tertiary amine TCAs, maprolitine, tranzodone, tranylcypromine in elderly [15]
    18. In mild acute depression, consider St. John's wort (not FDA approved) [25]
  7. Subsequent Pharmacologic Treatment [9,13,14]
    1. Second Line therapy includes SNRI, atypicals, NRI or adding second drug
    2. Following citalopram failure or intolerability, similar response rates were seen for second line buproprion SR, sertraline, or venlafaxine XR [48]
    3. Following citalopram suboptimal response, augmenting citalopram with either buproprion SR or buspirone improved responses; buproprion was better tolerated overall [49]
    4. Alternative Second LIne Agents: TCA, risperidone [65]
    5. MAO Inhibitors are reserved for more severe patients
  8. Duration of Therapy and Relapse
    1. Therapy continued at least >26 weeks after full remission of symptoms [5,9,13]
    2. Continued antidepressants prevent relapse by ~70% [58]
    3. Maintenance of antidepressants in patients with relapsed depression should be advocated
  9. Causes of Treatment Resistant Depression (TRD) [10]
    1. In patients with partial or nonresponse to SSRI, buproprion, nefazodone, OR venlafaxine
    2. ~45% of patients treated initially are nonresponders
    3. Causes include:
    4. Inadequate treatment: underdosing, poos adherence, drug interactions
    5. Substance abuse (concomitant)
    6. Cognitive impairment and/or neurological disease
    7. Incorrect diagnosis: psychosis, dementia
    8. Need for adjunctive psychotherapy or behavioral cognitive therapy
  10. Therapy for TRD [10,42,59]
    1. TCA should be tried when appropriate usually after SSRI and SNRI
    2. Failure to respond to one member of a class usually associated with all-class failures
    3. Combination of SSRI + TCA should be tried next
    4. SSRI + low dose of atypical antipsychotic such as olanzapine is often effective
    5. Lithium added to classic antidepressants (600-800mg/d for >1 week) increases treatment response to up to 50% in refractory depression [35]
    6. Thyroid hormone added to antidepressants of no clear benefit [10]
    7. For poor response to combination drug therapy, consider electroconvulsive therapy (ECT)
    8. Adjunctive psychotherapy or behavioral cognitive therapy
  11. Electroconvulsive Therapy (ECT) [13,39]
    1. Therapy of choice in severe depression, particularly in hospitalized patients
    2. More effective than drug therapy, particularly at higher electrical doses of ECT
    3. One or two treatments per week probably as effective as three treatments / week
    4. Bilateral ECT more effective than unipolar ECT but with greater cognitive effects
    5. Six to 9 treatments are usually required for full restoration
    6. Main side effects are cognitive with post-ictal confusional state
    7. Brief pulse stimuli or unilateral rather than bilateral electrodes reduce cognitive effects
    8. ECT is very effective during treatment, but nearly all patients relapse within 6 months of stopping treatments unless pharmacotherapy is instituted [41]
    9. ECT should be followed by continuation treatment with pharmacotherapy
    10. Pharmacotherapy with nortriptyline ± lithium has been advocated [41]
  12. Psychotherapy
    1. May be used as adjunct to pharmacological therapy
    2. Appears to be superior to placebo, but not as effective as medication monotherapy
    3. Combination psychotherapy and medication is optimal for maintenance therapy [20]
    4. In primary care setting, telephone psychotherapy for patients beginning antidepresant treatment improves patient satisfaction and clinical outcomes [34]
    5. Cognitive therapy reduced suicide attempts from 41% (control) to 24% within 18 months of initial suicide attempt [51]
  13. Decreased Libido
    1. May be due to testosterone deficiency
    2. Local application of testosterone gel to clitoris may improve libido in women
    3. Oral methyltestosterone in very low doses (0.25-1.25mg/d) appears to be safe
    4. Many of SSRIs also caused decreased libido
    5. Some of the atypical agents such as buproprion do not affect libido significantly
  14. Depression in Terminally Ill Patients [21]
    1. Should generally be treated to maximize quality of life
    2. Psychostimulants are probably first line in depressed terminally ill patients
    3. Psychostimulants include methylphenidate (Ritilan®), pemoline (Cylert®) preferred
    4. Dextroamphetamine can also be used
    5. SSRI's are also useful; sertraline and paroxitine preferred over fluoxetine
    6. TCAs, particularly secondary amines, may also be used, usually third line
    7. TCAs have multiple cardiac effects; are associated with increases in heart attacks [22]
    8. Doxepin can be used in patients with difficulty sleeping
  15. Major Depression with Pscyhotic Symptoms [13]
    1. First line is TCA + antipsychotic or SSRI (or venlafaxine) + antipsychotic
    2. Amoxepine used alone may be alternative first line
    3. If non-response without TCA, replace SSRI/NSRI with TCA+psychotic
    4. ECT should be used next
    5. Primary agent + lithium in patients with suboptimal response to ECT
  16. Smokers with a history of depression who refrain from smoking have high risk of depression relapse and should be closely followed [45]
  17. Therapy should be continued at least 26 weeks after full remission of symptoms [13]

H. Prognosis [5,13]

  1. Usually chronic, with alternating relapses and remissions
  2. About 35% of patients with single episode of major depression have another episode within one year of discontinuing therapy
  3. More than 50% of patients with single episode will have another within their lifetime
  4. Poor Prognostic Indicators
    1. Greater severity of depression
    2. Persistence of symptoms
    3. Higher number of prior episodes
    4. Psychotic depression has lower response rates
  5. Patients with multiple recurrences often develop chronic prolonged depression
  6. Antidepressant Therapy
    1. Initial response rates 60-70%
    2. Symptom free response rates in <25% however
    3. Lithium or triiodothyronine may be added to standard therapy to improve response
    4. Buspirone or ß-blockers may also have adjunctive effects
    5. Long term (1-3 year) antidepressant therapy appears to have a prophylactic effect

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