1. At least one of the following three abnormal moods which significantly interfered with the person's life:
   1. Abnormal depressed mood most of the day, nearly every day, for at least 2 weeks.

   2. Abnormal loss of all interest and pleasure most of the day, nearly every day, for at least 2 weeks.

   3. If 18 or younger, abnormal irritable mood most of the day, nearly every day, for at least 2 weeks.

2. At least five of the following symptoms have been present during the same 2 week depressed period.
   1. Abnormal depressed mood irritable mood if a child or adolescent [as defined in criterion A].

   2. Abnormal loss of all interest and pleasure [as defined in criterion A2].

   3. Appetite or weight disturbance, either:
      • Abnormal weight loss (when not dieting) or decrease in appetite.
      • Abnormal weight gain or increase in appetite.

   4. Sleep disturbance, either abnormal insomnia or abnormal hypersomnia.

   5. Activity disturbance, either abnormal agitation or abnormal slowing (observable by others).

   6. Abnormal fatigue or loss of energy.

   7. Abnormal self-reproach or inappropriate guilt.

   8. Abnormal poor concentration or indecisiveness.

   9. Abnormal morbid thoughts of death (not just fear of dying) or suicide.

3. The symptoms are not due to a mood-incongruent psychosis.

4. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode.

5. The symptoms are not due to physical illness, alcohol, medication, or street drugs

6. The symptoms are not due to normal bereavement

Essential Features

By definition, Major Depressive Disorder cannot be due to:

• Physical illness, alcohol, medication, or street drug use.
• Normal bereavement.
• Bipolar Disorder
• Mood-incongruent psychosis (e.g., Schizoaffective Disorder, Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified).

Major Depressive Disorder causes the following mood symptoms:

• Abnormal depressed mood:
  • Sadness is usually a normal reaction to loss. However, in Major Depressive Disorder, sadness is abnormal because it:
    • Persists continuously for at least 2 weeks.
    • Causes marked functional impairment.
    • Causes disabling physical symptoms (e.g., disturbances in sleep, appetite, weight, energy, and psychomotor activity).
    • Causes disabling psychological symptoms (e.g., apathy, morbid preoccupation with worthlessness, suicidal ideation, or psychotic symptoms).
  • The sadness in this disorder is often described as a depressed, hopeless, discouraged, "down in the dumps," "blah," or empty. This sadness may be denied at first. Many complain of bodily aches and pains, rather than admitting to their true feelings of sadness.

• Abnormal loss of interest and pleasure mood:
  • The loss of interest and pleasure in this disorder is a reduced capacity to experience pleasure which in its most extreme form is called anhedonia.
  • The resulting lack of motivation can be quite crippling.

• Abnormal irritable mood:
  • This disorder may present primarily with irritable, rather than depressed or apathetic mood. This is not officially recognized yet for adults, but it is recognized for children and adolescents.
  • Unfortunately, irritable depressed individuals often alienate their loved ones with their cranky mood and constant criticisms.

• Abnormal appetite:
  • Most depressed patients experience loss of appetite and weight loss. The opposite, excessive eating and weight gain, occurs in a minority of depressed patients. Changes in weight can be significant.

• Abnormal sleep:
  • Most depressed patients experience difficulty falling asleep, frequent awakenings during the night or very early morning awakening. The opposite, excessive sleeping, occurs in a minority of depressed patients.

• Fatigue or loss of energy:
  • Profound fatigue and lack of energy usually is very prominent and disabling.

• Agitation or slowing:
  • Psychomotor retardation (an actual physical slowing of speech, movement and thinking) or psychomotor agitation (observable pacing and physical restlessness) often are present in severe Major Depressive Disorder.

• Abnormal self-reproach or inappropriate guilt:
  • This disorder usually causes a marked lowering of self-esteem and self-confidence with increased thoughts of pessimism, hopelessness, and helplessness. In the extreme, the person may feel excessively and unreasonably guilty.
  • The "negative thinking" caused by depression can become extremely dangerous as it can eventually lead to extremely self-defeating or suicidal behavior.

• Abnormal poor concentration or indecisiveness:
  • Poor concentration is often an early symptom of this disorder. The depressed person quickly becomes mentally fatigued when asked to read, study, or solve complicated problems.
  • Marked forgetfulness often accompanies this disorder. As it worsens, this memory loss can be easily mistaken for early senility (dementia).

• Abnormal morbid thoughts of death (not just fear of dying) or suicide:
  • The symptom most highly correlated with suicidal behavior in depression is hopelessness.

Associated Features and Comorbidity

• Anxiety:
  • 80 to 90% of individuals with Major Depressive Disorder also have anxiety symptoms (e.g., anxiety, obsessive preoccupations, panic attacks, phobias, and excessive health concerns).
  • Separation anxiety may be prominent in children.
  • About one third of individuals with Major Depressive Disorder also have a full-blown anxiety disorder (usually either Panic Disorder, Obsessive-Compulsive Disorder, or Social Phobia).
  • Anxiety in a person with major depression leads to a poorer response to treatment, poorer social and work function, greater likelihood of chronicity and an increased risk of suicidal behavior.

• Eating Disorders:
  • Individuals with Anorexia Nervosa and Bulimia Nervosa often develop Major Depressive Disorder.

• Psychosis:
  • Mood congruent delusions or hallucinations may accompany severe Major Depressive Disorder.

• Substance Abuse:
  • The combination of Major Depressive Disorder and substance abuse is common (especially Alcohol and Cocaine).
  • Alcohol or street drugs are often mistakenly used as a remedy for depression. However, this abuse of alcohol or street drugs actually worsens Major Depressive Disorder.
  • Depression may also be a consequence of drug or alcohol withdrawal and is commonly seen after cocaine and amphetamine use.

• Medical Illness:
  • 25% of individuals with severe, chronic medical illness (e.g., diabetes, myocardial infarction, carcinomas, stroke) develop depression.
  • About 5% of individuals initially diagnosed as having Major Depressive Disorder subsequently are found to have another medical illness which was the cause of their depression.
  • Medical conditions often causing depression are:
    • Endocrine disorders: hypothyroidism, hyperparathyroidism, Cushing's disease, and diabetes mellitus.
    • Neurological disorders: multiple sclerosis, Parkinson's disease, migraine, various forms of epilepsy, encephalitis, brain tumors.
    • Medications: many medications can cause depression, especially antihypertensive agents such as calcium channel blockers, beta blockers, analgesics and some anti-migraine medications.

Mortality

Up to 15% of patients with severe Major Depressive Disorder die by suicide. Over age 55, there is a fourfold increase in death rate.

Premorbid History

10-25% of patients with Major Depressive Disorder have preexisting Dysthymic Disorder. These "double depressions" (i.e., Dysthymia + Major Depressive Disorder) have a poorer prognosis.

Laboratory Findings

There are no laboratory findings that are diagnostic for this disorder.

Gender

Males and females are equally affected by Major Depressive Disorder prior to puberty. After puberty, this disorder is twice as common in females as in males. The highest rates for this disorder are in the 25- to 44-year-old age group.

Prevalence

The lifetime risk for Major Depressive Disorder is 10% to 25% for women and from 5% to 12% for men. At any point in time, 5% to 9% of women and 2% to 3% of men suffer from this disorder. Prevalence is unrelated to ethnicity, education, income, or marital status.

Onset And Course

• Onset:
  • Average age at onset is 25, but this disorder may begin at any age.

• Psychological stress:
  • Stress appears to play a prominent role in triggering the first 1-2 episodes of this disorder, but not in subsequent episodes.

• Duration:
  • An average episode lasts about 9 months.

• Course:
  • Course is variable. Some people have isolated episodes that are separated by many years, whereas others have clusters of episodes, and still others have increasingly frequent episodes as they grow older.
  • About 20% of individuals with this disorder have a chronic course.

Recurrence

• The risk of recurrence is about 70% at 5 year follow up and at least 80% at 8 year follow-up.

• After the first episode of Major Depressive Disorder, there is a 50%-60% chance of having a second episode, and a 5-10% chance of having a Manic Episode (i.e., developing Bipolar I Disorder). After the second episode, there is a 70% chance of having a third. After the third episode, there a 90% chance of having a fourth.

• The greater number of previous episodes is an important risk factor for recurrence.

Recovery

For patients with severe Major Depressive Disorder, 76% on antidepressant therapy recover, whereas only 18% on placebo recover. For these severely depressed patients, significantly more recover on antidepressant therapy than on interpersonal psychotherapy. For these same patients, cognitive therapy has been shown to be no more effective than placebo.

Poor Outcome

Poor outcome or chronicity in Major Depressive Disorder is associated with the following:

• Inadequate treatment
• Severe initial symptoms
• Early age of onset
• Greater number of previous episodes
• Only partial recovery after one year
• Having another severe mental disorder (e.g. Alcohol Dependency, Cocaine Dependency)
• Severe chronic medical illness
• Family dysfunction

Familial Pattern And Genetics

There is strong evidence that major depression is, in part, a genetic disorder:

• Individuals who have parents or siblings with Major Depressive Disorder have a 1.5-3 times higher risk of developing this disorder.

• The concordance for major depression in monozygotic twins is substantially higher than it is in dizygotic twins. However, the concordance in monozygotic twins is in the order of about 50%, suggesting that factors other than genetic factors are also involved.

• Children adopted away at birth from biological parents who have a depressive illness carry the same high risk as a child not adopted away, even if they are raised in a family where no depressive illness exists.

• Interestingly, families having Major Depressive Disorder have an increased risk of developing Alcoholism and Attention-Deficit Hyperactivity Disorder.

Differential Diagnosis

1. Exclude depressions due to physical illness, medications, or street drug use:
   • If due to physical illness, diagnose: Mood Disorder Due to a General Medical Condition.
   • If due to alcohol, diagnose: Alcohol-Induced Mood Disorder.
   • If due to other substance use, diagnose: Other Substance-Induced Mood Disorder.

   Organic Causes Of Severe Depression

   Illnesses:
   Organic Mood Syndromes caused by: Acquired Immune Deficiency Syndrome (AIDS), Adrenal (Cushing's or Addison's Diseases), Cancer (especially pancreatic and other GI), Cardiopulmonary disease, Dementias (including Alzheimer's Disease); Epilepsy, Fahr's Syndrome, Huntington's Disease, Hydrocephalus, Hyperaldosteronism, Infections (including HIV and neurosyphilis), Migraines, Mononucleosis, Multiple Sclerosis, Narcolepsy, Neoplasms, Parathyroid Disorders (hyper- and hypo-), Parkinson's Disease, Pneumonia (viral and bacterial), Porphyria, Postpartum, Premenstrual Syndrome, Progressive Supranuclear Palsy, Rheumatoid Arthritis, Sjogren's Arteritis, Sleep Apnea, Stroke, Systemic Lupus Erythematosus, Temporal Arteritis, Trauma, Thyroid Disorders (hypothyroid and "apathetic" hyperthyroidism), Tuberculosis, Uremia (and other renal diseases), Vitamin Deficiencies (B12, C, folate, niacin, thiamine), Wilson's Disease.

   Drugs:
   Acetazolamine, Alphamethyldopa, Amantadine, Amphetamines, Ampicillin, Azathioprine (AZT), 6-Azauridine, Baclofen, Beta Blockers, Bethanidine, Bleomycin, Bromocriptine, C-Asparaginase, Carbamazepine, Choline, Cimetidine, Clonidine, Clycloserin, Cocaine, Corticosteroids (including ACTH), Cyproheptadine, Danazol, Digitalis, Diphenoxylate, Disulfiram, Ethionamide, Fenfluramine, Griseofulvin, Guanethidine, Hydralazine, Ibuprofen, Indomethacin, Lidocaine, Levodopa, Methoserpidine, Methysergide, Metronidazole, Nalidixic Acid, Neuroleptics (butyrophenones, phenothiazines, oxyindoles), Nitrofurantoin, Opiates, Oral Contraceptives, Phenacetin, Phenytoin, Prazosin, Prednisone, Procainamide, Procyclidine, Quanabenzacetate, Rescinnamine, Reserpine, Sedative/Hypnotics (barbiturates, benzodiazepines, chloral hydrate), Streptomycin, Sulfamethoxazole, Sulfonamides, Tetrabenazine, Tetracycline, Triamcinolone, Trimethoprim, Veratrum, Vincristine.

2. Exclude depressions having a previous history of elevated, expansive, or euphoric mood:
   • If previous history of a Manic Episode, diagnose: Bipolar I Disorder.
   • If previous history of recurrent Major Depressive Episodes and at least one Hypomanic Episode, diagnose: Bipolar II Disorder.
   • If previous history of recurrent Hypomanic Episodes and brief, mild depressive episodes (milder than Major Depressive Episodes), diagnose: Cyclothymic Disorder.

3. Exclude depressions that merely represent normal bereavement, instead diagnose: Uncomplicated Bereavement.

4. Exclude depressions associated with mood-incongruent psychosis:
   • If previous history of at least 2 weeks of delusions or hallucinations occurring in the absence of prominent mood symptoms, diagnose either: Schizoaffective Disorder, Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified.

5. Exclude mild depressions:
   • If only mild depression present for most of past 2 years (or 1 year in children), diagnose: Dysthymic Disorder.
   • If only brief mild depression clearly triggered by stress, diagnose: Adjustment Disorder with Depressed Mood, or Adjustment Disorder with Mixed Anxiety and Depressed Mood.
   • If mild depression is clinically significant, but does not meet the criteria for any of the previously described disorders, diagnose: Depressive Disorder Not Otherwise Specified.

6. In the elderly, it is often difficult to distinguish between early dementia or Major Depressive Disorder:
   • If there is a premorbid history of declining cognitive function in the absence of severe depression, diagnose: Dementia.
   • If there was a relatively normal premorbid state and somewhat abrupt cognitive decline associated with severe depression, diagnose: Major Depressive Disorder.