For a diagnosis of MDD to be considered, a patient must have five or more of the symptoms or signs listed in Box 1, and at least one of those symptoms must be either depressed mood or loss of interest. These symptoms must be present most of the time nearly every day for a period of 2 or more weeks.14 The well-known mnemonic SIG: E CAPS, developed by Carey Gross, MD, can be used to recall these important signs and symptoms (Box 2).

Box 1. Signs and Symptoms of a Major Depressive Episode

  • Depressed or sad mood*
  • Markedly diminished interest or pleasure in all or almost all activities, especially those the individual normally enjoys*
  • Sleep disturbance (insomnia or hypersomnia)
  • Feeling of worthlessness, or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick, but rather a firmly held conviction that might, in some instances, be considered delusional)
  • Fatigue or loss of energy
  • Indecisiveness, or diminished ability to think or concentrate
  • A change in appetite (typically decreased, but can be increased in atypical depression), or a significant weight change (>5% of body weight) when not intentionally trying to lose or gain weight
  • Psychomotor agitation or retardation nearly every day
  • Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, a specific plan for committing suicide, or a suicide attempt

*One or the other of these must be present for a diagnosis of major depressive episode.

Adapted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text rev. Washington, DC, American Psychiatric Association, 2000.

Box 2. Mnemonic Used for Diagnosis of Major Depressive Episode: SIG: E CAPS*

S Sleep disturbance. Typically, difficulty staying asleep; less often, difficulty falling asleep
I Interest, pleasure, or enthusiasm for usual activities is diminished
G Guilt, self-doubt, or loss of self-esteem that is excessive or unwarranted
E Energy level is diminished
C Concentration (or attention span) is poor or worse than usual

Appetite is impaired. Typically, it is diminished and associated with weight loss; in some cases, the patient overeats and gains weight
P Psychomotor activity is abnormal. Typically, the patient moves and thinks more slowly; some patients, especially the elderly, can be more restless, explosive, or agitated
S Suicidal thoughts, hopelessness, or thoughts that the patient (and often others) would be better off if the patient were dead

*Signatura (label or let it be printed) for energy capsules.

Adapted from Carey Gross, MD

A common error is to regard depressive symptoms as an understandable reaction to grave or disabling medical illness. Neither the severity nor meaning of a precipitating or stressful event is directly relevant to the diagnosis of an MDE. Whether or not a sufficient triggering event has occurred, the diagnosis of an MDE depends instead on the presence of a critical number of aforementioned signs and symptoms lasting a sufficient duration. If careful evaluation discloses a sufficient number and duration of signs and symptoms, then the clinician is obliged to make a diagnosis of MDE and recommend appropriate treatment regardless of the precipitating event.

MDD is diagnosed (Box 3) exclusively from information obtained at the clinical interview and mental-status examination. Collateral information from family and associates is helpful, particularly when the patient minimizes or ignores psychological features of depression. There are no laboratory findings pathognomonic of MDD. Laboratory testing is useful only to help rule out medical conditions that can mimic MDD (e.g., hypothyroidism, vitamin B12 deficiency, sleep apnea).

Box 3. Diagnostic Criteria for Major Depressive Disorder

Five or more of the 9 symptoms listed in Box 1, at least one of which is either:
  • Depressed or sad mood*
  • Markedly diminished interest or pleasure in all or almost all activities, especially those the individual normally enjoys*
  • Symptoms are present most of the day, nearly every day for at least 2 weeks
  • Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
  • Symptoms are not better accounted for by bereavement**
  • Symptoms do not meet criteria for a mixed episode

**On average, bereavement lasts 2 months or less. Grief-triggered symptoms lasting longer than 2 months suggest evolution of a major depressive episode.

†A mixed episode is defined by the presence of both depressed and manic symptoms. In addition to having depressive symptoms, the person with a mixed episode is typically irritable, explosive, labile (switches unpredictably from one emotion to another), and pressured (difficult to interrupt). A mixed episode is more consistent with a diagnosis of bipolar disorder rather than major depression and requires different treatment (see Bipolar Disorder).

Adapted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text rev. Washington, DC, American Psychiatric Association, 2000.

Symptom clustering is not the only criterion on which the diagnosis is based. The symptoms must also be present for a sufficient period (most of the time, nearly every day for at least 2 weeks) and in one way or another must be distressing or disabling.

The term major in MDD is potentially misleading because it suggests that severity or seriousness is a diagnostic criterion. In fact, MDEs are rated mild, moderate, or severe depending on what level they are distressing or disabling. An MDE can be a first and only lifetime occurrence of depression, or it can be a recurrent episode of MDD. Current protocol is to diagnose MDE as either "MDD, single episode" (DSM IV-TR, 296.20) if there is no past history of MDE, mania, or hypomania, or "MDD, recurrent" (DSM IV-TR, 296.30) if there has been at least one past MDE, and to specify whether the episode is mild, moderate, severe, or associated with psychotic features (the fifth digit of the diagnostic code is rated as 1, 2, 3, or 4, respectively).

Subtypes of MDD include seasonal, postpartum, atypical, and psychotic depressions:

Detection of an MDE in the context of debilitating medical illness is often difficult because the vegetative symptoms of depression (anorexia, insomnia, fatigue, and impaired attention) can occur as manifestations of severe medical or surgical illness itself. When the cause of these symptoms is ambiguous, the clinician is forced to rely on the presence or absence of typical psychological symptoms or behavior (e.g., crying, expressions of hopelessness or giving up, loss of motivation, excessively low self-esteem). The likelihood of MDD increases significantly when these psychological symptoms accompany the other, nonspecific vegetative symptoms.

Other data that can help confirm or support a clinician’s suspicion of MDD include past MDEs (not necessarily detected or formally treated), a family history of mood or anxiety disorders, alcoholism or suicide, and survey tools (Table 1) that screen for depression.

Table 1. Patient-Rated Screening and Case-Finding Instruments for Major Depressive Disorder

Beck Depression Inventory II* Harcourt Assessment. www.harcourtassessment.com Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiatry 1961;4:53-63.
Zung Self-Rating Depression Scale http://healthnet.umassmed.edu/ mhealth/ZungSelfRatedDepressionScale.pdf Zung WWK. A rating instrument for anxiety disorders. Psychosomatics 1971;12:371-379
PRIME-MD (self-report format)* http://www.montana.edu/wwweb/ Archives/PHQ.doc Spitzer RL, Williams JBW, Kroenke K, et al: Patient Health Questionnaire Study Group. Validity and utility of a self-report version of PRIME-MD: The PH Primary Care Study. JAMA1999;282:1737-1744.
Patient Health Questionnaire-9 http://www.phqscreeners.com/ Kroenke K, Spitzer RL, Williams JB. The PH-9: Validity of a brief depression severity measure. J Gen Int Med. 2002;16:606-613.
Shedler’s Quick PsychoDiagnostics Panel† www.digitaldiagnostics.com Shedler J, Beck A, Bensen S: Practical mental health assessment in primary care: Validity and utility of the Quick PsychoDiagnostics (QPD) panel. J Fam Practice 2000;49:614-621.

PRIME-MD, Primary Care Evaluation of Mental Disorders.

*Copyrighted material for purchase.

†These instruments provide measures of major depressive disorder as well as other behavioral disorders that are common in primary care (e.g., panic disorder, generalized anxiety disorder, eating disorders, alcohol abuse, and somatization).

Differential Diagnosis

Psychiatric diagnoses that warrant consideration when a patient presents with depressive signs and symptoms are listed in Box 4. Grief is a normal, expected response to loss or the threat of loss, and is not a diagnosis. Prolonged (unresolved) grieving, however, can become an MDE.

Adjustment disorder with depressed mood is a transient, dysfunctional, but generally self-resolving response to stress that lacks sufficient diagnostic criteria for a diagnosis of MDE. The recommended treatment for adjustment disorder with depressed mood is psychotherapy and not antidepressant medication.

Box 4. Differential Diagnosis of Major Depressive Disorder: Psychiatric Disorders

  • Bipolar disorder
  • Cyclothymia
  • Dysthymia
  • Agoraphobia
  • Generalized anxiety disorder
  • Post-traumatic stress disorder
  • Social anxiety disorder
  • Alcohol- or drug-induced mood disorder
  • Amphetamine or cocaine withdrawal
  • Hypochondriasis
  • Somatization disorder
  • Avoidant
  • Borderline
  • Histrionic
  • Narcissistic
Organic Mental
  • Delirium (hypoactive)
  • Dementias (subcortical)
  • Mild cognitive impairment
  • Adjustment disorder with depressed mood
  • Attention deficit disorder

MDD is one of a number of mood disorders including dysthymia, BPD, and cyclothymia.14 Dysthymia and cyclothymia are considered subsyndromal variants of MDD and BPD, respectively.

Dysthymia is diagnosed when chronic low-grade depressive symptoms (insufficient number and intensity to qualify as MDE) are present 50% of the time or more for 2 or more years. Dysthymia often accompanies chronic, disabling medical illness and is less responsive to antidepressant treatments than MDD. This may be explained in part by the continuing stress of enduring medical symptoms and disability, or it may be due to the ineffective coping of a patient with a personality disorder.

Bipolar disorder (BPD) is an essential consideration in the differential diagnosis of MDD. An MDE—not mania or hypomania—is the most common clinical presentation in patients with BPD. Correct identification of bipolar depression (MDE in the context of BPD) depends on eliciting a history of manic or hypomanic episodes. This can be difficult and time-consuming for even the most astute clinician. However, making the correct diagnosis has important implications for treatment selection and prognosis.

Diagnoses that resemble but by definition are not mood disorders include: adjustment disorder with depressed mood, depression secondary to a general medical condition, and substance-related mood disorder.14 Their causes are different from those of MDD, and they therefore warrant a different approach to management. In most instances, the diagnosis of adjustment disorder with depressed mood is relevant to persons who do not have a personal or family history of mood disorder. Depression secondary to a general medical condition and substance-related mood disorder imply that the MDE has been triggered by and will resolve with treatment of the underlying medical condition or chemical dependency.

Because depressive symptoms are nonspecific, both patient and primary care specialist generally feel obliged first to rule out other medical conditions (Box 5). When a full constellation of signs and symptoms that meet diagnostic criteria for an MDE is present, however, MDD should be handled as a diagnosis of inclusion rather than exclusion. Early and effective treatment with antidepressant medication need not interfere with a thorough medical workup. Moreover, a successful response to antidepressant medication could forestall unnecessary laboratory testing and repeat office visits.

Box 5. Differential Diagnosis of Major Depressive Disorder: General Medical Conditions

  • Fibromyalgia
  • Polymyalgia rheumatica
  • Adrenal insufficiency
  • Cushing’s syndrome
  • Diabetes
  • Hyperparathyroidism
  • Testosterone deficiency
  • Thyroid dysfunction
  • Infectious mononucleosis
  • Influenza
  • Tertiary syphilis
  • Tuberculosis
  • Viral hepatitis
  • Disseminated carcinomatosis
  • Pancreatic cancer
  • Dementias
  • Frontal lobe syndrome
  • Huntington’s disease
  • Mild cognitive impairment
  • Parkinson’s disease
  • Periventricular small vessel disease
  • Postconcussive syndrome
  • Sleep apneas
  • Anticholinesterases (donepezil)
  • Beta blockers (especially propranolol)
  • Corticosteroids
  • Contraceptives
  • Cyclosporine
  • H2 Blockers (cimetidine, famotidine, ranitidine)
  • Interferon
  • Methyldopa
  • Metoclopramide
  • Reserpine
  • Vincristine
  • Vinblastine
Vitamin Deficiency
  • B12
  • C
  • Folate
  • Niacin
  • Thiamine

*AIDS/HIV, acquired immunodeficiency syndrome or human immunodeficiency virus infection.

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