The differential diagnosis for depression includes a wide variety of medical disorders, such as the following:
Central nervous system diseases (eg, Parkinson disease, dementia, multiple sclerosis, neoplastic lesions)
Endocrine disorders (eg, hyperthyroidism, hypothyroidism)
Drug-related conditions (eg, cocaine abuse, side effects of some CNS depressants)
Infectious disease (eg, mononucleosis)
Related psychiatric disorders
Major depressive disorder must be differentiated from dysthymia. Patients with dysthymia present with low mood for at least 2 years as a primary symptom; they have insufficient symptoms to meet criteria for major depressive disorder. However, dysthymia may predate a depressive episode.
Misdiagnosis of bipolar disorder as recurrent unipolar depression may occur if the clinician does not identify the presence of hypomania between depressive episodes. This leads to inadequate treatment and, theoretically, could lead to a precipitation of a hypomanic, manic, or mixed episode.
Patients with anxiety disorders are at higher risk for developing comorbid depression. In such patients, it is important to identify the anxiety disorder, because affected individuals often require specific treatment approaches. Commonly encountered anxiety disorders include the following:
Generalized anxiety disorder
Patients with certain personality disorders (eg, borderline personality disorder) may present with mood changes as a prominent symptom. Remember that the presence of a personality disorder can be difficult to determine in the setting of active affective symptoms. Many depressed patients who appear labile, demanding, or pathologically dependent look dramatically different once the depressive episode has been treated adequately.
People with eating disorders also have a high rate of comorbid major depressive disorder and require specific treatment approaches. These disorders include bulimia, anorexia nervosa, and eating disorder not otherwise specified. A large percentage of individuals in this last group have binge-eating disorder.
Central nervous system disorders
Major depressive disorder does not cause focal neurologic signs. Such findings should prompt an evaluation for other organic syndromes.
A broad range of physiologic and structural CNS processes can produce changes in mood and behavior. Note that major depressive disorder can produce measurable cognitive deficits or a worsening of preexisting dementia. This decline in cognitive functioning, which on formal testing appears to arise from impaired concentration or motivation, is referred to as pseudodementia or as dementia of depression and should remit with successful treatment of the depressive episode.
Alzheimer disease and other degenerative and vascular dementias can be associated with affective symptoms, especially in the initial phases of dementia. Mood disorders are also very prominent in Parkinson disease, Huntington disease, multiple sclerosis, stroke, and seizure disorders. Neoplastic lesions of the CNS can cause changes in mood and behavior before the onset of focal neurologic signs.
Endocrinologic disorders involving the hypothalamic-pituitary-adrenal axis or thyroid are especially likely to produce changes in mood. These include Addison disease, Cushing syndrome, hyperthyroidism, hypothyroidism, prolactinomas, and hyperparathyroidism.
Pharmacologic agents can produce changes in mood. These substances include the following:
Antihypertensive medications (especially reserpine and methyldopa)
Smoking-cessation aids (eg, varenicline)
Sex hormones and medications that affect sex hormones (eg, estrogen, progesterone, testosterone, gonadotropin-releasing hormone [GnRH] antagonists)
H2 blockers (eg, ranitidine, cimetidine)
Chemotherapy agents (eg, vincristine, procarbazine, L-asparaginase, interferon, vinblastine)
Among antihypertensive agents, beta-blockers have a reputation for being strongly associated with depression. Research on this association has been somewhat contradictory, but suggests at most a minor role in this regard. For example, a review by Ko et al found no significant increased risk of depressive symptoms with beta-blockers, although there was a small but significant risk of fatigue and sexual dysfunction. 
Risk appears to vary with different beta-blockers. A study by Luijendijk in elderly patients found that highly lipid-soluble beta-blockers (mostly propranolol) were associated with depressive symptoms during the first 3 months of use.  In contrast, pindolol may accelerate or enhance the effects of antidepressant drugs. 
Case reports have suggested a possible link between calcium channel blockers and depression. The principal concern with these agents, however, is that they may cause resistance to antidepressants.
Substance use, abuse, or dependence can cause significant mood symptoms. This is especially true of alcohol, cocaine, amphetamines, cannabinoids, sedatives/hypnotics, and narcotics. Inhalant abuse should also be considered, particularly among young male patients. Other substance-related and psychiatric processes either can present with mood disturbance as the primary symptom or can occur together with major depressive disorder.
Infectious and inflammatory diseases
Infectious processes that can cause mood and behavior changes include Lyme disease, mononucleosis, human immunodeficiency virus (HIV) encephalopathy, and syphilis. Inflammatory conditions such as systemic lupus erythematosus (SLE) can produce a wide range of neuropsychiatric signs and symptoms. The likely mechanism in these cases is alterations in the blood-brain barrier and an autoimmune cerebritis.
Of the various sleep disorders, obstructive sleep apnea in particular can cause significant medical and psychiatric symptoms and is often missed as a diagnosis. Patients and, if necessary, their partners should be interviewed regarding their sleep quality, daytime sleepiness, and snoring. Obstructive sleep apnea is especially common in patients with obesity. Polysomnography can help make the diagnosis and guide treatment.
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- Physical Examination
- Major Depressive Disorder
- Depression with Anxious Distress
- Depression With Melancholic Features
- Depression With Catatonia
- Atypical Depression
- Postpartum Depression
- Seasonal Affective Disorder
- Major Depressive Disorder with Psychotic Features
- Other Specificed Depressive Disorders
- Metabolic Depression
- Cultural Influences on Expression of Depression
- Suicidal Ideation
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- Approach Considerations
- Pharmacologic Therapy for Depression
- Electroconvulsive Therapy
- Bright-Light Therapy
- Additional Therapies for Depression
- Treatment-Resistant Depression
- Pediatric Depression Treatment
- Depression During Pregnancy
- Postpartum Depression Treatment
- Diet and Activity
- Complications of Treatment for Depression
- Long-Term Monitoring
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