Sections

Depression

DDx

Diagnostic Considerations

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)
Sleep-related disorders

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.

Endocrine disorders

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. A 2018 study found that about 45% of people with depressive disorders and 30% of those with anxiety also have autoimmune thyroiditis (AIT).^[89]

Drug-related disorders

Pharmacologic agents can produce changes in mood. These substances include the following:

Antihypertensive medications (especially reserpine and methyldopa)
Smoking-cessation aids (eg, varenicline)
Steroids
Sex hormones and medications that affect sex hormones (eg, estrogen, progesterone, testosterone, gonadotropin-releasing hormone [GnRH] antagonists)
H2 blockers (eg, ranitidine, cimetidine)
Sedatives
Muscle relaxants
Appetite suppressants
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.^[90]

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.^[91]In contrast, pindolol may accelerate or enhance the effects of antidepressant drugs.^[92]

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.

Sleep disorders

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.

Differential Diagnoses

Workup

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Media Gallery

From 1991-2006, the suicide rate was consistently higher among males. Suicide rates declined among both sexes from 1991-2000; the rate among males decreased from 24.64 to 20.67 suicides per 100,000 and 5.48 to 4.62 suicides per 100,000 among females. From 2000-2006, however, the suicide rates gradually increased among females. Note: All rates are age-adjusted to the standard 2000 population. Rates based on less than 20 deaths are statistically unreliable. Source: Centers for Disease Control and Prevention. National suicide statistics at a glance: Trends in suicide rates among persons ages 10 years and older, by sex, United States, 1991-2006. Available at: http://www.cdc.gov/violenceprevention/suicide/statistics/trends01.html. Accessed: May 5, 2010.
Geriatric Depression Scale.
Geriatric Depression Scale-Short.
Hamilton Depression Scale.
Center for Epidemiologic Studies Depression Scale.
Cornell Scale for Depression in Dementia.
Suicide rate by age and gender. 2004 data compiled from CDC. The mean suicide rate for the entire population was 12.8/100,000/year.
Depression in the US Household Population, 2009–2012. Courtesy of National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC).
12-month Prevalence of Major Depressive Episode Among US Adults, 2015. Courtesy of National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC).

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Table.

level of support	Therapy
Efficacious and specific	Interpersonal psychotherapy (IPT)
	Cognitive behavior therapy (CBT)
	Problem-solving therapy (PST)
	Behavioral activation (BA)/contingency management
Possibly efficacious	Dynamic psychotherapy
	Cognitive behavioral analysis system for psychotherapy (CBASP)
	Emotion-focused therapy (EFT)

Table.

level of support	Therapy
Efficacious and specific	Prior CBT to prevent relapse
Efficacious	Mindfulness-based cognitive therapy (MBCT) to prevent relapse/recurrence
Possibly efficacious	Prior dynamic psychotherapy to prevent recurrence
	Maintenance IPT to prevent recurrence
	Continuation cognitive therapy (CT) to prevent relapse/recurrence
	Maintenance CBASP to prevent recurrence
	EFT to prevent relapse

Table 1. Treatment Response Over Time in the Treatment of Adolescents with Depression Study

Treatment	Response Rate (%)
	Week 12	Week 18	Week 36
Fluoxetine	62	69	81
Cognitive-behavioral therapy (CBT)	48	65	81
Fluoxetine plus CBT	73	85	86

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Author

Jerry L Halverson, MD Medical Director of Rogers Memorial Hospital at Oconomowoc; Voluntary Clinical Assistant Professor, Department of Psychiatry, University of Wisconsin School of Medicine and Public Health; Clinical Assistant Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Medical College of Wisconsin

Jerry L Halverson, MD is a member of the following medical societies: American College of Psychiatrists, American Medical Association, American Psychiatric Association

Disclosure: Nothing to disclose.

Coauthor(s)

Ravinder N Bhalla, MD Assistant Clinical Professor of Child Psychiatry, Rutgers New Jersey Medical School; Medical Director, Mental Health Clinic of Passaic; Consulting Staff, Christian Health Care Center

Ravinder N Bhalla, MD is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry

Disclosure: Received income in an amount equal to or greater than $250 from: Allergen.

Pascale Moraille-Bhalla, MD Medical Director, Outpatient Clinic of Hoboken University Medical Center; Staff Psychiatrist, Mental Health Clinic of Passaic

Pascale Moraille-Bhalla, MD is a member of the following medical societies: American Psychiatric Association

Disclosure: Nothing to disclose.

Louise B Andrew, MD, JD Medical-Legal, Risk Management and Trial Consultant, Litigation Stress Counselor

Louise B Andrew, MD, JD is a member of the following medical societies: American Association of Women Emergency Physicians, American College of Emergency Physicians, American Medical Association

Disclosure: Nothing to disclose.

Rachel C Leonard, PhD Clinical Director, Rogers Behavioral Health

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

David Bienenfeld, MD Professor, Departments of Psychiatry and Geriatric Medicine, Wright State University, Boonshoft School of Medicine

David Bienenfeld, MD is a member of the following medical societies: American Medical Association, American Psychiatric Association, Association for Academic Psychiatry

Disclosure: Nothing to disclose.

Acknowledgements

Iqbal Ahmed, MBBS, FRCPsych (UK) Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical Professor of Psychiatry, Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine

Iqbal Ahmed, MBBS, FRCPsych (UK) is a member of the following medical societies: Academy of Psychosomatic Medicine, American Association for Geriatric Psychiatry, American Neuropsychiatric Association, American Psychiatric Association, American Society of Clinical Psychopharmacology, and Royal College of Psychiatrists

Disclosure: Nothing to disclose.

Sarah C Aronson, MD Associate Professor, Departments of Psychiatry and Medicine, Case Western Reserve School of Medicine/University Hospitals of Cleveland

Disclosure: Nothing to disclose.

Barry I Liskow, MD Professor of Psychiatry, Vice Chairman, Psychiatry Department, Director, Psychiatric Residency Program, University of Kansas School of Medicine; Director, Psychiatric Outpatient Clinic, The University of Kansas Medical Center

Disclosure: Nothing to disclose.

Mohammed A Memon, MD Chairman and Attending Geriatric Psychiatrist, Department of Psychiatry, Spartanburg Regional Medical Center

Mohammed A Memon, MD is a member of the following medical societies: American Association for Geriatric Psychiatry, American Medical Association, and American Psychiatric Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Art Walaszek, MD Associate Professor of Psychiatry, Residency Training Director, Department of Psychiatry, University of Wisconsin School of Medicine and Public Health; Consulting Staff, University of Wisconsin Hospital and Clinics, Meriter Hospital

Art Walaszek, MD is a member of the following medical societies: American Association for Geriatric Psychiatry, American Medical Association, American Psychiatric Association, and Association for Academic Psychiatry

Disclosure: Terra Nova Learning Systems, Inc. Consulting fee Consulting; Wisconsin Psychiatric Association Honoraria Speaking and teaching; Care Wisconsin, Inc. Honoraria Speaking and teaching