AUTHOR INFORMATION	Section 1 of 9
Author Information Introduction Clinical Differentials Workup Treatment Follow-up Miscellaneous Bibliography

Author: Maureen C Nash, MD, Staff Psychiatrist and Internist, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital Coauthor(s): Bradley Watts

Maureen C Nash, MD, is a member of the following medical societies: American Association for Geriatric Psychiatry, American College of Physicians, American Psychiatric Association, and Association of Women Psychiatrists

Editor(s): Sarah C Aronson, MD, Associate Professor, Departments of Psychiatry and Medicine, Case School of Medicine/University Hospitals of Cleveland; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; David Bienenfeld, MD, Vice-Chair, Program Director, Professor, Department of Psychiatry, Wright State University School of Medicine; Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry, Assistant Professor, Department of Medicine, Froedtert Hospital, Medical College of Wisconsin; and Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA

Disclosure

	INTRODUCTION	Section 2 of 9
Author Information Introduction Clinical Differentials Workup Treatment Follow-up Miscellaneous Bibliography

Background: Drug-induced depression entered the medical lexicon when the association between reserpine and depression was noted in the 1950s. Although a number of cases have been reported over the years, few controlled studies of the phenomenon have been conducted.

The essential feature of drug-induced depression is the onset of symptoms in the context of drug use, intoxication, or withdrawal. Full criteria for a depressive spectrum disorder need not be met for a diagnosis.

Several categories of medications have been implicated in the onset of drug-induced depression. Hypotheses regarding the etiology of drug-induced depression are based on the known properties of these medications and their potential correlation with current neurophysiologic models of affective disorders. These include models of tryptophan depletion, catecholamine depletion, and alterations in the hypothalamic-pituitary-adrenal axis (see Pathophysiology). Notably, drug-induced depression is more likely to occur in individuals with risk factors for major depressive disorder (MDD) or dysthymia (an illness characterized by chronic low levels of depression), such as a personal or family history of depression.

Pathophysiology: The current psychiatric nosology uses the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic category of depressed-type, substance-induced mood disorder to name this disorder; however, no studies have used this diagnosis from the DSM-IV-TR as a frame of reference. The DSM-IV-TR describes the disorder but does not contain prevalence or incidence data. One study used the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) category of organic mood disorder, depressed type, implicating drugs as the probable etiology in 10% of patients. This study did not list the particular medications linked to the organic depression.

Researchers have noted several etiologic factors in depressive disorders. The amine-depleting effect of antihypertensive medications and the amine-restoring effect of the first successful antidepressants led to the catecholamine-deficit hypothesis. Endocrine factors have been correlated with depressive symptoms. Hypothyroidism may result in clinical depression, which may explain the efficacy of using triiodothyronine to augment antidepressants. Certainly, the fact that numerous T3 receptors are present throughout the brain is well known. Hypercortisolism and overreactivity of the hypothalamic-pituitary-adrenal axis have been implicated in patients with depressive illness, which may explain the clinically observable depressive, manic, and psychotic complications of steroid usage.

Many common symptoms of depression (eg, fatigue, sleep changes, GI problems) arise as adverse effects of medication. This similarity of symptoms makes linking a depressive spectrum disorder to a medication difficult; however, the temporal relationship of the medication to the development of the depressive symptoms is essential to diagnosing drug-induced depression.

The development of depressive symptoms related to a medication is more likely in a person who has a predisposition to depression.

Frequency:

• In the US: The DSM-IV describes drug-induced depression but contains no prevalence or incidence data. Depressive spectrum illness, including MDD and dysthymia, is common. According to the DSM-IV, the lifetime risk for MDD in community samples has ranged from 10-25% for women and from 5-12% for men. At any given time, the estimates range from 5-9% for women and from 2-3% for men. Dysthymia, which is sometimes called minor depression, has a lifetime prevalence of 6% and a point prevalence of 3%.

• Internationally: According to the World Health Organization, depression is the leading cause of disability worldwide.

Mortality/Morbidity: No evidence suggests that the morbidity and mortality from drug-induced depression are different from those of any depressive illness. A very few specific medications, including interferon, amantadine, isocarboxazid, and levetiracetam, have been implicated in suicide. No mechanisms of action have been proposed to explain these correlations.

In 2004, the US Food and Drug Administration (FDA), following the lead of the Medicines and Healthcare products Regulatory Agency (drug-monitoring agency in the United Kingdom), issued a warning about suicide in children and adolescents and certain antidepressants. In 2005, the FDA issued a similar warning regarding antidepressant use and suicidal behavior in adults. The 2004 and 2005 warnings are more controversial than a previous warning about interferon. Currently, premarketing and postmarketing data related to antidepressant use are being reviewed; however, no evidence has been found that suggests antidepressant use is associated with an increased risk of completed suicide in children, adolescents, or adults. No mechanism of action has been implicated linking suicide to antidepressant use. Multiple expert groups, including the Food and Drug Administration's Psychopharmacologic Drug Committee, are studying this issue.

Depressive illness is associated with a lifetime prevalence of suicide of approximately 15%. Estimates of lost wages and productivity due to depression are estimated at millions of dollars annually.

Sex: Although drug-induced depression has not been well studied, some evidence indicates that it is more likely to occur in women than in men. According to the DSM-IV, the lifetime risk for MDD in community samples has ranged from 10-25% in women and from 5-12% in men. At any given time, the estimates range from 5-9% in women and from 2-3% in men.

Age: No evidence suggests that the incidence or prevalence of depressive adverse effects of medications differs based on age. However, geriatric patients are more likely to take medications and therefore have a greater exposure to the risks of adverse drug-related effects such as depression.

	CLINICAL	Section 3 of 9
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History: As with many illnesses, a complete history helps confirm the diagnosis of an episode of drug-induced depression. The onset of symptoms must coincide with the administration of the medication, intoxication by the medication, or withdrawal of the medication. Quick resolution of symptoms (eg, days or weeks after cessation of the medication) is presumptive evidence that the drug has induced the depression. The DSM-IV designates the following characteristics as symptoms of drug-induced depression:

• A prominent and persistent mood disturbance dominates the clinical picture and is characterized by either or both of the following:

• The patient exhibits a depressed mood or a markedly diminished interest in all or most activities.

• The patient experiences elevated, expansive, or irritable moods.

• Evidence from the history, physical examination, or laboratory findings reflects the following:

• The mood disturbance dominating the clinical picture developed during or within a month of substance intoxication or withdrawal.

• Medication use is etiologically related to the disturbance.

• The disturbance is not better accounted for by a mood disorder that is not substance induced. The following symptoms indicate that a substance is not inducing the mood disorder:

• Symptoms precede the onset of the substance or medication use.

• Symptoms persist for a substantial period (ie, approximately 1 mo) after the cessation of acute withdrawal or severe intoxication, or symptoms are substantially in excess of what would be expected given the type or amount of the substance used or the duration of use.

• Evidence suggests the existence of an independent non–substance-induced mood disorder (eg, history of recurrent major depressive episodes).

Physical:

• The examination should exclude organic causes of mood changes.

• Many illnesses may cause depressive symptoms. Some of these include the following:

• HIV Infection and AIDS

• Systemic Lupus Erythematosus

• Hypothyroidism

• Delirium

• Dementia

• Parkinson Disease

• Hypercortisolism

Causes:

• Drugs with evidence of a link to depression include the following:

• Flunarizine - Epidemiologic survey, adverse effect noted in several clinical trials

• Corticosteroids - Prospective cohort study, cross-sectional medicine patients

• Digoxin - Prospective cohort study, cross-sectional epidemiologic study

• Minor tranquilizers - Prospective cohort study

• Sedatives - Prospective cohort study

• Interferon beta-1b, peginterferon alfa-2b - Very significantly increased incidence in randomized controlled trials (RCTs), although trials were not designed to study this as an endpoint

• Amantadine - Increased incidence in RCTs, although trials were not designed to study this as an endpoint

• Isocarboxazid - Increased incidence in RCTs, although trials were not designed to study this as an endpoint

• Levetiracetam - Increased incidence in RCTs, although trials were not designed to study this as an endpoint

• Drugs with weak or conflicting evidence of a link to depression include the following:

• ACE inhibitors - Prescription sequence symmetry analysis

• Propranolol and nadolol (ie, lipophilic beta-blockers) - Meta-analysis of antihypertensive clinical trials, record linkage studies

• Norplant - Series of case reports

• Leuprolide - Case series

• Isotretinoin - Case reports

• Antidepressants (ie, citalopram, bupropion, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, sertraline, venlafaxine) - Case reports

• Drugs or diet with evidence against a link to depression include the following:

• Diuretics, chlorthalidone - Prospective RCT (one multicenter)

• Cimetidine, ranitidine - Case control, marketing surveillance

• Low-cholesterol diet - Cross-sectional data

• Oral contraceptives - Cross-sectional data, case control (The evidence that oral contraceptive pills cause mood symptoms is conflicting. The more recent and complete studies suggest no correlation.)

• Simvastatin - Cross-sectional data

• Levodopa - Review of the literature of all major medications and behavioral complications used in treating Parkinson disease

	DIFFERENTIALS	Section 4 of 9
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Adjustment Disorders
Alcoholism
Anxiety Disorders
Dysthymic Disorder
Hypothyroidism

Other Problems to be Considered:

Adrenal Insufficiency and Adrenal Crisis
Delirium, Dementia, and Amnesia