Substance-Induced Mood Disorders: Depression and Mania ?>

Substance-Induced Mood Disorders: Depression and Mania

Substance-Induced Mood Disorders: Depression and Mania


Drug-induced depression entered the medical lexicon when the association between reserpine and depression was noted in the 1950s. Since that time there have been numerous reports of drug-induced mood disorders. Despite the number of cases that have been reported over the years, few controlled studies of the phenomenon have been conducted.

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

Several categories of medications have been implicated in the onset of drug-induced depression or mania. Hypotheses regarding the etiology of drug-induced mood disorders 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 mood disorder is more likely to occur in individuals with risk factors for major depressive disorder (MDD), dysthymia (an illness characterized by chronic low levels of depression), or bipolar disorder (mania often with depressive episodes). One of the most common risk factors is a personal or family history of a mood disorder or a substance disorder.

The current psychiatric nosology uses the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)1 diagnostic category of 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, implicating drugs as the probable etiology in 10% of patients. This study did not list the particular medications linked to the organic mood disorder.

Researchers have noted several etiologic factors in mood 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. Hyperthyroidism may result in clinical mania. 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 mood disorders, which may explain the clinically observable depressive, manic, and psychotic complications of steroid usage. See also, Causes.

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 substance-induced depression. Similarily, many symptoms of mania (eg, inattention, insomnia, excess motor movements) occur as adverse drug reactions. The temporal relationship of using or withdrawing from the medication and the mood symptoms is key to arriving at this diagnosis.

The development of mood symptoms related to a medication is more likely in a person who has a predisposition to a mood disorder.
United States

The DSM-IV-TR describes drug-induced mood disorders but contains no prevalence or incidence data. Depressive spectrum illness, including MDD and dysthymia, is common. Mania and hypomania are less common than depression but likely are more common than schizophrenia.

According to the DSM-IV-TR, 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%.

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

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 increased risk for suicidal behavior in children and adolescents using antidepressants. This warning has been updated several times, most recently in May 2007. Increased suicidal thinking and behavior in children and adolescents up to age 24 years has been linked to antidepressants during the first 2 months of use. Decreased suicidal thinking and behavior in adults older than 65 years has been linked to antidepressants in the first 2 months of use.

Since this black box warning has been added, the adolescent suicide rate has increased for the first time since the early 1990s. Two randomized controlled studies have shown that the risk of attempted and competed suicide attempts is highest prior to treatment and decreases in a linear fashion after treatment (either antidepressant medication or psychotherapy).

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. However, the recommendation for close monitoring of patients who have recently been started on treatment for depression is quite sound and is likely to decrease the risk for completed suicide.

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


Although drug-induced mood disorder 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-TR, 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.

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.2

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-TR designates the following characteristics as symptoms of substance-induced mood disorders:

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).
A mental status examination should be performed.
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
Alzheimer dementia
Vascular dementia
Parkinson Disease
Drugs with evidence of a link to depression or mania 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 or mania 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 or mania 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 (see Parkinson Disease Dementia)

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