eMedicine Specialties > Psychiatry > Addiction

Substance-Induced Mood Disorders, Depression and Mania

Maureen C Nash, MD, MS, Geriatric Psychiatrist, Tuality Forest Grove Hospital Center for Geriatric Psychiatry

Updated: Jul 23, 2008

Introduction

Background

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.

Pathophysiology

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.

Frequency

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%.

International

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 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.

Sex

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.

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.²

Clinical

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-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).

Physical

• 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
  • Hypothyroidism
  • Delirium
  • Alzheimer dementia
  • Vascular dementia
  • Parkinson Disease
  • Hypercortisolism

Causes

• 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)

Differential Diagnoses

Adjustment Disorders
Alcoholism
Anxiety Disorders
Dysthymic Disorder
Hypothyroidism

Other Problems to Be Considered

Adrenal Insufficiency and Adrenal Crisis
Delirium, Dementia, and Amnesia

Workup

Laboratory Studies

• If the patient is believed to be unreliable or if intoxication or overdose is suspected, obtain a urine or serum drug screen. Drug levels can be particularly helpful when evaluating a person who may be experiencing drug withdrawal.
• Other laboratory work is indicated for excluding any other illnesses suggested by the history and physical examination findings.
• Common screening tests include CBC count, thyrotropin test, electrolyte tests, BUN test, creatinine test, and LFTs.

Imaging Studies

• Focal neurologic signs and/or cognitive changes, an altered level of consciousness, and risk and/or history of head trauma should prompt consideration for imaging studies.
• Obtain a CT scan of the head if trauma, bleeding, normal-pressure hydrocephalus, or subdural is suspected.
• Obtain an MRI and/or magnetic resonance angiography of the head to exclude a mass if focal neurologic signs are present.

Other Tests

EEG may be used to differentiate a delirium from a mood disorder. An EEG usually does not differentiate between a delirium and a dementia.

Procedures

A lumbar puncture can exclude reversible normal pressure hydrocephalus if this is suggested by findings from the history and imaging studies.

Treatment

Medical Care

• If the substance-induced mood disorder symptoms are severe or cause significant risk of harm to the patient or others, inpatient psychiatric care needs to be considered. Specific indications for inpatient care include (1) serious suicidal ideation, which may include a plan, (2) homicidal ideation, (3) severe impairments in judgment leading to a moderate or high risk for danger to self or others, or (4) an inability to care for oneself safely. If unsure about the diagnosis, a prompt evaluation by the local emergency mental health system or a local emergency department is indicated.
• When substance-induced mood disorder is suspected, immediately discontinue the offending agent (when possible). The possibility of depressive or manic symptoms worsening if the drug is continued must be considered. However, if the patient truly has a medical or psychiatric need for the drug, consider a retrial of the medication under close supervision. 
• Regular assessment of suicide risk is mandatory in any patient with depression or mania. Other risk factors for suicide include agitation, psychosis, past suicide attempts, a family history of suicide, or recent psychiatric admission.
• If the mood symptoms do not subside within 4 weeks, consider other etiologies for the depression.
• No consensus has been reached on the initiation of treatment with medications. Watchful waiting is usually sufficient.

Consultations

If the patient is suicidal, psychosis or mania is suspected, or depressive symptoms are severe, consult a mental health professional. Patients may need intensive outpatient or inpatient mental health care until the severity of the symptoms decline.

Follow-up

Further Inpatient Care

If the patient is at risk of suicide or the symptoms are so severe that the person is unable to care for himself or herself, inpatient monitoring is indicated.

Any evidence of impaired reality testing or psychosis should lower the threshold for considering inpatient care. When patients are paranoid or having hallucinations they are much less likely to be able to communicate the extent of their symptoms.

Further Outpatient Care

Periodically monitor the patient until the mood symptoms have abated. If an abnormal mood persists, institute standard treatment for depression or mania and consider etiologies other than substance-induced mood disorders. 

Deterrence/Prevention

Idiosyncratic drug-induced depression or mania can be severe and life threatening. Cases of suicide have been reported. If a patient reports a history of mood symptoms upon exposure to a medication, avoid that medication in the future if at all possible.

Practice guidelines recommend treating with interferon-alpha for patients who develop any depressive symptoms with an SSRI antidepressant. Many clinicians also recommending prophylactic SSRI treatment for patients with a history of depression who need interferon-alpha. Patients with any history of mood symptoms who require steroid treatment may also be prophylactically treated with an antipsychotic concomitantly with the steroid treatment. This can decrease or prevent manic symptoms caused by steroids.

Complications

Potential complications include the following:

• Suicide
• Homicide: In some rare situations, a person who is depressed or manic may become homicidal. Homicidal behavior is another indication for inpatient treatment.
• Loss of work time
• Interpersonal problems
• Prolonged hospital stays

Prognosis

If a drug causes the mood disorder, removal of the offending agent usually results in total recovery to predrug functioning. The resolution of symptoms can take time but is usually less than 4 weeks. Careful monitoring is recommended until the mood symptoms resolve.

Patient Education

• Instruct patients on the following, especially if substance abuse is involved:
  • Cause: In view of the drug-induced cause of depression, the patient and the family must be made aware of the etiology of the depression. Education can prevent other episodes and allows families to monitor the patient.
  • Prognosis
  • Avoidance of offending agent
• For excellent patient education resources, visit eMedicine's Depression Center and Substance Abuse Center. Also, see eMedicine's patient education articles Depression, Suicidal Thoughts, and Substance Abuse.

Miscellaneous

Medicolegal Pitfalls

Failure to make and document a full assessment for suicide, homicide, or inability to care for self is the major risk.

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000.

2. Ganzini L, Walsh JR, Millar SB. Drug-induced depression in the aged. What can be done?. Drugs Aging. Mar-Apr 1993;3(2):147-58. [Medline].

3. Cornelius JR, Fabrega H, Mezzich J, et al. Characterizing organic mood syndrome, depressed type. Compr Psychiatry. Nov-Dec 1993;34(6):432-40. [Medline].

4. Craig TJ, van Natta PA. Medication use and depressive symptoms. N Y State J Med. Sep 1982;82(10):1439-43. [Medline].

5. Cummings JL. Behavioral complications of drug treatment of Parkinson's disease. J Am Geriatr Soc. Jul 1991;39(7):708-16. [Medline].

6. Debien C, De Chouly De Lenclave MB, Foutrein P, Bailly D. [Alpha-interferon and mental disorders]. Encephale. Jul-Aug 2001;27(4):308-17. [Medline].

7. Food and Drug Administration, Center for Drug Evaluation and Research. Antidepressant Use in Children, Adolescents, and Adults [online]. Accessed 7 July 2007. Available at http://www.fda.gov/cder/drug/antidepressants/default.htm. Accessed July 7, 2007.

8. Food and Drug Administration, Center for Drug Evaluation and Research. Endo Laboratories. Symmetrel (Amantadine Hydrochloride, USP) Tablets and Syrup [online]. Available at http://www.fda.gov/cder/drug/antivirals/influenza/symmetrellabel.pdf. Accessed August 20, 2004.

9. Food and Drug Administration, Center for Drug Evaluation and Research. Interferon beta-1b, Betaseron. Available at http://www.fda.gov/cder/foi/label/2003/ifnbchi031403LB.pdf. Accessed August 20, 2004.

10. Food and Drug Administration, Center for Drug Evaluation and Research. Keppra Consumer Information [online]. Available at http://www.fda.gov/cder/consumerinfo/druginfo/keppra.htm. Accessed August 20, 2004.

11. Food and Drug Administration, Center for Drug Evaluation and Research. Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Accutane (isotretinoin) [online]. Accessed August 20, 2004. Available at http://www.fda.gov/cder/drug/infopage/accutane/accutane_psychdisorders.htm. Accessed August 20, 2004.

12. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry. Jul 2007;164(7):1044-9. [Medline].

13. Moak DH, Anton RF, Latham PK, et al. Sertraline and cognitive behavioral therapy for depressed alcoholics: results of a placebo-controlled trial. J Clin Psychopharmacol. Dec 2003;23(6):553-62. [Medline].

14. Patten SB, Love EJ. Drug-induced depression. Psychother Psychosom. 1997;66(2):63-73. [Medline].

15. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry. Jul 2007;164(7):1029-34. [Medline].

16. Sit D. Women and bipolar disorder across the life span. J Am Med Womens Assoc. 2004;59(2):91-100. [Medline].

17. The Medical Letter. Some drugs that cause psychiatric symptoms. Med Lett Drugs Ther. Feb 13 1998;40(1020):21-4. [Medline].

Keywords

drug-induced depression, drug-induced mania, substance-induced depression, substance-induced mania, drug-related depression, organic depression, chemically induced mood disorder, depressive spectrum disorder, organic mood syndrome, depressive illnesses, suicide, suicidal ideation, depression, depressive disorder, depressive symptoms, mood disorder, mania, drug-induced bipolar disorder, substance-induced bipolar disorder

Contributor Information and Disclosures

Author

Maureen C Nash, MD, MS, Geriatric Psychiatrist, Tuality Forest Grove Hospital Center for Geriatric Psychiatry
Maureen C Nash, MD, MS is a member of the following medical societies: American Association for Geriatric Psychiatry, American College of Physicians, and American Psychiatric Association
Disclosure: Epocrates Honoraria surveys

Medical Editor

Sarah C Aronson, MD, Associate Professor, Departments of Psychiatry and Medicine, Case Western Reserve School of Medicine/University Hospitals of Cleveland
Sarah C Aronson, MD is a member of the following medical societies: American Academy of Family Physicians, American Medical Association, and American Psychiatric Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

David Bienenfeld, MD, Vice-Chair, Program Director, Professor, Department of Psychiatry, Wright State University School of Medicine
David Bienenfeld, MD is a member of the following medical societies: American Medical Association, American Psychiatric Association, and Association for Academic Psychiatry
Disclosure: Nothing to disclose.

CME Editor

Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin
Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: lilly Honoraria Speaking and teaching; Forest Labs Honoraria Speaking and teaching; AstraZeneca Honoraria Speaking and teaching; Pfizer Grant/research funds Speaking and teaching; Northstar Grant/research funds Research; Novartis Grant/research funds research; Pfizer  Speaking and teaching; Sanofi-avetis Grant/research funds research; Otsuke Grant/research funds reseach; GlaxoSmithKline Grant/research funds research

Chief Editor

Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA
Stephen Soreff, MD is a member of the following medical societies: American College of Mental Health Administration and American Psychosomatic Society
Disclosure: Nothing to disclose.

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