Substance/Medication-Induced Depressive Disorder

Substance/Medication-Induced Depressive Disorder is diagnosed when a substance (alcohol, illicit drugs, or prescribed medication) causes depressive symptoms while an individual is using the substance or during a withdrawal syndrome associated with the substance.

• In a nationally representative US adult population, the lifetime prevalence of substance/medication-induced depressive disorder is 0.26%.^[1]
• Most often, depressive symptoms has its onset within the first few weeks or 1 month of use of the substance/medication. Once the substance/medication is discontinued, the depressive symptoms usually resolve within days to weeks.

A prominent and persistent disturbance in mood that predominates in the clinical picture and is characterized by depressed mood or markedly diminished interest or pleasure in all, or almost all, activities.

There is evidence from the history, physical examination, or laboratory findings of both (1) and (2):

1. The symptoms in Criterion A developed during or soon after substance intoxication or withdrawal or after exposure to a medication.
2. The involved substance/medication is capable of producing the symptoms in Criterion A.

The disturbance is not better explained by a depressive disorder that is not substance/medication-induced. Such evidence of an independent depressive disorder could include the following:

• The symptoms preceded the onset of the substance/medication use; or
• The symptoms persist for a substantial period of time (e.g. - about 1 month) after the cessation of acute withdrawal or severe intoxication; or
• There is other evidence suggesting the existence of an independent non-substance/medication-induced depressive disorder (e.g. - a history of recurrent non-substance/medication-related episodes).

The disturbance does not occur exclusively during the course of a delirium.

The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

• This diagnosis is reserved for symptoms that are associated with the ingestion, injection, or inhalation of a substance (e.g. - drug of abuse, toxin, medication), and the depressive symptoms persist beyond the expected length of physiological effects, intoxication, or withdrawal period.
  • According to the diagnostic criteria, it needs to have developed during or within 1 month after use of the substance or medication.
• Some medications (in particular steroids, L-dopa, antibiotics, central nervous system drugs, dermatological agents, stimulants, chemotherapeutic drugs, and immunological agents) can cause depressive mood symptoms.
• Clinical judgment is used to assess whether the medication is associated with inducing the depressive disorder or whether the primary depressive disorder would have happened to have its onset while the person was receiving the treatment regardless.
  • For example, a depressive episode that begins with alpha-methyldopa treatment (an antihypertensive agent) in an individual with no history of depression would qualify for the diagnosis of medication-induced depressive disorder.

Medications/substances implicated in medication-induced depressive disorder, with varying degrees of evidence, include:^[2]

• Antiviral agents (efavirenz, especially at high plasma concentrations)
• Cardiovascular agents (clonidine, guanethidine, methyldopa, reserpine)
• Retinoic acid derivatives (isotretinoin)
  • Has a warning by the FDA for risk for suicide, though the association remains debated.^[3]
• Antidepressants
  • There is a known risk for the use of antidepressants in youth aged 18 to 24 years, and the increased risk for suicidal behaviours or ideation.
  • This has led to a blackbox warning for the use of antidepressants in youth.
• Anticonvulsants
• Anti-migraine agents (triptans)
• Antipsychotics
• Hormonal agents (corticosteroids, oral contraceptives, gonadotropin-releasing hormone agonists, tamoxifen)
  • High estrogen/progesterone content in oral contraceptives is a particular risk factor for depressive symptoms.^[4]
  • High doses of corticosteroids (greater than 80 mg/day prednisone-equivalents) is also a risk factor for depressive symptoms.^[5]
• Smoking cessation agents (varenicline)
• Immunological agents (interferon)
  • Increased immune activation prior to treatment for hepatitis C is associated with interferon-alfa-induced depression

• Determination of the substance of use can sometimes be made through laboratory assays of the suspected substance in the blood or urine to corroborate the diagnosis.

• Substance intoxication and withdrawal
  • Depressive symptoms are common in substance intoxication and withdrawal, and the diagnosis of the substance-specific intoxication or withdrawal is usually enough to categorize the symptom presentation.
  • The additional diagnosis of substance-induced depressive disorder should only be made when the mood symptoms are sufficiently severe to warrant additional independent clinical attention.
    • For example, depressed mood is a characteristic feature of cocaine withdrawal, and a cocaine-induced depressive disorder should be diagnosed instead of cocaine withdrawal only if the depressive symptoms are substantially more intense or longer lasting than what is typically seen in cocaine withdrawal and is a separate focus of attention and treatment.
• Primary depressive disorder (e.g. - major depressive disorder)
  • A substance/medication-induced depressive disorder is distinguished from a primary depressive disorder by the fact that a substance is judged to be etiologically related to the symptoms.
• Depressive disorder due to another medical condition
  • Because individuals with other medical conditions often take medications for those conditions, the clinician must consider the possibility that the mood symptoms are caused by the physiological consequences of the medical condition rather than the medication.
  • Sometimes, a change in the treatment for the medical condition (e.g. - medication substitution or discontinuation) may be required to determine whether the medication is the cause of the depressive symptoms.

• Once the substance or medication is discontinued, the depressive symptoms usually resolve within days to several weeks, depending on the half-life and withdrawal syndrome. If symptoms persist 4 weeks beyond the expected time course of withdrawal of a particular substance/medication, other causes for the depressive symptoms should be explored.