Depression and Mania in Substance-Induced Mood Disorders 

There have been numerous reports of substance-induced mood disorders (SIMDs) since the 1950s, when the association between reserpine and depression was noted. In addition to illicit drugs, several over–the-counter (OTC) and prescription medications have been implicated in the onset of drug-induced depression or mania. Despite the number of cases of SIMD that have been reported over the years, however, 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.

Hypotheses regarding the etiology of drug-induced mood disorders are based on the known properties of the medications involved 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.

Notably, drug-induced mood disorder is more likely to occur in individuals with risk factors for major depressive disorder, 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.

Drugs with evidence of a link to depression include interferon (IFN)-alpha, corticosteroids, and digitalis/digoxin. Antidepressants have been associated with mania.

Interferon-alpha

IFN-alpha significantly increased incidence of depression in randomized controlled trials (RCTs) and prospective cohort studies.^{[1, 2]} Although the trials were not designed to study this as an endpoint (with the exception of one) and did not use standardized interviews for psychiatric assessments, the relatively high proportion of depression in this population (20-45%) raises important questions about IFN tolerability/toxicity. Patients with hepatitis C and a previous history of psychiatric illness (and more specifically depression) before IFN treatment are at an even a higher risk for developing IFN-induced depression.^[1]

Different types of IFN may have different risk profiles. In a prospective study of 96 patients treated with different types of IFN, the highest incidence of depression was reported with IFN-alpha n1, the lowest incidence with IFN-alpha n3, and the most severe depression and the highest rate of suicidal ideation with IFN-alpha 2b.^[3]

Despite early evidence suggesting that IFN-beta might also be associated with depression, subsequent evidence based on large, randomized, controlled trials did not support an association of IFN-beta (1a and 1b) and depression.^[1]

Corticosteroids

Two large meta-analyses reported corticosteroid-induced psychiatric "reactions" ranging from 6% (for severe reactions, including psychosis, in addition to mania and depression) to 23% for moderate reactions.^[4] Euphoria and hypomania were the most common psychiatric symptoms reported during short courses of steroids; during long-term treatment, depressive symptoms were the most common. Higher steroid doses appear to carry an increased risk for such adverse effects; however, there was no relationship between dose and time to onset, duration, and severity of symptoms.^[5]

Digitalis/digoxin

Two nonrandomized studies reported a significant association of digitalis/digoxin with depression.^[4] A number of psychiatric effects, including depression, have been reported in patients taking digoxin.^[6]

Antiepileptic drugs

Two large epidemiologic studies,^{[7, 8]} and a large meta-analysis^[9] showed a significant increase in suicidality in patients taking antiepileptic drugs, particularly when the individuals had a preexisting history of depression.^[7]

Antidepressants

Antidepressant-induced mania has been reported in 20-40% of bipolar patients.^[10]

Weak or conflicting drug associations with SIMDs

The following are drugs with weak or conflicting evidence of a link to depression or mania; unless otherwise specified, these agents have been linked to depression:

• Sedatives-hypnotics - Two nonrandomized studies reported a significant association with depression.^[4]
• Leuprolide – This agent accounted for 5.3% cases of depression reported in randomized controlled trials^[11]
• Beta blockers^[4]
• H-2 Blockers^[4]
• Angiotensin-converting enzyme (ACE) inhibitors^[4]
• Calcium channel blockers^[4]
• Clonidine^[4]
• Gonadotropin-releasing-hormone agonists (GnRH-a) – A small, open-label, randomized study found an association of these agents with depressive symptoms;^[12] however, to date, no association has been reported by a large, open-label, randomized trial^[13]
• Finasteride – A small, open-label study reported that 19 of 23 patients receiving finasteride developed moderate to severe depression during the course of their treatment;^[14] however a large prospective study showed only a small—yet statistically significant—difference between the depression scores at the beginning versus the end of the trial^[15]
• HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors – Two observational population studies of simvastatin reported no association, or even a tendency toward improvement^[4]
• Flunarizine – Although there have been case series reports of depression linked to flunarizine, there have no randomized, controlled trial reports^[4]
• Isotretinoin^[4]
• Methyldopa^[4]
• Implanted progestin-releasing contraceptives – A population-based study reported increased odds ratios for depression in patients treated with medroxyprogesterone acetate;^[16] however, a large, multicenter, prospective, randomized, open-label study did not find an association between levonorgestrel (Norplant) and depression^[17]

The current psychiatric nosology uses the text-revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) diagnostic category of substance-induced mood disorder (SIMD) to name this condition.^[18] However, no studies have used the diagnosis from the DSM-IV-TR as a frame of reference.

One study used the category of organic mood disorder from the third edition of the DSM (DSM-III) and implicated drugs as the probable etiology in 10% of patients with this condition.^[19] However, 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. Hyperthyroidism, of natural causes or iatrogenic, may result in clinical mania. 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.

Although the text-revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) describes substance-induced mood disorders (SIMDs), it does not contain any prevalence or incidence data. According to the World Health Organization (WHO), depression is the leading cause of disability worldwide; however WHO also does not report specific incidence/prevalence data for SIMDs.

Although SIMD 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 major depressive disorder in community samples has ranged from 10% to 25% in women and from 5% to 12% in men. At any given time, the estimates range 5-9% in women and 2-3% in men.

Although 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,^[20] the evidence to date does not indicate that the incidence or prevalence of depressive adverse effects of medications differs based on age.^{[21, 22]}

Requirements for a diagnosis of a substance-induced mood disorder (SIMD), as specified in the text-revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), are discussed in this section.

Criterion A

The clinical picture is dominated by a prominent and persistent mood disturbance and is characterized by one or both of the following (Note: The full criteria for a mood disturbance [eg, for an episode of depression or mania] are not required for criterion A):

• The patient exhibits a depressed mood or a markedly diminished interest in all or most activities
• The patient experiences elevated, expansive, or irritable moods

Criterion B

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
• There is an etiologic relationship between the medication (substance) and the disturbance

Patients often report concomitant drug/substance use and affective/mood symptoms. The alcoholic patient who drinks because "the liquor is the only thing that helps me deal with my (emotional) pain" or the gym fanatic who reports using steroids because he finally "got it," meaning getting a "gym high" and a feeling of being at "the top of my game" over the previous few months, are typical examples.

The introduction of the timeline and relationship-to-use criteria, with the specific 1-month criterion, is meant to emphasize and clarify the temporal relationship between the drug/substance and its subsequent mood effects.

Criterion C

A mood disorder that is not substance induced cannot better account for the disturbance than an SIMD can. The following symptoms indicate that a mood disorder is not substance induced:

• Symptoms arise prior to the onset of the substance or medication use
• Symptoms do not disappear even after a substantial period (ie, approximately 1mo) has passed following the cessation of acute withdrawal or severe intoxication, or symptoms are substantially greater than expected given the type of substance used, the amount that was used, or the duration of use
• Evidence, such as a history of recurrent major depressive episodes, suggests that an independent non-SIMD is present

Criterion D

The mood disorder does not occur only when the patient is suffering delirium.

Criterion E

The mood disorder results in significant dysfunction in occupational, social, or other important domains of functioning.

As with many illnesses, a complete history helps to confirm the diagnosis of an episode of substance-induced mood disorder (SIMD). 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 mood disturbance.

Perform a mental status examination. In addition, as there are many somatic illnesses that may cause depressive/manic symptoms, a comprehensive physical examination is necessary to exclude organic causes of mood changes.

In cases of suspected substance-induced mood disorders (SIMDs), it is important to understand that many common symptoms of depression (eg, fatigue, sleep changes, gastrointestinal [GI] problems) arise as adverse effects of medication. This similarity of symptoms makes linking a depressive spectrum disorder to a medication difficult. Thus, the temporal relationship of the medication to the development of the depressive symptoms is essential to diagnosing substance-induced depression.

Similarly, many symptoms of mania (eg, inattention, insomnia, excess motor movements) may occur as adverse drug reactions. The temporal relationship between use or withdrawal 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.

When evaluating a patient for possible substance-induced depression and mania, consider the following conditions:

• Adjustment disorders
• Anxiety disorders
• Bipolar affective disorder
• Caffeine-related psychiatric disorders
• Delirium
• Depression
• Dysthymic disorder
• Schizophrenia
• Sedative-, hypnotic-, or anxiolytic-use disorders
• Generalized anxiety disorder
• Endocrine disorders - Eg, Addison disease, Cushing syndrome, adrenal insufficiency, adrenal crisis, and thyroid or parathyroid disease
• Brain disorders - Eg, delirium, dementia, amnesia, and Alzheimer, Huntington, or Parkinson disease
• Infectious conditions - Eg, viral hepatitis, mononucleosis, human immunodeficiency virus (HIV) infection, and syphilis
• Substance-induced disorders - Eg, alcoholism, nicotine addiction, cannabis compound abuse, opioid abuse, cocaine abuse, and selective serotonin-reuptake inhibitor (SSRI) toxicity^{[23, 24]}
• Pancreatic cancer
• Systemic lupus erythematosus

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.

Common screening tests include a complete blood count (CBC), thyroid-stimulating hormone (TSH) levels, electrolyte tests, blood urea nitrogen (BUN) and creatinine levels, and liver function tests (LFTs).

Other laboratory work is indicated for excluding any other illnesses as suggested by the patient’s history and physical examination findings.

Focal neurologic signs and/or cognitive changes, an altered level of consciousness, and a risk and/or history of head trauma should prompt consideration for imaging studies. Obtain a computed tomography (CT) scan of the head if trauma, bleeding, normal-pressure hydrocephalus, or subdural is suspected. (A lumbar puncture can exclude reversible normal-pressure hydrocephalus if this is suggested by findings from the patient’s history and imaging studies.)

Obtain a magnetic resonance imaging (MRI) and/or MR angiography (MRA) scan of the head to exclude a mass if focal neurologic signs are present.

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

When substance-induced mood disorder (SIMD) is suspected, immediately discontinue the offending agent (when possible). Consider the possibility of depressive or manic symptoms worsening if the drug is continued.

However, if the patient truly has a medical or psychiatric need for the drug, consider similarly efficacious, but less toxic, alternative medications. If no alternatives are available, lower the dose of the offending agent and/or shorten the duration of treatment—as medically indicated. Also consider a retrial of the medication under close supervision.

If the mood symptoms do not subside within 4 weeks, consider other etiologies for the mood symptoms.

No consensus has been reached on the initiation of treatment with medications. Watchful waiting is usually sufficient.

Patient education

Instruct patients with SIMDs regarding 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 the family to monitor the patient
• Prognosis
• Avoidance of offending agent

For patient education information, see the Depression Center, as well as Depression, Suicidal Thoughts, Bipolar Disorder, and Substance Abuse.

Consultations

For the majority of patients with an iatrogenic mood disorder, the place of first contact with the medical system is a primary care or specialty clinic. Consequently, primary care physicians should always be prepared to diagnose a mood disorder. Furthermore, one's threshold for detection of mood disturbances should be low for those patients who are prescribed medications known to have depression/mania as a possible side effect (eg, steroids, certain antihypertensive agents).

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

At the same time, for patients using illicit substances, a psychiatrist might be the first physician to diagnose an SIMD. Many times, psychiatrists, especially when working in a consultation-liaison service, are also responsible for the initial workup and diagnosis of an iatrogenic SIMD that could be mistaken for a primary mood disorder. In such cases, close cooperation and coordination with the primary team regarding treatment doses, duration, and alternatives are recommended.

Complications

The following are potential complications in patients with an SIMD:

• 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

Regular assessment for 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, other psychiatric comorbidity, and recent psychiatric admission.

Inpatient care

If the substance-induced mood disorder (SIMD) symptoms are severe or cause significant risk of harm to the patient or others, inpatient psychiatric care needs to be considered. In addition, any evidence of impaired reality 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.

If there is uncertainty about the diagnosis, a prompt evaluation by the local emergency mental health system or a local emergency department is indicated.

Specific indications for inpatient care include the following:

• Serious suicidal ideation, which may include a plan
• Homicidal ideation
• Severe impairments in judgment leading to a moderate or high risk of danger to the patient or others
• Inability of the patient to care for himself/herself safely

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.

Prophylactic treatment of SIMD can be recommended on a case-by-case basis when there is significant risk associated with a recommended drug (eg, interferon [IFN]-alpha or steroid-induced depression, or steroid-induced mania). The following needs to be considered when prophylactic treatment is recommended^[25] :

• The patient's past history, in which a history of previous affective episodes is an indicator of increased risk
• The degree of risk associated with the recommended treatment

With regard to the second item above, based on a few randomized, controlled trials, pretreatment with a selective serotonin-reuptake inhibitor (SSRI) can be considered for prevention of IFN-alpha–induced depression. Several case reports and open-label trials reported successful prophylactic use of lithium, valproic acid, chlorpromazine, olanzapine, and lamotrigine for steroid-induced mania.^[5]

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 an SSRI antidepressant for patients treated with IFN-alpha who develop any depressive symptoms. Many clinicians also recommend prophylactic SSRI treatment for patients with a history of depression who need IFN-alpha. For patients with a history of mood symptoms who require steroid treatment, prophylactic treatment with an antipsychotic agent (concomitantly with the steroid treatment) can prevent or decrease steroid-induced manic symptoms.

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 it is usually less than 4 weeks. Careful monitoring is recommended until the mood symptoms resolve.

No evidence suggests that the morbidity and mortality from drug-induced depression are different from those from any other depressive illness.^{[26, 27]} A very few specific medications, including interferon (IFN), amantadine, isocarboxazid, and levetiracetam, have been implicated in suicide. No mechanisms of action have been proposed to explain these correlations.

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.

Suicide risk in children, adolescents, and young adults

In 2004, the US Food and Drug Administration (FDA), following the lead of the Medicines and Healthcare products Regulatory Agency (MHRA) (a 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.^[28] Increased suicidal thinking and behavior in children and adolescents up to age 24 years have been linked to antidepressants during the first 2 months of use. Decreased suicidal thinking and behavior in adults older than 65 years have been linked to antidepressants in the first 2 months of use.

Since this black box warning was added, the adolescent suicide rate has increased for the first time since the early 1990s. Two randomized, controlled studies showed that the risk of attempted and completed suicide attempts is highest before 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.