substance induced mood disorder

8/3/2019 Substance Induced Mood Disorder

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Dr. Ravi Paul

SUBSTANCE INDUCED MOODDISORDER


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Drug-induced depression entered the medicallexicon when the association between reserpineand depression was noted in the 1950s

Since then, there have been numerous reports ofsubstance-induced mood disorders (SIMDs).

Despite the number of cases that have beenreported over the years, few controlled studies ofthe phenomenon have been conducted.

5/5/20122 Dr. Ravi Paul


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The essential feature of a drug-induced mooddisorder is the onset of symptoms in the contextof drug use, intoxication, or withdrawal. Fullcriteria for a depressive or bipolar spectrum

disorder need not be met for a diagnosis

In addition to illicit drugs, several overthe-counter (OTC) and prescription medications havebeen implicated in the onset of drug-induceddepression or mania


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5/5/2012Dr. Ravi Paul4

Hypotheses regarding the etiology of drug-induced mood disorders are based on the knownproperties of these medications and theirpotential correlation with current neurophysiologic

models of affective disorders. These includemodels of tryptophan depletion, catecholaminedepletion, and alterations in the hypothalamic-pituitary-adrenal axis (see Pathophysiology of

SIMD).


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Notably, drug-induced mood disorder is morelikely to occur in individuals with risk factors formajor depressive disorder (MDD), dysthymia (anillness characterized by chronic low levels of

depression), or bipolar disorder (mania often withdepressive episodes). One of the most commonrisk factors is a personal or family history of amood disorder or a substance disorder.
http://emedicine.medscape.com/article/290686-overviewhttp://emedicine.medscape.com/article/286342-overviewhttp://emedicine.medscape.com/article/286342-overviewhttp://emedicine.medscape.com/article/286342-overviewhttp://emedicine.medscape.com/article/286342-overviewhttp://emedicine.medscape.com/article/290686-overview


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disorders


Drugs with evidence of a link to depressioninclude interferon (IFN)-alpha, corticosteroids,and digitalis/digoxin. Antidepressants have beenassociated with mania.


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Interferon-alpha


IFN-alpha significantly increased incidence of

depression in randomized controlled trials (RCTs)and prospective cohort studies

There is relatively high proportion of depressionin this population (20-45%) raises important

questions about IFN tolerability/toxicity. Patients with hepatitis C and a previous history of

psychiatric illness (and more specificallydepression) before IFN treatment are at an even

a higher risk for developing IFN-induceddepression.


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Interferon-alpha


Different types of IFN might have different riskprofiles. In a prospective study of 96 patientstreated with different types of IFN, the highestincidence of depression has been reported with

IFN-alpha n1, the lowest incidence with IFN-alphan3, and the most severe depression and thehighest rate of suicidal ideation with IFN-alpha2b.

Despite early evidence suggesting that IFN-betamight also be associated with depression, morerecent evidence based on large randomizedcontrolled trials did not support an association of

IFN-beta (1a and 1b) and depression.


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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% formoderate reactions.

Euphoria and hypomania were the most commonpsychiatric symptoms reported during shortcourses of steroids; during long-term treatment,depressive symptoms were the most common.

Higher steroid doses appear to carry anincreased risk for such adverse effects; however,there was no relationship between dose and timeto onset, duration, and severity of symptoms


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Digitalis/digoxin

Two nonrandomized studies reported a

significant association of digitalis/digoxinwith depression.[4] A number of psychiatriceffects including depression have been

reported in patients taking digoxinAntidepressants

Antidepressant-induced mania has been

reported in 20-40% of bipolar patients


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Weak or conflicting drug associationswith SIMDs

The following are drugs with weak orconflicting evidence of a link to depressionor mania; unless otherwise specified, these

agents have been linked to depression: Sedatives-hypnotics Two nonrandomized

studies reported a significant associationwith depression.

Leuprolide This agent accounted for5.3% cases of depression reported inrandomized controlled trials

Beta-blockers


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H-2 Blockers[4]

Angiotensin-concerting 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 hasbeen reported by a large, open-label,randomized trial.[13]


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Finasteride A small open-label studyreported that 19 of 23 patients receiving

finasteride developed moderate to severedepression during the course of theirtreatment.[14] However a large prospectivestudy showed only a smallyet statistically

significantdifference between thedepression scores at the beginning versus theend of the trial.[15]

HMG-CoA (3-hydroxy-3-methylglutaryl-

coenzyme A) reductase inhibitors Twoobservational populational studies ofsimvastatin reported no association or even atendency toward improvement.[4]


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Flunarizine Although there have been caseseries reports of depression linked toflunarizine, there have no randomizedcontrolled trial reports.[4]

Isotretinoin[4]

Methyldopa[4]

Implanted progestin-releasing contraceptives A population-based study reportedincreased odds ratios for depression in

patients treated with medroxyprogesteroneacetate[16] ; however, a large multicenter,prospective, randomized, open-label study didnot find an association between Norplant and

depression.[17]


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Pathophysiology of SIMDs

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The current psychiatric nosology uses the text-revised, fourth edition of the Diagnostic andStatistical Manual of Mental Disorders(DSM-IV-TR) diagnostic category of substance-inducedmood disorder (SIMD) to name this disorder[18] ;however, no studies have used this diagnosis

from the DSM-IV-TRas a frame of reference. TheDSM-IV-TRdescribes the disorder but does notcontain prevalence or incidence data. One studyused the third edition of the Diagnostic andStatistical Manual of Mental Disorders(DSM-III)category of organic mood disorder and implicateddrugs as the probable etiology in 10% ofpatients.[19] However, this study did not list theparticular medications linked to the organic mood

disorder.


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Researchers have noted several etiologic factors inmood disorders. The amine-depleting effect ofantihypertensive medications and the amine-restoringeffect of the first successful antidepressants led to the

catecholamine-deficit hypothesis. Endocrine factorshave been correlated with depressive symptoms.Hyperthyroidism, of natural causes or iatrogenic, mayresult in clinical mania. Hypercortisolism andoverreactivity of the hypothalamic-pituitary-adrenalaxis have been implicated in patients with mooddisorders, which may explain the clinically observabledepressive, manic, and psychotic complications ofsteroid usage. (See Substances Linked to Depression

or Mania and SIMD Diagnostic Considerations).


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Epidemiology of SIMDs

Unfortunately, although the text-revised, fourthedition of the Diagnostic and Statistical Manual ofMental Disorders(DSM-IV-TR) describes

substance-induced mood disorders (SIMDs), itdoes not contain any prevalence or incidencedata. According to the World Health Organization(WHO), depression is the leading cause of

disability worldwide; however the WHO also doesnot report specific incidence/prevalence data forSIMDs.


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Although SIMD has not been well studied, someevidence indicates that it is more likely to occur inwomen than in men. According to the DSM-IV-TR, thelifetime risk for major depressive disorder (MDD) in

community samples has ranged from 10% to 25% inwomen and from 5% to 12% in men. At any giventime, the estimates range 5-9% in women and 2-3%in men.

Although geriatric patients are more likely to takemedications and therefore have a greater exposure tothe risks of adverse drug-related effects such asdepression,[20] the evidence to date does not indicatethat the incidence or prevalence of depressive

adverse effects of medications differs based on age.


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DSM-IV-TR Classification of SIMD

The text-revised, fourth edition of the Diagnosticand Statistical Manual of Mental Disorders(DSM-IV-TR) requirements for characteristics for a

diagnosis of a substance-induced mood disorder(SIMD) are discussed in this section.


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A. A prominent and persistent mood disturbancedominates the clinical picture and is characterized byeither or both of the following (Note: The full criteriafor a mood disturbance [eg, for an episode ofdepression or mania] are not required for criterion A):

The patient exhibits a depressed mood or a markedlydiminished interest in all or most activities.

The patient experiences elevated, expansive, orirritable moods.

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 substanceintoxication or withdrawal.

Medication (substance) use is etiologically related to

the disturbance.


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Oftentimes patients report concomitantdrug/substance use and affective/moodsymptoms. The alcoholic patient who drinksbecause "the liquor is the only thing that helps me

deal with my [emotional] pain" or the gym fanaticwho reports using steroids because he finally "gotit," meaning getting a "gym high" and feeling at"the top of my game" for the last few months, are

typical examples. The introduction of the timelineand relationship-to-use criteria, with the specific1-month criterion, is meant to emphasize andclarify the temporal relationship between the

drug/substance and its subsequent mood effects.


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C. The disturbance is not better accounted for by a mooddisorder that is not substance induced. The following symptomsindicate that a substance is not inducing the mood disorder:

Symptoms precede the onset of the substance or medicationuse.

Symptoms persist for a substantial period (ie, approximately 1

mo) after the cessation of acute withdrawal or severeintoxication, or symptoms are substantially in excess of whatwould be expected given the type or amount of the substanceused or the duration of use.

Evidence suggests the existence of an independent non-SIMD(eg, history of recurrent major depressive episodes).

The disturbance does not occur exclusively during the course ofa delirium.

The symptoms cause clinically significant distress or impairmentin social, occupational, or other important areas of functioning.

The disturbance does not occur exclusively during the course ofa delirium.

The symptoms cause clinically significant distress or impairmentin social occu ational or other im ortant areas of functionin .


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D. The mood disorder does not occur exclusivelyduring delirium.

E. The mood disorder results in significantdysfunction (occupational, social and in other

important domains of functioning).


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Evaluation of SIMD As with many illnesses, a complete history helps to

confirm the diagnosis of an episode of substance-induced mood disorder (SIMD). The onset ofsymptoms must coincide with the administration of the

medication, intoxication by the medication, orwithdrawal of the medication. Quick resolution ofsymptoms (eg, days or weeks after cessation of themedication) is presumptive evidence that the drug hasinduced the mood disturbance. (See DSM-IV-TRClassification of SIMD.)

Perform a mental status examination. In addition, asthere are many somatic illnesses that may causedepressive/manic symptoms, a comprehensivephysical examination is necessary to exclude organiccauses of mood changes (see SIMD Diagnostic

Considerations).


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SIMD Diagnostic Considerations In cases of suspected substance-induced mood disorders

(SIMDs), it is important to understand that many commonsymptoms of depression (eg, fatigue, sleep changes,gastrointestinal [GI] problems) arise as adverse effects of

medication. This similarity of symptoms makes linking adepressive spectrum disorder to a medication difficult;thus, the temporal relationship of the medication to thedevelopment of the depressive symptoms is essential todiagnosing substance-induced depression. Similarly, many

symptoms of mania (eg, inattention, insomnia, excessmotor movements) may occur as adverse drug reactions.The temporal relationship of using or withdrawing from themedication and the mood symptoms is key to arriving atthis diagnosis.

The development of mood symptoms related to amedication is more likely in a person who has a


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Differential Diagnosis 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

Generalized Anxiety Disorder

Schizophrenia

Sedative, Hypnotic, Anxiolytic Use Disorders
http://emedicine.medscape.com/article/292759-overviewhttp://emedicine.medscape.com/article/286227-overviewhttp://emedicine.medscape.com/article/286342-overviewhttp://emedicine.medscape.com/article/290113-overviewhttp://emedicine.medscape.com/article/288890-overviewhttp://emedicine.medscape.com/article/286759-overviewhttp://emedicine.medscape.com/article/290686-overviewhttp://emedicine.medscape.com/article/1356176-overviewhttp://emedicine.medscape.com/article/288259-overviewhttp://emedicine.medscape.com/article/290585-overviewhttp://emedicine.medscape.com/article/290585-overviewhttp://emedicine.medscape.com/article/288259-overviewhttp://emedicine.medscape.com/article/1356176-overviewhttp://emedicine.medscape.com/article/290686-overviewhttp://emedicine.medscape.com/article/290686-overviewhttp://emedicine.medscape.com/article/290686-overviewhttp://emedicine.medscape.com/article/286759-overviewhttp://emedicine.medscape.com/article/288890-overviewhttp://emedicine.medscape.com/article/290113-overviewhttp://emedicine.medscape.com/article/290113-overviewhttp://emedicine.medscape.com/article/290113-overviewhttp://emedicine.medscape.com/article/286342-overviewhttp://emedicine.medscape.com/article/286227-overviewhttp://emedicine.medscape.com/article/292759-overview


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Other conditions to consider include the following: Endocrine disorders, such as Addison disease,

Cushing syndrome, adrenal insufficiency and adrenalcrisis, and thyroid and parathyroid disease

Brain disorders, such as delirium, dementia, and

amnesia and Alzheimer, Huntington, and Parkinsondisease

Infectious conditions, such as viral hepatitis,mononucleosis, human immunodeficiency virusinfection, and syphilis

Substance-induced disorders, such as alcoholism,nicotine addiction, cannabis compound abuse, opioidabuse, cocaine abuse, and SSRI toxicity

Pancreatic cancer

Systemic lupus erythematosus
http://emedicine.medscape.com/article/1134817-overviewhttp://emedicine.medscape.com/article/1150165-overviewhttp://emedicine.medscape.com/article/1150165-overviewhttp://emedicine.medscape.com/article/1134817-overview


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Screening Laboratory Tests If the patient is believed to be unreliable or if

intoxication or overdose is suspected, obtain a urineor serum drug screen. Drug levels can be particularlyhelpful when evaluating a person who may beexperiencing drug withdrawal.

Common screening tests include a complete bloodcell (CBC) count, 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 patients historyand physical examination findings.


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Imaging Studies of the Head Focal neurologic signs and/or cognitive changes,

an altered level of consciousness, and a riskand/or history of head trauma should prompt

consideration for imaging studies.

Obtain a computed tomography (CT) scan of thehead if trauma, bleeding, normal-pressurehydrocephalus, or subdural is suspected.

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


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Electroencephalography Electroencephalography (EEG) may be used to

differentiate a delirium from a mood disorder. AnEEG usually does not differentiate between a

delirium and a dementia.

Lumbar Puncture

A lumbar puncture can exclude reversible normal

pressure hydrocephalus if this is suggested byfindings from the patients history and imagingstudies.
http://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overview


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Hospitalization in Patients With SIMDs 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 testing or psychosis shouldlower the threshold for considering inpatient care. When patients

are paranoid or having hallucinations, they are much less likelyto be able to communicate the extent of their symptoms.

If there is uncertainty about the diagnosis, a prompt evaluationby the local emergency mental health system or a localemergency 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 highrisk for danger to self or others

An inability to care for oneself safely


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SIMD Management When substance-induced mood disorder (SIMD) is suspected,

immediately discontinue the offending agent (when possible). Considerthe possibility of depressive or manic symptoms worsening if the drug iscontinued. However, if the patient truly has a medical or psychiatricneed for the drug, consider similarly efficacious but less toxic alternativemedications; if no alternatives are available lower the dose and/or

shorten the duration of treatmentas medically indicated. Also considera retrial of the medication under close supervision.

Failure to make and document a full assessment for suicide, homicide,or inability to care for self is a major pitfall. Regular assessment ofsuicide risk is mandatory in any patient with depression or mania. Otherrisk factors for suicide include agitation, psychosis, past suicideattempts, a family history of suicide, other psychiatric comorbidity or

recent psychiatric admission. 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 withmedications. Watchful waiting is usually sufficient.


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Patient education Instruct patients with SIMDs regarding the

following, especially if substance abuse isinvolved:

Cause In view of the drug-induced cause ofdepression, the patient and the family must bemade aware of the etiology of the depression.Education can prevent other episodes and allows

families to monitor the patient.

Prognosis (see SIMD Prognosis)

Avoidance of offending agent


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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 specialtyclinic. As such, primary care physicians should always be prepared todiagnose a mood disorder; furthermore, one's threshold for detection ofmood disturbances should be low for those patients who are prescribedmedications known to have depression/mania as a possible side effect

(eg, steroids, certain antihypertensive agents, etc) (see SubstancesLinked to Depression or Mania).

If the patient is suicidal, if psychosis or mania is suspected, ordepressive symptoms are severe, consult a mental health professional.Patients may need intensive outpatient or inpatient psychiatric care untilthe 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 timespsychiatrists, especially when working in a consultation-liaison service,are also responsible for the initial workup and diagnosis of an iatrogenicSIMD that could be mistaken for a primary mood disorder. In suchcases, close cooperation and coordination with the primary teamregarding treatment doses, duration, and alternatives is recommended.


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Complications The following are potential complications in

patients with an SIMD:

Suicide

Homicide In some rare situations, a person whois depressed or manic may become homicidal.Homicidal behavior is another indication for

inpatient treatment. Loss of work time

Interpersonal problems

Prolonged hospital stays


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Outpatient Care Periodically monitor the patient until the mood

symptoms have abated. If an abnormal moodpersists, institute standard treatment for

depression or mania, and consider etiologiesother than substance-induced mood disorders(see SIMD Diagnostic Considerations).


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Prevention of SIMD Prophylactic treatment can be recommended on a case-

by-case basis when there is significant risk associated witha recommended drug (eg, interferon [IFN]-alpha or steroid-induced depression, or steroid-induced mania). The

recommendation for prophylactic treatment needs toconsider the following[23] :

The patient's past history, in which a history of previousaffective episodes is an indicator of increased risk

The degree of risk associated with the recommended

treatment. Based on a few randomized controlled trials,pretreatment with a selective serotonin-reuptake inhibitor(SSRI) can be considered for prevention of IFN-alphainduced depression. Several case reports and open-labeltrials reported successful prophylactic use of lithium,

valproic acid, chlorpromazine, olanzapine and lamotriginefor steroid-induced mania.


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Idiosyncratic drug-induced depression or mania canbe severe and life threatening. Cases of suicide havebeen reported. If a patient reports a history of moodsymptoms 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-alphawho develop any depressive symptoms. Manyclinicians also recommend prophylactic SSRItreatment for patients with a history of depression whoneed IFN-alpha. For patients with a history of moodsymptoms who require steroid treatment, prophylactictreatment with an antipsychotic agent (concomitantly

with the steroid treatment) can prevent or decrease


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Prognosis of SIMD If a drug causes the mood disorder, removal of the

offending agent usually results in total recovery to predrugfunctioning. The resolution of symptoms can take time, butit 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 of anydepressive illness.[24, 25] A very few specific medications,including interferon (IFN), amantadine, isocarboxazid, and

levetiracetam, have been implicated in suicide. Nomechanisms of action have been proposed to explainthese correlations.

Depressive and manic illness is associated with a lifetimeprevalence of suicide of approximately 15%. Estimates of

lost wages and productivity due to mood disorders areestimated at millions of dollars annually.


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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) (drug-monitoringagency in the United Kingdom), issued a warning about increased risk forsuicidal behavior in children and adolescents using antidepressants. Thiswarning has been updated several times.[26] Increased suicidal thinking andbehavior in children and adolescents up to age 24 years has been linked toantidepressants during the first 2 months of use. Decreased suicidal thinking and

behavior in adults older than 65 years has been linked to antidepressants in thefirst 2 months of use.

Since this black box warning has been added, the adolescent suicide rate hasincreased for the first time since the early 1990s. Two randomized controlledstudies have shown that the risk of attempted and competed suicide attempts ishighest before treatment and decreases in a linear fashion after treatment (eitherantidepressant 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. Nomechanism of action has been implicated linking suicide to antidepressant use.However, the recommendation for close monitoring of patients who have recentlybeen started on treatment for depression is quite sound and is likely to decreasethe risk for completed suicide.
http://www.fda.gov/http://www.fda.gov/http://www.mhra.gov.uk/http://www.mhra.gov.uk/http://www.mhra.gov.uk/http://www.mhra.gov.uk/http://www.fda.gov/http://www.fda.gov/

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