Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes (either increases or decreases). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.

Has been associated with activation of hypomania and/or mania in bipolar patients. May worsen psychotic symptoms in some patients. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide should be dispensed with each prescription. Tranylcypromine is FDA approved for the treatment of depression in children 16 years of age.

Use with caution in patients at risk of seizures, or in patients receiving other drugs which may lower seizure threshold. Discontinue at least 48 hours prior to myelography. Use with caution in patients receiving disulfiram. Use with caution in patients with renal impairment.

The MAO inhibitors are effective and generally well tolerated by older patients. It is the potential interactions with tyramine or tryptophan-containing foods and other drugs, and their effects on blood pressure that have limited their use.

Cardiovascular: Orthostatic hypotension, edema

Central nervous system: Dizziness, headache, drowsiness, sleep disturbances, fatigue, hyper-reflexia, twitching, ataxia, mania, akinesia, confusion, disorientation, memory loss

Dermatologic: Rash, pruritus, urticaria, localized scleroderma, cystic acne (flare), alopecia

Endocrine & metabolic: Sexual dysfunction (anorgasmia, ejaculatory disturbances, impotence), hypernatremia, hypermetabolic syndrome, SIADH

Gastrointestinal: Xerostomia, constipation, weight gain

Genitourinary: Urinary retention, incontinence

Hematologic: Leukopenia, agranulocytosis

Hepatic: Hepatitis

Neuromuscular & skeletal: Weakness, tremor, myoclonus

Ocular: Blurred vision, glaucoma

Miscellaneous: Diaphoresis

Amphetamines: MAO inhibitors in combination with amphetamines may result in severe hypertensive reaction; these combinations are best avoided

Anesthetics, general: Discontinue tranylcypromine 10 days prior to elective surgery.

Anorexiants: Concurrent use of anorexiants may result in serotonin syndrome; contraindicated with dexfenfluramine; avoid use with fenfluramine or sibutramine

Barbiturates: MAO inhibitors may inhibit the metabolism of barbiturates and prolong their effect

Bupropion: May cause hypertensive crisis; at least 14 days should elapse before initiating bupropion; concurrent use with an MAO inhibitor is contraindicated

Buspirone: May cause hypertensive crisis; at least 10 days should elapse before initiating buspirone; concurrent use with an MAO inhibitor is contraindicated

CNS stimulants: MAO inhibitors in combination with stimulants (methylphenidate) may result in severe hypertensive reaction; these combinations are best avoided.

CYP1A2 substrates: Tranylcypromine may increase the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine.

CYP2A6 substrates: Tranylcypromine may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.

CYP2C19 substrates: Tranylcypromine may increase the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline.

CYP2D6 substrates: Tranylcypromine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Tranylcypromine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

Dextromethorphan: Concurrent use of MAO inhibitors may result in serotonin syndrome; concurrent use is contraindicated

Disulfiram: MAO inhibitors may produce delirium in patients receiving disulfiram; monitor

Guanadrel and guanethidine: MAO inhibitors inhibit the antihypertensive response to guanadrel or guanethidine; use an alternative antihypertensive agent

Hypoglycemic agents: MAO inhibitors may produce hypoglycemia in patients with diabetes; monitor

Levodopa: MAO inhibitors in combination with levodopa may result in hypertensive reactions; monitor

Lithium: MAO inhibitors in combination with lithium have resulted in malignant hyperpyrexia; this combination is best avoided

Meperidine: May cause serotonin syndrome when combined with an MAO inhibitor; concurrent use is contraindicated

Nefazodone: Concurrent use of MAO inhibitors may result in serotonin syndrome; these combinations are best avoided

Norepinephrine: MAO inhibitors may increase the pressor response of norepinephrine (effect is generally small); monitor

Reserpine: MAO inhibitors in combination with reserpine may result in hypertensive reactions; monitor

Serotonin agonists: Theoretically may increase the risk of serotonin syndrome; includes sumatriptan, naratriptan, rizatriptan, and zolmitriptan

SSRIs: May cause serotonin syndrome when combined with an MAO inhibitor; avoid this combination

Succinylcholine: MAO inhibitors may prolong the muscle relaxation produced by succinylcholine via decreased plasma pseudocholinesterase

Sympathomimetics (indirect-acting): MAO inhibitors in combination with sympathomimetics such as dopamine, metaraminol, phenylephrine, and decongestants (pseudoephedrine) may result in severe hypertensive reaction; concurrent use is contraindicated

Tramadol: May increase the risk of seizures and serotonin syndrome in patients receiving an MAO inhibitor

Trazodone: Concurrent use of MAO inhibitors may result in serotonin syndrome; these combinations are best avoided

Tricyclic antidepressants: May cause hypertension/seizures when combined with an MAO inhibitor; concurrent use is contraindicated

Tryptophan: Combined use with an MAO inhibitor has been reported to cause disorientation, confusion, anxiety, delirium, agitation, hypomanic signs, ataxia, and myoclonus; concurrent use is contraindicated

Tyramine: Foods (eg, cheese) and beverages (eg, ethanol) containing tyramine, should be avoided in patients receiving an MAO inhibitor; hypertensive crisis may result

Venlafaxine: Concurrent use of MAO inhibitors may result in serotonin syndrome; these combinations are best avoided

Ethanol: Avoid ethanol (many contain tyramine).

Food: Clinically-severe elevated blood pressure may occur if tranylcypromine is taken with tyramine-containing food. Avoid foods containing tryptophan or dopamine, chocolate or caffeine.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, ginseng. Avoid ginkgo (may lead to MAO inhibitor toxicity). Avoid ephedra, yohimbe (can cause hypertension).

Onset of action: Therapeutic: 2-3 weeks continued dosing

Half-life elimination: 90-190 minutes

Time to peak, serum: ~2 hours

Excretion: Urine

Dosing comments in hepatic impairment: Use with care and monitor plasma levels and patient response closely

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