Continuing Education Activity

The FDA-approved indications for phenelzine include the management of treatment-resistant depression, panic disorder, and social anxiety disorder. Phenelzine is also specifically useful for young women with depression and mood disorders. This activity reviews the indications, action, and contraindications for phenelzine as a valuable agent in treating and managing treatment-resistant depression. This activity will highlight the mechanism of action, adverse effects, and other key factors such as dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions pertinent for interprofessional team members in the treatment and care of patients with depression and related conditions.

Objectives:

• Summarize the mechanism of action of phenelzine.
• Describe the potential adverse effects of phenelzine.
• Review the appropriate monitoring of phenelzine.
• Discuss interprofessional team strategies for improving care coordination and communication to advance phenelzine and improve outcomes.

Indications

Phenelzine is a potent, non-selective monoamine oxidase inhibitor (MAOI) used in treating depression and as an anxiolytic in adults.[1][2][3] It is a hydrazine derivative drug and is one of the few remaining non-selective monoamine oxidase inhibitors (along with tranylcypromine and isocarboxazid) still in regular clinical use. Phenelzine has demonstrated effectiveness in treating depressed patients characterized clinically as "non-endogenous," "atypical," or "neurotic." Evidence for effectiveness is less conclusive in severely depressed patients with endogenous characteristics (now more commonly termed major depressive disorder).

It has no FDA-approved use in pediatric patients less than or equal to 16 years of age but has been investigated for use in selective mutism in pediatric patients; however, the data for this indication remains equivocal.[4] Older research from the 1980s investigated using phenelzine to treat bulimia nervosa, but this remains an unapproved, off-label use.[5][6] It has also been considered a therapeutic option for obsessive-compulsive disorder but is not approved for this indication at present.[7]

Non-selective MAOIs have largely fallen out of favor and been superseded by more recently developed antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs); this is largely the result of the prominent drug and food interactions of these agents. Clinically, they are often relegated to second-line treatment for recalcitrant cases that are resistive to first-line therapeutic options.[3] Phenelzine is also not FDA-approved for therapy for bipolar disorder.

Some authors have recently supported increased consideration of MAOI use, despite the typical concerns regarding the need for divided dosing, dietary concerns/limitations, and drug-drug interactions.[8][9]

Mechanism of Action

As stated above, phenelzine is a potent, nonselective monoamine oxidase A and B inhibitor (MAOI): phenelzine irreversibly these enzymes, preventing serotonin, norepinephrine, and dopamine from being broken down, allowing these neurotransmitters to have a more prolonged effect on their target receptors. It also increases levels of gamma-aminobutyric acid in the brain.[10] Phenelzine usually takes up to 2 two weeks to start showing clinical benefit. If by 6 to 8 weeks, therapy has not achieved the intended clinical results, a higher dosage may be necessary.

Monoamine oxidase is a complex enzyme system, and medications that inhibit monoamine oxidase in vitro demonstrate a variety of clinical effects. It remains unclear whether the observed clinical effects result from monoamine oxidase inhibition per see, other pharmacological actions, or the interplay of both. Clinicians considering using these agents need to familiarize themselves with all the potential effects associated with this class of medications.

Phenelzine has recently been studied concerning its potential neuroprotective and regenerative properties. This research has examined the effect of phenelzine and other MAOI agents on GABA-glutamate balance in the brain, sequestering of reactive aldehydes, and inhibition of primary amine oxidase. Phenelzine has also shown encouraging findings in animal models for stroke, traumatic brain injury, spinal cord injury, and multiple sclerosis. These actions and indications will require further study but represent a clinically intriguing possibility for these agents in the future.[11][12]

Administration

Phenelzine sulfate is available as a 15 mg film-coated tablet for oral administration. It should seldom be the first therapeutic choice but instead is more suited to patients who have failed to respond to the first-line agents more commonly used for its indications.[7] The drug should be protected from light during storage.

Dosing

Depression in Adults: Dosing regimens range from 15 mg orally every other day to 30 mg orally three times daily. Patients should typically start with 15 mg orally three times per day. Dosing can be increased to 60 to 90 mg daily in three or four divided doses; these increases seek to establish the minimal effective dose, with a maximum dose of 90 mg per day.[5]

Depression in the Elderly: The usual therapeutic dose is 15 to 60 mg daily in 3 or 4 divided doses. Initial dosing is 7.5 mg orally per day, with increases of 7.5 to 15 mg every three to four days as tolerated.

Pediatric Dosing (selective mutism - unlabeled indication): Dosing is 30 to 60 mg orally per day in divided doses.[4]

Dosing in severe renal insufficiency is contraindicated. Dosing in patients undergoing peritoneal or hemodialysis is undefined at present. The drug should not be administered to patients with a history of hepatic disease or elevated LFTs.[1]

When dispensing phenelzine as an outpatient prescription (new or refill), patients should receive the FDA-approved medication guide concerning the use of antidepressants in children, adolescents, and young adults when the patient will be taking the drug without direct clinician supervision. As with all antidepressants, this drug comes with an FDA Box Warning regarding the increased risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 124 years of age) who have major depressive disorder and other psychiatric conditions. Phenelzine is not FDA-approved for treating depression in children less than or equal to 16 years of age.

The mean elimination half-life of a single 30 mg dose of phenelzine is approximately 11 to 12 hours. According to the manufacturer, multiple-dose pharmacokinetics have not been studied in humans. The onset of the antidepressant effects of phenelzine takes 2 to 3 weeks to manifest. When discontinuing the medication, the dose should be tapered slowly to minimize possible withdrawal symptoms, and the prescriber should allow three to four weeks from discontinuing phenelzine to and initiating another antidepressant. If the clinician deems it necessary to administer phenelzine concurrently with another antidepressant or within 10 days of discontinuation of other antidepressant drug therapy, the prescriber must counsel the patient regarding the possibility of an adverse drug-drug interaction.[13]

Adverse Effects

Monoamine oxidase is widely distributed throughout the body. As a result, its inhibition can result in diverse pharmacological effects. Most of these unwanted effects are mild to moderate and may be controlled via dose adjustments; however, some more severe adverse events can occur. It is infrequent that the prescriber must discontinue phenelzine.

Although phenelzine's primary intended therapeutic action in treating depression is to block the enzymatic breakdown of serotonin via MAO inhibition, this enzymatic inhibition can also exert effects on GABA and melatonin receptors and potentiate insomnia. MAO inhibition also prevents the breakdown of norepinephrine, potentially affecting vascular smooth muscle. A profound decrease in blood pressure leading to orthostatic hypotension may also occur in patients taking phenelzine. Constipation, dry mouth, change in weight, anorgasmia/impotence, nausea, and weight gain are well-known side effects of this drug.[13]

Phenelzine may also cause drowsiness or dizziness; thus, the clinician should exercise caution in using this drug for patients who operate machinery or drive frequently. Patients diagnosed with asthma must use discretion due to the drug's effect on sympathetic neurotransmission.[14]

Rare but potentially serious reactions include but are not limited to:

• Hypertensive crisis (almost always from tyramine interaction -  see Contraindications)
• Intracranial hemorrhage (associated with severe hypertensive crisis)
• Serotonin syndrome (with or without other serotonergic agents)
• Exacerbation of psychosis or depression
• Toxic delerium
• Hepatic necrosis
• Lupus-like syndrome
• Suicidality
• Seizures
• Ataxia
• Withdrawal symptoms if discontinued abruptly

There is also research linking phenelzine to vitamin B6 deficiency; supplementation may be necessary.[15]

Contraindications

Phenelzine is contraindicated in patients who exhibit hypersensitivity to the drug or who have pheochromocytoma, congestive heart failure, severe renal impairment or renal pathology, abnormal LFTs, or a history of liver disease.

The most concerning potential adverse event associated with phenelzine is hypertensive crisis. This can occur via the potentiation of sympathomimetic substances by MAO inhibition. Therefore, phenelzine should not be used concurrently with sympathomimetic drugs (e.g., amphetamines, cocaine, methylphenidate, ephedrine, norephedrine, and dopamine.)[16]

Hypertensive crisis can also occur when taking phenelzine when patients consume foods with high levels of tyramine. During phenelzine therapy, patients should avoid high-protein foods that have undergone protein breakdown through fermentation, aging, smoking, pickling, or bacterial contamination /improper storage. Other foods to avoid include aged cheeses, pickled fish, beer and wine (including reduced alcohol products), liver yeast extract, dry sausages, salamis, pepperoni, Lebanon bologna, pods of broad beans (e.g., fava beans), and yogurt or buttermilk. Excessive intake of chocolate or caffeine can also potentiate hypertensive reactions. While complete elimination of tyramine is often unrealistic, the patient should avoid high-tyramine foods as much as possible.

Phenelzine therapy should not be combined with CNS depressants like alcohol and opioids; concurrent use of phenelzine and meperidine is mostly contraindicated; there are reports of seizures, delirium, circulatory collapse, hyperpyrexia, coma, and death in patients on MAOI therapy who received a single dose of meperidine. The combination of phenelzine and opioids is strongly discouraged.[17]

The list of potential drug interactions for phenelzine, as with other MAOIs, is extensive; therefore, thorough medication reconciliation is necessary before initiating phenelzine therapy. The following includes some of the more commonly encountered interactions that can contraindicate using phenelzine:

• Phenelzine may potentiate the vasopressive effects of direct-acting alpha or beta-agonists; therapy modification is recommended.
• With indirect-acting alpha or beta-agonists, phenelzine may increase the hypertensive effect, and the combination is contraindicated.
• Phenelzine may increase the CNS neurotoxicity of atomoxetine; this combination should be avoided.
• Concurrent use with buspirone may enhance the toxic effects of MAOIs and should be avoided.
• Serotonergic agents should be avoided in conjunction with phenelzine or other MAOIs because of the possibility of serotonin syndrome. This includes but is not limited to:
  • SSRIs, other MAOIs
  • Serotonin 5-HT1D agonists
  • TCAs
  • Cyclobenzaprine
  • Meperidine
  • Propoxyphene
  • Sibutramine
  • St. Johns Wort[18]

Phenelzine should be avoided during pregnancy; the drug is a Category C pregnancy risk agent. There is no human data available establishing the safe use of phenelzine during pregnancy and breastfeeding; clinicians must weigh the potential benefit of using phenelzine against the possible harm to the mother or fetus.[19] Contraindications to phenelzine therapy also include renal impairment and hepatic impairment due to potential drug toxicity. Phenelzine administration is permissible in patients with cardiac abnormalities, but close monitoring is required.[20]

Phenelzine may increase the risks associated with electroconvulsive therapy (ECT); clinicians should consider halting therapy prior to ECT.[21]

Monitoring

Monitoring parameters include blood pressure, heart rate, mood (when treating depressive symptoms), weight, dietary considerations, and suicidal ideation (particularly when initiating therapy or implementing dose increases.) Prescribers or their nursing staff can also evaluate therapeutic effectiveness and assess for any possible adverse reactions; this should occur when initiating treatment and again later with long-term therapy.

There is conflicting evidence regarding the effect of MAO inhibitors on glucose metabolism or whether they can potentiate hypoglycemic therapeutic agents. Therefore, it is prudent to closely monitor blood glucose levels in patients with diabetes who take phenelzine.[22]

Toxicity

Depressed patients may be prone to accidental or intentional overdosage. In a crisis situation, it is also prudent to consider the involvement of alcohol and/or other drugs. Assay methods are not practical for clinical or toxicological use.[23]

For patients who overdose on phenelzine, the symptoms can range from agitation to comatose status. Sympathetic overflow effects can also be observed, including hypertension, tachypnea, tachycardia, and dilated pupils. There may be observable involuntary movements of the eyes, face, and jaw.[24]

If phenelzine overdose is suspected, focused symptomatic and supportive treatment may be necessary. This could include gastric lavage via charcoal slurry with airway maintenance. Diazepam will address any excessive central nervous system stimulation. Dialysis and acidification of the urine may be necessary, but data do not support their routine use. Chlorpromazine may be another option if a hypertensive crisis secondary to suspected phenelzine overdose.

Enhancing Healthcare Team Outcomes

Phenelzine is used for treatment-resistant depression and presently is used less frequently because of its many side effects and drug interactions. Most clinicians prescribe newer and better-tolerated medications with fewer side effects, but it still has clinical benefits, and as mentioned earlier, there is a resurgence in interest in MAOI drugs.

An interprofessional healthcare team of clinicians (MDs, DOs, NPS, PAs), specialists, nurses, pharmacists, and mental health professionals should work cohesively regarding medication administration and subsequent monitoring. All interprofessional healthcare team members need to cover the topic of tyramine-containing foods so the patient does not accidentally precipitate a significant adverse event by ingesting these foods. Pharmacists must also keep a close eye on the patient's medication record since the chance for drug-drug interactions exists and report any concerns to the prescribing clinician immediately. A hepatologist may be necessary to monitor hepatic function if phenelzine use results in hepatotoxicity.

Primary care clinicians and psychiatrists must monitor for serotonin syndrome, tyramine-induced hypertensive crisis, and dose-related orthostatic hypotension. A pediatric psychiatrist consult should take place in those rare instances of administering phenelzine to patients 16 years of age and under: benefits vs. potential side effects merit strong consideration. Nurses can provide patient counseling, review dosing schedules (essential because of multiple times daily dosing), and caution patients regarding adverse effects. The pharmacist can verify dosing and provide additional medication counseling for the patient. This kind of interprofessional teamwork relies heavily on open communication channels, and all team members can openly voice their medical opinions. This interprofessional approach will increase therapeutic success while helping minimize adverse events. [Level 5]

If any acute crises develop from phenelzine therapy, the patient must report to the emergency department for resuscitation and monitoring.