Continuing Education Activity

The main FDA-approved indication of tranylcypromine is for major depressive disorder without melancholia. The non-FDA-approved indications for this medication include treatment-resistant depression, treatment-resistant social anxiety disorder, treatment-resistant panic disorder, and atypical depression. Atypical depression consists of hyperphagia, hypersomnia, rejection sensitivity, and leaden paralysis accompanying the depression. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, toxicity, and monitoring of tranylcypromine so providers can direct patient therapy where it is indicated as part of the interprofessional team.

Objectives:

• Summarize the mechanisms of action of tranylcypromine.

• Review the approved indications for using tranylcypromine.

• Describe how to prevent potential serotonin syndrome when initiating tranylcypromine therapy.

• Explain the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care with tranylcypromine therapy to improve patient outcomes for patients with indicated conditions.

Indications

The main FDA-approved indication of tranylcypromine is for major depressive disorder without melancholia.[1] The non-FDA-approved indications for this medication include treatment-resistant depression, treatment-resistant social anxiety disorder, treatment-resistant panic disorder, and atypical depression.[2][3] Atypical depression consists of hyperphagia, hypersomnia, rejection sensitivity, and leaden paralysis accompanying the depression.[4][5]

Mechanism of Action

Monoamine oxidase inhibitors (MAOIs) were discovered in 1952 and were the first class of antidepressants to be used clinically. Tranylcypromine was the second MAOI discovered. Originally, it was intended as a nasal decongestant. However, after it had failed as a nasal decongestant, it was found to be an effective antidepressant. Monoamine oxidase is the enzyme that degrades neurotransmitters such as dopamine, norepinephrine, and serotonin. There are two types of monoamine oxidase, MAOA and MAOB. MAOA breaks down serotonin and norepinephrine and is found mainly in the gut. MAOB metabolizes phenylethylamine and is present in high concentrations in the basal ganglia and platelets. Both MAOA and MAOB break down dopamine. This drug is mostly a nonhydrazine irreversible inhibitor of MAOA and is also an irreversible inhibitor of MAOB, but to a lesser degree. Tranylcypromine also blocks the reuptake of catecholamines and serotonin. As a result, the levels of norepinephrine, epinephrine, serotonin, and dopamine increase. Tranylcypromine is also structurally similar to amphetamine, which may contribute to why this drug has some stimulant-like effects. The onset of action for this drug is typically 2 to 4 weeks, and the duration is approximately 10 to 21 days.[6][7]

Administration

This medication comes in a 10 mg oral tablet. It also has a generic form available. The therapeutic dose is 30 mg/day in divided doses. The starting dose of tranylcypromine is usually 10 mg daily. The dose can then be titrated up to 30 mg daily. If the dosage needs to be titrated even further, after two weeks, the dose can be increased by 10 mg every 1 to 3 weeks until the maximum dosage of 60 mg daily is reached.[8]

Adverse Effects

Common side effects of tranylcypromine include dry mouth, headaches, diarrhea, urinary hesitancy, insomnia, agitation, anxiety, nausea, and sexual dysfunction. Postural hypotension, sometimes leading to syncope, is another common adverse effect that warrants special attention for elderly patients on this medication. This side effect is dose-related and may require splitting the dose into 3 to 4 doses each day. More serious side effects include hepatotoxicity, seizures, and induction of mania. Additionally, in the United States, there is a black-box warning stating that this medication may lead to the activation of suicidal ideation and behavior in children, adolescents, and young adults aged 18 to 24 with major depressive disorder and other psychiatric disorders.

It is important to monitor these patients during the first 1 to 2 months of treatment and when adjusting the dosage of this medication. A transient rise in blood pressure can also occur after dosing but usually resolves within 3 to 4 hours. This medication is less likely to cause weight gain in patients, and some patients may even experience weight loss. This MAOI risks hypertensive crisis, especially if it interacts with other sympathomimetics. Hypertensive crisis, severe increases in diastolic blood pressure of more than 120 mm Hg, will first present with an occipital headache followed by confusion, chest pain, blurred vision, nausea, vomiting, shortness of breath, palpitations, anxiety, or seizures. A special diet limited in tyramine is an absolute necessity for patients taking an MAOI to avoid a hypertensive crisis. When the MAOIs inactivate the MAO enzymes, the norepinephrine release by tyramine cannot be properly broken down either, potentially resulting in high circulating levels of norepinephrine in the blood. High blood levels of norepinephrine released by tyramine can lead to dangerous levels of increased blood pressure. Dietary tyramine as low as 10 mg can cause an increase in blood pressure in the presence of an MAOI. Some of the most important food and drink items that patients are not allowed to consume include all aged cheeses, all aged/smoked/pickled/cured meats/fish/poultry, sourdough bread, fava beans, soy sauce, and some tap/draft beers.[9]

There is also the risk of serotonin syndrome due to the interaction of this medication with other serotonergic medications. Serotonin syndrome results from the build-up of too much serotonin. The Sternbach criteria for assessing serotonin toxicity include the recent addition of or increase in a serotonergic agent, absence of other etiologies, no recent addition of or increase of a neuroleptic agent, and at least three of the following:[10]

• Agitation
• Myoclonus
• Hyperreflexia
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Ataxia or incoordination
• Fever.

If the patient switches from a serotonin reuptake inhibitor (SSRI) to MAOI, the SSRI should be stopped at least five half-lives, depending on each drug, usually 10 to 14 days before starting the MAOI. If the patient is switching from fluoxetine specifically, they should wait at least five weeks due to fluoxetine’s long half-life, preventing hypertensive crisis and serotonin syndrome from occurring. If the patient switches from an MAOI to an SSRI, they must wait at least two weeks.[11][12]

Contraindications

Patients must not use tranylcypromine if they are currently taking meperidine, fentanyl, guanethidine, dextromethorphan, buspirone, bupropion, sympathomimetic, or L-tryptophan. Additionally, patients should not be concurrently on another MAOI or any medications that could inhibit serotonin reuptake, including SSRIs, sibutramine, tramadol, milnacipran, duloxetine, venlafaxine, clomipramine, and others. If the patient has pheochromocytoma, cardiovascular or cerebrovascular disease, a history of liver disease, or frequent or severe headaches, they should not take tranylcypromine. If a patient is undergoing surgery that requires the administration of general anesthesia, avoid this medication. Patients must not be on any prohibited substance. Patients must be able to follow a low-tyramine diet and must not have any history of allergy to tranylcypromine.[9]

Monitoring

Monitoring parameters for this medication include renal function, hepatic function, heart rate, blood pressure, blood glucose, mental status, worsening depression, suicidality, or unusual behavioral changes. It is essential to prescribe this medication to only those patients who can be monitored closely and frequently.[8]

Toxicity

Toxic doses of this medication are possible if the dosage exceeds 60 mg/day; the lethal dose is 75 mg/kg. There have been 20 acute overdoses and 10 fatalities from tranylcypromine. If the patient takes this drug at toxic doses, you will see dizziness, sedation, insomnia, restlessness, headache, ataxia, cardiovascular effects, respiratory depression, or coma in your patient. A case report from January 2017 revealed that amphetamine and methamphetamine appeared in a patient's urine who had suffered from a fatal tranylcypromine overdose. This finding brings into question and prompts further research investigating the breakdown of tranylcypromine into amphetamine and methamphetamine and the dangers that it can impose.[9][6]

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team members involved with patients taking tranylcypromine should be fully aware of its side effect profile and rigid dietary requirements.[9]