Phenelzine, sold under the brand name Nardil among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine family which is primarily used as an antidepressant and anxiolytic to treat depression and anxiety.
Phenelzine is a monoamine oxidase inhibitor (MAOI) used primarily for the treatment of atypical, nonendogenous, or neurotic depression, often accompanied by mixed anxiety and depression.
It is particularly useful for patients who have not responded to more commonly used antidepressants.
The initial dosage of phenelzine is 15 mg three times a day, which can be increased to at least 60 mg per day. If necessary, the dosage may be further increased to 90 mg per day.
The maintenance dose can be as low as 15 mg daily or every other day.
It works by inhibiting the enzyme monoamine oxidase, which is involved in the breakdown of neurotransmitters such as serotonin and norepinephrine, thereby increasing their levels in the brain.
It is known to elevate brain levels of γ-aminobutyric acid (GABA) by inhibiting GABA transaminase, which contributes to its anxiolytic properties.
Phenelzine also inhibits primary amine oxidase (PrAO), an enzyme implicated in various conditions such as diabetes mellitus, Alzheimer’s disease, and cardiovascular disorders.
Phenelzine’s neuroprotective effects showing efficacy in reducing oxidative stress by sequestering reactive aldehydes like acrolein and 4-hydroxy-2-nonenal, which are implicated in neurodegenerative disorders.
Phenelzine and its active metabolite, β-phenylethylidenehydrazine (PEH), have been reported to reduce lipid peroxidative damage and exhibit neuroprotective effects in models of global ischemia, traumatic brain injury, and spinal cord injury.
The drug’s impact on neurotransmitter levels is also noteworthy.
Phenelzine increases brain levels of norepinephrine, dopamine, and serotonin, critical in its antidepressant effects.
Phenelzine‘s long-lasting inhibition of MAO activity and the sustained elevation of these neurotransmitters underscore its therapeutic potential in treating depression and anxiety disorders.
Phenelzine is a multifaceted MAOI with significant antidepressant, anxiolytic, and neuroprotective properties, making it a valuable option for patients with treatment-resistant depression and anxiety disorders.
Pregnancy category AU: B3
Routes of administration By mouth Drug class Monoamine oxidase inhibitor; Antidepressant
Pharmacokinetic data Metabolism Liver
Elimination half-life 11.6 hours
Excretion Urine
Phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use.
Phenelzine is primarily used in the treatment of major depressive disorder (MDD).
Patients with depressive “atypical,” “nonendogenous,” and/or “neurotic” respond particularly well to phenelzine.
The medication is also useful in patients who do not respond favorably to first and second-line treatments for depression, or are treatment-resistant.
Phenelzine is also effective in treating dysthymia, bipolar depression (BD), panic disorder (PD), social anxiety disorder, bulimia nervosa, post-traumatic stress disorder (PTSD), and obsessive–compulsive disorder (OCD).
Common side effects: dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, small fiber peripheral neuropathy, nausea and vomiting, diarrhea, constipation, urinary retention, mydriasis, muscle tremors, hyperthermia, sweating, hypertension or hypotension, orthostatic hypotension, paresthesia, hepatitis, and sexual dysfunction, consisting of loss of libido and anorgasmia.
Rare side effects may include hypomania or mania, psychosis and acute liver failure, the last of which is usually only seen in people with pre-existing liver damage, old age, long-term effects of alcohol consumption, or viral infection.
The MAOIs have dietary restrictions and drug interactions.
A hypertensive crisis may result from the overconsumption of tyramine-containing foods, although it is a rare occurrence.
Serotonin syndrome may result interactions with certain drugs which increase serotonin activity such as selective serotonin reuptake inhibitors, serotonin releasing agents, and serotonin agonists.
Phenelzine has also been linked to vitamin B6 deficiency.
The phenelzine metabolite phenylethylidenehydrazine is a GABA-transaminase inhibitor.
Both phenelzine and vitamin B6 are rendered inactive upon these reactions occurring.
The pyridoxine form of B6 is recommended for supplementation,as it reduces hydrazine toxicity from phenelzine and, in contrast, the pyridoxal form has been shown to increase the toxicity of hydrazines.
Phenelzine is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).
By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well as the trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine.
It leads to an increase in the extracellular concentrations of these neurochemicals and, therefore, an alteration in neurochemistry and neurotransmission.
This action is thought to be the primary mediator in phenelzine’s therapeutic benefits.
Phenelzine and its metabolites also inhibit at least two other enzymes to a lesser extent, of which are alanine transaminase (ALA-T), and γ-aminobutyric acid transaminase (GABA-T).
By inhibiting ALA-T and GABA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body.
GABA is the major inhibitory neurotransmitter in the central nervous system, and is very important for the normal suppression of anxiety, stress, and depression.
Phenelzine’s action in increasing GABA concentrations may significantly contribute to its antidepressant, and especially, anxiolytic/antipanic properties, the latter of which have been considered superior to those of other antidepressants.
Phenelzine metabolizes to phenethylamine (PEA).
PEA acts as a releasing agent of norepinephrine and dopamine.
Phenelzine usually requires several weeks of treatment to achieve full therapeutic effects. acetyltransferase.
A therapeutic response to MAOIs is associated with an inhibition of at least 80-85% of monoamine oxidase activity.
Phenelzine is administered orally in the form of phenelzine sulfate and is rapidly absorbed from the gastrointestinal tract.
The time to peak plasma concentration of phenelzine is 43 minutes, and the half-life is 11.6 hours.
Phenelzine irreversibly disables MAO.
Upon phenelzine treatment, its effects typically do not wear off until the body replenishes its enzyme stores, a process which can take as long as 2–3 weeks.
Phenelzine is metabolized primarily in the liver, by oxidation
Phenelzine metabolites are excreted in the urine: The major metabolites are phenylacetic acid and parahydroxyphenylacetic acid.
Phenelzine may also interact with cytochrome P450 enzymes.
Phenelzine showed promise in a phase II clinical trial in treating prostate cancer.