Nardil/phenelzine background info writeup

Here's the writeup with the background information on Nardil (phenelzine) that I said that I would post.

Nardil, or phenelzine, is a medication used to treat depressive and anxiety disorders. The mechanism of action thought to be primarily responsible for its therapeutic effects is the inhibition of the monoamine oxidase, or MAO, enzymes. Nardil is one of several monoamine oxidase inhibitors, or MAOIs, a class of medications that are usually used as second or third-line treatments for psychiatric disorders because of their potential to interact with certain foods and other medications. Warner-Lambert Company manufactured Nardil for the U.S. market from the time the medication was approved in the 1950s until Pfizer purchased the company in 2000 (U.S. Food and Drug Administration, 2002; Knox, 2000). Pfizer has manufactured Nardil for the U.S. market since 2000, changing the medication's formulation in 2003.

The first MAOI was a medication called iproniazid, a drug derived from hydrazine that was originally indicated for tuberculosis. In 1951, it was discovered that some patients taking iproniazid became euphoric (Anderson et al., 1962), and later studies found the compound to possess "psychic energizing," or antidepressant, properties (Furst, 1959). Iproniazid use, however, was associated with an unacceptably high risk of liver damage, which prompted American pharmaceutical companies to examine other hydrazine-derived chemicals for their potential as antidepressant medications (Furst, 1959). During the mid 1950s, Warner-Lambert Company developed and tested phenelzine sulfate, which they marketed under the brand name of Nardil years later. Phenelzine, which was known experimentally as W-1544-A, was made available for clinical screening in September 1958 (Furst, 1959).

A preliminary study of phenelzine by Furst (1959) found its therapeutic effectiveness in non-hospitalized depressed patients to approach that of iproniazid with the remission rate of participants completing the study being 69 percent and the overall remission rate being 50 percent. An analysis of 580 case records found that 85 percent of patients with endogenous depression responded favorably to phenelzine, with 66 percent of patients achieving remission on the drug (Arnow, 1959). Approximately half of patients with "various neuroses" whose reports were included in the analysis responded favorably to phenelzine. A study of 39 inpatient and 21 outpatient depressed individuals, most of whom were described as having "neurotic depression," found that 70 percent of participants who were treated with a combination of phenelzine and psychotherapy experienced symptomatic improvement and that 55 percent of those treated were considered to be "helped" in terms of the "total therapeutic outcome" (Sawyer-Foner et al., 1959).

In a study that compared the efficacy of Nardil with that of the tricyclic antidepressant imipramine and electroconvulsive therapy in 250 patients with depressive illness, the Medical Research Council (1965) found that Nardil was no more effective than placebo in male patients and even less effective than placebo in female patients. The study, however, has been criticized because the patients studied were inpatients and chosen because of their suitability for ECT. Pare (1985), who criticized the Medical Research Council (1965) study, suggested that the "general view" regarding the efficacy of Nardil and other MAOIs is that they can be effective treatments for any type of depression, but tend to be most effective in individuals without "classical endogenous" depression. An analysis by Quitkin et al. (1979) found that Nardil is "clearly effective" in the treatment of "atypical depression," which is also sometimes referred to as "neurotic depression." The analysis, however, stated that findings were inconclusive with respect to the medication's ability to treat endogenous depression.

The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (American Psychiatric Association, 2000), defines atypical depression as a subtype of depressive illness that is characterized by mood reactivity with at least two of the following symptoms: overeating, hypersomnia, a "leaden paralysis" feeling, and interpersonal rejection sensitivity. However, several of the comparative research studies that found Nardil and other MAOIs to be more effective than tricyclic antidepressants in treating atypical depressives were conducted before the DSM criteria for the depressive subtype were established. In older studies that examined the efficacy of various antidepressants in individuals with atypical depression, the term "atypical" was frequently used to refer to manifestations of depression that involved comorbid symptoms of anxiety or depressive symptoms that were believed to be characterological in nature (Quitkin et al., 1979). Other than being noted for its efficacy in treating atypical depression, Nardil has also been found to be useful in patients with treatment-refractory depression (Fiedorowicz & Swartz, 2004).

Nardil has demonstrated efficacy as an antidepressant not only in short-term clinical trials, but also in a controlled study that examined its use as a maintenance treatment. Robinson et al. (1991) found that patients who had experienced an initial response to Nardil responded significantly more favorably to two-year treatment with either 45 mg/day or 60 mg/day of Nardil than two-year treatment with placebo.

Although Nardil has only been approved by the U.S. Food and Drug Administration for the treatment of major depressive disorder, controlled studies have found the medication to be effective in the treatment of panic disorder with agoraphobia, social anxiety disorder, bulimia, posttraumatic stress disorder, and borderline personality disorder (Liebowitz et al., 1990). Nardil has been shown to be more effective than the tricyclic antidepressant imipramine in the treatment of dysthymic disorder (Vallejo et al., 1987), and there is some evidence from controlled trials that Nardil may be more effective than the tricyclics in treating anergic bipolar depression (Fiedorowicz & Swartz, 2004). Patients with obsessive-compulsive disorder, trichotillomania, dysmorphophobia, and avoidant personality disorder whose conditions have been responsive to Nardil have also been documented in the medical literature (Liebowitz et al., 1990).

One of four monoamine oxidase inhibitor antidepressants on the market in the U.S., Nardil inhibits both type A monoamine oxidase and type B MAO irreversibly, or for the lives of the enzymes (Thase et al., 1995). The compounds serotonin and adrenaline are metabolized primarily by MAO-A, while the compounds phenylethylamine, phenylethanolamine, benzylamine, tele-Methylhistamine, and MPTP are metabolized primarily by MAO-B. Both types of MAO metabolize the compounds norepinephrine, dopamine, tyramine, octopamine, and tryptamine (Glover & Sandler, 1986). In addition to reducing the breakdown of neurotransmitters by inhibiting the MAO enzymes, Nardil inhibits the enzymes GABA-transaminase (McKenna et al., 1994) and alanine-transaminase (Tanay et al., 2001).

Nardil and other MAOIs tend to be prescribed only after other antidepressant medications have failed to be effective because of their potential to interact with other medications and even some foods. Taking Nardil with sympathomimetic amine, anorexiant, and dopamine precursor medications can trigger a potentially fatal reaction known as a "hypertensive crisis" (Perry & Lund, 2001). A person experiencing this phenomenon typically experiences a severe occipital and temporal headache, diaphoresis, mydriasis, elevated systolic and diastolic blood pressure, neck stiffness, and neuromuscular excitation, but cardiac dysrhythmias, heart failure, and intracerebral hemorrhage can also occur (Perry & Lund, 2001). Several foods, particularly those containing the trace amine tyramine, may also trigger a hypertensive crisis if eaten while taking Nardil or other MAOIs. Gardner et al. (1996) recommended that patients taking MAOIs avoid aged cheeses; aged or cured meats; potentially spoiled meat, poultry, or fish; broad bean pods; Marmite concentrated yeast extract; sauerkraut; soy sauce and soybean condiments; and tap beer. Combining Nardil and other MAOIs with antidepressants that inhibit the reuptake of serotonin can result in a condition called "serotonin syndrome," which is characterized by hyperthermia, neuromuscular irritability, and confusion (Perry & Lund, 2001).

Other than Nardil, the MAOI antidepressants that are available on the U.S. market are Parnate (tranylcypromine), Marplan (isocarboxazid), and the transdermal patch EMSAM (selegiline). Like Nardil, Parnate and Marplan inhibit both MAO-A and MAO-B irreversibly (Thase et al, 1995). EMSAM has been found to pose a significantly smaller risk of triggering a hypertensive crisis than Nardil or Parnate (Dubitsky, 2005), which is likely due to the fact that selegiline is preferential in its inhibition of MAO-B over MAO-A, especially at lower doses (Amsterdam, 2003). A fifth MAOI, moclobemide, which reversibly inhibits MAO-A, is available in more than 50 countries, but not the U.S. (Lotufo-Neto et al., 1999).

American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text revision). Washington, DC: Author.

Amsterdam, J.D. (2003). A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. Journal of Clinical Psychiatry, 64, 208-214.

Anderson, F.E., Kaminsky, D., Dubnick, B., Klutchko, S.R., Cetenko, W.A., Gylys, J., et al. (1962). Chemistry and pharmacology of monoamine oxidase inhibitors: Hydrazine derivatives. Journal of Medicinal and Pharmaceutical Chemistry, 5, 221-230.

Arnow, L.E. (1959). Phenelzine: A therapeutic agent for mental depression. Clinical Medicine, 6, 1573-1577.

Fiedorowicz, J.G., & Swartz, K.L. (2004). The role of monoamine oxidase inhibitors in current psychiatric practice. Journal of Psychiatric Practice, 10, 239-248.

Furst, W. (1959). Therapeutic re-orientation in some depressive states: Clinical evaluation of a new mono-amine oxidase inhibitor (W-1544-A) (phenelzine (Nardil)). American Journal of Psychiatry, 116, 429-434.

Gardner, D.M., Shulman, K.I., Walker, S.E., & Tailor, S.A.N. (1996). The making of a user friendly MAOI diet. Journal of Clinical Psychiatry, 57, 99-104.

Glover, V., & Sandler, M. (1986). Clinical chemistry of monoamine oxidase. Cell Biochemistry and Function, 4, 89-97.

Medical Research Council (1965). Clinical trial of the treatment of depressive illness. British Medical Journal, 1, 881-886.

Liebowitz, M.R., Hollander, E., Schneier, F., Campeas, R., Welkowitz, L., Hatterer, J., et al. (1990). Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders. Acta Psychiatrica Scandinavica, Suppl 360, 29-34.

Lotufo-Neto, F., Trivedi, M., & Thase, M.E. (1999). Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology, 20, 226-247.

McKenna, K.F., McManus, D.J., Baker, G.B., & Coutts, R.T. (1994). Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: Effects on GABAergic function. Journal of Neural Transmission, 41 Suppl, 115-122.

Pare, C.M.B. (1985). The present status of monoamine oxidase inhibitors. British Journal of Psychiatry, 146, 576-584.

Perry, P., & Lund, B.C. (2001). Monoamine oxidase inhibitors: Adverse effects. Virtual Hospital: A Digital Library of Health Information. Retrieved September 30, 2005, from http://www.vh.org/adult/provider/psychiatry/CPS/19.html

Quitkin, F., Rifkin, A., & Klein, D.F. (1979). Monoamine oxidase inhibitors. Archives of General Psychiatry, 36, 749-760.

Robinson, D.S., Lerfald, S.C., Bennett, B., Laux, D., Devereaux, E., Kayser, A., et al. (1991). Maintenance therapies in recurrent depression: New findings. Psychopharmacology Bulletin, 27, 31-39.

Sawyer-Foner, G.J., Koranyi, E.K., Meszaros, A., & Grauer, H. (1959). Depressive states and drugs II: The study of phenelzine dihydrogen sulfate (Nardil) in open psychiatric settings. Canadian Medical Association Journal, 81, 991-996.

Tanay, V.A.-M.I., Parent, M.B., Wong, J.T.F., Paslawski, T., Martin, I.L., & Baker, G.B. (2001). Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain. Cellular and Molecular Neurobiology, 21, 325-339.

Thase, M.E., Trivedi, M.H., & Rush, A.J. (1995). MAOIs in the contemporary treatment of depression. Neuropsychopharmacology, 12, 185-219.

U.S. Food and Drug Administration. (2002). Office of Clinical Pharmacology and Biopharmaceutics review (NDA 11-909/SCM-032). City of publication not available: Author.

Vallejo, J., Gasto, C., Catalan, R., & Salamero, M. (1987). Double-blind study of imipramine versus phenelzine in melancholias and dysthymic disorders. British Journal of Psychiatry, 151, 639-642.

Has long-standing difficulties with energy and concentration, as well as psychotic and cognitive symptoms

Taking Abilify & supplements

Nardil/phenelzine background info writeup

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