Iproniazid and the Monoamine Oxidase Inhibitors

   (MAOIs)

   (from 1957).

   This is an early class of drugs noted to have a significant effect on depression. The prehistory: In 1937, Caecilia Pugh and Juda Hirsch Quastel (1899–1987) at the biochemical laboratory of Cardiff City Mental Hospital observed in the Biochemical Journal that the brain has a system for oxidizing (metabolizing) amines (chemicals that contain NH groups) and that this system deaminates, or removes amino groups from the higher amines. This is significant because the major neurotransmitters all contain amines and are referred to as the "monoamines." Then, in 1952 at Hoffmann-La Roche Laboratories in Nutley, New Jersey, in research reported in the Journal of Organic Chemistry, chemist H. Herbert Fox (1912–?), who was trying to create new compounds for the treatment of tuberculosis, synthesized from a form of isonicotinic acid a drug later called isoniazid (made from a hydrazine base, or two NH groups hooked together).* It turned out to be effective against tuberculosis (TB), and from isoniazid a variant was synthesized called iproniazid (the phosphate of iproniazid was given the trade name Marsilid). It was not capable of being patented.

   As clinicians gave iproniazid to TB patients, they noticed psychiatric "side effects."

   In the first clinical trial of the drug in 1952 for TB, Irving Selikoff (1915–1992) at the Paterson Clinic in New Jersey, together with associates, noted in the Journal of the American Medical Association that some of their patients had experienced "mild euphoria"; the authors reported this as an example of "drug toxicity." (Selikoff won an Albert Lasker Award in 1955 for codiscovering the treatment for TB.) In 1956, George E. Crane (1912–), a psychiatrist in the pulmonary division of Montefiore Hospital in the Bronx, noted in the American Journal of Psychiatry the psychiatric "side effects" of iproniazid in tuberculous patients with mental disorders. He viewed the patients’ "elation" and other symptoms as problematical rather than advantageous: "Iproniazid causes profound changes on certain psychic functions in the direction of an increase of mental capacity and vitality. . . . This new vitality, however, disturbs the emotional balance of some individuals by breaking down defenses and reactivating suppressed conflicts" (p. 500). Thus, when Nathan Kline of the Rockland State Hospital in Orangeburg, New York, took another look at iproniazid as a possible psychiatric drug, it constituted a fresh approach. At a meeting in April 1957 that was sponsored by the American Psychiatric Association at the Upstate campus at Syracuse of the State University of New York, Kline and co-workers reported that their depressed in- and outpatients had done very well on iproniazid; that it seemed to be a "psychic energizer." The paper was published in December 1957 in Psychiatric Research Reports.

   * In 1953, two Cincinnati psychiatrists, Harry M. Salzer (1906–) and Max L. Lurie (1920–), suggested in an article in the A.M.A. Archives of Neurology and Psychiatry that isoniazid had a therapeutic effect on anxiety and depression. Yet, isoniazid is not an MAO inhibitor, and other researchers were unable to confirm that it improved the mood of tuberculosis patients. In retrospect, the antidepressant effect of isoniazid was probably more owing to the enthusiasm with which patients receive any new drug rather than to its pharmacological usefulness. (This is the reason for making controlled trials the gold standard of evidence in psychiatry, although impressive anecdotal evidence, such as Salzer and Lurie supplied, should at least raise the level of curiosity.)

   Meanwhile, other researchers were trying to figure out how iproniazid worked. In 1938, Ernst Albert Zeller (1907–1987), then an assistant at the Physiology-Chemistry Institute of Basel University, separated monoamine oxidase from diamine oxidase, thus discovering the enzyme (see his article in Helvetica Chimica Acta). In 1952, Zeller, who had emigrated from Switzerland in 1948 and was now professor of biochemistry at Northwestern University in Evanston, Illinois, found that iproniazid inhibited monoamine oxidase. (Inhibiting the enzyme would make monoamines available longer to the brain.) (For Zeller et al., see Experientia, 1952, p. 349.) The crucial discovery here—one that unlocked the whole study of the monoamines in depressive illness and their treatment with drugs such as iproniazid—was guided by Alfred Pletscher (1917–), a Roche scientist who in 1955 was a guest worker at Bernard B. Brodie’s (1909–1989) Laboratory of Chemical Pathology of the National Heart Institute, part of the National Institutes of Health in Bethesda. Pletscher, Parkhurst A. Shore (1924–), and Brodie determined that giving rabbits reserpine drove down the levels of serotonin in their gut tissue. Because reserpine already had a history of psychiatric effectiveness, the authors wrote, in the August 26, 1955, issue of Science, that "some of the central [brain] effects of reserpine are mediated through the release of serotonin" (p. 375). But if reserpine drove serotonin down, what would maintain it? Shortly thereafter the same team, but this time with Brodie as the senior author, confirmed that the Rauwolfia alkaloids (reserpine) reduced the level of serotonin in the brain, whereas iproniazid maintained it (see their article in the Journal of Pharmacology and Experimental Therapeutics in 1956). (Back in Basel at Roche later in 1956, Pletscher and his colleague H. Besendorf demonstrated that iproniazid’s effect on brain serotonin was indeed a causal one; see their 1956 article in Helvetica Physiologica Acta.) This was really the beginning of pharmacological psychiatry: a drug that would maintain brain serotonin might be clinically useful.

   The significance of monoamine oxidase in the brain started to become clearer after Sidney Udenfriend (1918–) and collaborators in the Laboratory of Chemical Pharmacology at the National Heart Institute of the National Institutes of Health (NIH) established in 1957 that monoamine oxidase converted serotonin to a breakdown product (5-hydroindole acetic acid). When they gave iproniazid to animals (thus inhibiting monoamine oxidase), the animals experienced a rise in serotonin (see Udenfriend et al., Biochemical Studies on Serotonin, 1957).

   As Roche scientist William A. Davis (1908–) explained in the Journal of Clinical and

   Experimental Psychopathology in 1958, "The information that Marsilid [iproniazid], an energizer, was able to raise the level of serotonin in the brain and that reserpine, a tranquilizer, lowered serotonin in brain tissue stimulated much interest in the biochemistry of brain function" (p. 3). Indeed, these findings from the laboratories of NIH opened a kind of royal road in psychopharmacology that would lead to many subsequent discoveries.

   It should be added that this progress at the National Heart Institute was achieved only because in these years Brodie, Udenfriend, and Robert L. Bowman (1916–), the chief of the laboratory of technical development at the Institute, had constructed a spectrophotofluorimeter, a device that let them analyze small amounts of monoamines in the brain. They were thus able to follow levels of serotonin after the administration of drugs like reserpine and iproniazid. The device was first described in an article in Science in 1955, of which Bowman was senior author.

   In 1961, Marsilid was withdrawn as being too toxic for clinical use. Yet, other MAOIs came onto the market, including nialamide (Roerig-Pfizer’s Niamid, patented 1959 to Pfizer; U.S. launch 1959); isocarboxazid (Roche’s Marplan, patented 1959 to Roche; U.S. launch 1959); phenelzine (Parke-Davis’s Nardil, patented 1959 to Lakeside; U.S. launch 1959); tranylcypromine (Smith Kline Beecham’s Parnate, patented 1961 to Smith Kline & French; U.S. launch 1961); and pargyline (Abbott’s Eutonyl, patented in 1962 to Abbott; U.S. launch 1963). Nialamide, isocarboxazid, and phenelzine are all hydrazine derivatives.

   In 1968 Donald S. Robinson (1928–) and co-workers at the National Heart Institute determined in an article published in Biochemical Pharmacology that blood platelets are rich in monoamine oxidase, and they developed a simple test for measuring the blood level of MAOIs by monitoring the level of the enzyme in the platelets. This made it possible to titrate doses more effectively. Arising from this work, Robinson and Alexander Nies (1930–1989), an assistant professor of psychiatry at Vermont (where Robinson had in the meantime moved), conducted the first double-blind placebo-controlled trial of an MAOI—phenelzine—clearly establishing its effectiveness in depression-anxiety (see their article in Archives of General Psychiatry, 1973). On the scientific pathway of the monoamine oxidases, an important step was separating the two chemical variants, called A and B. This matters because some drugs act only on one or the other. In making this differentiation, two scientists in different laboratories reported more or less simultaneously: Moussa Youdim (1940–) was one; he had trained in pharmacology at McGill University and in the United Kingdom. In various papers from 1969 onward with Merton Sandler (1926–), professor of chemical pathology at several London institutions, Youdim characterized the two forms of monoamine oxidase. Working with Pletscher and pharmacologist Willi Haefely (1930–1993) at Roche, Youdim developed the drug moclobemide (Aurorix in some markets) for affective disorders, the first "reversible" (short-acting) MAO-A inhibitor without a potentially fatal side effect that plagued some of the older MAOIs (known as the "cheese reaction"). The other scientist simultaneously at work on MAOI subtypes was Joseph Knoll (1925–), a Budapest pharmacologist who in 1972 developed the drug selegiline (Deprenyl, among other trade names) for depression and Parkinsonism; selegiline is an MAO-B inhibitor and does not cause the cheese reaction.

   (See Knoll and K. Magyar’s article in Advances in Biochemical Psychopharmacology [1972]; they were apparently unaware of Youdim’s work.) In sum, the iproniazid story represents the initial discovery that modifying brain neurotransmitters could influence the course of psychiatric illness. As Alfred Pletscher later commented, "Although iproniazid has not been a commercially successful antidepressant, it was a remarkable breakthrough for drug research. It started research on MAO-inhibitors, which is still going on. . . . Iproniazid was one of the first modern psychotropic drugs shown to cause an alteration of cerebral neurotransmitter dynamics in vivo [in humans and animals]. This finding supported the general hypothesis that such changes might be causally connected with the action of antidepressant drugs in man" (in Ban, editor, Reflections on Twentieth-Century Psychopharmacology [2004], pp. 177–178).