Barbiturates

   (1903 and after)

   Although the organic-chemical industry had introduced numerous sedatives before the barbiturates (chloral hydrate, for example, was first used in psychiatry in 1869), the barbiturates enjoyed great popularity for half a century because they tasted better, had fewer side effects, and were less toxic than their predecessors.

   In 1903, Emil Fischer (1852–1919), professor of chemistry in Berlin who had extensive contacts with industry, and Joseph von Mering (1849–1908), professor of internal medicine at Halle University, announced in Today’s Therapeutics (Therapie der Gegenwart) their discovery of the therapeutic use of the barbiturates as sedatives and hypnotics. Fischer had suggested to the Bayer company of Leverkusen, Germany, the improved production of diethylbarbituric acid (the parent barbiturate)—a compound first synthesized in 1863—opening the door to the pharmaceutical use of the barbiturate class. Barbital sodium, a "substituted" form of diethylbarbituric acid that was synthesized in 1882, was the first of the barbiturates and was marketed in 1903 by the Bayer company as Veronal and by the Schering company as Medinal: both brand names soon became household words. In 1911, Bayer patented phenobarbital (Luminal), an even more powerful sedative and anticonvulsant, bringing it out the following year. During the next 40 years, more than 2500 different barbiturate preparations followed, including pentobarbital sodium (patented by Bayer in 1916; Abbott introduced it in the United States in 1941 as Nembutal), amobarbital sodium (patented in 1924; Lilly introduced it as Sodium Amytal), butabarbital sodium (patented by Lilly in 1932; McNeil introduced it as Butisol Sodium), secobarbital sodium (patented in 1934; Lilly introduced it in 1945 as Seconal Sodium), and thiopental sodium (patented in 1939; Abbott introduced it as Pentothal Sodium).

   See Deep-Sleep Therapy and Barbiturates.

   Narcotherapy and barbiturates (1930 and after). In 1930, William J. Bleckwenn (1895–1965), assistant director of the Wisconsin Psychiatric Institute, proposed in the Journal of the American Medical Association (JAMA) intravenous injections of amobarbital (Sodium Amytal) in a number of psychiatric conditions, including depression: "The depression is certainly less profound and the course of the illness is materially shortened, with the use of the drug." In schizophrenia, "normal lucid intervals" of 4 to 14 hours had been achieved. Later that year in the Wisconsin Medical Journal, Bleckwenn added for depression, "[The patients] are more active, more talkative, have less constrained and less awkward attitudes" (p. 694). Over time, this procedure became known as the "amytal interview." Bleckwenn was said to have originated the term "truth serum," although it is now widely disbelieved that amobarbital serves any such function.* (In this 1930 article in JAMA, Bleckwenn also * Bleckwenn mentioned in passing in his JAMA article, under the rubric "schizophrenia," that amobarbital had been of value in the relief of "catatonic excitement"; later, he said proposed amobarbital for the relief of catatonia, where it functioned better than as an antidepressant.)

   In 1931, Erich Lindemann (1900–1974) at the Psychopathic Hospital in Iowa City, Iowa, called attention in the Proceedings of the Society for Experimental Biology and Medicine specifically to the ability of intravenous Sodium Amytal to induce "a feeling of serenity and well-being, a desire to communicate and to speak about problems or personal matters usually not spoken of to strangers. There was also the feeling of being unable to guard against saying things which one does not want to and an inability to refuse to answer questions even if they refer to very intimate matters" (p. 865). Therapeutically, the drug made catatonic patients who had been mute for months again communicative, and silent, guilt-stricken depressed patients willing to talk about their feelings.

   Meanwhile, in 1936 John Stephen Horsley (lic. MRCS Eng., LRCP, 1932 [MRCS = Member of the Royal College of Surgeons; LRCP = Licentiate of the Royal College of Physicians]), a staff psychiatrist at Dorset Mental Hospital in England, described in the Journal of Mental Science intravenous injections of another barbiturate, pentobarbital sodium (Nembutal), to achieve what he called "narco-analysis"— "a practical substitute for the economically unavailable, if desirable, method of psychoanalysis." In 1945, Roy R. Grinker (sen.) (1900–1993) and John Paul Spiegel (1911–?) of Chicago, first in their book War Neuroses in North Africa (1943) then in Men Under Stress (1945), suggested "narcosynthesis" using intravenous sodium pentothal as a way of performing the "uncovering of anxieties and conflicts and the production of adequate abreactions" in the brief time available to military medicine. The technique: "The patient is given the drug until his counting aloud ceases and he begins to take deep, stertorous breaths." The interview begins at that point. "The best method is to start the patient talking and let him continue uninterrupted in spite of associations leading him far from the subject of war" (Men Under Stress, pp. 389–390). "Synthesis" meant the "recapture by the ego of alienated ideas and emotions" and "the synthesis of related feelings that have been separated by the process of dissocation" (p. 393).

   Narcotherapy represents one of the first important American contributions to the international narrative of psychiatry (if one exempts the diagnosis "neurasthenia" [from George M. Beard, an electrotherapist, 1839–1883] and the "rest cure" treatment [from Silas Weir Mitchell, a neurologist]).

   The restorative effects of barbiturates in schizophrenia (1948). A team of researchers led by neurophysiologist Seymour Kety (1915–2000) and including Carl Frederic Schmidt (1893–1988), Fritz Freyhan (1912–1982), and Kenneth E. Appel (1896–1979)—all at the Pennsylvania School of Medicine with the exception of Freyhan that it "awakened" catatonic patients, an observation that had considerable impact on the treatment of psychosis. Max Fink recalls, "One of the delights of being a medical student in 1942–1945 and then as a resident at Bellevue 1949–1951 was the opportunity to use amobarbital for catatonic patients. We were given syringe, needles, tourniquet, water and allowed (encouraged) to give IV injections when so ordered."

   (who was a psychiatrist at the Delaware State Hospital)—set out to study changes in the cerebral blood flow of schizophrenics produced by various therapies, including barbiturates. They found rather serendipitously that Sodium Amytal and pentothal produced a significant but temporary lessening of symptoms in schizophrenia. Of this publication in 1948 in the American Journal of Psychiatry Kety later said, "[Here] I saw the temporary but remarkable restoration in the thinking and affect of some schizophrenics under the influence of sodium amytal narcosis. I was impressed that a drug could produce such dramatic effects, which suggested that biochemical processes . . . were responsible for the psychotic symptoms" (Shepherd, Psychiatrists on Psychiatry, p. 85). On the basis of this research, in 1951 Robert Felix made Kety the first scientific director of the National Institute of Mental Health.

   The barbiturates as Delay’s "psycholeptics" (1949). In a paper in the Proceedings of the Royal Society of Medicine, Jean Delay called the sodium barbiturates "psycholeptic" because they produced a lowering of intrapsychic tensions "and are depressants of psychological tonus." By contrast, the amphetamine methamphetamine (Methedrine), at the time used therapeutically, was a "psychogogue" because it increased "intrapsychic tension."

   Charles Shagass’s "sedation threshold" (1954). In 1954 in Electroencephalography and Clinical Neurophysiology, Charles Shagass (1920–), a psychiatrist–electrophysiologist at McGill University, showed quantitatively that the presence of the "sedation threshold" with the barbiturates differs in different kinds of illnesses. (Schizophrenic and anxious patients require larger amounts of amobarbital than do patients with major depression and organic brain disease.) This was an early exercise in using psychopharmacology as a diagnostic torch.

   The Weinstein–Kahn amobarbital test for organic brain disease (1955). As a result of the Grinker–Spiegel reports (see above), military doctors became accustomed to using amobarbital freely. In 1955, Edwin Alexander Weinstein (1909– 1998),* a Washington, D.C., neurologist and psychiatrist who consulted widely in area military hospitals, and Robert L. Kahn (1918–), a psychologist at Mount Sinai Hospital in New York, proposed in their "denial hypothesis" of behavior that the administration of amobarbital in patients with organic brain disease would, in inquiries about orientation, elicit denial and minimization of illness but have no such effect in psychiatric patients with normal brain function. See their Denial of Illness (1955).

   The barbiturates revived in the treatment of catatonic mutism (1992). Many years after the above discoveries, W. Vaughn McCall (1958–) in the Department of Psychiatry at Duke University and co-investigators conducted a randomized controlled trial of amobarbital versus placebo in catatonic mutism: They found it fairly effective, placebo not at all. They chose amobarbital over a benzodiazepine because they felt it had maintained its historic reputation as the "gold standard" (see their article in the American Journal of Psychiatry, 1992). *Weinstein is also remembered for a medical biography of President Woodrow Wilson (1981); in 1968 he moved to New York, becoming professor of neurology at Mt. Sinai Medical School.