Neurotransmission Discoveries in 1950
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The document discusses what was known about neurotransmission and the treatment of mental illness in 1950. It notes that at the time, neurotransmission was thought to be purely electrical and acetylcholine was the only known neurotransmitter. Treatments for conditions like psychosis, depression and anxiety primarily involved sedation or therapies aimed at inducing sleep or seizures. The development of chlorpromazine and reserpine in the early 1950s provided the first effective antipsychotic and antidepressant medications and helped establish the concept of psychopharmacology.
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Neurotransmission Discoveries in 1950
- 3. WHAT DID WE KNOW IN 1950? Not much.
- 4. WHAT DID WE KNOW IN 1950? ⎯ Brain was thought to be entirely electrical ⎯ Acetylcholine was the only known neurotransmitter ⎯ Knew acetylcholine was inactivated by choline esterase
- 5. DISCOVERED BEFORE 1950 ⎯ Existence of serotonin in platelets ⎯ LSD (that it was a hallucinogen and that it was chemically related to 5HT) ⎯ The enzyme that oxidized adrenaline: “Amine Oxidase” ⎯ Antihistamines
- 6. “When I was an undergraduate 1950 student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… ⎯ that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Neurotransmission was thought to be an entirely electrical phenomena
- 7. “When I was an undergraduate 1950 student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… ⎯ that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Neurotransmission was thought to be an entirely electrical phenomena
- 8. 1950 Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only
- 9. WHAT DIDN’T WE KNOW IN 1950? A lot.
- 10. WHAT DIDN’T WE KNOW IN 1950? For example…
- 12. WHAT DIDN’T WE KNOW IN 1950? Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead.
- 13. THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST
- 14. HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums.
- 15. Physical Methods
- 16. Insulin coma Leucotomy ECT
- 17. Psychotropic Methods Bromides Barbiturates Paraldehyde Opioids
- 18. TREATMENTS OF CHOICE Psychosis Insulin Coma Deep Sleep Depression ECT Opioids Anxiety Various meds Leukotomy
- 19. A QUICK REVIEW… Chlorpromazine and Reserpine
- 21. Speaking of Antihistamines… What do Benadryl, Phenergan, Thorazine and Tofranil have in common?
- 22. Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively.
- 23. A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of)
- 24. HOW DO YOU MAKE AN ANTIHISTAMINE? Simple. 4 Easy Steps…
- 26. Example: diphenhydramine X = oxygen Aryl groups at R3 & R4 Methyl groups at R1 & R2
- 27. henri Experimented with various phenothiazine anti‐ laborit histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock
- 28. paul Charpentier charpentier synthesized a series of phenothiazines that Rhône‐Poulenc were strongly chemist antihistaminergic. phenothiazine The most prominent of expert synthesized the first these was tricyclic promethazine antihistamine, promethazine
- 30. Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting
- 31. Laborit wonders if there’s an even better compound than promethazine for his quot;lytic cocktailquot; Patients given promethazine were more calmer after surgery, needed less post‐op morphine and anesthesia
- 32. henri Laborit asks laborit Rhône‐Poulenc to make a more centrally‐acting antihistamine
- 33. PROMAZINE propyl (3‐carbon alkyl) Replaced isopropyl group with a straight carbon chain propyl
- 35. HOW DO YOU MAKE PROMAZINE MORE POTENT? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity…
- 36. so Charpentier added one chloride atom to Promazine and forever changed psychiatry. CHLORpromazine
- 39. imipramine
- 40. “ME TOO” DRUGS •Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). •Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin).
- 46. A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed)
- 47. RESERPINE SUMMARY Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis
- 50. Alternative to Serpasil for Mom Give the boy…
- 51. ..a bowl of
- 52. Reserpine’s popularity fades After a short‐lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming depressed and suicidal
- 53. Reserpine’s Relevance Large contribution to eventual development of catecholamine hypothesis of depression and dopamine hypothesis of psychosis
- 54. bernard Brodie at NIH found that ‘steve’ the brains of animals given brodie reserpine had very low levels of 5HT and NE Suggested that reserpine inactivates a mechanism to essential for 5HT storage first demonstration of a link between brain chemistry and behavior
- 58. J.R. GEIGY PHARMACEUTICAL FIRM Swiss firm founded in 1758 Geigy later merged with Swiss firm CIBA to form Ciba‐Geigy in 1970 Ciba‐Geigy and Sandoz Laboratories merge in 1996 to form Novartis
- 59. Staff Psychiatrist at roland kuhn Münsterlingen ‐ Head of Pharmacologic Initiatives Background in biochemistry, organic chemistry, and psychoanalysis Trained under Jakob Klaesi (“prolonged sleep therapy,” “deep sleep cure”) Geigy pharmacologist, Domenjoz, asks Kuhn to try new ‘sleeping pill’: G22150
- 60. THIS AIN’T NO SLEEPING PILL Kuhn to Domenjoz: “This is no sleeping pill, but (it) has curious effects on chronic schizophrenics − not on their sleeping pattern, but on their schizophrenic symptoms.”
- 61. 1953 KUHN GETS FREE CHLORPROMAZINE FOR SIX MONTHS Münsterlingen received a Largactil gratis Kuhn: “The whole clinic was swallowing Largactil”
- 62. R‐P SAYS “YOU GOT TO START PAYING” Kuhn (paraphrasing): After six months an R‐P rep said that the trial phase was over, and now we’d have to pay Münsterlingen’s pharmacy budget was 6000 Swiss Francs per year, which was needed foremost for morphine and scopolamine
- 64. G22350 DOESN’T COMPARE TO LARGACTIL Unpleasant side effects and not as efficacious as Largactil Kuhn to Geigy chemist: “You should use the same side chain as Largactil.” Substance already existed: G22355
- 65. THE MAJORITY OF PATIENTS WORSENED ON G22355 Kuhn’s verdict: “Not so good” as a neuroleptic, but worked on endogenous depression G22355 had a disinhibitory effect, “almost manic” “Converting quiet chronic patients into agitated whirlwinds of energy” Kuhn & Geigy scientists confused: Why such a bizarre response?
- 66. 1955 KUHN GIVES G22355 TO 40 DEPRESSED PATIENTS “Patients become generally more lively; their low depressive voices sound stronger. (They) appear more communicative, the yammering and crying come to an end. If the depression had manifested itself in a dissatisfied, plaintive, or irritable mood, a friendly, contented and accessible spirit comes to the fore. Hypochondriacal and neurasthenic complaints recede or disappear entirely.”
- 67. 1955 KUHN GIVES G22355 TO 40 DEPRESSED PATIENTS Kuhn told of patients who were ready to jump out of bed in the morning, to socialize easily with fellow patients… “…to amuse themselves and take part in the general life of the hospital, to write letters and interest themselves again in their family circumstances.”
- 69. G22355 GET SHELVED? It’s important to note that Geigy was searching for a neuroleptic to compete with Largactil Resistance stemmed from the thinking that if there was going to be an effective antidepressant (“psychic energizer”), that it would be a stimulant and not a sedative − the idea that a “sedative” could work as an antidepressant was counterintuitive.
- 70. INFLUENTIAL GEIGY SHAREHOLDER ALTERS THE COURSE Robert Böhringer was very influential within the company Had penchant for roaming about company asking people what they were working on Had a depressed relative − knew about G22355 − took some to her and she was “cured” in five days
- 71. BÖHRINGER: “KUHN IS RIGHT − IT IS AN ANTIDEPRESSIVE” • Geigy introduces drug in Switzerland • 1957 Kuhn presents remarkably positive results of trial to 2nd international congress of psychiatrists in Zürich • Only 12 people in attendance • “Nobody believed there could be a drug against depression.”
- 72. 1958 GEIGY NAMES G22355 “IMIPRAMINE” • Imipramine was the first “tricyclic” because of its 3‐ring chemical structure • Chlorpromazine molecule only 2 atoms different
- 73. Berlin psychiatrist refugee from Nazi heinz Germany, working in hospital in Montréal lehmann Author of one of the first North American papers on CPZ Never owned a car, cycled everywhere “No one in his right mind in psychiatry was working with drugs. You working with drugs used shock or various psychotherapiesquot;
- 74. heinz Lehmann published his results with imipramine lehmann in the Canadian Med Assoc J Impressed with Kuhn’s article, he obtained enough samples of imipramine by airmail to treat depressed patients with equally good results.
- 75. 1959 imipramine approved by FDA for the treatment of depression 1961 Rival TCA’s flood the market
- 77. 1959: Imipramine’s MOA Still Unknown Jacobsen (1959): “Where the effect of imipramine…is still a complete riddle which must await elucidation. Here our present ignorance is such that not even a preliminary hypothesis can be offered.” Jacobsen E: The theoretical basis of the chemotherapy of depression. Proceedings of the Symposium Held at Cambridge, 22 to 26 September, 1959, edited by Davies EB. New York, Cambridge University Press, 1964
- 78. • Found enzyme julius axelrod COMT • Discovered the P‐450 system • Nobel Prize 1970 “For discoveries concerning the humoral transmitters in the nerve terminals and the mechanism for their storage, release and inactivation.quot;
- 79. Where Did the NE Go? Studies showed NE was inactivated even when COMT and MOA were inhibited suggesting it was removed some other way. Where did the rest of it go? Axelrod proposes there’s a reuptake pump in nerve endings
- 80. Ignorance Isn’t Always a Bad Thing Reuptake? Pharmacologic theory at the time never considered such a mechanism existed. Axelrod later admitted that if he’d known more about pharmacology he would have never considered the idea.
- 81. 1961 Infused radiolabeled NE injected into animals is found in sympathetic fibers Axelrod Proves that a Reuptake Mechanism Exists
- 82. Gave imipramine to 1961 cats and measured the concentration of injected [3H]‐NE in various tissues. Imipramine Blocked the Reuptake of [3H]‐NE
- 83. joseph j. schildkraut Groundbreaking 1965 paper proposed the catecholamine hypothesis of depression.
- 84. joseph j. The catecholamine hypothesis of schildkraut affective disorders proposes that if some, if not all, depressions are associated with an absolute or relative decrease in catechol‐ amines, particularly norepinephrine, available central adrenergic receptor sites. Elation, conversely, may be associated with an excess of such amines.”
- 87. TUBERCULOSIS LEADS TO AN UNEXPECTED DISCOVERY
- 88. 1951 IPRONIAZID SYNTHESIZED Like isoniazid, iproniazid was found to be tuberculostatic
- 90. IPRONIAZID INHIBITS MONOAMINE OXIDASE • Zeller et al. had earlier discovered that anti‐TB drugs inhibited diamine oxidase • Also discovered that iproniazid (but not isoniazid) also inhibits monoamine oxidase
- 91. DELAY & DENIKER PARIS, 1951 • Delay and Deniker (of chlorpromazine fame) purport isoniazid’s “antidepressant” effects at Société Médico‐Psychologique • Never claimed credit for discovering antidepressants despite (?)
- 92. nathan The first to show that 1954 kline, md reserpine could be useful for treating psychoses Asked Roche to fund study of iproniazid in psychotic patients
- 93. Roche Not Interested Concerns regarding side effects Rockland Hospital physician asks Kline if he had any ideas how to help “regressed” inpatients who had failed reserpine and chlorpromazine
- 94. Kline administered nathan iproniazid to these 17 kline, md inpatients and 9 of his clinic outpatients “The drug…has produced ‘remarkable’ mood improvement and activity among long‐term ‘untouchable’ psychotics of the ‘burned‐out’ kind as well as among non‐ hospitalized neurotics”
- 96. Kline reports the beneficial nathan effects of iproniazid, an kline, md MAOI, in the treatment of severe depression “As a side effect…there developed an odd problem. The patients felt too good…overexerting themselves and… ignoring the medical safeguards their condition required. Iproniazid’s potential as a mood drug had gone largely unnoticed because psychiatrists at the time just weren’t thinking along those lines.”
- 99. IPRONIAZID’S FATE • 1959 Phenelzine (Nardil) Approved By the FDA • 1961 iproniazid (Marsilid) withdrawn as being too hepatotoxic for clinical use • 1964 Kline receives second Lasker award
- 103. CARTER-WALLACE Specialized In OTC Meds Carter’s Little Liver Pills “When you feel sour and sunk, and the world looks punk . . . Take a Carter’s Little Liver Pill.” In 1951 the FTC told Carter-Wallace to cut the word “liver” out of the product name
- 105. MEPHENESIN PARALYZES MICE During safety tests, mice developed a reversible flaccid paralysis of the voluntary skeletal muscles •Vital functions preserved •Remained conscious •Responded to painful stimuli •Corneal reflex was preserved
- 106. MEPHENESIN PARALYZES MICE Autonomic nervous system unaffected Recovery was spontaneous and complete in an hour Unlike barbiturates it had a quieting effect on the demeanor of animals without a stage of initial excitement This effect was termed “tranquilization” by the team in their first publication of this finding
- 107. Mephenesin introduced as a muscle relaxer for use in anesthesia Mephenesin was first introduced in clinical practice as an agent for producing muscle relaxation during light anesthesia by Mallison in 1947 as an alternative to tubocurarine Its anti‐anxiety effect was recognized only in brief case reports
- 108. Mephenesin’s Use Was Limited By Three Significant Drawbacks A very short duration of action Greater effect on the spinal cord than on supra‐spinal structures Weak action so that large doses were required
- 109. BERGER SOUGHT TO DELAY MEPHENESIN’S RAPID BREAKDOWN He found that its short duration of action was due to the rapid oxidation so he synthesized various derivatives that were less susceptible to enzymatic attack
- 110. 1951 MEPROBAMATE SYNTHESIZED MEPROBAMATE’S ADVANTAGES OVER MEPHENESIN •More stable •Duration of action 8X longer •Readily absorbed from the GI tract •Had tranquilizing effect on monkeys so that they lost their viciousness and could be more easily handled
- 111. “MILTOWN” Berger christened meprobamate “Miltown” after the New Jersey town Wallace laboratories was located in.
- 112. Wallace withholds financial support to market Miltown • Carter‐Wallace initially wouldn’t give Berger financial support ($500,000) to bring the meprobamate to market • There was no preexisting market for prescription‐only tranquilizers • Wallace conducted a survey of 200 doctors to gauge interest in prescription anxiolytics − the majority of respondents expressed little interest
- 113. WALLACE SHELVES MEPROBAMATE Carter‐Wallace doubted there would be a viable pharmaceutical anxiety drug market and what would later be the best‐selling psychotropic drug in American history was, for the time being, shelved.
- 114. WALLACE SHELVES MEPROBAMATE Wallace had a change of heart only after the phenomenal success of chlorpromazine in 1953 and meprobamate resurfaced from hibernation that year as the American answer to the French chlorpromazine albeit with a marketing strategy that focused on a different clientele! − The Healthy “Unwell.”
- 115. 1955 MILTOWN’S DEBUT Berger shows Miltown film at the 1955 meeting of the federation of American Societies for Experimental Biology in San Francisco
- 116. FILM SHOWED MONKEYS IN THREE DISTINCT CHEMICAL STATES Naturally vicious We Lov Unconscious on Mil e barbiturates tow n! Calm but awake on Miltown Film caught the attention of Wyeth executives
- 117. WYETH BUYS RIGHTS TO MARKET AS “EQUANIL” • The first drug to be sold specifically as an anxiolytic • Touted as able to ameliorate anxiety but not sedating
- 118. THE LAUNCHING OF MILTOWN IN 1955 WAS A WATERSHED 1957 35 million prescriptions sold One prescription per second Fastest‐growing drug in history
- 119. HAPPINESS BY PRESCRIPTION “The use of tranquilizers has spread to the masses of…neurotics and (others) vexed with problems and pressures.” Due to state laws permitting unlimited refills… “Miltown (was) the hottest (item) in many…big city pharmacies.” Family practice physician quoted: “The physician knows that if he doesn’t give them someone else will…Only a small number of people can get psychiatric help, so a lot of emotional problems are thrown back to the family physician; he turns to tranquilizers that he might not use if he had more time.”
- 120. HAPPINESS BY PRESCRIPTION Busy Beverly Hills Psychiatrist confesses that he sometimes pops down a tranquilizer himself to prepare for the nerve‐wrenching drive home from the office: “I wish the government would subsidize slot machines for tranquilizers on every corner.”
- 121. THE NON NARCOTIC ADDICTS 1965 article highlighting medical community’s recent discovery that so‐ called “minor tranquilizers,” e.g. barbiturates, meprobamate, chlordiazepoxide and amphetamines are as potentially addictive as narcotics and can lead to intoxication and dependence
- 122. Comedian Milton Berle: “It’s worked wonders for me. In fact, I’m thinking of changing my name to Miltown Berle.”
- 123. “MILTOWN” BECOMES A HOUSEHOLD NAME & PART OF THE CULTURAL LEXICON •“Penicillin for the In New York, the drug’s blues” fanatical following among •“Miltown‐ing” the white‐collar weary earned it the nickname •“Miltown cocktails” “executive Excedrin” •“dehydrated martini” “Happy pill” alternative •“peace pills” for harried housewives •“happiness pills and stressed‐out •“emotional aspirin” commuters Tranquilizer for the healthy “unwell”
- 124. ADVICE FROM MEDIA The Hollywood tabloid Uncensored! reassured patients they could take Miltown and Equanil with confidence because “They are not habit forming and even a severe overdose can’t kill you.”
- 125. MEPROBAMATE PHARMACOLOGY • Meprobamate does not affect benzodiazepine or GABA receptors. • It appears to act by potentiating the action of endogenously released adenosine; it blocks reuptake of adenosine, which is itself a sedative
- 130. POST‐MILTOWN: BENZODIAZEPINES Hoffmann – La Roche, New Jersey Leo Sternbach’s synthesis of the first benzodiazepines was inspired by chiorpromazine’s tricycic structure
- 132. ALSO TESTED ON PRISONERS “Classic psychopathic personalities with lifelong histories of antisocial behavior [who were formerly] mutilating themselves, setting fires and starting fights [on Librium became] placid and alert, despite their tension‐provoking environment.”
- 135. Questions?