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.
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
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
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.
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
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).
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
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
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.”
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.
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;
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.”
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.”
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
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
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.”
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
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
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”
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.”