Kevin Nasky, DO
May 31, 2015
Kevin Nasky, DO
Not much.
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
WHAT DID WE KNOW IN 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
DISCOVERED BEFORE 1950
“When I was an undergraduate student at Cambridge (late
50s) we were taught…there was no chemical transmission
in the brain…
NeurotransmissionNeurotransmission
was thought to be an entirely electricalelectrical
phenomena
19501950
⎯ that it was just an electrical machineelectrical machine”Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford
“When I was an undergraduate student at Cambridge (late
50s) we were taught…there was no chemical transmission
in the brain…
NeurotransmissionNeurotransmission
was thought to be an entirely electricalelectrical
phenomena
19501950
⎯ that it was just an electrical machineelectrical machine”Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford
Acetylcholine was known to be a neurotransmitter, but in the
peripheralperipheral
nervous system only
19501950
A lot.
WHAT DIDN’T WE KNOW IN 1950?
For example…
WHAT DIDN’T WE KNOW IN 1950?
…as late as 1960, (now Nobel
laureate) Arvid Carlsson
was
practically laughed out of town when
he proposed that dopamine might be
a neurotransmitter.
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.
WHAT DIDN’T WE KNOW IN 1950?
THE CONCEPT
OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST
HOW WERE WE TREATING MENTAL ILLNESS IN 1950?
Most “treatments”
were simply measures to sedate patients in
overcrowded asylums.
Physical Methods
Insulin coma
ECT Leucotomy
Bromides Barbiturates
Paraldehyde Opioids
Psychotropic Methods
Psychosis
Depression
Anxiety
TREATMENTS OF CHOICE
Insulin Coma
Deep Sleep
ECT
Opioids
Various meds
Leukotomy
Chlorpromazine and Reserpine
A QUICK REVIEW…
IN SEARCH OF BETTER ANTIHISTAMINES
What do Benadryl, Phenergan,
Thorazine and Tofranil have in common?
Speaking of Antihistamines…
Definitely not their
indications:
allergies, nausea,
psychosis and depression, respectively.
Speaking of Antihistamines…
A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine
(well, sort of)
Simple.
4 Easy Steps…
HOW DO YOU MAKE AN ANTIHISTAMINE?
Start with a substituted ethyl amine
Substitute methyl or other short alkyl groups in R1 and R2
X = C, O or NAdd an aryl group at R3 and R4
Example: diphenhydramine
Aryl groups at R3 & R4
Methyl groups at R1 & R2
X = oxygen
henri laboritExperimented with various
phenothiazine anti‐ histamines in his lytic
cocktails
to reduce analgesia required in
effort to reduce reduce surgical shocksurgical shock
paul charpentier
Charpentier synthesized a series of
phenothiazines that were strongly
antihistaminergic.The most prominent of
these was promethazine
Rhône‐Poulenc chemistphenothiazine expertsynthesized the first tricyclic antihistamine, promethazine
Promethazine fits the classic structure of an antihistamine
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 apprehensionTo produce light sleepTo reduce the incidence of nausea and vomiting
Laborit wonders if there’s an even better compound than promethazine
for his "lytic cocktail"Patients given Patients given
promethazine promethazine were more were more
calmercalmer
after after surgery, surgery,
needed needed lesslesspostpost‐‐op op
morphine morphine andandanesthesiaanesthesia
henri laborit
Laborit asksRhône‐Poulenc to
make a more centrally‐acting
antihistamine
PROMAZINEPROMAZINE
Replaced isopropyl group with a straight carbon chain propyl
propyl(3‐carbon alkyl)
Laborit has good results with Promazine, but said it was too weak.
Asks Charpentier: Can you make me a stronger Promazine?
It was well known that
adding a halogen adding a halogen to an organic molecule usually increased its potency and toxicity…
HOW DO YOU MAKE PROMAZINE MORE POTENT?
CHLORpromazine
so Charpentier added one chloride atom to Promazine
and forever
changed psychiatry.
Replace one sulfur atom…
BTW…
…with an ethylene linkage, preventing formation of the benzene ring and you get
imipramine
•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).
“ME TOO” DRUGS
Further manipulation of this molecular structure yielded numerous other agents with antipsychotic
activity.
“ME TOO” DRUGS
Summary (short version)
CHLORPROMAZINE
A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you
depressed)
Derived from Rauwolfia SerpentinaCommonly used antihypertensive in early
1950sNoted to have tranquilizing effectsNathan Kline (of iproniazid fame)
published a study in 1954 showing reserpine’s
effectiveness in treating
psychosis
RESERPINE SUMMARY
Ciba markets
“Serpasil”
I couldn’t resist the urge to
show this slide again
…acts as a gentle mood‐ leveling agent…sets up needed
‘tranquility barrier’
for many patients who, without some
help, are incapable of dealing calmly with a daily pile‐up of
stressful situations.
Give the boy…
Alternative to Serpasil for
Mom
..a bowl of
After a short‐lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming
depressed
and suicidal
Reserpine’s popularity
fades
Large contribution to eventual development of catecholamine hypothesis of depression and
dopamine hypothesis of psychosis
Reserpine’s Relevance
bernard ‘steve’
brodie
Brodie at NIH found that the brains of animals given 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
Inhibits ATP/Mg2+ pump responsible for the reuptake of NT into presynaptic vesicles
Results in NE and 5HT depletion
Reserpine’s Mechanism
A FAILED SLEEP AID AND ANTIPSYCHOTIC
Häfliger and Schinder Synthesize Imipramine
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
J.R. GEIGY PHARMACEUTICAL FIRM
roland
kuhnStaff Psychiatrist at
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
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.”
THIS AIN’T NO SLEEPING PILL
Münsterlingen
received a Largactil
gratis
Kuhn:
“The whole clinic was
swallowing Largactil”
1953 KUHN GETS FREE CHLORPROMAZINE FOR SIX MONTHS
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
R‐P SAYS “YOU GOT TO START PAYING”
Kuhn to boss: “You know, I’ve seen all this with a drug from Geigy”
Kuhn gets “huge bottles”
of G22350 from Geigy
MÜNSTERLINGEN CAN’T AFFORD − KUHN REMEMBERS GEIGY’S DRUG
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
G22350 DOESN’T COMPARE TO LARGACTIL
Kuhn’s verdict: “Not so good”
as a neuroleptic, but worked on endogenous depressionworked 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?
THE MAJORITY OF PATIENTS WORSENED ON G22355
“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.”
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.”
1955 KUHN GIVES G22355 TO 40 DEPRESSED PATIENTS
It’s important to note that Geigy
was searching for a neuroleptic to compete
with LargactilResistance 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.
G22355 GET SHELVED?
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
INFLUENTIAL GEIGY SHAREHOLDER ALTERS THE COURSE
•
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.”
BÖHRINGER: “KUHN IS RIGHT −
IT IS AN ANTIDEPRESSIVE”
•
Imipramine was the first “tricyclic”
because of its 3‐ring
chemical structure
•
Chlorpromazine molecule only 2 atoms different
1958 GEIGY NAMES G22355 “IMIPRAMINE”
heinz lehmann
“No one in his right mind No one in his right mind in psychiatry was in psychiatry was
working with drugsworking with drugs. You used shock or various
psychotherapies"
Berlin psychiatrist refugee from Nazi Germany, working in hospital in MontréalAuthor of one of the first North American papers on CPZNever owned a car, cycled everywhere
heinz lehmann
Impressed with Kuhn’s article, he obtained enough
samples of imipramine by airmail to treat depressed patients with equally good results.
Lehmann published his results with imipramine in the Canadian Med
Assoc J
1959imipramine
approved by FDA for the treatment of depression
1961 Rival TCA’s
flood
the market
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
1959: Imipramine’s MOA Still
Unknown
julius
axelrod•
Found enzyme
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."
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 pumpreuptake pump
in nerve endings
Where Did the NE Go?
Reuptake? 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.
Ignorance Isn’t Always a Bad Thing
Axelrod Proves that a Reuptake Mechanism Exists
Infused radiolabeled
NE
injected into animals is found in found in
sympathetic fiberssympathetic fibers
19611961
Imipramine Blocked the Blocked the ReuptakeReuptake of [
3H]‐NE
Gave imipramine to Gave imipramine to cats and measured cats and measured
the concentration of the concentration of injected [injected [33H]H]‐‐NENE
in various tissues.in various tissues.
1961
joseph
j. schildkraut
Groundbreaking 1965
paper proposed the catecholamine catecholamine hypothesis of depression. hypothesis of depression.
joseph
j. schildkraut
The catecholamine hypothesis of 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.”
TUBERCULOSIS LEADS TO AN UNEXPECTED
DISCOVERY
1951 IPRONIAZID SYNTHESIZED
Like isoniazid, iproniazid was found to be
tuberculostatic
Legendary Photo
Associated Press photo with patients dancing and clapping
a Staten Island TB sanitarium.
The caption under the photo supposedly referenced their recovery from TB as the reason for their levityreason for their levity, but others felt their
mood was more related to one of the drugs they had been given –
iproniazidiproniazid.
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
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 (?)
nathan kline, md
The first to show that
reserpine could be useful for treating
psychoses
Asked Roche to fund study of iproniazid in psychotic
patients
19541954
Roche Not InterestedRoche Not InterestedConcerns regarding side
effects
Rockland Hospital physician asks Kline if he had any ideas how to help “regressed”
inpatients
who had failed reserpine and chlorpromazine
nathan kline, md
“The drug…has produced ‘‘remarkableremarkable’’
mood mood
improvement improvement and activity among long‐term ‘untouchable’
psychotics
of the ‘burned‐out’ kind as well as among non‐
hospitalized neurotics”
Kline administered iproniazid to these 17
inpatients and 9 of his clinic outpatients
STILL NOT IMPRESSEDSTILL NOT IMPRESSED
Roche remained unenthusiastic but eventually acquiesced when Kline
threatened to publish his results anyway −
as publicly as possible
nathan kline, md
“As a side effectside effect…there developed an odd problem. The patients felt too patients felt too
goodgood…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.”
Kline reports the beneficial effects of iproniazid, an
MAOI, in the treatment of severe depression
A side effect of an anti‐ tuberculosis drug may have
led the way to chemical therapy for the unreachable,
severely depressed mental patient.. Dr. Nathan S.
Kline…
described the action of the drug as a kind of
"psychic energizer."
Dropped like a hot potato after 1951 trials against tuberculosis because of admittedly unpleasant
and possibly serious side effects, iproniazid was shunned until about
a year ago, when psychiatrists decided that it might be useful against deep, unshakable states of
depression.
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
IN SEARCH OF A BETTER ANTIBIOTIC
Frank Berger at Wallace working on synthetic bactericidal
compounds effective against penicillin‐resistant gram‐
negative bacteria
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
MEPHENESIN SYNTHESIZED
The disinfectant phenoxetol
was believed to be effective in combating gram‐negative
rods
Phenoxetol’s
carbon chain was lengthened to produce mephenesin, which showed
some efficacy
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
MEPHENESIN PARALYZES MICE
Autonomic nervous system unaffected Recovery was spontaneous and complete in an
hourUnlike barbiturates it had a
quieting effect on the demeanor of animals without a stage of
initial excitementThis effect was termed “tranquilization” by the
team in their first publication of this finding
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
Mephenesin’s
Use Was Limited By Three Significant Drawbacks
A very short duration of actionGreater effect on the spinal cord
than on supra‐spinal structuresWeak action so that large doses
were required
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
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
“MILTOWN”
Berger christened meprobamate “Miltown” after the New Jersey town Wallace laboratories was located in.
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 majority of respondents expressed little
interestinterest
WALLACE SHELVES MEPROBAMATE
Carter‐Wallace doubted there would be a viable pharmaceutical anxiety
drug market
and what would later be the bestthe best‐‐selling psychotropic drug selling psychotropic drug in American history wasin American history was, for the
time being, shelvedshelved.
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 The Healthy ““UnwellUnwell.”
1955 MILTOWN’S DEBUT
Berger shows Miltown film at the 1955 meeting of the federation of American
Societies for Experimental Biology in San Francisco
FILM SHOWED MONKEYS IN THREE DISTINCT CHEMICAL STATES
Naturally viciousUnconscious on barbituratesCalm but awake on Miltown
Film caught the attention of Wyeth executives
We Love Miltown!
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
THE LAUNCHING OF MILTOWN IN 1955 WAS A WATERSHED
195735 million prescriptions sold
One prescription per second
Fastest‐growing drug in history
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.”
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.”
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
Comedian Milton Berle:
“It’s worked wonders for me.
In fact, I’m thinking of changing my
name to Miltown Berle.”
“MILTOWN”
BECOMES A HOUSEHOLD NAME & PART OF THE CULTURAL LEXICON
•“Penicillin for the blues”
•“Miltown‐ing”•“Miltown cocktails”•“dehydrated martini”•“peace pills”•“happiness pills•“emotional aspirin”
In New York, the drug’s fanatical following among
the white‐collar weary earned it the nickname “executive Excedrin”
“Happy pill”
alternative for harried housewives and stressed‐out
commutersTranquilizer for the
healthy “unwell”
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.”
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
SIDE EFFECTS
The major side effects are sedation and mal‐coordination.
Toxic in high dosesLess lethal than intermediate‐acting
barbituratesA good deal more dangerous than
benzodiazepines
SIDE EFFECTS
Produces physical dependence and tolerance similar to barbiturates and the
benzodiazepines.
Significant withdrawal effects, such as convulsions, agitation, and delirium, occur
after clinically relatively lower doses
POST‐MILTOWN: BENZODIAZEPINES
Hoffmann – La Roche, New Jersey Leo Sternbach’s
synthesis of the
first benzodiazepines was inspired by chiorpromazine’s
tricycic
structure
TESTING LIBRIUM
Tested on a European lynx (noted to be among the least
tractable animals in captivity) in San Diego Zoo that had
bloodied its nose in a savage dash against the side of its
cage was treated with Librium and soon after was
frolicking frolicking ““like an alley like an alley kittenkitten.”
“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.”
ALSO TESTED ON PRISONERS
1960: LIBRIUM LAUNCHED
ROCHE’S CLAIMS:“Librium acts by allaying rage and anxiety
reactions without causing drowsiness or depressing mental activity.”
“Produces pure relief from strain without drowsiness or dulling of mental
processes…and unusual freedom from harmful side effects.”
Questions?