Grand rounds presentation reviewing the history of the development of the first antipsychotic medications: reserpine and chlorpromazine (Thorazine). Part one of a two-part presentation.
2. the restraints
pre‐neuroleptic ECT
era insulin coma
hydrotherapy
pharmacologic
chloral hydrate
paraldehyde
barbiturates
Goal was to control agitation
and reduce violence. No
other alternatives.
3. the restraints
pre‐neuroleptic ECT
era insulin coma
hydrotherapy
pharmacologic
chloral hydrate
paraldehyde
barbiturates
Solid treatment for severe
depression and an excellent
means of controlling extreme
agitation.
4. the restraints
pre‐neuroleptic ECT
era insulin coma
hydrotherapy
pharmacologic
chloral hydrate
paraldehyde
barbiturates
Sakel’s insulin‐induced coma
was the gentler and less
deleterious of the somatic
techniques
5. the restraints
pre‐neuroleptic ECT
era insulin coma
hydrotherapy
pharmacologic
chloral hydrate
paraldehyde
barbiturates
Sakel’s insulin‐induced coma
was the gentler and less
deleterious of the somatic
techniques
6. the restraints
pre‐neuroleptic ECT
era insulin coma
hydrotherapy
pharmacologic
Synthesized in 1832
chloral hydrate
Fulfilled need paraldehyde
barbiturates
for a sleep‐
Doesn’t disrupt sleep architecture
aid Withdrawal reactions virtually
unheard of.
Reasonably safe.
7. the restraints
pre‐neuroleptic ECT
era insulin coma
hydrotherapy
pharmacologic
disadvantages chloral hydrate
offensive paraldehyde
barbiturates
order
addictive Often the preferred
drug for treating
alcohol withdrawal
8. the restraints
pre‐neuroleptic ECT
era insulin coma
hydrotherapy
pharmacologic
Popular in chloral hydrate
paraldehyde
1930‐1940s barbiturates
Strong abuse potential
Lethal in overdose
9.
10. the BROMIDES
pre‐neuroleptic Used to tx canine seizures
Widely used in 19th Century
era “Sleeping salts”
Low doses were part of OTC
preparations up to 1960's
very small therapeutic index
Bromism (central reactions reaching from
somnolence to coma, cachexia, exicosis, loss of
reflexes or pathologic reflexes, clonic seizures,
tremor, ataxia, loss of neural sensitivity, paresis,
papillar edema of the eyes, abnormal speech,
cerebral edema, delirium, aggressiveness,
psychoses)
11. the BROMIDES
pre‐neuroleptic 1930 four of every 10
era prescriptions written by
doctors were for drugs
containing bromides
Early 1900s: millions of people taking bromides
prescribed as a cure for everything from
battlefield anxiety to masturbation; given to
pregnant women for quot;nerves,quot; two children for
quot;overactivity,quot; and to just about anybody who
couldn't sleep well at night.
12.
13. the Psychosurgery
pre‐neuroleptic
era • Portuguese neurologist Egas
Moniz introduced the
prefrontal leukotomy
• no alternative therapies
available for chronically
institutionalized patients
17. INDIA 1949 King Edward VII
Memorial Hospital,
Bombay
Rustom Jal Vakil publishes A Clinical Trial of
Rauwolfia Serpentina in Essential
Hypertension in The British Medical Journal.
18. His historical 1949
rustom jal vakil paper proclaimed
that Rauwolfia
was a powerful
tranquilizing agent.
His 1957 Lasker Award citation
noted that his work open up
“an entirely new method of
study of mental disorder itself.”
19. SWITZERLAND
1952
Emil Schlitter et al. publish the structure
of reserpine, which they claim was
active component of Rauwolfia
21. robert w HTN expert; AHA president
He & colleagues at Boston U. use
wilkins, md reserpine for the 1st time in the US
Noted its “remarkable therapeutic
effectiveness for the management
of hypertension.”
Also noted mental status
changes
“I haven't felt this good for
years,” … “nothing bothers
me anymore.”‐ Wilkins’s patients
22. NEW YORK
1954
Swiss pharm company Ciba
asks Dr. Nathan Kline to
undertake a study of Rauwolfia.
23. gave Rauwolfia to over 700 patients
nathan the first to show that reserpine
could be useful for treating
kline, md psychoses
Later, in 1957, first reported the
beneficial effects of iproniazid in
the treatment of severe depression
“Dr. Kline more than any other single
psychiatrist has been responsible for
one of the greatest revolutions
ever to occur in the care and
treatment of the mentally ill.” ‐ Lasker
Award Citation
28. Reserpine’s Role in the Advancement of
Psychopharmacology
The study of reserpine played a
pivotal role in the development
of the dopamine theory of
schizophrenia, and the biogenic
amine theory of depression
30. bernard Found that the brains of
‘steve’ animals given reserpine
brodie have 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
36. henri French Naval surgeon &
anesthetist
laborit sought pharmacological
prevention of surgical shock
because histamine lead to
hypertension…
…one hypothesis was
that histamine release
causes shock
37. Goal: reduce autonomic
henri activity during and after
laborit surgery via a complex
pharmacological regime
The “lytic cocktail” was
born
(i.e. sympatho‐parasympatho‐lytic)
This cocktail included
the phenothiazine,
promethazine.
40. observed patients who received
henri promethazine were more calm
laborit and relaxed after surgery
postoperative morphine was
unnecessary
lower doses of anesthetic
agents required
Laborit wonders if there’s an
even better compound than
promethazine for his quot;lytic
cocktailquot;
43. Rhône‐Poulenc chemist
paul phenothiazine expert
charpentier synthesized the first tricyclic
antihistamine, promethazine
chlorination was known to make
compounds more potent
Charpentier chlorinated a
phenothiazine derivative RP‐4560,
which he sends to Simone
Courvoisier
44. simone
courvoisier
Rhône‐Poulenc Head of Pharmacology
ran team that performed series of
screening tests for antihistamine effects
use of rope climbing test may be the first
use of a behavioral test to screen for
pharmacologic properties
45. Courvoisier’s tests demonstrated
that RP‐4560…
potentiated barbiturates
was an anti‐emetic
was an α‐blocker
inhibited conditioned avoidance
response ⎯ rope climbing test
46. Ingredients for rope climbing test
rats
platform with food
rope tied to the platform
shock stimulus
rats were conditioned to climb
rope after hearing auditory
stimulus associated with electrical
shock
rats given RP‐4560 didn’t climb
the rope to get the food, even
when alerted to the eminence of
a shock
47.
48. We don’t experiment the way
we used to.
Laborit participated in the first
administration of chlorpromazine to a
normal subject – his psychiatrist
friend, Dr. Quatri.
She described an initial period of
awkwardness, replaced later by ‘an
extreme feeling of detachment’ in
which perception was ‘filtered,
muted.’
50. First patient treated with
chlorpromazine
57 y/o laborer admitted to the Val‐de‐Grace
secondary to erratic uncontrollable behavior.
Before hospitalization, he’d made impassioned
political speeches in cafés, proclaimed a love of
liberty while walking down the street with a flower
pot, and intermittently assaulted strangers. Within
one day of receiving chlorpromazine, he was noted
to be more calm, and one week later he was joking
with the medical staff. After three weeks, the
patient appeared nearly normal and was
discharged.
52. Along with Pierre Deniker,
Jean Delay he was the first psychiatrist
to recognize the therapeutic
value of phenothiazines in
the treatment of
schizophrenia
Proposed the definition of
neuroleptic drugs
(literally, quot;substances that
take the nervesquot;)
54. MONTRÉAL
1953
Heinz Lehmann writes one of the
first North American publications
on chlorpromazine
55. Berlin psychiatrist refugee from Nazi
heinz Germany, working in hospital in
Montréal
lehmann Regularly read European journals;
learned of Delay and Deniker’s work
Never owned a car, cycled everywhere
One of the first psychiatrists in North
America to introduce imipramine
“No one in his right mind
in psychiatry was
working with drugs. You
used shock or various
psychotherapiesquot;
65. Wonder Drug of
1954?
Monday, Jun. 14, 1954
For several types of mental patients, especially senile psychotics, it
serves as a highly effective relaxer. After a few doses, says Dr. Scull of
Smith, Kline & French, patients who were formerly violent or withdrawn
lie quot;molded to the bed.quot; When a doctor enters the room, they sit up
and talk sense with him, perhaps for the first time in months. There is
no thought that chlorpromazine is any cure for mental illness, but it
can have great value if it relaxes patients and makes them accessible to
treatment. The extremely agitated or anxious types often give up
compulsive behavior, a surface symptom of their illness. It is, says Dr.
Scull, as though the patients said, quot;I know there's something disturbing
me, but I couldn't care less.quot;
66. Pills for the Mind
Monday, Jun. 11, 1956
Chlorpromazine (brand name: Thorazine), first of the ataraxics or tranquilizing
drugs used in North America, has clinched its leadership as the one most
generally effective in treating the severe mental illnesses that usually need
hospitalization. The earlier used, the better. It is best in agitated cases, least
effective (and occasionally harmful) in the depressed.
Reserpine, synthesis of which was announced by Harvard's Professor Robert B.
Woodward,*has the advantage over chlorpromazine that large doses can be
given to calm acutely disturbed patients. Mississippi's Dr. Veronica Pennington
finds that the most enduring tranquilization of state‐hospital patients comes
from reserpine; its effects persist as long as a month after the last dose has
been administered. To cut down the cases of depression caused by reserpine,
one manufacturer (Ciba) is combining it with a second drug, Ritalin, designed
to give a lift.
67. the fluphenazine
post‐thorazine promazine
era prochlorperazine
thioproperazine
methotrimeprazine
perphenazine
Within less than 10 years,
periciazine
12 antipsychotic phenothiazines
pipotiazine
were in development.
mesoridazine
trifluoperazine
thioridazine
68. paul HALOPERIDOL (1959)
Mice with induced
janssen amphetamine
intoxication responded
to haloperidol
“Even when he was pulled off his bike
and congratulated by a reporter, he
tried to continue cycling. It was obvious
that finding a treatment for
amphetamine intoxication would
provide a cure for paranoid
schizophrenia.”
74. A chronology of 1950s’ psychopharmacology
1949 Cade The antimanic effects of lithium salts
1950 Charpentier Chlorpromazine synthesized
1952 Hamon et al. 1st publication of the efficacy ofchlorpromazine
1952 Delay & Deniker First systematic evaluation of chlorpromazine
1952 Selikoff Mood‐elevating effects of isoniazid
1954 Steck & Thiebaux 1st formal accounts of parkinsonism with chlorpromazine
1954 Kline Reserpine
1954 Methylphenidate
1955 Meprobamate
1955 First trial of G22355 (Imipramine)
1956 Ayd Identification of dystonia with chlorpromazine
1957 Kline Introduction of MAOIs
1957 Kuhn 1st report of antidepressant effect of imipramine
1957 Randall Behavioral effects of 1,4 benzodiazepines
1958 Petersen Thioxanthenes
1958 Janssen Butyrophenones (haloperidol)
1958 Zeller MAO inhibition
1959 Introduction of imipramine
1959 Sigwald et al. First report of tardive dyskinesia
1959 Clozapine