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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.
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Psychopharmacologic Advances 1950‐60 Part 1: Reserpine and
Chlorpromazine
Kevin Nasky, DO
the pre‐neuroleptic
era
restraintsECTinsulin comahydrotherapypharmacologic
chloral hydrateparaldehydebarbiturates
Goal was to control agitation and reduce violence. No other alternatives.
the pre‐neuroleptic
era
restraintsECTinsulin comahydrotherapypharmacologic
chloral hydrateparaldehydebarbiturates
Solid treatment for severe depression and an excellent means of controlling extreme agitation.
the pre‐neuroleptic
era
restraintsECTinsulin comahydrotherapypharmacologic
chloral hydrateparaldehydebarbiturates
Sakel’s insulin‐induced coma was the gentler and less deleterious of the somatic techniques
the pre‐neuroleptic
era
restraintsECTinsulin comahydrotherapypharmacologic
chloral hydrateparaldehydebarbiturates
Sakel’s insulin‐induced coma was the gentler and less deleterious of the somatic techniques
the pre‐neuroleptic
era
restraintsECTinsulin comahydrotherapypharmacologic
chloral hydrateparaldehydebarbiturates
Synthesized in 1832
Fulfilled need for a sleep‐aid Doesn’t disrupt sleep architecture
Withdrawal reactions virtually unheard of. Reasonably safe.
the pre‐neuroleptic
era
restraintsECTinsulin comahydrotherapypharmacologic
chloral hydrateparaldehydebarbiturates
Often the preferred drug for treating alcohol withdrawal
disadvantagesoffensive orderaddictive
the pre‐neuroleptic
era
restraintsECTinsulin comahydrotherapypharmacologic
chloral hydrateparaldehydebarbiturates
Popular in 1930‐1940s
Strong abuse potentialLethal in overdose
the pre‐neuroleptic
era
BROMIDESUsed to tx canine seizuresWidely used in 19th Century“Sleeping salts”Low doses were part of OTCpreparations up to 1960'svery 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)
the pre‐neuroleptic
era
BROMIDES1930 four of every 10 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 tomasturbation; given to pregnant women for "nerves," two children for "overactivity," and to just about anybody who couldn't sleep well at night.
the pre‐neuroleptic
era • Portuguese neurologist EgasMoniz introduced the prefrontal leukotomy• no alternative therapies available for chronically institutionalized patients
Psychosurgery
Reserpine
Sen and Bose report success using Rauwolfia Serpentina
to lower blood pressure and induce a hypnotic effect in experimental animals
INDIA 193
2
first antipsychotic ever usedIndole alkaloidused in ancient India for 2000 yearsalso used to treat snakebites, epilepsy, cataracts, cholera
Rauwolfia Serpentina
INDIA 194
9
Rustom Jal Vakil publishes A Clinical Trial of Rauwolfia Serpentina in Essential
Hypertension in The British Medical Journal.
King Edward VII Memorial Hospital,
Bombay
rustom jal vakilHis historical 1949 paper proclaimed that Rauwolfiawas 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.”
SWITZERLAND
1952
Emil Schlitter et al. publish the structure of reserpine, which they claim was active component of Rauwolfia
BOSTON
1952
Hypertension expert Robert Wilkins studies Rauwolfia’s efficacy in western patients at Boston University.
robert w wilkins, md
HTN expert; AHA president
He & colleagues at Boston U. use 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
NEW
YORK
19
54
Swiss pharm company Ciba asks Dr. Nathan Kline to undertake a study of Rauwolfia.
nathankline, md
gave Rauwolfia to over 700 patients
the first to show that reserpine could be useful for treating psychosesLater, 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
Ciba markets “Serpasil”
…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.
After a short‐lived popularity from 1954 to 1957, the use of reserpine and other Rauwolfia alkaloids rapidly declinedReports had emerged of patients becoming depressed and suicidal on reserpine
Reserpine’s popularity fades
inhibition of the ATP/Mg2+ pump responsible for the reuptake of neurotransmitters into storage presynaptic vesiclesresults in NE and 5HT depletion from central and peripheral axon terminals
Reserpine’s Mechanism
The study of reserpine played a pivotal role in the development of the dopamine theory of
schizophrenia, and the biogenic amine theory of depression
Reserpine’s Role in the Advancement of Psychopharmacology
NIH 195
5
Brodie publishes study showing LSD suppresses 5HT action, while reserpine releases 5HT from its bound state
bernard‘steve’ brodie
Found that the brains of animals given reserpine 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
Chlorpromazine
TUNISIA
1949
French surgeon and anesthetist Henri Laborit uses promethazine
to prevent surgical shock
The operation was a success, but the patient died.
Surgical Shock: 1950s
Surgical Shock
Hemodynamic shock undermined the accomplishments ofeven the most technically skilled surgeons.
Despite manyhypotheses, the mechanism of shock remained an enigma.
Surgical Shock
henri laborit
French Naval surgeon & anesthetist
sought pharmacological prevention of surgical shock
because histamine lead to hypertension…
…one hypothesis was that histamine release causes shock
henri laborit
Goal: reduce autonomic activity during and after surgery via a complex pharmacological regime
The “lytic cocktail” was born
(i.e. sympatho‐parasympatho‐lytic)
This cocktail included the phenothiazine,promethazine.
discovery of the antimalarial…
… properties of the phenothiazine,methylene blue
1890s
French pharmaceutical companyDeveloped series of synthetic antihistamines (one was Benadryl)None had antimalarial propertiesHowever, many had potent antihistaminic activityOne of these was promethazine
henri laborit
observed patients who received promethazine were more calmand relaxed after surgerypostoperative morphine was
unnecessarylower doses of anesthetic agents required
Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail"
FRANCE
19
45
Laborit asked Rhône‐Poulenc to manufacture a more centrally‐acting antihistamine
R‐P goes to work ⎯ sends memo asking for
"chemical work that will provide substances with maximal activity in prolonging the action of
general anesthetics."
paul charpentier
Rhône‐Poulenc chemist
phenothiazine expert
synthesized the first tricyclic antihistamine, promethazine
chlorination was known to make compounds more potentCharpentier chlorinated a phenothiazine derivative RP‐4560, which he sends to Simone Courvoisier
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
potentiated barbiturates
was an anti‐emetic was an α‐blocker
inhibited conditioned avoidance response ⎯ rope climbing test
Courvoisier’s tests demonstrated that RP‐4560…
rats were conditioned to climb rope after hearing auditory stimulus associated with electrical shockrats given RP‐4560 didn’t climb the rope to get the food, even when alerted to the eminence of a shock
Ingredients for rope climbing testratsplatform with food rope tied to the platformshock stimulus
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.’
We don’t experiment the way we used to.
HÔPITAL VA
L‐DE‐
GRA
CE
PARIS, 1945
Laborit persuades Hamon, Paraire and Velluz to test the drug on psychotic patients
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.
First patient treated with chlorpromazine
PARIS
1952
Jean Delay and Pierre Deniker at Hôpital Saint‐Anne describe chlorpromazine’s clinical effects: slowed motor activity, affective indifference and emotional neutrality.
Jean DelayAlong with Pierre Deniker, he was the first psychiatrist to recognize the therapeutic value of phenothiazines in the treatment of schizophrenia
Proposed the definition of neuroleptic drugs (literally, "substances that take the nerves")
Presented clinical reports describing 38 acutely psychotic patients that
confirmed the therapeutic effectiveness as well as the poor
response in cases of depression and the negative symptoms of
schizophrenia
Delay hears of CPZ from Deniker’s surgeon brother‐in‐law
MONTR
ÉAL
1953
Heinz Lehmann writes one of the first North American publications on chlorpromazine
heinz lehmann
“No one in his right mind in psychiatry was working with drugs. You used shock or various psychotherapies"
Berlin psychiatrist refugee from Nazi Germany, working in hospital in MontréalRegularly read European journals; learned of Delay and Deniker’s workNever owned a car, cycled everywhereOne of the first psychiatrists in North America to introduce imipramine
Drug rep left literature with his secretary: "It isn’t necessary [to
speak to him directly], I'll leave this here, this is something new, and so good I don't have to explain it to
him, he will certainly pay attention to it once he reads it"
heinz lehmann
1952 Smith, Kline & French bought the North American rights1954 received U.S. FDA approval, as an antiemetic, to market it under trade name Thorazine1955 $75 million in profits1956 4 million patients in the United States had taken chlorpromazine
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 "molded to the bed." 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, "I know there's something disturbing me, but I couldn't care less."
Pills for the MindMonday, 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.
the post‐thorazine
era
fluphenazine
promazine
prochlorperazine
thioproperazine
methotrimeprazine
perphenazine
periciazine
pipotiazine
mesoridazine
trifluoperazine
thioridazine
Within less than 10 years, 12 antipsychotic phenothiazineswere in development.
paul janssen
HALOPERIDOL (1959)
Mice with induced 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.”
blocks postsynaptic dopamine receptors in the mesolimbic system and increases dopamine turnover by blockade of the D2 somatodendriticautoreceptor
strong anticholinergic and alpha‐adrenergic receptor blocking effects
CPZ
metabolism is extensive, and >100 metabolites have been identified
half‐life is 23—37 hours7‐hydroxychlorpromazine (active metabolite) half‐life of 10—40 hours
most of drug found in urine; only about 1% excreted unchanged
CPZ Metabolism
rapidly absorbed po
onset of sedation (not antipsychotic effect) occurs within 30—60 minutes and lasts for 4—18 hours
92—97% bound to plasma protein
distributes to breast‐milk and crosses the placenta
CPZ Pharmacokinetics
25 mg PO three times per day. increase by 25—50 mg q 3—4 d
minimal effective dose is roughly 200—400 mg/d
doses of 800 mg/d not uncommon
maximum total daily dosage should not exceed 2 g/day
CPZ Dosing
AIMS assessment
CBC (agranulocytosis)ophthalmologic exam (pigmentary retinopathy, corneal opacification)
serum prolactin
CPZ Monitoring Parameters
A chronology of 1950s’ psychopharmacology 1949 Cade The antimanic effects of lithium salts1950 Charpentier Chlorpromazine synthesized1952 Hamon et al. 1st publication of the efficacy ofchlorpromazine1952 Delay & Deniker First systematic evaluation of chlorpromazine1952 Selikoff Mood‐elevating effects of isoniazid 1954 Steck & Thiebaux 1st formal accounts of parkinsonism with chlorpromazine1954 Kline Reserpine 1954 Methylphenidate 1955 Meprobamate 1955 First trial of G22355 (Imipramine) 1956 Ayd Identification of dystonia with chlorpromazine1957 Kline Introduction of MAOIs 1957 Kuhn 1st report of antidepressant effect of imipramine1957 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
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