psychopharmacologic advances of the 1950s, part 1: reserpine and chlorpromazine

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.


era



Solid treatment for severe depression and an excellent means of controlling extreme agitation.


era



Sakel’s insulin‐induced coma was the gentler and less deleterious of the somatic techniques


era



Synthesized in 1832

Fulfilled need for a sleep‐aid Doesn’t disrupt sleep architecture

Withdrawal reactions virtually unheard of. Reasonably safe.


era



Often the preferred drug for treating alcohol withdrawal

disadvantagesoffensive orderaddictive


era



Popular in 1930‐1940s

Strong abuse potentialLethal in overdose


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)


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.


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

Questions?

psychopharmacologic advances of the 1950s, part 1: reserpine and chlorpromazine

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