Psychopharmacologic Advances of the 1950s, Part 1: Reserpine and Chlorpromazine
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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 of the 1950s, Part 1: Reserpine and Chlorpromazine
- 1. Psychopharmacologic Advances 1950‐60 Part 1: Reserpine and Chlorpromazine Kevin Nasky, DO
- 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
- 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.
- 13. the Psychosurgery pre‐neuroleptic era • Portuguese neurologist Egas Moniz introduced the prefrontal leukotomy • no alternative therapies available for chronically institutionalized patients
- 14. Reserpine
- 15. INDIA 1932 Sen and Bose report success using Rauwolfia Serpentina to lower blood pressure and induce a hypnotic effect in experimental animals
- 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
- 20. BOSTON 1952 Hypertension expert Robert Wilkins studies Rauwolfia’s efficacy in western patients at Boston University.
- 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
- 31. Chlorpromazine
- 32. TUNISIA 1949 French surgeon and anesthetist Henri Laborit uses promethazine to prevent surgical shock
- 33. Surgical Shock: 1950s The operation was a success, but the patient died.
- 34. Surgical Shock Hemodynamic shock undermined the accomplishments of even the most technically skilled surgeons.
- 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.
- 38. 1890s discovery of the antimalarial… … properties of the phenothiazine, methylene blue
- 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;
- 41. FRANCE 1945 Laborit asked Rhône‐Poulenc to manufacture a more centrally‐acting antihistamine
- 42. R‐P goes to work ⎯ sends memo asking for quot;chemical work that will provide substances with maximal activity in prolonging the action of general anesthetics.quot;
- 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
- 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.’
- 49. PARIS, 1945 HÔPITAL VAL‐DE‐ GRACE Laborit persuades Hamon, Paraire and Velluz to test the drug on psychotic patients
- 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.
- 51. PARIS 1952 Jean Delay and Pierre Deniker at Hôpital Saint‐ Anne describe chlorpromazine’s clinical effects: slowed motor activity, affective indifference and emotional neutrality.
- 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;)
- 53. Delay hears of CPZ from Deniker’s surgeon brother‐in‐law 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
- 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;
- 56. heinz lehmann Drug rep left literature with his secretary: quot;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 itquot;
- 57. 1952 Smith, Kline & French bought the North American rights 1954 received U.S. FDA approval, as an antiemetic, to market it under trade name Thorazine 1955 $75 million in profits 1956 4 million patients in the United States had taken chlorpromazine
- 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.”
- 69. CPZ blocks postsynaptic dopamine receptors in the mesolimbic system and increases dopamine turnover by blockade of the D2 somatodendritic autoreceptor strong anticholinergic and alpha‐ adrenergic receptor blocking effects
- 71. CPZ Pharmacokinetics 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
- 73. CPZ Monitoring Parameters AIMS assessment CBC (agranulocytosis) ophthalmologic exam (pigmentary retinopathy, corneal opacification) serum prolactin
- 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
- 75. Questions?