History of Psychopharm

These was the initial mindmap I used to prepare a powerpoint presentation on the psychopharmacologic advances during the 1950s.

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History of Psychopharm by Mind Map: History of Psychopharm

1. Pre-Neuroleptic Era

1.1. physical restraints

1.1.1. straitjackets

1.1.2. Restraining chairs

1.1.3. Untitled

1.2. 1930s

1.2.1. insulin coma

1.2.1.1. Manfred Sakel in Vienna introduced hypoglycaemic coma, produced by injections of insulin, as a treatment for schizophrenia

1.3. hydrotherapy

1.4. 1936

1.4.1. psychosurgery

1.4.1.1. Portuguese neurologist Egas Moniz introduced the prefrontal leukotomy

1.4.1.1.1. received the Nobel Prize in 1949

1.4.1.1.2. popular in 1940s

1.4.1.1.3. there were no alternative therapies available for chronically institutionalized patients

1.5. 1938

1.5.1. ECT

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

1.5.1.2. Cerletti and Bini introduced

1.6. pharmacologic

1.6.1. all psychopharmacological that had significant effects were those that resulted in major often critical alterations of psychophysiological functioning

1.6.1.1. perhaps attributable to the fact that the first major breakthrough in psychiatry had been Wagner-Jauregg's hyperpyrexic malaria treatment of general paresis

1.6.2. notion of an antipsychotic unheard of; goal was control agitation and reduce violence

1.6.2.1. chloral hydrate

1.6.2.2. paraldehyde

1.6.2.3. barbiturates

2. antipsychotics

2.1. reserpine

2.1.1. 1931

2.1.1.1. Sen and Bose reported in the Indian Medical Record of their success in inducing a mild lowering of blood pressure as well as a hypnotic effect in experimental animals and their subsequent clinical trials.

2.1.1.1.1. published in an Indian journal didn't reach the attention of the global scientific community until 1949

2.1.1.1.2. Rauwolfia serpentina

2.1.2. late 1940s

2.1.2.1. Rauwolfia used principally as an antihypertensive

2.1.3. 1949

2.1.3.1. India

2.1.3.1.1. Rustom Jal Vakil

2.1.4. 1952

2.1.4.1. Switzerland

2.1.4.1.1. Untitled

2.1.4.2. Boston, Massachusetts

2.1.4.2.1. Massachusetts General Hospital

2.1.5. 1953

2.1.5.1. New Jersey

2.1.5.1.1. Ciba Headquarters

2.1.6. 1954

2.1.6.1. New York

2.1.6.1.1. Nathan Kline

2.1.7. 1955

2.1.7.1. Michael Shepherd

2.1.7.1.1. Untitled

2.1.7.1.2. undertook first modern clinical trial of psychiatry to placebo in a group of anxious depressives

2.1.7.2. Bernard B. Brodie

2.1.7.2.1. established the Laboratory of Chemical Pharmacology at NIH

2.1.7.2.2. published study in Science - found LSD suppresses the action of serotonin, while reserpine (which was being used for schizophrenia) released serotonin from its bound state

2.1.7.2.3. Untitled

2.1.7.3. After a short-lived popularity from 1954 to 1957, the use of reserpine and other Rauwolfia alkaloids rapidly declined

2.1.7.3.1. reports emerged of hypertensive patients becoming depressed and suicidal on reserpine

2.1.7.4. akathisia

2.1.7.4.1. reports from the Mayo Clinic of reserpine causing some patients “increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable.”

2.1.8. Role in development of psychopharmacology

2.1.8.1. the study of reserpine played a pivotal role in the development of the dopamine theory of schizophrenia, and the biogenic amine theory of clinical depression

2.1.8.2. produce depression in a significant minority of cases and subsequently found to reduce NE levels in the brain

2.1.9. pharmacology

2.1.9.1. mechanism of action

2.1.9.1.1. inhibition of the ATP/Mg2+ pump responsible for the reuptake of neurotransmitters into storage vesicles located in the presynaptic neuron

2.1.9.1.2. results in depletion of catecholamines and serotonin from central and peripheral axon terminals

2.1.9.2. Untitled

2.1.9.3. Untitled

2.2. phenothiazines

2.2.1. methylene blue

2.2.1.1. 1876

2.2.1.1.1. synthesized by Caro

2.2.1.2. 1891

2.2.1.2.1. Paul Ehrlich

2.2.2. promethazine

2.2.2.1. 1950

2.2.3. chlorpromazine

2.2.3.1. 1945

2.2.3.1.1. Tunisia

2.2.3.2. 1950

2.2.3.2.1. Paris, France

2.2.3.3. 1951

2.2.3.3.1. chlorpromazine was released for clinical studies

2.2.3.3.2. Henri Laborit

2.2.3.4. 1952

2.2.3.4.1. Paris, France

2.2.3.5. 1953

2.2.3.5.1. Ontario, Canada

2.2.3.5.2. Montréal, Canada

2.2.3.5.3. Frank Ayd

2.2.3.6. 1954

2.2.3.6.1. Heinz Lehmann

2.2.3.6.2. United States

2.2.3.6.3. received U.S. FDA approval, as an antiemetic, to market it under trade name Thorazine

2.2.3.7. 1955

2.2.3.7.1. $75 million in profits

2.2.3.8. 1956

2.2.3.8.1. 4 million patients in the United States had taken chlorpromazine

2.2.3.9. Psychiatry Post-Thorazine

2.2.3.9.1. use of animal behavior indicators for antipsychotic effects accelerated pharmacological screening for chlorpromazine-like drugs

2.2.3.9.2. within less than 10 years, 20 antipsychotic phenothiazines with 3 distinct side chain structures were in development

2.2.3.9.3. simultaneously at least six other classes of antipsychotic drugs were advanced

2.2.3.9.4. dibenzodiazepine

2.2.3.10. pharmacology

2.2.3.10.1. hundred and 50 to 300 mg QD. Rapidly escalated to 1000 mg QD

2.2.4. prochlorperazine

2.2.4.1. 1956

2.2.5. perphenazine

2.2.5.1. 1957

2.2.6. thiopropazate

2.2.6.1. 1957

2.2.7. triflupromazine

2.2.7.1. 1957

2.2.8. trifluoperazine

2.2.8.1. 1958

2.2.8.1.1. Stelazine

2.2.8.2. made by replacing the chlorine group of chlorpromazine, with a trifluromethyl group

2.2.9. fluphenazine

2.2.9.1. 1959

2.2.9.2. made by adding a terminal ethyl alcohol group to Stelazine

2.2.10. thioridazine

2.2.10.1. 1959

2.2.11. acetophenazine

2.2.11.1. 1961

2.2.12. carphenazine

2.2.12.1. 1963

2.3. haloperidol

2.3.1. 1957

2.3.1.1. noted that one of their butyrophenone derivatives of normeperidine heady mixture of narcotic and neuroleptic effects in animals

2.3.1.1.1. modification of this compound led to the development of haloperidol and the potent mu opioid analgesic, fentanyl

2.3.2. 1958

2.3.2.1. haloperidol synthesized

2.3.2.1.1. byproduct of research with meperidine aiming to find a more potent analgesic

2.3.2.1.2. inherited a small Belgian company from his parents

2.3.2.1.3. Janssen

2.3.3. pharmacology

2.3.3.1. butyrophenone

2.4. clozapine

2.4.1. 1966

2.4.1.1. first paper clozapine appeared in the Medical Journal of Vienna

2.4.2. pharmacology

2.4.2.1. dibenzodiazepine

2.5. The Dopamine and Biogenic Amine Hypotheses

2.5.1. 1938

2.5.1.1. Hoffman

2.5.1.1.1. synthesizes LSD

2.5.2. 1943

2.5.2.1. Hoffman and Sandoz discover LSD-25

2.5.2.1.1. a prevalent theory from the 50s to the 70s was that an excess of tryptamine-like hallucinogenic substances wereeither partial agonist or antagonists of serotonin

2.5.3. 1963

2.5.3.1. Carlsson and Lindquist

2.5.3.1.1. founded seminal hypothesis that dopamine receptor blockade was responsible for the clinical effects of antipsychotic drugs

2.5.4. 1975

2.5.4.1. Creese et al demonstrated with X-ray crystallography that dopamine blockade actually took place

2.5.4.1.1. Creese I, Burt DR, Snyder SH. Dopamine receptor binding: differentiation of agonist and antagonist states with 3H-dopamine and 3H-haloperidol. Life Sci 1975;17:993–1002.

2.5.5. based on the dopamine hypothesis, for different theories were proposed to explain antipsychotic mechanism of action

2.5.5.1. 1. Blockade of the post synaptic D1 receptor

2.5.5.2. 2. Blocking of the post synaptic D2 receptor

2.5.5.3. 3. Interactive effects between D1 and D2 receptors

2.5.5.4. 4. Slowly developing decrease in presynaptic dopamine activity

3. mood stabilizers

3.1. lithium

3.1.1. 1949

3.1.1.1. John Cade

3.1.1.1.1. Australian physician

3.1.1.1.2. conduct a series of experiments involving the injection of urine from psychiatric patients into guinea pigs in the hope of identifying which factors might be psychotomimetic

3.1.1.1.3. A methodical assessment of the ability of certain urinary metabolites to reproduce or modify the apparently greater toxicity of the urine of manic patients followed

3.1.1.1.4. The importance of the report of that trial of 19 patients, which was published in 1949 in the Medical Journal of Australia (t), failed to be widely recognized by the international psychiatric community for many years

3.1.1.1.5. -for the following 15 years an average of only four experimental papers per year were published on the use of lithium in the treatment of mood disorders

3.1.1.1.6. Untitled

3.1.2. 1970

3.1.2.1. approved in the United States

4. anxiolytics

4.1. meprobamate

4.1.1. pre-Miltown

4.1.1.1. 1800s

4.1.1.1.1. Opiates or alcohol were the sedatives of choice

4.1.1.2. 1850s

4.1.1.2.1. bromides

4.1.1.3. 1870

4.1.1.3.1. chloral hydrate first used clinically

4.1.1.4. 1880s

4.1.1.4.1. Axenfeld, Auguste

4.1.1.5. 1882

4.1.1.5.1. paraldehyde first used clinically

4.1.1.6. early 1900s

4.1.1.6.1. millions of people taking bromides prescribed as a cure for everything from battlefield anxiety to masturbation; given to pregnant women for "nerves," two children for "overactivity," and to just about anybody who couldn't sleep well at night.

4.1.1.7. 1930

4.1.1.7.1. four of every 10 prescriptions written by doctors were for drugs containing bromides

4.1.1.8. 1950s

4.1.1.8.1. widespread use of paraldehyde

4.1.1.8.2. Thalidomide

4.1.1.8.3. The first of “mother’s little helpers,” Dexamyl, combining a stimulant and a sedative—dexamphetamine and amylobarbitone—appeared in the 1950s, producing dramatic benefits for “nerves” that are still not easily explained

4.1.1.9. sedative-hypnotics

4.1.1.9.1. barbiturates

4.1.1.10. "major tranquilizers"

4.1.1.10.1. thought too toxic for patients with less serious mental disorders

4.1.2. 1945

4.1.2.1. mephenesin

4.1.2.1.1. Carter-Wallace laboratories

4.1.3. 1946

4.1.3.1. mephenesin introduced as a muscle relaxing agent for use in anesthesia

4.1.4. 1950

4.1.4.1. meprobamate synthesized by Berger

4.1.4.1.1. Untitled

4.1.4.1.2. Carter-Wallace initially wouldn't give Berger financial support ($500,000) to bring the meprobamate to market

4.1.4.1.3. christened it Miltown after the New Jersey town Wallace Laboratories was located

4.1.5. 1955

4.1.5.1. Miltown's Debut

4.1.5.1.1. Berger shows Miltown film at the 1955 meeting of the Federation of American Societies for Experimental Biology in San Francisco

4.1.5.1.2. film showed monkeys in three distinct chemical states: naturally vicious, unconscious on barbiturates, and calm but awake on Miltown

4.1.5.1.3. the first drug to be sold specifically as an anxiolytic

4.1.5.1.4. The launching of meprobamate under the brand name Miltown in 1955 was a watershed

4.1.6. 1957

4.1.6.1. 35 million prescriptions sold; one prescription per second

4.1.6.1.1. fastest-growing drug in history

4.1.7. 1970

4.1.7.1. Placed on Schedule IV

4.1.8. cultural context

4.1.8.1. turning point in the history of psychopharmacology

4.1.8.2. Shorter considered meprobamate's success as a marker of "cosmetic psychopharmacology" in the American cultural history

4.1.8.2.1. Shorter E: A History of Psychiatry: From the Era of the Asylum to the Age of Prozac. 1997.

4.1.8.3. "lucky neurotics" of the new world: "Soon the specter of care will be banished from your world ... Soothed by reserpine, calmed by chlorpromazine, mellowed by 'Miltown' and elevated by 'Meratran', what need you fear from the uncertainties of fortune?"

4.1.8.4. "Miltown" becomes a household name in part of the cultural lexicon: "penicillin for the blues," "miltown-ing," "Miltown cocktails,"...more>>

4.1.8.5. tranquilizer for the healthy "unwell"

4.1.8.6. the first middle-class drug abuse phenomenon; "happy pill" alternative for harried housewives and stressed-out commuters. "dehydrated martini";"Miltown parties"

4.1.8.7. "Mother's Little Helper," The Rolling Stones, 1966

4.1.8.8. Milton Berle

4.1.8.8.1. "It's worked wonders for me. In fact, I'm thinking of changing my name to Miltown Berle."

4.1.8.9. 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."

4.1.8.10. Dr. Nathan Kline, director of New York's Rockland State Hospital, told readers of business week that its potential benefits to Americans, the advent of minor tranquilizers was "equal in importance to the introduction of atomic energy, if not more so."

4.1.8.11. nicknames

4.1.8.11.1. "peace pills"

4.1.8.11.2. "happiness pills

4.1.8.11.3. "emotional aspirin"

4.1.8.11.4. "penicillin for the blues"

4.1.8.11.5. "dehydrated martini"

4.1.8.11.6. "executive Excedrin"

4.1.8.12. The introduction of triplicate prescriptions for benzodiazepines in New York State (essentially placing them in Schedule II) reportedly led to an acute rise in prescriptions for meprobamate, which remained in Schedule IV—an unfortunate consequence of legislative action. The drug is less safe than are the benzodiazepines.

4.1.9. post-Miltown

4.1.9.1. Librium launched in March 1960

4.1.9.2. Carisoprodol (SOMA)

4.1.9.2.1. centrally-acting skeletal muscle relaxant whose active metabolite is meprobamate. Although several case reports have shown that carisoprodol has abuse potential, it continues to be widely prescribed

4.1.10. pharmacology

4.1.10.1. Untitled

4.1.10.2. Meprobamate does not affect benzodiazepine or GABA receptors. It seems to act by potentiating the action of endogenously released adenosine; it blocks reuptake of adenosine, which is itself a sedative.

4.1.10.2.1. Manual of Clinical Psychopharmacology, Sixth Edition. Alan F. Schatzberg, M.D., Jonathan O. Cole, M.D., and Charles DeBattista, D.M.H., M.D.

4.1.10.3. The clinical dosage of meprobamate is on the order of 400 mg three or four times a day, being approximately equivalent to 5 mg of diazepam three or four times a day

4.1.10.4. The major side effects are sedation and malcoordination. The drug is relatively safe in overdose—less lethal than intermediate-acting barbiturates like pentobarbital but a good deal less safe than diazepam.

4.1.10.5. produces physical dependence and tolerance in much the same way as do the barbiturates and the benzodiazepines

4.1.10.6. Significant withdrawal effects, such as convulsions, agitation, and delirium, occur after clinically relatively lower doses

5. antidepressants

5.1. MAOIs

5.1.1. iproniazid

5.1.1.1. originally intended to treat tuberculosis

5.1.1.2. 1957

5.1.1.2.1. Nathan Kline

5.2. TCAs

5.2.1. imipramine

5.2.1.1. 1956

5.2.1.1.1. Roland Kuhn

5.2.1.2. 1957

5.2.1.2.1. Kuhn published the results of his observations in Schweizerische Medizinische Wochenschrift (Swiss Weekly Medical Journal)

5.2.1.3. 1958

5.2.1.3.1. Lehmann and two co-workers published their results in the Canadian Medical Association Journal

5.3. serotonin

5.3.1. originally discovered in the gastrointestinal mucosa in the 1940s

5.4. Key players

5.4.1. Frank Ayd

5.4.1.1. Recognizing the Depressed Patient. 1961.

6. references

6.1. Links

6.1.1. Untitled

6.1.1.1. ARTICLES

6.1.2. History of the Discovery and Clinical Introduction of Chlorpromazine

6.1.3. Mother's Little helper

6.1.4. Listening to the Past: History, Psychiatry, and Anxiety

6.1.5. MEPROBAMATE-TRANQUILIZER OR ANXIOLYTIC?

6.1.6. The History of Psychopharmacology; Its Relation to Anesthesiology

6.1.7. Meprobamate: A Study of Irrational Drug Use

6.2. The Creation of Psychopharmacology by David Healy. 2004

6.3. The Antidepressant Era by David Healy. 1999.

6.4. The War of the Soups and the Sparks: The Discovery of Neurotransmitters and the Dispute Over How Nerves Communicate by Elliot S. Valenstein

6.5. Psychiatr Serv 51:333-335, March 2000 © 2000 American Psychiatric Association Historical Article The Introduction of Neuroleptics: A Psychiatric Revolution Robert Cancro, M.D.

6.6. Lehmann, H., Ban T. The History of the Psychopharmacology of Schizophrenia. Can J Psychiatry 1997;42:152–162)