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Psychopharmacology by Mind Map: Psychopharmacology
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Psychopharmacology

Pre-Neuroleptic Era

physical restraints

straitjackets

Restraining chairs

Untitled

1930s

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

hydrotherapy

1936

psychosurgery, Portuguese neurologist Egas Moniz introduced the prefrontal leukotomy, received the Nobel Prize in 1949, popular in 1940s, there were no alternative therapies available for chronically institutionalized patients

1938

ECT, superb treatment for severe depression and an excellent means of controlling extreme agitation, Cerletti and Bini introduced

pharmacologic

all psychopharmacological that had significant effects were those that resulted in major often critical alterations of psychophysiological functioning, perhaps attributable to the fact that the first major breakthrough in psychiatry had been Wagner-Jauregg's hyperpyrexic malaria treatment of general paresis

notion of an antipsychotic unheard of; goal was control agitation and reduce violence, chloral hydrate, paraldehyde, barbiturates

antipsychotics

reserpine

1931, 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., published in an Indian journal didn't reach the attention of the global scientific community until 1949, Rauwolfia serpentina, Untitled, Dr Leonard Rauwolf, the German botanist, was the first European to recognize the plant in the 17th century, hence the name Rauwolfia Serpentina, first antipsychotic used by humanity, 2000 years before Thorazine was synthesized, ancient India was using Rauwolfia as a herbal antipsychotic, ancient texts of Hindu Ayurvedic medicine describe its use in the treatment of "insanity" (Oonmaad in Sanskrit), also used to treat snakebites, epilepsy, cataracts, cholera, indole alkaloid

late 1940s, Rauwolfia used principally as an antihypertensive

1949, India, Rustom Jal Vakil, Indian physician, Untitled, Father of Modern Cardiology, (1911-1974), King Edward VII Memorial Hospital, Bombay, Untitled, published A Clinical Trial of Rauwolfia Serpentina in Essential Hypertension. British Heart Journal 1949;2: 350-5, Lasker award citation: together with chlorpromazine, his study of reserpine opened the way for "an entirely new method of study of mental disorder itself."

1952, Switzerland, Untitled, Swiss pharmaceutical company, Emil Schlitter, he and his group (Hugo Bein and J. Müller) published the structure of reserpine, which they claim was most important active principle behind the actions of Rauwolfia, Boston, Massachusetts, Massachusetts General Hospital, Robert Wilkins, study demonstrated its efficacy in western patients using "Serpina" tablets manufactured by the Himalaya drug company in Bombay, Wilkins immediately noticed mental status changes in his patients, "many patients became positively lyrical about their sense of well-being on the drug... with statements such as 'I've never felt as well', or 'haven't felt this good for years'...' nothing bothers me anymore.'", “An obscure (at least to the Western world) Indian folk medicine, rauwolfia, and its pure derivative, reserpine, were shown to possess remarkable therapeutic effectiveness in combination with other drugs, especially the diuretics, for the management of hypertension.”, From 1950-1951, Wilkins was the head of the Council of High Blood Pressure Research, the world's leading hypertension research organization., In 1954, he was named President of the American Heart Association

1953, New Jersey, Ciba Headquarters, Frederick F. Yonkman, at a symposium he used to term tranquilizer for the first time to capture this characteristic and distinguish it from sedation proper, when meprobamate and later the benzodiazepines hijacked this new term, reserpine and chlorpromazine became the "major" tranquilizers

1954, New York, Nathan Kline, His interest in the rauwolfia root was spurned by a New York Times article on Hakim, an Indian physician’s paper on indigenous drugs in the treatment of mental illness., Ciba asked Kline, then the director of the research Institute at Rockland State Hospital,to undertake a study, gave Rauwolfia to over 700 patients, published findings in the annals of the New York Academy of sciences, Kline NS. Use of Rauwolfia Serpentina Benth in neuropsychiatric conditions. Ann NY Acad Sci 1954;59:107–32., within six months, DeLay, Deniker and Lemperiere published similar findings with reserpine, the active principle itself, the first to show that reserpine and relatively large doses could be useful for treating psychoses, 1964 Lasker Award, Untitled

1955, Michael Shepherd, Untitled, undertook first modern clinical trial of psychiatry to placebo in a group of anxious depressives, Reserpine in the treatment of anxious and depressed patients. Lancet. 1955 Jul 16;269(6881):117-20., Bernard B. Brodie, established the Laboratory of Chemical Pharmacology at NIH, 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, showed that the 5HT content of rat and rabbit brain would become undetectable after an intravenous injection of reserpine, concluded only that he had provided evidence that "serotonin has a role in brain function.", would not go so far as to call serotonin, a neurotransmitter, suggested that reserpine inactivates a mechanism to essential for 5HT storage, first demonstration of a link between brain chemistry and behavior, established the field of Neuroscience, marked the beginning of the discipline of Neurochemical Pharmacology., Brodie's postulation that reserpine's psychotropic effect is intimately linked to changes in serotonin concentration provided the first building block for a bridge between neuropharmacology and psychopharmacology., Untitled, After a short-lived popularity from 1954 to 1957, the use of reserpine and other Rauwolfia alkaloids rapidly declined, reports emerged of hypertensive patients becoming depressed and suicidal on reserpine, akathisia, reports from the Mayo Clinic of reserpine causing some patients “increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable.”, Hans Steck and Hans Haase, labeled the problem akathisia

Role in development 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 clinical depression, produce depression in a significant minority of cases and subsequently found to reduce NE levels in the brain

pharmacology, mechanism of action, inhibition of the ATP/Mg2+ pump responsible for the reuptake of neurotransmitters into storage vesicles located in the presynaptic neuron, Vesicular monoamine transporters, results in depletion of catecholamines and serotonin from central and peripheral axon terminals, Untitled, Untitled

phenothiazines

methylene blue, 1876, synthesized by Caro, 1891, Paul Ehrlich, German bacteriologist, noted Muslim blue is effective in treating symptoms of malaria

promethazine, 1950

chlorpromazine, 1945, Tunisia, Henri Laborit, Untitled, French Navy surgeon and anesthetist, surgeon medic in the French army, a marine during WWII, surgeons were often also responsible for anesthesia at that time, sought pharmacological prevention of surgical shock, hypothesis at time was that surgical shock was secondary to excessive stress reaction, histamine is released in response to surgery (or other tissue damage), histamine is a potent stimulator of some autonomic sites, used promethazine for its antihistaminic action, used the antihistamine, promethazine to prevent surgical shock, observed patients were more calm and relaxed after surgery, different from morphine, postoperative morphine became unnecessary, "something to rejoice about every day", Laborit asked Rhône-Poulenc to manufacture a more centrally-acting antihistamine, he began experimenting with various phenothiazines sent to him from Charpentier at Rhône-Poulenc, found promethazine potentiated other anesthetic agents, he and Huguenard invented the lytic cocktail, Huguenard was an anesthetist, working in Paris, who had a penchant for combining drugs, "lytic cocktail" of promethazine and an analgesic, “artificial hibernation”: a mix of an analgesic and a hypnotic in order to induce a pharmacological disconnection of the neurovegetative system, patients required lower doses of anesthetic agents, better withstood the stress of surgical trauma, 1950, Paris, France, Rhône-Poulenc, Rhône-Poulenc begins a systemic study to synthesize a phenothiazine derivative that was a more centrally acting autonomic stabilizer, he wanted a better compound than promethazine to include in his "lytic cocktail", Paul Charpentier, Chemist - phenothiazine expert, synthesized and tested a series of phenothiazine amines, synthesized the first tricyclic antihistamine, promethazine, which had a strong sedative effect, Charpentier synthesized RP 4560, chlorinated phenothiazine derivative, chlorination was known to make compounds more potent, Charpentier sent RP-4560 to Laborit, Simone Courvoisier, Courvoisier performed physiologic testing on RP 4560, potentiates barbiturates, prolonged barbiturate-induced sleep in rodents, anti-emetic, prevents apomorphine induced emesis and dogs, inhibits the conditioned avoidance escaped response in mice, RP-4560 extinguished conditioned reflexes (animals would climb a rope after an auditory stimulus, when this was previously associated with an electrical discharge) without modifying the animal's strength, rope climbing test: devised in 1915 -- involved rats, a platform on which there was food, a rope tied to the platform, and a shock stimulus. On this tests animals given some of the new phenothiazines did not climb the rope to get the food the way untreated animals did even when alerted to the eminence of a shock. They seemed indifferent to the shock., D. Macht, Macht and Mora (28) coined the term “psychopharmacology” as “virgin soil, full of possibilities” in their study of opioid alkaloids on rat behavior in a circular maze, It was an alpha-adrenergic blocking agent that produced “epinephrine reversal.”, it have a little antihistamine- atropine-like actions, physiologist, R-P named it Largactil "Large Action" because they thought it had multiple applications ranging from treatment of nausea to pruritus, Untitled, In January 1999, Rhône-Poulenc merged with Hoechst AG to form Aventis who then went on to merge with Sanofi-Synthélabo forming Sanofi-Aventis, the third largest pharmaceutical company in the world., Untitled, 1951, chlorpromazine was released for clinical studies, pharmacophobic Paris psychiatrists resisted, Finally persuaded his Neuropsychiatry colleagues at Val-de-Grace (Joseph Hamon, Paraire and Velluz) to test the drug on psychotic patients, first known psychiatric patient to receive chlorpromazine: a manic patient was given a common nation of chlorpromazine, barbiturates and other drugs., Hôpital Val-de- Grace, Untitled, Henri Laborit, noted RP 4560 abolished anxiety and excitement in surgical patients (“chemical lobotomy”), in addition to stabilizing peripheral autonomic nervous system, it also mildly affected the CNS, resulting in a sort of indifference to stressful environment, noted ataraxy ("without care") in those patients, ataraxy: freedom from confusion and anxiety, THE ATARACTIC DRUGS: THE PRESENT POSITION OF CHLORPROMAZINE, FRENQUEL, PACATAL, AND RESERPINE IN THE PSYCHIATRIC HOSPITAL H. ANGUS BOWES Am J Psychiatry 113:530-539, December 1956, "the action of the drug... provokes... just a slight tendency to sleep and above all 'disinterest' for all that goes on around him.", preoperative desinteressement, "euphoric quietude.", began urging Paris psychiatrists to use this drug to treat psychoses, figured it would potentiate barbiturate sleep therapy, 1952, Paris, France, January 19, 1952 -- Pierre Hamon, Jean Paraire and Jean Velluz first used chlorpromazine in therapy of psychoses, Jean Delay and Pierre Deniker, described the clinical condition caused by chlorpromazine: slowing down of motor activity, affective indifference and emotional neutrality, "neuroleptic syndrome.", neuroleptic: "that take the nerve", Neuroleptic syndrome widely accepted in Europe but not in America, where it was considered an appropriate to define a family of drugs by their adverse effects rather than by their therapeutic qualities., Thus the preferred term in the US was initially "tranquilizer," and this was replaced by the expression "major tranquilizer" before introduction of the current term "antipsychotic" drug, Smith, Kline & French bought the North American rights in 1952, presented six clinical reports of the results of use and 38 acutely psychotic patients confirming the therapeutic effectiveness as well as the poor response in cases of depression into the negative symptoms of schizophrenia, these reports were published in the prestigious French journal Annales MedicoPsychologiques and curiously made no reference whatsoever to the previous experience of Laborit, nor the work of Hamon, Paraire & Velluz suggesting some degree of conflict between the two groups, PBS People and Discoveries, Hôpital Saint-Anne, Jean Delay, Untitled, Hospital Director, Pierre Deniker, Men's Service Chief, 1953, Ontario, Canada, Ruth Koeppe-Kajander, Psychiatry resident at mental hospital in London (Ontario), obtained permission to administer chlorpromazine to 25 patients and report her study results in a Toronto meeting, but never managed to publish those results, "calms excited or overactive patients, without sedating them to the level where they could not function. Patients lost their agitation level, but not their consciousness. They could talk about themselves and eat and sleep without difficulty.", Montréal, Canada, Hassan Azima and William Ogle, psychiatrists at McGill University in Montréal who also were treating patients with chlorpromazine, but delayed excessively and reporting of their data and therefore were not published until four months after Lehmann, Heinz Lehmann, Berlin psychiatrist refugee from Nazi Germany, working in hospital in Montréal, responsible for one of the first North American publications, drug rep left literature with his secretary: "It is 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 a once he reads it", Lehmann was attracted by the claim that chlorpromazine acted "like a chemical lobotomy." Thus, he decided to try the French drug, initially, on nursing students at his hospital who had volunteered for the tests. At small doses, the nurses felt an effect of drowsiness, but no intellectual functions were affected, as occurred with barbiturates, Untitled, "no one in his right mind in psychiatry was working with drugs. You used shock or various psychotherapies", Frank Ayd, Smith Kline & French asked him to evaluate, too?, 1954, Heinz Lehmann, a study of his use of much higher doses (up to 800 mg daily) in 71 psychotic patients a positive response in 66% of patients after four months of continuous treatment -- first data on use of chlorpromazine in chronic fashion, United States, William Winkelman, published 1st US study, 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, Psychiatry Post-Thorazine, use of animal behavior indicators for antipsychotic effects accelerated pharmacological screening for chlorpromazine-like drugs, induction of cataplectic immobility, reductions of spontaneous mobility, inhibition of intracranial cell stimulation, interference with classical conditioning and operant behavior, within less than 10 years, 20 antipsychotic phenothiazines with 3 distinct side chain structures were in development, of these, 12 were phenothiazines:, fluphenazine, promazine, prochlorperazine, thioproperazine, methotrimeprazine, perphenazine, pericyazine, pipotiazine, mesoridazine, trifluoperazine, thioridazine, none were superior to chlorpromazine in overall therapeutic efficacy, simultaneously at least six other classes of antipsychotic drugs were advanced, 1. thioxanthenes, chlorprothixine, clopenthixol, flupenthixol, thiothixene, zuclopenthixol, 2. benzothiazines, prothipendyl, isothipendyl, oxypendyl, 3. benzoquinolones, tetrabenzamine, benzquinamide, 4. diphenylbutylpiperidines, fluspiriline, penfluridol, pimozide, 5. dibenzoxepine, loxapine, 6. indole, oxypertine, molindone, dibenzodiazepine, clozapine, pharmacology, hundred and 50 to 300 mg QD. Rapidly escalated to 1000 mg QD, Texas was getting four to 5 g QD

prochlorperazine, 1956

perphenazine, 1957

thiopropazate, 1957

triflupromazine, 1957

trifluoperazine, 1958, Stelazine, made by replacing the chlorine group of chlorpromazine, with a trifluromethyl group

fluphenazine, 1959, made by adding a terminal ethyl alcohol group to Stelazine

thioridazine, 1959

acetophenazine, 1961

carphenazine, 1963

haloperidol

1957, noted that one of their butyrophenone derivatives of normeperidine heady mixture of narcotic and neuroleptic effects in animals, modification of this compound led to the development of haloperidol and the potent mu opioid analgesic, fentanyl

1958, haloperidol synthesized, byproduct of research with meperidine aiming to find a more potent analgesic, inherited a small Belgian company from his parents, Janssen, observed that a champion, amphetamine-using cyclist often kept raising after he crossed the finish line ahead to be stopped by force, test model used behavioral antagonism between haloperidol and amphetamine

pharmacology, butyrophenone

clozapine

1966, first paper clozapine appeared in the Medical Journal of Vienna

pharmacology, dibenzodiazepine

The Dopamine and Biogenic Amine Hypotheses

1938, Hoffman, synthesizes LSD

1943, Hoffman and Sandoz discover LSD-25, 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

1963, Carlsson and Lindquist, founded seminal hypothesis that dopamine receptor blockade was responsible for the clinical effects of antipsychotic drugs, Carlsson A, Lindquist M. Effect of chlorpromazine or haloperidol on the formation of 3-methoxytyramine and normetanephrine inmouse brain. Acta Pharmacologica Toxicologica 1963;20:140–4.

1975, Creese et al demonstrated with X-ray crystallography that dopamine blockade actually took place, 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.

based on the dopamine hypothesis, for different theories were proposed to explain antipsychotic mechanism of action, 1. Blockade of the post synaptic D1 receptor, 2. Blocking of the post synaptic D2 receptor, 3. Interactive effects between D1 and D2 receptors, 4. Slowly developing decrease in presynaptic dopamine activity

mood stabilizers

lithium

1949, John Cade, Australian physician, 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, guinea pigs rapidly became unresponsive to stimuli, 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, 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, -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, Untitled

1970, approved in the United States

anxiolytics

meprobamate

pre-Miltown, 1800s, Opiates or alcohol were the sedatives of choice, 1850s, bromides, Widely used in 19th Century: Sleeping salts, A "bromide" was a tiresome, boring person, Dangerous: accumulate in the body, depression develops, toxicity with repeated doses, dermatitis, and constipation, Low (ineffective) doses were part of OTC preparations up to 1960's, "Bromo-Seltzer", 1870, chloral hydrate first used clinically, synthesized in 1932, Mickey Finn, A Mickey Finn (or simply Mickey) is a slang term for a drink laced with a drug (especially chloral hydrate) given to someone without their knowledge in order to incapacitate them. Serving someone a Mickey Finn is most commonly referred to as slipping a mickey, sometimes spelled "slipping a mickie", 1880s, Axenfeld, Auguste, Des Nevroses. 1864, mild: reassurance, ether, water of cherry laurel, laurel water is distilled from the fresh leaves of the cherry laurel and contains the poison prussic acid, essentially, a solution of hydrogen cyanide, of uncertain strength, severe: potassium bromides, morphine or atropine, 1882, paraldehyde first used clinically, Synthesized in 1829, Very effective, Wide margin of safety, Widespread use in the 1950's, Problem: Horrible taste and odor that effects the breath of the user., early 1900s, 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., 1930, four of every 10 prescriptions written by doctors were for drugs containing bromides, 1950s, widespread use of paraldehyde, Thalidomide, sedative hypnotic, prescribed or in the late 1950s and early 1960s to pregnant women as an anti-emetic and sleep aid, 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, sedative-hypnotics, barbiturates, Fifty to sixty years ago, the only medications widely used in psychiatric patients for the treatment of anxiety or agitation were barbiturates, side effects—sedation, a potential for dependence, and life-threatening toxicity with overdose, 1951 article in The New York Times declared barbiturates to be more dangerous than heroin or cocaine, "major tranquilizers", thought too toxic for patients with less serious mental disorders

1945, mephenesin, Carter-Wallace laboratories, Frank Berger, (with William Bradley, chief chemist at Wallace) trying to develop bactericidal compounds against penicillin resistant gram-negative bacteria, mephenesin noted to be "tranquilizing", mice injected with it become temporarily paralyzed and demonstrate muscle relaxation, his new drug was less sedative than older drugs, Berger adopted a new term—tranquilizer, Berger investigates mephenesin's tranquilizing properties; begins quest to find better tranquilizer; which eventually leads to synthesis of meprobamate, mephenesin's half-life was too short and too large of a dose required

1946, mephenesin introduced as a muscle relaxing agent for use in anesthesia

1950, meprobamate synthesized by Berger, Untitled, Carter-Wallace initially wouldn't give Berger financial support ($500,000) to bring the meprobamate to market, there was no preexisting market for prescription-only tranquilizers, Wallace conducted a survey of 200 doctors to gauge interest in prescription anxiolytics -- the majority of respondents expressed little interest, Wallace shelves meprobamate, Carter-Wallace doubted there would be a viable pharmaceutical anxiety drug market and what would later be the best-selling psychotropic drug in American history was, for the time being, shelved., christened it Miltown after the New Jersey town Wallace Laboratories was located, Wallace did not have resources to promote the drug; Wallace specialized in over-the-counter medications

1955, Miltown's Debut, Berger shows Miltown film at the 1955 meeting of the Federation of American Societies for Experimental Biology in San Francisco, film showed monkeys in three distinct chemical states: naturally vicious, unconscious on barbiturates, and calm but awake on Miltown, film caught the attention of Wyeth executives, Untitled, Wyeth offers Wallace Carter a hefty sum to license meprobamate under the trade name "Equanil", the first drug to be sold specifically as an anxiolytic, ameliorate anxiety but not induce sedation or sleep, The launching of meprobamate under the brand name Miltown in 1955 was a watershed

1957, 35 million prescriptions sold; one prescription per second, fastest-growing drug in history

1970, Placed on Schedule IV

cultural context, turning point in the history of psychopharmacology, Shorter considered meprobamate's success as a marker of "cosmetic psychopharmacology" in the American cultural history, Shorter E: A History of Psychiatry: From the Era of the Asylum to the Age of Prozac. 1997., "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?", "Miltown" becomes a household name in part of the cultural lexicon: "penicillin for the blues," "miltown-ing," "Miltown cocktails,"...more>>, tranquilizer for the healthy "unwell", the first middle-class drug abuse phenomenon; "happy pill" alternative for harried housewives and stressed-out commuters. "dehydrated martini";"Miltown parties", "Mother's Little Helper," The Rolling Stones, 1966, Milton Berle, "It's worked wonders for me. In fact, I'm thinking of changing my name to Miltown Berle.", 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.", 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.", nicknames, "peace pills", "happiness pills, "emotional aspirin", "penicillin for the blues", "dehydrated martini", "executive Excedrin", In New York, the drug's fanatical following among the white-collar weary earned it the nickname "Executive Excedrin.", 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.

post-Miltown, Librium launched in March 1960, Carisoprodol (SOMA), 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

pharmacology, Untitled, 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., Manual of Clinical Psychopharmacology, Sixth Edition. Alan F. Schatzberg, M.D., Jonathan O. Cole, M.D., and Charles DeBattista, D.M.H., M.D., 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, 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., produces physical dependence and tolerance in much the same way as do the barbiturates and the benzodiazepines, Significant withdrawal effects, such as convulsions, agitation, and delirium, occur after clinically relatively lower doses

antidepressants

MAOIs

iproniazid, originally intended to treat tuberculosis, 1957, Nathan Kline, reported the beneficial effects of iproniazid, a monamine oxidase inhibitor, in the treatment of severe depression, "As a side effect, however, there developed an odd problem. The patients felt too good. They overexerted themselves and generally ignored the medical safeguards their condition required. Iproniazid's potential as a mood drug had gone largely unnoticed because psychiatrists at the time just weren't thinking along those lines.", Lehman H, Kiine NS: Clinical discoveries with antidepressant drugs, in Parnham Mi, Bruinvels J (eds): Discoveries in Pharmacology: Volume 1, Psycho- and Neuro-pharmacology. New York, Elsevier, 1983., credited with founding the field of psychopharmacology

TCAs

imipramine, 1956, Roland Kuhn, discovered imipramine's antidepressant effect, 1939, appointed to psychiatric hospital in Münsterlingen, Switzerland, director from 1960 to 1980, 1957, Kuhn published the results of his observations in Schweizerische Medizinische Wochenschrift (Swiss Weekly Medical Journal), Heinz Lehmann, read Kuhn's article, was duly impressed, and obtained enough samples of imipramine from Basle by airmail to treat depressed patients at that hospital with equally good results., 1958, Lehmann and two co-workers published their results in the Canadian Medical Association Journal

serotonin

originally discovered in the gastrointestinal mucosa in the 1940s

Key players

Frank Ayd, Recognizing the Depressed Patient. 1961.

references

Links

Untitled, ARTICLES

History of the Discovery and Clinical Introduction of Chlorpromazine

Mother's Little helper

Listening to the Past: History, Psychiatry, and Anxiety

MEPROBAMATE-TRANQUILIZER OR ANXIOLYTIC?

The History of Psychopharmacology; Its Relation to Anesthesiology

Meprobamate: A Study of Irrational Drug Use

The Creation of Psychopharmacology by David Healy. 2004

The Antidepressant Era by David Healy. 1999.

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

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

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