3.1 History and evolution of psychotropic compounds

Before modern drugs

• Early treatments such as alcohol, opium, bromides, chloral hydrate, paraldehyde and barbiturates mainly sedated, and dependence and overdose limited their safety.

• Reserpine, an early antipsychotic, comes from the root of Rauwolfia serpentina (Indian snakeroot), a plant of traditional Ayurvedic medicine.

• Reserpine depletes vesicular monoamines, and reports of depression during its use helped shape the monoamine theory.

Early physical treatments

• Meduna induced seizures because he believed epilepsy and schizophrenia were biologically opposed.

• Freeman popularised leucotomy, but the Nobel Prize went to Moniz.

Lithium and mood stabilisers

• John Cade, in Melbourne in 1949, experimented on guinea pigs and then reported lithium calming ten manic patients, reintroducing a drug used and forgotten in the nineteenth century.

• Mogens Schou, in Aarhus in 1954, confirmed lithium's antimanic effect in a placebo-controlled trial.

• Schou and Poul Baastrup then showed lithium's value in long-term relapse prevention.

• Lambert and colleagues in France reported in 1966 that valpromide, a valproate compound, stabilised mood in bipolar illness, a few years after valproate's anticonvulsant action was found by chance.

• Charles Bowden ran the 1994 multicentre trial of divalproex against lithium and placebo that established valproate as a treatment for acute mania.

Antipsychotics

Chlorpromazine

• Paul Charpentier, a chemist, synthesised chlorpromazine, a phenothiazine, in 1950 within an antihistamine programme, but he never used it clinically.

• Henri Laborit gave it before surgery in 1951 to reduce surgical shock, and the calm indifference he described prompted its psychiatric use.

• Jean Delay and Pierre Deniker introduced it into psychiatry in 1952 at Sainte-Anne hospital, Paris, giving it alone to agitated psychotic and manic patients, which began the antipsychotic era.

• Chlorpromazine reached psychiatry after lithium (1949) and before the benzodiazepines (1960s), and its efficacy was later linked to dopamine D2 blockade.

Later antipsychotics

• Haloperidol was synthesised in 1958 by Paul Janssen in Belgium.

• Clozapine, synthesised in 1958, was the first antipsychotic to work with little extrapyramidal disturbance, and this first defined an atypical drug.

• Clozapine was largely withdrawn after deaths from agranulocytosis in Finland in 1975, and it returned (UK 1990) only with registered blood monitoring.

• John Kane led the 1988 trial in treatment-resistant schizophrenia that brought clozapine back; he is linked with clozapine, not lithium (Cade) or valproate (Bowden).

• The class moved from phenothiazines to butyrophenones, second-generation drugs and partial agonists, each with different movement, prolactin and metabolic risks.

Major tranquilliser was the old term for the antipsychotics, while minor tranquilliser meant the anxiolytic sedatives such as meprobamate, benzodiazepines and barbiturates.

Antidepressants

The monoamine oxidase inhibitors came first in the 1950s, then the tricyclics, then the selective serotonin reuptake inhibitors (SSRIs).

Monoamine oxidase inhibitors

• Iproniazid, an antituberculous hydrazine, was the first antidepressant and founded the monoamine oxidase inhibitor (MAOI) class, after staff noticed by chance that it lifted mood in sanatorium patients.

• Nathan Kline, in New York in 1957, reported that iproniazid lifted mood in depression and called it a psychic energiser.

• Max Lurie coined the word antidepressant in the early 1950s for the mood-lifting effect of isoniazid.

• Moclobemide was the first reversible inhibitor of monoamine oxidase A (RIMA) in clinical use, with a much lower risk of tyramine reactions than irreversible MAOIs such as phenelzine.

Tricyclics

• Roland Kuhn, at Münsterlingen in 1956 to 1957, found that imipramine relieved depression.

• Imipramine was a Geigy compound related to chlorpromazine and first tried in schizophrenia; marketed in 1958, it was the first tricyclic.

Selective serotonin reuptake inhibitors

• Arvid Carlsson developed zimeldine at Astra in the early 1970s from the antihistamine brompheniramine, and it became the first SSRI.

• Zimeldine was sold in Sweden from 1982 and withdrawn in 1983 after Guillain-Barré syndrome and hypersensitivity reactions.

• Fluoxetine was the first SSRI approved and marketed in the United States (Food and Drug Administration, December 1987), followed by sertraline (1991), paroxetine (1992) and fluvoxamine (1994).

Anxiolytics

• Leo Sternbach synthesised chlordiazepoxide at Hoffmann-La Roche; animal testing revealed its calming effects in 1957, and it was marketed as Librium in 1960.

• Benzodiazepines replaced barbiturates because they have a wider safety margin, but they still cause dependence.

From drug effects to neurochemical models

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Drugs act on receptors quickly but improve symptoms slowly, which points to downstream adaptation; a drug response alone does not prove that a transmitter deficiency causes the illness.

Harms found after licensing

A licence shows a favourable benefit-risk balance for specified uses, so rare harms surface only through post-marketing surveillance such as Yellow Card reporting.

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