Kane is credited with the introduction of which drug into clinical practice?
Exam Question Nov 2008
Clozapine has an unusual history.
It was first used in Europe in the early 1970's. It showed promising results especially as it did not appear to lead to EPSE's. Unfortunately following several cases of agranulocytosis it's popularity plummeted.
Kane produced a study in 1988 that showed that it could be used safely with appropriate blood monitoring, this led to its introduction into the UK and the US.
Exam Question Nov 2008
Clozapine has an unusual history.
It was first used in Europe in the early 1970's. It showed promising results especially as it did not appear to lead to EPSE's. Unfortunately following several cases of agranulocytosis it's popularity plummeted.
Kane produced a study in 1988 that showed that it could be used safely with appropriate blood monitoring, this led to its introduction into the UK and the US.
History of psychiatric drugs and other interventions
The following points come up in exams regarding the history of psychiatric drugs and other interventions.
- Kane - introduced clozapine into clinical practice
- Carlsson - developed the first SSRI
- Blackwell - first described the 'cheese effect' seen in MAOI use
- Cade - discovered lithium's beneficial effect in mania
- Kline - discovered use of iproniazid (MAOI)
- Charpentier - synthesised chlorpromazine
- Delay and Deniker - introduced chlorpromazine as a treatment for schizophrenia
- Kuhn - discovered the antidepressant effects of imipramine
- Cerletti (and Bini) - first use of ECT
- Lurie - coined the term 'antidepressant'
- Sakel - insulin shock therapy
- Moniz - frontal leucotomy for psychosis
- Meduna - metrazol therapy
Antipsychotics
Chlorpromazine (thorazine) - Considered to be the first of the antipsychotics. First synthesised in 1950 by Paul Charpentier. Used in 1951 by Laborit and Huguenard, to patients for its potential anesthetic effects during surgery. Shortly thereafter, Hamon et al. and Delay et al. extended the use of this treatment in psychiatric patients and serendipitously uncovered its antipsychotic activity.
Between 1954 and 1975, about 40 antipsychotic drugs were introduced throughout the world. Thereafter, there was a hiatus in the development of antipsychotics until the introduction of clozapine treatment in 1990 opened the era of 'atypical' antipsychotics.
Clozapine - First synthesised in 1958 and used to some extent during the1960s but was held back due to association with agranulocytosis, 1990s brought back in with monitoring.
Antidepressants
The first antidepressants were the MOA inhibitors (namely iproniazid). Iproniazid was initially developed as a treatment for tuberculosis. After noting side effects (in the early 1950s) such as euphoria, increased appetite, and improve sleep, people started using iproniazid as a treatment for depression. Iproniazid is an irreversible MOA inhibitor and issues such as the cheese reaction ultimately led to its removal from psychiatric practice.
Lurie, a private psychiatrist, coined the term 'antidepressant' for the psychostimulatory effects of isoniazid (another antitubercular compound) in depressed patients.
The tricyclic antidepressants were developed though a separate route. After the success of chlorpromazine for schizophrenia the search was on for even more potent antipsychotic compounds. One such compound (interestingly enough develeoped from promethazine) was imipramine. It was noted that imipramine lacked antipsychotic properties but produced marked improvements in people suffering with depression.
In an essay written by Kuhn (1958), he states They commence some activity of their own, again seeking contact with other people, they begin to entertain themselves, take part in the games, become more cheerful and are once again able to laugh The patients express themselves as feeling much better, fatigue disappears, the feeling of heaviness in the limbs vanish, and the sense of oppression in the chest gives way to a feeling of relief (p. 459). Kuhn also stated that no serious side effects were recorded in the 500 patients treated with imipramine, which was a vast improvement over MAO inhibitors.
Imipramine was approved in 1959 by the Food and Drug Administration (FDA) for the treatment of depression, which established the class of drugs called tricyclic antidepressants (TCA).
The SSRIs were the only class of antidepressants that were actually developed for their intended use. In the late 1960s evidence had begun to emerge suggesting a significant role of serotonin in depression. As a result, the pharmaceutical company Eli Lilly began developing ligands that would selectively inhibit the reuptake of serotonin at serotonin transporters, and as a result would increase serotonin concentrations within the synaptic cleft to further stimulate postsynaptic serotonin receptors.
In 1974, the first report on the selective serotonin reuptake inhibitor (SSRI) LY110140 (fluoxetine) was published and in that publication the authors suggested that fluoxetine would be an antidepressant drug. Fluoxetine was approved by the FDA in December of 1987 and was launched to the market in January 1988 under the trade name Prozac.
Although fluoxetine was the first SSRI approved and marketed in the United States, the clinical trials (Phase I-Phase III) lasted more than seven years and during that time Astra AB introduced the first SSRI zimeldine (Zelmid®) to the European market in March 1982. Zimeldine, which was derived from pheniramine, was removed from the European market in September 1983 due to severe side effects such as hypersensitivity reactions and Guillain-Barre syndrome, which is acute peripheral neuropathy. The hypersensitivity reactions resembled a flu- like syndrome which included fever, joint/muscle pain, headaches and hepatic effects.
