clozapine history

Question 1

What is Clozapine?
A: Clozapine is an atypical antipsychotic drug used to treat schizophrenia in patients who are unresponsive to, or intolerant of, conventional antipsychotic drugs.

Question 2

When was Clozapine first synthesized?
A: Clozapine was first synthesized in 1958 by Wander AG, Switzerland.

Question 3

What were some of the limitations of first-generation antipsychotic drugs like chlorpromazine?
A: While first-generation antipsychotic drugs like chlorpromazine were somewhat effective at reducing positive symptoms of schizophrenia, their side effects were limiting.

Question 4

How was Clozapine initially tested in clinical trials?
A: Clozapine was first tested in clinical trials in the early 1960s in psychotic patients, including 12 schizophrenic patients.

Question 5

What were the results of the early clinical trials of Clozapine?
A: The results of the early clinical trials of Clozapine were disappointing, with 9 of the 19 patients getting worse.

Question 6

What was the significance of the Gross & Langner trial of Clozapine in 1966?
A: The Gross & Langner trial of Clozapine in 1966, which included 34 patients, mainly chronic schizophrenics, treated up to 700mg a day for up to six months, found that 24 patients were judged to have shown a “good or very good” response, with 7 of these resuming employment.

Question 7

What are some of the unique properties of Clozapine compared to first-generation antipsychotic drugs?
A: Clozapine has a lower D2 receptor occupancy and a higher D1 receptor occupancy on PET scans compared to first-generation drugs, as well as a unique ratio. It also causes no hyperprolactinaemia and very little movement disorders.

Question 8

What are some of the licensed indications for Clozapine in 2018?
A: Clozapine is licensed for the treatment of schizophrenia in patients unresponsive to, or intolerant of, conventional antipsychotic drugs, as well as for psychosis in Parkinson’s disease.

Question 9

What are some of the haematological problems associated with Clozapine?
A: Neutropenia and potentially fatal agranulocytosis have been reported with Clozapine, and patients must have normal leucocyte and differential blood counts before starting treatment. Leucocyte and differential blood counts must be monitored regularly during treatment.

Question 10

What are some of the other problems associated with Clozapine?
A: Other problems associated with Clozapine include myocarditis and cardiomyopathy, as well as impairment of intestinal peristalsis and constipation. Clozapine should also be used with caution in patients with a history of heart disease and in those receiving drugs that may cause constipation.

Question 11

What were some of the limitations of first-generation antipsychotics like chlorpromazine?
Although somewhat effective at reducing positive symptoms of schizophrenia, they were limited by significant side effects.

Question 12

When was clozapine first synthesised and what was its initial purpose?
Clozapine was first synthesised in 1958 and was initially tested in animal studies for its marked effects on autonomic function and reduced motor activity, as well as its strong anti-adrenergic and anticholinergic properties.

Question 13

What were the results of the first clinical trial of clozapine in psychotic patients?
The first clinical trial of clozapine in 19 patients, including 12 with schizophrenia, showed disappointing results, with 9 of the 19 patients getting worse.

Question 14

When was clozapine licensed for clinical use in Switzerland and how many other countries followed suit?
Clozapine was licensed for clinical use in Switzerland in the late 1960s, and by 1972, 34 other countries had followed suit.

Question 15

What happened in Finland in 1975 that led to clozapine being withdrawn in some countries and restricted in others?
In Finland, 16 out of 2260 patients (0.7%) developed agranulocytosis while taking clozapine, leading to eight deaths. This led to clozapine being withdrawn in some countries and restricted in many others.

Question 16

Why did the FDA permit the continued use of clozapine on a named-patient (or equivalent) basis in the US?
Clinical impressions suggested that clozapine was “better” than first-generation drugs like chlorpromazine and haloperidol, and improved symptoms in chronic schizophrenia patients, even those who had not responded to other treatments.

Question 17

What unique benefits did trials between 1977-88 show for clozapine in the treatment of refractory patients and those in whom side effects limited the dose?
Trials during this period showed that clozapine had unique benefits in the treatment of refractory patients (i.e., those for whom other drugs did not work well) and those in whom side effects limited the dose below what would be effective.

Question 18

What is the receptor profile of clozapine compared to first-generation antipsychotics?
Clozapine has the same D2 receptor affinity as first-generation antipsychotics but lower D2 receptor occupancy and higher D1 receptor occupancy on PET scans, as well as a unique ratio. Its role in relation to D4 receptors is uncertain.

Question 19

What are the licensed indications for clozapine in the UK as of 2018?
Clozapine is licensed for the treatment of schizophrenia in patients unresponsive to, or intolerant of, conventional antipsychotic drugs (both first and second-generation), as well as psychosis in Parkinson’s disease.

Question 20

What are some of the other problems associated with clozapine use besides hematological issues?
Other potential problems with clozapine use include myocarditis and cardiomyopathy (which can be fatal), as well as impairment of intestinal peristalsis leading to constipation, intestinal obstruction, fecal impaction, and paralytic ileus.