This page shows what was measured, who it was measured in, and what that does not settle.
What Clozapine does in the body
Used for schizophrenia after other antipsychotics fail, and to reduce suicide risk.
Clozapine blocks dopamine receptors, as all antipsychotics do, but weakly and briefly at the main one, while acting strongly on serotonin and several other receptor systems. That unusual combination is thought to explain why it works when others do not, and why it causes almost no movement side effects. Separately and unpredictably, in a small number of people it stops the bone marrow producing neutrophils, the white cells that fight bacterial infection, and without those cells an ordinary infection can kill.
What happened in people
Among people who had repeatedly not improved, 30% responded to clozapine and 4% to chlorpromazine.
✓ Reviewed first-read answer
Where this came from
A person wrote this and a reviewer approved it against this exact record. It carries no effect size.
A reviewer approved this against this record. The reviewed-claim record carrying the exact population and effect size does not exist yet.
No source is stored against this line.
The limit that matters most
Blood monitoring addresses one danger but not heart inflammation, pneumonia or severe constipation.
Where it acts
Mesolimbic and mesocortical dopamine pathways; the toxicity site is the bone marrow granulocyte lineage
Kind of result
The kind of result is not recorded
Supervision
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
What the registries record it as
The substance registry classes this as chemical.
FDA substance registry · J60AR2IKIC · read 2026-08-29
Where each sentence above came from
No recorded sentence describes the change this makes in a way that stands on its own. The page opens with what it is taken for instead, and the recorded explanation follows below.
Shown as the opening line on this page.
The limit a reviewer approved as the one that matters most here.
The four opening statements run to 110 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Comparator
A comparator is whatever the treatment was measured against.
A picture of it, and where the picture fails
It is like the other runner in a race.
Where that stops being true. A race has one winner. A study can show both arms improved.
What people get wrong. Results are read without asking what the other group got. Beating nothing is not beating a treatment.
The control condition against which the experimental intervention is assessed.
Randomisation
Randomisation means chance decides who gets which treatment.
A picture of it, and where the picture fails
It is like a coin toss deciding the groups.
Where that stops being true. A coin toss is fair once. Fairness here comes from doing it for everyone.
What people get wrong. It is thought to make groups identical. It makes them similar on average, including on things nobody measured.
Allocation of participants to arms by a chance process, so that unmeasured factors are balanced in expectation.
Absolute difference
An absolute difference is how many more people in a hundred were affected.
A picture of it, and where the picture fails
It is like counting heads in two rooms of a hundred.
Where that stops being true. Heads are easy to count. Study results carry a margin of error too.
What people get wrong. It is confused with a percentage change, which can look far larger.
The arithmetic difference in event rates between arms.
Confidence interval
A confidence interval is the range the true answer is likely to sit in.
A picture of it, and where the picture fails
It is like a weather forecast giving a range rather than one number.
Where that stops being true. A forecast range covers tomorrow. This one covers what the study could resolve.
What people get wrong. The middle number is read as the answer. A range crossing zero means no change is still possible.
An interval estimate that would contain the true parameter in a stated proportion of repeated studies.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
Responder rate against a priori criteria at six weeks in patients failing at least three neuroleptics and a prospective haloperidol trial
✓ The study showed what it set out to show
Who was studied
Clozapine versus chlorpromazine in treatment-resistant schizophrenia (Kane et al.)
How many people
268
Study design
Multicentre double-blind randomised trial after prospective confirmation of resistance
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
30 per cent responders on clozapine against 4 per cent on chlorpromazine, with significantly greater improvement on BPRS, CGI and NOSIE covering negative as well as positive symptoms
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Six weeks was too short to observe agranulocytosis, and none occurred. The authors nonetheless recommended restricting use to selected treatment-resistant patients on the strength of the prior evidence.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet, orally disintegrating tablet or oral suspension, titrated over weeks
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
Incidence of agranulocytosis under mandatory weekly white-cell monitoring, and effects of age and sex
✓ The study showed what it set out to show
Who was studied
Clozaril Patient Management System surveillance analysis (Alvir et al.)
How many people
11555
Study design
Post-marketing surveillance with survival analysis, February 1990 to April 1991
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
73 cases with 2 deaths; cumulative incidence 0.80 per cent (95% CI 0.61 to 0.99) at one year and 0.91 per cent (0.62 to 1.20) at eighteen months; 61 of 73 cases within three months; risk rising with age and higher in women
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. The incidence is measured under weekly monitoring, so it describes the hazard as managed rather than the untreated natural rate. Other clozapine harms — myocarditis, gastrointestinal hypomotility, pneumonia — are outside this analysis entirely.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet, orally disintegrating tablet or oral suspension, titrated over weeks
Interval reported. 95% CI 0
Written into the record, not signed off as a reviewed claim.
Suicide-related events over two years in patients with schizophrenia or schizoaffective disorder at high risk of suicide
✓ The study showed what it set out to show
Who was studied
InterSePT (clozapine versus olanzapine for suicidality)
How many people
980
Study design
Multicentre prospective randomised active-comparator trial, two years
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
Clozapine more effective than olanzapine in decreasing suicidality risk, regardless of which of the ten identified baseline risk factors were present
Repeated elsewhere
Partially Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. An open comparison against an active antipsychotic in a high-risk population; suicide-related events are a composite endpoint whose components differ in severity.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet, orally disintegrating tablet or oral suspension, titrated over weeks
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
RNAWiki holds 3 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Start
Clozapine
What a person takes: Oral tablet, orally disintegrating tablet or oral suspension, titrated over weeks.
The measurement behind this step
Oral clozapine started at 12.5 mg and titrated slowly upward over weeks to limit orthostatic hypotension, sedation and myocarditis risk. Metabolised principally by CYP1A2, so smoking cessation can raise plasma levels substantially, and metabolic rate differs across genetic ancestry groups.
Getting in
Oral tablets, titrated upward slowly over weeks
Taken by mouth, starting very low and increasing gradually, because rapid increases cause dangerous drops in blood pressure and sedation.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Oral clozapine titrated from 12.5 mg daily over weeks toward a target in the hundreds of milligrams, with orally disintegrating and suspension formulations available. Metabolised principally by CYP1A2, so smoking status and caffeine materially alter plasma levels.
Crosses into the brain and reaches limbic dopamine pathways
It enters the brain and reaches the circuits where dopamine signalling is disordered in schizophrenia.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Lipophilic with good central nervous system penetration, reaching mesolimbic and mesocortical dopamine pathways with preferential limbic over striatal action. Metabolised to norclozapine, which is itself pharmacologically active.
It touches an unusually wide set of receptors, and crucially it releases the main dopamine receptor fast rather than holding on to it.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Higher affinity at D4 than D2, with rapid D2 dissociation kinetics; potent 5-HT2A antagonism; substantial muscarinic, histamine H1 and alpha-1 adrenergic activity. No single-receptor account of the treatment-resistance efficacy has been established.
Psychosis improves without movement disorder — and marrow may fail
Symptoms improve where other drugs failed, and stiffness and tremor largely do not occur. Separately and unpredictably, neutrophil production can shut down.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Transient limbic D2 occupancy with 5-HT2A blockade produces antipsychotic effect with minimal nigrostriatal blockade, hence near-absence of extrapyramidal symptoms and tardive dyskinesia. Independently, oxidation of the dibenzodiazepine ring generates a reactive nitrenium ion implicated in neutrophil and myeloid progenitor injury.
Response in a third of resistant patients; agranulocytosis in about one in 125
Roughly a third of patients who had failed everything else responded, and suicidality fell. Under weekly monitoring, agranulocytosis occurred in about 0.8 per cent in the first year, with two deaths among 11,555 patients.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Measured: 30 per cent response against 4 per cent on chlorpromazine in prospectively confirmed treatment resistance. Measured: cumulative agranulocytosis 0.80 per cent (95% CI 0.61 to 0.99) at one year, 73 cases and 2 deaths in 11,555 patients, 61 cases within three months. Measured: greater reduction in suicidality than olanzapine over two years in 980 high-risk patients.
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 5 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Patients with treatment-resistant schizophrenia and those at recurrent risk of suicidal behaviour in schizophrenia or schizoaffective disorder. Haematological monitoring is now recommended rather than enforced through a centralised database.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What the label states about particular groups
On pediatric, the label states: “Safety and effectiveness in pediatric patients have not been established.”
US prescribing information · 5021d643-32d2-4167-b5d8-90870e68a787 · read 2026-08-30
On older people, the label states: “There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine.”
US prescribing information · 5021d643-32d2-4167-b5d8-90870e68a787 · read 2026-08-30
On people who are pregnant, the label states: “Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy.”
US prescribing information · 5021d643-32d2-4167-b5d8-90870e68a787 · read 2026-08-30
On people who are breastfeeding, the label states: “Risk Summary Clozapine is present in human milk.”
US prescribing information · 5021d643-32d2-4167-b5d8-90870e68a787 · read 2026-08-30
Where the result stopped carrying
Withdrawn in 1975 after eight agranulocytosis deaths in Finland
Returned in February 1990 only within a system requiring a weekly white-cell count before each supply
Under-prescribing persisted throughout the restriction era, with non-evidence-based treatments routinely tried first
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (11)
It was studied for a different goal
The studies measured something else entirely. Nothing in this record points to this reason.
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Prescription only
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Oral tablet, orally disintegrating tablet or oral suspension, titrated over weeks
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Suppression classes recorded: S5, S6.
No source is stored against this line.
What is in the pack
5 mg and titrated slowly upward over weeks to limit orthostatic hypotension, sedation and myocarditis risk. Metabolised principally by CYP1A2, so smoking cessation can raise plasma levels substantially, and metabolic rate differs across genetic ancestry groups.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold and what that means for what is in the pack.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
Agranulocytosis is the historically defining harm: cumulative incidence 0.80 per cent at one year under weekly monitoring, with 73 cases and 2 deaths in 11,555 patients and 61 of those cases within three months. The 2024 FDA meeting reported 0.03 per cent mortality from agranulocytosis at approximately 140,000 annual prescriptions. Other serious harms receive less attention and warrant more: myocarditis and cardiomyopathy typically in the first weeks, gastrointestinal hypomotility progressing to ileus, seizures at higher doses, pneumonia-related mortality, orthostatic hypotension during titration, hypersalivation, and substantial metabolic effects. Haematological monitoring is now recommended rather than enforced through a centralised database.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Oral tablet, orally disintegrating tablet or oral suspension, titrated over weeks
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
edation and myocarditis risk. Metabolised principally by CYP1A2, so smoking cessation can raise plasma levels substantially, and metabolic rate differs across genetic ancestry groups.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on which forms are sold and how they compare.
No source is stored against this line.
What is recorded as being sold
61 products list this as an active ingredient in the United States drug directory. 61 of them contain it and nothing else.
FDA National Drug Code directory · 72603-914 · read 2026-08-29
They are sold as powder, suspension, tablet and tablet, orally disintegrating, taken oral.
FDA National Drug Code directory · 72603-914 · read 2026-08-29
The regulator's established pharmacologic class for it is atypical antipsychotic [epc].
FDA National Drug Code directory · 72603-914 · read 2026-08-29
16 published labels name it as an active ingredient. 16 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · 5021d643-32d2-4167-b5d8-90870e68a787 · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · 5021d643-32d2-4167-b5d8-90870e68a787 · read 2026-08-29
CLOZAPINE is oral at 3 DOSAGE FORMS AND STRENGTHS Clozapine Tablets USP, 25 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘54’ on the other…, recorded as fda label in effect 2025-12-17 in the United States.
US prescribing information · 5021d643-32d2-4167-b5d8-90870e68a787 · read 2026-08-30
Recorded price in US: 0.25534–0.91602 USD per one unit as the pricing file counts it — a tablet, capsule, patch or single item, across 28 priced products whose strengths and pack forms differ, as of 2026-08-26, paid by retail pharmacies buying the product, as surveyed by the Centers for Medicare & Medicaid Services. It is not a list price, an insurance price, or what anyone pays at a counter..
Recorded source · 2026-08-26 · read 2026-08-28
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
Self-experiment planning is not offered for a prescription or clinician-supervised medicine. The questions below are for a clinician or pharmacist.
Questions worth asking
Which of the trials of Clozapine studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That white-cell monitoring constitutes comprehensive clozapine safety management — myocarditis, gastrointestinal hypomotility and pneumonia are not detected by it
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the modelled lives-saved figures from increased prescribing are measured outcomes; they are estimates built on assumed effect sizes
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the 0.80 per cent incidence describes the unmonitored hazard; it was measured under mandatory weekly counts
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Clozapine are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
30 per cent response against 4 per cent, in patients who had failed everything else
In plain words
In 268 patients who had already failed at least three antipsychotics and then a further six-week trial, 30 per cent responded to clozapine and 4 per cent to chlorpromazine.
What was measured
Responder rate against a priori criteria at six weeks, clozapine versus chlorpromazine, after prospective confirmation of treatment resistance
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Patients meeting DSM-III criteria for schizophrenia who had failed to respond to at least three different neuroleptics underwent a prospective single-blind six-week trial of haloperidol at a mean 61 plus or minus 14 mg daily. Those still unimproved were randomised double-blind to clozapine up to 900 mg daily or chlorpromazine up to 1800 mg daily for six weeks; 268 patients entered the double-blind comparison. Against a priori criteria, 30 per cent of clozapine patients were responders against 4 per cent on chlorpromazine, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale and Nurses' Observation Scale for Inpatient Evaluation, covering negative as well as positive symptoms. No agranulocytosis occurred during the short study, and the authors nonetheless recommended restricting use to selected treatment-resistant patients.
Written into the record, not signed off as a reviewed claim
Agranulocytosis in 0.80 per cent at one year, two deaths in 11,555 patients
In plain words
Under mandatory weekly blood counts, 73 of 11,555 patients developed agranulocytosis and two died. Most cases occurred in the first three months.
What was measured
Cumulative incidence of agranulocytosis at one year and eighteen months under weekly white-cell monitoring, with deaths
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The Clozaril Patient Management System, which required a weekly white-cell count before each drug supply, was evaluated by survival analysis for February 1990 through April 1991 with data on 11,555 patients. Agranulocytosis developed in 73, with death from infectious complications in 2. Sixty-one of the 73 episodes occurred within three months of starting treatment. Cumulative incidence was 0.80 per cent (95% CI 0.61 to 0.99) at one year and 0.91 per cent (95% CI 0.62 to 1.20) at eighteen months. Risk rose with age and was higher in women. The authors conclude that agranulocytosis is a substantial hazard that can be reduced by monitoring the white-cell count, and that the front-loading of risk and the age gradient give guidance for how monitoring should be structured.
Written into the record, not signed off as a reviewed claim
Withdrawn in 1975, back in 1990, de-restricted in 2025
In plain words
Eight deaths in Finland in 1975 took the drug off the market. It returned in 1990 only with weekly blood tests. In 2025 the enforcement system was removed and monitoring became a recommendation.
What was measured
Not recorded
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Clozapine was associated with eight agranulocytosis deaths in Finland in 1975 and withdrawn. It was approved in the United States in 1989 for treatment-resistant schizophrenia and became available in February 1990 only within the Clozaril Patient Management System, in which a weekly white-cell count was required for each drug supply, and in 2003 gained a suicide-prevention indication. On 19 November 2024 an FDA clozapine meeting reported approximately 140,000 annual prescriptions and 0.03 per cent mortality from agranulocytosis. The risk evaluation and mitigation strategy was subsequently eliminated, and in June 2025 the package insert removed the centralised database, with haematological monitoring becoming recommended rather than mandatory. Three regulatory positions in fifty years, on a molecule that has not changed.
Written into the record, not signed off as a reviewed claim
It reduces suicidality, and that was tested against an active comparator
In plain words
In 980 patients at high risk of suicide followed for two years, clozapine reduced suicidal behaviour more than olanzapine, whichever risk factors a patient had.
What was measured
Suicide-related events over two years, clozapine versus olanzapine, in 980 high-risk patients
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
A multicentre prospective study followed 980 patients with schizophrenia or schizoaffective disorder judged at high risk for suicide for two years after randomisation to clozapine or olanzapine. Ten baseline univariate predictors of subsequent suicide-related events were identified, including schizoaffective diagnosis, alcohol or substance use, smoking, lifetime suicide attempts, hospitalisations in the previous 36 months to prevent suicide, and baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale and Parkinsonism severity. Clozapine was in general more effective than olanzapine in decreasing suicidality risk regardless of which risk factors were present. This is an active-comparator trial against a modern antipsychotic, not a placebo comparison, which makes the result unusually strong for a suicide endpoint.
Written into the record, not signed off as a reviewed claim
The cost of the restriction was counted in the same units as the harm
In plain words
Advocates argued that the monitoring requirements deterred prescribing so effectively that they cost more lives to suicide than agranulocytosis ever took.
What was measured
Not recorded
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The 2024 FDA meeting recorded approximately 140,000 annual prescriptions and 0.03 per cent mortality from agranulocytosis, and heard patient advocates argue that restrictions were costing lives. Published analysis in the psychiatric literature puts the arithmetic explicitly: suicide takes about 5 per cent of patients with schizophrenia, long-term clozapine may prevent a large fraction of those deaths, and on the authors' figures every additional 10,000 long-term clozapine prescriptions would save roughly 400 United States lives from suicide at a cost of roughly 3 deaths from agranulocytosis. Those are modelled estimates rather than measured outcomes and should be read as such. What is not modelled is the direction: a restriction has a body count of its own, in deaths from the untreated condition, and this is the case where somebody insisted on counting it.
Written into the record, not signed off as a reviewed claim
Agranulocytosis absorbed the attention that other clozapine harms needed
In plain words
Focusing on the blood count meant other serious risks — myocarditis, pneumonia, severe constipation — got less structured attention than they warranted.
What was measured
That a white-cell monitoring programme constitutes comprehensive safety management for clozapine
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The published critique of the restriction era is that the regulatory focus on agranulocytosis came at the expense of other clozapine risks. The post-REMS review identifies the practical priorities as slower initial titration, differences in clozapine metabolism across genetic ancestry groups, awareness of inflammatory reactions, recognition of pneumonia-related mortality, and appropriate bowel care. Clozapine-induced gastrointestinal hypomotility can progress to ileus and death, and myocarditis typically presents in the first weeks. None of these is detected by a white-cell count. A monitoring programme built around one measurable hazard tends to define the drug's safety as that hazard, and the harms it does not measure become correspondingly invisible.
Written into the record, not signed off as a reviewed claim
The risk is front-loaded, and the monitoring schedule reflects that
In plain words
Sixty-one of the 73 agranulocytosis cases happened within three months of starting. Weekly testing forever was never what the data supported.
What was measured
Timing distribution of agranulocytosis episodes and risk gradients by age and sex
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Of 73 agranulocytosis episodes among 11,555 patients, 61 occurred within three months of starting treatment, and the authors identified the reduced incidence after the first six months as a specific guide for future monitoring. Risk also increased with age and was higher in women. That structure — an early, sharply declining hazard with identifiable demographic gradients — is exactly what allows a monitoring schedule to be tapered rather than held constant, and it is the empirical basis for the tiered schedules that followed and for the later judgement that the requirements had become overly cautious. The 1993 analysis contained the argument for its own relaxation.
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What is not here
7 questions this page could not answer
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How close this is to real life — found nothing in the sources checked.
Felt, measured, or meaningful — found nothing in the sources checked.
How long anything takes — found nothing in the sources checked.
What it may clash with — found nothing in the sources checked.
Other ways to the same goal — found nothing in the sources checked.
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The record as stored
The full record, for auditing
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The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
The only antipsychotic with demonstrated efficacy in treatment resistance — 30 per cent response against 4 per cent on chlorpromazine — withdrawn in 1975 after eight agranulocytosis deaths in Finland, returned in 1990 under mandatory weekly white-cell counts that brought the cumulative agranulocytosis incidence to 0.80 per cent at one year with two deaths among 11,555 patients, and released from its restriction programme in 2025 after an FDA meeting reported 0.03 per cent mortality from agranulocytosis.
Recorded evidence blocks (10)
Q2
On the Clozapine label: indicated for what?
"Clozapine tablets are an atypical antipsychotic indicated for: Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, clozapine tablets should be used only in patients…": indications and usage on Clozapine's label. DailyMed label · 61fe53d5-ed5c-4e45-9189-709d08d386cb · 2026-05-11
Q3
63 registered trials of Clozapine — at which phases?
Registered studies posting no result
55 of 63
63 registered studies of Clozapine: 27 phase4, 11 na or unstated, 10 phase3, 7 na, 4 phase1, 4 phase2, 1 early phase1. CLINICALTRIALS_SNAPSHOT · 2026-09-01
"Pairing D-Cycloserine with Clozapine was found to worsen negative side effects in patients with Schizophrenia, so the study was suspended."; 3 of 63 registered studies
Show the evidence
Trial
NCT00000372
withdrawn; "Pairing D-Cycloserine with Clozapine was found to worsen negative side effects in patients with Schizophrenia, so the study was suspended."
NCT02893371
terminated; "Per PI, this study is not a clinical trial and was inadvertently entered in the system"
NCT05741502
terminated; "Not able to recruit enough subjects"
recorded 2026-09-01 · last checked 2026-09-04
Q5
Human studies of Clozapine used Clozaril Tablet 100mg — over how long?
studies of Clozapine used the recorded amount. ClinicalTrials.gov · 2026-09-01
3 recorded entries; human; also "Clozaril Tablet 100mg", "clozapine 100 mg", "Clozaril 100 mg (Clozapine)"
Show the evidence
human
NCT01654601
Clozaril Tablet 100mg
NCT02751307
clozapine 100 mg
NCT04849026
Clozaril 100 mg (Clozapine)
recorded 2026-09-01 · last checked 2026-09-04
Q6
Clozapine's half-life is 8 hours — which schedules were studied?
8 hours, the half-life Clozapine's label states: "The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing." DailyMed label · 61fe53d5-ed5c-4e45-9189-709d08d386cb · 2026-05-11
tmax 2.5 hours.
Show the evidence
half lifepharmacokinetics
8 hours; The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing.
tmaxpharmacokinetics
2.5 hours; Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing.
metabolismpharmacokinetics
Metabolism and Excretion Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces.
recorded 2026-05-11 · last checked 2026-09-04
Q7
Which 24 trials of Clozapine posted no result?
Posted no result
24 of 24 completed trials
Registrations
NCT00004826, NCT00065273, NCT00169065, NCT00036582, NCT01123408 and NCT02640300, and 18 more
Completion dates
oldest 1997-11; newest 2022-08-14
Show the evidence
Trial
NCT00004826
1997-11
NCT00065273
2001-06
NCT00169065
2002-06
NCT00036582
2004-02
NCT01123408
2004-07
NCT02640300
2004-07
14 further recorded trials
NCT00649844
2004-09
NCT00014001
2004-12
NCT00031317
2005-06
NCT00029458
2005-10
NCT00048828
2006-06
NCT00501618
2009-07
NCT00154258
2009-12
NCT02582736
2012-12
NCT02751307
2015-01
NCT02625103
2016-02
NCT01663077
2016-12
NCT01498770
2017-12-21
NCT02600741
2018-07-05
NCT01431326
2019-11
Q8
At the median, Clozapine's trials enrolled 54.5 people — anything larger?
Median enrolment
54.5
Largest enrolment
1037352
Registered trials counted
62
Q9
What do 28622 spontaneous reports say about Clozapine — and not say?
These are reports people sent to a regulator. They do not show the medicine caused the reaction. Nobody counted how many people took the medicine and reported nothing. The same event can be reported more than once, and many reports are incomplete. News coverage, lawsuits and new warnings change how often people report. A count is not a rate and not a risk.
Clozapine appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 28622 reaction mentions were counted: hospitalisation 7035; neutropenia 5097; white blood cell count increased 2887; neutrophil count increased 2308. FAERS via Open Targets · CHEMBL42 · 2026-06-24
Show the evidence
hospitalisation
7035
neutropenia
5097
white blood cell count increased
2887
neutrophil count increased
2308
schizophrenia
2251
white blood cell count decreased
2206
4 more recorded rows
neutrophil count decreased
1853
granulocytopenia
1682
psychotic disorder
1672
tachycardia
1631
recorded 2026-06-24 · last checked 2026-09-04
Q10
Which 10 reactions does Clozapine's label not list?
Concomitant use of Strong CYP1A2 Inhibitors : Reduce clozapine dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin).
drug_interactions
( 2.7 , 7.1 ) Concomitant use of Strong CYP3A4 Inducers is not recommended.
drug_interactions
( 2.7 , 7.1 ) Discontinuation of CYP1A2 or CYP3A4 Inducers : Consider reducing clozapine dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued.
drug_interactions
( 5.7 , 5.15 , 7.1 ) 7.1 Potential for Other Drugs to Affect Clozapine Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6.
drug_interactions
CYP1A2 Inhibitors Concomitant use of clozapine and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions.
drug_interactions
Reduce the clozapine dose to one-third of the original dose when clozapine is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin).
2 more recorded rows
Interaction statementdrug_interactions
The clozapine dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.7) , Clinical Pharmacology (12.3) ].
Interaction statementdrug_interactions
Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine.
ChEMBL 37 — CC BY-SA 3.0 Unported · ChEMBL ATC CC BY-SA · ClinicalTrials.gov — US Government work · Open Targets 26.06 — CC0 · mixed register set; per-register licences in docs/specs/corpus-20k-sources.md · openFDA / DailyMed — US Government work
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