Enter a patient's clozapine dose and the factors that change clozapine metabolism to see the expected 12-hour trough level, where it sits against the therapeutic range, and how a measured lab value compares. Built for prescribers by the psychiatrists at TelepsychHealth; for clinician reference only. Always confirm against current prescribing information and your own clinical judgment.
Key facts about clozapine plasma levels
- Therapeutic reference range: 350–600 ng/mL (1.07–1.84 µmol/L). Response is less likely below 350 ng/mL (AGNP consensus guideline, 2017 update).
- Laboratory alert level: 1,000 ng/mL (3.06 µmol/L). Above it, seizures and other serious adverse effects become more likely and further benefit is unlikely for most patients.
- Draw a 12-hour trough (just before the morning dose) at steady state, at least 5 to 7 days after the last dose change. Clozapine's half-life is about 12 hours.
- Unit conversion: 1 µmol/L of clozapine = 327 ng/mL. ng/mL × 0.00306 = µmol/L, and ng/mL × 3.06 = nmol/L (molar mass 326.8 g/mol). Many laboratories outside the United States report µmol/L or nmol/L.
- Clozapine:norclozapine ratio at a true trough is usually about 1.3 to 2. A ratio below 0.5 points to missed doses in the preceding days; a ratio above about 3 points to a non-trough sample, a CYP1A2 inhibitor such as fluvoxamine, or an acute infection.
- The biggest everyday modifiers: tobacco smoking lowers levels (CYP1A2 induction); stopping smoking raises them by about 50% within a week; fluvoxamine raises them several-fold; an acute infection can roughly triple them.
How to use the calculator
- Enter the total daily dose, sex, age and smoking status, then tick any inhibitors, inducers or inflammatory illness that apply. The calculator estimates the steady-state 12-hour trough clozapine and norclozapine concentrations and plots the dose–concentration curve for that patient.
- Enter a measured clozapine and norclozapine level under "Actual lab levels". The calculator compares the result with the expectation and lists the most likely explanations when the two disagree by more than about 30%.
- Use "Copy summary" to paste the inputs and outputs into a note.
The estimate starts from published sex- and smoking-specific nomograms (Meyer and Stahl), scales for age (the Reeves 2024 population model of 5,960 patients, in which the dose needed for a 0.35 mg/L trough falls 56% between ages 20 and 80), and applies published interaction multipliers. Body weight is deliberately left out, because the published studies disagree on which way it moves a level; the table below explains. Real patients vary by roughly ±30% from any model, so the number is a starting point for interpretation, never a substitute for the laboratory result or for clinical assessment.
What is the therapeutic range for clozapine?
The therapeutic reference range for clozapine is 350 to 600 ng/mL (1.07 to 1.84 µmol/L), measured as a 12-hour trough at steady state. The lower bound is the best-supported number in clozapine pharmacology: below about 350 ng/mL a treatment-resistant patient is unlikely to respond, and raising the level above that threshold is the first step when response is poor. The upper bound is softer. Some patients respond only above 600 ng/mL, and the handbook this calculator follows treats 350 to 700 ng/mL as the typical range, but adverse effects rise with the level, and 1,000 ng/mL is the laboratory alert level above which seizures become a real risk.
| Clozapine level | In µmol/L | How to read it |
|---|---|---|
| Below 350 ng/mL | Below 1.07 | Below the response threshold. If the patient has not responded, confirm adherence and trough timing, then consider a higher dose. |
| 350–600 ng/mL | 1.07–1.84 | Therapeutic reference range. Judge the patient by response and tolerability, not by the number alone. |
| 600–1,000 ng/mL | 1.84–3.06 | Above the reference range. Some patients need it, but sedation, hypersalivation, constipation, tachycardia and seizures become more likely. |
| Above 1,000 ng/mL | Above 3.06 | Laboratory alert level. Look for the cause (infection, a new inhibitor, smoking cessation, a non-trough sample), reduce the dose unless there is a clear reason not to, and recheck. |
How do I convert a clozapine level from ng/mL to µmol/L?
Multiply ng/mL by 0.00306 to get µmol/L, or by 3.06 to get nmol/L. Going the other way, 1 µmol/L equals 327 ng/mL. The factor comes from clozapine's molar mass of 326.8 g/mol. Norclozapine is slightly lighter (312.8 g/mol), so for norclozapine 1 µmol/L equals 313 ng/mL and ng/mL × 3.20 = nmol/L.
| Clozapine ng/mL | nmol/L | µmol/L | Meaning |
|---|---|---|---|
| 350 | 1,071 | 1.07 | Response threshold |
| 450 | 1,377 | 1.38 | Middle of the reference range |
| 600 | 1,836 | 1.84 | Upper end of the reference range |
| 700 | 2,142 | 2.14 | Upper end of the "typical" range in some references |
| 1,000 | 3,060 | 3.06 | Laboratory alert level |
When should a clozapine level be drawn?
Draw the sample as a 12-hour trough: immediately before the morning dose, 10 to 12 hours after the previous evening dose, with the patient at steady state, which means at least 5 to 7 days on an unchanged dose. A sample drawn a few hours after a dose reads high and can look like toxicity. Check a level:
- at the end of the initial titration, once the target dose has been held for at least five days, to confirm the patient is in range (the de Leon 2022 guideline builds a trough level into the fourth week of every titration);
- when there is no response, or only a partial response, after 6 to 8 weeks at a stable dose;
- when toxicity is suspected: new sedation, confusion, myoclonus, seizures, marked tachycardia or hypotension, worsening constipation;
- whenever the patient starts or stops smoking, starts or stops an interacting drug (fluvoxamine, ciprofloxacin, carbamazepine, rifampin, oral contraceptives, omeprazole), or develops a fever or infection;
- when adherence is in doubt, where the clozapine:norclozapine ratio adds information the level alone cannot give;
- about a week after any dose change, before deciding the next step.
What raises or lowers a clozapine level?
Clozapine is cleared mainly by CYP1A2, with smaller contributions from CYP3A4, CYP2C19 and CYP2D6. Anything that induces or inhibits CYP1A2 moves the level, and so does inflammation, which suppresses CYP1A2 activity. The table lists the factors the calculator models and the size of each effect it applies.
| Factor | Effect on the clozapine level | Size the calculator uses | Note |
|---|---|---|---|
| Current tobacco smoking (7 or more cigarettes a day) | Lower | About 32% lower per milligram, so a smoker needs about 48% more clozapine for the same trough | The Rostami-Hodjegan 2004 nomogram figure (48% higher levels in nonsmokers), in line with the 2020 meta-analysis of 7,125 samples (about 30%, Wagner), the Reeves 2024 model (31%) and the Diaz 2018 trial (36%). Smoke, not nicotine, induces CYP1A2, and cannabis smoke does too. Vaping and nicotine replacement do not lower the level. |
| Stopping smoking | Higher | About +50% within a week | Recheck at about 7 and 14 days. A hospital admission that stops smoking is a classic cause of a sudden rise. |
| Fluvoxamine, ciprofloxacin, enoxacin, viloxazine (strong CYP1A2 inhibitors) | Much higher | Several-fold (×7.5 midpoint) | Published fluvoxamine effects run from an average of about ×3.6 (Diaz 2008) to dose cuts of one fifth to one tenth in some patients (de Leon 2022). Do not start clozapine with a strong CYP1A2 inhibitor; if unavoidable, use a much lower dose and measure levels. |
| Acute serious infection or systemic inflammation | Higher | Up to about ×3 | Check CRP. Hold dose increases and consider a temporary reduction with a repeat level. |
| High caffeine intake (about 400–1,000 mg a day) | Higher | About +20% | A sudden drop in coffee lowers the level too. |
| Strong CYP2D6/3A4 inhibitors (paroxetine, fluoxetine, diltiazem, macrolides, azoles) | Higher | About ×1.5 | |
| Valproate | Variable | +16% in non-smokers, −22% in smokers | Evidence runs both ways; monitor. |
| Carbamazepine, phenytoin, phenobarbital, St John's wort, omeprazole | Lower | About half | The measured phenobarbital effect in one sample was a 28% fall (Diaz 2008). Carbamazepine is also avoided with clozapine because of the additive risk to neutrophils. |
| Rifampin | Much lower | About ×0.3 | |
| Female sex | Higher per milligram | About 20% higher levels in women at the same dose, which is the same as saying a man needs about 20% more clozapine than a woman to reach the same trough | The large monitoring datasets agree: 17% higher in women (Rostami-Hodjegan 2004, 3,782 patients), an 18% lower dose requirement for the same trough (Reeves 2024, 5,960 patients), and higher dose-corrected levels in women in a 2026 Dutch series of 2,548 patients, where the gap is largest under age 45 and fades after 55, consistent with estrogen inhibiting CYP1A2. One small controlled trial of 47 patients found a two-fold gap (Diaz 2018); the calculator uses the smaller, better-replicated figure. |
| Older age | Higher per milligram | Clearance falls steadily with age; the model more than doubles the concentration per milligram from age 20 to 80 | Reeves 2024: apparent clearance about 26 L/h at 20, 20 L/h at 40 and 12 L/h at 80 (a 1.3% fall per year), so the dose for a 0.35 mg/L trough falls 56% from 20 to 80; a 40-year-old nonsmoking White man needs about 275 mg/day and the same man at 80 about 175 mg/day. The calculator applies that curve, anchored at age 40. Older analyses found a smaller effect (about 4% per 5 years in the 2004 nomogram), so the calculator sits at the stronger end, which errs toward predicting higher levels in older patients. |
| Body weight | Unsettled | Not applied | The data disagree. Two studies that measured it found heavier patients run higher levels on the same dose: 5% per 10 kg between patients in the 3,782-patient nomogram (Rostami-Hodjegan 2004) and 1.4% per kilogram gained during treatment in a 47-patient trial (Diaz 2018), consistent with clozapine depositing in fat. The 5,960-patient Reeves 2024 model instead assumed the usual allometric scaling, under which a heavier patient clears more drug and runs lower. Until that is settled the calculator applies no weight term. For a very heavy or very light patient, let the measured level decide. |
| Recent COVID-19 vaccination | Transiently higher | About ×1.2 | Also reported with other inflammatory triggers. |
What does the clozapine:norclozapine ratio mean?
Norclozapine (N-desmethylclozapine) is clozapine's main metabolite. It matters less for efficacy than clozapine itself, but the ratio of clozapine to norclozapine at a trough is a useful check on how the sample was taken and how the drug is being cleared. At steady state in a true 12-hour trough the ratio is usually about 1.3 to 2; the calculator's baseline of 1.32 is the reference value of the Rostami-Hodjegan 2004 nomogram, and the median in 104,127 monitoring samples was 1.25 at levels below 350 ng/mL (Couchman 2010).
| Ratio (clozapine ÷ norclozapine) | What it suggests |
|---|---|
| About 1.3 to 2 | The expected pattern for a trough sample at steady state. |
| Below about 1 | Faster clearance (smoking, an inducer), or a dose missed in the last day or two. |
| Below 0.5 | Several missed doses: clozapine falls faster than norclozapine once dosing stops, so the ratio inverts around the third missed day. |
| Above about 2 to 3 | Slower clearance (a CYP1A2 inhibitor, infection or inflammation), a sample drawn too soon after the dose, or N-demethylation saturating at high clozapine levels: the median ratio was 2.08 in samples above 1,000 ng/mL (Couchman 2010). |
How is a clozapine dose adjusted to a level?
Clozapine kinetics are close to linear in the usual dose range, so the dose and the trough level move roughly in proportion: new dose ≈ current dose × (target level ÷ measured level). A patient on 300 mg a day with a trough of 250 ng/mL who needs about 450 ng/mL would be expected to get there on about 300 × 450 ÷ 250 = 540 mg, which in practice means stepping up by 25 to 50 mg at a time toward 500 to 550 mg with a repeat level a week after each change. Before adjusting, rule out the reasons a level misleads: a non-trough draw, missed doses, a recent change in smoking, caffeine or an interacting drug, or an infection. For a patient who is still being started on clozapine, use the clozapine dose titration calculator instead of adjusting to a level.
For clinicians
TelepsychHealth is a psychiatrist-led telepsychiatry practice that sees adults by video in Arizona, California, Connecticut, Florida, Georgia, Illinois, Michigan, Minnesota, New York and Texas, including patients who need clozapine-level monitoring and treatment-resistant care coordinated with their local team. We also run a free biweekly webinar for practice owners.
Frequently asked questions
What is a normal clozapine level?
There is no "normal" level for a healthy person, because clozapine is only present in people taking it. The therapeutic reference range is 350 to 600 ng/mL (1.07 to 1.84 µmol/L) as a 12-hour trough at steady state. Many patients respond within that range, some need more, and a level below 350 ng/mL is the most common reason a treatment-resistant patient has not responded.
What is a toxic clozapine level?
Adverse effects rise with the level rather than appearing at a single cutoff, but 1,000 ng/mL (3.06 µmol/L) is the laboratory alert level in the AGNP consensus guideline, above which seizures, severe sedation, delirium, hypotension and tachycardia become considerably more likely. A level that high usually has a cause worth finding: an infection, a new CYP1A2 inhibitor, stopping smoking, or a sample drawn too soon after the dose.
How do I convert a clozapine level from ng/mL to µmol/L?
Multiply by 0.00306. A level of 500 ng/mL is 1.53 µmol/L (1,530 nmol/L). To go from µmol/L to ng/mL, multiply by 327. The reference range of 350 to 600 ng/mL is 1.07 to 1.84 µmol/L.
When should I check a clozapine level after a dose change?
About a week after the change, at a 12-hour trough. Clozapine's half-life of roughly 12 hours means a new steady state is reached in 3 to 5 days, and waiting a full week gives a reading that is not still rising. Checking sooner reads low and tempts a second increase that overshoots.
Why is my patient's clozapine level high?
The common causes are, in roughly descending order: the sample was not a trough; the patient stopped or cut down smoking; an acute infection or other inflammatory illness; a new CYP1A2 inhibitor such as fluvoxamine or ciprofloxacin; a large increase in caffeine; an oral contraceptive; and, rarely, a genetic poor-metabolizer status. Older age and female sex raise the level per milligram, and body weight may, although the evidence on weight is mixed, which is why the same dose produces very different levels in different patients.
Why is my patient's clozapine level low?
Missed doses are the first thing to exclude, and a clozapine:norclozapine ratio below 0.5 makes them likely. Beyond adherence, the usual causes are smoking (or an increase in smoking), an enzyme inducer such as carbamazepine, phenytoin, rifampin or St John's wort, omeprazole, a level drawn before steady state, or a laboratory error. Younger men who smoke often need the highest doses.
Does smoking affect clozapine levels?
Yes, substantially. The hydrocarbons in tobacco smoke induce CYP1A2, so smokers run levels about a third lower than non-smokers on the same dose (30 to 36% across the large datasets; the calculator uses 32%). The effect reverses within days of stopping: a level can rise by about half within a week, which is why a smoker admitted to a smoke-free ward needs a dose review and a repeat level. Nicotine patches, gum and vaping do not induce CYP1A2.
Can I use this calculator to decide a dose on its own?
No. It estimates a level from population pharmacokinetics and typical interaction effects, and individual patients vary by roughly 30% from any such estimate. Use it to form an expectation, to interpret a measured level, and to decide when a level is worth repeating. Dose decisions rest on the measured level, the patient's response and tolerability, and the current prescribing information.
References
- Hiemke C, Bergemann N, Clement HW, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62.
- Meyer JM, Stahl SM. The Clinical Use of Antipsychotic Plasma Levels: Stahl's Handbooks. Cambridge University Press; 2021. Chapter 13, Clozapine. ISBN 978-1-009-00989-8.
- de Leon J, Schoretsanitis G, Smith RL, et al. An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels. Pharmacopsychiatry. 2022;55(2):73-86.
- Reeves S, Bertrand J, Obee SJ, Hunter S, Howard R, Flanagan RJ. A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status. British Journal of Clinical Pharmacology. 2024;90(1):135-145.
- Diaz FJ, Josiassen RC, de Leon J. The effect of body weight changes on total plasma clozapine concentrations determined by applying a statistical model to the data from a double-blind trial. Journal of Clinical Psychopharmacology. 2018;38(5):442-446.
- Tees, Esk and Wear Valleys NHS Foundation Trust. Clozapine and the role of therapeutic drug monitoring. 2021.
- Diaz FJ, Santoro V, Spina E, et al. Estimating the size of the effects of co-medications on plasma clozapine concentrations using a model that controls for clozapine doses and confounding variables. Pharmacopsychiatry. 2008;41(3):81-91.
- Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. Journal of Clinical Psychopharmacology. 2004;24(1):70-78.
- Anderson SG, Livingston M, Couchman L, et al. Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey. Annals of General Psychiatry. 2015;14:39.
- de Beer F, Brand BA, Wijnen B, et al. The impact of sex and age on antipsychotic serum concentrations. Schizophrenia Bulletin. 2026;52(2):sbaf217.
- Wagner E, McMahon L, Falkai P, Hasan A, Siskind D. Impact of smoking behavior on clozapine blood levels: a systematic review and meta-analysis. Acta Psychiatrica Scandinavica. 2020;142(6):456-466.
- Couchman L, Morgan PE, Spencer EP, Flanagan RJ. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993-2007. Therapeutic Drug Monitoring. 2010;32(4):438-447.