Clozapine
Summary
Clozapine is an atypical (second-generation) antipsychotic that is the most effective treatment for treatment-resistant schizophrenia (TRS). It is reserved for patients who have failed at least two other antipsychotics at adequate doses for adequate duration. Clozapine reduces positive symptoms, negative symptoms, and importantly reduces suicidality in schizophrenia. However, it has significant side effects requiring mandatory monitoring, most notably agranulocytosis (~1%), which is potentially fatal. Other serious complications include myocarditis, cardiomyopathy, severe constipation (leading to ileus), and seizures. Clozapine is only available through a registered monitoring service (CPMS in UK). Patients require regular blood tests: weekly for the first 18 weeks, then fortnightly for up to 1 year, then monthly thereafter.
Key Facts
- Indication: Treatment-resistant schizophrenia (failed 2 antipsychotics)
- Efficacy: Most effective antipsychotic; reduces suicidality
- Mechanism: Weak D2 antagonist; strong 5-HT2A antagonist; binds D4, H1, M1, α1
- Agranulocytosis: ~1% risk; requires mandatory FBC monitoring
- Monitoring: Weekly (18 weeks) → Fortnightly (52 weeks) → Monthly (lifelong)
- Myocarditis: Usually within first month; can be fatal; monitor troponin/CRP
- Constipation: Potentially fatal (ileus); anticipate and treat proactively
- Sialorrhoea: Common (hypersalivation); treat with hyoscine or glycopyrrolate
- Re-titration: Required if >48 hours missed (risk of hypotension, collapse)
- Traffic light system: Green/Amber/Red for neutrophil count
Clinical Pearls
"Clozapine Is the Most Effective Antipsychotic": For treatment-resistant schizophrenia, clozapine is uniquely effective. It's also the only antipsychotic proven to reduce suicide risk (InterSePT trial).
"Traffic Light = Life or Death": The Green/Amber/Red monitoring system is mandatory. Red means STOP immediately — agranulocytosis is fatal without intervention.
"Myocarditis in the First Month": Clozapine-induced myocarditis usually occurs within 4 weeks. Monitor for tachycardia, fever, chest pain. Check troponin, CRP, and ECG. Fatal if missed.
"Constipation Can Kill": Clozapine causes severe constipation due to anticholinergic effects. Ileus and bowel obstruction are major causes of death. Proactive laxatives are essential.
"48-Hour Rule": If clozapine is missed for >48 hours, re-titration from a low dose is mandatory. Rapid reinitiation can cause severe hypotension or cardiac arrest.
Why This Matters Clinically
Clozapine is a life-changing medication for patients with TRS but requires meticulous monitoring. Every clinician prescribing or caring for patients on clozapine must understand the monitoring protocols, recognise side effects, and know when to stop treatment. The UK CPMS (Clozapine Patient Monitoring Service) is mandatory.[1,2]
Use in Clinical Practice
| Parameter | Data |
|---|---|
| Patients on clozapine (UK) | ~45,000 |
| Treatment-resistant schizophrenia prevalence | ~30% of schizophrenia patients |
| Time to clozapine initiation | Often delayed; 4-5 years after diagnosis on average |
| Underprescription | Clozapine is underused despite being most effective |
Risk Factors for Agranulocytosis
| Factor | Notes |
|---|---|
| Age | Higher risk in elderly |
| Sex | Females at higher risk |
| Ethnicity | Benign ethnic neutropenia (BEN) in Black patients may complicate monitoring |
| Concurrent medications | Risk with other bone marrow suppressants |
| First 18 weeks | Highest risk period |
Mechanism of Action
Receptor Pharmacology:
| Receptor | Action | Clinical Effect |
|---|---|---|
| D2 (dopamine) | Weak antagonist | Less EPS than typical antipsychotics |
| 5-HT2A (serotonin) | Antagonist | Efficacy for negative symptoms; less EPS |
| D4 (dopamine) | Antagonist | May contribute to efficacy |
| H1 (histamine) | Antagonist | Sedation, weight gain |
| M1 (muscarinic) | Antagonist | Constipation, dry mouth, sialorrhoea (paradoxically) |
| α1 (adrenergic) | Antagonist | Hypotension, sedation |
Why Clozapine Works in TRS
- Unique receptor binding profile (multi-receptor)
- Higher 5-HT2A:D2 ratio than other antipsychotics
- Effects on glutamatergic system (NMDA modulation)
- Fast dissociation from D2 receptors ("fast-off" hypothesis)
- Effects on neural plasticity
Agranulocytosis Mechanism
| Feature | Details |
|---|---|
| Mechanism | Immune-mediated (antibodies to neutrophils) or direct toxicity |
| Metabolite | Norclozapine may be responsible |
| Timing | Usually within first 18 weeks; can occur later |
| Incidence | ~1% (higher than other drugs) |
| Mortality | ~3% if untreated; now <0.1% with monitoring |
Indications for Clozapine
Treatment-Resistant Schizophrenia (TRS):
| Criteria | Details |
|---|---|
| Definition | Failed adequate trials of ≥2 antipsychotics |
| Adequate trial | At least 6 weeks at therapeutic dose with ≥80% adherence |
| Includes | At least one atypical (second-generation) antipsychotic |
| Documentation | Must document non-response to previous treatments |
Other Uses (Off-label/Specialist):
Clinical Features Requiring Clozapine
| Feature | Notes |
|---|---|
| Persistent positive symptoms | Hallucinations, delusions despite treatment |
| Cognitive symptoms | May improve on clozapine |
| Negative symptoms | May improve |
| Suicidality | Clozapine uniquely reduces suicide risk |
| Violence/aggression | Often responds |
Baseline Assessment Before Clozapine
| Assessment | Purpose |
|---|---|
| Full physical examination | Baseline health; cardiorespiratory status |
| Cardiovascular | BP, HR; ECG (exclude arrhythmia, prolonged QTc) |
| BMI | Baseline weight |
| Bowel habit | Document baseline; constipation is major issue |
| Neurological | Exclude movement disorders from previous antipsychotics |
Ongoing Monitoring Parameters
| Parameter | Frequency | Threshold |
|---|---|---|
| FBC (neutrophils) | Weekly (18 wks), Fortnightly (52 wks), Monthly | Green/Amber/Red |
| Weight | Monthly | Track metabolic effects |
| Blood glucose | Baseline, 1 month, then 4-6 monthly | Diabetes risk |
| Lipids | Baseline, 3 months, then annually | Metabolic syndrome |
| ECG | Baseline | QTc prolongation |
| Troponin/CRP | If myocarditis suspected | Myocarditis screen |
| Bowel function | Every consultation | Constipation screening |
Mandatory Blood Monitoring
Traffic Light System for Neutrophils:
| Status | Neutrophil Count | Action |
|---|---|---|
| 🟢 GREEN | ≥2.0×10⁹/L | Continue clozapine; routine monitoring |
| 🟡 AMBER | 1.5-1.99×10⁹/L | Increased monitoring (2x weekly); watch closely |
| 🔴 RED | <1.5×10⁹/L | STOP CLOZAPINE IMMEDIATELY; never rechallenge |
Benign Ethnic Neutropenia (BEN)
| Feature | Details |
|---|---|
| Definition | Lower baseline neutrophil counts in some individuals (especially Black African/Caribbean) |
| Adjustment | Modified thresholds may be used (Green ≥1.5; Amber 1.0-1.49; Red <1.0) |
| Requires | Haematologist confirmation before modified monitoring |
Investigations for Complications
| Complication | Investigations |
|---|---|
| Myocarditis | Troponin, CRP, ECG, Echocardiogram |
| Cardiomyopathy | Echocardiogram, BNP |
| Ileus/bowel obstruction | Abdominal X-ray, CT |
| Seizures | EEG; consider levels; dose adjustment |
Management Algorithm
CLOZAPINE PRESCRIBING PATHWAY
↓
┌─────────────────────────────────────────────────────────────┐
│ PRE-TREATMENT ASSESSMENT │
├─────────────────────────────────────────────────────────────┤
│ ➤ Confirm diagnosis of schizophrenia (ICD/DSM criteria) │
│ ➤ Document failure of ≥2 antipsychotics at adequate │
│ dose/duration │
│ ➤ Baseline investigations: │
│ • FBC (neutrophils ≥2.0) │
│ • U&E, LFTs │
│ • Fasting glucose, lipids │
│ • ECG (QTc) │
│ • Weight, BMI │
│ • Document bowel habit │
│ ➤ Register with Clozapine Monitoring Service (CPMS) │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ INITIATION │
├─────────────────────────────────────────────────────────────┤
│ DAY 1: 12.5 mg once or twice daily │
│ Increase gradually over 2-3 weeks: │
│ ➤ 12.5-25 mg increments every 1-2 days │
│ ➤ Target dose: 200-450 mg/day (divided doses) │
│ ➤ Maximum: 900 mg/day (rarely used) │
│ │
│ INPATIENT vs OUTPATIENT: │
│ ➤ Inpatient initiation traditionally preferred │
│ ➤ Outpatient initiation possible with MDT support │
│ │
│ MONITORING DURING INITIATION: │
│ ➤ BP, HR (postural hypotension risk) │
│ ➤ Temperature (fever = myocarditis concern) │
│ ➤ Weekly FBC (CPMS) │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ ONGOING MONITORING (CPMS) │
├─────────────────────────────────────────────────────────────┤
│ BLOOD MONITORING SCHEDULE: │
│ ➤ Weeks 1-18: Weekly FBC │
│ ➤ Weeks 19-52: Fortnightly FBC │
│ ➤ After 52 weeks: Monthly FBC (lifelong) │
│ │
│ TRAFFIC LIGHT RESULTS: │
│ 🟢 GREEN (≥2.0): Continue clozapine │
│ 🟡 AMBER (1.5-1.99): Monitor 2x weekly; liaise with CPMS │
│ 🔴 RED (<1.5): STOP IMMEDIATELY; never rechallenge │
│ │
│ OTHER MONITORING: │
│ ➤ Metabolic (glucose, lipids): 3-6 monthly │
│ ➤ Weight: Monthly │
│ ➤ Bowel function: Every review │
│ ➤ Clozapine levels: If suboptimal response, toxicity, │
│ or smoking change │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ MANAGING SIDE EFFECTS │
├─────────────────────────────────────────────────────────────┤
│ CONSTIPATION: │
│ ➤ Proactive laxatives (docusate, senna, macrogol) │
│ ➤ Ask about bowel function at EVERY review │
│ ➤ If severe: Abdominal X-ray; gastroenterology referral │
│ ⚠️ Ileus is a FATAL complication │
│ │
│ SIALORRHOEA (hypersalivation): │
│ ➤ Hyoscine hydrobromide patches │
│ ➤ Glycopyrrolate │
│ ➤ Nighttime worst; use absorbent pillows │
│ │
│ SEDATION: │
│ ➤ Give larger dose at night │
│ ➤ Often improves with time │
│ │
│ WEIGHT GAIN / METABOLIC: │
│ ➤ Diet and exercise counselling │
│ ➤ Consider metformin adjunct │
│ │
│ TACHYCARDIA: │
│ ➤ Common initially (may resolve) │
│ ➤ If persistent + fever + malaise: exclude myocarditis │
│ │
│ SEIZURES: │
│ ➤ Risk increases with dose (>600 mg/day) │
│ ➤ Add sodium valproate prophylaxis if high-dose │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ MISSED DOSES / RE-TITRATION │
├─────────────────────────────────────────────────────────────┤
│ IF MISSED >48 HOURS: │
│ ➤ DO NOT resume at previous dose │
│ ➤ Re-titrate from 12.5-25 mg │
│ ⚠️ Rapid reinitiation → severe hypotension, collapse │
│ │
│ IF MISSED >3 DAYS: │
│ ➤ Full re-titration as per initiation protocol │
│ ➤ Resume weekly FBC monitoring │
└─────────────────────────────────────────────────────────────┘
Clozapine Levels
| Level | Interpretation |
|---|---|
| <350 ng/mL | Possibly subtherapeutic |
| 350-600 ng/mL | Therapeutic range |
| >1000 ng/mL | Toxicity risk |
Factors affecting levels:
- Smoking (induces CYP1A2 → lowers levels)
- Caffeine (inhibits CYP1A2 → raises levels)
- Infections (transiently raise levels)
- Concurrent medications
Agranulocytosis
| Feature | Details |
|---|---|
| Definition | Neutrophils <0.5×10⁹/L |
| Incidence | ~1% |
| Timing | Usually first 18 weeks |
| Symptoms | Fever, sore throat, infections |
| Action | STOP clozapine; admit; haematology; G-CSF |
| Outcome | Usually reversible if caught early |
| Rechallenge | NEVER — lifetime contraindication |
Myocarditis and Cardiomyopathy
| Feature | Myocarditis | Cardiomyopathy |
|---|---|---|
| Timing | Usually first 4 weeks | Can occur later |
| Symptoms | Fever, tachycardia, chest pain, fatigue | Heart failure symptoms |
| Investigations | Troponin, CRP, ECG, Echo | Echo, BNP |
| Management | STOP clozapine; cardiology; supportive | Depends on severity |
| Rechallenge | Usually contraindicated | Case-by-case |
Constipation and Ileus
| Severity | Features | Management |
|---|---|---|
| Mild | Infrequent bowel movements | Increase laxatives |
| Moderate | Straining, hard stools | Combination laxatives |
| Severe | Abdominal distension, pain | AXR; surgical review |
| Ileus | Bowel obstruction; surgical emergency | STOP clozapine; surgery |
Efficacy Outcomes
| Outcome | Data |
|---|---|
| Response rate in TRS | ~30-60% respond to clozapine |
| Superiority | Superior to all other antipsychotics in TRS |
| Suicide reduction | 25% reduction in suicidality (InterSePT) |
| Time to response | May take 6-12 months for full effect |
Long-Term Outcomes
| Factor | Impact |
|---|---|
| Continued use | Improves functioning, quality of life |
| Discontinuation | High relapse risk |
| Metabolic effects | Require ongoing management |
| Mortality | Reduced suicide; increased metabolic risk |
Key Guidelines
| Guideline | Organisation | Year | Key Points |
|---|---|---|---|
| Maudsley Prescribing Guidelines | SLaM | 2021 | Comprehensive clozapine guidance |
| NICE Schizophrenia (CG178) | NICE | 2014 | Clozapine for TRS after 2 failures |
| BAP Schizophrenia Guidelines | BAP | 2020 | Evidence-based prescribing |
Landmark Trials
InterSePT Trial (2003)
- Clozapine vs olanzapine for suicidal schizophrenia patients
- Clozapine reduced suicidal behaviour by 25%
- Led to FDA approval for suicidality indication
- PMID: 12505305
Kane et al. (1988)
- Landmark RCT establishing clozapine for TRS
- Clozapine superior to chlorpromazine in TRS
- PMID: 3047143
What is Clozapine?
Clozapine is a medication used to treat schizophrenia that hasn't responded to other medications. It's very effective, but requires regular blood tests because of potential side effects.
Why is it used?
Clozapine is used when at least two other antipsychotic medications haven't worked well enough. It can help control symptoms like hearing voices, paranoia, and disorganised thinking.
Why are blood tests needed?
Clozapine can rarely cause a serious drop in white blood cells (which fight infection). Regular blood tests check for this. You'll need blood tests:
- Every week for the first 18 weeks
- Every two weeks for the rest of the first year
- Every month after that
Traffic light system
Your blood test result gives a colour:
- Green: Everything is fine
- Amber: Need more frequent tests
- Red: Stop the medication immediately
What side effects might I notice?
- Drowsiness — often improves over time
- Drooling — especially at night
- Constipation — very important to prevent; use laxatives
- Weight gain — healthy diet and exercise help
- Fast heartbeat — tell your doctor if this happens
Important things to remember
- Never stop suddenly without talking to your doctor
- If you miss doses for more than 2 days, you'll need to restart slowly
- Tell your doctor if you feel unwell with a fever or sore throat
Guidelines
-
Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry. 14th ed. Wiley-Blackwell; 2021.
-
NICE. Psychosis and schizophrenia in adults: prevention and management (CG178). 2014. nice.org.uk/guidance/cg178
Key Trials
-
Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91. PMID: 12505305
-
Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789-796. PMID: 3047143
High-Yield Exam Topics
| Topic | Key Points |
|---|---|
| Indication | Treatment-resistant schizophrenia (failed ≥2 antipsychotics) |
| Agranulocytosis | ~1% risk; mandatory FBC monitoring; never rechallenge if Red |
| Monitoring schedule | Weekly (18 wks) → Fortnightly (52 wks) → Monthly |
| Myocarditis | First month; fever + tachycardia + raised troponin |
| Constipation | Can cause fatal ileus; proactive laxatives essential |
| 48-hour rule | If missed >48 hrs, re-titrate from low dose |
| InterSePT trial | Clozapine reduces suicidality |
Sample Viva Questions
Q1: What are the indications for clozapine and how is it initiated?
Model Answer: Clozapine is indicated for treatment-resistant schizophrenia — defined as failure of at least two antipsychotics at adequate dose and duration (at least 6 weeks each). Before initiation: baseline FBC (neutrophils ≥2.0), ECG, metabolic screen, register with CPMS. Initiation: start at 12.5 mg once or twice daily, increase by 12.5-25 mg every 1-2 days. Target dose 200-450 mg/day. Inpatient initiation traditionally preferred but outpatient possible with support. Weekly FBC for first 18 weeks; watch for hypotension, tachycardia, fever (myocarditis).
Q2: A patient on clozapine has a neutrophil count of 1.3×10⁹/L. What do you do?
Model Answer: A neutrophil count of 1.3×10⁹/L is a RED result. I would STOP clozapine immediately and never rechallenge this patient. I would inform CPMS urgently, arrange repeat FBC, assess for signs of infection (fever, sore throat), and refer to haematology. Consider admission for monitoring. If neutropenia worsens, G-CSF may be required. The patient cannot be rechallenged with clozapine; alternative antipsychotics will be needed.
Q3: What are the life-threatening complications of clozapine?
Model Answer: The major life-threatening complications are:
- Agranulocytosis (~1%): Severe neutropenia; risk of overwhelming infection; usually first 18 weeks; requires immediate cessation.
- Myocarditis/Cardiomyopathy: Usually first month; presents with fever, tachycardia, chest pain; raised troponin; can be fatal.
- Ileus/Bowel obstruction: Severe constipation due to anticholinergic effects; can cause toxic megacolon and death. Proactive laxatives essential.
- Seizures: Risk increases with high doses (>600 mg); prophylactic valproate may be used.
- Pulmonary embolism: Higher risk in sedentary patients.
Common Exam Errors
| Error | Correct Approach |
|---|---|
| Not knowing monitoring schedule | Weekly (18) → Fortnightly (52) → Monthly |
| Forgetting 48-hour rule | Must re-titrate if missed >48 hours |
| Thinking constipation is minor | It can be FATAL (ileus); proactive laxatives |
| Not mentioning CPMS | Mandatory registration in UK |
Last Reviewed: 2025-12-24 | MedVellum Editorial Team
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.