Author: Daniel Carlat M.D.
Last Updated: 4/1/20
If a patient has failed at least two adequate trials of antipsychotics, consider a trial of clozapine. It is FDA approved for both treatment resistant schizophrenia and reduction of suicide risk in schizophrenia. In one study of patients with an inadequate response to three trials of antipsychotics, the response rate of patients randomly assigned to clozapine was 30% vs. only 4% of those assigned to Thorazine.
The first hurdle is to convince your patient and the family that the potential benefits are worth the risks. Introduce the use of clozapine with a discussion about how other medications haven’t been completely effective. Tell patients, “I know the medications you’ve tried haven’t completely helped you. Clozapine is a medication that is more effective for people when other antipsychotics haven’t worked. It has a bunch of side effects, but we can monitor for them. Should we try it for a little while? If it works, I think you might decide that the side effects are worth putting up with.”
- Labs: Before starting, order a WBC with diff. The ANC (absolute neutrophil count) must be > 1500. The montoring thereafter goes like this: First 6 months, get weekly ANC; Months 6-12: ANC every two weeks; After one year, ANC monthly.
- Dosing: Start 12.5-25 mg; increase by 25-50 every few days; target 300-450 mg. Avoid higher than 600 mg (seizure risk). Higher doses may be needed in smokers.
- Here’s a suggested cross taper/titration method for switching patients from their ineffective antipsychotic to clozapine. This is only a guideline—some patients may need to go slower depending on side effects, while others might be able to tolerate a more aggressive schedule. Also, this schedule is for otherwise fairly healthy adults; in the elderly, cut this schedule in half.
- Day one: Decrease drug A by 25% and start clozapine 12.5 mg BID.
- Day two: Decrease drug A by another 25% (half of the original dose) and increase clozapine in 25 mg BID.
- Day three: Decrease drug A to 25% of the original dose, and increase clozapine to 75 mg BID.
- Day four: Discontinue drug A and increase clozapine to 100 mg BID.
- Thereafter, increase incrementally to achieve a target dose of 300 mg or so by the end of one to two weeks.
- Note that if the dosing is interrupted by more than 48 hours you are supposed to re-titrate from scratch.
- Clozapine serum levels. Some psychiatrists like to get serum levels, based on some evidence that the optimal serum concentration is 350-450 ng/mL. The problem is that some patients improve at low serum levels, while other need higher levels for a response. Testing can be expensive and can take a long time because the sample usually has to be sent to an outside lab. I recommend to get serum levels only when you are not sure if the patient is actually taking the medication.
- Side effects to watch out for early: Sedation, orthostasis, tachycardia, hypersalivation, constipation, eventually weight gain.
- Avoid use with other drugs that can cause bone marrow suppression, such as Tegretol or Lamictal.
- Sometimes you need to really increase clozapine. This comes up when you admit a patient with a long history of clozapine use and many instances of the need for increasing doses to maintain response. We try not to go any higher than 600 mg, because the seizure risk is higher (4.2% above 600 mg vs. 2.4% below) (Grove S, East Asian Arch Psychiatry. 2015;25(2):73–78). If you do go higher, consider adding Depakote for its combination of anti-seizure and psychiatric properties.
Managing Clozapine Side Effects
| Side Effect | Incidence | Monitoring | Treatment |
|---|---|---|---|
| Bradycardia Orthostatic Hypotension Syncope | 9%-13% | Pulse Blood pressure Orthostatic blood pressure Dizziness | Divided dose (2-3 times daily) Start with low dose Slow titration Adequate fluid intake Behavioral changes (sit on edge of the bed with legs hanging down for a minute before getting up) Fludrocortisone, if necessary |
| Constipation | 15%-25% | Clinical interview | Drink fluids Increase fiber Exercise Minimize other anticholinergics (eg, benztropine, diphenhydramine) Consider bowel regimen (similar to opioids) eg, docusate 100 mg-250 mg bid |
| Drowsiness Sedation | 2%-45% | Clinical interview | Bedtime dosing Lowest dose possible |
| Hyperglycemia | 27% increased to ≥126mg/dL | Baseline and quarterly fasting glucose or HGBa1c | Dietary intervention Exercise If A1c >6.5/7% add metformin (6.5 for younger people with long life expectancy) |
| Hypertriglyceridemia | 50% mean increase of ≥ 71mg/dL | Baseline, week 12 and annually | Dietary intervention Exercise Omega-3 fatty acids Fibrates (caution with statins) |
| Myocarditis Cardiomyopathy | .002% | Troponin & CRP weekly for 1st 4-8 weeks | Discontinue if CRP > 100mg/L Troponin ≥2 x ULN |
| Seizures | 2.4% – 4.2% | Clinical interview/contact from ER or hospital | Use lowest dose possible (<600mg ideally) Concomitant valproate |
| Sialorrhea | 15%-40% | Clinical interview | Glycopyrronium 2-4mg at bedtime Botulinum toxin |
| Tachycardia | 15%-25% | Pulse | Lower dose Beta blockers (eg metoprolol) |
| Weight gain ≥7% from baseline | 35% | Baseline weight/BMI at weeks 4, 8, 12 and quarterly | Dietary intervention Exercise If gain >5 lbs in 1st month or > 10 lbs from baseline, consider metformin |
Published on 4/13/2020. Copyright 2020 Inpatient Psychiatry Today.