Academy of Consultation-Liaison Psychiatry How To Guide: Clozapine Consultation
How to Provide Psychiatric Consultation for Patients on Clozapine
Conflict of Interest: The author had no conflict of interest to disclose
Learning Objectives:
1) Appreciate the role of CL psychiatrists in maintaining clozapine
2) Recognize pharmacokinetic factors that affect clozapine effectiveness and risk of toxicity
3) Learn strategies to prevent and manage adverse effects of clozapine
Step 1: Appreciate the unique role of clozapine
• Clozapine is effective for treatment refractory schizophrenia, aggression in dementia, and
psychosis in Parkinson and related disorders.
o Ongoing need for clozapine may be questioned in cases of sedation, delirium,
pneumonia, seizures, and other adverse effects.
o Consulting for patients on clozapine involves educating about clozapine being more
effective than other antipsychotics in specific cases and about strategies for managing
treatment-limiting adverse effects.
o If clozapine doses have been missed for more than 48 hours clozapine will need to be
gradually retitrated. Educating about swift initiation of clozapine at admission to avoid
retitration can prevent clinical relapse
• If a decision is made to discontinue clozapine, it should not be abruptly discontinued (unless
myocarditis or severe neutropenia are present); it should be gradually tapered over 1-2 weeks.
Sudden discontinuation can lead to exacerbation of underlying psychiatric illness, clozapine-
withdrawal catatonia, and cholinergic rebound
o Treatment of clozapine withdrawal catatonia includes resuming clozapine in addition
to standard treatment for catatonia. Even low doses of clozapine can reverse the course
of a clozapine-withdrawal catatonia.
o reverse the course of a clozapine-withdrawal catatonia.
Step 2: Learn basic clinical pharmacology of clozapine
• 95% protein bound; half-life 4-8 hours; extensive first pass effect; 45-65% bioavailable;
available as a tablet and as an oral suspension
• Clozapine is typically initiated at 25 mg PO QHS nightly and maintained at this dose for 3-4
days. It is conservatively titrated as follows: 50 mg nightly for 3-4 days → further increases of
25 mg twice weekly until a target dose of 300 mg is reached (100 mg in elderly). Levels
should then be checked and dose adjusted based on clinical response and drug levels (see
below)
o Standard daily dose of clozapine: 300-600 mg/day; maximum daily dose of
900 mg/day.
i. In elderly patients target dosing is 100-200 mg/day
ii. In Parkinson and related disorders target dose is approximately 50 mg/day
o Dangers of rapid titration include sedation, hypotension, seizures, agranulocytosis,
neuroleptic malignant syndrome, mucus plugs and subsequent respiratory collapse
Mallika Lavakumar M.D., Residency Education Subcommittee
Vers. 03/09/2022
Vers. 10/09/2020
Academy of Consultation-Liaison Psychiatry How To Guide: Clozapine Consultation
o Initial dose and speed of titration can be adjusted based on risk factors for adverse
effects, tolerability and ability to monitor the patient. For example, an initiation dose
of 6.25 mg or 12.5 mg nightly may be trialed in elderly patients with hypotension
rather than 25 mg nightly.
• Therapeutic drug monitoring optimizes effectiveness and prevents adverse events. A trough
steady-state concentration of 350–600 μg/L is recommended in schizophrenia.
• Clozapine is primarily metabolized in the liver by the cytochrome P450 (CYP P450)
isoenzyme 1A2 into norclozapine
o Systemic inflammation, infection [e.g., COVID-19 (1)], and nicotine discontinuation
can decrease CYP1A2 activity potentially leading to higher levels and possible
clozapine toxicity
i. In COVID-19 and other respiratory infections with a systemic inflammatory
response (evidenced by fever, increase in CRP) decrease dose of clozapine by
at least 50%
ii. Tobacco induces CYP1A2 and increases metabolism of clozapine; abstaining
from smoking in the hospital → decreases in clozapine metabolism →
potentially leading to higher levels/toxicity; consider decreasing dose of
clozapine during hospitalization.
o Some East Asians may be slow metabolizers of clozapine (data from Korean, Chinese,
Vietnamese populations). Lower doses than listed above are effective.
o Important drug interactions with clozapine are listed in Table 1.
Step 3: Describe adverse effects of clozapine and their management
• Clozapine has many non-serious adverse effects. The serious and fatal adverse effects of
clozapine are seizures, myocarditis, and agranulocytosis
• The prevention and management of common adverse effects encountered by CL psychiatrists
are described in Table 2.
References
1. Tio N, Schulte PFJ, Martens HJM. Clozapine Intoxication in COVID-19. Am J Psychiatry.
2021;178(2):123-7.
2. Kennedy WK, Jann MW, Kutscher EC. Clinically significant drug interactions with atypical
antipsychotics. CNS Drugs. 2013;27(12):1021-48.
3. Gurrera RJ, Gearin PF, Love J, Li KJ, Xu A, Donaghey FH, et al. Recognition and management
of clozapine adverse effects: A systematic review and qualitative synthesis. Acta Psychiatr Scand.
2022.
4. Grainger BT, Arcasoy MO, Kenedi CA. Feasibility of myelosuppressive chemotherapy in
psychiatric patients on clozapine: A systematic review of the literature. Eur J Haematol.
2019;103(4):277-86.
5. Knoph KN, Morgan RJ, 3rd, Palmer BA, Schak KM, Owen AC, Leloux MR, et al. Clozapine-
induced cardiomyopathy and myocarditis monitoring: A systematic review. Schizophr Res.
2018;199:17-30.
Mallika Lavakumar M.D., Residency Education Subcommittee
Vers. 03/09/2022
Vers. 10/09/2020
Academy of Consultation-Liaison Psychiatry How To Guide: Clozapine Consultation
Table 1: Important drug interactions with clozapine (2)
Medications/Substances Effects
Cigarette smoking May ↓ reduce clozapine levels via CYP 1A2 or 3A4 induction
Carbamazepine, rifampin, phenytoin, phenobarbital, St. resulting in decreased efficacy of clozapine
John’s Wort
Fluvoxamine, ciprofloxacin, oral contraceptives, May ↑ increase clozapine levels via CYP 1A2 or 2D6 inhibition
caffeine leading to adverse reactions
antidepressants: (fluoxetine, escitalopram, paroxetine,
duloxetine, sertraline), antibiotics: (erythromycin),
cimetidine, quinidine, terbenafine
Anticholinergics (e.g., benztropine, diphenhydramine, Additive anticholinergic activity. Monitor closely for significant
hydroxyzine) anticholinergic adverse effects (e.g., constipation, hypotension).
Lithium Combined use is associated with neurotoxicity (delirium,
movement disorders, myoclonus, and seizures)
Bone marrow suppressants (e.g., antineoplastics) Caution due to increased risk and/or severity of bone marrow
suppression.
CNS depressants and general anesthesia (e.g., alcohol, Caution because of additive CNS depressant effects including
opioids, benzos) respiratory effects
Medications that lower seizure threshold (e.g., Extreme caution when coadministering with clozapine due to
bupropion) increased risk of seizures
Highly protein bound drugs (e.g., warfarin, digoxin) Clozapine may increase levels of protein bound drugs and vice
versa. Adjust dose if necessary.
Table 2: Prevention, and management of clozapine related adverse effects
Description Prevention/Monitoring Management
Sialorrhea • Increases risk of aspiration pneumonia • None • Cover pillow with towel
• Stigmatizing • Elevate head of bed and encourage
• Thought to be due to muscarinic-4 antagonism, sleeping on side reduces risk of
alpha-2 antagonism with unopposed beta aspiration
agonism, decreased laryngeal peristalsis, • Ipratropium oral spray 0.06% up to
decreased swallowing via reduction of GI 3 sprays TID → Ophthalmic
motility atropine 1% up to 2 drops TID
sublingually → Oral glycopyrrolate
2-4 mg PO QHS → Terazosin 1-2
mg PO QHS
• Botox in refractory cases
Academy of Consultation-Liaison Psychiatry How To Guide: Clozapine Consultation
Description Prevention/Monitoring Management
Constipation, • 50-80% prevalence of constipation • Patients with schizophrenia may not • Constipation and ileus: Docusate →
ileus, bowel • Due to anticholinergic and antiadrenergic report symptoms due to higher pain polyethylene glycol → bisacodyl →
perforation effects thresholds and negative symptoms. sennakot or dulcolax → magnesium
• Risk factors: high dose, high level, concomitant Regular inquiry into bowel function is citrate/other enemas/manual
administration with other anticholinergic necessary. disempaction
medications • Hydration • Obstruction: nasogastric suction;
• Presentation: constipation, abdominal • High fiber diet surgery may sometimes be
distension, nausea, emesis • Exercise necessary
• Diagnosis: subjective report, exam, abdominal • Start stool softeners or laxatives in
X-ray, CT of abdomen patients at high risk
o Docusate → polyethylene glycol →
sennakot or dulcolax → lubiprostone
Clozapine toxicity • Delirium, neutropenia, orthostatic hypotension,• Recognize of drug-drug and drug disease • Decrease or hold dose of clozapine.
tachycardia, ileus, urinary retention, interactions that can lead to elevated • Check level. May take several days
mydriasis/miosis, hypersalivation, and seizures. clozapine levels and clozapine toxicity; for results to be available but level
prophylactically decrease clozapine doses aids in confirming suspected
clozapine toxicity)
Seizures • Prevalence of 3.5-8 % • Prophylaxis with anticonvulsants for • Obtain EEG
• Tonic-clonic seizures are most common patients with: • Neurology consultation
• Risk factors: o Seizure disorder • Add anticonvulsant (e.g., valproic
o Epilepsy o myoclonic jerks (may be precursor to acid)
o High doses (doses > 600 mg/day) (3) generalized tonic clonic seizures for • Clozapine rarely needs to be
o Rapid titration during initiation phase patients on clozapine) discontinued
o Paroxysmal spike/sharp wave discharges
o Clozapine plasma level > 500 ug/L
o Clozapine dose > 500 mg/day
Academy of Consultation-Liaison Psychiatry How To Guide: Clozapine Consultation
Description Prevention/Monitoring Management
• Rare, idiosyncratic reaction Severity Monitoring Management
• Neutropenia • Makes body vulnerable to bacterial infections. Normal ANC Weekly from Continue treatment
Frequently present with fever, headache, >1500/mcL initiation to 6
cough, sore throat, bleeding gums or sepsis months
• The Clozapine REMS program provides Every 2 weeks
from 6 to 12
centralized clozapine access to minimize the
months
risk of clozapine-associated severe neutropenia Monthly after
• Benign ethnic neutropenia (BEN) is common 12 months
in people of African or Eastern Mediterranean Mild ANC 3x/week Continue treatment
heritage. Alternate monitoring parameters exist 1000- monitoring
for those with established BEN 1499/mcL until ANC ≥
• For patients who have been on long-term 1500/µl
clozapine without neutropenia and have new Moderate ANC Daily until Interrupt treatment for
onset neutropenia with other constitutional 500- ANC ≥ 1000/µl suspected clozapine
symptoms, premature attribution of 999/mcL then, 3x/week induced neutropenia
neutropenia to clozapine should be avoided. To until ANC ≥ Hematology consultation
this end, a broad differential diagnosis and 1500/µl Consider filgrastim or
lithium
thorough work-up for neutropenia is warranted.
Severe ANC < Daily until Interrupt treatment for
500/mcL ANC ≥ 1000/µl suspected clozapine
then, 3x/week induced neutropenia
Transfer to hospital
Place in reverse isolation
Administer filgrastim
Aggressively work up
signs and symptoms
Report to Clozapine
REMS
• For patients on chemotherapy
o Psychosis can interfere with cancer care management and is distressing; clozapine
should ideally be continued if the patient is well established on this treatment (4);
in order to do so Clozapine REMs program will need to be contacted
o Multidisciplinary team discussion with heme-onc regarding alternate monitoring
parameters, threshold for discontinuation of clozapine, and increased frequency of
blood draws
o Consider initiation of filgrastim during neutropenic nadir of chemotherapy to
support neutrophil count and facilitate both clozapine and chemotherapy regimens
Academy of Consultation-Liaison Psychiatry How To Guide: Clozapine Consultation
Description Prevention/Monitoring Management
Myocarditis • 1-3% prevalence • Monitor vitals, cardiac enzymes, and CRP• Discontinue clozapine and admit to
• High mortality (10 – 30%) weekly during first 4 weeks of titration intensive care unit
• Typically seen in first 4 weeks post-initiation • Obtain baseline ECG • Supportive use of medications to
• Most likely IgE mediated hypersensitivity improve cardiac functioning and
reaction minimize the risk of cardiac failure
• Presentation: chest pain, palpitations, dyspnea, such as diuretics, beta-blockers, and
tachycardia ACE inhibitors, corticosteroids
• Diagnosis: History and exam along with CRP,
cardiac enzymes, eosinophil count, ECG
findings, CXR, cardiac echo (5)
