Neutrophils, a type of white blood cell, are the immune system's first line of defense against infections. Not having enough neutrophils is referred to as neutropenia. Patients taking clozapine may develop agranulocytosis (black box warning)¹, a severe, life-threatening form of neutropenia.

Though no longer required by the FDA, monitoring neutrophil count in patients on clozapine is recommended

.

Constipation

In addition to blocking dopamine (D2) receptors, clozapine also blocks acetylcholine receptors. Acetylcholine promotes GI motility and produces bowel movements; therefore, the anticholinergic effects of clozapine can cause constipation in mild cases and gastrointestinal obstructions in severe cases.¹ Patients on clozapine should be monitored for regular bowel movements, bloating, and abdominal pain. Additionally, adequate hydration should be encouraged as a preventative measure.

Mild cases of clozapine-induced constipation may be treated with stimulant or osmotic laxatives, but bulk-forming laxatives should be avoided.³

Stimulant Laxatives ✅	Sennosides Bisacodyl (Dulcolax)
Osmotic Laxatives ✅	Polyethylene Glycol 3350 (Miralax) Lactulose
Bulk-forming Laxatives ❌	Psyllium Husk Increasing fiber intake

Myocarditis

Clozapine also has a black box warning for myocarditis, or inflammation of heart muscle.

Signs and symptoms of myocarditis include unexplained fatigue, difficulty breathing, increased or irregular heartbeat, electrocardiogram abnormalities, chest pain, and fever.

Patients should be monitored for myocarditis while on clozapine, especially during the first month of treatment when the risk of myocarditis is highest.¹

Seizure

Seizures are another safety issue that has led to a black box warning for clozapine. Higher doses of clozapine are more likely to cause a seizure. Therefore, clozapine doses should be increased slowly over time.¹ Clozapine should be avoided in patients with uncontrolled epilepsy and used with caution in patients with a history of seizures, head injuries, or are taking medications, like bupropion, which increase the risk for seizures.^{1, 4}

Medications that Increase Seizure Risk *
Bupropion Fluoroquinolones Isoniazid Stimulants (e.g., amphetamines, cocaine) Systemic steroids Theophylline Tramadol Tricyclic Antidepressants (especially imipramine)

^*

List is not all inclusive ⁴

Sialorrhea

Though the cause is not clear, studies have found that 30-80% of patients on clozapine develop sialorrhea, also known as excessive salivation or drooling.⁵ At first glance, drooling may not seem like a significant side effect; however, excess saliva can cause speech difficulties, social embarrassment, and increase the risk of choking, especially at night.

Non-pharmacological recommendations include chewing sugar-free gum to promote swallowing and sleeping on the side or with an elevated head to decrease choking risk.

Evidence supporting the use of medications to treat clozapine-induced sialorrhea is limited. Still, anticholinergic medications, like hyoscine, atropine eye drops (used under the tongue), and glycopyrrolate, are commonly used in practice.⁶

Orthostatic Hypotension

Clozapine blocks alpha-1 adrenergic receptors, which relaxes blood vessels and decreases blood pressure.⁷ This additional effect puts patients at risk for orthostatic hypotension, or low blood pressure after standing, resulting in an additional black box warning for clozapine.¹ Patients with orthostatic hypotension commonly feel lightheaded or dizzy and may fall or lose consciousness. The risk for orthostatic hypotension is highest when a patient first starts clozapine and when clozapine doses are increased. Patients on clozapine should be encouraged to slowly change position from lying to standing to reduce the risk of orthostasis.

Metabolic Syndrome

Clozapine blocks histamine (H1) receptors, which likely plays a major role in the development of metabolic syndrome, a group of conditions that increase the risk for diabetes, heart disease, and high cholesterol.⁸ Metabolic labs should be monitored regularly, as clozapine has a higher risk for metabolic syndrome than other antipsychotics.⁹ If a patient develops metabolic syndrome on clozapine, studies suggest metformin may be helpful.¹⁰