Pretest self-assessment question (answer at the end of the case)

Clozapine (Clozaril)-induced sialorrhea (CIS), or excessive drooling, is caused by what theoretical pharmacologic mechanism?

A. Dopamine-2 receptor antagonism

B. Alpha-2 receptor antagonism

C. Serotonin-2A receptor antagonism

D. Muscarinic-3 receptor antagonism

E. B and D

F. A and C

G. All of the above

Patient evaluation on intake

26-year-old man met initially on an inpatient unit while paranoid

Psychiatric history

This patient was admitted to a psychiatric inpatient unit in the middle of a second paranoid psychotic schizophrenia episode

Symptoms consisted mainly of paranoid- and guilt-based delusions, thought blocking, and mild negative symptoms

During his first psychotic break, he was released after successful inpatient treatment with haloperidol (Haldol) 10 mg/d

Despite this treatment, the symptoms increased to the point of requiring a second inpatient stay where an increase in haloperidol (20 mg/d) was ineffective

At this time, risperidone (Risperdal) was the only atypical antipsychotic available and he was switched and titrated to 6 mg/d with relief of psychosis, and discharged from the hospital

Over the next year while followed in an outpatient setting, he was noted to be very compliant with his medication and appointments

Family was supportive and involved in his care, and he wished to return to college to obtain an advanced degree

Things were going well clinically and psychosocially; discussions were begun about long-term treatment, the risk of TD, and what his wishes were if he began a third psychotic break

Unfortunately, the psychosis returned, and while an inpatient again

• – Risperidone (Risperdal) 10–12 mg/d was ineffective, and based upon previous discussions regarding the most effective and least TD-prone antipsychotic and with written advanced treatment, Psychiatric Advance Directives signed by the patient, he was started on clozapine (Clozaril), which was titrated to 400 mg/d

• – Psychosis resolved

• – Has been relatively symptom free for several years

• – Plasma levels are therapeutic at 500 ng/ml (levels >350 ng/ml have been shown to be clinically effective)

• – White blood cells have been stable (>3000/mL)

• – Mild sedation and moderate CIS are experienced

Question

Of the following choices, what would you do?

Lower the clozapine (Clozaril) to lower CIS while trying to maintain a reasonable blood level to avoid breakthrough psychosis

Lower the clozapine (Clozaril) to lower CIS while trying to maintain a reasonable blood level but combine with another atypical antipsychotic to maintain remission

Lower the clozapine (Clozaril) to lower CIS while trying to maintain a reasonable blood level but combine with a typical antipsychotic to maintain remission

Switch to oral, dissolving clozapine (FazaClo) tablets or liquid clozapine (Versacloz) to lower CIS

Switch to an atypical antipsychotic monotherapy now that more are available

Try to use an augmentation as an antidote to CIS while maintaining his effective current clozapine dose

Case outcome

Patient was very cautiously switched to aripiprazole (Abilify) over several weeks

• – There was a prompt relapse into psychosis

• – Switched back to clozapine (Clozaril) 400 mg/d with symptom resolution but with a return of CIS

Eventually the clozapine dose was lowered to 300 mg/d and the CIS lowered partially

• – Plasma levels ranged from 200–350 ng/ml

Later, a trial of oral dissolving clozapine (FazaClo) lowered his CIS to a mild and better-tolerated level

He declined CIS antidotes as he felt he was able to tolerate his mild CIS as it is and did not want to have to take extra medication

He remains positive symptom free, and has mild negative symptoms only

He completed college and is gainfully employed in entry-level management at a local business