Case debrief

This treatment-refractory schizophrenia case embraces the idea that schizophrenia is progressive and with each successive psychotic break, medication failure that more resistance develops

This is contrary to the other treatment-resistant case where the schizophrenia patient was dosed on several typical and atypical antipsychotics for years prior to a trial of clozapine

To counter this clinically, the theory was to use the most effective antipsychotic medication as soon as possible in this young adult’s life

The rationale was to offer the best chance of psychotic symptom remission with the hope of halting the progression of schizophrenia

With advanced treatment planning, family consultation and proxy, written consent for the use of clozapine (Clozaril) early in treatment (he had only been on one typical and one atypical antipsychotic beforehand), he was placed on the most effective, albeit most side-effect prone, antipsychotic earlier in the course of his illness

In this case, this was an excellent clinical decision as he had no TD/EPS or metabolic issues

The mild sedation abated, and his CIS became much less problematic, avoiding the need for antidote-based polypharmacy, as clozapine dosing was refined to the lowest therapeutic dose in this particular patient

Psychosocial decline was halted and actually reversed

Two-minute tutorial

Clozapine sialorrhea statistics and etiology

CIS may occur in 10%–80% of patients taking clozapine

The mechanism of CIS is poorly understood, but theoretically

• – Salivary flow is under parasympathetic control and mediated possibly by muscarinic M3 receptors

  • Agonism here produces more saliva output

• – Noradrenergically, alpha-2 receptor antagonism in salivary tissue may increase blood flow and saliva output. This blockade leaves beta-adrenergic receptors unopposed, causing salivary output as well

Muscarinic receptor agonism and anticholinergic receptor antagonism (M1, M2, M3, M4)

• – M3 receptors are the most predominant receptors in salivary tissue and these are initially antagonized by clozapine (Clozaril)

  • Salivary secretions increase

  • M4 receptors are now unopposed and secondarily stimulated

  • This occurs to a lesser degree by clozapine, resulting in more predominant CIS

Possible antidotes for cis

Antidotes for CIS include

• – Alpha-2 agonists such as clonidine, lofexidine, guanfacine, alpha-methyldopa, and moxonidine

• – Anticholinergics such as pirenzepine, atropine, trihexiphenidyl, benztropine, procyclidine, biperiden, propantheline, scopolamine, glycopyrrolate, ipratropium (nasal)

• – Miscellaneous agents such as benztropine and terazocin combination, beta-blockers, and botulinum toxin injection

Posttest self-assessment question and answer

Clozapine (Clozaril)-induced sialorrhea (CIS), 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

Answer: E

CIS is felt to be initiated by (B) alpha-2 receptor agonism and (C) muscarinic-3 receptor antagonism, making answer E correct. Dopamine-2 receptor antagonism alleviates psychosis but does not contribute to salivary flow. Serotonin-2A receptor antagonism alleviates EPS but does not contribute to salivary flow.

References

1.Stahl SM. Stahl’s Essential Psychopharmacology, 4th edn. New York, NY: Cambridge University Press, 2013.

2.Praharaj SK, Arora M, Gandotra S. Clozapine-induced sialorrhea: pathophysiology and management strategies. Psychopharmacology 2006; 185:265–73.

3.Iqbal A, Rahman MJL, Schwartz TL, et al. Therapeutic options in the treatment of clozapine induced side effects. J Pharm Technol 2004, 20:155–64.

4.Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide, 5th edn. New York, NY: Cambridge University Press, 2014.

Patient file

The Case:

The figment of a man who looked upon the lady

The Question:

Are atypical antipsychotics anti-manic, antidepressant, anxiolytic, and hypnotic as well?

The Psychopharmacological Dilemma:

How to improve insomnia that is caused by depression, anxiety, mood swings, and hallucinations

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

Which of the following properties of certain atypical antipsychotics lend to their ability to promote and maintain sleep?

A. Histamine-1 receptor antagonism

B. Serotonin-2A receptor antagonism

C. Serotonin-7 receptor antagonism

D. A and B

E. All of the above