Uses

• Improve positive symptoms in Sz (hallucinations , delusions, disordered thoughts and agitation)
• Improve negative symptoms e.g. withdrawal, flat affect, anhedonia, poverty of speech, catatonia, cognitive impairment
• They carry smaller risk of extrapyramidal side effects than the DA receptor antagonists → anticholinergic drugs not required concurrently

Pharmacological Actions

• Rapidly absorbed from the GIT & peak plasma levels at 1-4h, steady - state ½ life of 10-16h, usually reached in 3-4 days (if twice daily dosing used).
• The 2 major metabolites have minimal pharmacological activity
• An antagonist of serotonin & dopamine

Adverse Effects

• Most common: sedation, dizziness, syncope, tachycardia, hypotension, ECG changes (non specific ST – T wave changes), nausea & vomiting
• Paradoxical HTN in 4%
• Leukopenia, granulocytopenia, agranulocytosis (a ↓ in absolute neutrophil count, usually occurring within the 1st 6/12 of Rx – thus should not be prescribed to patients that have a WCC <3500 or a Hx of bone marrow disorder), fever – in 1% of population that take the drug
• Others: fatigue, sialorrhoea, weight gain (of up to 40-50lbs), constipation, muscle weakness
• Changes in insulin metabolism
• Rusk of seizures in 4% taking >600mg/day
• Myocarditis & cardiomyopathy

Dosage & clinical guidelines

• Initially prescribe 25mg od/bd → gradual ↑ 25mg/day every 2-3 days →300mg in divided doses (bd/tds).  Maximum of 900mg can then be used
• Weekly WBC counts for the 1st 18/52 then fortnightly thereafter (agranulocytosis):
• If WCC <2000/mm3 or granulocyte count <1000/mm3 → discontinue clozapine

Switching from typical to atypical antipsychotics

• Taper off the typical slowly while titrating up the SDA