PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Neuroleptic Drugs - Clozapine.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Neuroleptic Drugs - Clozapine

Neuroleptic Drugs - Clozapine

Date Created: 07/02/2000   Last Modified: 27/05/2001   Last Checked: 02/05/2002Clozapine is the most potently anti-muscarinic neuroleptic of them all; it's side effect profile reflects that. It can cause severe constipation and even 'toxic mega-colon'.

Clozapine is an example of a 'dirty' drug (pharmacologically speaking) which has superior efficacy; this might be remembered when next you hear someone espousing the advantages of 'selective' or 'specific' drugs like SSRIs.

A recent analysis of nearly 13,000 patients on clozapine has some useful data.

First, definitions:--

  1. neutropenia, neutrophil count of 0.5-1.5 x 109/L
  2. agranulocytosis, < 0.5 x 109/L

This study shows:--

  1. Dose; at 12 weeks mean of 400 mg, typical max dose 450 mg
  2. Overall discontinuation rate; 34% in year one, 10% in year two, 3% in year seven
  3. Cumulative incidence of agranulocytosis was 0.73% (93 patients out of 13000). Two died.
    Peak risk was 6-18 weeks (incidence 0.7%)
  4. Neutropenia; 344 cases ceased treatment because of neutropenia. Cumulative incidence was 2.7%. Of those who had to cease treatment 50% did so by week 19 and 75% in the first 12 months.

Risk factors for agranulocytosis

  1. Age, 50% risk increase for each decade
  2. Dose, inverse relationship, 20% decrease for each 100 mg increase in dose

Risk factors for neutropenia

  1. For each 1.0 x 109/L decrease in basal WCC risk increased by 30%

Suicides

There were 13 confirmed suicides

The usual risk increase in schizophrenia seems to be around 20 times that of the national population standardised mortality rate (SMR) ie about 2000. The risk in this group was an SMR of about 500; ie 4 x less than typical figures for schizophrenia.

The inverse risk finding is counter-intuitive and one would want to be confident that this is not an artifact caused by dose lowering in those perceived (correctly) to be at risk. An intriguing possibility is that it is related to auto-inhibition of a cytochrome P450 enzyme responsible for the production of a toxic metabolite.