Who would respond to Clozapine? Journal of Clinical Psychopharmacology:October 2012

28.09.2012

Most guidelines suggest clozapine should be used as a third-line drug, after patients have not responded to at least 2 antipsychotic drugs.  Prescription studies show that psychiatrists are reluctant to use clozapine and more often use poly pharmacy, even in the early course of schizophrenia, despite the lack of evidence for this strategy.

Previous studies have shown many variables associated with poor response.

1. Less severity of schizophrenia with more negative symptoms

2. More extrapyramidal symptoms at baseline

3.Earlier onset of schizophrenia

4.Female sex

5. Lack of early response to clozapine.

What about predictors of good response?

Nielsen and colleagues used the Danish Central Psychiatric Research Registry and the National Prescription Database to look in to this.Multiple logistic regression models were used to identify predictors of psychiatric hospitalization (ie the outcome of interest). During the study period ( 1997- 2005), 633 patients with schizophrenia were newly started on clozapine. Mean age at first schizophrenia diagnosis was 26.2 years , and mean age at first at clozapine prescription was 27.8 years . Patients had an average of 8.3  psychiatric admissions before clozapine initiation and 2.9  different outpatient antipsychotic trials before clozapine. More than half of the subjects received clozapine only after at least 3 prior outpatient antipsychotic trials; one third had undergone at least 4 failed trials, and as many as 1 of 8 males and 1 of 4 females had 5 or more antipsychotic trials before clozapine was initiated.

Major findings:  lower number of admissions and of different antipsychotic outpatient trials before treatment with clozapine were associated with a better response to clozapine. Increasing dosage of clozapine was associated with better outcome.  The number of bed-days and admissions reduced dramatically after the initiation of clozapine.

They did not find an association between clozapine response and schizophrenia subtype.  Although in general, female sex has been associated with better response in schizophrenia, this study suggests that this may not be the case regarding clozapine response in patients with refractory schizophrenia. In this study , male sex was associated with better response to clozapine.

Total of 3 antipsychotic outpatient trials were used before treatment with clozapine was initiated. This is low compared with an average of 5 trials found by in other studies.  This may be due to the fact that antipsychotic trials that were started and discontinued during inpatient treatment were not counted because of lack of access to these data.

There are limitations to use admission and bed days as outcome parameters of medication success as social factors may play a role in admission and inpatient stay duration.Authors consider this a less likely factor.

It is important to note that each different out- patient antipsychotic trial reduced the likelihood of response to clozapine by 8% to 11%, and each admission reduced the likelihood of response by 4% to 8%.  This study is supporting the idea that clozapine should be considered early in the treatment.

Summary of the article:

Predictors of clozapine response in patients with treatment-refractory schizophrenia: results from a danish register study. Nielsen J, Nielsen RE, Correll CU.J Clin Psychopharmacol. 2012 Oct;32(5):678-83.

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