The first of the atypical antipsychotics, clozapine (Novartis’ Clozaril), could be a more than useful third-line treatment for schizophrenia in children and adolescents, a US study suggests.

The head-to-head comparison of clozapine with olanzapine (Eli Lilly’s Zyprexa) in children aged 10 to 18 years found that the former – long genericised and a relatively inexpensive option for schizophrenia – was nearly twice as likely to achieve a treatment response as olanzapine. But the restrictive nature of clozapine’s side-effects, most notably the risk of agranulocytosis, will continue to complicate off-label prescribing in these populations.

The first generation of atypicals have not historically been tested in, or indicated for, the treatment of paediatric and adolescent schizophrenia, although they have been widely – and controversially – prescribed off-label in these groups.

Last August, though, the US Food and Drug Administration (FDA) cleared Johnson & Johnson’s Risperdal (risperidone) for the short-term treatment of schizophrenia in adolescents aged 13 to 17 years and of manic or mixed episodes of bipolar I disorder in children aged 10-17 years. Previously, lithium was the only FDA-approved paediatric drug for treating schizophrenia and bipolar disorder in these age groups.

Subsequently, Bristol-Myers Squibb and its Japanese partner Otsuka Pharmaceutical won US approval to market Abilify (aripiprazole) for the treatment of adolescent (13-17 years old) schizophrenia in November 2007. And Eli Lilly is awaiting a green light from the FDA to expand Zyprexa’s indications to the treatment of adolescents with schizophrenia and acute mania/mixed episodes in bipolar disorder.

Noting the recent label extensions for Risperdal and Abilify, Dr Sanjiv Kumra, an affiliate of the Department of Child and Adolescent Psychiatry at the University of Minnesota in Minneapolis, said there were, nonetheless, few data from controlled clinical trials available “to help guide clinicians regarding the management of children and adolescents with schizophrenia who fail to respond to these standard ‘first-line’ antipsychotic treatments”.

Dr Kumra and colleagues recruited 39 children, aged 10-18, who had already failed to respond to at least two antipsychotic treatments for a 12-week, double-blind, randomised study in which participants were given either flexibly dosed clozapine or high doses (i.e., exceeding the package insert recommendation) of olanzapine (up to 30mg per day).

The primary efficacy measure was response (improvement), defined as a reduction of 30% or more in total Brief Psychiatric Rating Scale score from baseline and a Clinical Global Impression Scale improvement rating of ‘1’ (very much improved) or ‘2’ (much improved).

Doubly effective
A total of 66% of the patients on clozapine met the response criteria, compared with 33% of those on olanzapine. From baseline to endpoint, both positive (psychosis) and negative (blunted emotional response, reduced motivation) symptoms responded better to clozapine. However, both treatments were associated with significant weight gain and associated metabolic abnormalities.

The results were published in the journal Biological Psychiatry, whose editor Dr John Krystal commented: “Olanzapine is among the most effective antipsychotic medications, so the distinctive effectiveness of clozapine in this study could be very important”. He also pointed out, though, that clozapine “has important side-effects that have discouraged its prescription to children”.

Other concerns have been expressed about the extension of antipsychotic labelling to adolescents and children, with critics claiming psychiatric disorders are already heavily overdiagnosed in these populations and that companies like Lilly are seeking out younger patients in an efforts to counter flagging sales and the approach of generic competition.

Clozaril is already firmly genericised but the drug also raises issues beyond the customary problems, such as weight gain, encountered with antipsychotics. As Dr Kumra pointed out, clozapine is often regarded as a treatment of last resort due to its association with agranulocytosis, a potentially life-threatening condition involving the severe loss of white blood cells.

Accordingly, clozapine is available only through a restricted distribution system that ensures white blood cell and absolute neutrophil counts before, during and for at least four weeks after the end of treatment. The drug also carries an increased risk of seizures, myocarditis, other adverse cardiovascular and respiratory side-effects such as orthostatic hypotension and, in the elderly, mortality.

All the same, Dr Kumra believes the “striking symptom reduction observed in this clinical trial makes apparent that clozapine has truly revolutionised the care of youth with treatment-refractory schizophrenia”. He stressed that the majority of the youths involved in the study “had histories of multiple hospitalisations, extreme violence, suicidality and trauma prior to study enrollment”.

Without appropriate intervention, Dr Kumra warned, “it is likely that many would have ended up in long-term care institutions, psychiatric prison settings, and/or experienced early death from drug use, violence, or suicide”.

The long-term risks of treatments such as clozapine and olanzapine will have to be weighed against their potential benefits, he concluded. “Thus, additional research will be needed to follow-up on this exciting but very preliminary finding,” Dr Kumra said.