Time to Re-evaluate Clozapine Use for Improved Schizophrenia Outcomes

By Marvin Ross

The gold standard treatment for schizophrenia has been available since the 1960s but, other than in China, it is rarely used. Given its superiority over other treatments and the improvements those on it demonstrate, it is time for governments to rethink its use. It has the potential to improve lives and to reduce the costs associated with chronic schizophrenia.

Clozapine (clozaril) was introduced in the early 1960s by the Swiss pharmaceutical company Sandoz (now Novartis) as a treatment that avoided many of the side effects of the drugs then in use. Unfortunately, it was quickly withdrawn when a rare blood disorder called agranulocytosis was discovered. This is a condition that represses the white blood cells leaving the person open to infections. The incidence of this condition is only 1-2% and it can be prevented by ensuring (as is done now) that everyone on clozapine have regular blood tests.

Because the incidence of this side effect is minimal, can be prevented before it becomes a problem with blood testing, and clozapine has shown to be superior for all symptoms of schizophrenia, it was granted a license in the US and Canada in 1990 and 1991. At the same time, a number of new anti-psychotics were introduced that were hoped to be as efficacious as clozapine but without the blood side effect.

Clozapine still shows greater efficacy than all the others. I’ve heard psychiatrists say that if they had a child develop schizophrenia, they would put him/her on it. But, it is reserved only for people who have treatment resistant schizophrenia and have failed to show significant improvement with 2 or 3 of the other agents. Most jurisdictions will only fund its use through a special drug program so they can monitor blood as is the case in Ontario. That makes it difficult for many doctors to enroll their patients who might benefit.

And while regular blood testing may be expensive, it is likely considerably less expensive than poor outcomes. A 2013 study of Canadians taking clozapine found that “In the pre-clozapine period more than 50% of the patients had at least 2 hospitalizations, this proportion decreased dramatically to 13% after clozapine was initiated. More than 55% of patients had no hospitalizations during clozapine therapy.”

A 2012 US study summarized the benefits of clozapine as:

reducing the number of suicides;

greater reduction in the positive symptoms (delusions, voices);

improvement in cognition contributing to better work and social function; higher quality of life and longer time to discontinuation; and,

decreased relapse.

This last point, the author suggests, results in those taking it preferring it to other treatments.

The most recent study on clozapine came out this June and was conducted by scientists at the Centre for Addiction and Mental Health in Toronto. They found that the major metabolite of clozapine helps protect or enhance working memory function in people with schizophrenia. Commenting on this research, Carrie Jones of Vanderbilt University who was not involved in the work had this to say. “This study is very encouraging because the current treatments for the cognitive deficit in schizophrenia are only marginally effective. To have data that suggest a path forward for enhancing cognition by any approach is tremendously important”.

Despite these positives, the use of clozapine remains underutilized in the US, UK, Canada, New Zealand and Australia. In the US, it is estimated that only 3% of patients are on clozapine. In fact, According to Herbert Y. Meltzer, MD, Professor of Psychiatry at the Vanderbilt University School of Medicine, “leading economists have cited underuse of clozapine for treatment resistance and suicide as one of the two greatest failures of mental health providers to practice evidence based medicine.”

Meltzer also commented that “The fear of agranulocytosis is grossly exaggerated. The risk of its occurrence is way under one percent and the risk of death from agranulocytosis, with monitoring and treatment, is less than one percent of that.” When monitored correctly, the frequency of agranulocytosis with clozapine has been estimated to be as low as 0.38 percent.

As any new and improved treatments for this horrific disease seem to be way off in the future, policy makers really should look at increasing the availability of clozapine. In China, clozapine is the most used anti-psychotic and we should catch up for the sake of those who are ill.

Disclosure – I am not funded nor am I in the pay of Novartis or any pharmaceutical companies that manufacture clozapine/clozaril.