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 Unfortunately, it was quickly withdrawn when a rare blood disorder called agranulocytosis was discovered.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.

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19 thoughts on “Time to Re-evaluate Clozapine Use for Improved Schizophrenia Outcomes

  1. My son has schizophrenia and was put on Clozapine but only lasted on it for about a week. It is a pill and like so many people with this horrible illness, they are not compliant when it comes to taking their medication as needed. He is on Invega..a monthly injection which for years was a monthly struggle to have him to agree to receiving it.. He is like soo many others, I think about 50% of people with the illness, that have very little or no insight into their diagnosis. I am praying for an injectable version of Clozapine…is there any hope for that in the future??

    Liked by 1 person

    1. An interesting question and one that I’ve not considered. I guess as long as so few use clozapine, it wouldn’t be worthwhile for them to try to develop that. You might consider contacting Novartis.

      Liked by 1 person

  2. My son was so ill he was put on clozapine in 1992…no more Hosp, able to work, and only one wht blood scare in past 20+ years!! Gold standard indeed but local Psy discourage because they don’t want to do the follow up required…

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    1. It has often seemed to me that people are taken off Chlozpine with the first scare when there may have been more obvious explanations for the blood count…. like an infection of a temporory nature. Clearly agranulocytosis can be fatal, caution is therefore necessary, but often drug effect is not the only explanation. The drug itself has been so good at turning symptoms around to the benefit of the individual !

      Liked by 1 person

  3. I remember when clozapine came on the market. Families were very hopeful it would be beneficial for their loved ones. But possible side effects scared them off. I didn’t hear much about the numbers it affected, no struggle by the producer to set things straight.

    I agree we should take another look at this record to get to the truth about side effects.

    June Conway Beeby

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  4. Thank you for taking a closer look at the reluctance of the medical profession to use clozapine. I appreciate the fact that you are putting some of these current practices used in the mental illness care system under closer scrutiny. When some of these barriers to better treatment are reconsidered there will be a better chance of positive change, in my opinion.
    For example, the system’s misuse of privacy legislation which was documented as far back as 1990 by Harriet Lefley needs also to be scrutinized. I do not argue that people have the right to have their health information protected, but the continued misuse can act to shield the service provider from accountability. Or it can be interpreted in such a way as to hobble the service provider from giving necessary help. It can even be ignored by the health professional when the client has specifically said that it is ok for the family caregiver to have necessary information. I have never witnessed one case in all my years of working within the system of someone taking a service provider to court over a lapse in privacy, yet the negative consequences of the misuse of privacy legislation continues.
    The use of euphemistic language such as “mental health issues” and the misleading term “recovery” also act as barriers to progress. Why fund serious mental illness research when it is widely communicated that it is only an “issue” and “recovery” is possible.
    Serious mental illness is as deserving as any other profound medical illness of more generously funded research and effective and compassionate treatment and services.

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  5. Clozapine has given back my sons life. The side effects are easier to deal with then the paranoia and scare he has dealt with the last five years.
    The doctor kept my son in the hospital for a month while starting clozapine which made a difference for him to see the change.
    I also wish this came in an injection.
    I understand the other comments of the caregivers and if I could encourage you to don’t forget to do your self care and fine a family education support group. JC

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    1. You raise an important here JC. It has been obvious to many of us that supervision and often inpatient care is vital in terms of medical supervision when a new drug is tried and this often sets the patient in amore fruitful direction. The patient moving in the right direction is essential for stability and effective therapy. Adjustment to a medical condition is hard for most of us. it is particular hard for those with serious illness that effect the mind.

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  6. Clozaril does work wonders. We use it more than 3% of the time at Napa State Hospital . But the problems – as have been pointed out – are very real. The main issue, as with all psych treatments, is that it comes only in pill form. Many persons afflicted with chronic schizophrenia suffer from anosognosia – denial of illness. So they simply refuse. The blood work required in burdensome as well and will only be entered into with a complaint patient. Novartis runs the blood program and handles the medication dispensing. No blood test. No meds. The answer: find an injectable. That way Clozaril could be given involuntarily – and most involuntary patients become voluntary once the get better….

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    1. I’m fortunate to live in what is considered the clozapine capital of Canada so it is used quite a bit here too. I don’t think this research was ever finished or published but I did attend an in service presentation at the local psych hospital (the Hamilton Psychiatric Hospital now known as St Josephs W 5th campus) by a psychiatrist who was doing research on quality of life. He argued that his research suggested that the blood testing resulted in greater compliance because it introduced a regular event. He wasn’t willing to go public with his work at that time and I don’t think it was ever finished.

      The other advantage is that you can also do clozapine blood levels to monitor compliance but it is expensive so not done as often as it should be here at any rate.

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  7. My son was put on Clozapine in 1997 after having been in and out of the state hospital for the previous 13 years. He had 11 wonderful years till he developed the blood condition that could be fatal and could no longer take the medication. In between medications he somehow got MRSA the super bug that took his life at age 43 in 11/11/08. He was wonderful those 11 years and responsible for taking his own medications and going for the blood test at the local hospital. He had a life worth living those 11 years. The first Christmas after being put on Clozapine he gave me a card thanking me for always being there for him with a warm smile, a gentle truth, and a understanding heart. Thanks Mom for making such priceless gifts a part of my life and for being the most wonderful Mother a son could ever want. He gave all the family a card this just blew me away what a amazing feeling after all the in-voluntary commitments before Clozapine. Absolutely, no regrets! At least he got a wonderful 11 years that he may never have had without Clozapine! Wouldn’t it be wonderful if there was a way to reverse the blood problem with Clozapine.

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  8. both my sons are on Clozapine . One has Bi Polar and one with Schizophrenia. After.3 years of both being in and out of hospitals and virtually hitting rock bottom . I am finally glad to say they are both doing great. A pleasure to be around . Both boys were on multiple drugs with very little effect until Clozapine. They both take there drugs willingly now. Thank goodness we have peace in our lives now!

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  9. My son will be hospitalised in 2 weeks to start clozapine. He’s been on 4 different
    medications and injectable monthly over the past 5 years. These medications improved his symptoms about 50% then seemed to come to a standstill, progressing no further. After reading all this positive feedback it sounds like there is some hope for my sons recovery. It’s been a very long road & would be good to see a light at the end of the tunnel. So thankyou & wish you all the very best

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  10. I really appreciate Marvin’s comments and agree with them whole heartedly. For the last 8 years my son has been on clozapine with dramatic results. Of course like so many others he had to cycle through multiple other anti psychotics for 18 months before his Psychopharmacologist agreed to start. My son has Schizophrenia and at the start of his illness we were told how limited his life would be. I am happy to report at the age of 24 he just graduated from college with honors and is now living independently in NYC. He is pursuing a career as a Stand Up comic. Daniel was given not only clozapine but CBT, Cognitive remediation, a vigorous exercise regimen, an excellent diet, and support with his education. The dreaded metabolic affects we were told were inevitable, were not so. With diet, exercise, and metformin Daniel once he started clozapine was able to shed over 15 kgs. Clozapine is not the whole answer but should be the cornerstone medicine used when an anti psychotic is needed. Given the risk for suicide in the psychotic illnesses clozapine should be not the medicine of last resort but the first medicine prescribed. I have now been practicing Psychiatric Internal Medicine for the last several years and have learned that my N of 1 is quite generalizable. Please, I refer you to my website teamdanielrunningforrecovery.org. There is a fair amount of information on the optimal use of clozapine.

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