Clozapine Reconsidered

[kugel]

Psychiatry/Neuroscience

Effective Schizophrenia Drug Under-Prescribed?
Neil Wagner

July 29, 2009
The average schizophrenia sufferer dies about 20 years sooner than a member of the general population. An 11-year Finnish study has found that the most effective drug at shrinking this gap is clozapine. Yet clozapine is rarely prescribed, particularly in the U.S., because of various health concerns surrounding its use. The new Finnish study authors are highly critical of this under-prescribing and claim that the benefits of clozapine treatment far outweigh its risks.

Clozapine was first introduced in Europe in 1971. It was voluntarily withdrawn from the market by the manufacturer in 1975 after it was shown to cause a condition called agranulocytosis in about 1% of all patients. Agranulocytosis is a drastic lowering of certain types of white blood cells and can be fatal. Clozapine has also been shown to increase the risk of myocarditis and other heart problems. Because of its effectiveness at treating schizophrenia, in 1989 the FDA approved clozapine for use in treating schizophrenia patients who were unresponsive to all other drugs. In 2002, the FDA widened availability to include schizophrenia patients thought to be at risk of suicide.

Despite its availability, physicians in the U.S. have been reluctant to prescribe clozapine. After all, the physician’s credo is to first do no harm, and clozapine certainly has the potential to cause harmful side effects. Also, patients taking clozapine are required to have weekly blood cell counts to allow for early detection and treatment of any developing agranulocytosis for six months, and there is concern about schizophrenia patients following this routine.

Nevertheless, the current study authors claim that not prescribing clozapine has led to thousands of needless deaths. They suggest that the original restrictions on clozapine were arbitrary—not based on overall risk to benefit assessment. They also question the role of the drug companies in prescription practices; clozapine is inexpensive and unprofitable compared to most of the newer antipsychotics.

The study examined the cause of death in 67,000 Finnish schizophrenia patients between 1996 and 2006. Long term usage (7-11 years) of any antipsychotic lowered the death rate by about 20%. Clozapine was the most effective of the six most commonly prescribed antipsychotics at lowering the death rate.

The study was not originally focused on clozapine. It was undertaken because of concerns that some newer antipsychotics were actually increasing the death rate among schizophrenia patients. This was found not to be true. They all reduced the death rate, but varied greatly in effectiveness. When compared to the older antipsychotic perphenazine, the drug quetiapine was the least effective (a 41% higher death rate), while clozapine was the most effective (a 26% lower death rate). The effectiveness of clozapine caught the researchers by surprise

Despite its potential for adverse side effects, those who took clozapine lived the longest. Jari Tiihonen, M.D., Ph.D, a co-author of the study and a professor in the department of forensic psychology at the University of Kuopio in Finland. Tiihonen sums up: “Our results raise the issue of whether clozapine should be used as a first-line treatment, because it seems to be the safest antipsychotic in terms of mortality and it is also the most effective.”

The results of the study were published in an early, online version by The Lancet on July 13, 2009.

http://www.cyberounds.com/content/news/psych/0729/clozapine.html

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[whopper]

Henry Nasrallah brought up a similar argument a few months ago in his editorial in Current Psychiatry.

Dr. Nasrallah mentioned that due to recent findings that atypicals are likely to stop the neurodegeneration involved in schizophrenia, that the paradigm that typicals may be just as good as typicals due to data from the CATIE study needs to rethough, possibly even abandoned. The CATIE study, while highly respectable did not cover the aspect of neurodegeneration.

Dr. Nasrhallah then went to mention Clozaril's effectiveness over other atypicals, even though it has more side effects, which he mentioned should possibly lead us to rethink using it as a medication of "last resort."

Literally, 2 years ago, I treated less than five patients on Clozaril. Now I've treated dozens. Why? Well working on a forensic unit, you get people with a higher degree of severity in their psychosis vs a typical community or even university hospital. You get people who, for example, killed others while psychotic. You also get a lot more psychotic people in the unit--almost everyone on the unit is psychotic, manic or malingering. Hardly anyone commits a crime because they were anxious or depressed.

Several of these people needed Clozaril. This is purely anectdotal, and I haven't conducted a study on this, but I've developed my own algorithm when giving antipsychotics.
1) give an atypical--try to make that atypical match what you are clinically seeing (e.g. consider it's metabolic effects, go for Risperdal if you see more (+) sx)
I shy away from Seroquel because of it's low efficacy as per the CATIE trial, and because Zyprexa is of the same chemical compound group, and is more effective.

2) If the atypical does not work (AT ALL, or little benefit), try an atypical of a different chemical compound group. E.g. if Risperdal was tried first and didn't work, try Zyprexa.

3) If the 2nd atypical does not work ((AT ALL, or little benefit), then go to a different antipsychotic (atypical or not) of a different chemical compound group not tried before. In African Americans--consider the use of a phenothiazine since there is data showing that these medications may be more effective in those of African descent.

I always try someone of African descent on a phenothiazine (usually prolixin or trilafon) before I try them on Clozaril. I've had too many patients where none of the atypicals worked on them, but a phenothiazine did. When I finally saw a paper showing that those of African descent may have a genetic polymorphism that makes phenothiazines more effective--it made sense with what I was clinically seeing.
(Nuts I can't find the paper right now, but I do know where it's pinned on a bulletin board at a different hospital.)

4) If the 3rd does not work (AT ALL, or little benefit), repeat the above.

Before I try Clozaril, I will try the patient on a mega dose of Zyprexa with or without Loxitane since both of are of the same chemical compound family. I've noticed, anectdotally (and I haven't found any studies that back this up, I've looked) that if Zyprexa works on the patient, so too will Loxitane. They are almost chemically identical. In fact for those who can't afford Zyprexa, I've switched them to Loxitane.

Of course consider mood stabilizer augmentation if the 1st atypical does not work. I however will tend to completely take them off the first antipsychotic if I see no improvement whatsoever.

And Loxitane may be an atypical despite that the textbooks label it as a typical.
http://www.ncbi.nlm.nih.gov/pubmed/...med_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2

A very good point is several argue that Clozaril may only be more effective because it requires that the patient get weekly to monthly lab work. Therefore a patient who stops the labwork (who is likely more to be noncompliant with the medication) will signal noncompliance to the therapist. It will also prejudice the data because those who stay with the medication are likely more of a group that would have been compliant anyway on another medication.

I've seen evidence for that. I've had a few patients on Clozaril, they came to my unit after being noncompliant, and I put them on another antipsychotic and they were fine on it. In fact since they were fine on another medication, they begged me not to go back to Clozaril because they hated the frequent labwork. I asked them why they were put on it in the first place. They usually answered "because that's what my doctor told me to do." They didn't have the knowledge of Clozaril on it's differences with other antipsychotics.

Likewise, I've treated several where it seemed that it was only Clozaril that showed some improvement.

 

[kugel]

Whopper,
I think you have an excellent informal algorithm.
Most patients who really could benefit from clozapine wait many years for someone to let them try it. Same with ECT for severe psychosis - very few will ever get to try it even when it's a reasonable alternative. When pt's have had an episode of leukopenia on clozapine in the past but with good clinical benefit - consider an additional clozapine challenge in the future, esp during an inpatient stay. Enough pt's respond without neutropenia that it's worth trying.

I think your use of Loxitane is important, esp in this era of tightening budgets - where hundreds/month spent on one pt means several patients who will be denied any treatment at all. It's perfectly reasonable to think of Loxitane as a sort of "cheap atypical."

Of course, don't forget the importance of pt and family education and involvement, psychosocial programs, partial hospitalization, supported employment programs, etc. Although this is another set of treatments cut out entirely when we spend huge $ on atypicals that may not be necessary.
NAMI can provide education and advocacy training without your treatment organization spending a dime.

If you're getting results on high-dose atypicals but terrible metabolic effects, consider reducing the atypical and adding Moban for it's lack of weight gain. Any time you are particularly worried about weight gain (or current obesity, diabetes, etc), think about Moban. (I'm pretty ticked that our hospital pharmacy doesn't carry it an our Dept Head won't push for that to change.)