Lots about Clozapine

I think I made a footnote in a previous post about the dangers of clozapine, but I kind of want to go into it more here. Personally clozapine had saved my life, by truly giving me a life worth living. At my worst, the paranoia and hallucinations made me isolate myself, and the loneliness was in my opinion the worst feeling of all. Clozapine is the only anti-psychotic that I respond to, and it helped me live a normal life.

I remember that it took about a year in out and of institutions before I was finally put on clozapine at all. It is a wonder how such an effective drug has the reputation of a last resort drug. It was delayed to the point that by the time my psychiatrist tried to start me on clozapine, I was so unwell my hallucinations told me not to take it. The voices told me they were dangerous. And thus when my psychiatrist told me either to take it or go to a long term facility, I chose the long term facility. There the psychiatrist didn’t know my condition, so I was put on ziprasidone instead. It had no effect on me, and I started doing strange things again, until finally I was put on an effective dosage of clozapine.

Anyways, I’ve decided to dig up some research about clozapine, just because it seems like a very interesting and important medication to me. It is crazy how restricted the drug. I have to do blood work every month, otherwise the pharmacy can’t give me my medication. Furthermore, only one pharmacy in my area is allowed to dispense it.

History of Clozapine

Here, I want to present the history of clozapine to understand why it is last resort:

Clozapine was one of the first antipsychotics ever to be made. Its predecessor is chlorpromazine. On a side note, it has no chemical relation to clozapine. Before this invention, schizophrenia was mainly treated with shock therapy and fever-induced therapy, scary things that I went over in a previous post. Not only were these treatments kind of scary, but remission would only be temporary. This meant that before the invention of chlorpromazine, schizophrenic patients would be stuck in a psychiatric ward for years on end. And as a huge plus, medications like it allowed for very scary things, like the lobotomy, to fall out of favour.

Chlorpromazine is important in the development of clozapine, because being the first anti-psychotic inspired other pharmaceutical companies to try making anti-psychotics of their own. Thus clozapine was birthed by the Swiss pharmaceutical company “Wander AG”. Even in the beginning it was proven to be extremely effective through drug trials. By 1966, 100 subjects had symptoms in remission due to clozapine.

Ironically the first reason clozapine did not dominate in the market was because it actually lacked one of the bad side effects of chlorpromazine and other anti-psychotics of the time. These other antipsychotics caused ‘extra-pyramidal symptoms’ (EPS)—a syndrome which resulted in uncontrollable jerks of movement. They believed that clozapine was ineffective because it didn’t cause EPS. But after Wander AG was acquired by a huge pharmaceutical company, Sandoz, Sandoz was able to push clozapine usage all across Europe using their strong influence. By the end of 1969, 2200 subjects were using clozapine. (Crilly, 2007)

First Signs of Problems for Clozapine and Resolution

Back in 1973, the FDA (Food and Drug Administration) in the US required Sandoz to perform clozapine studies on “healthy, young, male volunteers in prisons, [a] routine practice at the time” (Crilly, 2007). They found that at a 75 mg start dose, they would experience orthostatic hypotension—a form of low blood pressure— and thus collapse. To put dosages into perspective, I take 325 mg of clozapine daily. In the trials, they noticed that the higher the dosage off the bat, the more likely hypotension would occur. Luckily, this issue was resolved, by starting from a lower dosage and gradually increasing avoids this side effect. I was first put on 25 mg of clozapine, bringing it up by 25mg every other day in order to avoid this problem. (Crilly, 2007)

As time passed, studies in both Europe and American proved that clozapine was an effective medication, and thus it gained popularity.

However, while the drug was being used in Finland, they found that within four months, 18 subjects on clozapine developed blood disorders, of which nine died. It was mainly due to agranulocytosis—a condition where the white blood cells count drops until the person cannot fight minor infections and can die. While Sandoz ended up proving that Finland was an anomaly, the issue was over-exaggerated and clozapine was seen as dangerous. (Crilly, 2007)

And thus in 1976, Sandoz HQ stopped all R&D towards clozapine due to its toxicity, but still offered it in countries of where it was already being sold. It was during this time that psychiatrists truly began to notice the effectiveness of clozapine in spite of its toxicity. From 1976 to 1982 the usage of clozapine increased in light of these problems. It became further popularized for effective treatment of Tourette’s syndrome. This, coupled with the discovery that agranulocytosis can be non-fatal if it was discovered right away and treated—allowed Sandoz put clozapine back on the map in 1982. At that point in time it was the consensus that agranulocytosis is manageable. They were also able to prove that incidences of agranulocytosis from clozapine were similar to chlorpromazine, a drug that was very popular at the time. (Crilly, 2007)

And with demand, Sandoz was able to implement safety measures to prevent fatal agranulocytosis. Being that health care in Europe is state run, Sandoz was able to incorporate mandatory weekly blood-work for the first six months as a safety measure for prescription. Unfortunately, in the US the process was not so simple. The issue in the US market is that there is no one state-owned insurer—there are multiple health insurance providers. It was hard for Sandoz to convince the FDA that these measures would be followed in every case of clozapine prescription. They ended up creating something called the “Clozaril Patient Management System”. Basically Sandoz contracted “a home health care company and a blood sampling and analysis services” (Crilly, 2007) to perform their nationwide service. However, this resulted in the high cost of the medication, from which Sandoz profited greatly. Furthermore, Medicaid and other insurers wouldn’t cover it, because clozapine was not priced by dosage, but rather by visit for the “bundled service”.

Luckily people were able to show that this specific monitoring system was unnecessary—an antibiotic Methicillin also had a low risk of agranulocytosis, but the states and federal officials were able to handle it independently.

As many political forces arose, there was significant drive due to the fact that the mentally ill needed access to clozapine, even though they could not afford it. With legislation being passed, this became a reality.

To be honest, the invention of clozapine has a positive impact on schizophrenia in general. Not only did its release lead to remission in treatment-resistant schizophrenia, but it lead other drug companies to develop newer antipsychotics, such as risperidone, ziprasidone, olanzapine, and quetiapine. These have less side effects than first generation anti-psychotics and are proven to be more effective as well. (Crilly, 2007)

Takeaway Message and Clozapine Nowadays

Even though the history component is rather long, I included it to discuss clozapine’s image nowadays, particularly in the US and Canadian market. I just wanted to see more into why clozapine is considered a last-resort drug.

I found a modern day article where the author refers to clozapine as “a form of chemotherapy for schizophrenia—the most effective but possibly also seen as the most toxic in its class” (Seed & Mark, 2011). The question is that with the safety measure for agranulocytosis, is clozapine really that dangerous? However, I would agree with this article that clozapine is underutilized. (Seed & Mark, 2011)

The fact is that there are many clinical studies proving how much more effective clozapine is to other medications. The FDA had required Sandoz to prove its efficacy to other medications as one of the requirements of drug-approval. (Crilly, 2007)

I guess clozapine could be considered last resort due to it increasing the likelihood of myocarditis, cardiomyopathy, a lowered seizure threshold, and weight gain. The fact is that other anti-psychotics can cause myocarditis and cardiomyopathy as well. Risperdal, the first anti-psychotic I was put on, also can increase my risk of getting myocarditis, though currently only a trend has been established, not causation (Francois & Sztajzel, 2007). Findings even show that clozapine actually reduces numbers in death in contrast to those on other anti-psychotics or not taking anti-psychotics at all, due to its anti-suicidal effects. Furthermore, clozapine rated equivalent to other anti-psychotics in regard to ischaemic heart disease (Seed & Mark, 2011).

Out of all the side effects, I feel that psychiatrist don’t prescribe due to outdated view on agranulocytosis.

I wrote this post with an open mind about the dangers of clozapine, but after doing the research I have trouble seeing why it took so long before I was put on clozapine. I understand that it shouldn’t be used as a first-resort sort of drug, especially if it means that doing bloodwork every week can be avoided. What I don’t understand is why I was tried on four different medications, over the course of a couple of months, before clozapine is suggested for me. After doing my research, it seems the stigma towards clozapine is purely historical. I hope this view changes in the future.

Works Cited

Crilly, John. (2007). The history of clozapine and its emergence in the US market: a review and analysis. History of Psychiatry, 18(1), 039-060. doi: 10.1177/0957154X07070335

Farooq, Saeed and Taylor, Mark (2011) Clozapine: dangerous orphan or neglected friend? British Journal of Psychiatry, 198, 247-249. doi: 10.1192/bjp.bp.110.088690

Girardin, Francois and Juan Sztajzel (2007) Cardiac adverse reactions associated with psychotropic drugs. Dialogues Clin Neurosci. 9(1). 92-95.