The pharmaceutical companies are subject to a lot of criticism, but if they don't make a profit they can't invest in the research and development for better medications. There are tropical diseases for which medication has never been developed because there is no market for them. Lots of people die without these medications, but neither they nor their governments can afford $800 million dollars that would justify the development costs. So in a way we're lucky that schizophrenia strikes 1% of the population around the world, rich and poor. Even though people with schizophrenia generally can't afford the medications, their governments and health insurance can. It is a cheaper cost than not treating people. After twenty years of patent protection medication can become very inexpensive. A months supply of Stellazine is about $2 and that is in Canadian dollars.
Before the advent of Chlorpromazine in 1954 almost everyone with schizophrenia lived in lunatic asylums. They were too ill to live in the community. After 1954 other medications like Chlorpromazine which blocked Dopamine D2 receptors came on the market and large numbers of people were discharged from the lunatic asylums to live in the community. For the next forty years there were no real advances in the treatment of schizophrenia until Clozapine was re approved in 1991.
With schizophrenia the pattern is usually one of treating a first psychosis episode with medication for a year or two and then reassessing the need for medication. Over 100 medical conditions can cause a psychosis, including schizophrenia, substance abuse, bipolar disorder, depression, sleep deprivation, high fever, etc. People diagnosed with schizophrenia are often on a maintenance dose of medication to prevent a relapse of psychotic symptoms for the rest of their life. I'm one of those people. A first psychosis generally responds very well to a very low dose of medication but years later the dose of medication needed is considerably greater and the response not so good. Nobody is quite sure why, but many researchers believe it is an effect of repeated relapses. A response to medication can be apparent the next day in some people. The standard hospitalization in Ontario is about two weeks. The drug trials to determine response curves to new medications typically go for six to eight weeks. With some medications like Clozapine it can take six months to get a response and with the atypicals you generally see continuing improvement for two years or more. They don't do many studies longer than that because they become very expensive beyond that.
Response to medication is quite variable. Asian people, from India and China for example are generally more sensitive to antipsychotics and generally respond to lower doses than Caucasian people. One US study found 6.6% of all first psychotic episode patients treatment resistant and 9% to 17% of the whole population with schizophrenia treatment resistant. People become treatment resistant through repeated relapses over time, but a significant percentage are treatment resistant right from the start. The definition of treatment refractory or treatment resistant is technical but generally means the individual is having trouble with psychotic symptoms in spite of medication. Clozapine works well for 30% of that treatment resistant population.
A first episode, treated in the first six months, is ideal and generally has the best prognosis
and the quickest recovery. It often takes much longer then 6 months to get
someone treated partly because the public is so unfamiliar with what a
psychosis is. With a gradual or insidious onset, as it is called, people tend to lose the human relationships that would help them get treatment.
Many people then develop a
long history of going
off their medication, and relapsing repeatedly. For some it takes several relapses
to realize the effectiveness of medication in preventing them. The following chart illustrates the impact of relapses on outcomes which isn't
desirable.
Theoretical outcomes
Theoretical outcomes
The main cause of relapse is noncompliance with medication. Many studies have shown this
and the following chart from Lundbeck is a composite of many studies.
Relapse rates chart
Relapse rates chart
Back in the days of Haldol and
other conventional antipsychotics people stopped taking their medication
because the side effects known as the Extra Pyramidal Symptoms (EPS) were very
unpleasant. EPS such as parkinsonism, akathisia and dystonia are movement
disorders that occur through D2 dopamine blockade in the nigrostriatal regions of the brain and
appear to lead to another more permanent movement disorder known as tardive
dyskinesia which is irreversible. People used to have to take a
second medication like Cogentin to treat EPS side effects. Nobody wants
to have schizophrenia though and people continue to stop taking their medication
in the belief they are better and no longer need
medication. A lot of people don't want to have schizophrenia and never realize that
is what they are experiencing, especially after they have improved with medication.
And there are still side effects taking atypical medication that can be quite
uncomfortable.
Almost everybody with schizophrenia has been switched to, or started on an atypical medication. They generally do not cause any EPS side effects. Some people don't trust new medications, some people are on depot medications which I discuss below, some people can't afford the new medications, and some haven't been approved in their country, but generally, if you have schizophrenia, you are taking an atypical medication. There are four atypicals available in Canada: Clozapine (approved in 1991), Risperidone (approved in 1993), Olanzapine, (approved in 1996) and Seroquel (approved in 1998). There are 15 other atypicals in the development and research trials phase at the moment. Some of these trial drugs are regulating medications. They don't indiscriminately block dopamine or serotonin, they regulate the amount reaching the receptors. If there is too little these medications will increase the amount, if there is too much they will block the flow of the neurotransmitter. They tend to normalize the very abnormal neurotransmitter activity in schizophrenia. Abilify™ (Aripiprazole) recently approved by the FDA in the United States is the first of this type to be approved.
The available atypicals are better drugs then the older conventional, but being new and patent protected they are considerably more expensive. In Canada Clozapine costs $16 a day. Stellazine by comparison cost me 27 cents a day and that's including the monthly dispensing fee of $6. Olanzapine at 10 mg a day costs $7 a day and Risperidone at $3-$4 a day is currently the most widely prescribed medication for schizophrenia in the world. When Risperidone first came out in 1993 it was prescribed at 6-8 mg a day but now they prescribe it at 3-4 mg. Seroquel is also about $4 a day according to my source.
Each atypical is quite unique really, but chemically there are two types, the ones like Clozapine and the ones like Risperidone. Atypicals by definition do not cause EPS side effects and they alleviate negative symptoms by stimulating prefrontal cortex activity. They also have mood stabilizing qualities and reduce suicidal behaviour. Cognitive scores improve on atypicals as well although that research is just beginning. Used early in the illness they also prevent cognitive deterioration.
Clozapine is considered the best for the treatment refractory. Other people don't usually get to try it. It was the first atypical, developed in the sixties I think, but taken off the market in the seventies when it was found to be responsible for a number of deaths from agranulocytosis. It was reapproved in 1991, when research showed it was the only drug that worked with the treatment refractory with the condition of regular blood sampling to prevent agranulocytosis. People on Clozapine are still improving years after having started on it. At Schizophrenia 96 in Vancouver one psychiatrist from Sweden, where Clozapine was never pulled off the market, had been working with Clozapine since the seventies. Forty per cent of his patients have returned to work, 20% full time and 20% half time. That is really quite remarkable. Compliance is very high too, in spite of the blood work, and suicide attempts decrease to normal for the rest of the society.
In Ontario people on Clozapine have to have their blood sampled every two weeks. The Ministry of Health in Ontario restricts the access to Clozapine to the point that it is the last resort. In Communist China it is apparently used widely for all schizophrenia. One psychiatrist at a conference said that they don't do any blood work in Communist China but another speaker said they do. I can't understand how one of the poorest countries in the world can afford the best medication that isn't freely available in the richest countries.
Dr. Weinberger once explained that dopamine is part of a very powerful reward system in the brain. He thinks there is too little in the prefrontal cortex in schizophrenia which then causes too much to be produced in the mesolimbic areas. Risperidone preferentially blocks 5HT2a serotonin receptors before Dopamine D2 receptors. The 5HT2a serotonin receptor is involved somehow in the prefrontal dopamine system. Essentially by blocking the 5HT2a Serotonin receptors, dopamine transmission is stimulated in the prefrontal cortex, which reduces dopamine transmission in the mesolimbic areas. With Risperidone you only see EPS at high doses. If you raise the dose you get more Dopamine D2 blocking. At a luncheon I recently attended the researcher said that Risperidone should never be prescribed at a dose higher than 6mg daily. You would expect better control of psychosis at higher doses but he said that doesn't happen. You actually get a better response to Risperidone at doses less than 6 mg a day. Risperidone can raise prolactin levels though, which cause disturbances in sexual function and other medical problems many years later.
Olanzapine and Seroquel are slight variations of the
Clozapine molecule although with Clozapine and Seroquel an individual is taking 200-700 mg and with Olanzapine
the individual is usually taking 5-20 mg.
Chemical Structures
Chemical Structures
I've been on 10 mg of
Olanzapine since it was approved in 1996 and I'm very happy with it. I think
it has added a depth and richness to my life experience that I didn't have on
Stellazine. Within a few months many family members I know in
Guelph commented on the improvements they saw in me on Olanzapine. My face was more expressive, my voice had more intonation, I wasn't
as sluggish as I used to be. It did take several months to get used to. I
was taking 15 mg of Stellazine and switched to 10 mg of Olanzapine overnight, which
I wouldn't recommend. A couple of years ago I added 75 mg of Seroquel daily which is a very
low dose. I don't know if it is responsible or not but I've started exercising again, lost some weight as a result and
feel a little more laid back. There was a psychiatrist I heard who recommended combining Olanzapine or Clozapine with Seroquel. He hadn't done any double blind studies though.
If one could fault the drug companies, it would be that they don't do any studies combining medications. One rep explained to me that this would be asking
General Motors to build a truck using Ford parts. There probably are some advantages to combining medications, but that research hasn't been done yet.
I also take Effexor for depression, which I took for the first time this winter, and I'm wondering if I shouldn't be on it all the time. I've never expereinced as pleasant and active
a winter as the one I was taking Effexor, Olanzapine,and Seroquel.
There is consensus that all antipsychotics, atypcial or otherwise, work by blocking dopamine D2 receptors. There is an ideal percentage 60% to 80%,
where you get the greatest symptom relief and prevention without uncomfortable side effects.
All antipsychotics ideally occupy receptors within that range. Kapur and Seeman from Toronto have recently been doing PET scan studies of actual
receptor occupancy by different medications, Haldol, Olanzapine, and Risperidone. The results should have confirmed the dosing that occurs in real life for
schizophrenia, and it did for Risperidone and Olanzapine. Haldol though was a different story. Instead of the 20mg that was commonly prescribed before
the atypicals came on the scene, people really only needed 2mg to 5mg.
Dopamine D2 and 5HT2 occupancy
Dopamine D2 and 5HT2 occupancy
Seroquel and Clozapine were originally thought to work very differently because the PET scans showed virtually no dopamine D2 blocking, but somebody suggested that those drugs have a very transient binding and if you ran the PET scan soon after taking the medication they would also reach 60%to 80% blocking. It looks like that is true. The fact that Seroquel and Clozpaine only block dopamine D2 for a few hours a day raises the probability that it is not necessary to block dopamine D2 twenty four hours a day for an antipsychotic to be effective. That means you could take your medication at night and be virtually medication free for most of the waking day.
All atypicals also block Serotonin 5HT2a and that appears to have a significant benefit. The Clozapine like drugs block several other receptors as well.
They were known to chemists as "dirty" drugs, because they are so active chemically, but some marketing people
changed that to "receptor rich" drugs.
They interact with dopamine, serotonin, muscarinic, histaminergic and adrenergic systems, up to
ten
different receptors. It is not known yet how many of those receptors are involved in schizophrenia.
Olanzapine and Seroquel each have a slightly different profile than Clozapine.
receptor occupancy rates.
receptor occupancy rates
black and white rates chart
black and white rates chart
It is presumed that all the conventional antipsychotics
act like Haldol on only D2 dopamine receptors, although Haldol is the most
disliked for some reason.
You can't help but wonder at
the diverse
chemical activity of atypicals.
It is, at the moment, impossible to predict which atypical will work best with which individual. One hears anecdotal evidence of remarkable recovery for each of the atypicals. When any of them works well it really can be quite remarkable. Clozapine is still considered the best but it is not a first line medication. At the same time I've heard of people who didn't do as well on Clozapine as on Risperidone. I prefer Olanzapine to Risperidone, but my only experience with Risperidone was at twice the current recommended dose. I am a little slow getting going in the mornings on Olanzapine, but I just don't schedule early morning meetings if I can avoid it.
One side effect of all atypicals so far is weight gain, with Clozapine causing the most, followed by Olanzapine and then Risperidone. I gained 20 lb. on Olanzapine the first month I took it and seven years later I've been able to lose at least half. From research trials it looks like Geodone (Ziprasidone) and Abilify™ (Aripiprazole), don't cause any significant weight gain. I know some people who would probably like to switch because they find the weight gain very uncomfortable. The weight gain from atypicals varies from individual to individual, and is a health risk in its own right.
The other downside of Clozapine like drugs is an increased risk of diabetes independent of that associated with weight gain. This is still fairly new. Just having schizophrenia increases your risk for diabetes independent of any medication, as does other factors, like your weight, especially what they call central obesity, your age, your genetic predisposition, and especially your activity level. No one is quite sure how much of a factor the atypical medications are given the increase of other factors, and the apparent association of schizophrenia and diabetes independent of medication. It looks like these drugs can increase insulin resistance whch can lead to an increased risk of diabetes. I know several people who have developed type Two diabetes, but they have several other risk factors. I go for blood glucose tests on a regular bassis. In good weather I run 33 minutes almost every day. In winter I ride a stationary bicycle for 36 minutes every day. I think I've become addicted to aerobic exercise now. An endocrinologist told me that developing type two diabetes is reversible to some degree, if one loses weight and develops an exercise routine, but some risk factors like genetic predisposition will still be there. Both Geodone and Abilify are said to be free of this side effect, but neither is available in Canada yet. Geodone may be approved in Canada in a few years. Abilify will take longer. Apparently Abilify sales in the US are slow, and if it was available in Canada, Americans would buy it over the internet from Canada, and hurt US sales even more.
Another drawback with all the atypicals so far is that they cannot be formulated as depot injections. Depot injections are commonly used to guarantee compliance, the individual getting an injection every two to three weeks. The medication is slowly released over the two week to three week period. Janssen is in the middle of a trial of a depot form of Risperidone and it won't be long until it is publicly available in a depot formulation. Eli Lilly is working on a depot form of Olanzapine as well.
Clopixol had gained some popularity as a depot medication partly because it can be combined with Acuphase which only lasts 72 hours. The two are the same chemical in different formulations. When a severely agitated, disorganized and aggressive patient is admitted to the hospital with psychotic symptoms you want to establish quick stabilization of symptoms with minimum intervention. Acuphase is fast acting and very sedating. It basically knocks people out. It acts quickly, within 2 to 4 hours and Lorazepam (Ativan) can be used to cover the initial 4 hours. Maximum sedation is achieved in 8 hours. The sedation effect wears off in a couple of days even with repeated administration.
Acuphase is also a fast acting antipsychotic, reaching a maximum serum level in 24-48 hours. Other antipsychotic medications take longer to achieve their antipsychotic effect. The number of times medication has to be administered and the amount of medication administered over the initial six days is therefore reduced considerably. Because of the lower dosing and faster response you see only half the EPS that you would using Haldol or another conventional antipsychotic. There are benefits for the patient and benefits for the hospital staff. Acuphase has been documented to reduce the number of aggressive incidents in the hospitals of Denmark by half. In Ontario it is considered a chemical restraint and can't be used as freely by Schedule 1 facilities.
If governments are able to take advantage of the effective treatment strategies using the new medications, the next generation will not to have to follow in my footsteps. The real gains to be made are in treating someone with atypicals in the first six months of the first psychosis, and preventing relapses caused by noncompliance. One of the saddest truths I've had to face about having schizophrenia, is that nothing to date can undo the damage caused by schizophrenia, once it has happened, and that damage increases with delays in treatment, and with each relapse into psychosis. I think it is realistic to set a standard that no one will ever experience more than one psychosis in their life time, in the same manner that no one expects to ever have two heart attacks. One day they will find a cure for this disease but I think it is more likely that they will find a way to prevent the damage first.