The pharmaceutical industry is the only major component of the mental health
system that is market driven. These are large international corporations that have
to make a profit to survive. A new medication costs $800 million and takes 10 to
15 years to be publicly available. Eli Lilly Statistical Highlights For the
pharmaceutical companies, medications are like racing horses they have bet
heavily on. One drug rep was explaining to me that two will break even in terms
of their development costs, one will lose money, and one will make a profit. Even
though a new medication is patent protected for twenty years, the patent starts at
the beginning of development. That means the window for selling the medication
and making a profit is only about eight years. For some reason pharmaceutical
companies have never been allowed to advertise and market their medications to
the general public. They count on convincing physicians and governments that
their drug is a better drug and worth the cost. These two groups are only
convinced by double blind studies where one group is getting the trial drug and
one is getting a placebo and no one knows who is getting what, until after the trial
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
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
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
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.
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
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.
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
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.
suggestions for compliance
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