All discussions of schizophrenia should begin with the recognition is that
the diagnosis is often uncertain and covers a range of disorders that have
different causes and different consequences. Few people with the diagnosis
escape drug treatment and psychiatrists generally believe that schizophrenics
have to take drugs every day for the rest of their lives. This is an irrational
belief that obstructs the study of the natural course of the disorder and
prevents the discovery of better methods of management. You can argue two ways:
1. Drugs used to treat schizophrenics are wonderful inventions that control
the disease and allow patients to live in the community.
2. Antipsychotic drugs are chemical straight-jackets that are toxic and leave
patients more disabled than they would have been if no drugs were ever used.
A corollary to argument 2 is that if other solutions were developed for
schizophrenics, such as diet revision and rehabilitation in natural settings,
better long-term results may be achieved.
Phenothiazines were the first drug class available to treat schizophrenia.
They were called “antipsychotics,” “major tranquilizers.” and “neuroleptics.”
Chlorpromazine was the grand-daddy drug and numerous offspring were developed
and marketed. These drugs have multiple modes of action and the antipsychotic
effect is attributed to dopamine blocking. With long term use, drug-induced
Parkinson’s disease is a major, disabling adverse effect. Kapur suggests that
delusions develop when excessive dopamine release occurs in response to mundane
events. Delusions are the stories that patients construct to explain increased
salience of common events. Antipsychotic drugs block dopamine-2 neuroreceptors
and reduce the salience of ordinary experiences: the patient may say that the
government is spying on him, but that it doesn't bother him anymore. Kapur
claims that resolution of symptoms occurs within the first week of antipsychotic
All early antipsychotics inhibit dopamine (DA) neurotransmission by blocking
postsynaptic DA receptors. Other neurotransmitter systems, such as those for
serotonin (5-HT), glutamate, noradrenalin and acetylcholine, are also
implicated, and “atypical antipsychotics” are also antagonists of serotonin
(5-HT) receptors. Blocking DA receptors in some brain regions is also
responsible for negative effects such as Parkinson’s effects and hormonal
In the 1980’s drugs with different chemical profiles and actions appeared and
were often called, “atypical or novel antipsychotics.” Clozapine, olanzapine,
quetiapine and risperidone have all been used to treat schizophrenia. Some
physicians believed that the newer drugs were more effective and safer to use
than the original antipsychotic medications.
A US government study did not
support their view; 1,493 people received one of five drugs: Risperdal, from
Johnson & Johnson; Seroquel from AstraZeneca; Geodon from Pfizer; Zyprexa; and
an older drug, perphenazine. A month's supply of perphenazine costs about $60,
compared with $520 for Zyprexa, $450 for Seroquel, $250 for Risperdal and $290
for Geodon. The study found that at all five reduced the symptoms of schizophrenia,
but three-quarters of the participants stopped taking the drugs because of
little improvement and/or side effects.
In 2002, olanzapine (Zyprexa; Eli Lilly) and risperidone (Risperdal; Janssen)
were the two best-selling atypical antipsychotics in the seven major
pharmaceutical markets, with sales for schizophrenia of US $1.7 billion and US
$1.1 billion, respectively. Among the problems created by these “novel” drugs
are weight gain, hyperglycemia and diabetes 2. Eli Lilly & Company agreed to pay
$690 million to settle about 8,000 lawsuits filed by people who claimed they
developed diabetes and other diseases after taking Zyprexa, used to treat
schizophrenia and bipolar disorder.
Sernyak et al reported: ”A total of 38,632 patients
were included in their study: 15,984 (41.4%) received typical neuroleptics and
22,648 (58.6%) received any atypical neuroleptic (1,207 [5.3%] received
clozapine; 10,970 [48.4%], olanzapine; 955 [4.2%], quetiapine; and 9,903
[43.7%], risperidone; 387 patients received prescriptions for more than one
atypical neuroleptic). When the effects of age were controlled, patients who
received atypical neuroleptics were 9% more likely to have diabetes than those
who received typical neuroleptics, and the prevalence of diabetes was
significantly increased for patients who received clozapine, olanzapine, and
quetiapine, but not risperidone. However, for patients less than 40 years old,
all of the atypical neuroleptics were associated with a significantly increased
prevalence of diabetes. In this large group of patients with schizophrenia,
receipt of a prescription for atypical neuroleptics was significantly associated
with diabetes 2.”
Some continue to suggest that one drug, clozapine is superior but serious
toxicity limits its use. In addition
clozapine has anti-aggressive action that is independent of its benefit in
schizophrenia. Kraus and Sheitman reported that violent patients often require
seclusion and/or restraints and typically receive high doses of medication and
polypharmacy. They found clozapine to be effective in reducing aggression in
patients with psychosis.
Sernyak MJ; Leslie DL; Alarcon RD; Losonczy MF;
Rosenheck R Association of diabetes mellitus with use of atypical neuroleptics
in the treatment of schizophrenia. Am J Psychiatry 2002 Apr;159(4):561-6
Miriam Naheed, Ben Green. Focus on Clozapine.
Curr Med Res Opin 17(3):223-229, 2001
J Neuropsychiatry Clin Neurosci. 2005;17:36-44
Grady MA, Gasperoni, Kirkpatrick P. Fresh from the pipeline:
Aripiprazole .Nature Reviews Drug Discovery 2, 427-428 (2003); doi:10.1038/nrd1114
Berenson, A. Lilly to Pay $690 Million in Drug Suits. NYT June 10,
Dr. Shitij Kapur, MD, PhD, Canada Research Chair, Schizophrenia and
Therapeutic Neuroscience; Speaking at the 157th Annual Meeting of the American
Psychiatric Association. May 2004, New York, NY,USA
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