Brain & Drugs 

Schizophrenia

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 treatment.

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 changes.

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, 2005.

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 http://www.psychiatrysource.com/psychsource/Congress_Reports/


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