Dear Yola:
I agree with everything you are saying. I'm sorry if you inferred that I didn't believe you about poor metabolism being the reason some people are affected more than others by antidepressants and anti-psychotics.
I have no doubt that I had akathisia from being overdosed with both antidepressants and antipsychotics. I am disappointed that my doctor never informed me about it and I only discovered it on my own by chance.
Some of the other undesirable side-effects which were debilitating for me were sexual dysfunction and inability to sleep. It only made me more depressed.
Thank goodness I was able to take myself off these drugs after taking them for almost 3 years without actually having completed suicide.
cheers,
bob47

I believe that genetic metabolism is absolutely a factor in ADRs, but I don't understand it very well. Does that mean that a drug/chemical is only toxic to people who cannot metabolize it, but that it doesn't have any toxicity to others? Is it safe for anyone that can metabolize it, ie, it isn't toxic generally?

How far away is a drug that can cause sometimes fatal ADRs to anyone who cannot metabolize it, to a substance like arsenic or cyanide that presumably is toxic to anyone/everyone. Is cyanide only toxic because nobody has the enzymes that can metabolize it?

The whole issue of the line between toxicity and genetic predisposition puzzles me a little in that way. Can anyone explain?

How do we get the whistleblower out of coventry?

November 17, 2008

FDA Finds Zyprexa Has Killed 3,400 People, Worse Than Vioxx
I was reviewing an FDA staff document this morning, wherein FDA staffers recommend additional warnings for Zyprexa for pediatric cases (ie, teens) and ran across a startling statistic. According to the agency's own adverse events database summarized in the report, the controversial atypical antipsychotic has killed 3,455 people (see page 7 of the above document) between 1997 and early 2008.

Roughly half of the deaths are known to have occurred in the US while the remainder are from unidentified locations (likely a mix of US and foreign deaths).

What startles me is that last fall I reported on a study of the FDA's adverse events database in which researchers reported that Zyprexa had killed 1,005 people from 1998 to 2005, so this new accounting represents a large increase in deaths associated with the drug. Even more, according to that same study, Vioxx had killed 932 people. So why do Vioxx cases get all the media attention while Zyprexa does not? Why is Zyprexa still on the market and raking in $4 billion or so a year in sales while Vioxx is off the market?

Why on earth has this drug been marketed for casual use far beyond its initial use as an antipsychotic?

As of now, Zyprexa is not approved for use in children and teens, but Eli Lilly has an application before the FDA to gain approval for its use in teens diagnosed with schizophrenia. Amazingly, one published study of Zyprexa in teens found that in a three-week trial of the drug patients gained an average of eight pounds, which is a lot for such a short time period. That's why the FDA staff in the above document is recommending additional warnings about weight gain in pediatric populations.

(Via Pharmalot.)

Since you asked

Characterization of Metabolic Types CYP450 enzyme-mediated drug metabolism displays wide interindividual variability. Most variants result in synthesis of enzymes that are diminished or devoid of metabolic activity or result in increased activity.

Extensive Metabolizers (EM) the normal genotype—is free of inactivating polymorphisms‚ deletions‚ or duplications. In Caucasian populations‚ EM is the most common genotype. Current drug dosing recommendations typically assume that the patient is an extensive metabolizer and can tolerate a standard dose.

Poor Metabolizers (PM). These have 2 inactivating mutations, which may be in one or two genes. Severity varies among those with a PM genotype. Most lack a functional enzyme. They receive no therapeutic benefit from drugs that are activated by CYP450 metabolism. Additionally‚ deficient enzyme function may result in an inability to clear medications‚ which may lead to toxicity and serious to sometimes life threatening side effects.

Intermediate Metabolizers (IM) these individuals have 1 normal allele and 1 allele with an inactivating polymorphism. Individuals with an IM genotype demonstrate a wide range of levels of enzyme activity. Some produce sufficient functional enzyme‚ others do not. IMs are particularly susceptible to the residual functional CYP450 enzyme being totally abolished by other drugs or metabolites, if they inhibit CYP450. Individuals with an IM genotype become poor metabolizers (phenotype) in response to a “second hit” by a CYP450 inhibitor or environmental factor.

Ultra rapid Metabolizers (UM) These individuals are rare among Caucasian but psychiatrists think they are the majority, judging from how they prescribe more not less when the drug is ineffective. The have gene resulting in too fast metabolism. UM metabolizer genotypes have been found for the CYP2D6 and 2C19 (*17) enzyme. The drug may be rapidly cleared and not reach therapeutic levels so response is poor or nonexistent. However, if the first metabolite is toxic or even active and it needs a CYP450 enzyme that is already in short supply, or being used up or inhibited, toxic side effects are the outcome. UM patients are almost always non-responders to antidepressants and some other drugs. They have problems in withdrawal as blood levels change too fast.

Good to see the very important issue of cytochrome P-450 raised.
Convinced that this is DNA damage triggered by pharmaceutical, industrial and agricultural chemicals that target the mitochondria and the protein forming enzymes, of which CYP450 is an important part.
In Gulf War Syndrome and Organophosphorus poisoning cases changes are seen in the CYP450 suggesting in the former caused by exposure to toxins but in the latter explaining genetic susceptibility to the chemicals, known to damage both DNA and the mitochondria, which are also vital to cardio-respiratory function, cell reproduction and cell death.
We interfere with these vital functions at our peril.

Cindy Duehring (1996) - cytochrome P450 enzymes are critical to human metabolic function as well as the detoxification and metabolism of the majority of chemicals…. in spite of the magnitude of their significance, the typical biochemistry textbook devotes at most one page to this important enzyme system…. 2,000+ studies each year are published on some aspect of P450 research… Over 400 P450 enzymes have been identified in living systems' including plants and animals,… research indicates over 40 different P450s can be expressed in a single mammalian species. Research into cancer prevention is just one area of P450 research. Because of the P450s' role in detoxification, .. research on the manipulation of P450s for cancer prevention and/or cancer treatment has been growing considerably.

Impaired or disrupted P450 enzyme activity has widespread ramifications in the body…play a vital role in numerous biological activities, including production and metabolism of steroid hormones …and fatty acids…. P450-dependent substances are involved in neurotransmission and central nervous system metabolism, blood clotting blood flow, gastrointestinal function and activity, cardiovascular and hematological metabolism,
carbohydrate and fat metabolism, electrolyte balance arid muscle activity, pancreatic endocrine function, anti-inflammatory activities, and glucose metabolism.....
.. a person's individual P450 makeup or status, one person may be able to handle 40 times the amount of a particular chemical than another person. The person with lesser detoxification capacity would experience the toxic effects of the chemical at a level that would seem ludicrously small to the one who could handle the large amoun