In the mid 1980’s GlaxoSmithKline began marketing a drug it called Wellbutrin (bupropion) as an antidepressant, and later as an anti-smoking agent dubbed Zyban. In 1986 bupropion was briefly withdrawn from the marketplace due to the high rate of convulsions associated with its use; later, and inexplicably, it was reintroduced to the marketplace.

By 2002 bupropion was recognized as the third most common cause of drug-related seizures (Journal of Emergency Medicine 2002 April; 22(3):235-9J); cocaine was number one.

Bupropion is often placed in the same category as Prozac-type drugs, but its exact mode of action remains unclear after many years of study.

Since 1998, statistics indicated some serious adverse effects were occurring among patients taking the drug. Complaints were flowing in to Health Canada, to the UK regulator and to the manufacturer, and GlaxoSmithKline. GSK received 1127 adverse reports about the drug from Canada alone between May 1998 and May 2001, including 19 deaths.

Meanwhile, the Medicines Control Agency, the UK’s version of the FDA, reported 3,457 adverse reaction reports to the drug, including 18 deaths. Since then there have been 7,500 adverse reactions and 58 deaths in the UK through the end of April 2002.

In 2000, GlaxoSmithKline lodged an application to the Australian Therapeutic  Goods Association to sell bupropion as the anti-smoking drug called Zyban. Australia's "Zyban experience" — an unusual number of reported adverse reactions and deaths — proved similar to the Canadian and UK figures. 1,237 reports of adverse reactions were linked to Zyban, as reported to the TGA through August 31st, 2001, including 18 deaths.

Construction of a comprehensive narrative for this GlaxoSmithKline drug is in the works. In the meantime, the following article links, along with a personal narrative (by Alison Cintorrino), will provide somewhat fragmented but nonetheless compelling insight into the subject matter.

Side-effects Worry over Drug to Quit Smoking
Kicking the Habit: Can Anti-smoking Pill Kill?
Zyban: Is the Cure Worse Than the Craving it Treats?
Zyban Problems?
Debating Zyban's Safety
Family Seeks Probe in Zyban Death
Smokers' 'Cure' may Prove Fatal
Anti-smoking Drug Linked to Death
Hundreds of Adverse Effects to Anti-smoking Drug Zyban Reported
Zyban Linked to Spike in UK Adverse Drug Reactions
Doctors Say Zyban May Be Linked to Deaths
UK Says 57 Die After Taking Anti-Smoking Drug
EU Agency to Review Zyban Smoking Cessation Drug
Wellbutrin/Zyban (bupropion): Medical Reports, Cases & Reviews

The following personal narrative has been edited for content; hyperlinks have been added.

by Alison Cintorrino

Imagine going to your family doctor to get a referral for a stress test. Your blood pressure is high and you have some other minor complaints. Your wife’s uncle is a cardiologist and he suggested that this is what you do. Nothing scary about that. Your doctor tells you that you should not get that stress test. They’re dangerous. Instead, you really ought to stop smoking and there is a pill that can get you to do just that. (You later read in your medical records that you were “counseled strongly” to stop smoking although you were “pre-contemplative” about the whole idea.) He hands you a prescription and heads for the door, saying something about leaving for vacation and running late. You take your first pill later that day because it was prescribed by a licensed medical doctor and its safety and efficacy has been confirmed by the United States Food and Drug Administration. And everyone knows that smoking is bad for your health. Five weeks later you lose your mind. Later on you start losing control of the rest of your body.

Zyban plunged my husband into a nightmare of insanity and physical illness. While caring for my two small boys — and a husband whose behavior came to resemble that of the acid freaks and cokeheads that populated my youth — I began desperately searching for the answers that the “medical profession” had been unable or unwilling to provide.

My uncle who recommended the stress test happens to be a very prominent and extensively published MD and research scientist: a fact that impresses the heck out of a lot of people. (This would hardly be the first time that I imposed upon him for free medical advice, but it would prove to be one of the last.) He had a friend and colleague who was researching Gulf War Syndrome which, as my uncle was quick to recognize, has a strikingly similar list of symptoms to what my husband Anthony was experiencing post-Zyban. This list includes a chemically-induced porphyria that was also often found in people exposed to Agent Orange. I won’t explain porphyria here except to say that it is a serious enzyme disorder. (I had to spell it once for an MD in the emergency department, and I’m lucky I can do that.)

In fact, all of the drug’s victims that I would eventually encounter who were tested for this form of porphyria tested positive. Of course, I was never to hear from this friend of my uncle. By then I was not surprised. I’d learned that most doctors attempt to achieve financial nirvana by repeating the mantra “it’s never the drug, it’s never the drug….”

I was slowly becoming conversational in "Jargon," a language which doctors tend to use — the way my mother and grandmother used Yiddish — to avoid being understood. It was becoming more difficult for doctors, including my uncle, to evade my questions. During one phone conversation I pressed my uncle for information on metabolic pathways and the toxic accumulation of metabolites he responded, “That’s what lawyers are for!” I took the hint. Though at the time I had not yet become aware of the connection between getting published and kissing pharmaceutical company behind, I knew this much: I was on my own.

Prior to this point in my life I had never considered the Internet to be a very useful, let alone vital, source of information. My opinion would undergo a drastic change. I scoured the Internet for information. I came across others who had the same experiences on the same drug as [my husband]. Part of that common experience was the diagnosis of “bipolar disorder” subsequent to their adverse reaction. It seems that everyone who was forthcoming with the details of their Zyban/Wellbutrin experience had been blissfully unaware of the fact that they were suffering from bipolar disorder ... until the drug brought their affliction out of it’s hiding place. Not surprisingly, it seems that most doctors are blissfully unaware of the diagnosis of “Bipolar IV” — drug-induced bipolar disorder.

Ironically, the first person to respond to my "cyber SOS" was the only victim of this drug that I personally know who escaped the “bipolar” label. This was largely due to the fact that her initial reaction to the drug involved dystonia, a movement disorder, which meant that she couldn’t move. She survived on large doses of Valium, which most likely prevented the onset of mania. Having extensive medical documentation of the physical damage that Wellbutrin caused her to suffer she was able to retain the legal services of Thomas Girardi (of “Erin Brockovitch” fame). She since entered into a secret settlement with the drug’s manufacturer, GlaxoSmithKline.

Several years prior to her settlement with GSK this woman had teamed up with Debby Painter, a Michigan wife, mother and smoker who tried to stop smoking using Zyban. This caused her to stop breathing at times. The two women wound up starting a message board and a website offering information to others who found themselves in similar circumstances.

In April of 2000 they were contacted by Thomas Hatfield, a Ph.D. environmental chemist at 3M Corp. Hatfield had used Zyban (a.k.a. Wellbutrin) to stop smoking and wound up with a heart attack, a diagnosis of bipolar disorder, two additional inches in height, and an assortment of painful and disturbing side effects that didn’t seem to be going away.

With access to 3M’s state-of-the-art equipment Hatfield began testing blood and pill samples donated by those who had been experiencing adverse effects of the drug far longer than the manufacturer would admit was possible. What he found was metabolites (substances produced by metabolism) of the drug in blood drawn months and even years after the sample donor had taken their last pill. Some of the pills he tested contained more impurities and degradation products than “active ingredient” (bupropion). He suggested a possible cause for the unexpectedly high levels of impurities:

"Zyban is manufactured for Glaxo-Wellcome by Catalytica Pharmaceuticals. Although Catalytica’s address is given as Greenville, North Carolina, only a small office is maintained at that site. Zyban is actually manufactured in Italy at a facility owned by Catalytica. As recent as May of 2000 Catalytica, under contract with Glaxo, was sent a warning letter from the FDA regarding unsafe sanitation practices. They weren’t cleaning up one production batch to specifications before beginning production of the next."

Addressing the issue of instability and degradation, Glaxo has since submitted several patent applications for bupropion with a stabilizer. One patent application reads “It is clearly again seen that even at low temperature there is sizeable degradation.” After compiling all his data, Hatfield submitted his findings to the FDA.

Debby Painter and I have since requested FDA documents through the Freedom of Information "It’s OK For You to Have" Act. We eventually received the FDA’s MedWatch data on Wellbutrin from 11/01/97 through some unspecified time up until February 2003 (the date on the attached letter). The FDA made every attempt to avoid being specific. They also did not specify which formulations of Wellbutrin these reports referred to. The report I received listed 37,822 total adverse reactions and “total death outcomes” of 468, which I’m assuming included my personal favorite: 16 reports of “pulse absent.” There were 202 reports of “completed suicide” and 152 suicide attempts listed as such, although others were given more euphemistic designations like the 216 “non-accidental” overdoses.

Bear in mind when discussing MedWatch statistics that — according to the FDA — they only represent between 1% and 10% of the actual numbers. Most people never heard of MedWatch, and doctors are not inclined to spend their valuable time making MedWatch reports or informing you of its existence.

I filled out a MedWatch report for my husband and checked off the box on the form that said I do not want the FDA to give my information to the manufacturer. (I later received a lovely letter from GlaxoSmithKline expressing their regret upon learning of my husband’s experience and asking that I have him sign a release form so that they can access his medical records for the advancement of science and the good of all mankind.)

We eventually received very abbreviated and much redacted copies of portions of the NDAs (New Drug Applications) for all Wellbutrin formulations, the last one arriving over a year after the FDA received the request. The Wellbutrin IR (immediate release) NDA documented 14 deaths, including 9 suicides, in the initial clinical trials. There were also 14 suicide attempts. Glaxo reported to the FDA that these “adverse events” were “not attributable to the study drug” and that was good enough for the FDA. Somehow these “events” (deaths) never appeared in the Product Information Guides (PIGs) or the PDR (Physician’s Desk Reference) under “warnings and precautions” or “adverse reactions” which is supposed to include all adverse events observed during clinical trials — not just those that the company decides that it’s o.k. for us to know about. However, being masters in the art of covering their corporate butt, Glaxo nonchalantly tossed this disclaimer into the PIG: “all treatment emergent adverse events are included except ... those events not reasonably associated with the use of the drug....” So, you have 23 non-suicidal people (suicidal people were excluded from participating in these antidepressant drug tests) who "coincidentally" take the same experimental drug and "coincidentally" wind up wanting to kill themselves.

In September of 2004, with the statute of limitations running out, I filed suit against Glaxo as a pro se plaintiff, in other words — without a lawyer. I filed my complaint in the Supreme Court of New York State and included Hatfield’s findings. GSK’s lawyers had the case moved to federal court where I would be required to provide expert testimony. Hatfield, a colleague and his superiors at 3M were subsequently contacted by Glaxo’s lawyers who seemed very interested in what Dr. Hatfield might know. 3M said that none of Hatfield’s research into bupropion took place at 3M.

When a patient is given a drug “everything is a crap shoot” according to SmithKline Beecham executive George Poste. Adverse drug reactions are the 4th largest cause of death in this country. It’s only #4 because most drug reaction deaths are blamed on something else, like suicide or heart attack or "lack of a pulse." If that statistic isn’t disturbing enough here’s a fact that’s more disturbing: pharmaceutical companies know how to prevent many of these deaths but they’re not telling you — pharmacogenetics.

Included in my Complaint against GSK is that my husband has a genetic polymorphism of the CYP450 enzyme system. This means that a gene that controls an enzyme that breaks down, or metabolizes, certain chemicals so that they can be eliminated from the body is defective. If a chemical/drug is not metabolized properly it can accumulate in the body, potentially reaching toxic levels. Glaxo funded research on pharmacogenetics* (how genetics affect drug metabolism) prior to my husband’s adverse event. About 10% of the population are likely to experience the toxic effects of this drug up to, and including, death. Now I know it, too ... I found out the hard way.

Morality dictates that this ability to predict whose life would be at greatest risk would be used to prevent tragedy. Economics dictates that you don’t intentionally scare off 10% of your customers. In corporate America economics trumps morality. Being a fiscally responsible corporate entity with their eye on the bottom line, Glaxo has used their genetic know-how to weed volunteers out of their clinical trials who might screw up their numbers by, say, going insane or dying. Then they gladly sell their toxic concoctions to 100% of their potential customers.

Recently, Allen Roses, Glaxo’s own Worldwide Vice President of Genetics, made this statement: “The vast majority of drugs — more than 90% — only work in 30-50% of the people.” He chose not to go into detail about what happened to everyone else.

At an FDA Science Advisory Board meeting on the subject of pharmacogenetics a “representative of industry” (pharmaceutical company executive), Dr. Shine, posed the question to Dr. Janet Woodcock of the FDA “First of all, just for clarification, Janet, when you made the statement ‘free exchange of data’ I presume that means between the FDA and industry, and that it doesn’t mean that it goes on the web?” Dr. Woodcock eventually replied “To answer your question, no.”

Search the FDA for bupropion.

*A New Era in Drug Development: Legal and Ethical Implications of Pharmacogenomics (RTF document)