Fda @ MindSay

Anyone out there heard of this or used it before?  What do you think?

 

http://mastercleansesecrets.com/blog/stevia/stevia-the-natural-sweetener-the-fda-doesnt-want-you-to-know-about/61/

 

Mary had a little lamb / And when she saw it sicken / She shipped it off to Packingtown / And now it’s labeled chicken.”

That little ditty famously summarized the message of “The Jungle,” Upton Sinclair’s 1906 exposé of conditions in America’s meat-packing industry. Sinclair’s muckraking helped Theodore Roosevelt pass the Pure Food and Drug Act and the Meat Inspection Act — and for most of the next century, Americans trusted government inspectors to keep their food safe.

Lately, however, there always seems to be at least one food-safety crisis in the headlines — tainted spinach, poisonous peanut butter and, currently, the attack of the killer tomatoes. The declining credibility of U.S. food regulation has even led to a foreign-policy crisis: there have been mass demonstrations in South Korea protesting the pro-American prime minister’s decision to allow imports of U.S. beef, banned after mad cow disease was detected in 2003.

How did America find itself back in The Jungle?

It started with ideology. Hard-core American conservatives have long idealized the Gilded Age, regarding everything that followed — not just the New Deal, but even the Progressive Era — as a great diversion from the true path of capitalism.

Thus, when Grover Norquist, the anti-tax advocate, was asked about his ultimate goal, he replied that he wanted a restoration of the way America was “up until Teddy Roosevelt, when the socialists took over. The income tax, the death tax, regulation, all that.”

The late Milton Friedman agreed, calling for the abolition of the Food and Drug Administration. It was unnecessary, he argued: private companies would avoid taking risks with public health to safeguard their reputations and to avoid damaging class-action lawsuits. (Friedman, unlike almost every other conservative I can think of, viewed lawyers as the guardians of free-market capitalism.)

Such hard-core opponents of regulation were once part of the political fringe, but with the rise of modern movement conservatism they moved into the corridors of power. They never had enough votes to abolish the F.D.A. or eliminate meat inspections, but they could and did set about making the agencies charged with ensuring food safety ineffective.

They did this in part by simply denying these agencies enough resources to do the job. For example, the work of the F.D.A. has become vastly more complex over time thanks to the combination of scientific advances and globalization. Yet the agency has a substantially smaller work force now than it did in 1994, the year Republicans took over Congress.

Perhaps even more important, however, was the systematic appointment of foxes to guard henhouses.

Thus, when mad cow disease was detected in the U.S. in 2003, the Department of Agriculture was headed by Ann M. Veneman, a former food-industry lobbyist. And the department’s response to the crisis — which amounted to consistently downplaying the threat and rejecting calls for more extensive testing — seemed driven by the industry’s agenda.

One amazing decision came in 2004, when a Kansas producer asked for permission to test its own cows, so that it could resume exports to Japan. You might have expected the Bush administration to applaud this example of self-regulation. But permission was denied, because other beef producers feared consumer demands that they follow suit.

When push comes to shove, it seems, the imperatives of crony capitalism trump professed faith in free markets.

Eventually, the department did expand its testing, and at this point most countries that initially banned U.S. beef have allowed it back into their markets. But the South Koreans still don’t trust us. And while some of that distrust may be irrational — the beef issue has become entangled with questions of Korean national pride, which has been insulted by clumsy American diplomacy — it’s hard to blame them.

The ironic thing is that the Agriculture Department’s deference to the beef industry actually ended up backfiring: because potential foreign buyers didn’t trust our safety measures, beef producers spent years excluded from their most important overseas markets.

But then, the same thing can be said of other cases in which the administration stood in the way of effective regulation. Most notably, the administration’s refusal to countenance any restraints on predatory lending helped prepare the ground for the subprime crisis, which has cost the financial industry far more than it ever made on overpriced loans.

The moral of this story is that failure to regulate effectively isn’t just bad for consumers, it’s bad for business.

And in the case of food, what we need to do now — for the sake of both our health and our export markets — is to go back to the way it was after Teddy Roosevelt, when the Socialists took over. It’s time to get back to the business of ensuring that American food is safe.

Can there be a connection between more frequent food illness outbreaks and the funding of government agencies?

 

From the article on CNN.com from May 18,2007:  http://www.cnn.com/2007/HEALTH/05/17/food.safety.law/index.html

 

"Critics point to the FDA, in particular, as needing reform. The FDA oversees 80 percent of the food supply but receives only 20 percent of the funding.

"I call it 'Katrina on your plate.' You've got an agency, the FDA, that's understaffed, under-funded, without leadership, and it's not doing its job. And it's causing a real life suffering and death for people," said Andrew Kimbrell, director of the Center for Food Safety, a nonprofit watchdog group in Washington.

By the FDA's own accounting, the agency is operating under a $135 million shortfall. Since 2003, the FDA has cut field staff (inspectors and their support staff) by 12 percent, from 2,217 to 1,962. Inspections dropped 32 percent during the same period, according to FDA budget documents."

The United Kingdom's National Institute of Clinical Excellence ("NICE"), citing cost (about $40,000 per patient) has decided that their National Health Service will not provide Avastin, a endothelial growth factor inhibitor, to patients with metastatic colon cancer. NICE might be right.

 

Cancer treatment philosophy is veering from Archimedes Hammer (“Give me a place to stand and a big enough hammer and I will crush the cancer”) to a paraphrased Ghandi’s Admonition (“Response attained by violence is tantamount to a defeat, for it is momentary”).

 

“Some cancer experts believe that targeted therapies might eventually be used in combination to hold cancer at bay indefinitely, turning the disease into a chronic condition instead of a likely death sentence,” is how the Wall Street Journal described this transformation.(1) Now that one such biological therapy, Iressa, (a tyrosine kinase inhibitor with similar action to Avastin, though with a different target) has been reported not to show any survival benefit after a small trial had showed one which had led to “fast track” FDA approval), it may be time to carefully wonder if much of the “progress” claimed for new “blockbuster targeted biologicals” is really an illusion. Iressa's FDA approval has now been severely curtailed so that it is basically not available to new patients in the U.S.

 

One of many potential 1.5 billion dollar questions about these newer, gentler, targeted treatments was addressed in the New England Journal of Medicine report on the use of Avastin coupled with chemotherapy for advanced colon cancer: Does targeted therapy improve outcome?(2)

 

A NEJM editorialist answered: “The study unequivocally demonstrated the superiority of IFL plus bevacizumab [Avastin/IFL] to IFL [chemotherapy] alone in terms of median overall survival….” (3)

“Unequivocal” is a word that should be used very judiciously in science.

 

At the risk of being mistaken for H. L. Mencken’s cynic (“A cynic is a man who, when he smells flowers, looks around for a coffin”), I cannot unequivocally agree with this conclusion for three reasons: First, the NEJM report omits the outcomes for over 10% of the patients enrolled (and probably a larger percent of events); second, the Avastin/IFL group got about 30% more IFL chemotherapy than the IFL chemotherapy alone group and Avastin responders continued to receive study treatment beyond 96 weeks while the chemotherapy responders did not; and third, the trial design assumes that response (i.e., tumor shrinkage) is always required for survival benefit.

 

The clinical trial here in question was really two experiments with one left unreported. The first experiment was a kind of phase 2 trial where the toxicity of three regimens was compared. After about the first 100 patients were allocated to each of three arms, an analysis was performed. This analysis apparently revealed that unspecified limits for toxicity of the Avastin/IFL were not exceeded. As a result, the Avastin/FL arm was dropped, and results for these 100 patients were not reported. The rationale for this scheme is understandable. The trial was funded by the Avastin manufacturer, but the potential $1.5 billion in sales is a secondary gain when compared with improved cancer outcomes. Speedy answers are nice, but science abhors short cuts. Failure to report results on this group defies a basic principle of clinical trials: accounting for all enrolled patients. This “selective” censoring was prospectively planned, but was selective and non-random just the same.

 

An earlier small study of Avastin/FL versus FL chemotherapy alone showed a slightly greater differential survival advantage for the Avastin/FL group (21.5 months versus 13.8 months = 7.7 months) than the corresponding difference between Avastin/IFL versus IFL (20.3 v 15.6 months= 4.7 months), with the absolute survivals very similar.(4) Furthermore, this earlier study permitted FL failures to cross over to Avastin, which might tend to minimize differences if Avastin is active alone. Curiously, the Avastin/IFL trial did not permit such crossovers, while permitting Avastin patients to continue the drug. (This is an arcane point: apparently events were recorded beyond the 96 week “study period”. This must be so because the life table shows a curve extending to 32 months (128 weeks). The report alludes to a “separate extension study” but some effects of the extension are included in the current report.)

 

No large body of evidence supports a conclusion that IFL chemo is better than FL chemo when combined with Avastin. What occurred in the trial here under discussion was basically a race between IFL and two other horses from the Avastin stable, with one Avastin horse to be disqualified at the quarter pole. All devotees of the “Sport of Kings” know that horses don’t pay off on results at the quarter pole. We should at least have been told if the disqualified arm was in the win, place, or show position when scratched. The trial design was to disqualify one or the other Avastin regimens based on possible toxicity, but with a clear bias toward Avastin/IFL, which would win a tie. (This first decision was to decide no difference in toxicity – a null hypothesis with a potentially very large type II error given the small numbers and short follow up). This is the classis “absence of proof is not proof of absence" fallacy.

 

Some will argue that dropping 100 patients out of 900 is not quantitatively significant, regardless of the theoretical arguments about the validity of statistical inference. But dropping 100 of the first 300 in a trial to be analyzed based on a log rank test may be a big deal, since events (progression and/or death) are more important than numbers enrolled. Obviously, the first 300 patients will suffer many more events than the last 300 during the study period. Therefore any confounding of the results based on this early censoring, whether due to bias or random effects, could be meaningful. For example, oxaliplatin chemotherapy was approved for colon cancer by the FDA in August 2002 in the US, and would have been available to later enrolled patients who had progression, and a larger number of stable Avastin patients or upon progression of their tumors.

 

A second concern is that the Avastin/IFL group got 30% more IFL chemotherapy than the IFL group, and more overall study therapy. To be precise, the Avastin/IFL group got 12.8 weeks more of IFL treatment and achieved an 18.8 week survival advantage. In addition, many Avastin/IFL patients continued to receive Avastin after IFL. IFL responders apparently got no additional therapy, not even Avastin, as part of the study.

 

Why could this matter? Patients with progression based on x-ray imaging were deemed failures and treatment was stopped. Much of this x-ray imaging was based on computerized axial tomogram scans that depend in part on a contrast agent that arrives to the tumor by blood vessels – Avastin affects blood vessels. Also, a “time to response” bias could lurk here. Progression assessment was a “one and done”, whereas response required a 4 week confirmation (a tacit admission of the imperfections inherent in these determinations). Therefore two treatments with ultimately equal survival outcomes but different times to response could put the patients in the “slow” response group at greater risk for a “false positive” determination of progression, and therefore premature termination of ultimately effective treatment. Irinotecan (the “I” in IFL) is known to produce delayed responses. The median time to response according to the package insert is about 10 weeks.

Avastin conceivably could hasten response to IFL or alter the x-ray measurement of tumor and still have no effect on survival. Remember, “salvage therapy” was not standardized as to type or timing. One arm may have received more salvage therapy with different timing. This asymmetry of treatments forced by the trial design (fatally?) damages the science.

 

My third reservation is that the trial in question was designed around what might be an obsolete assumption: response is necessary for survival benefit. The enormously successful and decades old leukemia and lymphoma treatment model holds that complete response (i.e., remission) is required for cure, and this drove the “bigger hammer” approach to solid tumors. The apex (nadir?) of this approach may have been reached in the now largely discredited (because of scientific fraud in South Africa) stem cell “rescue” from otherwise lethal chemotherapy for breast cancer. A corollary to this model gave temporary popularity to the now thoroughly discredited “responder/non-responder” survival comparisons (studies without a “control” arm) contained in most alphabet soup chemotherapy clinical trials of 25 years ago.

 

Inherent in the logic of the Avastin/IFL trial is the assumption that response is a mandatory way point along all roads to benefit. Remember this dictum has its origins in the notion that response precedes remission, which is required for cure. This fixation on “objective” response can introduce many kinds of confounding influences and biases. Even beyond that, an overweening focus on x-ray imaging response may cause researchers to lose sight of the important clinical end points that relate to quality of life.

 

I am not one who would argue that a treatment that prolongs median survival by a few months is inconsequential. When skeptical patients and their family members question the wisdom of embarking on such treatments, I remind them of the statistician who drowned in a river with an average depth of six inches. A treatment that produces a small net benefit to a large group might shorten the lives of a few members by toxicity, and improve the survival of some members by a substantial time. The way we quantify these benefits is an imperfect science. I cannot help but notice that the two survival curves in the Avastin/IFL trial come back toward an agonizing intersection a scant 24 months after the start of treatment.

 

The US FDA may need to re-think it’s fast track approval for drugs like Avastin and Iressa in light of the recent experience with Iressa. (FDA: Considering Regulatory Action On Iressa, WSJ Dec 17, 2004). These drugs were studied in a few hundred patients prior to approval. Vioxx was studied in many thousands of patients before heart problems came to the attention of the public, ironically in part due to a trial that shows Vioxx might prevent cancer.

 

A numerical description can be fashioned to calculate when costs and toxicities balance benefits. However, determining the exact point to place the fulcrum for this balance beam is a vexing exercise, and cannot be accomplished by paraphrasing historical maxims.

 

Even Joseph Stalin may have grasped the concept, if not the ethics, when he said: “A single death is a tragedy; a million deaths is a statistic.”

 

1) Hamilton DP: THE WALL STREET JOURNAL; June 7, 2004; Page B6

2) Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.

3) Mayer R. Two Steps Forward in the Treatment of Colorectal Cancer. N Engl J Med 2004;350:2406-2408.

4) Kabbinavar F, Hurwitz H, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60-65.

5) N Engl J Med 2004;350:2335-2342

What I am about to post is a clear revelation to me, not only as a voter and taxpayer to the power of the pharmaceutical lobby in politics, but to me as a patient, vulnerable in their suffering from depression, who trusted their doctor and the drugs they prescribed to help me when I needed it most.  I openly admit that I have been diagnosed with depression for the purposes of informing others of the effects of the drugs I have taken. Hopefully it will not go unheeded: Clinical depression affects about 7% - 18% of the population before the age of 40.  Personally, I know at least 6 people in my family and friends alone that have also taken antidepressants at some time in their lives or are still taking them. 

Coping with depression and treatment is difficult. I have experienced some stigma associated with taking the drugs, including having to leave a job because my admitting to being treated with drugs caused undeserved skepticism about my performance and general mental capacity (in general, prejudice).  I have had to convene with many university officials and associate deans in order to attempt to explain poor performance in school influenced directly by side effects caused by the potency of the drugs, and in these meetings was accused openly of being ill prepared for life's demands or basically proposing an excuse for my poor performance.  The only time I have ever done poorly in school was during my time under treatment with antidepressants. Not only that, but the multi-year treatment with the drugs has of course inflicted many side effects, including some that rendered necessary a trip to the Emergency Room.  Subsequently, the additional suffering I've dealt with over the years came to me unexpectedly, as I was never informed of the extent of these side effects; furthermore, now that I wish to end my treatment with antidepressants, I was ill-informed on how to go off of them and the often debilitating withdrawal symptoms to accompany cessation of the drugs. 

I wanted to post the following for any of you who have ever taken or considered taking an antidepressant drug.  I do not want to be fully negative and say that these drugs are not at all beneficial; in fact, they probably saved my life when I first began to take them.  However, I believe without proper warning about their potential side-effects and the severe withdrawal symptoms that may occur when stopping the drug when taken on a long-term basis, that they have wrought and will continue to cause untold harm to the patients who need them, including myself. These drugs need to be carefully considered before a program is began.  According to recent studies, the diagnostic criteria for depression are far too broad, leading to people who are not truly clinically depressed being diagnosed due to a normal reaction to negative events. However, most importantly, the information on their powerful effects needs to be openly provided.  Below, I have provided the checklists of both side effects and withdrawal symptoms, and reported my own experiences.  If I experienced these symptoms, I will mark it with an asterisk. I will add more asterisks depending on the severity--the more asterisks, the more severe the side effect or withdrawal symptom.This long list is to provide fair warning to any who would consider these drugs lightly.

CHECKLIST OF ANTIDEPRESSANT SIDE EFFECTS
(my note: These are often mistaken for a worsening of the patient's underlying psychiatric condition, which then causes doctors to prescribe more of the drug to 'treat it', often making the side effects worse)

Side effects that may make patients suicidal:
Insomnia**
Anxiety/panic attacks*
Akathisia (drug-induced agitation or aggression)*
Irritability/hostility/impulsivity (disinhibition)
Mania-like reactions (rapid speech, racing thoughts, distractibility, reckless behavior, delusions) (often mistaken for undiagnosed Bipolar Disorder)
Paranoid reactions
Psychotic reactions (delusions, hallucinations)

CHECKLIST OF ANTIDEPRESSANT WITHDRAWAL SYMPTOMS:
(my note: withdrawal symptoms are experienced when the patient accidentally misses a dose, lowers their dosage, or tries to stop the drug too quickly or abruptly)

Psychiatric Symptoms

That Mimic Depression:

1. Crying spells**
2. Worsened mood*
3. Low energy (fatigue, lethargy, malaise)***
4. Trouble concentrating*
5. Insomnia or trouble sleeping*
   
6. Change in appetite
7. Suicidal thoughts**
8. Suicide attempts

That Mimic Anxiety Disorders:

9. Anxious, nervous, tense*
10. Panic attacks (racing heart, breathless)**
11. Chest pain
12. Trembling, jittery, or shaking*

Irritability and Aggression:
13. Irritability*
14. Agitation (restlessness, hyperactivity)
15. Impulsivity
16. Aggression
17. Self-harm**
18. Homicidal thoughts or urges

Confusion and Memory Problems:
19. Confusion or cognitive difficulties
20. Memory problems or forgetfulness

Mood Swings:
21. Elevated mood (feeling high)
22. Mood swings
23. Manic-like reactions

Hallucinations:
24. Auditory hallucinations
25. Visual hallucinations

Dissociation:
26. Feeling detached or unreal**

Other:
27.  Excessive or intense dreaming***
28. Nightmares**

Medical Symptoms:

That Mimic the Flu:
29. Flu-like aches and pains
30. Fever
31. Sweats
32. Chills
33. Runny nose
34. Sore eyes

That Mimic Gastroenteritis:
35. Nausea
36. Vomiting
37. Diarrhea
38. Abdominal pain or cramps*
39. Stomach bloating

Dizziness:
40. Disequilibrium
41. Spinning, swaying, lightheaded***
42. Hung over or waterlogged feeling***
43. Unsteady gait, poor coordination*
44. Motion sickness

Other:
45. Headache***
46. Tremor

Sensory Abnormalities:
47. Numbness, burning, or tingling
48. Electric zap-like sensations in the brain
49. Electric shock-like sensations in the body** (in my case, it was around my eye socket)
50. Abnormal vision sensations
51. Ringing or other noises in the ears
52. Abnormal smells or tastes

Other:
53. Drooling or excessive saliva
54. Slurred speech*
55. Blurred vision
56. Muscle cramps, stiffness, twitches
57. Feeling of restless legs
58. Uncontrollable twitching of the mouth

These can be anywhere from mild or moderate to severe.


Even for those of you have not or never will experience debilitating depression or anxiety, the widespread corruption and sway pharmaceutical companies hold over medical information and legal regulation is something we should all know, if only to try to stem the tide, and make informed decisions when voting for candidates that may stand a chance of opposing this dangerous trend.

The following article is lengthy, but I assure you it is eye-opening. Thank you to any who read this and understand my predicament and the predicament of millions of consumers of antidepressants in this country alone.


From The Antidepressant Solution, by Joseph Glenmullen, M.D.

This should never have needed to be written.  When Paxil was introduced, GlaxoSmithKline reported that withdrawal reactions are "rare" with the new drug, which became a multibillion-dollar-a-year best seller.  When Zoloft was introduced, Pfizer made a similar claim that withdrawal reactions are "rare" with its best selling drug.  For perspective, keep in mind that officially the pharmaceutical industry itself defines rare side effects as occuring in less than one patient in a thousand, or .01 percent.  Paxil and Zoloft have since been shown to cause withdrawal reactions not in .01 percent but in 66 percent and 60 percent of patients, respectively.  How could pharmaceutical companies with their vast scientific and financial resources have been so wrong?  How could companies miss withdrawal reactions that occur in 66 and 60 percent of patients so egregiously that they claimed they occurred in only .01 percent of patients?

When pharmaceutical companies test new antidepressants to win FDA approval, withdrawal reactions are typically not evaluated.  The studies usually only last six to eight weeks, a remarkable fact given that patients subsequently take the drugs for years, even decades.  At the end of the six to eight weeks,  the studies are over when the patients take their last dose.  Since the studies are over, withdrawal symptoms are not assessed after the patients stop taking their drugs.  This is sometimes referred to as the "Don't ask and you won't know" approach to evaluating--or, more accurately, not evaluating--side effects.  That is how the companies were able to declare that withdrawal side effects rarely occur in patients.  Elsewhere in the fine print of their official information on the drugs, the pharmaceutical companies note that dependence has "not been systematically studied."

Why would pharmaceutical companies not want their drugs to be associated with withdrawal reactions?  The answer is: Withdrawal implies dependence and addiction.  In fact, in the modern era virtually all blockbuster psychiatric drugs have fallen on the sword of withdrawal, dependence, and addiction, along with other serious side effects.  The drugs include Valium-type anti-anxiety agents, barbiturates, amphetamines, narcotics, and cocaine (originally a popular prescription drug, as described below).  With Valium-type anti-anxiety agents, the last best sellers prior to today's best-selling antidepressants, by the 1990s pharmaceutical companies and the profession had learned the general principle that psychiatric drugs with short half-lives cause worse withdrawal and dependence.  Withdrawal, dependence, and addiction have been the side effect that has plagued blockbuster psychiatric drugs.  Why did we have to spend over a decade relearning this with today's antidepressants while countless patients and their families suffered?

Of the earlier classes of popular psychiatric drugs, today's antidepressants are most closely related to cocaine.  A little over a hundred years ago, cocaine was the first prescription antidepressant of the modern era.  In the late 1800s and early 1900s, cocaine was the most popular prescription medication in Europe, prescribed for everything from depression to shyness, just as today's antidepressants are.  At the turn of the century, Freud wrote three famous "cocaine papers" extolling cocaine's benefits.  At the height of its popularity, cocaine was [of course] the essential ingedient in Coca-Cola, which is named after cocaine.  It took pharmaceutical companies decades to acknowledge cocaine's dangerous side effects, including severe withdrawal reactions and addiction.  Only afterwards did caffeine replace cocaine in Coca-Cola.

Surprisingly, cocaine is a "reuptake inhibitor" that increases the signals of three "feel good" neurotransmitters, or chemical signals, in the brain: serotonin, dopamine, and noradrenalin, the form of adrenalin found in the brain.  I say surprisingly, because as seen in the following data A.1, today's popular antidepressants are promoted as also increasing one or more of these closely related "feel good" signals.  Indeed, most of today's antidepressants boost these signals by the same principle mechanism as cocaine.  Like cocaine they are "reuptake inhibitors."  The first of today's popular antidepressants, Prozac,  boosts serotonin and is marketed as a selective serotonin reuptake inhibitor, or SSRI.  The next one, Zoloft, boosts serotonin and dopamine.  Effexor boosts serotonin and noradrenalin; it is marked as a serotonin and noradrenalin reuptake inhibitor, or SNRI.  Wellbutrin boosts dopamine. Many patients are prescribed "cocktails" or two or three antidepressants, such as Effexor and Wellbutrin, which together boost all three neurotransmitters, much like cocaine.  All of the drugs listed in the following data A.1 have secondary effects on other neurotransmitters that are not fully understood.  None of the drugs are identical to one another but they are closely related in their mechanisms of action and effects on brain chemicals.

Data A.1 Comparison of Cocaine with Today's Antidepressants
                   
Cocaine - Serotonin, Noradrenalin, Dopamine
Prozac - Serotonin
Zoloft - Serotonin, Dopamine
Paxil - Serotonin
Luvox - Serotonin
Celexa - Serotonin
Lexapro - Serotonin
Effexor - Serotonin, Noradrenalin
Cymbalta - Serotonin, Noradrenalin
Serzone - Serotonin, Noradrenalin
Wellbutrin - Dopamine
Remeron - Serotonin, Noradrenalin
"Cocktail" of Wellbutrin and an SSRI - Serotonin and Dopamine
"Cocktail" of Wellbutrin and an SNRI or Remeron - Serotonin, Noradrenalin, Dopamine

According to Goodman & Gilman's The Pharmalogical Basis of Therapeutics, the leading medical textbook of pharmacology, when cocaine is taken orally at doses that are not excessive (ie, at doses that are legally prescribed), it produces increased energy, alertness, ability to concentrate, self-confidence, and a sense of well-being, much like today's anti-depressants.  The overstimulating, "high" effects associated with cocaine occur when it is abused in high doses, especially when taken via routes of administration more rapid than oral adminstration--that is, via snorting or intravenous injection.  The cravings associated with cocaine occur when it is abused in these illicit ways.  When taken at prescription doses, cocaine did not cause the cravings seen in patients who abuse the drug but it did cause withdrawal reactions if stopped abruptly.

If cocaine were discovered today and promoted as a new antidepressant, it would likely be marketed as a serotonin, noradrenalin, and dopamine reuptake inhibitor, or SNDRI.  Since this is a mouthful, cocaine would probably be promoted as a "super neurotransmitter" reuptake inhibitor, because it boosts all three "feel good" chemicals in the brain.  In fact, "new" antidepressants that boost all three signals are already in the pipeline.  THey are on the cutting edge of research and development of "new" antidepressants.  Indeed, they have already been named "super neurotransmitter" reuptake inhibitors.  But, isn't this all too much like reinventing cocaine?  How could the pharmaceutical industry have thought drugs this closely related to cocaine would not cause withdrawal and dependence?

Some fifteen years after today's popular antidepressants were first introduced, writing like this was necessary to set the record straight: to provide patients and doctors with the information they need on antidepressant withdrawal and dependence... The current attention being given to the serious side effects of today's antidepressants is appearing....10-20, and even 30 year[s] after the fact. Once new drugs are released on the market, the FDA lacks a systematic program for monitoring their side effects.  Instead, the agency relies on spontaneous reports from doctors who are typically too busy to notify the FDA of all the side effects they see in patients.  Indeed, Dr. David Kessler, former head of the FDA and now dean of Yale School of Medicine, has stated "only about 1 percent of serious [side effects] are reported" to the agency.

As a result, it often takes a decade before the most serious side effects of a new class of psychiatric drugs are identified.  Because pharmaceutical companies have adamantly denied the side effects, it takes another decade for enough data to accumulate for the problems to be undeniable and for a number of patient advocates to be sounding the alarm.  Yet a third decade typically decade typically elapses before the slow bureaucracies of regulatory agencies and professional organizations act to change treatment guidelines and prescribing pattern patterns.  By this time, what were once "new" drugs have become old, their patents have expired, and they are no longer profitable.  The pharmaceutical companies have abandoned the drugs and moved on to newly patented, more profitable ones that can be promoted as "safer" largely because their side effects are unknown.  Indeed, in some instances the companies turn on their old drugs whose patents have expired, helping to discredit them to pave the way for new ones...

In some instances, the manufacturers of certain drugs will fund and publicize studies of the side effect of a competing company's drug in an effort to gain market share for their own drug.  For example, in the mid-1990s, the manufacturers of Wellbutrin and Serzone funded studies of antidepressant-induced sexual side effects, comparing their drugs to SSRIs like Prozac and Zoloft.  The studies corroborated the high incidence of sexual side effects found in patients taking SSRIs, some 60 percent of patients, and claimed an advantage for Wellbutrin and Serzone.  Company-funded researchers even held a press conference to announce the results.  The resulting publicity was largely responsible for alerting doctors and the public to the high incidence of sexual side effects in SSRI-type antidepressants.  Unfortunately, many other serious side effects of antidepressants do not receive this kind of careful study and publicity when no one drug has such a clear advantage.  Under these circumstances, no company is motivated to fund the necessary studies [for further information on side effects].  That such politics and marketing play a large role in what side effects we have good data on is regrettable.

In the case of antidepressant withdrawal reactions, Prozac has an advantage.  In a large-scale, systematic study of over 200 patients, 14 percent of patients stopping Prozac had withdrawal reactions.  By contrast, 66 percent of patients stopping Paxil and 60 percent of patients stopping Zoloft experienced withdrawal reactions.  Not surprisingly, Eli Lilly, the maker of Prozac, is the company that funded the study comparing its own drug Prozac to competitors Paxil and Zoloft....While "educating" doctors about the advantages of Prozac, Lilly had to avoid called unwanted attention to the phenomenon of antidepressant withdrawal, with its serious implication--that is, dependence--for all antidepressants.  Negotiating this tricky balance, Lilly is also the company that funded the campaign to rename antidepressant withdrawal reactions to "antidepressant discontinuation syndrome." In a carefully orchestrated effort, the Lilly-funded campaign deflected attention away from the more serious implications of antidepressant withdrawal reactions while Prozac gained the advantage over competitors...

Prozac's advantage in the Lilly-funded study on withdrawal has been controversial...because of Prozac's long half-life, withdrawal reactions typically do not appear within five to eight days.  Rather, they take two to three weeks or more.  In the study Lilly conducted to test for withdrawal reactions, patients stopped their antidepressants abruptly for only five to eight days...

Lilly conducted a separate study that addresses this issue.  In this study, patients stopped Prozac for six weeks.  However, in this study, patients were not systematically monitored, not requiring checklists of specific withdrawal symptoms, but only asked open-ended questions about "general well-being..."  In other words, Prozac was not held to the same standard that Paxil and Zoloft had been...

To conduct and publish such studies, pharmaceutical companies work closely with industry-friendly academic psychiatrists.  Jerrold Rosenbaum, professor of psychiatry at Harvard Medical School and chief of psychiatry at Massachusetts General Hospital, conducted the key study of Eli Lilly that compared Prozac to Paxil and Zoloft...Rosenbaum also coauthored the study specifically looking at Prozac withdrawal that did not hold Lilly's drug to the same standard to which its competitors were held.  And, Rosenbaum was a key player in the Lilly-funded campaign to replace the term "antidepressant withdrawal" with the less threatening "antidepressant discontinuation syndrome." ...

Rosenbaum is no stranger to controversy over his relationship with Eli Lilly and Prozac.  He played a pivotal role in the controversy over the suicidal effects of today's antidepressants when the controversy first exploded in the media in the early 1990s.  At the time, only Prozac, the first of today's antidepressants, was on the market.  As the controversy raged, Rosenbaum came to Prozac's defense in 1991, publishing the definitive study in the Journal of Clinical Psychiatry insisting Prozac does not make adults suicidal.  In the study, Rosenbaum compared data on Prozac with data on earlier classes of antidepressants, claiming that his statistical analysis showed that Prozac does not cause higher rates of suicidality.  Rosebaum's study was hugely influential in large part because he appeared to be an academic psychiatrist independent of Eli Lilly.  Similar defenses of Prozac published by in-house Eli-Lilly psychiatrists did not have the same impact.  But a May 7, 2000 Boston Globe expose revealed that Rosenbaum's "1991 study on Prozac and suicide [has been] criticized by at least two sets of researchers as well as the FDA."  The critiques the Boston Globe was referring to, including the one by the FDA, argued Rosenbaum got his statistics wrong: his own data show that Prozac is associated with a threefold greater incidence of suicidality than older, comparison antidepressants, the critics said.  What is more, the  Boston Globe revealed that Rosenbaum had a "cozy" relationship advising Eli Lilly's marketing department on Prozac since "before Prozac was launched," in the late 1980s.  Rosenbaum did not reveal his behind-the-scenes ties to Lilly's marketing department, yet his was the key study silencing the controversy over antidepressant-suicide for more than a decade.  This is the same side effect in adults that has reemerged in recent years because of newly revealed studies showing that children and adolescents become suicidal on many of today's antidepressants.  In the meantime, pharmaceutical companies have paid scores of secret settlements in lawsuits involving antidepressant-induced suicides and murder-suicides of adults and children.  If Rosenbaum had divulged this information earlier, perhaps these could have been prevented...

Internal GlaxoSmithKline documents reveal that the manufacturer of Paxil lost no time organizing a response to Lilly...a June 5, 1997 memo from GlaxoSmithKline's public relations firm, Ruder Finn, describes the steps it is taking for the pharmaceutical giant to refute "what Rosenbaum et al. state or allege."

The Ruder Finn memo provides a rare glimpse into how the public relations firm of pharmaceutical behemoths seek to influence the practice of medicine behind the scenes.  The Ruder Finn memo states that the public relations firm has ghostwritten two proposed responses to Rosenbaum and his colleagues' articles.  The memo suggests the GlaxoSmithKline-friendly psychiatrists will issue the responses.  The memo proposes that one of the pieces will be authored by Dr. Bruce Pollock, professor of psychiatry at the University of Pittsburgh School of Medicine.  Four months later, Dr. Pollock published a response to Rosenbaum...in the October 1998 issue of the Journal of Clinical Psychiatry.  Pollock's published piece is expanded and elaborated in more formal, academic language...but if follows the same line of argument as Ruder Finn's work.  ...The Ruder Finn memo provides direct evidence of pharmaceutical company public relations firms seeking to influence academic publications authored in the name of seemingly independent psychiatrists.  Pollock's published piece does not mention his apparent behind-the-scenes relationship to GlaxoSmithKline or Ruder Finn.  Though it isn't mentioned, he has been a consultant to the company and has received grant research money, been paid honoraria, and been a member of the company's...advisory boards.

In the late 1990s, GlaxoSmithKline went to considerable effort to train its sales force in how to "educate" doctors about the growing concerns of Paxil withdrawal.  Repeated studies have shown that pharmaceutical company sales representatives have enormous influence over doctors who rely on them for up-to-date information.  GlaxoSmithKline instructed its sales representatives...to assure doctors that "discontinuation syndrome" symptoms are "generally mild," "transient," and "infrequent."  Indeed, despite a confidential, internal comapny report describing studies indicating as many as 62 percent of people stopping Paxil developed withdrawal symptoms that in some cases could be "severe" and "disabling," a GlaxoSmithKline "Business Plan Guide" told its sales force to continue to reassure doctors that Paxil withdrawal occurs in "two in 1,000 patients or 0.2%" (Note that the guide also had the math wrong: two in 1,000 patients is .002 percent.) ...

A transmittal memo that accompanied one confidential, internal GlaxoSmithKline report on "Paxil and the incidence of discontinuation symptoms" cautions: "Please not that this information is for in-house use only and is not to be passed to regulatory authorities [such as the FDA], external investigators, or clinicians [ie practicing doctors]."  It also raissed the question: "Discontinuation: Why this is an issue." It answers: "Paxil sales to end [of] Sept. [1997] already exceed $1 BILLION."  The "$1 BILLION" is in large, bold letters.  Beneath the bold headline is artwork showing a huge moneybag with a dollar sign emblazoned on it.

One internal GlaxoSmithKline memo to the "Paxil selling team" on "discontinuation syndrome" ends with a particularly offensive cartoon of a woman patient.  The headline of the cartoon says: "Let's face it...The only thing the anxious and agitated patient will be saying is 'Where's my Paxil!!!!!!'"  The cartoon depicts a hysterical-looking woman sitting at her desk, screaming at the top of her lungs, throwing her hands up, and tossing all her papers into the air while yelling "Where's my Paxil!!!!!!"...Most people would be surprised by such a derogatory attitude toward patients and by such a carefully orchestrated effort to mislead doctors and patients.  The cruel irony is that patients can be distraught enough to ask, "Where's my Paxil?" when they are in severe Paxil withdrawal...

For over a decade "cozy" relationships have flourished between pharmaceutical companies and a small coterie of academic psychiatrists who can each make millions consulting to the companies, advising their marketing departments, doing research for them, and publishing papers that can be ghostwritten by the companies.  When pharmaceutical companies design research so that it is biased in favor of their drugs or when they selectively publish only those results that are favorable to their drugs, they are misleading practicing physicians who need complete, unbiased information to exercise their professional judgment in the best interest of patients....

Unfortunately, in the last decade deceptive practices have become routine in the researching, publishing, and marketing of psychiatric drugs, making it extremely difficult for patients and even for doctors to get accurate, balanced information.  Now, since the FDA has issued a warning that antidepressants may may children and adults suicidal and with the British equivalent of the FDA, the MHRA, placing a ban on many antidepressants for children, these practices are coming under closer scrutiny.  Both GlaxoSmithKline and Pfizer paid settlements worth hundreds of millions of dollars on charges of deceptive marketing before the cases could go to trial...The FDA has not done enough to hold pharmaceutical companies and their appointed "opinion leaders" (friendly psychiatrists) accountable.

Indeed, the FDA has contributed significantly to the problem of both of the antidepressant side effects currently receiving widespread attention: withdrawal reactions and antidepressant-related suicide.  In the case of the drugs making patients suicidal, the FDA learned of this side effect more than a decade ago, in the early 1990s, shortly after Prozac was introduced.  The FDA convened an advisory panel of nine experts and held a hearing on the issue in September 1991 because of widespread public and professional concern. Unfortunately, due to the five of the nine commitee members' ties to the pharmaceutical industry, and even though 1/3 of the committee voted for a warning, nothing was done.

With regard to antidepressant withdrawal reactions, the FDA has not demanded that pharmaceutical companies assess withdrawal symptoms adequately when they test new antidepressants for FDA approval.  The FDA knew or should have known from experience with earlier classes of psychiatric drugs that antidepressants with short and ultra-short half-lives would inevitably cause withdrawal and dependence.  The FDA has allowed pharmaceutical companies to call withdrawal reactions antidepressant "discontinuation" symptoms in their official information on the drugs.  Withdrawal reactions are still listed as "rare" side effects of drugs like Paxil and Effexor in the companies' offical information....The FDA approves the companies' official information word-for-word and lets them get away with this semantic gamesmanship at the expense of patients and doctors.  Hiding behind the term "antidepressant discontinuation syndrome," the industry has repeatedly denied that today's antidepressants cause withdrawal reactions.  The companies have promoted antidepressants as "non habit-forming," "not associated with dependence or addiction," and "causing mild, usually temporary, side effects" with FDA approval.  When a patient advocacy lawsuit convinced a California judge to ban such deceptive advertising, the FDA intervened on behalf of the pharmaceutical industry, claiming the judge had no jurisdiction.  The FDA's mandate is to protect consumers, not company profits.  The FDA's actions are another example of the unprecedented behind-the-scenes political power wielded today by the pharmaceutical industry lobby.  In addition to political pressure on the FDA, critics point to lucrative pharmaceutical company consulting contracts awarded to FDA officials even while they are working at the agency or just after they leave it.

Another federal agency expected to be an objective, impartial protector of the public interest is the National Institute of Health, NIH.  Unfortunately, it, too, has been rocked by scandal: In December 2003, a Los Angeles Times expose revealed that top NIH scientists received hundreds of thousands of dollars--and in some cases, over a million dollars--in consulting fees from pharmaceutical companies.  In some instances,  NIH department heads received behind-the-scenes consulting fees while their departments were providing the pharmaceutical companies with millions of taxpayer dollars in NIH research grants.  The FDA's and NIH's pro-industry stances have left the American public with inadequate consumer protection and patient advocacy in the face of pharmaceutical company political clout.

Dr. Marcia Angell, former editor-in-chief of the New England Journal of Medicine and a senior lecturer in social medicine at Harvard Medical School, describes the pharmaceutical industry's pervasive influence over academic medicine, the FDA, and the NIH as examples of the industry's ability to "co-opt every institution that might stand in its way."  As one of the most profitable industries in the country,  the pharmaceutical industry is awash with money with which to buy influence.  Pharmaceutical companies defend their price gouging and outrageous profits as necessary to support their research and development activities.  Yet in reality the pharmaceutical industry's spending on research and development is dwarfed by its spending on marketing and advertising campaigns.  The industry spends more than a third of its revenues on marketing, more than two and half times more than what it spends on research and development.  Because heavy advertising and marketing substantially increase the costs of drugs, costs that are ultimately paid for by health insurance, the pharmaceutical industry's exorbitant promotion of its drugs drains the financially strapped health care system. (My note: our country is the only one of two countries in the world that allow television commercials and marketing for prescription drugs.  The other is New Zealand, which is considering a ban because of misleading content which companies devise in order to make an increasingly receptive public that they are in need of medication when in most cases they are not.)

...Unfortunately, psychiatry is particularly vulnerable to the pharmaceutical industry's deceptive practices when researching and marketing drugs.  This is because the diagnosis of psychiatric conditions and the response to psychiatric medication is so subjective and therefore so easily manipulated.

Practicing doctors do not want to mislead patients.  Most doctors want to make decisions in the best interests of their patients.  Not surprisingly, doctors are upset to discover that pharmaceutical companies and the "expert" doctors who work closely with the industry have misled them.  Doctors and patients need to take medicine back from the pharmaceutical industry and its appointed "experts."  An independent FDA committed to consumer advocacy and protection would seem a reasonable expectation for a publicly funded government agency.

To make amends for misleading patients and doctors about antidepressant withdrawal and dependence, at a minimum, pharmaceutical companies should be required to:

• Make pills available in many more milligram sizes to facilitate tapering today's antidepressants
• Conduct a well-funded campaign to educate doctors and the public about antidepressant withdrawal, including television, newspaper, and magazine advertisements
• Abandon the misleading term "antidepressant discontinuation syndrome" for the straightforward "antidepressant withdrawal reaction" in all descriptions of the phenomenon
• Include warning labels on patients' antidepressant prescription bottles that the drugs can cause severe withdrawal symptom, should not be stopped abruptly, and need to be taken every day exactly as prescribed to avoid withdrawal reactions that could be confused with a worsening of the patient's underlying psychiatric condition.
• When testing all future antidepressants for FDA approval, systematically monitor and accurately report the percentage of patients who have withdrawal symptoms
• Publish all psychiatric drug studies, not just those favorable to the companies' marketing interests