Forbes: Prozac Nation? Is the Party Over?

August 20, 2004

Thanks to Lynn for sending this.

You know when a publication like Forbes tackles SSRIS, the party is just

about over for the drug lords. Lights out, folks!

FORBES.com

Prozac Nation? Is the Party Over?

Fri Aug 20,11:53 AM ET

http://news./news?tmpl=story & cid=64 & u=/fo/20040820/bs_fo/6fd966a3bbd7f3\

c511ec4152a7b4d08e & printer=1

By C. Morais

Hugo, a 57-year-old housewife in Corvallis, Ore., had recently been

prescribed the antidepressant Zoloft by her internist when she found herself

in the bathroom, looking at a Bic shaver and wondering if she could get the

blade out of its plastic. In the living room she zeroed in on a pair of long

scissors she had inherited from her grandmother. " I kept on wanting to pick

them up and gouge my eye out, " she recalls. Trying to occupy her mind at the

computer, she fought the " urge to slam the phone into the side of my head. "

About to Crash?

America's top-selling antidepressants could soon experience a downturn. Now

off-patent, Prozac is no longer a bestseller.

Top five antidepressants

Drug Manufacturer 2003 sales*($bil)

ZoloftPfizer$2.9

XR EffexorWyeth 2.1

Wellbutrin SR Glaxokline1.8

PaxilGlaxokline1.5

Celexa Forest Laboratories1.4

*Wholesale prices of drugs, not including mail service. Source: IMS Health.

Hugo survived the weekend; her drug doses were reduced and she was switched

to antidepressant Paxil. This time, however, she experienced akathisia'a

medicine-induced agitation and restlessness that some patients on

antidepressants describe as the feeling of bugs crawling through the

skin'and an extreme bout of mania. " What spooks me now is that I thought I'd

recognize when I was having trouble with the medications, " she says. " But it

was a week later before I realized, 'Oh, my God, what have I done?' "

Both Zoloft and Paxil are Prozac-type drugs known as SSRIs, or selective

serotonin reuptake inhibitors. Do such drugs cause mania and violent

obsessions? That question is now being debated in many a doctor's office,

court of law and legislature. Whatever the correct scientific answer, the

mere fact that the question is being asked represents a new phase in the

evolution of SSRI medications and a threat to the well-being of the

companies that make the drugs.

Since SSRIs arrived 16 years ago with the introduction of Eli Lilly & Co.'s

Prozac, the category has expanded into a collection of blockbusters for

Lilly, Pfizer, Glaxokline and other manufacturers. All told, the

antidepressants category accounts for $14 billion a year of wholesale

revenues just in the U.S., according to IMS Health. In the first five months

of this year American doctors wrote 46 million prescriptions for

antidepressants, up 5% over the same period last year, according to

NDCHealth. Yes, this is a Prozac nation. Dr. Mark Vanden Bosch, an

anesthesiologist at the Berkshire Medical Center in Pittsfield, Mass., who

must be alert to drugs that might interact with anesthesia, estimates that a

third of the patients checking into his hospital, for a wide range of

operations, are on antidepressants.

When Prozac was new, it was heralded (in, for example, the 1993 hit

Listening to Prozac) as a wonder drug with little in the way of side

effects. The few naysayers were for the most part fringe sorts like

Scientologists. Now a giant pall of misgiving is descending on SSRIs:

Tearful family members are telling their congressmen how the drugs caused

their children to commit suicide; Britain has limited their use in children;

a suit by New York Attorney General Eliot Spitzer claims Glaxokline

suppressed evidence that the drugs don't work in children and can endanger

them; and the Food & Drug Administration is studying whether it should

mandate ominous warning labels.

It's a pattern we have seen before in psychiatric drugs, says Harvard

Medical School (news - web sites) psychiatrist ph Glenmullen. A new

class of chemicals creates a wave of euphoria in the medical community,

while a handful of celebrities (such as, in the case of SSRIs, Mike Wallace

of 60 Minutes) swear by the new pills. A decade later reports of side

effects accumulate and doctors begin to have second thoughts. Another decade

later the world discovers a new miracle drug and the old one is relegated to

niche uses. It happened to the major tranquilizers (like Thorazine)

introduced in the 1950s, and it happened to supposedly less addictive and

relatively side-effect-free substitutes for morphine. Dr. Glenmullen made

this point about the SSRIs five years ago in his book Prozac Backlash. He

looks prescient now.

The second-guessing about SSRIs comes just as the earliest patents have

expired, or are about to. The combination of potentially dampened

prescription volume and new price competition could bring a lot of

disappointment to investors in Pfizer and its competitors.

The touchiest issue is whether SSRIs provoke suicides in children.

was on Solvay Pharmaceuticals' SSRI, Luvox, when he and Dylan Klebold

went on their murder-suicide rampage through Columbine High School in

Littleton, Colo. in 1999. Did the powerful drug push him into a dangerous

mental zone, like the one Hugo experienced, or was it unable to stop what

was already there? It's hard to know. (A Columbine survivor's lawsuit

against Solvay was settled out of court, without any admission of liability,

and resulted in a token contribution from Solvay to a charity.) The British

health authorities have ruled that the side effects of SSRI antidepressants

other than Prozac put children at an unacceptable risk of suicide. The

National Institute of Mental Health in the U.S., in contrast, says that

" some research " points to a drop in suicides among children since the drugs

were introduced, " but it is not known if SSRIs are directly responsible. "

" The suicides under SSRIs are violent, " says Vera Sharav, president of the

Alliance for Human Research Protection, a group headquartered in New York

City that is crusading for full disclosure of the drugs' side effects. " It's

not like someone going into the bathroom and taking pills. It's jumping,

knives, hanging. They're in pain. They're jumping out of their skins. "

Glenmullen says he himself prescribes SSRIs when appropriate but is dismayed

to see patients who have been prescribed antidepressants for every

triviality, from nail-biting to boyfriend breakups. It is easy to see where

overprescribing could become a habit. General practitioners, internists and

family doctors are, at times, penalized by health insurers for making

referrals to psychiatrists. These first-line doctors write 73% of all

antidepressant scrips in America. Fact: We now spend more on mood-altering

drugs for our children, including antidepressants, than we spend on

antibiotics.

Harried GPs do not always discuss with their patients such possible problems

as withdrawal symptoms on discontinuance or the need for ever-increasing

doses as the drug's efficacy wears off. In 1997 C.W. Tillman, a county

official in Missouri, had an anxiety attack and was prescribed Paxil by his

doctor; a few days later his adverse reactions included severe agitation,

extreme sensitivity to light and noise, claustrophobia, diarrhea and

vomiting. His doctor told him to stop taking the drug, let the symptoms

clear up and start again. A month later Tillman had descended into a deep

depression and took an overdose. Tillman'subsequently diagnosed as bipolar

and now the Web site editor of NAMI, the National Alliance for the Mentally

Ill, in Arlington, Va.'is grateful for SSRIs for eventually helping him

manage his illness, but says doctors are undertrained in recognizing side

effects.

The brain runs on a cocktail of feel-good chemical transmitters, among them

adrenaline, serotonin and dopamine. Basically, serotonin flows across a

synapse briefly, from one nerve cell to another, after which the cell that

sent it out mops up the excess. SSRIs work by blocking the sending cell's

ability to reabsorb the excess serotonin. Result: The receptors in the

second cell get a prolonged bath of the feel-good juice. The miracle in this

class of drug is that SSRIs are better tolerated than earlier

antidepressants and less likely to be fatal in an overdose.

Now the downside: The brain adjusts to the artificial increase in serotonin

with a compensatory drop in dopamine. No one knows the long-term effect of

this drop in dopamine in the brain. " The gaping loophole in our drug safety

system, " says Glenmullen, " is long-term safety. It takes decades for enough

consumers to have had ill effects for problems to come to the authorities'

attention. " Pfizer, the manufacturer of Zoloft, says it carefully monitors

safety after drugs are approved and shares that information with the FDA

(news - web sites).

Doctors and patients have for some time been reporting mild tics and jerks

in SSRI users. The tics are usually overlooked, but can develop into tardive

dyskinesia (manifested by a freakish " involuntary tongue " that darts out of

the mouth, twitching or " running " legs, jerking or wildly swinging arms and

gagging). Do patients know they may be in for this? Knowing, they might, of

course, still opt for medication. " A little discomfort is a small (price) to

pay for a normal level of happiness! " writes Archibald Hart in Unmasking

Male Depression.

Thorazine, it turns out, creates similar side effects, but it was a while

before doctors were aware of how frequently. Prescribed for everything from

insomnia to anxiety, this type of tranquilizer was taken by an estimated 250

million worldwide. In 1973, at the 20-year mark, 2,000 cases of tics had

been reported. Critics surfaced and were dismissed as alarmists. But by 1980

systematic studies using neurological screening tests discovered that 40% of

all patients treated with the Thorazine class of tranquilizers had tics.

Reclassified as antipsychotics, the Thorazine-style drugs were given a long

list of FDA warnings and are used today only for severe mental illness.

SSRI patients are also reporting memory loss. It's mostly anecdotal evidence

at this point. But Harvard's Glenmullen says the reports of memory loss,

tics and jerking side effects found in SSRI patients suggests to him the

possibility of long-term brain damage. Is there a risk that, a decade hence,

we will see an epidemic of Alzheimer's- or Parkinson's-like diseases? The

regulators haven't given enough thought to the possibility, he says.

Whatever the true hazards in SSRIs, there is no doubt that tort lawyers can

make hay out of the situation. No overall litigation and settlement data are

available on antidepressants (opponents claim pharma is settling cases

quietly and sealing the records), and there are just the early signs of

clustering activity'trial lawyers advertising for SSRI " victims, " seminars

and other legal teamwork'familiar to mass torts, but watch events gather

pace.

" We went through a whole period of overprescribing SSRIs, " says

Kodroff, a Philadelphia lawyer suing Pfizer over Neurontin, an epilepsy

drug. " When the market started getting to the point of saturation, the

market started emphasizing juvenile use, also for the purpose of getting

patent extensions. If the studies show they are not only not efficacious,

but cause problems, you're going to see a big backlash in usage of SSRIs. "

The New York Attorney General's suit against Glaxokline, filed in June,

alleges that Glaxo committed fraud by suppressing or selectively quoting

from clinical studies that showed Paxil to be no better, or even worse, than

a dummy pill in treating children with depression. Spitzer has also

requested documents from Forest Laboratories, maker of SSRIs Celexa and

Lexapro. Glaxo says Spitzer's allegations are bunk; it never targeted kids.

To see what a successful Spitzer prosecution could provoke, look at what

recently happened to Pfizer. Warner-Lambert's Neurontin was FDA approved for

epilepsy, but the company, it was alleged, was encouraging doctors to

prescribe it for " off-label " uses like bipolar disorders. A whistle-blower

triggered federal and state criminal investigations into the marketing, and

this May Pfizer (which had subsequently acquired Warner-Lambert) settled

with the government, taking a $427 million pretax hit in criminal and civil

fines.

Four days after the settlement the Teamsters Health & Welfare Fund of

Philadelphia & Vicinity, joined by Aetna and the Alaska State Employees

Association health benefits trust, filed class actions against Pfizer

alleging, among other things, that Warner-Lambert suppressed a Harvard

Bipolar Research Program study finding that " patients did worse on Neurontin

than those who were on a sugar pill. " Two years after the study was

suppressed, the Teamsters suit alleges, " Neurontin accounted for $1.3

billion in sales, with over 80% of its use coming from nonapproved uses,

such as treatment of bipolar disorder. " Pfizer says it will " vigorously

defend " itself against any suits following its Neurontin settlement, and

says " it is worth noting that those investigations did not result in a

charge of fraud by Warner-Lambert. "

A user of SSRIs for almost a decade, who says she can't wean herself off the

drugs and spoke to us on the condition of anonymity, recently wrote her

former Park Avenue psychiatrist: " I simply pray Glaxo follows the path of

(Dow) Corning, who endangered women's lives with silicone implants they knew

were dangerous. Bankruptcy. "

Even if Pfizer, Glaxo and Lilly are right about the science, they could be

on the wrong end of a tort suit. Look at the breast implant cases.

Scientific studies showed that there was no connection between silicone and

the autoimmune diseases supposedly caused by it. But still the implant

manufacturers had to spend billions of dollars to settle lawsuits.

August 20, 2004