Selective Serotonin Reuptake Inhibitors (SSRIs)

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Selective Serotonin Reuptake Inhibitors (SSRIs)

Postby palmspringsbum » Sat Jan 17, 2009 4:21 am

1.5 Maniacs Waiting to Explode:

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Paxil Addiction - Discontinuation Syndrome

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My Paxil Addiction:

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Gwen Olsen speaks out

Postby palmspringsbum » Sat Jan 17, 2009 4:23 am

Manipulating Doctors:

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Ex-Pharmaceutical Rep Speaks Out:

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BBC: Seroxat Taken On Trust

Postby palmspringsbum » Sat Jan 17, 2009 4:28 am

Part 1:
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Part 2:
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Part 3:
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Part 4:
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Part 5:
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Part 6:
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Part 7:
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SSRI Pushers under Fire

Postby palmspringsbum » Sat Jan 17, 2009 4:37 am

Scoop News wrote:Scoop News
Friday, 2 January 2009, 4:47 pm

SSRI Pushers under Fire
By Evelyn Pringle

Throughout the 1990's, most doctors who attended conferences, medical seminars and other events were not aware that the so-called "key opinion leaders" encouraging them to prescribe the new generation of antidepressants for everything under the sun, including to children as young as infants, were nothing more than highly paid drug pushers for Big Pharma.

For years, the research that showed SSRI antidepressants (selective serotonin reuptake inhibitors) were dangerous and practically useless was kept hidden, while the studies published and presented to potential prescribers painted a glowing picture of success. These days, a person would be hard pressed to find someone who does not have a family member or friend labeled mentally ill and taking drugs like Prozac, Paxil, Zoloft, Lexapro and Celexa, or their chemical cousins Effexor, Cymbalta and Wellbutrin.

About once a year, a new round of headlines about all the money made by the SSRI pushers comes and goes; but nothing really ever seemed to stick, until now.

The Senate Finance Committee, with the ranking Republican, Senator Charles Grassley, leading the charge, is investigating GlaxoSmithKline regarding new revelations in a report filed in litigation showing that the company manipulated the numbers on adverse events related to suicidality in clinical trials back in 1989, to make it appear that Paxil did not increase the risk of patients experiencing suicidal behavior when, in fact, trial subjects on Paxil were eight times more likely to attempt or commit suicide than patients taking placebos.

Quite a few of the top pushers are also under investigation by the Committee due to revelations that millions of dollars has changed hands between the SSRI makers and the academics who signed off on some of the most fraudulently reported research in the history of modern medicine. A full list of names is easy to compile by scanning the literature on SSRI studies conducted on children. The same names appear repeatedly.

In alphabetical order, the Fortune 500 team of pushers, at a minimum, includes Drs Joseph Biederman, David Brent, Jeffrey Bridge, Daniel Casey, David Dunner, Graham Emslie, Daniel Geller, Robert Gibbons, Frederick Goodwin, Martin Keller, Andrew Leon, John Mann, John March, Charles Nemeroff, John Rush, Neal Ryan, David Shaffer, and Karen Wagner.


<span class=postbold>Truth Buried in Litigation Graveyard</span>

On February 6, 2007, the world famous historian on psycho-pharmacology, Dr David Healy, published a commentary entitled, "Why you should never trust new wonder drugs," in the UK's Daily Mail stating:

"Ten years ago, I sat faced with boxes and boxes that contained a dirty secret. Inside were thousands of confidential internal company documents about Prozac."

"The secret they revealed was that public statements about the safety of the drug were a lie; that the company knew Prozac was responsible for a raised risk of suicide and was only slightly more effective than a placebo."

Several years later, Dr Healy recounts, he was faced with the secrets of Paxil. "No one outside the two companies, and few within them," he writes, "knew what those boxes contained; I saw them because I was an expert witness in a court case."

"Documents prised out of companies by American court cases," he says, "have become the main way we have of discovering the truth about some of our best-selling drugs."

"The scientific literature, the very place doctors would look for a warning," he writes, "contained barely a hint of problems.”

"What's more, no one seems likely ever to have to answer for what appears to be fraud," he points out.

"In other organizations when evidence of disregard for public safety emerges, heads roll," Dr Healy said. "But there have been no resignations following these drug disasters - barely a flicker of embarrassment."

The UK's medicines “watchdog,” the British Medicines and Healthcare Products Regulatory Agency, he reports, "has never taken any action against the academics who make fraudulent claims in ghostwritten articles, nor doctors working for the companies who repeat such claims, even when they have been shown to be untrue."

"And no one in Britain," he points out, "has any means of finding out why their husband or child might have died."

Seven years before Dr Healy wrote this commentary, in a Prozac case for which he served as an expert witness, the plaintiff's legal team learned that Eli Lilly had withheld evidence in a jury trial when the May 7, 2007 Boston Globe reported that Lilly had agreed to pay $20 million for the rights to a patent on a new version of Prozac that would reduce "akathisia," the very side effect long believed to increase the risk of suicidal behavior, three months before the trial began.

While testifying under oath, Lilly researcher, Gary Tollefson, had told the jury, "there is absolutely no medically sound evidence of an association between any antidepressant medicine, including Prozac, and the induction of suicidal ideation or violence."

When in fact, the wording in the patent for the new formula stated "fluoxetine (Prozac) produces a state of inner restlessness (akathisia), which is one of its more significant side effects," and the "adverse effects which are decreased by administering the R(-) isomer of fluoxetine include but are not limited to headaches, nervousness, anxiety, insomnia, inner restlessness (akathisia), suicidal thoughts and self mutilation."

Patients who lived to talk about a failed suicide attempt have described the SSRI-induced akathisia, as being so unbearable that their only option for relief seemed to be death.


<span class=postbold>America’s Most Wanted</span>

Dr Daniel Casey was a major player in the SSRI drug-push and useful in many ways to the companies promoting the drugs. He was the chairman of the very first FDA advisory committee that met in 1991, to decide whether a warning about the increased risk of suicide should be added to the label of Prozac, the first SSRI approved in the US, and voted it down. He was also the chairman of the advisory panel that voted to approve Zoloft for Pfizer later that same year.

Bob Sorenson was a sales representative for Pfizer for 21 years. He moved to Oregon shortly before Zoloft was approved. During the first week at his new location, Pfizer’s chief of marketing at the time told him he needed to start calling on a doctor by the name of Dr Daniel Casey at the V.A. in Portland because he was very important to the company.

Dr Casey worked at the V.A., but never treated patients for depression, Mr Sorenson says. "His expertise [was] psychotropic drugs and experimentation."

The chief of marketing said he was interested in finding out what Dr Casey thought of the company's new drug, Zoloft. The company tried to call on him that day, but Dr Casey was not in. Mr Sorenson called on him later in the week and learned that Dr Casey was the lead investigator on Zoloft, which was up for approval by the FDA advisory committee Dr Casey chaired.

"He said I shouldn't be there, but I did ask how it looks for the drug and he said very well," Mr Sorenson recalls.

Dr Casey ended up making a ton of money from Zoloft. "He told me personally one time that he made enough from Pfizer in one year to purchase two cars," Mr Sorenson reports.

Dr Casey became a member of Pfizer's Advisory Board for Zoloft, which meant "all expense paid trips," including honorariums, to anywhere Pfizer wanted him to advise, at any location in the world, Mr Sorenson explains.

"Many speakers were sought out that would only give lectures that put Zoloft in a positive light," he notes, "there was no room for a balanced lecture."

"Dr Casey later became one of the most sought after speakers for the Pfizer promotion of Zoloft," he says, "the reps loved him because of his positioning of Zoloft."

Mr Sorenson was often told to take information to speakers, "including Dr Casey, to have them add the information to their lectures," he reports. "I look back at it now and see how wrong it was," he states.

"As far as the suicide issue," Mr Sorenson says, "the standard company line was that parents and doctors should be monitoring these kids because after being on Zoloft they finally feel good enough that they can carry out their suicide tendencies."

"Another tactic was to blame Paxil and Effexor," he recalls, "it was those drugs that caused suicidal tendencies, not Zoloft."

"Finally," he notes, "the statement was made that if they didn't take Zoloft, they probably would have committed suicide anyway."

Sales reps would practice and rehearse these statements at sales meetings to be able to respond to concerns or objections raised by Doctors about Zoloft’s relationship to suicidality, he says. "There would be contests as to who could detail the drug the best with objections," he recalls.

Pfizer was able to get rid of employees and still keep them quiet, he says, by offering severance packages of up to a year's salary, while forcing them to sign a confidentiality agreement, in which they promised not to sue, or speak adversely about Pfizer, as part of the deal.

Many people were so surprised at being terminated that they felt forced to sign because Pfizer kept the pressure on, he explains. They feared they wouldn’t find another job before financial problems set in, but regretted signing the agreement later, he says.

Mr Sorenson did not sign an agreement when he was fired. His young son had developed cancer, but Pfizer expected him to continue to attend out-of-town meetings and refused to believe that his son was terminally ill, he recalls. After 20 years with the company, Mr Sorenson was let go when he insisted that he needed to remain near his dying son and distraught wife. The Sorenson's son passed away on April 1, 2005.


<span class=postbold>Going rate for Legal Drug Pushers</span>

SEC filings for Cypress Bioscience provide a good source for estimating how much money legal drug pushers can make each year, from each company, because the names of several appear in these filings. According to its website, “Cypress Bioscience is committed to developing and commercializing pharmaceutical products and personalized medicine laboratory services that allow physicians to serve unmet medical needs.”

Drs Martin Keller and Charles Nemeroff, two of the most prolific depression-mongers, have served on the company’s board of directors, on its scientific advisory board and as consultants for this company. Under their 2004 Consulting Agreements, Cypress was required to pay them $50,000 per year for services rendered up to and including “two days per fiscal quarter.” In addition, the company could request additional services at a rate of $5,000 per day.

During 2003, Dr Nemeroff was paid $19,000 for additional services under his agreement, and Dr Keller was paid an extra $18,000. But they were only making $2,000 per day that year. As members of the Psychopharmacology Advisory Board, Dr Nemeroff earned $19,000 and Dr Keller $18,000 in 2003.

For their service as directors of the company in 2002, they each received $24,000. They were also offered stock options regularly. Cypress is only company. A bio on Dr Keller in a July 25, 2002 agenda for an annual meeting states that he is also a consultant to, "Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen, Merck, Inc, Organon, Otsuka Pharmacia/Upjohn, Pharmastar, Pfizer, Inc. and Wyeth-Ayerst Laboratories."

It also shows he serves on the scientific advisory boards of, "Bristol-Myers Squibb, Cephalon, Cyberonics, Inc., Eli Lilly, Forest Laboratories, Merck, Inc, Mitsubishi, Organon, Pfizer, Sepracor, Scirex, SmithKline Beecham, Somerse, Vela Pharmaceuticals and Wyeth-Ayerst."

Dr David Dunner and a few more of the usual suspects appear in the Cypress SEC filings as advisory board members as well.

Dr Nemeroff's role in the prostitution of research is legendary. In April 2004, Shannon Brownlee, author of, "Overtreated," wrote an article in the Washington Monthly entitled, "Doctors Without Borders," after he was caught failing to disclose his financial ties to the companies whose treatments he promoted in a paper in Nature Neuroscience, and noted:

"With financial ties to nearly two dozen drug and biotech companies, Dr. Charles B. Nemeroff may hold some sort of record among academic clinicians for the most conflicts of interest.

"A psychiatrist, a prominent researcher, and chairman of the department of psychiatry and behavioral science at Emory University in Atlanta, Nemeroff receives funding for his academic research from Eli Lilly, AstraZeneca, Pfizer, Wyeth-Ayerst--indeed from virtually every pharmaceutical house that manufactures a drug to treat mental illness.

"He also serves as a consultant to drug and biotech companies, owns their stocks, and is a member of several speakers' bureaus, delivering talks--for a fee--to other physicians on behalf of the companies' products."

Dr Nemeroff stood to "reap as much as $1 million in stock" from just one company that manufactured one of the products in his Nature Neuroscience paper, she noted.

"But the drug industry's most powerful means of boosting the bottom line is funding research," Ms Brownlee writes, "which allows companies to control, or at least influence, a great deal of what gets published in the medical journals, effectively turning supposedly objective science into a marketing tool."

She notes how companies are able to routinely delay or prevent the publication of data and specifically how the majority of studies which found antidepressants to be no better than placebos, "never saw print in medical journals."

In conclusion, she states, "I'm struck more than anything by the apparent lack of shame among clinicians when it comes to this issue."

Two years later, on July 19, 2006, the Wall Street Journal reported that the journal, Neuropsychopharmacology, published by the American College of Neuropsychopharmacology (ACNP), planned to publish a correction of a favorable review of a new depression treatment device because it failed to list the ties of the eight academic authors to the device maker, Cyberonics, including lead author Dr Nemeroff, the editor of Neuropsychopharmacology at that time. The FDA had approved the VNS device in July 2005 over the objections of "more than 20" FDA scientists, Bloomberg reported a day earlier on July 18, 2006.

"This is about as classic an example as you'll ever find of conflict of interest and manipulation by thought leaders who are beholden to corporations," Dr Bernard Carroll, a member of the ACNP, told Bloomberg. "This article is a piece of a slick, skillfully coordinated PR campaign directed by the corporation," he said.

Ten days before the Wall Street Journal article, Cyberonics had sponsored a little noticed symposium on treatment-resistant depression at the annual Collegium Internationale Neuro-Psychopharmacologicum Meeting. The main presenters at the July 9, 2006 event were Drs Nemeroff, Dunner, and Keller (the lead author of the infamous Paxil “Study 329” on adolescents).

"In recent years, new treatment modalities have emerged, among them, the only FDA-approved treatment option specifically designed for this patient population, VNS Therapy," Dr Dunner stated in a press release for the event.

Dr Dunner was one of the authors vouching for the new device in the Neuropsychopharmacology paper. However, a “stamp of approval” from this guy should be taken with a grain of salt. Back in March 1995, he also vouched for Paxil as lead author of a study titled, "Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo," in the journal of European Neuropsychopharmacology. However, he later admitted that he never reviewed any of the actual data from that study.

Dr Nemeroff apparently learned nothing from the public embarrassment of the previous scandals. Last week, he was forced to step down as Chair of Emory’s psychiatry department. According to a December 23, 2008 posting by Ed Silverman, on the popular blog, Pharmalot:

"Under pressure from a US Senate Finance Committee investigation, renowned psychiatrist Charles Nemeroff is giving up the post he held for 17 years and must follow new restrictions on his outside activities, according to an Emory University statement.”

“Emory’s own investigation found Nemeroff received more than $800,000 from Glaxo, which paid Nemeroff more than any other drugmaker, but he never reported the fees. There were more than 250 speaking engagements between 2000 and 2006.”

"Moreover, Emory will not submit any National Institutes of Health grant or other sponsored grant or contract requests in which Nemeroff is listed as an investigator or has any other role for a period of at least two years,” Pharmalot reports.

All total, Dr Nemeroff earned more than $2.8 million from drug companies between 2000 and 2007, but failed to disclose at least $1.2 million to Emory, according to the Senator.

Dr Keller’s disclosure records are under investigation as well He also appears center stage in a new book by former Boston Globe reporter, Alison Bass, called, "Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial," The book contains a treasure trove of insider revelations with specifics on Dr Keller's endless conflicts of interest, along with other academics on the take. However, Ms Bass first broke the Keller story back on October 4, 1999, in the Globe, when she reported that he was forced to forfeit "hundreds of thousands of dollars" in state grant money in 1998.

She explained how in the same year that Dr Keller authored a review article in "Biological Psychiatry," and concluded that the newer antidepressants Zoloft, Bristol-Meyer’s Serzone, and Wyeth’s Effexor were more effective, he received $77,400 in personal income and $1.2 million in research funding from Bristol-Myers, as well as $8,785 in personal income from Wyeth.

In "Side Effects," she notes that Dr Keller did not report any income to the IRS from Glaxo for 1998, but says he did receive money from the Paxil maker, and also earned $62,500 from Celexa maker Forest Labs that year.

Dr Keller published 3 studies, "with colleagues," in the Journal of the American Medical Association and the Journal of Clinical Psychiatry, touting the efficacy of Zoloft in 1998, and received $218,000 in personal income and more than $3 million in research funding from Pfizer the same year, Ms Bass reports.

The "colleagues," referred to include the all-time champion of child drugging, Dr Joseph Biederman, the main promoter of the bogus epidemic of childhood bipolar disorder. He too is under investigation for taking $1.6 million from drug companies between 2000 and 2007, and only disclosing a fraction of that amount to Harvard. On December 30, 2008, Harvard’s teaching hospital, Massachusetts General announced that Dr Biederman was no longer participating in several industry-funded trials and had agreed to “not to participate in any outside activities that are paid for or sponsored by industry, such as consulting activities or speaking engagements.”

In most of the SSRI trials conducted on children, "colleagues," will also include Dr Graham Emslie of Prozac fame, and the Zoloft Czar, Dr Karen Wagner, both from the University of Texas.

Back in April 2004, the British Medical Journal published a paper by a research team led by Dr Jon Jureidini, head of the department of psychological medicine at Women's and Children's Hospital in Australia, after a review of the clinical trial data on the safety and efficacy of antidepressant use with children. The review included the published trials, along with some unpublished data made public by the Committee on Safety of Medicines in the UK.

The Australian team was extremely critical of the published papers on the major trials of Prozac, Paxil and Zoloft, with Emslie, Wagner and Keller listed as lead authors. "In discussing their own data," the team wrote, "the authors of all of the four larger studies have exaggerated the benefits, downplayed the harms, or both."

"It is vital," they wrote, "that authors, reviewers, and editors ensure that published interpretations of data are more reasonable and balanced than is the case in the industry-dominated literature on childhood antidepressants."

Seven months later, the New York Times ran a report by Barry Meier on November 29, 2004, throwing another spotlight on the trail of corruption within the SSRI research factories, and zeroed in on Dr Wagner. He noted that, from 1998 to 2001, she was one of several researchers participating in more than a dozen industry-funded pediatric trials of antidepressants and other drugs, and that some of the results were published, but many were not.

In her Zoloft study, Dr Wagner acknowledged that she had received "research support" from several drug makers including Pfizer, which paid $80,000 to the center in connection with the test, Mr Meier reports. But she did not state that she received “sizable payments” from Pfizer for work related to the study, he says.

The same month that patients were first recruited for the Zoloft trial, in a financial filing with the school in December 1992, Dr Wagner reported that she received more than $10,000 from Pfizer, with no further details. A lawyer for the school told Meier that Dr Wagner said Pfizer had paid her $20,500 during the course of the Zoloft trial. But records for payments she received in speaking and consulting fees could not be located.

In September, Dr Wagner’s name was added to the Senator Grassley’s investigative roster, along with Dr John Rush. Between 2000 and 2005, Glaxo alone paid Dr Wagner $160,404, but only $600 was disclosed to the University, according to the Senator. She was also paid over $11,000 in 2002, by Eli Lilly, and that money was not disclosed either. Lilly paid Dr Rush $17,802 in 2001, but he only reported $3,000, Senator Grassley said.

Dr Emslie’s financial trail to the drug makers gained media attention last summer due to his prominent role in the “Texas Children's Medication Algorithm Project,” and the creation of a drug formularies for children. He was chairman of the panel that wrote guidelines instructing doctors to prescribe SSRIs off-label to kids for depression in 1998. On August 18, 2008, the Dallas Morning News ran the headline: “Conflict of interest fears halt children's mental health project.”

“A state mental health plan naming the preferred psychiatric drugs for children has been quietly put on hold over fears drug companies may have given researchers consulting contracts, speakers fees or other perks to help get their products on the list,” the News reported. University disclosure forms indicate that Dr Emslie “has made at least $130,000 in drug company speakers fees and consulting contracts since 2002,” the paper noted.

In discussing the investigation of Dr Wagner on the Senate floor, Dr Grassley pointed out that she was a co-author on Paxil Study 329. In 2001, when the study was published, Glaxo “reported paying her $18,255,” he said. “Study 329 was cited in a New York case where GlaxoSmithKline was charged with ‘repeated and persistent fraud,’” the Senator added.

Dr Emslie was also a co-author on the Paxil study and a check of the full list for 329, reveals that 5 of the co-authors appear with Dr Emslie on the guidelines for the “Children's Medication Algorithm Project,” including Karen Wagner, Boris Birmaher, Barbara Geller, Neil Ryan and Michael Strober. Dr Rush’s name is also on the Texas guidelines but he moved to Singapore last August.

********

<small>Evelyn Pringle
epringle05@yahoo.com

(Written as part of the SSRI Litigation Round-Up, Sponsored by Baum, Hedlund, Aristei & Goldman’s Pharmaceutical Litigation Department www.baumhedlundlaw.com)

(Evelyn Pringle is a columnist for Scoop Independent News and an investigative journalist focused on exposing corruption in government and corporate America)</small>


<span class=postbold>See Also:</span> "Prescription Drugs Are 4th Leading Cause of Death, Heath may still be teaching us a lesson" By Robert I Bender, M.D., FAAFP, HOLLYWOOD, CA (Hollywood Today) 9/29/08
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Prozac, used by 40m people, does not work say scientists

Postby palmspringsbum » Mon Jan 26, 2009 1:35 pm

The Guardian wrote:

Prozac, used by 40m people, does not work say scientists

<span class=postbigbold>Analysis of unseen trials and other data concludes it is no better than placebo</span>

Full text: the PLoS paper

* Sarah Boseley, health editor
* The Guardian, Tuesday 26 February 2008

<table class=posttable align=right width=200><tr><td class=postcell><img class=postimg src=http://www.palmspringsbum.org/bbs/bin/prozac10c.jpg width=200 alt="A single Prozac capsule"></td></tr></table>Prozac, the bestselling antidepressant taken by 40 million people worldwide, does not work and nor do similar drugs in the same class, according to a major review released today.

The study examined all available data on the drugs, including results from clinical trials that the manufacturers chose not to publish at the time. The trials compared the effect on patients taking the drugs with those given a placebo or sugar pill.

When all the data was pulled together, it appeared that patients had improved - but those on placebo improved just as much as those on the drugs.

The only exception is in the most severely depressed patients, according to the authors - Prof Irving Kirsch from the department of psychology at Hull University and colleagues in the US and Canada. But that is probably because the placebo stopped working so well, they say, rather than the drugs having worked better.

"Given these results, there seems little reason to prescribe antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed," says Kirsch. "This study raises serious issues that need to be addressed surrounding drug licensing and how drug trial data is reported."

The paper, published today in the journal PLoS (Public Library of Science) Medicine, is likely to have a significant impact on the prescribing of the drugs. The National Institute for Health and Clinical Excellence (Nice) already recommends that counselling should be tried before doctors prescribe antidepressants. Kirsch, who was one of the consultants for the guidelines, says the new analysis "would suggest that the prescription of antidepressant medications might be restricted even more".

The review breaks new ground because Kirsch and his colleagues have obtained for the first time what they believe is a full set of trial data for four antidepressants.

They requested the full data under freedom of information rules from the Food and Drug Administration, which licenses medicines in the US and requires all data when it makes a decision.

The pattern they saw from the trial results of fluoxetine (Prozac), paroxetine (Seroxat), venlafaxine (Effexor) and nefazodone (Serzone) was consistent. "Using complete data sets (including unpublished data) and a substantially larger data set of this type than has been previously reported, we find the overall effect of new-generation antidepressant medication is below recommended criteria for clinical significance," they write.

Two more frequently prescribed antidepressants were omitted from the study because scientists were unable to obtain all the data.

Concerns have been raised in recent years about the side-effects of this class of antidepressant. Evidence that they could prompt some young people to consider suicide led to a warning to doctors not to prescribe them for the under-18s - with the exception of Prozac, which was considered more effective than the rest.

In adults, however, the depression-beating benefits were thought to outweigh the risks. Since its launch in the US in 1988, some 40 million people have taken Prozac, earning tens of billions of dollars for the manufacturer, Eli Lilly. Although the patent lapsed in 2001, fluoxetine continues to make the company money - it is now the active ingredient in Sarafem, a pill sold by Lilly for premenstrual syndrome.

Eli Lilly was defiant last night. "Extensive scientific and medical experience has demonstrated that fluoxetine is an effective antidepressant," it said in a statement. "Since its discovery in 1972, fluoxetine has become one of the world's most-studied medicines. Lilly is proud of the difference fluoxetine has made to millions of people living with depression."

A spokesman for GlaxoSmithKline, which makes Seroxat, said the authors had failed to acknowledge the "very positive" benefits of the treatment and their conclusions were "at odds with what has been seen in actual clinical practice".

He added: "This analysis has only examined a small subset of the total data available while regulatory bodies around the world have conducted extensive reviews and evaluations of all the data available, and this one study should not be used to cause unnecessary alarm and concern for patients."

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Against Depression, a Sugar Pill Is Hard to Beat

Postby palmspringsbum » Wed Mar 25, 2009 10:30 am

Chelation Therapy Online wrote:<small>Chelation Therapy Online</small>


Against Depression, a Sugar Pill Is Hard to Beat

<span class=postbigbold>Placebos Improve Mood, Change Brain Chemistry in Majority of Trials of Antidepressants</span>


By Shankar Vedantam
Washington Post Staff Writer
Tuesday, May 7, 2002; Page A01

After thousands of studies, hundreds of millions of prescriptions and tens of billions of dollars in sales, two things are certain about pills that treat depression: Antidepressants like Prozac, Paxil and Zoloft work. And so do sugar pills.

A new analysis has found that in the majority of trials conducted by drug companies in recent decades, sugar pills have done as well as -- or better than -- antidepressants. Companies have had to conduct numerous trials to get two that show a positive result, which is the Food and Drug Administration's minimum for approval.

What's more, the sugar pills, or placebos, cause profound changes in the same areas of the brain affected by the medicines, according to research published last week. One researcher has ruefully concluded that a higher percentage of depressed patients get better on placebos today than 20 years ago.

Placebos -- or dud pills -- have long been used to help scientists separate the "real" effectiveness of medicines from the "illusory" feelings of patients. The placebo effect -- the phenomenon of patients feeling better after they've been treated with dud pills -- is seen throughout the field of medicine. But new research suggests that the placebo may play an extraordinary role in the treatment of depression -- where how people feel spells the difference between sickness and health.

The new research may shed light on findings such as those from a trial last month that compared the herbal remedy St. John's wort against Zoloft. St. John's wort fully cured 24 percent of the depressed people who received it, and Zoloft cured 25 percent -- but the placebo fully cured 32 percent.

The confounding and controversial findings do not mean that antidepressants do not work. But clinicians and researchers say the results do suggest that Americans may be overestimating the power of the drugs, and that the medicines' greatest benefits may come from the care and concern shown to patients during a clinical trial -- a context that does not exist for millions of patients using the drugs in the real world.

"The drugs work, and I prescribe them, but they are not what they are cracked up to be," said Wayne Blackmon, a Washington psychiatrist whose practice largely comprises patients who suffer from depression. "I know from clinical experience the drugs alone don't do the job."

Still, drugs may have become the reflexive treatment for the vast majority of Americans receiving medical attention for depression: As the number of doctor visits for depression rose from 14 million in 1987 to almost 25 million last year, medications were prescribed for nine in 10 patients, according to research published last week.

It is not clear how many patients received medicines in a context of therapy, although research has indicated that combining medicines with psychotherapy produces the best results.

But Randall Stafford, the Stanford University physician who conducted the study on doctor visits, found that less than one-third of them in 2001 were to psychiatrists and two-thirds of them were to primary care physicians. The former are more likely to situate the medicines in a larger context of therapy, while the latter are less knowledgeable about therapy, more pressed for time and less likely to offer patients anything like the attention they would receive in a clinical trial.

The average participant in an eight-week trial spends about 20 hours being examined by top experts and highly trained caregivers, said Seattle psychiatrist Arif Khan, who studied the placebo effect in trials submitted to the FDA. Participants -- including those being given sugar pills -- are asked detailed questions about how they are feeling, and their every psychological change is closely noted.

In comparison, Khan noted, the average patient with depression sees a doctor perhaps 20 minutes a month.

His analysis of 96 antidepressant trials between 1979 and 1996 showed that in 52 percent of them, the effect of the antidepressant could not be distinguished from that of the placebo. Khan said the makers of Prozac had to run five trials to obtain two that were positive, and the makers of Paxil and Zoloft had to run even more. He analyzed trials that were made public in the medical literature, which tend to show positive results, and those that were not.

"It speaks to the difficulty we have in classifying and identifying the disorders we deal with," said Thomas Laughren, who heads the group of scientists at the FDA that evaluates the medicines. "Psychiatric diagnosis is descriptive. We don't really understand psychiatric disorders at a biological level."

Patients with similar symptoms, he explained, may have different problems with their brain chemistry. Scientists don't understand the neural mechanisms of depression -- or why medicines like Prozac and Paxil work.

"We like to think we give people treatments and they get better," said Andrew Leuchter, a professor of psychiatry at UCLA. "We have this fallacy of success, but we don't know in any individual why they get better. Undoubtedly one of those factors is the time we spend with people and the connectedness that gives patients."

In January, Leuchter published a study in the American Journal of Psychiatry, in which he tracked some of the brain changes associated with drugs such as Prozac and Effexor, which are called selective serotonin reuptake inhibitors. When Leuchter compared the brain changes in patients on placebos, he was amazed to find that many of them had changes in the same parts of the brain that are thought to control important facets of mood.

Patients who got better on placebos showed heightened activity in the prefrontal lobe, and that activity continued to rise during the eight weeks of the study. Those who responded to medicine initially showed a decline in prefrontal brain activity, then a rise that eventually tapered off. Thirty-eight percent of patients responded to the placebo, and 52 percent to the medicines.

Once the trial was over and the patients who had been given placebos were told as much, they quickly deteriorated. People's belief in the power of antidepressants may explain why they do well on placebos. Patients in trials are not told which they are receiving.

Likewise, sea changes in the treatment of depression -- including the reduction in the stigma attached to mental illness, the widespread use of antidepressants and the immense marketing efforts by their manufacturers -- may explain why Timothy Walsh, a psychiatrist at Columbia University, recently found that the placebo effect has grown in recent years. He found that greater percentages of people tended to get better on placebos during trials of antidepressants in 2000 than in 1981.

Some observers assert that the medicines themselves work because of the placebo effect, but most psychiatrists believe the drugs do have an effect of their own. Drugs are a "placebo-plus" treatment, said Helen Mayberg, head of neuropsychiatry at the Rotman Research Institute at the University of Toronto.

In a study published last week in the American Journal of Psychiatry, Mayberg evaluated brain changes during trials using a sophisticated brain imaging technique. She found that medicines, besides working on areas that are activated by placebos, also work on areas deep in the brain stem, the hippocampus and striatum.

Since both depression and the effect of the medicines are still not well understood, it's not clear what these changes mean. While they could be irrelevant effects, Mayberg said a better explanation is that the drugs affect areas deep within the brain and then work upward to affect parts of the brain that control mood. Placebos may work in the reverse direction. In part, this may explain why drug effects tend to be more reliable than placebos in the long run.

Mayberg likened depression to a room with a hole in one window.

"You are trying to set a thermostat -- it's 100 degrees outside and you want it to be 70," she said. "If you set the thermostat to 70, that doesn't work. But if I set my thermostat to 50, that fools the system and gets the temperature back to 70."

Both drugs and placebos -- chemicals and beliefs -- may impose different chemical pressures on the brain that reset the "temperature." The real problem, of course, is that no one knows how to fix the hole in the window, or even where exactly it is. "This is a thousand-piece puzzle with no picture on the box," sighed Mayberg.

Blackmon, the Washington psychiatrist, said it behooved mental health clinicians to better integrate the power of biological treatments with the effects of belief and therapy.

"We would say it's absurd if an internist says, 'I believe in penicillin, so everyone should get penicillin whether they have cancer or a broken bone," he said.


"We would say it's absurd if an internist says, 'I believe in penicillin, so everyone should get penicillin whether they have cancer or a broken bone," he said.

American Journal of Psychiatry January 2002;159(1):122-9

American Journal of Psychiatry May 2002;159(5):728-37

Journal of Clinical Psychiatry February 2002 22(1):40-5

<table class=posttable><tr><td class=postcell><img class=postimg src=http://www.palmspringsbum.org/bbs/bin/placebo-effect.jpg align=center></td></tr></table>
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The Soma State and A Brave New World

Postby palmspringsbum » Tue Jun 09, 2009 11:04 am

16 Apr 2008 - Alex is joined in-studio by Robert Manciero and Gwen Olsen to discuss the exponential increase in the use of psychotropic drugs and how a big pharma Soma State is being forced upon us turning our children into zombies as we enter into a Brave New World.

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Another view: Talking back to Prozac

Postby palmspringsbum » Sat Jul 04, 2009 3:21 pm

Psychology Today wrote:Published on Psychology Today | 1 Jul 1994

Another view: Talking back to Prozac

by Peter and Ginger Breggin

The Declaration of Independence affirms our right to the pursuit of happiness, but the Founding Fathers did not anticipate that laboratory-de-signed drugs such as Prozac would become the preferred path for so many. Prozac has become the most widely prescribed psychiatric drug in America.

Does it really improve depression? Long a skeptic about claims for new psychiatric wonder drugs, I decided to undertake a comprehensive analysis of the drug and its effects. Making extensive use of the Freedom of Information Act to obtain FDA documents pertaining to the approval of Prozac, what I found was more dismaying than my initial skepticism suggested. The full results are published in a new book, Talking Back to Prozac (St. Martin's) I co-wrote with Ginger Breggin.

Contrary to widespread public belief, the FDA does not conduct any of the studies used for drug approval; they are financed, constructed, and supervised by drug companies using doctors they hire. While it may take a decade for a drug to get through the FDA bureaucracy, the actual controlled scientific studies last--as in the case of Prozac--just four to six weeks. Anecdotal material is collected on longer-term patients, but for Prozac, only 63 patients were followed for more than two years before the drug's approval.

For starters, seriously suicidal patients and hospitalized patients were excluded. Of the included patients, many were allowed to take sedatives and minor tranquilizers to overcome Prozac's stimulant-like side effects, vastly compromising data interpretation.

After weeding out the most badly flawed studies, the FDA found only four that were adequate enough to consider. One of these showed that Prozac was no better than placebo. Three others supposedly showed Prozac to be somewhat superior to the sugar pill, but not as good as older antidepressants. However, due to adverse drug effects and lack of drug effectiveness, the dropout rates in most of these studies was very high.

While the gross number of patients receiving Prozac in all the trials was more than 5,000, the actual number finishing the trials used for approval was very small. When I counted the actual number of patients who completed the four- to six-week trials used for the approval of Prozac, it turned out to be a grand total of 286. It bears restating--only 286 patients finished the four- to six-week trials used to determine Prozac's efficacy.

Because of the high dropout rates and because Prozac was often no better than place-bo in many trials, many statistical maneuvers were required to make the studies look positive. In one of the key studies, involving six different sites around the country, results at five sites showed Prozac to have no benefit. One site--representing 25 percent of the patients who finished the trials--was discarded. Then the data from the remaining sites were pooled. This is such a scientifically unacceptable practice that the FDA prohibits drug companies from doing it in the studies used to support advertising claims. Yet the FDA allowed it in this case. Otherwise Prozac could not have been approved.

If Prozac was largely ineffective in the FDA studies, how and why has it become so popular? Controlled studies routinely show that placebo is highly effective in relieving depression. When a drug becomes a social fad, placebo can gain miraculous powers.

There is, however, another, more disquieting reason for Prozac's popularity. The FDA's own analysis--expunged from its published conclusions--originally determined that Prozac is a stimulant-like drug. Nearly all of Prozac's clearly established effects are indistinguishable from those of classic stimulants such as the amphetamines and cocaine: activation or energizing, nervousness, anxiety, agitation, insomnia, nightmares, sweating, anorexia, weight loss, and in the extreme, hypomania and mania. There is also evidence that Prozac can produce behavioral abnormalities consistent with stimulants including paranoia and violence, and crashing, with depression and suicidality.

Americans have always loved stimulants. During the 1960s, amphetamines were prescribed in even greater numbers than Prozac, and they were touted for the same disorders, including depression and fatigue. Cosmetic psychopharmacology, presented as a unique Prozac phenomenon, has a long history in association with stimulants. Sigmund Freud, as he became hooked on cocaine, wrote glowingly about how it transformed his personality entirely for the better without any negative side effects.

Prozac's seemingly good effects are probably based on a combination of placebo and stimulation, with no specific "antidepressant" effect. Being artifically jazzed up can be tempting for meeting the demands of our high-stress, high-production lifestyles.

Many people do not feel high or euphoric on Prozac, but react with a narrowing of their emotional spectrum. They lose touch with themselves and others, and may perceive this as a kind of relief. Commonly, Prozac--like other stimulants--acts as an "anti-empathy" agent. It disconnects a person from the rest of the world and from his or her own real-life issues.

Sometimes it dulls the perception of emotional despair. Other times it produces an artificial euphoria that can progress toward mania. At best, people who use Prozac may become "better adjusted" to circumstances that do not truly meet their needs or fulfill their ideals. Worse, an individual can develop drug-induced apathy or euphoria.

Since recorded time, humankind has suffered from depression. Many individuals can recall periods in their lives when they were depressed (try remembering adolescence, for instance). Usually through the personal evolution of one's life, the sadness passes. Sometimes therapy, a spiritual awakening, or life changes help restore or initiate a more enthusiastic, hopeful outlook. Depression--and its mirror image, enthusiastic involvement in life--are the result of a complex interrelationship of environmental, social, spiritual, psychological, and sometimes physical factors.

Despite the enthusiasm with which the psychiatric community has embraced the biological theory of depression, it remains unproven. No genetic factors have been proven in depression or in the severe mood swings of manic depression despite 200 years of claims. At times, depression is produced by a recognized hormonal flaw such as hypothyroidism, which should be treated medically.

The emotional factors in depression are well known. From chimpanzees in the wild to human children enduring institutional care, it has been shown that most higher animals respond to the loss of love, liberty, or hope with degrees of depression that can become life-threatening. When so many Americans feel depressed and hopeless, we are dealing with a social phenomenon. The very idea that drugs are the answer suggests a moral, psychological, or spiritual vacuum.

That the specific causes of depression in our own lives often seem mysterious to as is no surprise. At the root of depression is a feeling of helplessness in the face of life--a sense that nothing can be done to make life worth living. If the causes of despair were known to us, we might feel frightened, but not be as like lapse into hopelessness.

Depression tells us that something is the matter with our lives. It can be a signal for personal transformation. In therapy as well as in other approaches to life improvement, overcoming depression often means finding greater appreciation for oneself and all other aspects of life, plus increased determination to live in a more self-fulfilling and loving way.

Is Prozac a short-cut to happiness? There can be no quick fixes of the human spirit. With or without drugs happiness can not be directly sought It comes, if at all, as a bonus for living a principled, rational, and loving life. The frailty and elusiveness of happiness is a tragic reality. Even wisdom, ethics, and courage cannot guarantee it.

Golda Meir once said, "Those who do not know how to weep with their whole heart don't know how to laugh either." Today we view depression and all distress in a medicalized way, divorced from our personal histories and family background, our ongoing conflicts and circumstances, and the values of the society in which we live. Instead of doing the tough work of self-transformation, we blame biochemistry.

When mental health professionals point to spurious genetic and biochemical causes, they encourage psychological helplessness and discourage personal and social growth. Even if we feel "better adjusted; we have not faced what life is all about--finding our own ethical and spiritual path, the one that brings enthusiasm and hope to all we do.

Source URL: http://www.psychologytoday.com/node/22582

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Antidepressants and Violence

Postby palmspringsbum » Wed Nov 11, 2009 7:14 pm

The Public Library of Science wrote:Healy D, Herxheimer A, Menkes DB (2006)

Antidepressants and Violence: Problems at the Interface of Medicine and Law.

PLoS Med 3(9): e372. doi:10.1371/journal.pmed.0030372

<small>Citation: Healy D, Herxheimer A, Menkes DB (2006) Antidepressants and Violence: Problems at the Interface of Medicine and Law. PLoS Med 3(9): e372. doi:10.1371/journal.pmed.0030372

Published: September 12, 2006

Copyright: © 2006 Healy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors received no specific funding for this article.

Competing interests: DH has been an expert witness in nine cases involving antidepressants and suicide or violence. He has given views that the antidepressant was unlikely to be involved in approximately 100 further cases. He has been a consultant or speaker for most of the major pharmaceutical companies. AH has been an expert witness in 12 cases involving antidepressants and suicide or violence. He has given views that the antidepressant was unlikely to be involved in approximately two further cases. DBM has been an expert witness in six cases involving antidepressants and suicide or violence. He has given views that the antidepressant was unlikely to be involved in approximately 20 further cases. He has received research support from Roche and Eli Lilly, and has spoken for most of the major pharmaceutical companies.

Abbreviations: CI, confidence interval; DSRU, Drug Safety Research Unit; GP, general practitioner; MHRA, Medicines and Healthcare Products Regulatory Agency; OCD, obsessive-compulsive disorder; SSRI, selective serotonin reuptake inhibitor

* To whom correspondence should be addressed: Healy_Hergest@compuserve.com

David Healy is at the North Wales Department of Psychological Medicine, Cardiff University, Bangor, United Kingdom. Andrew Herxheimer is at the United Kingdom Cochrane Centre, Oxford, United Kingdom. David B. Menkes is at the North Wales Department of Psychological Medicine, Cardiff University, Wrexham, United Kingdom.</small>

<hr class="postrule">

<span class="postbigbold">Summary</span>
Recent regulatory warnings about adverse behavioural effects of antidepressants in susceptible individuals have raised the profile of these issues with clinicians, patients, and the public. We review available clinical trial data on paroxetine and sertraline and pharmacovigilance studies of paroxetine and fluoxetine, and outline a series of medico-legal cases involving antidepressants and violence.

Both clinical trial and pharmacovigilance data point to possible links between these drugs and violent behaviours. The legal cases outlined returned a variety of verdicts that may in part have stemmed from different judicial processes. Many jurisdictions appear not to have considered the possibility that a prescription drug may induce violence.

The association of antidepressant treatment with aggression and violence reported here calls for more clinical trial and epidemiological data to be made available and for good clinical descriptions of the adverse outcomes of treatment. Legal systems are likely to continue to be faced with cases of violence associated with the use of psychotropic drugs, and it may fall to the courts to demand access to currently unavailable data. The problem is international and calls for an international response.

<span class="postbigbold">Introduction</span>
In 1989, Joseph Wesbecker shot dead eight people and injured 12 others before killing himself at his place of work in Kentucky. Wesbecker had been taking the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine for four weeks before these homicides, and this led to a legal action against the makers of fluoxetine, Eli Lilly [1]. The case was tried and settled in 1994, and as part of the settlement a number of pharmaceutical company documents about drug-induced activation were released into the public domain. Subsequent legal cases, some of which are outlined below, have further raised the possibility of a link between antidepressant use and violence.

The issue of treatment-related activation has since then been considered primarily in terms of possible increases in the risk of suicide among a subgroup of patients who react adversely to treatment. This possibility has led regulatory authorities to warn doctors about the risk of suicide in the early stages of treatment, at times of changing dosage, and during the withdrawal phase of treatment. Some regulators, such as the Canadian regulators, have also referred to risks of treatment-induced activation leading to both self-harm and harm to others [2]. The United States labels for all antidepressants as of August 2004 note that “anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric” [3]. Despite these developments, few data are available on the links between antidepressant usage and violence. We here offer new data, review the implications of these data, and summarise a series of medico-legal cases.

This paper focuses on paroxetine primarily because we have access to more illustrative medico-legal case material for this drug than for other antidepressants. Secondly, the manufacturer, GlaxoSmithKline, submitted data on the rates of occurrence of “hostile” episodes on paroxetine for the recent review of antidepressant drugs undertaken by the British regulator [4,5]. It is not clear that the review team obtained comparable data for other antidepressants.

<span class="postbigbold">Sources of Data</span>

<span class="postbold">Data presented to regulatory agencies</span>

The data submitted by GlaxoSmithKline on paroxetine for review by the Committee on Safety of Medicines Expert Working Group are described as a complete set of data from all placebo-controlled trials of this drug [5]. The use of this dataset thus involves no selection by the authors, and any selection bias there might have been on the part of the company seems unlikely to have increased the size of the problem. Data from placebo-controlled trials of sertraline in children are also presented, as these also offer a complete dataset, so minimising any selection bias.

Data from United Kingdom Drug Safety Research Unit (DSRU) prescription-event monitoring studies on paroxetine and fluoxetine [6,7].

<span class="postbold">Legal cases in which the authors have given evidence</span>

We have selected these only to illustrate the range of medico-legal problems such cases can pose. In the majority of other cases in which the authors were consulted, they considered that the drug in question was not linked to the behaviour for which the defendant was charged.

E-mails from 1,374 patients in response to a BBC programme on paroxetine broadcast in 2002. One of us (AH) had the opportunity to analyse a complete set of these responses.

<span class="postbigbold">Summary of Evidence Found</span>
<span class="postbold">Data from regulatory agencies</span>

In paroxetine clinical trials, aggression and violence were commonly coded under the rubric of hostility. This coding term includes homicide, homicidal acts, and homicidal ideation as well as aggressive events and “conduct disorders”, but no homicides were reported from these trials. The material posted on the company Web site (http://www.gsk.com) suggests that these hostile behaviours in children primarily involved aggression rather than frank violence. When hostile events occurring in both adult and paediatric trials are summed, both on therapy and during the 30-day drug-free phase after taper had finished, 60 (0.65%) of 9,219 patients overall had hostile events. Table 1 shows the results [5].

In these trials, hostile events are found to excess in both adults and children on paroxetine compared with placebo, and are found across indications, and both on therapy and during withdrawal. The rates were highest in children with obsessive-compulsive disorder (OCD), where the odds ratio of a hostile event was 17 times greater (95% confidence interval [CI], 2.22–130.0).

In their submissions to the Committee on Safety of Medicines Expert Working Group, GlaxoSmithKline also reported that 11,491 patients entered trials comparing paroxetine with other antidepressants [5]. In this patient cohort, 44 hostile events occurred on paroxetine or other drugs, a rate of 0.38%. In the subset of trials comparing paroxetine with another SSRI, there were 16 hostile events in 2,418 patients (0.66%). These SSRI comparator trials may be confounded by indication; the SSRI comparator trials might, for instance, have included a higher proportion of patients with OCD.

Finally, in healthy volunteer studies, hostile events occurred in three of 271 (1.1%) volunteers taking paroxetine, compared with zero in 138 taking placebo [5]. Although not statistically significant, this finding is striking because hostile events are unusual in healthy volunteer trials, and this figure was higher than the rate reported in clinical populations above. GlaxoSmithKline ascribed these episodes to the fact that the volunteers were confined, although this applied to both paroxetine and placebo volunteers. One other healthy volunteer study has reported aggressive behaviour in one volunteer taking sertraline [8].

In data from sertraline paediatric trials submitted by Pfizer, aggression was the joint commonest cause for discontinuation from the two sertraline placebo-controlled trials in depressed children [9]. In these trials, eight of 189 patients randomised to sertraline discontinued for aggression, agitation, or hyperkinesis (a coding term for akathisia), compared with no dropouts for these reasons in 184 patients on placebo (95% CI, 1.72–infinity). When discontinuations for any manifestation of treatment-induced activation (suicidal ideation or attempts, aggression, agitation, hyperkinesis, or aggravated depression) were considered, there were 15 discontinuations on sertraline compared with two on placebo, a relative risk of 7.3 (95% CI, 1.70–31.5; p = 0.0015). The report of these studies does not include an analysis of these data [9]. In the only other placebo-controlled sertraline paediatric trial, undertaken in children and adolescents with OCD, there were ten dropouts out of 92 patients on sertraline, five of whom discontinued for behavioural activation, two for agitation, one for aggression, one for nervousness, and one for emotional lability. In comparison, there was one discontinuation for hyperkinesis out of a total of two dropouts from 95 patients on placebo [10].

Finally, in paediatric trials of venlafaxine (Wyeth), two percent of children dropped out because of hostility, more than double the rate of dropout on placebo [11].

By 2003, 121 cases of aggression on paroxetine had been reported to the Medicines and Healthcare Products Regulatory Agency (MHRA), and by January 2006 that number had risen to 211 [12]. It should be noted that such reporting systems estimate that physicians report between one and ten percent of adverse effects on treatment [13].

<span class="postbold">DSRU data</span>

Evidence from two DSRU prescription-event monitoring studies of paroxetine and fluoxetine [6,7] is shown in Table 2, summarising details of aggressive events and assaults in patients prescribed fluoxetine and paroxetine in primary care after the launches of these two drugs. These data are consistent with the clinical trial data reported above. The greatest frequency of events was during the first month of treatment (unpublished data).

<span class="postbigbold">The medico-legal casess</span>

Nine illustrative cases in which we have between us acted as expert witnesses are summarised in Table 3. In eight of them the person who was taking an antidepressant was the defendant; in one (DS; see Annex), the patient killed three members of his family and then himself, and his son-in-law sued SmithKline Beecham. We have chosen the cases to demonstrate the diversity of the issues they raise. They are described in the Annex.

<span class="postbold">E-mails from patients to a BBC television programme</span>

After a programme on paroxetine in 2002, the producers of the BBC television programme Panorama received 1,374 e-mails from viewers, mostly patients. One of us (AH) was able to analyse the full set of these responses. Many linked emotional storms and thoughts and acts of violence or self-harm to paroxetine, both to starting drug treatment and to dosage change. These were not simple anecdotal reports, in that the analysis clearly pointed to a linkage with dosage. Second, they were self-reports of violence from patients with no apparent background of violent behaviour [14]. Third, the analysis was consistent with an analysis of reports of thoughts and acts of violence or self-harm on paroxetine that doctors had sent to the MHRA about other patients between 1991 and 2002 [15]. In both patient and medical reports, severe mood changes were commonly associated with changes of drug dosage during the first week of treatment, with later dosage increase, or with dosage decrease or drug withdrawal. The accounts reported in both the medical and the patient series had much in common, including time frame and a linkage to dosage [15].

<span class="postbigbold">Discussion</span>
<span class="postbold">Mechanisms of antidepressant-induced violence</span>

A link between antidepressant use and violence needs a plausible clinical mechanism through which such effects might be realised. There are comparable data on increased rates of suicidal events on active treatment compared to placebo [16,17]. In the case of suicide, several explanations have been offered for the linkage. It is argued that alleviating the motor retardation of depression, the condition being treated, might enable suicides to happen, but this cannot explain the appearance of suicidality in healthy volunteers. Mechanisms linking antidepressant treatment, rather than the condition, to adverse behavioural outcomes include akathisia, emotional disinhibition, emotional blunting, and manic or psychotic reactions to treatment. There is good evidence that antidepressant treatment can induce problems such as these and a prima facie case that akathisia, emotional blunting, and manic or psychotic reactions might lead to violence.

<span class="postbold">Akathisia</span>

Some of the best descriptions of akathisia come from the medical literature on the use of reserpine as an anti-hypertensive in the mid-1950s [18]:

“Increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable”.

“On the first day of treatment he reacted with marked anxiety and weepiness, on the second day felt so terrible with such marked panic at night that the medication was cancelled”.

“The first few doses frequently made them anxious and apprehensive. They reported increased feelings of strangeness, verbalised by statements such as ‘I don't feel myself’ or ‘I'm afraid of some of the unusual impulses I have'’.

Events such as these in clinical trials of antidepressants have commonly been coded under headings such as agitation, emotional lability, and hyperkinesis (overactivity), and only rarely to akathisia. In clinical practice the term has sometimes been restricted to states of demonstrable motor restlessness, but by definition it cannot be a simple motor disorder or it would be classified as a dyskinesia [19]. There is good evidence that akathisia can exacerbate psychopathology in general [20] and consensus that it can be linked to both suicide and violence [21,22]. A link between akathisia and violence, including homicide, following antipsychotic use has previously been reported [23–25].

Substantial evidence from SSRI clinical trials shows that these drugs can trigger agitation. Approximately five percent of patients on SSRIs in randomised trials drop out for agitation against 0.5% on placebo. The current data sheets for SSRI antidepressants specify that the drugs can cause akathisia and agitation, and warn about developing suicidality in the early phase of treatment, on treatment discontinuation, and in the wake of a dosage increase during the course of treatment. In the US, these warnings explicitly apply to not only depressed patients but also people being treated for anxiety, smoking cessation, or premenstrual dysphoric disorder. In Canada, warnings specify an increased risk of violence in addition to suicide.

<span class="postbold">Emotional blunting</span>

Another mechanism that may contribute to hostile events is treatment-induced emotional blunting. Several reports published since 1990 have linked SSRI intake with the production of emotional blunting, detachment, or an amotivational syndrome, described in one report as the equivalent to a “chemical lobotomy” [26–29]. It is quite common in clinical practice to find people who say they simply are not bothered any more. Things that would previously have worried them no longer do so. However, clinical trials of antidepressants have so far not assessed this phenomenon and its frequency is not reliably known.

<span class="postbold">Mania and psychosis</span>

Another mechanism that may link SSRIs to violence are the manic or psychotic states reported to be induced by drug treatment. These drug-induced states often resolve once the medication is removed. However, the full dimensions of treatment-induced psychotic or manic reactions have yet to be mapped; some may continue for a long period after treatment has stopped [30]. It has recently been estimated that these drug-induced manic or psychotic states may account for up to eight percent of admissions to psychiatric facilities [31–35].

The development of a psychotic episode or of command hallucinations has traditionally been linked to both violence and suicide. The labels for most SSRIs now concede a causal relationship to psychosis and to hallucinations.

A proportion of these cases with superficially manic or psychotic reactions and unrecognised confusion may be delirious states reflecting organic brain disturbances rather than a functional psychosis or mania. Delirium is an absolute defence against murder, while psychosis and mania may not be.

<span class="postbigbold">Somnambulism</span>

Another mechanism that may be relevant to violence and murder is sleepwalking. Somnambulism can provide an absolute defence against murder, in that the defendant in such a case does not have the capacity to form intent. Several reports have been published of an association of paroxetine with sleepwalking in people not previously known to have sleepwalked [36,37]; somnambulism has also been reported for other SSRIs [37]. Among the drugs linked to sleepwalking in reports to the UK MHRA up to January 2006, paroxetine came second with 12 reports, and zopiclone first with 13 reports, with antidepressants occupying eight of the top 17 slots.

Paroxetine has also been reported to the MHRA more often than any other drug for nightmares (206 reports). The second most commonly reported drug is mefloquine (Lariam), a drug noted for triggering psychosis, with 132 reports. Antidepressants occupy six of the top ten slots for reports of nightmares. As mentioned above, clinicians report between one and ten percent of adverse events to regulators and thus the incidence of nightmares on paroxetine is substantial.

<span class="postbigbold">What Our Findings Add to Earlier Reports</span>
Our main finding is that unselected sets of placebo-controlled trials of antidepressants show evidence for an increased relative risk of aggressive behaviours on treatment, although such outcomes apply to only a small subset of patients. The relative risks cited here reflect a net balance of treatment-induced benefits and adverse outcomes. If treatment with an antidepressant, such as paroxetine, lowers the overall risk of aggression in a proportion of patients in a trial population, then the real rate of treatment-induced difficulties with paroxetine may be somewhat higher than the net figures from placebo-controlled trials indicate. Studies in healthy volunteer populations in which treatment would not be expected to reduce aggressive episodes stemming from an underlying clinical condition might help clarify this point.

Data from pharmacovigilance studies support these clinical trial findings, and the literature on antidepressant drugs offers several plausible mechanisms through which such effects might be mediated.

One strength of the current study is that the data are unselected. The data are consistent, although they come from a variety of sources. A weakness of the study is that we have been able to include only a subset of existing data in the analysis. Data on aggression on other antidepressants will necessarily have been collected as part of the development programmes for these drugs, but these data are not in the public domain. The sample of patients cited here is therefore relatively small, especially when selected age-groups and indications are considered. The wide confidence intervals reflect these limitations.

Earlier reports have linked antidepressants to violence [38], but this is the first independent study to offer a quantitative analysis of the issue; no other studies exist with which our results can be compared.

<span class="postbigbold">Legal Implications</span>
The legal system has in recent years been faced with a number of cases of violence in which antidepressant treatment may have played a part. If antidepressants can in principle trigger violence, a need will always remain to establish whether such a general possibility might have been realised in an individual case. The principles involved in making such assessments will involve a consideration of the timing of the events in relation to treatment, the merits of competing explanations, and the existence of evidence in a particular case for a mechanism through which treatment may have led to violence.

At present, different jurisdictions take differing approaches to the issue of whether treatment with a prescription drug can be invoked as a possible defence or mitigating factor in cases of murder or violence. The question of what legal defences are appropriate in such cases needs to be addressed, as do the possible implications of such defences for a defendant and society.

Broadly speaking, treatment-related difficulties of this sort fall under the heading of automatisms. An automatism is defined as a transient, non-recurrent mental malfunction caused by an external factor, whether physical or psychological, that the mind of an ordinary person would be unlikely to have withstood and that produces an incapacity to control his or her acts. However, the question of automatisms has not been mapped onto the domain of potential problems that might result from prescription drug use, as outlined here.

In the DS and DH cases (see Annex), it seems reasonable to argue for an automatism. These men may have been overwhelmed by the effects of prescribed medication to the extent that they may not have been able at the time to form a clear intention to engage in the acts that resulted in the deaths of their families. The case of MC may have involved a case of sleepwalking, which provides a classic defence of automatism. The CP case may have involved command hallucinations. JB had a clear delusional belief system and was therefore found not guilty by reason of insanity.

If these cases are relatively straightforward medico-legally, the cases of NH, MB, AT, and LD are more complex, and may require medico-legal developments. The notion of an automatism is typically invoked to cover behaviours occurring during events such as sleepwalking or epileptic seizures, where normal consciousness is significantly disturbed and the disturbance is of acute onset and brief duration. In contrast, MB, NH, and LD found themselves involved in an extended disturbance, in which consciousness was functioning well enough to allow them to maintain the semblances of normal behaviour for several weeks. Aside from the element of duration, there is a further factor. The situation is more like that of someone whose drink has been adulterated. In such circumstances, some of those affected may guess what has happened and be able to compensate for the hazard, while others may not. In the case of these prescription drugs, one of the mechanisms by which an individual might compensate is to check with his or her physician. In the cases of NH and LD, perceptions of difficulties may have been confounded by professional advice that the drug could not be the source of the problem.

If an element of the hazard posed by treatment stems from a lack of warnings or information, one might argue a particular case against the background of current or recent warnings. Should these drugs in due course come complete with clear warnings that were implemented in clinical practice, one might potentially take a quite different view, closer to the view taken about alcohol and violence.

Further complexities emerge in considering some of the mechanisms listed above. For instance, in the case of AT, how should the possibility of emotional blunting be handled? In the case of a drug that quells normal fearful responses and concern for consequences, it is difficult to know how to determine degrees of responsibility.

For this area to move forward, more data are needed. Pertinent clinical trial data have been generated but remain unavailable. Combining datasets might make it possible to establish whether the risks of treatment are related to age and gender, or whether those with and without prior histories of aggression are affected similarly. While it may be that further data would show that the risk associated with certain SSRIs and tricyclic antidepressants may be less than others, or may not exist in all antidepressants, there is no way to make that determination without access to these data. Indeed, the issue of violence triggered by older antidepressants has been raised before [38]. Current warnings in the US and Canada are consistent across antidepressants, but in other countries, for instance in the UK (see Summaries of Product Characteristics on the Electronic Medicines Compendium Web site, http://emc.medicines.org.uk), the wording differs from drug to drug. Given the new medico-legal issues some of these cases pose, it may well fall to the courts to demand that data now unavailable be made public.

<span class="postbigbold">Conclusion</span>
The new issues highlighted by these cases need urgent examination jointly by jurists and psychiatrists in all countries where antidepressants are widely used. The problem is international, and it would make sense to organise an international effort now.

In practice, clinicians need to be aware of the issues, but serious violence on antidepressants is likely to be very rare. When violence is a suspected outcome, every case has to be considered carefully, on the principle that individuals are responsible for their conduct, unless there is clear evidence of compromised function that cannot be otherwise explained.

<span class="postbigbold">Annex: The Illustrative Medico-Legal Cases Top</span>
<span class="postbold">Case 1</span>

DS was a 60-year-old man with a history of five prior anxiety/depressive episodes. These did not involve suicidality, aggressive behaviour, or other serious disturbance. All prior episodes had resolved within several weeks. In 1990 DS had had an episode of depression, which his doctor treated with fluoxetine. He had a clear adverse reaction to fluoxetine involving agitation, restlessness and possible hallucinations, which worsened over a three-week period despite treatment with trazodone and propranolol that might have been expected to minimise the severity of such a reaction. After fluoxetine was discontinued DS responded rapidly to imipramine.

In 1998, a new family doctor, unaware of this adverse reaction to fluoxetine, prescribed paroxetine 20 mg to DS, for what was diagnosed as an anxiety disorder. Two days later having had, it is believed, two doses of medication, DS using a gun put three bullets each through the heads of his wife, his daughter who was visiting, and his nine-month-old granddaughter before killing himself.

At jury trial in Wyoming in June 2001, instigated by DS' surviving son-in-law, a jury found that paroxetine “can cause some people to become homicidal and/or suicidal” [39]. SmithKline Beecham was deemed 80 percent responsible for the ensuing events [1]. The documentary evidence included an unpublished company study of incidents of serious aggression in 80 patients, 25 of which involved homicide.

Experts for the plaintiff suggested that the mechanism through which paroxetine contributed to these events was probably akathisia or psychosis. A central problem with both akathisia and psychosis in such contexts is that the takers of medications often fail to recognise the fact that the state they are in is drug-induced and that discontinuing treatment can alleviate the symptoms.

<span class="postbold">Case 2</span>

NH was 18 when prescribed paroxetine 20 mg/day by her general practitioner (GP) in Scotland following the death of her grandmother, at the end of November 2001. Within days, she became markedly somnolent, agitated, and emotionally labile. There was an increasing series of arguments at home, and unprecedented aggression. After eight weeks, her parents, concerned about the situation, brought her back to the GP, who increased the dose of paroxetine to 30 mg. One week after the increase of dose and two months after the initial prescription, NH was involved in an incident at a nightclub in which she assaulted another person.

The dose of paroxetine was reduced to 20 mg. Her behaviour remained unstable, disinhibited, and there was at least one suicidal act. Three months later she stopped treatment. She had significant withdrawal problems, but her behaviour normalised. Having been out of work for close to a year she went back to work and has remained in employment since.

NH pled not guilty by virtue of an automatism. The case was heard in open court where the jury found her guilty but added “that antidepressants had contributed to her actions on the day in question”. The judge imposed a suspended sentence, stating that “but for Seroxat you wouldn't be standing here”. This case appears to have involved treatment-induced akathisia.

<span class="postbold">Case 3</span>

DH was a 74-year-old man from New South Wales with a history of mixed anxiety/depressive episodes, many of which resolved without drug treatment. He had no history of violence or suicidality, and had remained gainfully employed throughout.

During one of these episodes, DH was given sertraline (Zoloft) by a GP and clearly responded adversely to this, most notably with agitation. He stopped treatment the following day on medical advice. In July 1999, he sought help from his GP, who was on leave. DH was seen by a locum who admitted in Court that he had not checked DH's file before prescribing sertraline 50 mg. That night, apparently feeling worse after a first dose of sertraline, DH took four more doses of sertraline.

The next morning, after his wife got up he met her in the kitchen and strangled her. He then set off in his car, having decided to kill himself, but turned round and contacted the police to tell them what had happened. He decided he should accept the consequences of his actions and did not want to distress his family further.

DH's lawyers had intended to defend the case on the basis of non-insane automatism or involuntary intoxication, but before the proceedings in May 2001, the Crown made an offer that if DH pleaded guilty to manslaughter on the basis of substantial impairment, the Crown Prosecutor would not contest any defence submission that DH be released from gaol on the date of his sentence. Further, the Crown accepted the case put forward by the defence implicating sertraline. DH accepted that offer in view of his age (78). The judge in his summing-up released DH and stated: “I am satisfied that but for the Zoloft he had taken he would not have strangled his wife” [40].

This case might best be explained in terms of a treatment-induced akathisia or delirious state.

<span class="postbold">Case 4</span>

MB was a 33-year-old woman with two children who had untreated nervous problems since her teenage years. In 2001 she approached her GP who prescribed paroxetine. An initial 20 mg dose was increased to 30 mg. MB appeared to become more anxious and agitated. This deterioration led to a switch to venlafaxine, which was successively increased to 300 mg/day. During these increases, the medical notes record her as being more anxious and agitated, but did not link this to treatment.

She made plans to take her own and her children's lives, and taking the children for a drive, attached a hosepipe to the exhaust. In the course of two efforts to execute this plan, she thought better of it and informed both the police and child-care authorities what had happened. Her children were taken into care and she was charged with attempted murder.

During the sentencing in the Supreme Court of Western Australia in April 2004, the judge stated there were substantial grounds for implicating venlafaxine in MB's behaviour, and gave her a suspended sentence [41]. This case again appears to involve treatment-induced akathisia.

<span class="postbold">Case 5</span>

AT had a baby daughter in December 2000 at the age of 17. In June 2003, her GP noted that she had been “low for 2 years, worse recently”, and prescribed fluoxetine 20 mg. Before treatment she was noted to be “self-harming with superficial abrasions to her lower limbs underneath her trousers and has been thinking of hanging herself. She has not planned to as she would not do that to her daughter and has no immediate plans of suicide of any description.”

Three weeks later she robbed a 14-year-old boy of his phone and watch. Two days later she stole another phone. Four days later, a psychiatrist noted: “She tells me that the intensity and the distress caused by [the suicidal] thoughts have subsided since starting treatment with fluoxetine. [She] feels that her mood did initially improve on fluoxetine but that this effect is now wearing off.” He concluded “it seems that she has partially responded to treatment with fluoxetine…I have advised her to increase the dose of fluoxetine to 30mg in the morning.” She did as advised but the day after, as well as five days later, she engaged in further robberies. Three weeks later she attempted robbery with an offensive weapon.

In October, a forensic psychiatrist examining her in prison noted that for the preceding two months, while in prison she had been prescribed mirtazapine 30 mg nightly (a non-SSRI), and had become calmer and better able to discuss her situation. The writer “would now be surprised if she reverted to her [previous criminal] behaviour.”

AT had never before been involved in criminal behaviour. Her first two offences took place 17 and 19 days after she started fluoxetine. They appear to have been impulsive and were marked by complete lack of feeling. The third, fourth, and fifth offences occurred after a dose increase. The fifth offence involved brutal violence and use of a flick knife. The prison assessment took place when she had been off the drug for about ten weeks, long enough to eliminate the drug.

Her final charges involved robbery and assault as well as child neglect. Based on the medical records, one of us (AH) noted in his report to the court that AT appeared to have suffered treatment-induced emotional blunting. However, the judge in this English case doubted that the effects of the drug could explain the deliberate planning of robberies and she was found guilty and sentenced to three years in prison with no allowance for any contribution from fluoxetine. An appeal was rejected.

<span class="postbold">Case 6</span>

MC started drinking alcohol socially in 1995 at the age of 17. He used ecstasy in 1999 but stopped after a bad experience. He began using cocaine from February 2001, increasing during October through to June 2002, ultimately using 6 g/day for a short time. After July 2002 MC's cocaine use reduced to nil, apart from four minor relapses. He had none after May 2003. MC's alcohol use increased to four to five cans of lager a night in 2002.

He was prescribed paroxetine 20 mg/day for depression in late May 2002. During the first two months on paroxetine he experienced “terrible shaking of the hands; couldn't pick up a glass of milk without spilling it”, felt nausea and had “a constant dull headache, as if squinting in sunlight”. When he missed a tablet of paroxetine, he wanted to hide under a duvet and to stay away from everybody; his hands shook, and he had headaches and nausea. These symptoms lasted a couple of days, and he learned not to miss a dose.

In September, his GP increased paroxetine to 30 mg “because he was still very anxious”, and advised him to take the paroxetine earlier, when its stimulant effects would be more acceptable, rather than late. He was also started on a regular zopiclone prescription at this point to counter paroxetine stimulation. Soon after, another doctor in the practice changed him to the more sedating dothiepin, but after a few weeks he asked to be put back on paroxetine. He subsequently stopped cocaine but began drinking more heavily. Prescriptions of paroxetine and zopiclone continued through to July 2003.

At this stage he was estranged from an ex-partner with whom he had a now 18-month-old daughter. In August 2003, at her home, after ten pints of lager, he took two zopiclone tablets. Following an argument, they had a pint of beer each, during which there was another bout of quarrelling, and she went to bed alone, leaving him to sleep on the sofa. MC may have taken four more zopiclone tablets. He appeared later that night blood-stained in the local police station with his daughter in his arms. The police found his partner dead from multiple stab wounds. He was charged with murder.

In prison paroxetine 30 mg was continued; zopiclone was stopped. During his initial period on paroxetine, and then in prison, MC complained of “terrible nightmares, waking dripping with sweat, soaking the bed”. Intense frightening nightmares have been reported regularly in healthy volunteers taking paroxetine. MC had no reported episodes of sleepwalking before using paroxetine, but he had a number of documented episodes of sleepwalking after starting the drug, and two first-degree relatives had a history of sleepwalking. Sleepwalking has been reported in association with zolpidem, a hypnotic related to zopiclone [42–44], but no case of sleepwalking on zopiclone has been reported in the scientific literature. However, as noted above, zopiclone is the drug most commonly linked to sleepwalking in Yellow Card reports to the MHRA.

Clearly violence follows domestic arguments, and is a known effect of alcohol, but this case offers grounds also to implicate paroxetine and zopiclone. Zopiclone is known to cause a dose-dependent confusion and amnesia comparable to that found with benzodiazepines [45]. Violence cannot however be attributed to a direct effect of paroxetine alone, since MC had been maintained on this for almost one year with no prior violence. In these circumstances MC pleaded guilty at his trial on 27 February 2006. The judge did not accept that paroxetine and zopiclone had played any part, and sentenced him to 13 years prison. An appeal against the sentence is being prepared.

<span class="postbold">Case 7</span>

JB was 66 years old, married to a second wife ten years his junior. They had marital difficulties, with frequent arguments but no history of violence. JB had medical complaints and longstanding depression and anxiety. Digestive symptoms were treated with an antispasmodic combined with chlordiazepoxide (5 mg four times daily); generalised anxiety was also treated with chlordiazepoxide (10 mg twice daily); an undiagnosed movement disorder, characterized by twitches and tics, was treated with clonazepam (0.5 mg at night). In addition, JB had been treated with the antidepressant doxepin 75 mg at night for years.

Concerned about the sedative effects of his medication, JB's wife began replacing active doxepin powder with sugar in an attempt to offset this effect. JB suspected the capsules had been tampered with. His wife admitted doing this when they saw a new psychiatrist in mid-August 1994. The doctor considered JB to have major depression with anxiety, complicated by physical symptoms and marital strife. He noted that JB was not psychotic or suicidal, and agreed that doxepin be discontinued, instead prescribing fluoxetine 10 mg daily, continuing the other medications as before.

JB was meticulous about compliance and even kept a medicines log. He remained concerned that his wife was tampering with his pills, and after four weeks fluoxetine accused her of being unfaithful. Alarmed at his suspicions, his wife rang the psychiatrist and disposed of the household gun. Meanwhile, JB's friends noted that, normally placid, he had become tense, strange, and suspicious; he asked for a replacement gun to defend himself; described a plan to escape an expected attempt on his life; feared poisoning of food and drink; feared an ambush when visiting his mother's grave. Two months after starting fluoxetine JB had become floridly deluded, expecting to be attacked or poisoned by his wife, or her agent. The psychiatrist received phone calls of concern from friends and family but did not alter his treatment. One evening in mid October 1994 JB approached his neighbours, covered in blood, reporting an attack by his wife. He had several minor cuts to his arms. His wife was found dead in their hallway, in a pool of blood with 200 stab wounds.

In 1996, a Mississippi court found JB not guilty of murder by reason of insanity [46]. He was confined to a mental hospital, where he remains, even though on review of his medical notes by one of us (DM), it was clear that his psychosis cleared on withdrawal of fluoxetine, and further treatment. His physicians are concerned about the risk should he be discharged. Although prescription drugs were not invoked in his defence, a subsequent civil case seeking damages from Eli Lilly (Prozac) and Hoffman LaRoche (benzodiazepines) was settled in 2005 (personal communication from plaintiff's lawyer, R. Boyd). This homicide case involves a treatment-induced psychosis.

<span class="postbold">Case 8</span>

LD, a 31-year-old mother, separated from the father of her 3-year-old twin boys in 2001. After a protracted custody battle, she began experiencing episodes of dizziness, sweating, shaking, nausea, and pressure in the chest. She was well between episodes, experienced no suicidality, irritability, or aggression, and continued to care for her sons as before, living in the same house as her father and his second wife.

Reading a magazine, she saw an advertisement for “panic disorder”, and recognised many of the symptoms described in it. She contacted her family doctor, but no appointments were available and she saw the nurse practitioner instead. She was given a free starter pack of sertraline 25 mg, and a prescription for alprazolam 0.5 mg twice daily to start immediately.

LD found the drugs stopped her panic attacks, but she experienced increasing tension, restlessness, and agitation, which worsened when the “starter pack” dose of sertraline increased after one week from 25 to 50 mg/day. Other unexpected effects were that her previous moderate alcohol intake took on a compulsive quality, and she became increasingly depressed and began to think of suicide. On one occasion she found herself in the closet holding her father's pistol before “coming to” and realising what she was doing. Alarmed, she tried to see her doctor, but he was not available. She again saw the nurse, who switched her from sertraline, which she had taken for a month, to a starter pack of paroxetine 20 mg/day and advised continuing alprazolam at 1 mg/day.

LD's agitation, restlessness, depression, and suicidal ideas worsened. Two days after the switch to paroxetine, she claims she took double the prescribed amount of both paroxetine and alprazolam, hoping this would help. It didn't. She drank alcohol and sounded intoxicated on the phone. Claiming she saw no future for herself or her children, she shot both in the head just before their afternoon nap. She recalls intending to kill herself as well, but did not do this immediately as she noticed one son was still breathing. Unwilling to “leave him behind”, she waited but passed out from her overdose of alprazolam and alcohol, and was discovered deeply asleep with her twins dead next to her. Her blood and urine alcohol levels showed marked intoxication.

The Florida State Attorneys initially sought to have LD convicted of murder and sentenced to death, but later dropped pursuit of the death penalty. The defence team contended that LD was not guilty by reason of temporary insanity caused by the prescription drugs provided by the nurse practitioner. Prior to trial a “Frye” hearing was held to consider whether evidence regarding SSRI-induced akathisia, involuntary alcohol intoxication, suicidality, and homicidality would be admissible. The judge ruled that evidence could be admitted indicating that akathisia was associated with SSRI treatment, but that a causal relationship could not be argued. With this restriction on defence testimony, the State Attorneys convinced the jury that the drugs did not play a causal role in the homicides. LD was convicted, and sentenced to life without possibility of release [47].

<span class="postbold">Case 9</span>

According to an independent forensic report compiled a year after the events for which CP was charged in November 2001, CP was a 12-year-old, 5'2”, 95-lb boy with a family background involving considerable social dislocation. Despite the difficulties of his social situation, he had no record of treatment for nervous disorders or of violence or behavioural disturbance. Following an argument with his father at the end of October 2001, he was admitted to a behavioural centre for six days where he was started on paroxetine. His behaviour worsened daily on paroxetine. He was discharged against medical advice to the care of his grandparents, who, when his paroxetine ran out, took him to their primary-care physician who prescribed sertraline 50 mg, increasing this to 100 mg two days before the killings for which CP was charged. The duration of sertraline treatment was three weeks.

After the prescription of sertraline, CP was involved in a number of aggressive incidents at school, the first on record for him, and was reported by family members and church members to be restless and talking unusually volubly. Relatives noted a series of risky behaviours. On the day of the killings, his grandparents had told him that he could not take the school bus following an episode of aggression toward one of the other children on the bus. Later that evening he attended choir practice with his grandparents, who in response to escalating difficulties had warned him he might have to be returned to his father.

The independent forensic report on the case notes CP as saying that that night: “something told me to shoot them”. He had initially reported this to be hallucinations and then said he thought it was his own thoughts. When asked to specifically describe what the experience was like, he said it was “like echoes in my head saying ‘kill, kill’, like someone shouting in a cave”. According to the forensic report, “He reported this began happening after he went to bed…He reported he had never considered harming his grandparents before and this was unlike anything he had previously experienced. He reported that the voices were coming from inside his head and they bothered him so much that he got up. He reported that the voices continued until he killed his grandparents. He reported that he couldn't control himself and reported the echoes stopped after he shot his grandparents. He set fire to the house but could not explain these actions saying the thoughts just popped up”. He then took a vehicle and began driving but reported that he had no idea where he was going and that it all felt like a dream. He recalled asking the police about his grandparents after he was picked up because he was not sure if it had really happened or not.

These events and CP's overall behaviour and history led an independent forensic child psychiatrist to diagnose substance-induced mania and psychotic disorder. The charges of double murder and arson were heard by jury trial in an adult rather than juvenile court. In the process of jury selection, 32 of 75 prospective jurors declared that they or someone related to them were on or had been on an antidepressant. Court TV covered the trial in its entirety. Both prosecution and defence from the outset accepted that CP had shot his grandparents. Media coverage focused heavily on the question of “‘Evil’ or ‘chemically compelled’?”

In February 2005, after a two-week trial, a jury found CP guilty of murder and he was sentenced to 30 years in prison [48]. Questioned by the media afterwards, “Steven Platt, a 26-year-old accounting clerk for an electrical supply wholesaler, said the group believed that Christopher exhibited side effects from Zoloft but did not feel it was severe enough to let him escape criminal responsibility” [49]. Summing up some of the points at issue, the judge Daniel Pieper stated: “There is no case in South Carolina that addresses involuntary intoxication by prescription drugs…It seems to turn the whole medical system on its side if you can't rely on the medication your doctor prescribes. It could potentially force you into a situation of lifetime commitment if that drug induces an effect of which you're not aware… There's something disconcerting about that, albeit probably something of a legal nature that is troubling me” [50]. The verdict is currently under appeal in the South Carolina Supreme Court.

<span class="postbigbold">Acknowledgments</span>
We thank the MHRA for data on the frequency of yellow card reports of certain adverse reactions in their database.

<span class="postbigbold">References</span>
<small>
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</small>
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