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Gli antidepressivi come i placebo

SSRI

New Research on the Antidepressant-vs.-Placebo Debate

(Updated) In the 1990s, everyone was “Listening to Prozac,” after best-selling author Peter Kramer described sparkling personality transformations in patients who took the titular antidepressant drug. Then came the backlash: by the early 2000s, studies showed that Prozac and other selective serotonin reuptake inhibitors, or SSRIs, weren’t exactly miracle pills but were instead associated with suicide, especially in kids and teens. Another whiplash-inducing turn came in 2008, when a review of the research found that the drugs were actually no more effective than sugar pills, except in cases of the most severe depression.

Last month, research published in the Archives of General Psychiatry sought to help explain the paradoxical findings on SSRIs and other new generation antidepressant drugs, the increasingly popular medications that are now used by more than 1 in 10 Americans over 12. Using a new statistical approach, researchers led by Dr. John Krystal at Yale University School of Medicine reanalyzed data from seven clinical trials involving 2,515 patients, whose results were used to win FDA approval for the SNRI (a drug that affects both serotonin and norepinephrine) duloxetine (Cymbalta).

Known as growth-mixture modeling, the statistical technique allowed the authors to track how individual patients improved or worsened over time in response to medication or a placebo. The researchers found that roughly three-quarters of patients did better on medication than on a placebo. “That’s much more than half and half. That’s quite favorable,” says Krystal.

However, Krystal adds, just under a quarter of patients did not respond well to drug treatment and in fact did worse on antidepressants than did patients who were given a placebo.

MORE: Report: 1 in 5 American Adults Takes Mental Health Drugs

The benefit of growth-mixture modeling is that it reveals treatment trajectories of patients rather than looking at outcomes on average. When some patients get better while others get worse, the true impact of the drug may be “canceled out” in the data if they are considered only in the aggregate, obscuring both the drug’s harms and its benefits. That may help explain why some research finds that antidepressants work no better than a placebo.

“This has enormous implications for understanding the limits of the effectiveness of our current medications,” says Krystal. “These data really caution against the demonization of antidepressants as merely placebo, but they do raise a concern that some people are better off on placebo than on the antidepressant that they’re getting.”

Irving Kirsch, professor of psychology at the University of Hull in England and author of a 2008 meta-analysis in PLoS Medicine that found little benefit of antidepressants for most patients, is less sanguine about the new study. He characterizes the results as “indeed important” but says they suggest that “while many people may benefit from antidepressant treatment (although most of them to a degree that is not clinically significant), about 1 in 4 are made worse.”

“What makes this particularly problematic is the fact that we don’t know who these people are,” Kirsch says. “Although placebo may not be a viable treatment option, there are other treatments that on average work as well as antidepressants, [such as] physical exercise and cognitive behavioral psychotherapy. As far as we know, these alternatives don’t make people worse.

“This suggests to me that antidepressants should be kept as a last resort, and if a person does not respond to the treatment within a few weeks, it should be discontinued,” says Kirsch.

Krystal agrees that if one-quarter of patients with depression are made worse by antidepressant treatment, “we need to find ways to identify who those people are and find other ways to reach that group of people.”

MORE: Study Shows Antidepressants Affect Brain Differently than Placebo

Krystal’s study also found that people who improved on a placebo did so as quickly as those who improved with medication. This is important because it suggests that using a “washout period,” a technique used in some clinical trials to weed out placebo responders by eliminating participants who respond quickly, may not work with antidepressant studies.

“It counteracts the expectations that the field has that placebo response is fast and drug response is slow. Simply having a brief placebo-exposure period is not likely to eliminate the impact of placebo on outcome,” Krystal says.

That further complicates efforts to figure out the true effects and mechanism of antidepressant drugs. “We’re going to have to study people who are worse off on drug than placebo, and [not knowing who they are] will make it harder to determine whether there’s a statistically significant effect of the drug.” And given that it may be difficult to eliminate placebo responders simply through clever study design, questions about how antidepressants work, and in whom, may not be resolved until genetic or other tests can be devised to predict individual responses.

“This going to remain a challenge for study for some time,” concludes Krystal, whose latest study was funded by the government but who has received industry funding for other research.

MORE: Study: Stress-Depression Connection Sheds Light on Antidepressant Effects

A separate study published in the American Journal of Psychiatry (AJP) in December highlights other potential complications. The authors of that paper report that since 1980, the percentage of depressed patients responding to a placebo in clinical trials has risen by 7% per decade, reaching 50% in some studies.

Why? In the early years, participants for antidepressant trials were recruited from psychiatric hospitals, which meant that only the most severe cases were included. Today, however, participants are often recruited through advertisements and are paid to be in the trials. That introduces two problems that skew study populations: the most seriously depressed people often lack the capacity even to make a phone call in response to an ad and are thus overlooked, while other people may be persuaded to exaggerate symptoms of depression in order to participate in the trials and get the money. The authors of the AJP study report cases of “professional guinea pigs” who faked symptoms or enrolled in several trials at once.

Given the complexities of studying antidepressants — which appear to be placebos for some, poisons for others and miracle pills for yet others — it seems that data analysis in antidepressant research will likely remain a growth industry for decades to come. Until scientists can work it out, patients and psychiatrists will have to try multiple methods to treat depression until they hit on something that helps, keeping in mind that antidepressant drugs may backfire for some patients.

MORE: Why American Presidents (and Some Oscar Winners) Live Longer

Correction [Jan. 23, 2012]: The original version of this story mischaracterized Cymbalta as a selective serotonin reuptake inhibitor, or SSRI. The antidepressant drug is an SNRI, which affects both norepinephrine and serotonin.

Maia Szalavitz is a health writer for TIME.com. Find her on Twitter at @maiasz. You can also continue the discussion on TIME Healthland‘s Facebook page and on Twitter at @TIMEHealthland.

Read more: http://healthland.time.com/2012/01/18/new-research-on-the-antidepressant-versus-placebo-debate/#ixzz2Jdn2N6Ft

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Psichiatria

The shooters

Film Title: ShooterShooters

Steven Taylor

Several writers of my acquaintance, such as Allen Ginsberg and Ed Sanders, developed the habit of keeping extensive files of press clippings on stories of personal interest. Noam Chomsky, we’re told, does the same thing. An individual news report may mention something in passing that may seem secondary to the main narrative, but when multiple stories collected over time repeat the same seemingly secondary data, important patterns can become apparent.

For example, for many years Ginsberg clipped New York Times articles having to do with the international traffic in narcotics. This collection eventually served as one of the sources for historian Alfred W. McCoy’s definitive study linking the heroin trade to U. S. government agencies, The Politics of Heroin.

Now, amid the sickening media parade endlessly looping, one aspect of the mass shooter phenomenon is continually skipped, but a survey of press reports on the spate of bizarre violence that has arisen since the 1990s reveals a pattern.

In the past few days, following the Newtown murders, various experts have weighed in on the difficulty of profiling the mass shooter type. (An accurate psychological profile, presumably — and hideously problematically — could enable parents, teachers, doctors, and law enforcers to predict which individual is headed toward being the next shooter.)

Despite the difficulty of such profiles and predictions, there are two things that such characters have in common. First, they are mostly young white males. Second, many of the perpetrators are reported to have been taking psychoactive prescription medication.

The website “SSRI Stories: Antidepressant Nightmares” offers a sortable database of more than 4,800 newspaper articles, scientific journal reports, and TV news items linking antidepressant use to cases of extreme violence.

It is important to note that this site is not peddling some conspiracy theory. It is not speculative at all. The website is an index to reputable sources reporting on actual criminal cases, and in all cases reported, prescription meds are implicated.

The articles show that these violent acts were perpetrated by consumers in the 50 billion dollar a year selective serotonin reuptake inhibitor (SSRI) industry. This is a class of drugs whose warning labels and pharmaceutical literature note that a small percentage of SSRI consumers fantasize about and/or exhibit extreme violence.

I was originally tipped to this in July of 2012 in an article by RS regular Jonathan Zap, which he wrote in the wake of the so-called Batman shootings of that summer.

Zap notes as follows.

“Mass shootings, like the one that just happened in Aurora [Colorado], have become a recurrent nightmare that haunts the collective psyche. As the nightmare repeats, we see patterns emerging. One, which we don’t have confirmation on yet in this case, is that the shooter will almost always turn out to be on an SSRI (selective serotonin reuptake inhibitor). For example, Colorado’s other most famous mass shooting, Columbine, was masterminded by 18-year-old Eric Harris who was on the SSRI medication Luvox. Here’s an index of shootings and the SSRI connection someone put together.”

The website Jonathan links us to, “SSRI Stories: Antidepressant Nightmares,” concentrates on reports implicating Prozac (the FDA’s number 2 drug for violence), Zoloft, Paxil (number 3 for violence), Celexa, Lexapro, Luvox, Remeron, Anafranil, Effexor, Cymbalta, Pristiq, and Wellbutrin.images

Here are a few samples of reports from the site, with comments.

“Tim Kretschmer . . . walked into Albertville Secondary in Winnenden, near Stuttgart, at 9.30am on Wednesday armed with a 9mm Beretta he had stolen from his gun enthusiast father and wearing a K4-Schutz bulletproof vest and the black fatigues of Germany’s elite forces, the Kommando Spezialkräfte. . . . He killed nine pupils at Albertville, all but one a girl, and three teachers, all women, in less than 10 minutes. He then shot and killed three bystanders as he tried to escape, before taking his own life after a shootout with police. . . . It emerged that Kretschmer had been suffering from depression . . . and receiving medication for the condition.” –Scotland On Sunday, Edinburgh, March 14 2009.

“Hours before he walked into a Northern Illinois University lecture hall and inexplicably started a shooting rampage that ended five lives and his own, Steve Kazmierczak called one of the people he was closest to and said what would be a final goodbye. . . . [According to his girlfriend] ‘he was anything but a monster. He was probably the nicest, most caring person ever’. . . . [She said] he saw a psychiatrist monthly but stopped taking Prozac a few weeks ago. She said the medicine ‘made him feel like a zombie’.” –Chicago Sun Times, February 8, 2008.

What we might call the “zombie effect” seems to come up in many of these cases. Also common is that the violent behavior tends to occur when the patient is either having the dosage adjusted, or has just stopped taking the pills.

SSRIThe “SSRI Stories” site notes the following.

“The danger of withdrawal from antidepressants and antipsychotics is well documented. The brain tries to compensate for the blockage of the serotonin and dopamine receptors by growing additional receptors for these neurotransmitters. When the medications are discontinued, these additional receptors contribute to an ‘overload’ of serotonin and dopamine flooding the receptor. This is known as ‘supersensitivity psychosis’ and ‘antidepressant discontinuation syndrome’.”

“BEMIDJI, MINN. — Jeffrey Weise had ‘a good relationship’ with the grandfather he shot and killed on Monday as prelude to his deadly assault on students and others at Red Lake High School, according to relatives who are struggling to understand what might have pushed the teenager from sometimes bizarre behavior to mass murder and suicide. . . . They wondered, too, about medication he was supposedly taking for depression, and a recent increase in his prescribed dosage. . . . 60 milligrams a day of Prozac.” –Star Tribune (Minnesota), March 24, 2005.

Consistent with the “zombie effect” noted above, many sources indicate that some perpetrators who survive their crime scenes report being in a dreamlike state in which they feel they are watching their actions but not in control of them. Some of the literature notes sleep disorders, and speculates that the drugs induce a state of waking dream in which one becomes a passive witness to one’s actions. (Christopher Pittman, who killed his grandparents and set fire to their house told his father afterward that it had been like watching a TV show.) Other sources say the shooters do not remember their crimes or do not associate themselves with what occured.

“Huntsville, AL. — 15 year old Hammad Memon is free on bond, awaiting trial on murder charges for the February 2010 shooting death of fellow Discovery Middle School student Todd Brown. . . . Memon has a history of being treated for Attention Deficit Hyperactivity Disorder and Depression. He was being medicated with Zoloft and other drugs for the conditions. . . . Memon’s mother is quoted as saying ‘My son is not normal. He is immature (mentally) for his age. He has become very depressed and withdrawn for the past 2 years, especially in the last 12 months. He does not have insights into what crime he has committed’.” –The Free Republic (Alabama), Feb 5 2012.

“CARTHAGE, NC — Jurors in the Robert Stewart murder trial reached a verdict Saturday. He was found guilty of eight counts of second-degree murder in a shooting rampage at a North Carolina nursing home in 2009. . . . Stewart’s defense lawyers said the 47-year-old was essentially sleepwalking at the time due to taking a combination of prescription drugs. . . . Defense attorney Jon Megerian said Ambien and other drugs in Stewart’s system caused him to be in a zombie-like state of mind when he entered the nursing home. . . . In pleading Stewart’s case, his defense said he was full of remorse, but couldn’t remember anything. –WTVD television, North Carolina.

There have been a number of cases where defendants have been found not responsible for their actions due to the effects of the medication.

“STAMFORD, CT — A Stamford lawyer who shot at a motorist, then broke into his ex-wife’s house was found not guilty by reason of mental disease or defect yesterday. Eric Witlin, 40, will be committed to Whiting Forensic Institute for evaluation until he returns to court July 14. Judge Richard Comerford could commit Witlin for the time he could have been sentenced to prison, a total of 70 years. . . . Two psychiatrists, including one hired by the prosecution, testified that Witlin suffered a psychotic episode brought on by Adderall and Prozac, which were prescribed to treat attention deficit disorder and depression. . . . Senior Assistant State’s Attorney James Bernardi said Witlin’s mental state on the night of the incident was uncontested, since both psychiatrists agreed. –Stamford Advocate, May 20, 2008.

“Anna L. Tang, the troubled former Wellesley student, is finally free to resume her life and has been discharged from court custody. . . . Tang came to the attention of most MIT students in October 2007 when she stabbed her ex-boyfriend, Wolfe B. Styke, then a freshman, in his Next House dormitory room. . . . Tang has bipolar disorder, which she sought help for when she first arrived at Wellesley in 2005. At that time, she was diagnosed with depression and was prescribed an antidepressant. However, as Tang’s psychopharmacologist Michael J. Mufson testified during the trial, bipolar disorder cannot be treated with antidepressants. Doing so creates oscillatory behavior. ­ ‘It made her lows lower and her highs get higher’, Mufson said. That combination of misdiagnosis and mistreatment led to her attack on Styke. Judge Henry found in December that Tang lacked the substantial capacity to conform her actions to the requirements of the law and that she lacked the capacity to appreciate the wrongfulness of her actions. The Tech (MIT student newspaper), Feb 8, 2011.

In other legal news, there have been some 450 suicide-related lawsuits settled out of court by GlaxoSmithKline, the maker of Paxil.
“Since Paxil came on the market in 1992, there have been three separate types of failure to warn lawsuits filed: birth defects, suicide, and addiction. Roughly 150 suicide cases were settled for an average of about $2 million, and about 300 cases involving suicide attempts were settled for an average of $300,000, according to a December 14, 2009 report by Bloomberg News. Glaxo paid an average of about $50,000 each to resolve about 3,200 cases linking Paxil to addiction problems. . . . All total, Glaxo has paid out close to $1 billion to resolve Paxil lawsuits since the drug came on the market in 1992. The company’s provision for all legal matters and other non-tax disputes as of the end of 2008 was listed as $3.09 billion in its annual report.” –Dissidentvoice.org.

To summarize, FDA warnings, court finding, and too many news reports to count make a connection between one of the most widely prescribed drug types and bizarre, ostensibly “inexplicable” violence. And though there are thousands of sources and multiple vectors of association implicating the 50-billion-dollar business in SSRIs to some of the most hideous crimes of our day, the major media continue to spin their wheels about the “unexplainable.” This story needs to go viral. Now.

Image by Carsten Achertzer, courtesy of Creative Commons license.

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