02/3/17

“Political” Science?

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A 2014 study by a well known researcher from Columbia University indicated that “Sexual minorities living in communities with high levels of anti-gay prejudice experienced a higher hazard of mortality than those living in low-prejudice communities.” The press release for the study said it was the first study to look at the consequences of anti-gay prejudice for mortality. The study’s lead author, Mark Hatzenbuehler, said: “The results of this study suggest a broadening of the consequences of prejudice to include premature death.” The authors thought their study’s results highlighted the importance of examining structural forms of stigma and prejudice as social determinants of health and longevity among minority populations. A significant and potentially important finding—except it may not be true.

The original study, “Structural Stigma and All-Cause Mortality in Sexual Minority Populations” by Hatzenbuehler et al. was published in the February 2014 issue of Social Science & Medicine. Another researcher, Mark Regnerus, set out to replicate the Hatzenbuehler et al. study, but was not able to do so. Regenerus included a more refined imputation strategy in his replication, but still failed to find any significant results. “No data imputation approach yielded parameters that supported the original study’s conclusions.” Regenerus said:

Ten different approaches to multiple imputation of missing data yielded none in which the effect of structural stigma on the mortality of sexual minorities was statistically significant. Minimally, the original study’s structural stigma variable (and hence its key result) is so sensitive to subjective measurement decisions as to be rendered unreliable.

Writing for the National Review, Maggie Gallagher said that Regenerus’s failure to replicate the Hatzenbuehler et al. study amounted to a repudiation of that study. She also thought the study was faked. “When social justice displaces truth as the core value of academics, bad things happen to science.” She implied Hatzenbuehler might have slipped a bogus study into a major social-science journal, “confident that nobody would want to review and contest its findings, which so please the overwhelmingly liberal academy.”

Gallagher then referred to Mark Regenerus as an emerging scientific hero; a “modern-day Galileo standing up to the new theology of the Left.” But I think she misses the point. Both Hatzenbuehler and Regenerus are doing exactly what they are supposed to do in science: publishing their results and attempting to replicate the research of others. Henry Bauer, a professor of Chemistry & Scientific Studies at Virginia Polytechnic Institute and State University, describes how the “knowledge filter” in science can help uncover the real failures and confirm the true successes.

Bauer asks what would happen if most scientists rounded off or fudged their findings. What if they thought more about who wanted results and less about what an experiment actually showed? “To understand why science may be reliable or unreliable, you have to recognize that science is done by human beings, and that how they interact with one another is absolutely crucial.” He then went on to describe how frontier science leads to publication in the primary literature.

If those [findings] seem interesting enough to others, they’ll be used and thereby tested and perhaps modified or extended – or found to be untrue. Whatever survives as useful knowledge gets cited in other articles and eventually in review articles and monographs, the secondary literature, which is considerably more consensual and reliable than the primary literature.

Regenerus’s findings themselves have to be replicated; by more than one additional study before Gallagher’s assessment that Regenerus repudiated Hatzenbuehler et al. is confirmed. Concluding the study was faked or bogus based just upon his findings is irresponsible and goes beyond what Regenerus himself said.

Regenerus said the findings of the Hatzenbuehler et al. study seemed to be very sensitive to subjective decisions made about the imputation of missing data, “decisions to which readers are not privy.” He also thought the structural stigma variable itself was questionable, “Hence the original study’s claims that such stigma stably accounts for 12 years of diminished life span among sexual minorities seems unfounded, since it is entirely mitigated in multiple attempts to replicate the imputed stigma variable.” He thought his study highlighted the importance of cooperation and transparency in science.

The unavailability of the original study’s syntax and the insufficient description of multiple imputation procedures leave unclear the reasons for the failed replication. It does, however, suggest that the results are far more contingent and tenuous than the original authors conveyed. This should not be read as a commentary on missing data or on the broader field of the study of social stigma on physical and emotional health outcomes, but rather as a call to greater transparency in science (Ioannidis, 2005). While the original study is not unique in its lack of details about multiple imputation procedures, future efforts ought to include supplementary material (online) enabling scholars elsewhere to evaluate and replicate studies’ central findings (Rezvan et al., 2015). This would enhance the educational content of studies as well as improve disciplinary rigor across research domains.

Regenerus is not a scientific hero and Hatzenbuehler is not a research villain. But two other individuals identified by Gallagher in her article may fit within those categories.

Michael LaCour co-authored a paper along with Donald Green that was published in the prestigious journal Science in December of 2014. The original article abstract said: “LaCour and Green demonstrate that simply a 20-minute conversation with a gay canvasser produced a large and sustained shift in attitudes toward same-sex marriage for Los Angeles County residents.” Green is a highly respected political science professor now at Columbia. LaCour was a political science grad student at UCLA.

Back in September of 2013, Michael LaCour met with David Broockman at the annual meeting of the American Political Science Association and showed him some of the early results of his study. Writing for NYMag.com, Jesse Singal noted how Broockman was “blown away” by some of the results LaCour shared with him. LaCour also told him he was looking to get Donald Green as a coauthor on the paper. Coincidentally, Green happened to be Broockman’s undergraduate advisor when they were both at Yale.

Singal pointed out that LaCour’s results were so noteworthy because they contradicted every established belief about political persuasion. “The sheer magnitude of effect LaCour had found in his study simply doesn’t happen — piles of previous research had shown that.” In early 2015, Broockman decided to replicate LaCour’s findings. The first clue there was something wrong was when he realized the estimated cost for a replication would be a cool million dollars. Where would a grad student like LaCour get the money or funding for a study like that? That first anomaly eventually led to: “Irregularities in LaCour (2014),” a 27 page report he coauthored with Josh Kalla and Yale University political scientist, Peter Arnow.

“Irregularities” is diplomatic phrasing; what the trio found was that there’s no evidence LaCour ever actually collaborated with uSamp, the survey firm he claimed to have worked with to produce his data, and that he most likely didn’t commission any surveys whatsoever. Instead, he took a preexisting dataset, pawned it off as his own, and faked the persuasion “effects” of the canvassing. It’s the sort of brazen data fraud you just don’t see that often, especially in a journal like Science.

Green quickly emailed the journal and asked for a retraction, which he received. When contacted about comments that he had failed in his supervisory role for the study, Green said that assessment was entirely fair: “I am deeply embarrassed that I did not suspect and discover the fabrication of the survey data and grateful to the team of researchers who brought it to my attention.”

LaCour had a job offer as an incoming assistant professor at Princeton rescinded. He also reportedly lied about several items on his curriculum vitae, including grants and a teaching award. You can review a post mortem of the LaCour controversy by Neuroskeptic for Discover Magazine here. Neuroskeptic thought LaCour’s objections to Broockman et al. were weak. He also thought Lacour’s objections to the findings of Broockman et al. failed to refute their central criticism.

Cases of seeming scientific fraud, like that of LaCour, draw attention to themselves when they are discovered. Writing for STAT News, Ivan Orlansky and Adam Marcus described a survey by researchers in the Netherlands of working scientists. They were asked to score 60 research misbehaviors according to their impressions of how often the misbehaviors occur, their preventability, the impact on truth (validity), and the impact of trust between scientists.  The respondents were more concerned with sloppy science than scientific fraud. Fraud, when it occurred, has a significant impact on truth and public trust. But those cases are rare; and detected cases are even rarer. They concluded:

Our ranking results seem to suggest that selective reporting, selective citing, and flaws in quality assurance and mentoring are the major evils of modern research. A picture emerges not of concern about wholesale fraud but of profound concerns that many scientists may be cutting corners and engage in sloppy science, possibly with a view to get more positive and more spectacular results that will be easier to publish in a high-impact journal and will attract many citations. In the fostering of responsible conduct of research, we recommend to develop interventions that actively discourage the high-ranking misbehaviors from our study.

So it would seem that problems with the Hatzenbuehler et al. study are not fraud, but could be due to smaller more pervasive issues in its research, such as a shoddy methodology. The LaCour case catches more attention and generates mistrust because of its apparent fraud. Orlansky and Marcus are right. Although not as flashy as fraudulent research, the smaller, less outrageous research sins are a greater threat to scientific credibility. Gallagher may have let her own ideology influence how she emphasized these two cases, but she was unquestionably right in her concluding remarks:  “Science is not right-wing or left-wing. But to work, it needs scientists fearlessly committed to truth over their preferred outcomes.”

01/24/17

Herding Pharma “Cats”

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The Chinese government released a report in September of 2016 by the State Food and Drug Administration (SFDA) that found fraudulent clinical trial practices on a massive scale. The SFDA concluded that over 80% of clinical trial data was fabricated. The scandal was the result of a “breach of duty by supervision departments and malpractice by pharmaceutical companies, intermediary agents and medical staff.” More than 80% of the applications for the mass production of new medications have been cancelled, with warnings by the SFDA that further evidence of malpractice might still emerge.

Radio Free Asia also reported the SFDA indicated much of the clinical trail data was incomplete at best. But it also failed to meet basic analysis requirements or was untraceable. “Some companies were suspected of deliberately hiding or deleting records of adverse effects, and tampering with data that did not meet expectations.” Apparently, this came as no surprise to industry insiders. “Clinical data fabrication was an open secret even before the inspection.”

Many of the new drugs were combinations of existing ones. Clinical trial outcomes were written beforehand, and their data presented so it agreed with the fabricated outcomes. A doctor at a top Chinese hospital said the problem lay with the failure to implement regulations governing clinical trial data. “Guangdong-based rights activist Mai Ke said there is an all-pervasive culture of fakery across all products made in the country.” Reporting for Pharmafile, Ben Hargreaves said:

The root of the issue is then not regulation, with regulation for clinical trials running on similar lines to Western practises, but in the lack of adherence to them. China’s generic drug industry has struggled with quality problems and therefore there is a temptation for companies to manipulate data to meet standards. The report found that many of the new drugs were found to be a combination of existing drugs, with clinical trials outcomes written beforehand and the data tweaked to fit in with the desire outcomes.

Sadly, clinical trial problems are not unique to China. An editorial published in the British journal The Lancet Psychiatry described multiple issues beginning with how subjects are recruited, moving on to determining what the control group should be, and ultimately defining meaningful outcome measures. Sometimes, trial recruits receive “care” they didn’t agree to. “Researchers and ethics review boards need to examine the ethical arguments and practical procedures from other areas of medicine where consent is problematic.” If such trials are done, regular and rigorous monitoring is essential. Patient safety and autonomy needs to be a priority.

In his discussion of the editorial, Justin Carter elaborated on one of the problems with recruiting subjects. An individual was recruited into a study on three antipsychotics while under a forced commitment order from a judge. “The psychiatrist who recruited him was in charge of the study and was his treatment provider and was also empowered to report on the patient’s progress to the judge.” The individual died by suicide during the drug trial.

The work of Irving Kirsch and others has shown the problem with inert placebos (sugar pills). The side effects from medication make it easy for participants to guess which study group they are in.

And when the trial is over and the data in, do the outcome measures really provide something meaningful for people’s lives? If the ultimate goal is for people to fell better and resume their prior level of functioning, should outcome measures by primarily patient self-reports, clinical assessment, or differences shown by imaging or the as-yet-to-be-clearly-identified biomarkers?

Given the problems running and interpreting psychiatry trials, it is essential to learn how even the most successfully tested interventions work in real clinics with the broad patient population. Implementation, uptake, and effectiveness in real-life settings must be analysed, and delivery of new innovations modified accordingly. Future research should be thought of not as a plain linear process from innovation to trial to implementation, but as a virtuous circle where research feeds into the clinic and vice versa.

Another issue pointed to by Carter was the validity and reliability of the diagnosis or classification system used to determine who to include and who to exclude from the trials. The DSM system, now in its fifth edition (DSM-5), is the current “bible” for assessing and diagnosing problems the psychiatric medications in clinical trials are supposed to “treat” in the U.S. Yet there have been questions about the reliability and validity of the DSM dating from an argument raised by Robert Spitzer and others in the 1970s that ushered in changes still embedded in the DSM-5. Rachel Cooper gave a brief history of the reliability questions with the DSM in “How Reliable is the DSM-5?” You can also refer to “Psychiatry Has No Clothes,” “Where There’s Smoke …”, and  “The Quest for Psychiatric Dragons,” Parts 1 and 2.

A few weeks before the release of the DSM-5, Thomas Insel, then the NIMH Director, announced the NIMH would be “reorienting” its research away from DSM categories. The agency’s new approach is called the Research Domain Criteria (RDoC) project. For now, RDoC is a research framework and not a clinical tool. But NIMH has high hopes for it: “RDoC is nothing less than a plan to transform clinical practice by bringing a new generation of research to inform how we diagnose and treat mental disorders.” While Tom Insel has moved on to work for Alphabet (Google), RDoC is alive and well within NIMH. You can keep up with news about RDoC on the “Science News About RDoC.”

The Science Update for February 16, 2106 noted the March 2016 issue of the journal Psychophysiology would be devoted to the RDoC initiative. Dr. Bruce Cuthbert said the special issue was a unique opportunity for researchers to engage with one another and reflect on work being done in various laboratories throughout the country. He thought it was encouraging to see many investigators already engaged in the kind of work RDoC advocates. “What this shows is that while the RDoC acronym may be new, the principles behind RDoC are certainly not new to psychiatric research.”

If the principles behind RDoC are not new to psychiatric research, how can it bring “a new generation of research to inform how we diagnose and treat mental disorders” in order to transform clinical practice? It sounds a lot like using the same deck of cards to just play a new card game. RDoC may not be the transformative framework it’s touted to become.

Added to these issues is the failure of pharmaceutical companies to publically report the results of clinical trials, as they are required by law to do. New reporting rules will take effect on January 18, 2017. But advocates for transparency in clinical research have cautioned the success of the new rules will depend upon the willingness and vigor of government enforcement of those rules. The failure to enforce the existing rules, which went into effect in 2008, led to widespread noncompliance with reporting requirements. If the FDA had fined the violators, they could have collected an estimated $25 billion.

Reporting for STAT News, Charles Piller said studies have indicated only a small fraction of trials will comply with the law. Yet there are no current plans to increase enforcement staffing at the FDA and NIH. That’s a big problem, according to Ben Goldacre, an advocate for full disclosure in clinical research. Francis Collins, the NIH director said they are serious about this and will withhold funds, if needed. “It’s hard to herd cats, but you can move their food, or take their food away.”

The legislation that created ClinicalTrials.gov emerged from numerous cases of drug manufacturers withholding negative trial results, making drugs look more effective and less harmful. Efforts to market the antidepressant Paxil for teenagers more than a decade ago stimulated the push for better reporting. A recent analysis in the journal BMJ found that GlaxoSmithKline, Paxil’s manufacturer, failed to disclose 2001 data showing the drug to be no more effective than a placebo, and was linked to increased suicide attempts by teens.

Writing for Time, Alexandra Sifferlin reported on a new study that suggested many of the medical reviewers for the FDA go to work for the drug companies they oversaw while working for the government. One of the study’s authors said: “I don’t think there is overt collusion going on, but if you know in the back of your mind that a major career opportunity after the FDA is going to work on the other side of the table, I worry it can make you less likely to put your foot down.”

Returning to the Francis Collins metaphor, it seems that the willingness to try and herd Pharma cats is dependent on whether or not you are afraid they will scratch you in the attempt.

01/13/17

Iatrogenic Gun Violence

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Whenever I read about horrific violence like the incident in the Fort Lauderdale airport, I wonder what role psychiatric medications played. I wonder if the violent behavior was iatrogenic—was it caused by psychiatric medications? This question will sound counter intuitive for many people. Surely the reverse is true. Psychiatric medication and proper diagnosis should have prevented it. Let’s see if it is.

Esteban Santiago was deployed to Iraq from April 2010 to February 2011 with the 130th Engineer Battalion, the 1013th Engineer Company of the Puerto Rico National Guard. After flying from Alaska to Fort Lauderdale Florida, he retrieved his baggage, which incidentally contained a semi-automatic handgun. Santiago had followed proper protocol, checking the weapon with TSA. He went into the men’s bathroom, loaded his weapon and opened fire in Terminal 2 of the airport, killing five people and wounding six others. A witness said he was just randomly shooting people, with no rhyme or reason to it.

Family members reported that he was a changed man when he returned from Iraq. His aunt said his mind was not right. At times he seemed normal, but other times he seemed lost. In Iraq, his unit cleared roads of improvised explosive devices and maintained bridges. Two people in his unit died while he was in Iraq. His aunt said: “He talked about all the destruction and the killing of children. He had visions all the time.” He had changed.

His brother Bryan confirmed that recently Esteban was hallucinating, but said he was receiving psychological treatment. Bryan said he believes the shooting rampage resulted from mental issues that surfaced after the Iraq tour. When Esteban’s tour ended, he was hospitalized for mental problems. Upon his release, he went to Puerto Rico where his father was ill and eventually died. While in Puerto Rico, he received mental health therapy. Esteban eventually moved to Alaska, where he joined the Alaska National Guard in November 2014. He was discharged in August of 2016.

Over the course of 2016, Santiago was repeatedly reported to Anchorage police for physical disturbances. In January of 2016 he was arrested and charged with assault and criminal mischief after an argument with his girlfriend. He allegedly yelled at her while she was in the bathroom and broke down the bathroom door. She told investigators that he tried to strangle her and struck her on the side of the head.

Santiago pleaded no contest to criminal mischief and assault charges. Under a deferred prosecution agreement, his charges would have been dismissed if he complied with the conditions. He was due back in court on March 28th, 2017 to assess his progress.

While living in Alaska, Esteban continued to receive psychological treatment, according to his brother. Although his girlfriend alerted the family to the situation in Alaska, Bryan said he did not know what mental health problem Esteban was being treated for; they never spoke about it by phone.

His son was born in September of 2016. In November of 2016, Esteban walked into an FBI office in Anchorage to report that his mind was being controlled by a U.S. intelligence agency. He told officials he had a firearm in his car, along with his newborn son. Santiago was checked into a mental health facility; his firearm was logged as evidence for safe keeping. The infant’s mother came for their child. FBI special agent Marlin Ritzman said:

During the interview, Mr. Santiago appeared agitated, incoherent and made disjointed statements. Although he stated he did not wish to harm anyone, as a result of his erratic behavior our agents contacted local authorities, who took custody of Mr. Santiago and transported him to the local medical facility for evaluation.

After conducting database reviews, interagency checks and interviews with his family members, the FBI closed its assessment of Santiago. Agents found no ties to terrorism during their investigation. A CNN senior law enforcement analyst and former FBI assistant director said Santiago hadn’t been adjudicated a felon and he hadn’t been adjudicated as mentally ill. So they couldn’t keep his weapon. The Walther 9-millimeter pistol was returned to him in the beginning of December. Authorities told CNN it was the pistol he used in the shooting incident in Fort Lauderdale.

Typically, Esteban was considered to be a calm young man who was never violent. Recently he began selling his possessions, including his car. Friends and associates noticed more erratic behavior. He bought a one-way ticket to Fort Lauderdale and packed his pistol and two magazines. His carryon bag with the pistol was his only luggage. He flew from Anchorage to Minneapolis to Fort Lauderdale. He retrieved his bag from the baggage claim area and went into a men’s room stall to load his pistol.

He shot the first people he saw, going up and down the carousels of the baggage claim, shooting through luggage to get at people that were hiding. He thinks he fired 15 bullets, aiming at his victim’s heads. A witness said Esteban showed no remorse. He didn’t say anything. “No emotion, no nothing. About as straight-faced as you get.” Afterwards, he just lay face down, spread eagle, waiting for the deputies to come and get him.

The above report was pieced together from information contained in the following reports by The New York Times here,  NJ.com here, CNN here, and NPR here.

There was no explicit mention of Santiago’s repeated involvement in “psychological treatment” involving psychiatric medications, but it highly probable he was taking psychiatric medication of some sort. The lack of any mention of his being prescribed medication may simply be due to confidentiality regulations. Or this silence could be due to the chicken-and-egg argument often applied to incidents involving violence and individuals with known psychiatric problems. Their mental illness, not the drugs to treat it, caused their horrific behavior.

Several psychiatrists have voiced concerns with psychiatry, its over reliance upon medication and denial of serious adverse effects from medication, like violence and suicide. Joanna Moncrieff said she’s sad her profession has not taken the harms drug treatments can do more seriously. She said it has a long history of ignoring the adverse effects of drugs, or attributing them to the underlying disease—of blaming the patient instead of the drug. “Too many psychiatrists have just accepted that drug treatments are good, and have not wanted to contemplate that actually these treatments could be harmful.”

First and foremost, she said, psychiatry needs to adopt a drug-centered model for understanding its drug treatments and what they do to people. Psychiatrists need more information, knowledge and training on what the drugs do—what effects they produce in people; “how they change the way that people think and feel and what sort of impact those changes have on people’s lives.” Watch two brief videos of her expressing her concerns here. You can read more about her “drug-centered model” here on this website: “A Drug is a Drug is a Drug.”

Peter Breggin has raised concerns with the association of violence and antidepressants since the early days of Prozac. In his 1991 book, Toxic Psychiatry, Dr. Breggin related newspaper and scientific reports pointing to an association between Prozac and “compulsive, self-destructive and murderous activities.” He said then he was personally familiar with several cases of compulsive suicidal or violent feelings that developed after taking Prozac. Over the years, his familiarity grew.

In “Psychiatry Has No Answer to Gun Massacres,” Breggin described how the Columbine High School shooter, Eric Harris had a “therapeutic” level of Luvox (fluvoxamine) in his body at the time of the murders.  He had a dose increase in his medication 2 ½ months before the assault and showed signs of drug toxicity five weeks before the event. James Holmes, the Aurora Colorado theater shooter, was in psychiatric treatment with the medical director of student health services, who was considered an expert on campus violence. She was concerned enough about Holmes to report him to the campus police and the campus threat assessment team a few weeks before the assault. When the assessment team suggested putting him on a 72-hour involuntary hold, she rejected the idea. “When Holmes quit school, the school washed its hands of all responsibility for him.”

In a 2010 journal article, “Antidepressant-Induced Suicide, Violence, and Mania: Risks for Military Personnel,” Dr. Breggin related how the adverse effects described in the 2009 edition of the Physicians’ Desk Reference for Zoloft (sertaline) resembled the most frequent psychiatric disorder associated with combat—PTSD—with its hyperalert overstimulated symptoms. He said identical or nearly identical warnings can be found in all antidepressant labels. “All these potentially dangerous symptoms are also commonly seen in PTSD in military personnel, posing the risk of worsening this common military disorder.”

Looking at the revised 2016 medication guide for Zoloft, we see that nothing much has changed with regard to adverse effect warnings. It said Zoloft and other antidepressant medications could increase suicidal thoughts or actions. Symptoms needing immediate attention included: acting aggressively or violent, feeling agitated, restless angry or irritable, an increase in activity or talking more than what is normal, acting on dangerous impulses, trouble sleeping, new or worse anxiety or panic attacks, trouble sleeping, other unusual changes in behavior or mood.

A condition known as “serotonin syndrome” has symptoms such as: agitation, hallucinations, coma and other changes in mental status. Symptoms of potential manic episodes included: greatly increased energy, racing thoughts, unusually grand ideas, severe trouble sleeping’s, reckless behavior, excessive happiness, talking more or faster.

Dr. Breggin concluded his article with the following cautions and recommendations. He said there was a strong possibility the increased suicide rates among active-duty soldiers were in part caused or made worse by the widespread prescription of antidepressant medication. Alone, they can cause a stimulant-like series of adverse effects. “These symptoms of activation can combine adversely with similar PTSD symptoms found so commonly in soldiers during and after combat.” He recommended the military study the relationship between psychiatric drug treatment and suicide as well as random or personal violence. He also suggested that antidepressants should be avoided in the treatment of military personnel.

Another emerging concern of an association between antidepressants and violence is in the research done by Yolande Lucire. She suggested that mutations in CYP450-encoding genes contributed to problems metabolizing psychiatric drugs, and thus were contributing factors in three cases of antidepressant-induced akathisia-induced homicide. The cytochrome P450 family of enzymes is responsible for metabolizing most of the drugs used in psychiatry. You can read her article here. You can also find another article: “Psych Drugs and Violence” on this web site. Within that article you will find a link to another article by Lucire on antidepressant-induced akathisia-related homicide and the CYP450 genes.

Hasn’t there been enough evidence associating suicide and violence with psychiatric medications, especially antidepressants, for open dialogue and more comprehensive scientific research into this public health issue? How many more Columbines, Auroras and Fort Lauderdales need to happen before we begin to address the association of psychiatric drugs and violence?

01/3/17

Like Footprints in the Sand

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An amazing letter was sent to the president of the American Psychiatric Association (APA) on August 1, 2016 by no less than sixteen well known medical and psychological professionals from around the globe. They are attempting to have an article published in a 2004 issue of the American Journal of Psychiatry retracted. Their concern was that a recent analysis of that study found “gross misrepresentations” made in the article with regard to use of citalopram (Celexa) in treating child and adolescent depression. As of the beginning of December of 2016, the original journal article is still available; nor does there seem to have been any response to the letter requesting the retraction. Perhaps the APA hopes that if they simply ignore the issue, it will just go away.

The article was ghostwritten by agents of the manufacturer and seriously misrepresented both the effectiveness and the safety of citalopram in treating child and adolescent depression.

The letter was addressed to Dr. Maria Oquendo, the 2016 President of the APA. The coauthors of the letter expressed concerns with the “gross misrepresentations” made within the 2004 article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents.”

Since the publication of the analysis alleging the problems with the 2004 Celexa article, there were three different attempts to have it retracted. In response to a May 9, 2016 letter, the current editor for the American Journal of Psychiatry refused to retract the original study. Two other attempts, one to the former editor of the American Journal of Psychiatry who accepted the article, received no response. Given the failure of the American Journal of Psychiatry to retract the article, the letter’s authors are concerned that children and adolescents are put at risk of unnecessary harm because well-intentioned physicians who continue to prescribe citalopram to children and adolescents are being misled.

The 2004 citalopram study said it provided evidence that “citalopram produces a statistically and clinically significant reduction in depressive symptoms in children and adolescents.” It was said to be superior to placebo and the adverse events were mild.

In conclusion, citalopram treatment significantly improved depressive symptoms compared with placebo within 1 week in this population of children and adolescents. No serious adverse events were reported, and the rate of discontinuation due to adverse events among citalopram-treated patients was comparable to that of placebo. These findings further support the use of citalopram in children and adolescents suffering from major depression.

Yet there have been a series of lawsuits against Forest Laboratories, the manufacturer of Celexa, because of its serious side effects; and for Forrest’s failure to warn about the risks when using Celexa and other SSRIs. Drugwatch noted that Celexa is the best-selling antidepressant in 13 countries. Yet it has been linked to several congenital birth defects as well as autism. FindLaw noted evidence that Celexa and other antidepressants have been linked to an increased risk of suicidal behavior in patients under the age of 25.

Forest Laboratories also pleaded guilty in a 2010 criminal case for misbranding Celexa for a use not approved by the FDA. “According to the Department of Justice, Forest Pharmaceuticals had illegally promoted Celexa for the treatment of depression in children and adolescents. The company also pleaded guilty to obstructing justice and distributing an unapproved drug.” Forest Pharmaceuticals was fined $150 million.

A class action law suit, Celexa and Lexapro Marketing and Sales Practice Litigation, was brought by plaintiffs who alleged that Forest Laboratories misrepresented the safety and efficacy of Celexa and Lexapro when marketing the drugs for off-label pediatric use. Over 63,000 documents from Forest were deposited in a database maintained by the plaintiff’s attorneys. Jureidini, Amsterdam and McHenry reviewed 750 internal documents from this database in their 2016 article for the International Journal of Risk & Safety in Medicine.

They found that the published article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents,” contained efficacy and safety data that was inconsistent with the protocol criteria. Although the published article concluded citalopram was safe and significantly more efficacious than placebo for children and adolescents, the outcome measures “showed no statistically significant differences between citalopram and placebo.”

Unreported procedural deviations contributed to the claimed statistical significance of the primary outcome and negative secondary outcomes were not reported. Moreover, post hoc measures were introduced; and adverse events were misleadingly analyzed. The Wagner et al. citalopram study failed to mention five citalopram-treated subjects who discontinued treatment due to hypomania, agitation, or akathisia. “None of these potentially dangerous states of over-arousal occurred with placebo.” There were also many more adverse gastrointestinal events for citalopram than placebo. Yet the final report grouped the data in a way that masked the evidence for potential gastrointestinal intolerance.

In conclusion, corporate mischaracterisation of clinical trial results is of concern in psychiatry where outcome measures are more subjective and easily manipulated. Because few industry-sponsored studies gain public scrutiny and even fewer are ever formally retracted, it is important to make these articles transparent to correct the scientific record. It is furthermore imperative to inform the medical community of mischaracterized data that could lead to potential harm to children and adolescents who are vulnerable to the effects of medication on the growing brain and may increase suicidal thinking and behaviour.

STAT News reported the retraction request comes after years of controversy over the extent to which some drug makers massaged clinical studies to broaden their medicines’ market. Four years ago, GlaxoSmithKline paid $3 billion to settle civil and criminal charges of “preparing, publishing, and distributing a misleading journal article” about the use Paxil with children and adolescents. “The pill had not been approved for that use and the study cited by federal authorities had been ghostwritten.” David Healy, John Nardo, and Jon Jureidini, three of the sixteen individuals who submitted the letter to the APA requesting that the 2004 citalopram study be retracted, have been actively involved in critiquing the misrepresentation of Study 329 and attempting to get it retracted as well. See a series of articles Healy has written on this issue here, in the Mad in America archives.

After a running a gauntlet of reviews, Le Noury et al. were able to successfully publish a reanalysis of Study 329 in the British Medical Journal. But getting there wasn’t easy, see: “Restoring Study 329: Letter to BMJ” and “The Troubled Life of Study 329: Consequences of Failure to Retract.” However, the original article, “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial,” was never retracted by Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP).

Hmmm. Perhaps my opening comment that the APA is hoping the request to withdraw the 2004 citlopram article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents,” wasn’t all that smarmy. They could be hoping that it will just fade away like footprints in the sand.

12/23/16

Listening to Antidepressants

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Prozac took the U.S. by storm when the FDA approved it in 1987.  It also had a similarly radical effect on the thinking of a forty year-old psychiatrist named Peter Kramer. In the Introduction of his now classic book, Listening to Prozac, Kramer described how people became “better than well” with Prozac and how they and he began to “listen” to what Prozac told them. Kramer said it “transformed my views about what makes people the way they are.” But even by 1993, when Listening to Prozac was published, the stories of violence and suicide after taking the first SSRI antidepressant were circulating as well.

Toxic Psychiatry by another psychiatrist named Peter Breggin, was published two years earlier and documented reports of suicidal behavior in both the popular press and the professional literature. “Suicidal Behavior Tied to Drug,” was published on February 7, 1991 in The New York Times. The article said two cases of suicidal behavior and fantasies (with no prior history) were reported in The New England Journal of Medicine that same day. Eli Lilly was facing more than 50 lawsuits at the time and of course denied that there was any scientific merit to the claim the medication could prompt suicidal or violent acts. The year before, “Emergence of Intense Suicidal Preoccupation During Fluoxetine Treatment,” was published in the February 1990 issue of The American Journal of Psychiatry. Its abstract read:

Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine treatment. This state persisted for as little as 3 days to as long as 3 months after discontinuation of fluoxetine. None of these patients had ever experienced a similar state during treatment with any other psychotropic drug.

Breggin also seems to have predicted the rise of what is now called “treatment resistant depression” with SSRIs. He said: “If Prozac can indeed alleviate depression by making more serotonin available in the brain, then with time it may produce incurable depression by making the brain relatively unresponsive to any amount of serotonin.” In Talking Back to Prozac in 1995, Breggin “blew the whistle” on the newer antidepressants and antidepressant-induced violence, suicide and mania. Finally in 2004 the FDA finally required black box warnings to be placed on the newer antidepressants, warning of the potential for the increased risk of suicidal thoughts and behavior in children and adolescents.

Yes, Dr. Kramer did say as far back as Listening to Prozac that the chemical imbalance theory (the amine hypothesis) was at least incomplete and perhaps false. But then Kramer published Against Depression in 2005, arguing that the socio-economic costs of depression were so large, that modern societies should strive to eradicate it as they did with smallpox. On his blog in 2008 he argued that the chemical imbalance theory was prematurely declared dead, even though “the neurotransmitter theory is incomplete and not fully proven.”  He asserted that since 1993 the evidence for it had been steadily growing.

Jonathan Leo and Jeffrey Lacasse did an in depth critique of the evidence Dr. Kramer used to support the chemical imbalance theory. They noted several qualifications used when scientists discuss the biological basis of mood with other scientists. “Yet, in the popular press all these qualifications disappear and instead the public is inundated with declarations about ‘chemical imbalances causing mental illness.’” They said there were two different discussions going on about the theory—a simple, straightforward one in the media and advertisements, but a tenuous nuanced one in scientific circles. In scientific circles, the discussion was about the appropriateness of using the chemical imbalance theory with patients and not so much about the strength of the theory.

In the late 1990s, Irving Kirsch decided to research the placebo effect with the newer (SSRIs and SNRIs) antidepressants. He began with the assumption that there actually was a therapeutic effect with antidepressants, but he wanted to assess the placebo effect: “I was not particularly interested in the drug effect. I assumed that antidepressants were effective.” He was surprised to discover how small the drug effect was. Seventy-five percent of the improvement in the drug group also occurred with people who were given placebo pills with no active ingredient in them.

Critics of his findings said the meta-analysis he and his co-author had done was biased; that they had an unrepresentative sample of clinical trials. So Kirsch and three others replicated the original study with the identical data set used by the pharmaceutical companies for the FDA approval of six of the new generation antidepressants at the time. These six accounted for the bulk of antidepressant prescriptions being written at the time, 2002. “In the data sent to us by the FDA, only 43% of the trials showed a statistically significant benefit of drug over placebo. The remaining 57% were failed or negative trials.” The results here were that 82% of the response to antidepressants was due to the placebo effect.

Kirsch again did a replication in 2008 with a larger number of clinical trials and again found the 82% placebo effect. In both analyses, the mean difference between drug and placebo was less than two points (1.8) on the HAM-D depression scale, used in all the FDA clinical trials for antidepressants at the time. The difference was clinically insignificant. In other words, these miniscule differences were too small to be observable in a normal clinical setting with someone who was depressed. Others, including the FDA, have repeatedly replicated their results. The above history can be found in a 2014 article by Irving Kirsch, “Antidepressants and the Placebo Effect,” or in his 2010 book, The Emperor’s New Drugs. There he speculated:

Antidepressants may be nothing more than active placebos, producing side effects through chemical means and therapeutic effects through psychological means.

Twenty-three years after Listening to Prozac, Peter Kramer published his latest book, Ordinarily Well: The Case for Antidepressants. According to Jonathan Rosen, who wrote “The Assault on Antidepressants” for The Atlantic, Kramer said he believed in the utility of antidepressants, despite their flaws. He not only sought to make a case for antidepressants, he also tried to make a case for psychiatry as “a humanistic science that bridges the impersonal ideals of the laboratory and the pragmatic exigencies of clinical intervention.”

In a book review of Ordinarily Well for The New York Times, Jennifer Senior referred to the original Kirsch research and said Kramer was wary of these studies because they flew in the face of his clinical experience. Indicating that when his own patients asked if their improved mood could be due to a placebo effect, “Dr. Kramer’s answer is an unequivocal no.” And Ordinarily Well attempted to prove his belief. Senior indicated Kramer argued that Kirsch deliberately “’seemed to cull studies in which antidepressants underperformed,’ and treated some drugs as placebos even though they may have had antidepressant effects.” Either Senior or Kramer was unaware of, or failed to mention the above-described replications done by Kirsch and others. She did point out how Kramer used meta-analyses to make his own points, but failed to acknowledge that fact. Another area of concern for Kramer was the mechanism for recruiting subjects for clinical trials.

He is particularly devastating on the subject of recruiting test subjects. One of the most damning chapters features an unnamed facility where antidepressant trials are frequently conducted. Many of the participants are unemployed or underemployed — lonely, dispossessed and eager for the money. Suddenly, they’re getting paid, interacting with others and receiving the careful attention of doctors and nurses. “Even on placebo,” Dr. Kramer writes, “these patients ought to get better.”

There is an indication that evidence-based medicine has some flaws; and that the gold standard of meta-analysis can be undermined by flawed analysis, especially in psychiatric drug research. And there really is a problem with recruiting clinical trials subjects; and sometimes with the methodologies used by researchers in those clinical trials. But remember that if Kramer’s concerns are accepted (and I think they should be), then the newer antidepressants were approved using questionable scientific methods and an unreliable approval process. See “Evidence-Based Treatment … Lacks Evidence.”

If that is the case, where is the protection that FDA approval of pharmaceuticals is supposed to provide? And why aren’t more people pressing for regulatory reform of the FDA clinical trial process? If we accept Kramer’s arguments, we should also acknowledge that the clinical trials used for FDA approval of SSRIs were invalid. Kramer’s rationale for dismissing the evidence for the placebo effect with antidepressants also calls into question the methods used for their approval—and many of the studies afterwards touting their continued effectiveness.

A recent review article by Andrews et al., “Is Serotonin a Downer or an Upper?” challenged the assumptions of the therapeutic effects of SSRIs. “Although the idea that a single neurochemical is the cause of depression is now considered simplistic, the low serotonin hypothesis still lies at the foundation of most research on depression.” The authors noted how many types of depression seem to correspond to higher levels of serotonin, not lower ones. They proposed a radical new way of understanding the role of serotonin in the brain, according to Shannon Peters in, “How Do Antidepressant Really ‘Work’?” They suggest that serotonin coordinates metabolic processes with the storage, mobilization, distribution, production and utilization of energy resources.

Under this theory, there are higher levels of serotonin when there is a need to redistribute limited energy resources. “Serotonin cannot be simply described as an ‘upper’ or a ‘downer’; its symptomatic effects depend on the organism’s state,” write the authors.

When listening to antidepressants, we hear a history of effectiveness that can’t be clearly attributed to the therapeutic effect of the drugs. Expectation or placebo plays a significant role in whether or not these drugs will help an individual “overcome” their depression. Peter Kramer continues to hold on to a narrative that the chemical properties of SSRIs actually do help some depressed individuals, with “little of the benefit coming from the classical placebo effect.” But in debunking the science used to affirm the antidepressant placebo effect, he also calls into question the methods used to approve those same SSRIs in the first place.

What about Peter Breggin? He’s still around and critiquing the use of other classes of psychiatric drugs as well as antidepressants. He was recently the expert witness in a 2016 court case, awarding $11.9 million in a Paxil suicide malpractice case. He has a video series on YouTube, “Simple Truths About Psychiatry,” which is also linked on his website: breggin.com. There is plenty of additional material there to support the ineffectiveness and danger of antidepressants. In 2011, Dr. Breggin was the expert witness in a court case where Prozac was found to be a contributing factor to the murder of a teenager by his friend. “This was the first criminal case in North America where a judge has specifically found that an antidepressant was the cause of a murder.”

There’s more discussion of Irving Kirsch and the placebo effect here on my website. Start with: “Dirty Little Secret” or do a search of the website for his name.

12/13/16

The Vicious Spiral of Suicidality

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A study published in the November 2016 issue of JAMA Psychiatry suggested that patients were at an increased risk of suicide during the three months immediately following their discharge. They were fifteen times more likely to commit suicide than similarly matched patients who were treated for non-mental health issues. Individuals without any outpatient care in the months before their hospitalization were at an even higher risk. Individuals diagnosed with depressive disorders were at the highest risk, followed by those with bipolar disorder and then schizophrenia.

The lead author of the study, Mark Olfson, was interviewed on the JAMA network about the study. He said one of the limitations of the study was it didn’t have the level of detail to get at why depression and depressive disorders were the highest short-term risk of suicide. However, he speculated that since one of the symptoms (diagnostic criteria) for depression was related to suicide, and many individuals are hospitalized because of suicide attempts or suicide risk, this is “probably what conveys their short-term risk of suicide following hospitalization discharge.” He added that effective approaches to suicide risk reduction should involve strengthening a patient’s connectedness, reducing social isolation, and engaging them in outpatient care. In his review of the study for Mad in America, Justin Karter quoted the study authors as saying:

These patterns suggest that complex psychopathologic diagnoses with prominent depressive features, especially among adults who are not strongly tied into a system of care, may pose a particularly high risk. As with many studies of completed suicide, however, the low absolute risk for suicide limits the predictive power of models based on clinical variables. These constraints highlight the critical challenge of predicting suicide among recently discharged inpatients based on readily discernible clinical characteristics.

The association of suicide risk and hospitalization has been evident in previous studies. For example, a 2005 study reported in the Archives of General Psychiatry, found there were two sharp peaks of suicide risk around psychiatric hospitalization. There were during the first week after admission and in the first week after discharge. The length of hospitalization was also a factor, with individuals receiving less than the median length of stay having a significantly higher risk. The study also confirmed previous reports that prior admission to a psychiatric hospital is also associated with a higher risk of suicide.

This study, to our knowledge, is the first to explore how suicide risk differs by diagnosis across the phase of psychiatric hospitalization. We find that affective disorders increased the risk for suicide the strongest across all phases of time since hospitalization compared with other diagnostic groups. We also find that affective and schizophrenia spectrum disorders tend to have a more intensive effect on the risk of suicide, whereas substance abuse disorders have a more prolonged effect on the risk of suicide.

In an article for the website, Speaking of Suicide, Stacey Freedenthal cited the recommendation by David Rudd, a nationally known suicide expert, who recommended initially seeing an individual at least twice in the week after discharge. The elevated risk of suicide after hospitalization was not necessarily related to a premature discharge. Referencing David Rudd, she said:

Instead, suicidal intent is fluid, impossible to predict from one moment to the next, let alone day-to-day. Of course, whatever led to hospitalization in the first place, whether a suicide attempt, mental illness, or some other crisis, places a person at higher risk than normal for suicide.

However, there was a 2014 study reported in Social Psychiatry and Psychiatric Epidemiology that found psychiatric admission in the previous year was highly associated with completed suicide. “Furthermore, even individuals who have been in contact with psychiatric treatment but who have not been admitted are at highly increased risk of suicide.” The authors said the relationship was one of association, rather than causation. “People with increasing levels of psychiatric contact are also more severely at risk of dying from suicide.”

An editorial in the same issue by Large and Ryan said that compared to those who had no psychiatric treatment in the previous year, those who received medication were 5.8 times the risk of suicide; those with at most outpatient psychiatric treatment had 8.2 times the risk; patients with emergency department contact without an admission had 27.9 times the risk; and admitted patients had 44.3 times the risk of suicide. These ratios were after controlling for other risk factors.

The strongest risk factors for suicide after discharge were: prior suicide attempts and depressive symptoms. Additional risk factors include: hopelessness, worthlessness, guilt and a family history of suicide. Large and Ryan said they believed it was likely that a proportion of individuals who suicide during or after an admission to hospital do so because of factors inherent in the hospitalization. They argued that such suicides should be considered as “nonsocomial”—acquired in a hospital.

There was a significant positive correlation between a PTSD diagnosis and suicidality in a study by Panagioti, Gooding, and Tarrier. Comorbid major depression was a compounding risk factor. The association of suicidality and PTSD persisted across “studies using different measures of suicidality, current and lifetime PTSD, psychiatric and nonpsychiatric samples, and PTSD populations exposed to different traumas.”  Another study of national suicide rates in 25 European countries concluded that stigma towards persons with mental health problems could influence suicide rates within a country. The authors hypothesized that possible mechanisms could include stigma as a stressor, or social isolation as a result of stigma. Large and Ryan said:

There is now little doubt that suicide is associated with both stigma and trauma in the general community. It is therefore entirely plausible that the stigma and trauma inherent in (particularly involuntary) psychiatric treatment might, in already vulnerable individuals, contribute to some suicides.

So it seems there is a vicious spiral with suicidality. Together, depression and suicidality may lead to hospitalization, which itself is a risk factor for suicide. Hospitalization, particularly when it is involuntary, can lead to stigma and trauma, which exacerbates feelings of worthlessness and hopelessness—-themselves further risk factors in suicide.

How then do we help the chronically depressed and suicidal person? Perhaps the place to start is by not harming them any further. We need to recognize and minimize the potential for stigma and trauma from hospitalization. We need to address feelings of helplessness and worthlessness from very beginning of any contact with a depressed and suicidal person. In Cruel Compassion, as he reflected on how to avoid further harm with chronic mental patients, Thomas Szasz gave the following quote of C.S. Lewis that I think is helpful here.

Of all the tyrannies a tyranny sincerely exercised for the good of its victim may be the most oppressive. . . . To be “cured” against one’s will and cured of states which we may not regard as disease is to be put on a level with those who have not yet reached the age of reason or those who never will; to be classed with infants, imbeciles, and domestic animals. . . . For if crime and disease are to be regarded as the same thing, it follows that any state of mind which our masters choose to call “disease” can be treated as a crime and compulsorily cured. . . .Even if the treatment is painful, even if it is life-long, even if it is fatal, that will be only a regrettable accident; the intention was purely therapeutic.

Szasz went on to add:

To help the unwanted Other, we must therefore first relinquish the quest to classify, cure and control him. Having done so, we can try to help him the same way we would try to help any person we respect—asking what he wants and, if his request is acceptable, helping him to attain his goal or accept some compromise.

12/2/16

Pharma and Advertising

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The FDA recently held public hearings on the off-label advertising of approved medications and medical devices on November 9 and 10, 2016. “FDA is engaged in a comprehensive review of its regulations and policies governing firms’ communications about unapproved uses of approved/cleared medical products, and the input from this meeting will inform FDA’s policy development in this area.” There were specific questions asked at the hearing, but the FDA was also interested in “any other pertinent information participants would like to share.” If you weren’t able to be in Maryland for the hearing, electronic or written comments will be accepted until January 9, 2017. A videotape of the hearing will be available for one year afterwards.

Your initial reaction may be one of “Boring!” That is unless you are aware of the crossroads we are approaching with regard to the off-label advertising of medications and medical devices. On March 8, 2016, the FDA made a settlement agreement with the pharmaceutical company Amarin that allows the company to promote its drug Vascepa for off-label use. What is this important breakthrough medication? Vascepa is prescription strength fish oil. This action was the outcome of a struggle between Amarin and the FDA going back several years.

Amarin wanted to widen the population for whom they could recommend Vascepa to include patients with different cardiovascular diseases—patients other than what Vascepa was initially approved to treat. But the FDA ruled against their request. Amarin’s stock price took a nosedive. Concerned with how their investors were reacting, the company fought back by suing the FDA. Then in August of 2015, a judge ruled that Amarin could market its drug to the broader population. He also ruled the company could claim that Vascepa “may reduce the risk of coronary heart disease.” This was despite the fact that the FDA had called the claim misleading, as there was “supportive but not conclusive research” to that effect.

Amarin successfully argued that it had a First Amendment right to market its drug for a broader patient group, “despite the lack of regulatory approval and the lack of evidence of an outcomes benefit for patients.” Justin Karter noted how the FDA settlement strikes at the heart of the drug regulatory system in the U.S. Amarin argued that companies should have the right to market their products consistent with what “a judge would consider to be neither false or misleading.” Be clear on what Amarin was saying. A judge, not the FDA, should rule on whether or not the marketing claims by a pharmaceutical company for their product were truthful and not misleading.

Amarin argued that this system is unconstitutional, and that companies should instead be allowed to market their products in any way that a judge would consider to be neither false nor misleading.

Commenting on the FDA settlement agreement in Amrain Pharma v. U.S. Food & Drug Administration, lawyer and mental health advocate Jim Gottstein said he thought that for all practical purposes, the FDA ban against off-label promotion of drug companies was dead. He noted that the ruling in the Amarin case was based upon a 2012 decision in Unites States v. Caronia that reversed a criminal conviction for off-label promotion.

In light of the settlement I think it is fair to ask where things stand with the FDA’s enforcement of its ban against off-label promotion and Department of Justice prosecutions of drug companies for off-label promotion leading to false claims.  I think the ban against off-label promotion is dead for all practical purposes.  The FDA could try and get a different ruling in another circuit and, if successful, ask the Supreme Court to rule, but since it didn’t ask the Supreme Court to take the case in Caronia, it doesn’t seem likely that it has any intention of trying to overturn Caronia. This will give the drug companies free rein for off-label promotion.  Of course, anything that is false or misleading is still grounds for charges, but that is a far harder case to make.

So if this is the supposed future for off-label drug advertising unless there is some radical change by Congress, let’s now take a look at the past—what has been taking place under the existing FDA rules. In his book Saving Normal, Allen Frances published a chart that he called the drug company “hall of shame.” Prepared by Melissa Raven, PhD, it listed the fines and settlements by Pharma companies for off-label promotion, marketing and fraudulent misbranding of 20 well know pharmaceuticals.

Here is a sampling of the companies and their total fines and settlements between 2004 and 2012 recorded in the Saving Normal chart. The fines and settlements listed below combine both civil and criminal cases. Johnson & Johnson ($1.44 billion); GlaxoSmithKline ($3 billion); Abbott ($1.5 billion); Novartis ($422.5 million); Forrest ($313 million); AstraZeneca ($520 million); Pfizer ($2.3 billion); Eli Lily ($1.415 billion); Bristol-Myers Squibb ($515 million); Purdue (almost $635 million). I think it’s clear why Pharma is going after the FDA. The sum total in fines and settlements from the chart was $12.06 billion in fines and settlements between 2004 and 2012.

On March 31, 2016, the nonprofit organization Public Citizen published an updated analysis of all major financial settlements and court judgments between pharmaceutical companies and the federal and state governments. The time period covered by their analysis ran from 1991 through 2015 and included 373 settlements for a total of $35.7 BILLION. Financial penalties have declined sharply since 2013. The most striking decrease occurred with criminal penalties. “For 2012 and 2013 combined, criminal penalties totaled $2.7 billion, but by 2014-2015, the total had fallen to $44 million, a decrease of more than 98%.”

From 1991 through 2015, GlaxoSmithKline and Pfizer reached the most settlements—with 31 each— and paid the most in penalties, $7.9 billion and $3.9 billion respectively. Six additional companies, Johnson & Johnson, Merck, Abbott, Eli Lilly, Teva, Schering-Plough, Novartis, and AstraZeneca paid more than $1 billion in financial penalties. Six of the above eight were listed in the top 14 pharmaceutical companies by global sales in 2014. Thirty-one companies entered repeat settlements. Pfizer (11), Merck (9), GlaxoSmithKline, Novartis, and Bristol-Myers Squibb (8 each) finalized the most federal settlements. It seems these fines were simply the cost of doing business.

Financial penalties continued to pale in comparison to company profits, with the $35.7 billion in penalties from 1991 through 2015 amounting to only 5% of the $711 billion in net profits made by the 11 largest global drug companies during just 10 of those 25 years (2003-2012). To our knowledge, a parent company has never been excluded from participation in Medicare and Medicaid for illegal activities, which endanger the public health and deplete taxpayer-funded programs. Nor has almost any senior executive been given a jail sentence for leading companies engaged in these illegal activities. Much larger penalties and successful prosecutions of company executives that oversee systemic fraud, including jail sentences if appropriate, are necessary to deter future unlawful behavior. Otherwise, these illegal but profitable activities will continue to be part of companies’ business model.

Since the U.S. approved direct-to-consumer advertising of prescription drugs in 1997, there has been a dramatic increase in spending on pharmaceuticals. A New England Journal of Medicine study by Donohue, Cevasco and Rosenthal in 2007 found that spending on pharmaceutical promotions increased from $11.4 billion in 1996 to $29.9 billion in 2005. This was a 330% increase. Promotion to physicians was still the primary marketing strategy, but spending on direct-to-consumer advertising increased both in absolute terms and as a percentage of pharmaceutical sales.

Becker and Midoun recently published an article that investigated the effects of direct-to-consumer advertising (DTCA) on patient prescription requests in the Journal of Clinical Psychiatry. Of the 989 articles they initially identified, they read full-text reviews of 69 articles, but only found four that met their inclusion criteria for investigating the consequences of these ads on prescription rates and treatment quality. They conclusion was: “Findings suggest that DTCA requests are typically accommodated, promote higher prescribing volume, and have competing effects on treatment quality.” They called for methodlogically stronger studies to increase the confidence in their conclusions.

Reporting for Mad in America on the study, Justin Karter noted where the U.S. is only one of three countries globally that allows DTCA. He said the pharmaceutical industry spent $3.83 billion on DTCA in 2013 and $4.53 billion in 2014. He also noted that the American Medical Association (here) and the American Society of Health-System Pharmacists (ASHP) (here) have called for a ban on DTCA. The AMA Board Chair, Patrice Harris, commented that physicians were concerned with the negative impact of DTCA and the role marketing costs play in fueling escalating drug prices. “Direct-to-consumer advertising also inflates demand for new and more expensive drugs, even when these drugs may not be appropriate.” The ASHP approved a new policy at their 2016 meeting that would advocated for Congress to ban DTCA for prescription drugs and medication-containing devices.

Pharmaceutical companies have whittled away at existing FDA regulations that restrict direct-to-consumer advertising. And they seem to be poised to begin an era of DTCA that will massively overshadow what has already taken place under the existing rules. Healthcare organizations representing physicians and pharmacists in the U.S. have publically voiced their opposition to DTCA. Individuals and organizations have an opportunity to voice their concern for this practice, which is implicated in the rising cost of healthcare and medications. Congress also has an opportunity to enact new legislation that would eliminate this predatory marketing practice. But it will have to overcome the horde of lobbyists—more than there are members of Congress—and the $272,000 in campaign donations Pharma spent per member of Congress in 2015.

11/22/16

Antidepressant Misuse Disorder

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Chances are you know someone who is using an antidepressant. But that doesn’t necessarily mean the person you know has a problem with depression. In 2015, Takayanagi et al. published a study in The Journal of Clinical Psychiatry found that: “Among antidepressant users, 69% never met criteria for major depressive disorder (MDD); and 38% never met criteria for MDD, obsessive-compulsive disorder, panic disorder, social phobia, or generalized anxiety disorder in their lifetime.” Their data indicate that antidepressants were commonly used in the absence of “clear evidence-based indications.”

Writing for Mad in America, Justin Karter noted that previous studies revealed antidepressants were being over-prescribed and prescribed off-label. But others countered that these studies underestimated the lifetime prevalence of so-called mental disorders. The Takayanagi et al. study sought to address this criticism by conducting in-depth interviews to estimate whether participants met criteria for “mental disorders” over their lifetime. The study also indicated an individual was more likely to be prescribed an antidepressant if they were a woman, white, reported physical pain or discomfort to their doctor, or had recently visited a mental health care facility.

Another 2015 report by Kanton et al. published in JAMA found that the percentage of Americans on antidepressants increased from 6.8% to 14% between 1999 and 2012. The report’s authors speculated that the increase could in part reflect shifting attitudes regarding depression. Commenting on this report, Justin Karter pointed out how the increase likely includes a large proportion of off-label use of antidepressants. As was noted above, 69% of antidepressant users did not meet the criteria for major depression.

A JAMA study published in May of 2016 by Wong et al. found that 45% of the prescriptions given for antidepressants were to treat anxiety disorders, pain, insomnia and various other conditions. The study, which was done in Quebec Canada, looked at all adult prescriptions written for antidepressants (100,000 patients) between January 1, 2006 and September 30, 2015. Prescriptions for monoamine oxidase inhibitors were excluded. Prescriptions were classified as on or off label depending upon whether the drug was approved by Health Care of Canada or the FDA for the indication noted by September 0f 2015. Physicians prescribed antidepressant off-label for anxiety disorders (18.5%), insomnia (10.2%), pain (6.1%) and panic disorders (4.1%).

An online survey of long-term antidepressant patients by Cartwright et al., published in Patient Preference and Adherence, found that almost 90% reported some degree of improvement, with 30% also saying they had moderate to severe bouts of depression during treatment.  Ten different adverse effects were reported by over 50% of the participants. The five most common were: withdrawal effects (73.5%), sexual dysfunction (71.8%), weight gain (65.3%), feeling emotionally numb (64.5%), and failure to reach orgasm (64.5%). “Between 36% and 57% of respondents experienced these adverse affects at either a moderate or severe level.” Additional adverse effects reported included: agitation (55.1%), feeling not like myself (54.4%), reduced positive feelings (45.6%), caring less about others (36.4%), suicidality (36.0%), and feeling aggressive (31.6%).

Some patients in this study were particularly concerned about severe withdrawal symptoms that undermined their confidence to discontinue should they wish to and therefore limited their choices. In line with this, 45% patients also believed that they had some level of addiction to the antidepressant. Some patients were also critical of the lack of information given by prescribers with regard to adverse effects, including withdrawal symptoms. Some also expressed disappointment or frustration with the perceived lack of support available to them in managing withdrawal.

Limitations of the study include the fact that the data were self-reported and that the study was not a randomized control study—the gold standard methodology for evidence-based medicine. However, there are relatively few long-term outcome studies of antidepressant use.

A 2009 systematic review published in the Journal of Affective Disorders, concluded that long-term outcomes in depression were poor, with no clear relationship between drug treatment and positive outcomes.  The outcomes for non-antidepressant treatment were no worse than those for antidepressant treatment.

Overall 40% to 85% of patients experienced a recurrence during follow-up. Average time to recurrence was around 3.2 years across eight studies that provided data on this outcome. Around 25% of patients achieved a global rating of well or improved at the end of the study and a similar number had a poor outcome marked by multiple recurrences or continuous impairment. Most participants recovered from the index episode, but experienced multiple recurrences.

The August 2016 issue of Psychotherapy and Psychosomatics published a literature review of long-term use of newer generation antidepressants (i.e., SSRIs and SNRIs and others) by Carvalho et al. While many side effects were transient, disappearing after a few weeks, other potentially serious adverse events may persist or occur later. The main adverse events related to using newer antidepressant drugs included the following:

  • Gastrointestinal issues
  • Weight gain and metabolic disturbances
  • Genitourinary issues (issues related to the genital or urinary organs)
  • Sexual dysfunction
  • Hyponatremia (low sodium level in the blood)
  • Osteoporosis and risk of fractures
  • Bleeding
  • Central nervous system issues
  • Sweating
  • Sleep disturbances
  • Affective disturbances
  • Suicidality
  • Discontinuation syndromes

You can read more information on the above adverse effects and others in the Carvalho et al. review. What follows is a brief discussion of their findings for weight gain and diabetes, bleeding, sleep disturbances, affective disturbances, suicidality, and discontinuation syndromes.

Several studies have shown that long-term use of antidepressants (more than 6 months) is associated with weight gain. Paroxetine (Paxil) may be the worst offender. A population-based study indicated the use of antidepressants could be associated with a higher risk of obesity. The association between antidepressants and diabetes mellitus is inconclusive. Some reports indicate a higher risk; others do not. But a recent review and meta-analysis found that SSRIs were associated with an increased risk of diabetes mellitus.

All SSRIs have been associated with an increased risk of bleeding. “The most likely mechanism responsible for these adverse reactions is a reduction of serotonin reuptake by platelets.” Fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft) have a higher risk of platelet dysfunction than other SSRIs. Veniafaxine (Effexor) and mirtazapine (Remeron) have been associated with an increased risk of bleeding. SSRIs have been associated with a higher risk of bleeding during operations.

Sleep disturbances are one of the hallmark symptoms of depression. However,  studies have shown that SSRIs and Effexor are associated with increased REM sleep latency and an overall reduction in the time spent in REM sleep. These effects are usually associated with the initial period of treatment and may return to baseline after 8 weeks. Remeron and trazodone have been associated with improving sleep. In my clinical experience, trazadone is regularly used off-label to help promote sleep.

Many individuals taking SSRIs report they experience emotional blunting. They say their emotions have been “toned down.” Others say they just don’t care about issues that were significant to them before. “Evidence indicates that these adverse affective manifestations may persist even after the symptoms of depression have improved and can occur in patients of all ages.” Mania or agitation can occur. These response have been said to unveil unrecognized bipolar disorder. But since this can also occur in previously unipolar patients, the mania could be drug-induced. An activation syndrome, where patients experience anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness and impulsivity can occur.

Carvalho et al. limited the occurrence of these adverse effects to the first three months of treatment. However, psychiatrist Peter Breggin has documented the emergence of agitation and activation with antidepressants in Medication Madness and other writings. Carvalho et al. said using antidepressants could also be associated with the return of depressive symptoms during baseline treatment, and the appearance of new symptoms or paradoxically, exacerbate the baseline clinical picture. The occurrence of paradoxical effects was reported in random control trials with Prozac and Zoloft.

The emergence of suicidality and self-injurious behavior with antidepressant treatment is one of the most debated and controversial risks. Nevertheless, the FDA has required a black box warning regarding the risk of suicidality for children and adolescents using antidepressants since 2014. The incidence of successful and attempted suicide has been frequently underreported in antidepressant RCTs. Carvalho et al. said:

Two recent meta-analyses have not identified a clear increased risk of treatment-emergent suicidality in adult individuals treated with antidepressants in RCTs. Notwithstanding that the use of antidepressants is efficacious for the treatment of MDD in adults, there is no clear evidence for either specific protective effects or increased risk related to suicidality.

Often underappreciated, is the emergence of withdrawal symptoms of varying degrees with treatment discontinuation and/or interruption with almost all SSRIs and SNRIs. These reactions have been described as “discontinuation syndromes” in an attempt to avoid the suggestion of dependence that could effect marketing. A review suggested the dependence and withdrawal with newer antidepressants was comparable to those experienced with benzodiazepines. “Due to the severity and unpredictability of these manifestations, it has been recently suggested that the term ‘discontinuation syndrome’ should be replaced by ‘withdrawal syndrome.’” These symptoms can include:

flu-like symptoms, tremors, tachycardia, shock-like sensations, paresthesia, myalgia, tinnitus, neuralgia, ataxia, vertigo, sexual dysfunction, sleep disturbances, vivid dreams, nausea vomiting, diarrhea, worsening anxiety and mood instability.

In their conclusion, Carvalho et al. said the common belief of fewer side effects with the newer generation antidepressants (especially the SSRIs) only pertains to their safety in overdose. “On the contrary, the long-term use of SSRIs and SNRIs is likely to yield important side effects.” The likelihood of treatment-emergent adverse effects is related to the duration of antidepressant treatment—particularly with weight gain, diabetes, and osteoporsis. Some adverse side effects may persist long after discontinuation of the drug. Particularly following long-term use, antidepressants,

 … may increase the risk of experiencing additional psychopathological (e.g. treatment emergent affective switches and paradoxical symptoms), or medical (e.g. obesity and bleeding) problems that do not necessarily subside after discontinuation of the drug.

This leads to their conclusion that: “The findings of this review suggest that long-term treatment with new generation ADs should be avoided if alternative treatments are available.”

11/11/16

Help the Medicated Military

© Oleg Dudko | 123rf.com

© Oleg Dudko | 123rf.com

A U.S. Air force pilot was assigned to transport a B-1 bomber from near the Persian Gulf to South Dakota. The trip took nineteen hours and crossed nine time zones. Every four hours, he took a “go pill”—a tablet of Dexedrine. After landing, he went out for dinner and drinks with a friend from the base. When they were driving back to the base, he began hitting his friend, saying that “Jack Bauer” had told him they were going to try and kidnap him. He was eventually charged with auto theft, drunk driving and two counts of assault.  But a court martial judge found him not guilty “by reason of mental responsibility.”

 

 

Four military psychiatrists concluded that Burke suffered from “polysubstance-induced delirium” brought on by alcohol, lack of sleep and the 40 milligrams of Dexedrine he was issued by the Air Force.

In her article for the LA Times, Kim Murphy went on to say a growing number of lawyers are blaming the U.S. military’s heavy use of psychotropics for their client’s aberrant behavior and the related health problems. In 2012 the U.S. Army surgeon general indicated there were almost 8% of active duty Army on sedatives and more than 6% using antidepressants. This was an eightfold increase since 2005.

A former military psychologist said: “We have never medicated our troops to the extent we are doing now … And I don’t believe the current increase in suicides and homicides in the military is a coincidence.” An Army pharmacy consultant said the military’s use of prescription drugs is comparable to the civilian world. “It’s not that we’re using them more frequently or any differently.” Grace Jackson, a former Navy staff, psychiatrist said: “The big difference is these are people who have access to loaded weapons, or have responsibility for protecting other individuals who are in harm’s way.”

According to a 2007 review in Military Medicine, the modern Army psychiatrist’s deployment kit will likely contain “nine kinds of antidepressants, benzodiazepines for anxiety, four antipsychotics, two kinds of sleep aids, and drugs for attention-deficit hyperactivity disorder.” Military doctors believe it would be a mistake to send battalions into combat without these medications, which they see as helping to prevent suicides, calm shattered nerves and help soldiers rest.

Psychiatrist Peter Breggin said that before the Iraq war, soldiers couldn’t go into combat if they were using psychiatric drugs. “You couldn’t even go into the armed services if you used any of these drugs, particularly stimulants,” just 10 or 12 years ago. Now some people are saying psychiatrists won’t approve their deployment unless they take psychiatric drugs.

An Army Pfc. Pleaded guilty to murdering a Taliban commander in Afghanistan. After the death of a good friend, he began hearing a harsh female voice. He was also depressed. He didn’t tell doctors about the voice—only that he was depressed and thinking of suicide. He was prescribed Zoloft for depression and trazodone for sleep. The voices became worse and he began seeing hallucinations of his dead friend. Eventually he walked into the cell of the Taliban commander and shot him in the face. He was eventually sentenced to a ten-year prison term.

Both the American Psychological Association and the American Psychiatric Association in a 2010 hearing urged the Army to stay the course on psychotropic drugs.

Military Times reported that many troops are mixing several different kinds of pills—an antidepressant and an antipsychotic to prevent nightmares, an anticonvulsant or anti-epileptic to prevent headaches. And these medications are being prescribed, consumed and swapped in combat zones. Dr. Grace Jackson said: “It’s really a large-scale experiment. We are experimenting with changing people’s cognition and behavior.”

Data obtained from the Defense Logistics Agency (DLA) showed the DLA spent $1.1 billion on psychiatric and pain medications from 2001 to 2009. The use of psychiatric medication has increased by 76%, with the use of some drug classes more than doubling. Orders for antipsychotic medications were up over 200%; annual spending more than quadrupled from $4 million to $16 million. Anticonvulsant use increased 70%; spending more than doubled from $16 million to $35 million. Spending on antidepressants decreased from $49 million in 2001 to $41 million in 2009, a drop attributed to cheaper generic versions hitting the market during that same time period.

The Army’s highest-ranking psychiatrist told Congress that 17% of the active-duty troops and as much as 6% of deployed troops are on antidepressants. Doctors and lawmakers are questioning whether the drugs are responsible for the spike in suicides within the military—trend that parallels the increase in psychiatric drug use. Dr. Peter Breggin said there was overwhelming evidence that the newer antidepressants commonly prescribed can cause or worsen suicidality, aggression, and other dangerous mental states. “Imagine causing that in men and women who are heavily armed and under a great deal of stress.” But many military doctors believe the risks are overstated and not fully treating depressed troops would be the greater risk.

Military Times said the Defense Department repeatedly denied its requests for copies of autopsy reports that would show the prevalence of these drugs.

From 2001 to 2009, the Army’s suicide rate increased more than 150 percent, from 9 per 100,000 soldiers to 23 per 100,000. The Marine Corps suicide rate is up about 50 percent, from 16.7 per 100,000 Marines in 2001 to 24 per 100,000 last year. Orders for psychiatric drugs in the analysis rose 76 percent over the same period. Other side effects can include increased irritability, aggressiveness and hostility.

Dr. Peter Breggin published an article in Ethical Human Psychology and Psychiatry, “Antidepressant-Induced Suicide, Violence, and Mania: Risks for Military Personnel.”  He noted where the activation side effects of newer antidepressant mimicked the symptoms of PTSD, increasing the hazard when they are prescribed to military personnel. He recommended that the military study the relationship between psychiatric drug treatment and suicide as well as random or personal violence. He also recommended that antidepressant be avoided when treating military personnel. See his website for more information on the relationship between antidepressants, suicide and violence in soldiers.

There is a strong probability that the increasing suicide rates among active-duty soldiers are in part caused or exacerbated by the widespread prescription of antidepressant medication. By themselves, these drugs cause a dangerous stimulant-like profile of adverse reactions. These symptoms of activation can combine adversely with similar PTSD symptoms found so commonly in soldiers during and after combat.

In September 28, 2016, US Senator John McCain introduced the Veteran Overmedication Prevention Act (S. 3410), a companion bill to HR 4640, the Veteran Suicide Prevention Act. Psychologist Philip Hickey reported the bills seek to fight against suicide deaths in military personnel by ensuring that accurate information is available on the relationship between suicides and prescription medication. If passed, these bills would bring information currently being withheld from the public on these relationships. A press release from Senator McCain said:

This legislation would authorize an independent review of veterans who died of suicide or a drug overdose over the last five years to ensure doctors develop safe and effective treatment plans for their veteran patients. We have a long way to go to eradicate veteran suicide, but this legislation builds on important efforts to end the tragedy that continues to claim far too many lives far too soon.

“Data suggests that every 65 minutes a veteran takes his or her own life.” One way to address this is by determining if there is any association between suicide and the medical treatments being received by veterans for service-related conditions. Congressman David Jolly said the following in a press release about his sponsorship of the Veteran Suicide Prevention Act:

Specifically, the Veteran Suicide Prevention Act would require the VA to record the total number of veterans who have died by suicide during the past five years, compile a comprehensive list of the medications prescribed to and found in the systems of such veterans at the time of their deaths, and report which Veterans Health Administration facilities have disproportionately high rates of psychiatric drug prescription and suicide among veterans treated at those facilities.  The VA would then be required to submit to Congress a publicly available report on the results of their review, along with their plan of action for improving the safety and well-being of veterans.

As suggested by Philip Hickey, honor the veterans who have served our country by writing your legislators in the Senate and the House in support of these bills:

Senate: S 3410 – Veteran Overmedication Prevention Act

House: HR 4640 – Veteran Suicide Prevention Act

11/1/16

Ketamine Desperation

© Novic | stockfresh.com

© Novic | stockfresh.com

Jeff wants to smile again and know what happiness is like again. He wants to not feel the urge to kill himself again. He has been hospitalized in psychiatric facilities and has taken a variety of antidepressants and mood stabilizers for his bipolar disorder, but nothing worked. He remained employed as a football analyst until the sky fell in on him and he lost his job. “He was suicidal; so overwhelmed with despair, that he couldn’t even leave his house.” He finally found a treatment option at the Ketamine Clinics of Los Angeles. And so goes one of many testimonies of ketamine’s potential as a rapid treatment for depression.

Steven Mandel MD, the President and founder of the Ketamine Clinics of Los Angeles, is an anesthesiologist who uses ketamine to treat patients who are depressed and suicidal. The standard protocol is to give low dose IV infusions of ketamine. It worked for Jeff. He said, “It’s been remarkable.” His wife looked at him and saw the smile on his face and had the biggest smile herself in response. Jeff thought it was immoral to withhold ketamine from the general public. You can watch a four-minute video on Jeff and Dr. Mandel’s treatment here.

Over the last ten to fifteen years, ketamine has been getting a significant amount of research and media attention as a fast-acting treatment for depression. Reporting for The Washington Post, Sara Solovitch quoted Dennis Hartman as saying: “My life will always be divided into the time before that first infusion and the time after.” But the relief is temporary. “Clinical trials at NIMH have found that relapse usually occurs about a week after a single infusion.”  And it can cause intense hallucinations or a kind of lucid dreaming or dissociative state where some patients lose track of time.

NIMH studies suggest the psychedelic experience with ketamine may play a small but significant role in the drug’s efficacy. Steven Levine, a psychiatrist who has treated 500 patients with ketamine said:

With depression, people often feel very isolated and disconnected. Ketamine seems to leave something indelible behind. People use remarkably similar language to describe their experience: “a sense of connection to other people,” “a greater sense of connection to the universe.”

Hartman travels back-and-forth to an anesthesiologist in New York City for his bimonthly infusions of ketamine. He doesn’t consider himself permanently cured, “but now it’s something I can manage.” In 2012 he helped to found an organization called the Ketamine Advocacy Network, a group that screens ketamine clinics, advocates for insurance coverage and spreads the word on the effectiveness of ketamine to treat depression. The problem is the treatment is not FDA approved. And in higher doses, ketamine is known as the club drug, “Special K.” See previous articles, “Ketamine to the Rescue?” and “Falling Down the K-Hole.”

The promise of ketamine as a fast-acting alternative to other antidepressant medications had led to a growth industry for ketamine clinics around the U.S. and multiple pharmaceutical companies doing their own research into developing ketamine derivatives without the side effects. Ketamine is known to interact with the NMDA receptor involved in learning and memory. So scientists assumed the same receptor was responsible for the anti-depressive action of ketamine. STAT News reported this led to more than a dozen companies trying to develop drugs that target the NMDA receptor. “But these drugs haven’t worked as well as ketamine.” AstraZeneca pulled out of developing its own highly touted ketamine derivative, lanicemine in 2013 when it failed to show long-term benefits.

Iadarola et al. published a 2015 article in the journal Therapeutic Advances in Chronic Diseases that reviewed the growing literature on ketamine efficacy as an antidepressant treatment. They confirmed the temporary effects from ketamine; the effects waned after several days in most patients. The authors suggested that after achieving the antidepressant response from ketamine, the effects could be maintained with intermittent doses of ketamine as described above with Dennis Hartman. Pharmaceutical companies aren’t really interested in moving forward with ketamine infusion since the drug has been long off patent and they can’t make a billion dollar profit on a drug that is off patent. So they seek to develop biosimilars to ketamine.

The latest pharma compound to target the NMDA receptor is esketamine, which Janssen Pharmaceuticals, a division of Johnson & Johnson, is developing as an intranasal spray. Johnson & Johnson announced on August 16, 2016 that the FDA granted esketamine a Breakthrough Therapy Designation. This is the second time esketamine has received a Breakthrough Therapy Designation. The first was in November of 2013. The Breakthrough Therapy Designation is to expedite drug development when a drug demonstrates the potential to be a substantial improvement over available therapies for serious or life-threatening conditions.

But the real excitement may still be ahead. The STAT article cited above reported on a new research study published in the May 26th 2016 issue of the journal Nature that demonstrated a derivative of ketamine could achieve the same benefit, but without the side effects. The study was done on mice, so it has a ways to go in drug development before it can compete with esketamine. Dr. Todd Gould, who led the Nature study, suggested the ineffectiveness of previous studies that targeted the NMDA receptor were because they were looking in the wrong place. His research team showed that the effectiveness of ketamine as an antidepressant doesn’t come from the NMDA receptors—at least not in mice.

In the body, ketamine turns into a molecule called hydroxynorketamine — or HNK — and that molecule is actually what treats the depression. Gould’s team also found that HNK does not interact with the NMDA receptor, and it doesn’t have some of the side effects that ketamine does.

Gould said they have a game plan to move forward with the clinical development of HNK. He and his coauthors have filed a patent application for certain uses of HNK. Outside researchers thought the study was well-done science, but they aren’t convinced it’s time to give up on the NMDA receptor. Their drugs targeting the NMDA receptor are further along in drug development. And they are not convinced they are beating a dead horse just yet. STAT reported that Dr. John Krystal, a psychiatrist and neuroscientist who consults for companies developing NMDA-target drugs said: “In my view, it is quite premature to move away from the hypothesis that NMDA receptor antagonists have antidepressant activity based on this single study.” True, but to you rush to bring your ketamine-like drug to market first?

There will still be the same adverse effects as with ketamine, won’t there? And the temporary nature of the mood elevation is still there, isn’t it? The lack of long-term effects led to the AstraZeneca decision to stop development with lanicemine. And esketamine is “an investigational antidepressant medication, for the indication of major depressive disorder with imminent risk for suicide.” That sounds like a short-term use designation.

Uli Hacksell, chief executive of Cerecor, a Baltimore company that has a Phase 2 drug candidate directed at the NMDA pathway, also took issue with the claim that such drugs might be going after the wrong target, and he said that the paper will have no implications for his company’s development plans. “We think that the clinical data we get with our molecule will speak for themselves,” he said.

One outside researcher, Dr. Francis Collins, the director of the National Institutes of Health (NIH), was quite supportive of Gould’s research. In his NIH Director’s blog, Collins described the background work leading up to the Gould study. He then said:

 HNK appears to come without the side effects of ketamine. After receiving HNK, mice didn’t show changes in their physical activity, coordination, or sensory perception, as is normally seen after a dose of ketamine. HNK also doesn’t appear to have the same potential for abuse either. When given the option, mice will choose to self-administer ketamine, but not HNK.

The new evidence confirms that HNK doesn’t block NMDA receptors like ketamine does. While there’s more to discover about how HNK works, the evidence reveals an important role for AMPA receptors, another type of glutamate receptor in the brain.

Long-term ketamine users can have irreversible urinary tract and bladder problems. Erowid, a pro-drug website, conducted an online survey that indicated there was a clear correlation between total lifetime use of ketamine and the likelihood of reporting bladder/urinary problems. Now these are health problems that occur with higher doses of ketamine than those used to treat depression. Lower doses over the long-term may not have the same adverse effects. However, these known health concerns should not be overlooked in the rush to bring a new fast-acting antidepressant to market. Ketamine (and its derivatives) to the rescue of depression may not turn out to be the super cure some think it is.