12/30/16

The “Hotel California” Effect

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Alkermes is a believer in the classic idiom, the third time’s the charm. The pharma company recently announced success on its third-late stage clinical for ALKS 5461, which it hopes will become a new antidepressant blockbuster. In January of 2016 two previous phase III trials failed to achieve their primary endpoints and the company’s stock price took a nosedive. After the positive results of the FORWARD-5 study, shares were up over 30%. Alkermes plans to meet with the FDA in order to argue that despite failing in its two previous phase III clinical trials, the FDA should approve ALKS 5461 and “bring this new medication to patients with MDD [major depressive disorder].”  FDA regulations require a total of two successful phase III trials with statistical significance over placebo. What’s going on here?

The FORWARD-4 clinical trial tested two dose levels of ALKS 5461, 2mg and .5 mg and it failed to meet its initial primary endpoint, “change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score.” Post-hoc statistical analysis done on the FORWARD-4 data indicated the group receiving the higher 2mg dose of ALKS 5461 had a statistically significant difference on the MADRS. Alkermes then decided to “update” their methodology and analysis for FORWARD-5. In other words, Alkermes used statistical analysis of the failed FORWARD-4 trial to uncover a significant result within a subpopulation of the study that was not targeted in their initial study design. They then modified their methodology and analysis of the FORWARD-5 trial to match the post-hoc analysis.

In a previous article on the FORWARD-3 and FORWARD-4 failed clinical trials, “Nearsighted Drug Development,” I expressed the opinion that this seemed a bit like cheating. Nevertheless, it seems that changing the methodology from what was initially proposed for an ongoing trial is permitted. But would it be appropriate for the FDA to reconsider the post-hoc analysis of the FORWARD-4 trial as a “successful” clinical trial? It seems a bit like trying to argue that the FDA should give Alkermes credit for positive results in FORWARD-4 even though those positive results only became apparent after the fact—when they began to fiddle around with the data to see if they could find something positive.

Another disturbing claim by Alkermes is with how they describe ALKS 5461. It is “designed to rebalance brain function that is dysregulated in the state of depression.” As I pointed out in “Nearsighted Drug Development,” the chemical imbalance theory of depression is now said to be an urban myth even by pro drug psychiatrists like Ronald Pies.

If approved, ALKS 5461 is proposed as an add-on, adjunctive medication in the treatment of major depression for patients “with an inadequate response to standard antidepressant therapies.” However, there is a hint that if approved ALKS 5461 could be put forward by the company as a standalone treatment for depression. Elliot Ehrich, the CMO of Alkermes, said the studies in the FORWARD program contributed data useful in assessing the safety and efficacy of ALKS 5461 on a standalone basis and if taken as an adjunct medication.

It also appears that if the FDA does not agree to approve ALKS 5461 as a treatment for MDD based upon the above discussed rationale, Alkermes will drop it. Richard Pops, the chairman of Alkermes, said they are not planning to conduct any additional studies on ALKS 5461. Is this just a cut your losses decision to forego the additional cost of another clinical trial for the company? Or is it a veiled threat to the FDA that Alkermes will shelve any future work on a product that was once approved by the agency for a fast track drug development status? In other words will the FDA permit post hoc analysis of a phase III clinical trial turn a failed trial into a successful one?

What is at stake here is that the active ingredient in ALKS 5461 is a known opioid, with an acknowledged addictive potential—buprenorphine. Buprenorphine is a Schedule III controlled substance.  Combining it with an opioid antagonist (samidorphan) does not lessen its addictive potential. In higher doses buprenorphine is used as a maintenance drug therapy for opioid dependence (Suboxone; Subutex; Zubsolv). Regularly, opioid dependent individuals have told me that getting off of buprenorphine was harder than heroin or methadone.

Higher doses and longer term use of buprenorphine influence the length of time for withdrawal or discontinuation. And guess what, depression is one of the commonly experienced withdrawal symptoms. The Addiction Blog posted some helpful information on “How long does buprenorphine withdrawal last?” Note that the website is not taking an anti-buprenorphine position. It begins by saying “Buprenorphine can be a useful drug prescribed to treat opiate addiction.”

Within the first 24 to 72 hours, physical withdrawal symptoms peak in severity and intensity with common symptoms such as: diarrhea, sweating, nausea, dilated pupils, watery eyes and restlessness. As the first week progresses, aches, stomach cramps, and joint pain will probably continue. General feelings of discomfort and problems sleeping can occur. “Mood swings are also common, with bouts of anxiety or depression.”  After two weeks, the pain and discomfort of acute physical withdrawal should be less severe, but depression and an extreme loss of motivation can set in.

After [the] three to four week mark, most of the physical withdrawal symptoms will be gone, however … intense drug cravings may be present for those addicted to buprenorphine. Depression is also common. This time is very important, as you will be very vulnerable to relapse. . . . However, psychological withdrawal symptoms can last for months after cessation.

Now “relapse” here refers to resuming active opioid use or abuse. But in reviewing the withdrawal symptoms described above, the relapse experienced could just as easily be interpreted as a depression relapse by individuals attempting to taper off of long term ALKS 5461 use.

So someone could add ALKS 5461 to their antidepressant of choice, take it for an extended period of time and see a clear remission of their depressive symptoms. If they were to then attempt a taper off of ALKS 5461, they would likely experience the above described buprenorphine withdrawal symptoms, interpret them as a return of depressive symptoms, and resume using ALKS 5461. If ALKS 5461 is used as a stand-alone treatment for depression, a misinterpretation of withdrawal symptoms as a relapse of depression is also likely occur. Similar to long-term antidepressant users, there could be a “Hotel California” effect—you can taper down any time you want, but you can never leave.

With continued use of buprenorphine, there comes a point where the brain produces an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS [post acute withdrawal syndrome] manifest long lasting changes in the brain as a result of long term use. These changes are slower to reverse and can persist for many months, depending on the frequency and amount of past dosing.

I don’t know whether the above concerns will be considered in an FDA review of the Alkermes request to approve ALKS 5461. I hope they are. But if Alkermes is successful in bringing its drug to market, “where new therapeutic options are highly sought after as millions of patients in the U.S. do not respond to standard courses of antidepressant therapy,” be prepared for what seems to be an unavoidable cycle of depression treatment perpetuating depression and further treatment. While the rhetoric appears overblown to some, I do believe there is a “Coming Depression Apocalypse” if ALKS 5461 is approved by the FDA.

12/27/16

Exceptional in Ordinary Things

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When reading a devotional based upon the writings of Puritan authors, I was struck by a quote attributed to the Puritan minister, Edmund Calamy. I then discovered the quoted work, Evidence for Heaven, was actually written in 1657 by an anonymous ‘gentlewoman’ woman in his congregation. She was anonymous by request. But her work received the unreserved endorsement of Calamy, who said: “I hope no man will condemn this Book, because written by a Woman but rather admire the goodnesse, love, and power of God, who is able to do such great things, by such weak instruments.” Although it sounds sexist to a modern reader some 360 years after it was written, nevertheless, Calamy thought enough about this work to see that it was published.

This piqued my interest in Evidence for Heaven, so I wrote several articles reflecting what the anonymous author had said in it. Then I stumbled across another female Puritan author, Sarah Fiske. Her only literary work, A Confession of Faith: Or, a Summary of Divinity, was originally a confession of her faith, which she submitted upon her admission into full membership of the Church of Braintree, Massachusetts. A Confession was published posthumously, twelve years after her death on December 2, 1692.

Wendy Martin and Sharone Williams noted in The Routledge Introduction to American Women Writers that most spiritual autobiographies were intended only for the edification of a small group, such as a family or church community. The faithful were expected to be able to demonstrate their awareness of the basics of orthodox belief; and occasionally those texts were published in the hopes of both drawing readers to booksellers, and converts to Christ. A small number of these accounts were written by women. Forbidden to speak or teach in most churches of the time, mothers were considered the first instructors of their children in the faith, particularly in Puritan communities, according to Martin and Williams.

The ability to articulate principles of faith and to relate personal spiritual experiences was thus paradoxically entwined with motherhood, the most sacred of feminine responsibilities. Within a fairly rigid set of boundaries, then, both privately circulated and published religious writing was an arena in which seventh-century women were able to find their voices.

Reflecting on her Confession within the context of the time and culture she lived in, I see also how Sarah’s life speaks loudly about how we all are truly instruments in the hand of a Redeemer God who truly cares for us and guides us.

Sarah Symmes was born in 1652 to a respected justice of the peace in Charleston Massachusetts, William Symmes. Her mother, who was also named Sarah, died when baby Sarah was only a year old. Given the death of her mother when Sarah was one, perhaps she was an only child. Her grandfather, Zachariah Symmes, was a noted New England minister. At the age of nineteen she married the Harvard graduate, Moses Fiske. Remember this was Harvard of 1672, not 2016. Moses was himself the son of a clergyman who immigrated to the colonies from Suffolk, England. He was ten years older than Sarah. They had fourteen children together; only eight of which survived childhood. Three of her daughters married ministers and one son was himself a minister.

Sarah’s death at the age of 40 came at the end of a year that saw her give birth to two children: Ruth who lived about two and a half months (March 24, 1692 to June 6, 1692); and Edward, who only lived five days (October 20, 1692 to October 25, 1692). Moses remarried in January of 1701. He was the minister of the church at Braintree from 1672 until the time of his death in August of 1708. He was succeeded in the ministry at the church in Braintree, now known as Quincy, by the Reverend Joseph Marsh, who married Anne, the daughter of Moses and Sarah. This information appeared in The Symmes Memorial a Biograqphical Sketch of Rev. Zechariah Symmes, by J.A. Vinton.

When Sarah became a full member of her husband’s church and submitted what would become known as A Confession of Faith, she was a 25 year-old mother of two girls, Mary, aged 4 and Sarah aged 3. She had lost a third daughter, Martha at 3 days of age two years before. And she was either pregnant or caring for the newborn Anna, who would die at 10 months of age in June of 1678. The Encyclopedia of American Literature said A Confession moved logically and steadily though theological subjects not considered to be typical or even appropriate for a 17th century woman’s spiritual biography. Her command of language, grammar and style suggested: “She received a solid education despite the rural environment, modest circumstances, and gender.”

Benjamin Elliot, who published Fiske’s A Confession, thought it would be helpful to children and young ones who could “gather the Fragrant Flowers of Divine Knowledge” of the main articles of their creed discussed therein. What seems to have been missed is how Elliot saw the echoes the Westminster Confession of Faith and its Larger and Shorter Catechisms in Sarah’s Confession. These would have been the Creed and Catechisms that she likely affirmed in her church membership; and seems to have studied before writing her personal Confession. The parallels affirm and do not detract from the above comment on her solid education. Here are a few examples. Sarah’s opening article is:

I Believe, That the Holy Scriptures, the Books of the Old & the New Testament, Penned by the Prophets & Apostles, are the Infallible Word of God, the Subject of true Divinity; That only Rule of Faith & Manners, teaching what man ought to Believe concerning God, and what Duty God requires of man.

The Westminster Confession of Faith affirms that the Old and New Testaments are the infallible truth and Word of God. Question 5 of the Larger Catechism asks what the Scriptures principally teach; then answers: “The scriptures principally teach, what man is to believe concerning God, and what duty God requires of man.”

Sarah affirms that God is pure, powerful, eternal, unchangeable being. He is independent, incomprehensible, invisible. The Westminster Confession and Larger Catechism agree that God is eternal, all-sufficient, unchangeable, incomprehensible, invisible. They affirm with Sarah that there is but one God in three Persons in the Godhead: Father, Son and Holy Ghost.

Sarah said she believed the decrees of God were His determinate purpose in all things, according to the counsel of His will. And God executes his decrees in the works of creation and providence. The Larger Catechism said God’s decrees are “the free and holy acts of the counsel of his will, whereby, he hath, for his own glory, unchangeably foreordained whatsoever comes to pass in time.” And he executes his decrees “in the works of creation and providence.” The parallels move on through Jesus Christ as Redeemer, union with Christ, faith, repentance, justification, adoption, sanctification, saving faith, baptism, communion and more.

Sarah’s life was unremarkable within the context of her time. Possibly raised as an only child, she was thoroughly educated in the teaching of “the Fragrant Flowers of Divine Knowledge” of the Westminster Confession of Faith and its Catechisms, the creeds of her faith. She was married at the age of nineteen to a popular minister, who would serve his congregation over 30 years. She had a clear talent as a writer, ably communicating the faith she had been taught and believed in with her whole heart. Along with her husband, Moses, she seems to have passed that faith on to her children.

As a twenty something mother of three girls under the age of 4, she was able to put together a coherent, logical expression of her faith—without computers to record and edit her thoughts or DVDs to distract her young daughters as she tried to write. Too soon, she died at the age of 40. This happened within three months of what seems to have been the premature birth of her 14th child. No information is available on the cause of her death, but we can speculate that fourteen births in seventeen years was a contributing factor to whatever health’s problems led to her death. Yet in the midst of being a pastor’s wife and mother to eight children, she was able to write a Confession of her faith so clear and concise, that a publisher would print it twelve years after her death.

A Confession of Faith: Or, a Summary of Divinity may be an illustration of orthodoxy and radicalism in women’s religious writings of the 17th century, as Martin and Williams state. But I think it is a more powerful example of how God inhabits the ordinary lives of believers. Sarah Fiske’s life was an example of being exceptional in ordinary things. Oswald Chambers said the following in his classic devotional, My Utmost for His Highest:

We do not need the grace of God to stand crises, human nature and pride are sufficient, we can face the strain magnificently; but it does require the supernatural grace of God to live twenty-four hours in every day as a saint, to go through drudgery as a disciple, to live an ordinary, unobserved, ignored existence as a disciple of Jesus. It is inbred in us that we have to do exceptional things for God; but we have not. We have to be exceptional in the ordinary things, to be holy in mean streets, among mean people, and this is not learned in five minutes.

12/25/16

Psychedelic Santa and Christmas Mushrooms

Here is a “throw back Christmas”  article on the mixing of two different myths about Santa. Enjoy!

Falling in the strange, but true category is the association of Christmas and a hallucinogenic mushroom called the Ananita muscaria (the holy Mushroom) or fly agaric. Collecting, preparing and using fly agaric mushrooms was part of winter solstice celebrations among many northern European and Asian peoples.  According to anthropologist John Rush, “Santa is a modern counterpart of a shaman, who consumed mind-altering plants and fungi to commune with the spirit world.”

As the winter solstice approaches, fly agaric mushrooms appear under trees, mostly firs and spruces. As you can see, its cap is dark red, with small creamy-white patches. In central Asia, shamans wore special garments when they gathered the mushrooms—red coats and pants trimmed with white fur along with black boots. They would collect the mushrooms in a special sack. When they returned to the village, they would enter the dwellings through the smoke hole in the roof and share the mushrooms with the residents in a sacred ceremony.

The smoke hole was a gateway or portal into the spiritual world where the people would experience many visions. Among the Sami (Laplander) peoples, the hallucinations associated with ingestion of fly agaric gave the sensation of flying in a “spiritual sleigh” pulled by reindeer or horses (i.e., Santa in his sleigh journeying out into the night to give gifts).

There are those like Ronald Sutton, a history professor at the University of Bristol, who dispute the psychedelic Santa connection. He said his studies of Siberian shamanism showed they didn’t travel by sleigh; didn’t usually deal with reindeer spirits; rarely used mushrooms to have trances; and didn’t wear red and white clothes.  Sutton believes that the Santa Claus known to us was invented by a New Yorker—Clement Clarke Moore—in 1822.  Moore wrote the poem: “The Night Before Christmas.”

The more traditional “history” of Santa Claus is built upon the life of St. Nicholas, a fourth century Greek bishop. Nicholas became bishop of Myra, a small town in modern Turkey and was imprisoned for his faith during the “Great Persecution” of 303-311. One legend says he secretly gave money to a local nobleman who had three daughters with no money for their dowries. “He was going to have to sell them into prostitution because of his poverty.” “Father” Nicholas, as he was called, secretly gave him the money for the dowries on Christmas Eve. So began the custom of Christmas gift giving.

In 325, Nicholas, was one of the bishops invited to the Council of Nicea. It is said that he physically assaulted Arius at the Council because Arius suggested that Jesus was merely a man. Nicholas died and was buried in Myra, where his bones became venerated as relics, granting miracles and exuding a liquid they called ‘manna,’ that supposedly smelled like rosewater. Myra became a center for Christian pilgrimage and Nicholas became a saint.

In 1087 sailors from the Italian port city of Bari were hired by merchants to steal Nicholas’s bones and bring them back to Bari. Their aim was to build a basilica and make Bari a lucrative center for pilgrimage. The sailors were supposed to share in the profits, but the Church reneged on the contract and kept all the proceeds.  The modern town of Bari still celebrates the sailors’ successful theft of Nicholas’s bones. Within the link “history of Santa Claus” is a BBC documentary sectioned into four YouTube videos that tells the story in more detail and includes a modern forensic reconstruction of what Nicholas would have looked like.

Nevertheless, the psychedelic Santa version of the myth continues, with even some suggestion that Moore himself adapted it for a modern audience in his poem. Watch this short YouTube video, Magic Mushrooms & Reindeer.” Fly agarics are also common images in many aspects of popular culture. They dance in Fantasia. Mario Brothers video game players eat them for power and extra energy. Here is a satire of Realistic Mario eating a mushroom. You can even buy fly agaric Christmas ornaments and cards, which have been traditional Christmas images in some northern European cultures.

Independent of the alleged Christmas connection, there is a clear history of humans using Ananita muscaria as a psychoactive substance. Its use in Siberia predates the Pleistocene migration across the Bering Straits into North America. After the migration, the use of fly agaric fell off in the Americas, as liberty cap mushrooms became “the preferred psychoactive fungi” because of their less severe side effects and more intense experiences.

The earliest suggestive evidence of Ananita muscaria use stems from linguistic analysis of languages from northern Asia. The Uralic languages from around 4,000 BCE contained root words for inebriation or intoxication that also signified the A. muscaria mushroom. Petroglyphs along the Pegtymel River in northeastern Siberia depict figures with mushrooms attached to their heads. There is a fresco in the Plaincourault Abbey in Indre France from 1291 AD that depicts Adam and Eve standing beside a Tree of Knowledge stylized as an Ananita muscaria. They use mushroom caps to cover their nakedness.

Vintage holiday cards with fly agaric mushrooms.

There has even been a theory put forth by John Marco Allegro in The Sacred Mushroom and the Cross that early Christian theology was derived from a fertility cult centered on the use of Ananita muscaria. Allegro argued that Jesus never existed; and that he was a mythical figure created by early Christians under the influence of psychoactive mushrooms. He said the Plaincourault fresco depicted “an accurate ingestion of Ananita muscaria as the Eucharist.” I could easily see the fresco as a stylized depiction of Adam and Eve eating something that would make them wise like God; but not his theory of Christianity and other religions originating as fertility cults. I think Allegro ate one too many mushrooms himself. At any rate, his theories were widely dismissed. His book was said to be: “possibly the single most ludicrous book on Jesus scholarship by a qualified academic.”

I don’t think we have to choose between these two Santa Claus legends, there seems to be enough room to accommodate both of them. But whether he was originally a shaman or a saint, Santa Claus has become an internationally known figure. Now if we could just get the ‘peace on earth’ part right.

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.

12/20/16

The Opioid Buzzard

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The U.S. is in the midst of a health crisis from the use and abuse of opioids. Since 1999, the rate of overdose deaths from opioids—prescription pain relievers and heroin—nearly quadrupled. On an average day in the U.S. more than 650,000 opioid prescriptions are dispensed; 3,900 people begin nonmedical use of opioids; 580 people start using heroin; and 78 people die from an opioid-related overdose. Economically, there is a $20 billion cost in emergency department and inpatient care for opioid poisoning each year; and $55 billion spent on health and social costs related to prescription opioid abuse.

In order to address this opioid epidemic, the U.S. Department of Health and Human Services (HHS) launched an initiative in March of 2015 aimed at improving prescribing practices, expanding the access to and use of medication-assisted treatment and expanding the use of naloxone. So far, the Substance Abuse and Mental Health administration (SAMHSA) has awarded $10.7 million to 11 high-burden states for medication-assisted treatment (MAT). Applications were due in May of 2016 and awards were to be made to an additional 11 states. The above information and statistics were drawn from a Health and Human Services report, “The Opioid Epidemic: By the Numbers.”

Then in July of 2016, the HHS Secretary announced new rules that permit doctors licensed to dispense buprenorphine to see as many as 274 patients per year. The old limit was 100. HHS estimated that change permits as many as 70,000 more people to access buprenorphine. The former limit of 100 was seen by many as a barrier to individuals seeking to access MAT. “The rule aims to increase access to medication-assisted treatment and associated behavioral health supports for tens of thousands of people with opioid use disorders, while preventing diversion.” Clearly buprenorphine products like Suboxone are seen as a crucial element in our attempts to combat the opioid health crisis.

There are issues with this approach to treatment for the opioid crisis that I’ve addressed previously in articles such as: “The Seduction of Opioid Substitution” and “A Double-Edged Drug.” Here I want to look at how the company that brought buprenorphine treatment to market, Indivior/Reckitt Benckiser, tried to position itself as the primary service provider for buprenorphine-based MAT in the U.S. It’s kind of like a buzzard chasing off smaller scavengers from the carcass of an overdose victim. At one point, Reckitt Benckiser had 85% of the U.S. MAT market—almost all of it subsidized by taxpayers.

In 1994 Reckitt Benckiser established the Buprenorphine Business Group to develop buprenorphine as a treatment for opioid dependence. In 2000 legislation (DATA 2000) was passed in the U.S. permitting office-based treatment of opioid dependence. In 2002 the FDA approved Subutex (buprenorphine) and Suboxone (buprenorphine and naloxone) for the treatment of opioid dependence in the U.S. These products came to market in 2003. In 2007 the initial cap of 30 patients was raised to 100 for physicians with at least one year’s experience with buprenorphine. That same year Reckitt Benckiser acquired the rights for the sublingual film version of Suboxone from MonoSol Rx. Then in 2010 Suboxone sublingual film was launched in the U.S. Subutex tablets were discontinued in 2011; and Suboxone tablets met the same fate in 2012. In December of 2014, Reckitt Benckiser spun its specialty pharmaceutical company into a separate business and Indivior was born.

This history was taken directly from the Indivior website, where the company estimated they had treated 5 million individuals in the U.S. with Suboxone film and tablets and Subutex tablets. Here are some additional facts to add to the above timeline from a 2013 article, “Pharma Gamemanship.”

Reckitt Benckiser (RB) knew it only had patent exclusivity for their buprenorphine products until 2009. But they had a plan to circumvent the pending loss. As noted above, they acquired the rights for the sublingual film version of Suboxone in 2008. In October of 2008 they submitted a New Drug Application to the FDA for the film version of Suboxone; and it was approved in August of 2010. Reckitt Benckiser has patent exclusivity on the newer film version until 2023.

In their 2011 annual report (no longer retrievable from its website), RB indicated to their shareholders that competition from generics could take up to 80% of the revenue and profit from the U.S. Suboxone market. But they expected “that the Suboxone film will help to mitigate the impact.” In September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. They said they would take the tablet form off the market to “protect public health and safety.”

The very same day RB filed a “Citizen’s Petition” with the FDA calling for the agency to postpone the approval of generic version of Suboxone in the interests of public safety. Reporting for The Daily Beast, Christopher Moraff said the “data” they based their withdrawal of Suboxone tablets on was a single study RB had paid for itself. RB reportedly said the study demonstrated the risk factor for accidental ingestion was eight times higher in bottled tablets than for the individually packaged film. Yet its own data told a different story.

Compared to the more than 20,000 deaths in 2012 from prescription opiates and heroin, pediatric poisoning from Suboxone was far from a public health crisis. A preliminary study commissioned by Reckitt Benckiser found just 46 cases of serious injury or death out of more than 2,200 accidental pediatric exposures to Suboxone tablets between 2010 and 2012—which researchers described as not significantly different from poisonings from the film.

The FDA thought the RB study was inconclusive and did not demonstrate any difference in the safety profile or abuse potential of the two formulations. They said the study was poorly designed and conducted. “Reckitt’s own actions also undermine, to some extent, its claims with respect to the severity of this safety issue.” Despite the first report of pediatric death in June of 2010, RB continued marketing the tablets in multi-dose containers for two more years. And it continues to sell them throughout Europe, where Suboxone tablets are still under patent.

In June 2013 the FTC opened an investigation into whether Reckitt Benckiser abused public regulatory processes and fought for nearly two years to obtain more than 20,000 documents the company was fighting to withhold. That case is ongoing. In December of that year, federal agents raided Reckitt Benckiser’s West Virginia offices after the Department of Justice launched a criminal probe into the company’s Suboxone business. That investigation continues.

Public Citizen said that few, if any, companies went as far as RB to pre-emptively withdraw an off-patent drug from the market to make room for a newly patented successor. A year before the withdrawal of the tablets from the market, RB stated in its 2011 report that its goal was to convert as many tablet users as possible to the film version.

To this end, the company initiated a marketing campaign to persuade physicians to switch patients from the tablet to film form. It also employed more direct tactics to complement the marketing push, raising the price of the tablets to levels higher than the film versions. As a result of these efforts, tablet sales fell 19 percent between August 2011 and August 2012, while sales of Suboxone film doubled during the same period. By September 2012, the film version had captured 70 percent of the Suboxone market, clearing the way for the announcement of the withdrawal of the tablets that month.

So it should come as no surprise that a lawsuit has been filed by 35 states and the District of Columbia alleging that Indivior violated antitrust laws by trying to extend its monopoly over Suboxone. Reporting for CNN, Susan Scutti said the lawsuit charges that Indivior/RB and MonoSol Rx “conspired to block generic competitors for Suboxone by switching the drug from a tablet to a dissolving film.” A September 23, 2016 press release on the Indivior website said: “The Company intends to continue to vigorously defend its position.”

The International-Dictionary.com said there are two meanings for the word “buzzard.” The first one is zoological, referring to a bird of prey of the hawk family. The second meaning is “a blockhead; a dunce.” A quote attributed to Goldsmith reads: “It is common, to a proverb, to call one who can not be taught, or who continues obstinately ignorant, a buzzard.” It seems to me that either sense can be applied to Reckitt Benckiser and Indivior.

12/16/16

What Americans Believe

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There is a new poll out on the state of American theology. The “2016 State of American Theology Study” was sponsored by Ligonier Ministries and completed by LifeWay Research, the research arm of the Southern Baptist Convention. The poll looked at six doctrinal areas, asking about: God, goodness and sin, salvation and religious texts, heaven and hell, the church, and authority. And it seems that there were some surprising findings.

First, a little background information. Ligonier Ministries had previously commissioned LifeWay Research to do a 2014 poll, “The State of Theology.” Many of the questions in both polls seem to be word-for-word the same, but some questions were new to 2016 poll and some were reworded. Both polls were national, online panels, with 3,000 surveys each. The 2014 poll was completed between February 25th and March 5th of 2014, and the 2016 poll was completed between April 14th and April 20th of 2016. Both polls sought to use wording that would be understood by typical Americans. Both asked multiple questions on each topic. Each doctrine or heresy was stated as fact, with respondents then asked to indicate their level of agreement.

According to Joe Carter of The Gospel Coalition, Ligonier Ministries will post articles that interpret the key findings of the 2016 poll, but I thought it would be interesting to compare the 2014 and 2016 polls and reflect on the similarities and the differences between them. One significant difference between the two polls was how “Evangelicals” were identified. In the 2014 poll, Evangelicals were self-declared or self-identified. In the 2016 poll to be an Evangelical, respondents had to strongly agree with the following four statements:

  • The Bible is the highest authority for what I believe.
  • It is very important for me personally to encourage nonChristians to trust Jesus Christ as their Savior.
  • Jesus Christ’s death on the cross is the only sacrifice that could remove the penalty of my sin.
  • Only those who trust in Jesus Christ alone as their Savior receive God’s free gift of eternal salvation.

In conjunction with the organization, the National Association of Evangelicals (NAE), LifeWay research constructed the criteria for Evangelical belief from historian David Bebbington’s four primary characteristics evangelicalism. See the “What is an Evangelical?” page on the NAE website. The NAE said they believe these distinctives and theological convictions define evangelicals—“not political, social or cultural trends.” They note how many evangelicals rarely use the term to describe themselves. Rather, they focus on “the core convictions of a triune God, the Bible, faith, salvation, evangelism and discipleship.”

Self-declared evangelicals are largely a different species than those individuals who strongly agree with the above four statements. Self-identification creates a larger evangelical population, while strong agreement with the four statements of faith limits the number of evangelicals. Given the radically different ways in which the faith groups of evangelicals were identified, it would have been helpful for each poll to give the percentages of individuals who fit the criteria of “Evangelical.” They did not. So when looking at how “Evangelicals” responded in the two polls, this difference should be kept in mind.

With regard to certain beliefs about God, there were largely no changes among Americans. For the statement: “God is a perfect being and cannot make a mistake”, 50% of the 2016 respondents strongly agreed and 16% agreed somewhat. 2014 Evangelicals strongly agreed with this statement; 97% of the 2016 evangelicals agreed. The 2016 figure seems to be a combination of strong agreement and somewhat agreement from the respondents.

For the statement: “There is one true God in three persons: God the Father, God the Son, and God the Holy Spirit”, 53% of the 2016 respondents strongly agreed and 16% agreed somewhat; 50% of the 2014 respondents strongly agreed and 21% agreed somewhat. Unfortunately, the responses for evangelicals were again not consistently reported for the two polls. 2016 evangelicals were more likely to agree (97%)—again a combination of strong agreement and somewhat agreement. 2014 evangelicals were only noted to somewhat agree (14%) with the triune declaration of God as Father, Son and Holy Spirit.

The question on the bodily resurrection of Jesus has similar results. 45% of 2016 and 2014 respondents strongly agreed; and 23% of 2014 respondents somewhat agreed while 19% of 2016 respondents somewhat agreed. 2016 Evangelicals were more likely to agree (98%) than 2014 Evangelicals (76%). But the data for 2016 seems to again combine strong agreement and somewhat agreement, while 2014 Evangelicals are only reported for strong agreement.

The same frustrating difference in reporting on evangelical agreement existed with the question on the two natures of Jesus Christ—divine and human. Americans in 2014 and 2016 again had similar levels of agreement—62% of 2016 respondents agreed, while 60% of 2014 respondents agreed. Then 85% of 2016 Evangelicals agreed (the combination of strong and somewhat agreement), while 77% of 2014 Evangelicals strongly agreed.

Two statements unique to the 2016 poll had some interesting results. Reflecting the false dichotomy between science and faith, 18% of Americans strongly agreed that modern science discredits the claims of Christianity; 26% agreed somewhat. While 17% disagreed somewhat and 23% strongly disagreed, 16% were not sure. There were no significant differences compared to those with Evangelical beliefs.

A second statement assessed religious differences by stating: “God accepts the worship of all religions, including Christianity, Judaism and Islam.” Forty-four percent of Americans strongly agreed; 20% agreed somewhat; 7% disagreed somewhat; 17% strongly disagreed; and 12% didn’t know. Americans with Evangelical beliefs were less likely to agree.

This failure to provide comparable results from the two polls for the sense of Evangelicals continued through the other doctrinal areas. So I’ll stop commenting on those differences. Perhaps as Ligonier Ministries posts other discussions of their 2016 poll results, the distinction between self-identified Evangelicals of the 2014 poll and the NAE defined Evangelicals of the 2016 poll will be more clearly looked at. Unless specified, the following discussion is about the 2016 poll’s findings.

With regard to beliefs about goodness and sin, salvation and religious texts, there were similar percentages of agreement. With regard to whether “everyone sins at least a little, but most people are good by nature,” 22% of respondents strongly agreed; 43% agreed somewhat; 15% disagreed somewhat; 13% strongly disagreed; and 6% weren’t sure. The same agreement occurred with a statement of whether people have the ability to turn to God on their own initiative. Most 2016 respondents strongly agreed this was possible (55%), while 24% agreed somewhat; 5% disagreed somewhat; 9% strongly disagreed and 7% weren’t sure. The wording for the 2014 statement was reversed, but the results were still similar.

Most people strongly disagreed that even the smallest sin deserved eternal damnation (62%), 11% strongly agreed and 8% agreed somewhat. Fifty-five percent of Americans thought their good deeds contributed to their earning a place in heaven. A bare majority of Americans agreed that salvation always began with God changing the person (53%), while 76% agreed the person must contribute their own effort for personal salvation.

With regard to the Bible, 44% of Americans agreed that Bible was not literally true, although it contained helpful accounts, like all sacred writings. Thirty percent strongly disagreed, while 15% disagreed somewhat and 11% weren’t sure. Yet 52% agreed the Bible alone was the written word of God; and 47% agreed it was accurate in all it teaches. Most Americans (51%) thought the Bible was written for each person to interpret as he or she chooses. When a church does not preach from the Bible, 23% agree it should not be considered a Christian church.

Fifty-eight percent of Americans agree that humans exist to bring God glory and enjoy Him. With regard to sex outside of marriage, 49% agree it is sin; 16% disagree somewhat and 27% strongly disagree. Ninety-one percent of Americans with Evangelical beliefs agree sex outside of marriage is sin. Americans with Evangelical beliefs are more likely to agree that abortion is sin (87%), while 49% of Americans disagree that it is sin. A similar divide exists regarding whether or not the biblical condemnation of homosexual behavior applies today. Forty-two percent think it does not apply today, while 44% think it does apply.

Where to begin? Half of Americans deny the eternal existence of Jesus as the Son of God, and believe that He was “the first and greatest being created by God.” Yet 61% agree that Jesus is truly God and truly man, and 69% agree there is one God in three persons, Father, Son and Holy Spirit. However, 56% of Americans agree that the Holy Spirit is a force but not a person; He is divine, but not equal to the Father and Jesus (28%). Further, many Americans (77%) believe they contribute to their salvation; that by their good deeds they partly contribute to earning their place in heaven (52%); and that while everyone sins a little, most people are good by nature (65%).

I wonder if the attempt by these polls to express theological truths in language understood by the typical American undermined their intent to “ascertain the state of theological awareness and belief” of Americans. For example, take these statements seen as Beliefs About Goodness and Sin. “Everyone sins a little, but most people are good by nature” and “People have the ability to turn to God on their own initiative” probe a belief in original sin. If the person understood “nature” as having the sense of the personality of a “good-natured” person, or thought of their life experience when “turning to God” in a time of difficulty, they might agree with these statements. Such agreement would not necessarily reflect their theological understanding of original sin, or their belief (or lack of belief) in original sin.

There is clearly a low level of theological sophistication among Americans. More Americans—especially those who see themselves as “Evangelical”—need a greater understanding of what is contained in the historic creeds and catechisms. While 58% thought there was value in studying and reciting historical creeds or confessions, 26% thought there was little value in studying and reciting them. If Evangelical churches and individual believers were more aware of how creeds and confessions provided a theological common ground, a statement of “mere” Christianity (a nod to C.S. Lewis here), perhaps they would not have had such high percentages of individuals agreeing with heresies and disagreeing with classic Christian beliefs.

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.

12/9/16

Channeling Your DXM Personality

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5© ljupco | 123rf.com

June of 2016 was a confusing month for DXM. Alaska became the 11th state to limit the sale of products containing dextromethorphan (DXM) to individuals 18 and older. Representative Charisse Millett of Anchorage thanked her colleagues for passing a bill that will protect Alaska teens. On the other hand, there was a study published in the journal, Substance Abuse Treatment Prevention, and Policy by Spangler, Loyd and Skor that same month which said DXM was a safe, effective cough suppressant, available without a prescription since 1958. The article reported how the annual prevalence of DXM abuse has sharply decreased since 2010. So why would so many states be restricting the sale of a “safe, effective cough suppressant”?

Adding to the issue, there is H.R. 3250, The DXM Abuse Prevention Act, which was sent to both the House and Senate for consideration on April 27, 2016. H.R. 3250 seeks to prevent the abuse of DXM and would restrict its sale to individuals 18 and over. Civil penalties for retailers violating H.R. 3250 would range from a warning for a first offense up to $5,000 for four or more violations. If implemented, the federal law would take precedence over any existing state legislation.

The pro-drug website Erowid noted that while DXM is still unscheduled in the US, and legal to buy, possess and ingest without a prescription, it is becoming increasingly difficult to purchase. “Some pharmacies and mega-stores like WalMart have instituted voluntary procedures to reduce the sale of DXM-containing products to minors.” Erowid listed and commented on the legal status of DXM in 25 different states and was soliciting more information on its status in other states.

In 2007 the DEA requested that the FDA evaluate whether dextromethorphan should be scheduled as a controlled substance. Three years later the FDA held an Advisory Committee meeting on the matter. After hearing presentations on DXM and its abuse potential, the committee voted 15 to 9 against scheduling DXM. An Erowid assessment of the presenters was they did not believe that scheduling was warranted, but were concerned about abuse.

The DXM article by Spangler, Loyd and Skor said that to address reports of abuse, the Consumer Healthcare Products Association (CHPA) initiated a plan to raise awareness of the behavior and “address prevention by focusing on the factors that impact teen behavior.” All three authors were employees of the CHPA, “which represents manufacturers of over-the-counter medicines and dietary supplements.”  And funding for the research, collection of the data, analysis, interpretation, plan implementation, and writing of the manuscript was provided by CHPA member companies. They concluded:

It is noteworthy that the annual prevalence of over-the-counter cough medicine abuse has sharply decreased since 2010. While a true cause-and-effect relationship cannot be assured, the Consumer Healthcare Products Association and its member companies believe that the increased awareness of the issue since the 2010 Food and Drug Administration Advisory Committee meeting, and the subsequent implementation of a well-delivered and targeted abuse mitigation plan that addressed the levers influencing teen decisions is contributing to the observed reduction in abuse. During the period of 2010–2015, reported abuse of dextromethorphan by 8th, 10th, and 12th graders decreased 35 %. The authors believe this reduction supports the view of the Consumer Healthcare Products Association at the outset of the abuse mitigation plan effort and today: Controlled substance scheduling or prescription requirements would result in a reduction in the legitimate use of this medicine that has benefits that far outweigh its risks. Instead, there are more targeted, more effective, and less disruptive interventions to address dextromethorphan abuse.

Writing for The Fix, John Lavitt reported that one in 30 adolescents use DXM to get high because it is cheap and accessible. In 2014 there were six DXM-related deaths, according to the American Association of Poison Control Centers. Non-medical use of DXM leads to around 6,000 ER visits per year. Adolescents account for almost 50% of those visits. The effects range from mild stimulation to euphoria and hallucinations. There can be an out-of-body dissociative state, complete dissociation with unresponsiveness and even overdose.

Medline Plus lists some of the many products that contain DXM, including NyQuil, DayQuil, TheraFlu, Tylenol Cold, Dimetapp DM, Robitussin DM, Triaminic DM, and Alka-Seltzer Plus Cold and Cough.  Some of the symptoms of a DXM overdose listed included: breathing problems, bluish-colored fingernails and lips, blurred vision, coma, Convulsions, drowsiness, hallucinations, heart palpitations, nausea and vomiting, rapid heart beat.

Now here is some DXM history from Erowid. It was approved by the FDA in 1958. In the early 1960s, there were reports that beat poets like Allen Ginsberg and Peter Orlovsky and the author Jack Kerouac were using DXM in the form of Romilar tablets. Incidentally, Romilar was introduced as a replacement for codeine cough remedies in an attempt to cut down on abuse. In 1973, Romilar DXM tablets were removed from the market after an increase in recreational use was noted. DXM continued to be available as a syrup, with the thinking that consuming large quantities of syrup would be deterrent for recreational use. OTC DXM tablets have been back on the market now for number of years. In the late 1980s DXM use was prominent among the punk subculture.

By the way, codeine cough syrup is main ingredient in the concoction “Sizzurp” that sent rapper Lil Wayne to the hospital with multiple seizures. He even wrote a song about his love for Sizzurp, “Me and My Drank.”  Then there’s Justin Beiber and his street-racing-DUI-Sizzrup arrest. Teens and others without ready access to a codeine prescription cough formula can substitute OTC DXM formulas in their Sizzurp knockoff. Add some Jolly Ranchers to make the concoction more drinkable.

So while DXM may be safe and effective when used as recommended, it was being used as a recreational high almost from the time it came onto the market as a substitute for codeine. It has ebbed and flowed in its consideration for classification as a controlled substance. Currently it isn’t one. However, it does seem likely to face restricted sales to anyone under the age of 18. Eleven states have already passed legislation to that effect, and larger chains like WalMart, Walgreens, Target, Rite-Aid and others now require ID and limit sales to two DXM-containing products. And there is pending federal legislation that has a 38% of passing that would make it illegal to sell DXM products to minors. The last word on DXM is from Erowid.

Recreational DXM use continues. A number of deaths have been documented due to the recreational use of DXM although a majority of these have been the result of products (such as Coricidin Cough and Cold) that combine DXM with other substances that become dangerous in high doses.

So if you decide to try and contact your inner beat poet, or channel your punk rock personality through DXM, be careful.

12/6/16

Is It Well with Your Soul?

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© krsmanovic | stockfresh.com

Sometimes Puritan authors seem to put an entire introduction into their book titles. John Owen’s work, Indwelling Sin in Believers, is a good example of this tendency. It’s original title was: “The Nature, Power, Deceit, and Prevalency of the Remainders of Indwelling Sin in Believers; Together with the Way of Its Working and Means of Prevention, Opened, Evinced, and Applied: With a Resolution of Sundry Casts of Conscience Thereunto Appertaining.” In chapter two Owen discusses why and how indwelling sin is a law—“an inward effective principle.”

In chapter one, Owen argued why he sees Paul contemplating the existence of indwelling sin after his conversion in Romans 7. “Your enemy is not only upon you, as on Samson of old, but is in you also.” In chapter two Owen described why indwelling sin is properly understood in general to be a law, and then elaborated what is “peculiar and proper” in such a law.

The first thing that underlies any law is dominion. Owen pointed to Romans 7:1, where Paul said the law was binding (has dominion) over an individual. He suggested there are two aspects to this dominion. There is a moral authoritative dominion, and there is a real effective dominion. The first is an affection of the law of God; the second is an affection of the law of sin. Although the law of sin does not have any rightful moral dominion or authority over any person, “it hath that which is equivalent unto it.”  Owen sees indwelling sin as a usurper to the throne of grace that God intended for humanity when He made us in His image.

Because of the work of Christ, indwelling sin has lost its complete dominion over believers. Nevertheless, it still is a law in them. “But even in them it is a law still; though not a law unto them, yet, as was said, it is a law in them.” It does not have complete dominion, yet it will act with power and bind us with regard to some things. “Though it be weakened, yet its nature is not changed.”

Laws also have the ability to goad those who oppose it to obey what it requires through reward and punishment. All laws influence our minds through the rewards and punishments that accompany them. “The pleasures of sin are the rewards of sin;” ones that many people lose their souls to obtain. Owen sees the discussion of Moses in Hebrews 11 as an example of the contest in the minds of believers between the law of sin and the law of grace. Moses refused to be called the son of Pharaoh’s daughter, rejecting the pleasures that went along with it. “He considered the reproach of Christ greater wealth than the treasures of Egypt, for he was looking to the reward” (Hebrews 11:26).

The motive on the part of the law of sin, wherewith it sought to draw him over, and wherewith it prevails on the most, was the reward that it proposed unto him,—namely, that he should have the present enjoyment of the pleasures of sin. By this it contended against the reward annexed unto the law of grace, called “the recompense of reward.”

The law of sin also has punishment for those who would oppose it, or who attempt to “cast off its yoke.” Whatever the evil, trouble, or danger that exists in the world when someone attempts to obey the gospel—whatever the hardships someone seeking to mortify their flesh faces—“sin makes use of.” Owen thought it was difficult to discern which approach was more effective, the pretended rewards or the pretended punishments of indwelling sin. But one thing was certain, whether it was by the promises of pleasures or the threats of temporal evils or the loss of pleasure, it has a great effect on the minds of believers and unbelievers alike.

Owen then turned to consider what was “peculiar and proper” in the law of sin.  He again asserted it is not an outward, written law. Such a law cannot compete with “an inbred, working, impelling urging” one. An inbred law is necessarily effectual. To illustrate his point, he pointed to how the law of God was at first naturally inbred to humanity. It had power to enable obedience, even to make this obedience easy and pleasant. Although this law (with regard to its rule and dominion) has been cast out of the soul, there are yet sparks that remain which are very powerful and effectual (Romans 2:14-15).

God renewed this law, writing it on tablets of stone. He knew as an outward, written law it could not enable us to perform the things it required. It would have to again become internal. It would have to turn from an outward moral rule into a real, inward principle. So God made His law internal again, implanting it in our hearts (Jeremiah 31:31-33). The written law, He knew, would not do it. “Mercies and deliverances from distress will not effect it; trials and afflictions will not accomplish it.” Therefore He turned the written law into “an internal living principle.”

The same applies to sin. “It is now an indwelling law.” It is in us. The flesh is its seat and throne. From this, we can see that it has some advantages for increasing its strength and furthering its power. It always abides in the soul. It is never absent. It is always ready to apply itself to every end and purpose that it serves. Because it is an indwelling law, it can easily apply itself with great ease.

It needs no doors to be opened unto it; it needs no engines to work by. . . . Hence it is easy for it to insinuate itself into all that we do, and to hinder all that is good, and to further all sin and wickedness. It hath an intimacy, an inwardness with the soul; and therefore, in all that we do, doth easily beset us. It possesseth those very faculties of the soul whereby we must do what we do, whatever it be, good or evil. Now, all these advantages it hath as it is a law, as an indwelling law, which manifests its power and efficacy. It is always resident in the soul, it puts itself upon all its actings, and that with easiness and facility.

This is the law Paul said he found within him. This is what he said remains even in believers. Owen said that from what he has described, if such a law is in believers, it is their duty to discover it. Upon this one hinge, finding and experiencing the law of sin, turns the whole course of our lives. Ignorance of it breeds “senselessness, carelessness, sloth, security, and pride.” All of this the Lord abhors. The eruptions of great, open scandalous sins are the result of a failure to consider this law. “Inquire, then, how it is with your souls.”

What do you find of this law? What experience have you of its power and efficacy? Do you find it dwelling in you, always present with you, exciting itself, or putting forth its poison with facility and easiness at all times, in all your duties, “when you would do good?” What humiliation, what self-abasement, what intenseness in prayer, what diligence, what watchfulness, doth this call for at your hands! What spiritual wisdom do you stand in need of! What supplies of grace, what assistance of the Holy Ghost, will be hence also discovered! I fear we have few of us a diligence proportionable to our danger.

Simply put, is it well with your soul?

A digital copy of Owen’s work, Indwelling Sin in Believers, is available here.

12/2/16

Pharma and Advertising

© Maksim Kabakou | 123rf.com

© Maksim Kabakou | 123rf.com

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.