1 Boring Old Man

Do antidepressants increase the risk of suicide?

Suicidal thoughts and behaviors are more common during adolescence than at any other time, but suicide is more common among adults. In any year about 16 percent of high school students think about suicide and about 3-8 percent show suicidal behaviors. Fortunately, very few of them commit suicide. Children and adolescents with depression are much more likely to think about suicide and to attempt it than other children. Although not all suicidal children have depression, untreated depression increases the risk of suicide.

The Food and Drug Administration [FDA] described an increase in reports of suicidal thoughts and/or behaviors in children and adolescents taking antidepressants. But, there were no suicides in the cases they studied. Autopsies of teenagers who have committed suicide show that very few of them had traces of an antidepressant, making the link between antidepressant use and suicide even weaker.

Between 1992 and 2001, there was a large increase in the number of adolescents being prescribed SSRI antidepressants. But, during that time the rate of suicide among American youth ages 10–19 actually dropped by more than 25 percent. This was the first time in nearly 50 years that the suicide rate declined in young people.

What is a black box warning?

…The FDA did not ban the use of antidepressant medications for youth. The purpose of the warning was to alert physicians and parents to watch children and adolescents to see if their symptoms got worse, or if they showed unusual changes in behavior. The FDA also specifically said that “depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions”.

Why did the FDA issue a black box warning?

In 2004, the FDA reviewed 23 clinical trials involving more than 4,300 child and adolescent patients. These patients received any of nine different antidepressant medications. No suicides occurred in any of these studies. … A more recent study found that the risk was even smaller—around 3% in those on medication and 2% in those on placebo. Most of these events were increases in suicidal thoughts. Only a few were actual suicide attempts, and NONE were suicide completions.

Through careful monitoring, the development of a safety plan, and the combination of medication with psychotherapy, the risks for increased suicidal thoughts can be managed. For moderate to severe depression, there is benefit in the use of medication because of a higher rate of relief, and more complete relief, from depressive symptoms than not using any medication.

Since the FDA issued the black box warning, there has been a decline in antidepressant use, but an increase in completed suicides in adolescents in both the US and the Netherlands. Although it is not yet clear how these trends may be related, this has been the first increase in the adolescent suicide rate reported in over a decade.

[see also something terribly wrong here…]

What should treatment consist of?
When possible, treatment for depression childhood depression should include both psychotherapy and medication. In milder forms of depression, it is reasonable to start with a psychotherapy, but treatment with a medication and psychotherapy should be considered for moderate to severe forms of major depression. Before starting treatment, a doctor will discuss it’s risks and benefits, as well as how the treatment should be monitored.

Are medications safe? Do they increase risk of suicide?
When prescribed and monitored carefully, medications are both safe and effective ways to treat of depressed youth. Fluoxetine or Prozac, a selective serotonin reuptake inhibitor, is the medicine that so far has proved most safe and effective. There are times, however, when other medications can and should be used. While medications have been associated with a small increase in thoughts of suicide, there is no evidence that antidepressants actually increase the risk of suicide. For moderate to severe depression, the potential benefits from medication treatment seem to outweigh the potential risks.

So it’s hard to mount a rational explanation for why our two major professional organizations [APA and AACAP] are still making an assault on the Black Box Warning. Except for Prozac®, they’re advocating off-label prescribing for marginal efficacy at best. There’s unlikely much push from PHARMA now that the drugs are off-patent. In spite of the limitations, they’re still prescribing at a moderate pace. Seems to me they’d let this sleeping dog lie…

1. The relationship between antidepressant medication use and rate of suicide.
   Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
   Arch Gen Psychiatry. 2005 Feb;62(2):165-72.
2. The relationship between antidepressant prescription rates and rate of early adolescent suicide.
   Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
   Am J Psychiatry. 2006 Nov;163(11):1898-904.
3. Impact of Publicity Concerning Pediatric Suicidality Data on Physician Practice Patterns in the United States
   Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg
   Arch Gen Psychiatry. 2007 Apr;64(4):466-472.
4. Association of suicide and antidepressant prescription rates in Japan, 1999-2003.
   Nakagawa A, Grunebaum MF, Ellis SP, Oquendo MA, Kashima H, Gibbons RD, Mann JJ.
   J Clin Psychiatry. 2007 Jun;68(6):908-16.
5. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets.
   Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ.
   Am J Psychiatry. 2007 Jul;164(7):1044-9.
6. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. [see peaks and valleys…]
   Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ.
   Am J Psychiatry. 2007 Sep;164(9):1356-63.
7. The role of randomized trials in testing interventions for the prevention of youth suicide.
   Brown CH, Wyman PA, Brinales JM, Gibbons RD.
   Int Rev Psychiatry. 2007 Dec;19(6):617-31.
8. Mixed-effects Poisson regression analysis of adverse event reports: the relationship between antidepressants and suicide.
   Gibbons RD, Segawa E, Karabatsos G, Amatya AK, Bhaumik DK, Brown CH, Kapur K, Marcus SM, Hur K, Mann JJ.
   Stat Med. 2008 May 20;27(11):1814-33.
9. News coverage of FDA warnings on pediatric antidepressant use and suicidality
   Barry CL and Busch SH.
   Pediatrics. 2010 125[1]:88-95.
   [full text online]
10. Strategies for quantifying the relationship between medications and suicidal behaviour: what has been learned?
    Gibbons RD, Mann JJ.
    Drug Saf. 2011 May 1;34(5):375-95.
11. Suicidal Thoughts and Behavior With Antidepressant Treatment: Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine
    Robert D. Gibbons, Hendricks Brown, Kwan Hur, John M. Davis, and J. John Mann
    Arch Gen Psychiatry. 2012 Jun;69(6):580-587.
12. Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study
    Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B Soumerai
    BMJ. 2014 348:g3596.
    [full text online]

FDA Actions on Antidepressants and Suicidality:
10 Years Later

PSYCHIATRICNEWS

by Mark Moran

12/30/2014

[full text on-line]

Abstract: This is the first of a two-part series on the 2004 FDA hearings on antidepressants and suicidality in adolescents. Part two will focus on the effect of the antidepressant label warning on prescribing and adolescent health.

---

From the beginning, and in the decade since, APA has protested the warning, predicting that it would prevent parents from seeking care for their children—and clinicians from prescribing antidepressants—and insisting that by far the greater danger was untreated depression.

‘We are concerned that the publicity surrounding this issue may frighten some parents and discourage them from seeking help for their children,’ child psychiatrist David Fassler, M.D., told the 2004 panel. ‘The most important point that I can make is that the biggest risk for a child with depression is to be left untreated…’

Darrel Regier, M.D., M.P.H., who is the former director of the APA Division of Research and testified at the hearings against the warning, noted that there were in fact no actual suicides among the thousands of teens treated in clinical trials reviewed by the FDA panel. Moreover, the FDA data on suicidal ideation associated with SSRI use was based on spontaneous reports, not on studies prospectively designed to systematically define and identify the incidence of suicidal thoughts or behaviors in teenagers taking the medications.

Regier believes the extraordinary media attention the hearings attracted is a case study in how data pertinent to public health can be obscured or distorted by overinterpretation of spontaneous reporting. “I think it calls into question the FDA’s entire system of spontaneous reporting,” he said. Regier said a promising step is the agency’s adoption, for use in future phase 3 clinical trials, of the Columbia Suicide Severity Rating Scale for any drug that is thought to have some potential for suicidal ideation [including dermatologic drugs such as Accutane].

‘I think the solution is more systematic reporting, which the FDA will start to move toward as the agency begins to have access to electronic health records used by large health systems and HMOs,’ Regier said. ‘This will give the FDA access to phase 4–type data on the long-term effects of medication side effects and associations with suicidal attempts and mortality from all causes.’

The Clinical Inadequacy of Evidence-Based Medicine and the Need for a Conceptual Framework Based on Clinical Judgment

by Fava GA, Guidi J, Rafanelli C, and Sonino N

Psychotherapy and Psychosomatics. 2015 84:1-3.

[full text on-line]

[full text on-line, pdf]

My own opinions are embedded in my narrative. I came into the world equipped for science – aptitude, interest, a father who taught chemistry and geometry. After a degree in mathematics, I headed to medical school intending a medical research career and, in fact, wound up my training in a lab bench based NIH fellowship. I lived and breathed evidence-based medicine [I would like to think I still do]. My first post-training posting was as an general internist in an Air Force hospital overseas [by special invitation from the US government – AKA drafted]. I had been well trained as a clinician, but what I quickly realized was that in training, I had always been located somewhere in the hierarchy of a team of some sort, and when it was just me and a patient, medicine was a different game altogether. What Giovanni Fava is calling clinical judgement is as good a way as any to describe the difference.

I think of that three years as the most important and intense period of my own medical training. I became so interested in the individual illnesses and unique experience of my patients that I returned to a psychiatry residency and added a psychoanalytic training program that ran in parallel. My post academic career was as an individual psychotherapist in a world where clinical judgement was on the front burner of every day.

There was another important and intense period of my own medical training after my psychiatry residency. I directed a psychiatry training program for a decade before leaving for practice during the storm in psychiatry that followed the coming of the DSM-III. And I noticed something in my dealing with my residents during those days. I often found myself preaching the gospel of evidence-based medicine – quoting studies, handing out articles, sending a resident to the library. But at other times, my sermon was equally passionate, but was much more in the range of Fava’s clinical judgement. When I noticed that contrast, I quickly realized that the theme of my message depended on which resident I was talking to, and what I thought that particular resident needed to learn. The point being that I don’t slightly see evidence-based medicine and clinical judgement as a dichotomy – in opposition. Medicine as I know it is practiced at the interface of group data and unique human experience [including  my own].

I saw a seventeen year old who was very depressed with good reason. His mother had remarried a man who was a retired Drill Sergeant [really] and this kid and his step-father were oil and water – at war. The boy had an impending interview for a training program that would’ve paid his way to move 200 miles away and study something he had dreamed of all his life. His mother and I were both worried that he was so depressed that he wouldn’t "pass" the interview. So I prescribed an SSRI. In a few days, he developed the full Akathisia syndrome in spades, including being intensely suicidal [for the first time]. His mother stopped the medication, didn’t leave his side, and it cleared within 48 hours.

When I look at that dozen articles I listed above, or read what Dr. Regier has to say, I’m aware that I’m a total snob. There’s not anyone that I would consider to be a clinician on the bylines of the articles on the list, or speaking in the PSYCHIATRICNEWS article. They’re Statisticians, Academicians, Researchers, or Administrative types. Even putting aside all the Conflict of Interest and Methodological issues in those papers [which are prodigious], I’m sure that I still wouldn’t change my mind about this no matter how long that list of population studies gets. And, by the way, I sense that the PSYCHIATRICNEWS article is a harbinger of yet another assault on the Black Box Warning [as if what it says on a package insert defines the truth].

I personally take this issue as a microcosm of a much more general point. I most respect the opinions of people who are deeply steeped in the findings of evidence-based medicine, but who remain immersed in clinical medicine throughout their careers [and show the tell-tale signs of having developed clinical judgement]. I don’t think that’s a tall order – more a baseline requirement. Back in 1980, the people who brought the DSM-III revolution in psychiatry to my own neck of the woods saw themselves as the prophets of evidence-based medicine. I sure didn’t object to that, but they were specifically disdainful of anything that slightly smacked of clinical judgement [as in "How do you know that?" or "But that’s just what you think" ad nauseum]. They were followed by a second wave who were even worse, in the range of contemptuous – the generation that became what we now call the KOLs [some of whom inhabit those author bylines above in the flesh]. They came at a time when psychiatry may have needed an encounter over its reliance on matters subjective, but in the process they turned clinical judgement into an object of ridicule rather than one for examination and inquiry.

There’s a strong pressure pushing this same trend in medicine in general – simplifying medical practice into the rote application of large group findings to the care of individual patients based on averages and statistics. That pressure comes from third party carriers, pharmaceutical companies, hospital conglomerates, governments, even professional organizations, etc. – anyone who tries to quantitatively deal with the healthcare of populations. So the amount of allowed contact, the access to diagnostic tests, the available treatments, just about everything is regulated based on algorithms and guidelines derived from large group studies. Meanwhile, patients increasingly clamor for individual attention, and are driven to distraction along with their doctors by the hoops they have to jump through when they get sick. Dr. Regier’s comment is typical of this particular mindset, "I think the solution is more systematic reporting, which the FDA will start to move toward as the agency begins to have access to electronic health records used by large health systems and HMOs."

The conceptual model that has generated EBM and guidelines clashes with clinical reality and fosters a dichotomy between medical science and clinical judgment. EBM has certainly made an important contribution to questioning unsubstantiated therapeutic claims. The time has come, however, to become more aware of its considerable limitations, including overall reductionism, disregard of patient-physician relationships and patient preferences, and insufficient consideration of problems related to financial conflicts of interest. As an increasing body of literature indicates, EBM offers only a restrictive interpretation of the scientific approach to clinical practice.

I looked at the ClinicalTrials.gov Results Database several years ago, and decided it was an improvement over just having the published paper because of its strucyure, but was far short of having the raw data  [see eyes wide shut open I…, eyes wide shut open II…, eyes wide shut open III…, and eyes wide shut open IV…]. But I have to say that it’s far more helpful to have it than not. And using it, you can get closer to knowing if you can trust the published article. So I’m all for Dr. Collins’ proposal to make it really non-optional, turning it into what it was intended to be [Honoring Our Promise: Clinical Trial Data Sharing and see promises, promises…].

Weight and vital signs. Mean baseline-to-endpoint weight change [LOCF] was significantly greater for OFCtreated patients [4.4 kg, standard error [SE]=0.2] than placebo-treated patients [0.5 kg, SE=0.3; p<.001]. Using MMRM methodology to model expected weight gain if all patients completed the 8-week study, mean weight change from baseline to week 8 was 5.1 kg [SE=0.3] for OFC-treated versus 0.6 kg [SE=0.4] for placebo-treated patients [p<.001]. Baseline-to-endpoint mean change in body mass index was also significantly greater for the OFC group [1.5 kg/m2, SE=0.1] than the placebo group [0.1 kg/m2, SE=0.1; p<.001]. Incidence of gaining ≥7% of baseline body weight was significantly greater for the OFC group relative to placebo [52% vs. 4%, p<.001], as was incidence of gaining ≥15% of baseline body weight [14% vs. 0%, p<.001]. No placebo patients and 2 OFC-treated patients gained ≥25% of their baseline.

It sounds like a lot of hoops to make the trialists jump through, but it’s not. All of that information is already available. It would probably take them less time to put all that stuff up than it took me to write these three blogs. The pharmaceutical companies don’t want to do that because they want to be able to continue to accent the positive and eliminate the negative. And if they continue to act like they’ve acted in the last couple of decades, they’re going to lose the right to test their own products. Disease treatment is between the medical profession and our patients, not a playground for entrepreneurship and scientific deceit.

This was a phase 4, randomized, double-blind, placebo-controlled study conducted between March 2009 and February 2012 at 41 centers in the United States, Mexico, and Russia.
and
A total of 255 patients [170 OFC, 85 placebo] comprised the mITT population.

• United States, California: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon – Fri from 9 AM to 5 PM Eastern Time (UTC/GMT – 5 hours, EST), or speak with your personal physician. San Diego, California, United States, 92123
• Russian Federation: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon – Fri from 9 AM to 5 PM Eastern Time (UTC/GMT – 5 hours, EST), or speak with your personal physician. Lipetsk, Russian Federation, 399313

But where there’s a will, there’s a way. The ClinicalTrials.gov site includes a small link, History of Changes, with each trial up at the top of the opening page [go ahead, click it]. And when you get a pop-up window, there’s another link, ClinicalTrials.gov Archive Site [don’t be shy, click it too]. It has all the changes made over the course of the study. I’ve looked at a lot of these, but I’ve never seen one that looks remotely like this!

There are over thirty changes that have to do with recruitment and site location. If you have the energy, click on the second one [2009_03_16], then uncheck the box that says "Hide non-essential portions (contact info, locations, etc.)". You can scroll through the changes by clicking the arrow on the right. What you’ll see is them moving all over the world adding and shutting down different sites. The CRO must’ve had a hell of a time with recruitment and had to pull out all stops to find subjects. I want to know if that happened [and it ought to be easier to do]. It makes me think that the Pediatric Bipolar patients with a Depressive episode [or whatever these cases are] just aren’t that easy to find – but who knows?

A 2:1 randomization ratio was used to reduce potential exposure to placebo.

If you’ve made it this far, you probably are wondering why I’m being so picky. Remember back in November, NIH Director Francis Collins announced that he was going to put teeth into the ClinicalTrials.gov website [Honoring Our Promise: Clinical Trial Data Sharing and see promises, promises…]. For one thing, the pharmaceutical companies and even academic researchers had just ignored the Results Section of ClinicalTrials.gov – a requirement for a lot of these trials [see transparency…]. They just didn’t ever get around to filing the results. And while the Results Section is pretty skimpy, it’s a right move in the right direction for DATA TRANSPARENCY. And part of that move was to enforce and even expand the Results Section. He put out a call for comments on his proposed plan, so I’ve been waiting for an industry RCT to come along so my comment will have example to show the why of my complaints – and this study is the very thing I’ve been waiting for. So the last blog, this one, and the nextl are my formulating what I want to say. Hope springs eternal in the new year. [This is the working link for comments: http://www.regulations.gov/#!documentDetail;D=NIH-2011-0003-0003 with a deadline of February 19, 2015].

Study Finds Olanzapine-Fluoxetine Combo Superior to Placebo for Bipolar Disorder in Children

PSYCHIATRICNEWS alert

[The Voice of the American Psychiatric Association and the Psychiatric Community]

December 30, 2014

A combination of the antipsychotic olanzapine and the antidepressant fluoxetine proved superior to placebo for acute treatment of bipolar I depression in patients aged 10-17 in a randomized control trial published online in the Journal of the American Academy of Child and Adolescent Psychiatry.

The double-blind study by researchers at Eli Lilly and Company randomized 170 young patients with bipolar I disorder experiencing an acute depressed episode to the olanzapine/fluoxetine combination [OFC] and 85 to placebo for up to eight weeks of treatment. The primary efficacy measure was mean change in the Children’s Depression Rating Scale-Revised [CDRS-R]…

The double-blind study by Dr Melissa DelBello with the Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, randomized 170 young patients with Bipolar I disorder experiencing an acute depressed episode to the olanzapine/fluoxetine combination [OFC] and …

Olanzapine/Fluoxetine Combination in Children and Adolescents With Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Trial

by Holland C. Detke, Ph.D., Melissa P. DelBello, M.D., John Landry, M.Math, and Roland W. Usher, M.S.

Journal of the American Academy of Child and Adolescent Psychiatry. published online 12/24/2014

Objective: To assess the efficacy and safety of olanzapine/fluoxetine combination [OFC] for the acute treatment of bipolar depression in children and adolescents.

Method: Patients 10-17 years of age with bipolar I disorder [BP-I], depressed episode, baseline Children’s Depression Rating Scale-Revised [CDRS-R] total score ≥40, Young Mania Rating Scale [YMRS] total score ≤15, and YMRS-item 1 ≤2 were randomized to OFC [6/25-12/50 mg/day olanzapine/fluoxetine; n=170] or placebo [n=85] for up to 8 weeks of double-blind treatment. The primary efficacy measure was mean change in CDRS-R using mixed-model repeated measures methodology.

Results: Baseline-to-week-8 least-squares mean change in CDRS-R total score was greater for OFC-treated patients than for placebo-treated patients [-28.4 vs. -23.4, p=.003; effect size=.46], with between-group differences statistically significant at week 1 [p=.02] and all subsequent visits [all p<.01]. Rates of and times to response and remission were statistically significantly greater for OFC- than placebo-treated patients. The most frequent treatment-emergent adverse events in the OFC group were weight gain, increased appetite, and somnolence. Mean weight gain at patient’s endpoint was significantly greater for OFC- than placebo-treated patients [4.4 kg vs. 0.5 kg, p<.001]. Treatment-emergent hyperlipidemia was very common among OFC-treated patients. Abnormal increases in hepatic analytes, prolactin, and corrected QT interval [QTc] were also common or very common but generally not clinically significant.

Conclusion: OFC was superior to placebo and approved by the US Food and Drug Administration [FDA] for the acute treatment of bipolar I depression in patients 10-17 years of age. Benefits should be weighed versus the risk of adverse events, particularly weight gain and hyperlipidemia.

"The authors also thank Shannon Gardell, PhD, and Rodney Moore, PhD, of inVentiv Health Clinical [funded by Eli Lilly and Co.] for assistance in drafting/editing the manuscript."

Dr. DelBello has received grant or research support from … Amylin Pharmaceuticals, Eli Lilly and Co., Pfizer, Otsuka, Merck, Martek, Novartis, Lundbeck, Purdue, Sunovion, and Shire. She has served as a consultant to Bracket, Guilford, Pfizer, Dey Pharma, Lundbeck, Springer, Sunovion, and Supernus…

It’s not my intention to specifically challenge these results. But since the DSM-III, there has been a steady creep in diagnosing Bipolar Disorder from the classic Manic-Depressive Illness of Kraepelin’s days. And I see a remarkable number of people who announce that they’ve been "told they are Bipolar" and they simply don’t fit. Also, in reviewing the more papers on Pediatric Bipolar Disorder, my skepticism level hovers around DEFCON 1. Likewise, I see no reason for a COMBO medication. Taking two pills a day if they’re needed is no great burden. So my suspicions that the goals here are commercial rather than medical. But I don’t doubt that depressed adolescents feel better taking Zyprexa® or Symbiax®. I question whether it’s a good idea to prescribe it, particularly in the fixed dose COMBO pills. But the fact that it is a likely ghost-written, industry produced, COI-laden, commercially-driven RCT is not all that bothers me about this study.

“I have no financial relationship with respect to this educational activity”

Fear and Loathing in Bioethics

by Carl Elliot

December 16, 2014

Well, no conflict of interest unless you count a $13,781 fee paid by the University of Minnesota to give expert testimony on this exact issue.  So yeah, if you want to get all technical and everything, then I guess that might count as a conflict. But can you really expect a research ethics expert to keep up with arcane issues like conflicts of interest? I mean, come on.

Ernest Prentice, an associate vice-chancellor at the University of Nebraska, seems to have trouble with conflicts of interest, and not just his own.  According to Dr. Judy Stone, who attended Prentice’s talk on the Markingson case at this year’s PRIM&R meeting, Prentice also claimed to be unaware of the astonishing conflicts of interest on the IRB whose performance he defended…

An Ethics Conference Where an Expert Gets it Wrong

Scientific American

Blog:  Molecules to Medicine

by Judy Stone

December 15, 2014

[full text on-line]

• Aesculapian authority: Authority is granted to the physician with the implicit contract that it will be used in the service of the patient, and for no other reason.
• Primum Non Nocere: "First, do no harm." This injunction comes from antiquity and essentially says that there will be vigilance for anything that will hurt the patient, including therapeutic zeal.

An Overview of Vortioxetine

by Alan F. Schatzberg, MD; Pierre Blier, MD, PhD; Larry Culpepper, MD, MPH; Rakesh Jain, MD, MPH; George I. Papakostas, MD; and Michael E. Thase, MD

Journal of Clinical Psychiatry 2014 75[12]:1411–1418.

[full text on-line]

Six clinicians provide an overview of the serotonergic antidepressant vortioxetine, which was recently approved for the treatment of major depressive disorder in adults. They discuss the pharmacologic profile and receptor-mediated effects of vortioxetine in relation to potential outcomes. Additionally, they summarize the clinical trials, which demonstrate vortioxetine’s efficacy, and discuss findings related to safety and tolerability that have high relevance to patient compliance.

^{… highlights from a series of teleconferences held in the spring of 2014. The series was chaired by Alan F. Schatzberg, MD… The faculty were Pierre Blier, MD, PhD…; Michael E. Thase, MD…; George I. Papakostas, MD…; Larry Culpepper, MD, MPH…; and Rakesh Jain, MD, MPH…}

^{This evidence-based peer-reviewed Academic Highlights was prepared and independently developed by Healthcare Global Village, Inc., with support from Physicians Postgraduate Press, Inc…}

^{Financial disclosure: Dr Schatzberg received grant funding and/or honoraria for lectures and/or participation in advisory boards for … Lundbeck/Takeda… Dr Blier received grant funding and/or honoraria for lectures and/or participation in advisory boards for … Lundbeck … Takeda … Dr Culpepper received grant funding and/or honoraria for lectures and/or participation in advisory boards for … H. Lundbeck A/S … Takeda. Dr Jain received grant funding and/or honoraria for lectures and/or participation in advisory boards for … Lundbeck … Takeda. Dr Papakostas received grand funding and/or honoraria for lectures and/or participation in advisory boards for Lundbeck … Takeda. Dr Thase received grant funding and/or honoraria for lectures and/or participation in advisory boards for … H. Lundbeck, A/S … Takeda.}

^{[from the FDA Medical Review]}

"Robinson et al in a 2005 study estimated that primary care providers are the sole contacts for more than half of patients with mental illness and that depressive symptoms are present in nearly 70% of patients visiting primary care providers. A patient in a primary care setting, particularly one who has recently acquired mental health coverage through the ACA or Mental Health Parity and Addiction Equity Act, may have one or more coexisting acute or chronic conditions, and to the extent possible, an antidepressant that will not aggravate and might be helpful for these conditions is preferable. A favorable tolerability profile also may improve patient adherence to treatment, leading in turn to not only a reduction in depressive symptoms but a reduced risk of behavioral or social actions that could adversely affect the patient’s overall health and well-being."

At times, when I wear thin with all the anti-psychiatry criticism, the kind that assumes all psychiatrists think the same [stupid] [wrong] things, I’m tempted to get defensive or argue. Then I read an article like this, in a journal like this, by authors like these, and it helps me hold my tongue and turn the other cheek. There’s absolutely nothing here to defend. Fortunately, we don’t see articles like this so much any more, at least in any places that matter. But it’s bad enough that we ever had them in the first place [or that anybody is still writing them].

In the FDA Medical Report on Brintellix®, the reviewer conveniently included a list of all of the FDA approved treatments for Major Depressive Disorder:

It reminded me of my early days in psychiatry. The drugs available then were the ones in the top two boxes [pink]. In those days, the phrase Major Depressive Disorder would’ve referred to a group of severe conditions I think of as the Melancholic Depressions. I thought of them as diseases, nouns, entities [Depression with a capital "D"]. They aren’t common, but when you see a case, there’s nothing routine about it. The patients are quantitatively profoundly depressed. But there are qualitative features that are striking. It’s as if the affect-generator has been turned to a single frequency – self-hating gloom. Those were the patients we treated with the Tricyclic antidepressants. Sometimes they responded. Sometimes they didn’t. And sometimes they were treated with ECT. People like me who usually spend their days talking to depressed people [depression with a little "d"] are stopped in their tracks when Melancholic Depression is the problem. It’s something else.

"… primary care providers are the sole contacts for more than half of patients with mental illness and that depressive symptoms are present in nearly 70% of patients visiting primary care providers. A patient in a primary care setting, particularly one who has recently acquired mental health coverage through the ACA or Mental Health Parity and Addiction Equity Act, may have one or more coexisting acute or chronic conditions, and to the extent possible, an antidepressant that will not aggravate and might be helpful for these conditions is preferable."

"A favorable tolerability profile also may improve patient adherence to treatment, leading in turn to not only a reduction in depressive symptoms but a reduced risk of behavioral or social actions that could adversely affect the patient’s overall health and well-being."

Why MacArthur is Backing a Popular Blog About Flawed and Fraudulent Science

Inside Philanthropy

by Tate Williams

December 23, 2014

MacArthur just gave $400,000 to a popular blog about flawed and fraudulent science, so it can deepen its coverage and build a comprehensive database of journal retractions. We chatted with the program officer behind the grant about why got Mac into the science watchdog game, and the foundation’s adventurous side program for such grants. 

Since editor and physician Ivan Oransky and science writer Adam Marcus launched Retraction Watch in 2010, the blog cataloging retracted articles in science journals has drawn a lot of attention, and had more fodder than it can keep up with.

Now, thanks to a two-year grant from the MacArthur Foundation, Retraction Watch is going to expand from a scrappy watchdog to a full-fledged monitoring program that will catalog nearly all retractions issued by major journals in a database, and do deeper analysis of the root causes. 

As Ivan Oransky told the program BioCentury This Week, “It’s easy and fun — and useful — to write about the fraud in particular cases, but looking at the big picture is always much more interesting and important. And so we’re going to be able to do that and to look at the scale of these things and see what’s actually happening”…

Ben Goldacre tweeted a document, a letter to UK doctors from Pfizer. I don’t know the specifics of the UK regulatory agencies and how they differ from the FDA. I don’t know what a CCG is. But I don’t think we need to  know those things to get what Pfizer is trying to get said in their letter – their unimaginable letter. He posted a jpeg that was too small to read, so I transcribed it for all to experience first hand.

hu·bris ‘hyu br?s
noun.
Overbearing pride or presumption; arrogance:

After being fined $2.3B for off-brand promotion with their non-product Neurontin®, Pfizer brought out Lyrica®, a molecular clone, ran it for its patent life, and now want to extend the exclusivity for a secondary patent for the same use they got fined for in the first place. And the way they propose to do that is threaten GPs and Pharmacists.

I’ve never prescribed Lyrica®, and only refilled Neurontin®. The thing I’ve noticed is that patients are reticent to stop Neurontin®, and I suspect it is because it has a mild Benzo-like antianxiety effect. The problem with this system is contained in this letter. "This runs contrary to the government’s established policy of rewarding additional research by granting a second medical use patent". That’s built on the notion that pharmaceutical companies should be rewarded in return for developing new drugs for the betterment of our patient’s lives. They’ve turned that into a mechanism to make gajillions off of medications that have a minimal effect [if that] and then sell that effect to the public that clamors for the drug so they can be like the pretty lady on the television dancing her way through an exotic vacation.