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The cumulative effect of reporting and citation biases on the apparent efficacy of treatments: the case of depression

Figure 1 demonstrates the cumulative impact of reporting and citation biases. Of 105 antidepressant trials, 53 (50%) trials were considered positive by the FDA and 52 (50%) were considered negative or questionable (Fig. 1a). While all but one of the positive trials (98%) were published, only 25 (48%) of the negative trials were published. Hence, 77 trials were published, of which 25 (32%) were negative (Fig. 1b). Ten negative trials, however, became ‘positive’ in the published literature, by omitting unfavorable outcomes or switching the status of the primary and secondary outcomes (Fig. 1c). Without access to the FDA reviews, it would not have been possible to conclude that these trials, when analyzed according to protocol, were not positive. Among the remaining 15 (19%) negative trials, five were published with spin in the abstract (i.e. concluding that the treatment was effective). For instance, one article reported non-significant results for the primary outcome (p = 0.10), yet concluded that the trial ‘demonstrates an antidepressant effect for fluoxetine that is significantly more marked than the effect produced by placebo’ (Rickels et al., 1986). Five additional articles contained mild spin (e.g. suggesting the treatment is at least numerically better than placebo). One article lacked an abstract, but the discussion section concluded that there was a ‘trend for efficacy’. Hence, only four (5%) of 77 published trials unambiguously reported that the treatment was not more effective than placebo in that particular trial (Fig. 1d). Compounding the problem, positive trials were cited three times as frequently as negative trials (92 v. 32 citations in Web of Science, January 2016, p < 0.001, see online Supplementary material for further details) (Fig. 1e). Among negative trials, those with (mild) spin in the abstract received an average of 36 citations, while those with a clearly negative abstract received 25 citations. While this might suggest a synergistic effect between spin and citation biases, where negatively presented negative studies receive especially few citations (de Vries et al., 2016), this difference was not statistically significant (p = 0.50), likely due to the small sample size. Altogether, these results show that the effects of different biases accumulate to hide non-significant results from view.

What you don't look for can't hurt your share price...

Only nine of 185 randomized clinical trials and 23 of 259 non-randomized studies and patient reports of methylphenidate in children and adolescents with ADHD reported assessment of psychotic symptoms.

Painting a Nuanced Picture of Brain System Regulation Moods and Movements - Neuroscience News

What’s more, the group found that the serotonin neurons themselves were more complex than originally thought. Rather than just transmitting messages with serotonin, the cortical-projecting neurons also released a chemical messenger called glutamate – making them one of the few known examples of neurons in the brain that release two different chemicals. “It raises the question of whether we should even be calling these serotonin neurons because neurons are named after the neurotransmitters they release,” Ren said. Taken together, these findings indicate that the brain’s serotonin system is not made up of a homogenous population of neurons but rather many subpopulations acting in concert. Luo’s team has identified two groups, but there could be many others. In fact, Robert Malenka, a professor and associate chair of psychiatry and behavioral sciences at Stanford’s School of Medicine, and his team recently discovered a group of serotonin neurons in the dorsal raphe that project to the nucleus accumbens, the part of the brain that promotes social behaviors.

Painting a Nuanced Picture of Brain System Regulation Moods and Movements - Neuroscience News

In a series of behavioral tests, the scientists also showed that serotonin neurons from the two groups can respond differently to stimuli. For example, neurons in both groups fired in response to mice receiving rewards like sips of sugar water but they showed opposite responses to punishments like mild foot shocks. “We now understand why some scientists thought serotonin neurons are activated by punishment, while others thought it was inhibited by punishment. Both are correct – it just depends on which subtype you’re looking at,” Luo said.

Antidepressants don't work, or depression doesn't exist (as a meaningful category)

The real truth isn't found within the published paper but rather within a busy table on page 142 of the online appendix. It is here where the authors report what we want: the actual difference between drugs and placebo, before and after treatment, on the depression rating scales. Here we see that the Cohen's d standardized mean difference effect sizes range from a low of 0.19 to a high of 0.62 with amitriptyline. Thus, amitriptyline exceeds the clinically meaningful threshold of 0.50, with a traditional meta-analytic method. No other drug does so, with the closest second place being fluvoxamine, with a Cohen's d value of 0.44. Looking at all of the agents, 10 drugs have Cohen's d values less than 0.30, which is very small and clinically meaningless, whereas four have effect sizes from 0.30 to 0.34. Thus, 74% (14/19) of antidepressants clearly have little or no clinically important benefit in this analysis (for some reason, no data are provided in this table with two of the drugs). Four drugs have effect sizes of 0.37-0.44, and as noted, one agent exceeds the 0.50 threshold (amitriptyline). Perhaps a clearer conclusion than anything else is the well-proven fact that the tricyclic antidepressants are more effective than newer agents (there were no monoamine oxidase inhibitors in this meta-analysis).

Nonprescription use of Ritalin linked to adverse side effects, UB study finds - University at Buffalo

“We saw changes in the brain chemistry in ways that are known to have an impact on the reward pathway, locomotor activity, and other behaviors, as well as effects on body weight,” Thanos says. “These changes in brain chemistry were associated with serious concerns such as risk-taking behaviors, disruptions in the sleep/wake cycle and problematic weight loss, as well as resulting in increased activity and anti-anxiety and antidepressive effects.” Further research indicated that female subjects were more sensitive to the behavioral effects of methylphenidate than the males. Thanos hopes that studying the effects of methylphenidate on those without ADHD may lead to a greater understanding of how the drug works on the brain and behavior, and can help researchers understand the impact of the drug on young people throughout development. “Understanding more about the effects of methylphenidate is also important as people with ADHD show greater risk to be diagnosed with a drug dependency problem,” Thanos says. “In addition, this study highlights the potential long-range risks college students take in using Ritalin for a quick study boost.”

Cash interests taint drug advice | Nature

Only one author declared a conflict of interest, but further checks by the CSPI revealed that four other authors had failed to disclose research funding from relevant drug companies. The problem could be even worse in guidelines that don't contain conflict-of-interest declarations, warns Merrill Goozner, director of the CSPI's Integrity in Science project. “It is usually the journals and supplements that rely heavily on industry advertising that are least likely to have good disclosure policies.”

Drug Companies & Doctors: A Story of Corruption | by Marcia Angell | The New York Review of Books

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of TheNew England Journal of Medicine.

The Selling of Attention Deficit Disorder - The New York Times

In an interview last month, Dr. Dodson said he makes a new diagnosis in about 300 patients a year and, because he disagrees with studies showing that many A.D.H.D. children are not impaired as adults, always recommends their taking stimulants for the rest of their lives. He said that concern about abuse and side effects is “incredibly overblown,” and that his longtime work for drug companies does not influence his opinions. He said he received about $2,000 for the 2002 talk for Shire. He earned $45,500 in speaking fees from pharmaceutical companies in 2010 to 2011, according to ProPublica, which tracks such payments. “If people want help, my job is to make sure they get it,” Dr. Dodson said. Regarding people concerned about prescribing physicians being paid by drug companies, he added: “They like a good conspiracy theory. I don’t let it slow me down.”

Pharma’s broken business model — Part 2: Scraping the barrel in drug discovery – Endpoints News

Ac­cord­ing to the Human Pro­tein Atlas, there are 19,613 pro­teins en­coded by the human genome.  Of these, 14,545 (74%) have no known link or re­la­tion­ship with dis­ease, which rules them out as po­ten­tial new drug tar­gets be­cause they fail to meet cri­te­rion 1 above.  Per­haps these pro­teins are non-es­sen­tial, as any de­fi­cien­cies can be com­pen­sated by other pro­teins or path­ways; or per­haps they are es­sen­tial, how­ever any de­fi­cien­cies are lethal be­fore birth so they never have the chance to cause any dis­ease.  In any case, we have no rea­son to be­lieve that tar­get­ing these pro­teins will do any­thing for any known human dis­ease. Now of the 5,068 pro­teins that have any link to dis­ease, 3,131 (16% of all human pro­teins) are con­sid­ered to be “un­drug­gable”, ei­ther be­cause they have no ob­vi­ous pocket ca­pa­ble of bind­ing small mol­e­cule drugs, or be­cause they are in­tra­cel­lu­lar and thus in­ac­ces­si­ble to large pro­teins that can­not pen­e­trate the cell mem­brane.  We must rule out these pro­teins as po­ten­tial new drug tar­gets be­cause we cur­rently have no way to tar­get them, so they fail to meet cri­te­rion 2 above.

Research Misconduct Identified by the US Food and Drug Administration: Out of Sight, Out of Mind, Out of the Peer-Reviewed Literature | Medical Journals and Publishing | JAMA Internal Medicine | JAMA Network

Fifty-seven published clinical trials were identified for which an FDA inspection of a trial site had found significant evidence of 1 or more of the following problems: falsification or submission of false information, 22 trials (39%); problems with adverse events reporting, 14 trials (25%); protocol violations, 42 trials (74%); inadequate or inaccurate recordkeeping, 35 trials (61%); failure to protect the safety of patients and/or issues with oversight or informed consent, 30 trials (53%); and violations not otherwise categorized, 20 trials (35%). Only 3 of the 78 publications (4%) that resulted from trials in which the FDA found significant violations mentioned the objectionable conditions or practices found during the inspection. No corrections, retractions, expressions of concern, or other comments acknowledging the key issues identified by the inspection were subsequently published.

Big Pharma Is America’s New Mafia

While $90 million went to drug-company sponsored meals in 2013, according to the Open Payments database, at least $1.4 Billion went to research. If we can believe that doctors can be bought with a slice of pizza pie, then we cannot underrate the influence of research monies. And by the way, that $1.4 billion is probably a fraction of what is spent on researchers. Obamacare allows a four-year delay in the reporting of research grants for reasons that really don’t make any sense. An explanation from Medscape does little to satisfy: “The thinking is that if there were public transparency, it might stifle companies from getting involved in very early research…. And that’s again to specifically protect that research space.”

60 doctors took speaker fees from drug giant - The Boston Globe

The use of physicians in speakers programs or “bureaus’’ like Lilly’s, in which doctors generally use company-prepared materials to explain a drug’s uses and dosing to their colleagues, is widespread in the drug industry. But the practice is under growing scrutiny and some academic medical centers are barring their doctors from participating, believing that physicians essentially become hired advertising guns, with weakened credibility.

Now you see it (2011) now you don't

Eli Lilly and Company (NYSE: LLY) today announced the launch of a physician payment registry (www.lillyphysicianpaymentregistry.com) to help the public better understand how the company works with U.S. physicians and compensates them for their services — and how these collaborations benefit patient care. The website allows visitors to search payments to individual U.S.-based physicians and the institutions or research organizations that receive payments on behalf of a physician. Payments are reported in several categories — including research-related payments, educational programs and other services, such as commercial consulting. The registry also discloses non-cash forms of value provided (such as business meals), as well as travel expenses paid by Lilly when a physician is performing services for the company.

The happiness project | Science

Today, lab mice live in shoebox-size cages hundreds of thousands of times smaller than their natural ranges, and rats can't forage or even stand upright. Both spend their days blasted by ventilation and bright fluorescent lighting that disrupts their day-night cycles. “We're doing the exact opposite of what we should be doing to make these animals happy,” Garner says. Lab animals tend to be obese, have weak immune systems, and develop cancer—all before scientists do any experiments on them.

Frontiers | The Role of Infection and Immune Responsiveness in a Case of Treatment-Resistant Pediatric Bipolar Disorder | Psychiatry

P’s behavior appeared treatment resistant with minimal improvement despite multiple medication trials prior to and during hospitalizations.

drug losers

Some patients suffering from schizophrenia fail to respond to or tolerate adequate doses of available antipsychotic medications.

Funding Trends for Clinical Trials in ClinicalTrials.gov | Research, Methods, Statistics | JAMA | The JAMA Network

In 2005, registration of trials became required for publication in major journals. Registration is also required for trials that meet the definition of an “applicable clinical trial” from the US Food and Drug Administration Amendments Act 801 and that were either initiated after September 27, 2007, or initiated on or before that date and were still ongoing as of December 26, 2007. There are legal repercussions if sponsors or principal investigators do not register accurately. We hypothesized that the number of NIH-funded trials has decreased. We investigated trends in funding of trials using the NIH-built database, ClinicalTrials.gov, with a focus on NIH and industry funding.

Redactions in protocols for drug trials: what industry sponsors concealedJournal of the Royal Society of Medicine - Mikkel Marquardsen, Michelle Ogden, Peter C. Gøtzsche, 2018

In the first systematic review comparing protocols with published trial reports, we found that at least one primary outcome had been changed, introduced or omitted in two-thirds of the reports, and this change was not mentioned in a single published report.4

Psychiatrists Roadblock Drug Withdrawal: Part 2 | Psychiatric Drug Facts

As I was surprised by this prioritization, I looked at the programme for the 2017 meeting, which, like the 2018 meeting, ran over three days. There was a symposium called “Mortality and antipsychotics.” Psychiatrist Jimmi Nielsen announced it by stating that the risks for life-shortening adverse effects of antipsychotics should be weighed against the risk of untreated psychosis where there is an increased risk of suicide and unnatural deaths. He also noted that, “In recent years, large studies have been published that show that the use of antipsychotics is associated with increased average survival. The aim of this symposium is to elucidate the relation between antipsychotics and mortality, including a discussion of the strengths and weaknesses of the studies.” I do not know how Jimmi Nielsen interpreted the large observational studies of neuroleptics or what he told people at his symposium. But I do know that many leading Danish psychiatrists believe that neuroleptics improve survival and that they usually refer to a deeply flawed Finnish study by Tiihonen et al. in The Lancet (6), which Joanna Moncrieff and I have criticised in our books (2,5). People classified as not taking neuroleptics included those who had recently stopped them, although they are at increased risk of suicide because of withdrawal reactions. In accordance with this, the mortality in patients who were not on drugs was very high and didn’t concur with other Finnish data. There were other fatal flaws in this study, e.g. 64% of the deaths were not accounted for.

America's Most Popular Mind Medicines

Another cause for concern is Seroquel (No. 11), the most popular antipsychotic drug. Many patients get it at low doses for uses that have not been well studied, such as treating insomnia and agitation in Alzheimer's disease. Earlier this year AstraZeneca agreed to pay the feds $520 million to settle allegations it illegally marketed the drug for unapproved uses.

Star Neuroscientist Tom Insel Leaves the Google-Spawned Verily for ... a Startup? | WIRED

“I spent 13 years at NIMH really pushing on the neuroscience and genetics of mental disorders, and when I look back on that I realize that while I think I succeeded at getting lots of really cool papers published by cool scientists at fairly large costs—I think $20 billion—I don’t think we moved the needle in reducing suicide, reducing hospitalizations, improving recovery for the tens of millions of people who have mental illness,” Insel says. “I hold myself accountable for that.”

With health care cuts looming, low-cost magnesium a welcome option for treating depression -- ScienceDaily

The researchers at the University of Vermont's Larner College of Medicine conducted an open-label, blocked, randomized cross-over trial involving 126 adults in outpatient primary care clinics. The study participants, who were currently experiencing mild-to-moderate depression, had a mean age of 52, with 38 percent of them male. Participants in the active arm of the study received 248 milligrams of elemental magnesium per day over six weeks, while those in the control arm received no treatment. Depression symptom assessments were conducted on all participants on a bi-weekly basis. The study team found that in 112 participants with analyzable data, consumption of magnesium chloride for six weeks resulted in a clinically significant improvement in measures of depression and anxiety symptoms. In addition, these positive effects were shown quickly, at two weeks, and the supplements were well tolerated and similarly effective regardless of age, sex, or use of antidepressants, among other factors.

Psychiatric drugs killing more users than heroin, cocaine: experts | Vancouver Sun

“The interesting thing about this is that it’s a prescription drug and people think they’re safe,” Ahamad said. “But as it turns out, we’re probably prescribing these drugs in a way that’s leading to harm.” Kerr noted that the rise in BZD-related deaths — “It’s been an epidemic brewing for many, many years” — very closely mirrors a rise in opioid-related deaths that has been widely documented. He cited a fourfold increase in BZD-related deaths in the United States between 1999 and 2014, and also noted that there are 50 per cent more deaths each year in the U.S. due to psychiatric medicine than heroin. “These studies really reveal how very dangerous these drugs are, and they should be used with great caution,” Kerr said. “We can’t just focus on opioids, we need to look at other medications that are used in combination.”

Abysmally primitive

as Dr. Sophia Vinogradov, Chief of Psychiatry at the University of Minnesota Medical School, recently wrote in Nature Human Behavior, “There's a secret that we psychiatrists do not like to talk about: the abysmally primitive state of how we assess, understand, and treat mental illness.”

Why Are There No Biological Tests in Psychiatry? - Scientific American Blog Network

we must also not minimize the grave practical problems and limitations associated with not having biological tests to identify psychiatric disorders. Most troubling is the fact that the overwhelming majority of prescriptions for psychotropic medicines are written by primary care physicians who often have little training in psychiatry; little time to perform an adequate diagnostic evaluation; a tendency to depend on tests rather than talking to patients; and too great a susceptibility to quick trigger diagnosis and poorly chosen pill solutions (fostered by aggressive and misleading drug company marketing). The lack of precise and easily available biological tests in psychiatry permits much loose diagnosing and cowboy prescribing.