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Key psychiatric drug target comes into focus: Team determines first high-resolution structure of dopamine receptor -- ScienceDaily

One way or another, many psychiatric drugs work by binding to receptor molecules in the brain that are sensitive to the neurotransmitter dopamine, a chemical signal that is central to how our experiences shape our behavior. But because scientists still don't understand the differences between the many kinds of dopamine receptors present on brain cells, most of these drugs are "messy," binding to multiple different dopamine receptor molecules and leading to serious side effects ranging from movement disorders to pathological gambling.

The Lilly Suicides - Adbusters | Journal of the mental environment

Reports that Prozac might be unsafe at any dose had Lilly running scared. As early as 1990, one executive stated in an internal memo that, if Prozac is taken off the market, the company could “go down the tubes.” With the US Food and Drug Administration asking questions, Lilly was pressed to show that their drug was safe. The result was published on September 21, 1991. Authored by Lilly employees, the report claimed to represent all existing data comparing Prozac with either older antidepressants or placebos. In fact, the data had been handpicked to favor the drug and the company. The analysis dealt with 3,065 patients, less than 12 percent of the total data from Prozac studies at the time. Among those whose data were left out was the very population most likely to become suicidal –the five or so percent of patients who dropped out of the clinical trials because they experienced unpleasant side effects after taking Prozac.

Happy drug Prozac can bring on impulse to suicide, study says | Science | The Guardian

Volunteers taking part in the early trials were never asked whether they experienced any suicidal feelings or the restless agitation which can be the precursor of a suicide attempt. If patients in later trials said they felt suicidal, it was recorded as part of their depression.

I Helped Create Facebook's Ad Machine. Here's How I'd Fix It | WIRED

But modern digital advertisers constantly tweak and experiment with ads. When big brands requested the ability to post lots of different creative, it posed a real problem. Brands wanted to show a dozen different ad variations every day, but they didn’t want to pollute their page (where all posts necessarily appear). ‘Dark posts’ were a way to shoehorn that advertiser requirement into the Pages system, allowing brands to create as many special, unseen posts as they’d like, which would only be seen by targeted audiences in their Feeds, and not to random passers-by on their page. The unfortunate term ‘dark post’ assumed a sinister air this past election, as it was assumed that these shady foreign elements, or just certain presidential candidates, were showing very different messages to different people, engaging in a cynical and hypocritical politicking. Zuckerberg’s proposes, shockingly, a solution that involves total transparency. Per his video, Facebook pages will now show each and every post, including dark ones (!), that they’ve published in whatever form, either organic or paid. It’s not entirely clear if Zuckerberg intends this for any type of ad or just those from political campaigns, but it’s mindboggling either way. Given how Facebook currently works, it would mean that a visitor to a candidate’s page—the Trump campaign, for instance, once ran 175,000 variations on its ads in a single day—would see an almost endless series of similar content.

New study on the placebo effect and antidepressants in children and adolescents -- ScienceDaily

The results of the meta-analysis show that, although antidepressants work significantly better than placebos across the range of disorders, the difference is small and varies according to the type of mental disorder. However, the results also showed that the placebo effect played a significant role in the efficacy of antidepressants. The study also found that patients treated with antidepressants complained of greater side effects than those who received a placebo. The side effects included everything from mild symptoms such as headaches to suicidal behavior. Placebo effect stronger in cases of depression According to the study, the effects of antidepressants and placebos vary according to the type of mental disorder: antidepressants have a greater specific effect in the case of anxiety disorders than depressive disorders. On the other hand, placebos have a stronger effect in depressed patients than in those with an anxiety disorder. Lead authors Dr. Cosima Locher and Helen Koechlin from the Division of Clinical Psychology & Psychotherapy at the University of Basel's Faculty of Psychology see potential here for new treatment concepts. These would make use of factors contributing to the placebo effect, applying them specifically to the treatment of depression.

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence | The BMJ

Conclusions Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.

Feasibility of PRIME: A Cognitive Neuroscience-Informed Mobile App Intervention to Enhance Motivated Behavior and Improve Quality of Life in Recent Onset Schizophrenia

The UCD process resulted in the following feature set: (1) delivery of text message (short message service, SMS)-based motivational coaching from trained therapists, (2) individualized goal setting in prognostically important psychosocial domains, (3) social networking via direct peer-to-peer messaging, and (4) community “moments feed” to capture and reinforce rewarding experiences and goal achievements. Users preferred an experience that highlighted several of the principles of self-determination theory, including the desire for more control of their future (autonomy and competence) and an approach that helps them improve existing relationships (relatedness). IDEO, also recommended an approach that was casual, friendly, and nonstigmatizing, which is in line with the recovery model of psychosis. After 12-weeks of using PRIME, participants used the app, on average, every other day, were actively engaged with its various features each time they logged in and retention and satisfaction was high (20/20, 100% retention, high satisfaction ratings). The iterative design process lead to a 2- to 3-fold increase in engagement from Stage 1 to Stage 2 in almost each aspect of the platform.

Sexual Consequences of Post-SSRI Syndrome

There are some indications that antidepressant-emergent sexual dysfunctions do not always resolve after discontinuation of the medication and can persist indefinitely in some individuals. Although some or all sexual side effects that start with the use of SSRIs might continue after stopping the medication, other sexual complaints can develop. Decreased capacity to experience sexual pleasure is the most frequent characteristic of this syndrome.

Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype - ACS Chemical Neuroscience (ACS Publications)

Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Selective serotonin reuptake inhibitors (SSRIs) are the most common treatment for depression, and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS, and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2–/– mice on the sucrose preference test, tail suspension test, and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2–/– mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2–/– mouse questions the role of 5HT in depression. Furthermore, the TPH2–/– mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system.

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response - ScienceDirect

The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.

A DIY Pharmaceutical Revolution Is Coming—If It Doesn’t Kill Us First

At Harvard’s Wyss Institute, biochemist Peter Nguyen is developing a system for medical field operatives that he hopes will make preparing life-saving drugs much like making a Cup of Noodles. Last fall, he co-authored a paper in the journal Cell on how to use freeze-dried pellets and water to make drugs on the fly. The pellets contain the necessary chemical building blocks for certain drugs, cells stripped of their inner materials that translate genetic instructions into molecules, then frozen, and dried out. They also freeze-dried the DNA carrying the instructions for how to make specific drug-creating molecules. Add water, and kickstart the chemical reactions that would turn them into therapies.

A DIY Pharmaceutical Revolution Is Coming—If It Doesn’t Kill Us First

If you’ve ever built Ikea furniture though, you might quibble with how easy it really is to put together without error. Instructions for an alpha version of the “Apothecary MicroLab” offered on Four Thieves Vinegar’s website were difficult to understand at best, explaining how to build an automated lab reactor using, among other things, an open-source sous vide controller and a mason jar. Laufer envisions that his army of DIY chemists will build and then program this minilab to manufacture small quantities of their drug of choice. Recently, he uploaded instructions on how to make Daraprin, the medication that Martin Shkreli controversially raised from $13.50 to $750 per tablet.

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.

Emergency room patients routinely overcharged, study finds: 'Price gouging' is worst for minorities and uninsured -- ScienceDaily

Makary and his team found that emergency departments charged anywhere from 1.0-12.6 times ($100-$12,600) more than what Medicare paid for services. On average, emergency medicine doctors had a markup ratio of 4.4 (340 percent in excess charges), or emergency medicine physician charges of $4 billion versus $898 million in Medicare allowable amounts. The researchers also analyzed billing information for 57,607 general internal medicine physicians 3,669 hospitals in all 50 states to determine whether any markup differences, and how much, existed between emergency medicine physicians practicing in a hospital's ER, and general internal medicine physicians who see patients at hospitals. On average, charges were greater when a service was performed by an emergency medicine physician rather than a general internal medicine physician. Overall, general internal medicine physicians had an average markup ratio of 2.1 compared to the Medicare allowable amount. Makary found that wound closure had the highest median markup ratio at 7.0, and interpreting head CT scans had the greatest within-hospital variation, with markup ratios ranging between 1.6 and 27. For a physician interpretation of an electrocardiogram, the median Medicare allowable rate is $16, but different emergency departments charged anywhere from $18 to $317, with a median charge of $95 (or a markup ratio of 6.0). General internal medicine doctors in hospitals charged an average of $62 for the same service. Overall, emergency departments that charged patients the most were more likely to be located in for-profit hospitals in the southeastern and Midwestern U.S., and served higher populations of uninsured, African-American and Hispanic patients. Our study found that inequality is then further compounded on poor, minority groups, who are more likely to receive services from hospitals that charge the most," says Makary. While the study was limited by lack of data on facility and technical fees also charged by the hospital, as well as lack of patients' insurance type and the actual amount patients ultimately paid, Makary says the study highlights the urgent need for legislation that will protect uninsured patients.

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.”

Even small quantities of opioids prescribed for minor injuries increase risk of long-term use -- ScienceDaily

patients who received their first opioid prescription for an ankle sprain treated in U.S. emergency departments (EDs) commonly received prescriptions for anywhere from 15 to 40 pills, according to new research from the Perelman School of Medicine at the University of Pennsylvania. Those who received 30 or more pills compared to less than 15 pills were twice as likely to fill an additional opioid prescription within three to six months.

Generic drug collusion

Embattled drugmaker Perrigo said that federal agents executed search warrants at company headquarters, as part of a wide-ranging investigation into price collusion in the generics industry. Shares fell more than 6% Wednesday morning. Several other companies have received subpoenas as part of this investigation. The Government Accountability Office issued a report last year that found that prices of 300 out of 1,441 generic drugs doubled at least one time between 2010 and 2015.

Can Big Data Help Psychiatry Unravel the Complexity of Mental Illness? - Scientific American

Psychiatrist Charles DeBattista of Stanford University and colleagues, compared electroencephalograms (EEGs) collected from depressed patients, with a database of EEGs from over 1,800 patients that included information about response to specific treatments. Using EEG measures to guide decisions about treatment alternatives led to significantly better outcomes than clinical treatment selection.

data driven future... or not

As Harvard Psychiatrists John Torous and Justin Baker recently wrote in JAMA Psychiatry, “Data science and technology can provide a nearly limitless set of decision-support and self-monitoring tools. However, without individual psychiatrists and the field at large making a concerted push to drive the technology forward…these advances will likely fail to transform our troubled system of care.”

The Rise of Evidence-Based Psychiatry - Scientific American Blog Network

Psychiatry remains an outlier in the medical profession regarding the use of data; even after the rigorous Osheroff v. Chestnut Lodge debate, the importance of data in practice remains unsettled. In particular, objective data and data science remain underutilized by the psychiatric community. Has your therapist ever used a predictive algorithm to guide your treatment?

Why was truth about saturated fat buried for 40 years?

It’s possible, Bob Frantz said, that his father’s team was discouraged by the failure to find a heart benefit from replacing saturated fats with vegetable oils. “My feeling is, when the overall objective of decreasing deaths by decreasing cholesterol wasn’t met, everything else became less compelling,” he said. “I suspect there was a lot of consternation about why” they couldn’t find a benefit. The coleader of the project was Dr. Ancel Keys, author of the Seven Countries Study, Time cover subject, and the most prominent advocate of replacing saturated fat with vegetable fat. “The idea that there might be something adverse about lowering cholesterol [via vegetable oils] was really antithetical to the dogma of the day,” Bob Frantz said.

DSM versus neuroscience

Compared with the psychiatric diagnoses listed in the Diagnostic and Statistical Manual of Mental Disorders (D.S.M.), which can be vague and flawed, brain-based research holds out the promise of a precise and truly scientific understanding of mental illness.

Dr. Nestler is dean for academic and scientific affairs and director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai. Dr. Hyman is a past director of the National Institute of Mental Health.

Virtually all of today’s treatments are based on serendipitous discoveries made six decades ago.

Highest odds for stimulants: male, US, upper year medical student

Psychostimulant use was significantly correlated with use of other drugs (Table 1). Lifetime use of psychostimulants was significantly associated with male gender (21 % male (519/1,087) versus 15 % female (568/1,087), Chi squared p = 0.007, 28 no response). Students who mainly grew up outside the U.S. were significantly less likely to report any lifetime psychostimulant use than their U.S.-reared counterparts (outside of U.S. psychostimulant use prevalence = 4 % vs. 20 % U.S. reared; Chi squared p = 0.013). Overall prevalence of psychostimulant use while in medical school was significantly associated with current year in medical school, with first year students being least likely to report use compared to their second, third, fourth and fifth-year colleagues (41 % first year (n = 42/196), 66 % second year (n = 59/196), 60 % third year (n = 52/196), 71 % fourth year (n = 41/196), 50 % fifth year or beyond (n = 2/196); Chi squared p = 0.048, two no response). Students who self-reported attending a school that determined class rank were significantly more likely to respond that they had used psychostimulants while in medical school (class rank assessed 68 % versus no class rank 51 %, Chi squared p = 0.018). Items not significantly correlated with psychostimulant use included age, marital status, estimated class rank (split by quartiles), tobacco use, caffeine intake, or weight loss supplementation.

Cognitive Enhancement Drug Use Among Future Physicians: Findings from a Multi-Institutional Census of Medical Students

Of these, 11 % (117/1,115) of students reported use during medical school (range 7–16 % among schools). Psychostimulant use was significantly correlated with use of barbiturates, ecstasy, and tranquilizers (Pearson’s correlation r > 0.5, Student’s t-test p < 0.01); male gender (21 % male versus 15 % female, Chi squared p = 0.007); and training at a medical school which by student self-report determined class rank (68 % versus 51 %, Chi-squared p = 0.018). Non-users were more likely to be first year students (Chi-squared p = 0.048) or to have grown up outside of the United States (Chi-squared p = 0.013).