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Serotonin receptors in depression: from A to B

Despite the relative success in treating depression by increasing extracellular serotonin, there is a lack of strong evidence supporting a direct correlation between low serotonin signaling and depression. While some studies report an association between levels of platelet serotonin and depression, this has not been a consistent finding in large sample sets, and it is also unclear how platelet levels are related to brain levels of serotonin 10, 11. Additionally, few studies report direct correlations between cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, and depression 12, 13. Low levels of tryptophan have been consistently linked to depression; however, these effects could be independent of serotonin 14, 15. The lack of consistent clear-cut abnormalities in global measures of serotonin signaling isn’t surprising if one considers the complexity of the receptors at which serotonin binds, the intricate neuroanatomical circuitry of the serotonin system, and the developmental role serotonin plays as a neurotrophic factor 16– 18. Many recent studies have focused on understanding the mechanisms through which serotonin affects depression by studying the impact of 5-HTT and the 15 known receptors through gene-association studies, human brain imaging, and pharmacological and genetic mouse models 19.

Patients react better when doctors imply uncertainty, rather than state it directly -- ScienceDaily

Diagnostic uncertainty is widespread in clinical practice and physician guidelines generally recommend that doctors explain the degree of uncertainty associated with their diagnosis. However, how exactly doctors should communicate uncertainty is a matter of debate. This communication can lower visit satisfaction, decrease adherence to doctor instructions, lessen trust, and decrease confidence in the doctor. The researchers here surveyed parents of pediatric patients who hypothetically received a diagnosis with an element of uncertainty. The uncertainty in the diagnosis was communicated in one of three ways; either with an explicit expression of uncertainty (such as "I'm not sure which disease this is"), an implicit expression of uncertainty using broad differential diagnoses (such as "it could be this disease or this other disease"), or another implicit expression of uncertainty (such as "it is most likely this disease"). Researchers found that explicit expressions of uncertainty were associated with lower perceived technical competence of the doctor, less trust and confidence, and a less willingness to adhere to doctors' advice. "Misdiagnosis is common in medical practice and to enable improvements, uncertainty of diagnosis is something both doctors and patients will need to embrace" said Hardeep Singh, MD, MPH, senior author and researcher at the Houston Veterans Affairs Center for Innovations in Quality, Effectiveness and Safety and Baylor College of Medicine. "Our study provides a foundation for future development of evidence-based guidance on how doctors can best communicate diagnostic uncertainty to patients to improve diagnosis and care outcomes."

Pong paddles and perception: Our actions influence what we see: A new study faces head-on the notion that previous experimental subjects have been victims of response bias -- ScienceDaily

Response bias happens when subjects guess or infer the purpose of an experiment, so they adjust their behaviors or answers - consciously or subconsciously. For example, a Psychology 101 student, familiar with how scientists run experiments, might volunteer as a study subject in which they are asked to wear a backpack, and guess the incline of a hill. They might infer, "I bet the hypothesis is that the backpack will affect how I see the slant of the hill," so they might say the slant is 25 degrees, rather than 20.

Manufacturing the truth: from designing clinical trials to publishing trial data (PDF Download Available)

During the development of a new drug, manufacturers sponsor (or act as authors of ) articles on the clinical trials of the new drug, and these articles are submitted to medical journals. Publication of these articles acts as an essential tool for advertising to the medical community who will be the future prescribers of the new drug. Richard Smith, a former editor of The BMJ, considered that medical journals are “an extension of the marketing arm of pharmaceutical companies” (4). To illustrate, at an estimated cost of up to US$ 836,000, Merck & Co. purchased 900,000 reprints of the VIGOR trial article from the NEJM to circulate to doctors to promote Vioxx® (5,6). Wilson (7) argues that in the public interest, the potential for capture of medical journals represented by this commercial role must be acknowledged and addressed.

When Your Patient Is on Too Many Psych Meds

Despite years of treatment and a lot of medications, Mr A continued to have significant depressive and anxiety symptoms—specifically a lot of lethargy and hypersomnolence, and then alternating with anxiety and restlessness that he found very troubling. He wasn't making progress with his psychiatrist. In fact, when Mr A showed up in my office, he was on nearly a dozen medications that included lorazepam up to 4 mg daily, amphetamine mixed salts (Adderall®) 40 mg daily, buspirone 30 mg daily, lithium 900 mg daily, topiramate 300 mg daily, escitalopram (Lexapro®) 30 mg daily, temazepam 60 mg daily at bedtime, ziprasidone (Geodon®) 80 mg a day, paliperidone (Invega®) 6 mg daily, and metformin 1000 mg daily. He actually hadn't had a lithium level checked in quite some time.

Swimming rats

More troubling, these screens occasionally became imposters for disease models in the academic literature as well as in industry, despite scant corroborative evidence. In the widely used forced-swim and tail-suspension tests, for example, a compound is considered to be an antidepressant when, compared with a control, it causes a rat or mouse to continue swimming or actively struggling longer. Forced-swim and tail-suspension tests do not even model the therapeutic action of antidepressants, because in these rodent screens, a single dose of antidepressant is active, whereas in depressed patients, antidepressant drugs require weeks of administration to exert a therapeutic effect.

Withdrawing -- and what helped

Maybe dealing with life’s distresses has its own chemistry. I know I hated every second of it. I don’t know if the medication helped. But I do know that I’m very glad I’m off.

The negative side of negativity

In fact, researchers have long documented how certain emotional reactions from family members correlate with higher relapse rates for people who have a diagnosis of schizophrenia. Collectively referred to as “high expressed emotion,” these reactions include criticism, hostility and emotional overinvolvement (like overprotectiveness or constant intrusiveness in the patient’s life). In one study, 67 percent of white American families with a schizophrenic family member were rated as “high EE.” (Among British families, 48 percent were high EE; among Mexican families the figure was 41 percent and for Indian families 23 percent.)

Non medical treatment succeeds in third world

The research showed that patients outside the United States and Europe had significantly lower relapse rates — as much as two-thirds lower in one follow-up study. These findings have been widely discussed and debated in part because of their obvious incongruity: the regions of the world with the most resources to devote to the illness — the best technology, the cutting-edge medicines and the best-financed academic and private-research institutions — had the most troubled and socially marginalized patients. Trying to unravel this mystery, the anthropologist Juli McGruder from the University of Puget Sound spent years in Zanzibar studying families of schizophrenics. Though the population is predominantly Muslim, Swahili spirit-possession beliefs are still prevalent in the archipelago and commonly evoked to explain the actions of anyone violating social norms — from a sister lashing out at her brother to someone beset by psychotic delusions. McGruder found that far from being stigmatizing, these beliefs served certain useful functions. The beliefs prescribed a variety of socially accepted interventions and ministrations that kept the ill person bound to the family and kinship group. “Muslim and Swahili spirits are not exorcised in the Christian sense of casting out demons,” McGruder determined. “Rather they are coaxed with food and goods, feted with song and dance. They are placated, settled, reduced in malfeasance.” McGruder saw this approach in many small acts of kindness. She watched family members use saffron paste to write phrases from the Koran on the rims of drinking bowls so the ill person could literally imbibe the holy words. The spirit-possession beliefs had other unexpected benefits. Critically, the story allowed the person with schizophrenia a cleaner bill of health when the illness went into remission. An ill individual enjoying a time of relative mental health could, at least temporarily, retake his or her responsibilities in the kinship group. Since the illness was seen as the work of outside forces, it was understood as an affliction for the sufferer but not as an identity.

Chemical imbalance boosts negative viewsof mentally ill

“The results of the current study suggest that we may actually treat people more harshly when their problem is described in disease terms,” Mehta wrote. “We say we are being kind, but our actions suggest otherwise.” The problem, it appears, is that the biomedical narrative about an illness like schizophrenia carries with it the subtle assumption that a brain made ill through biomedical or genetic abnormalities is more thoroughly broken and permanently abnormal than one made ill though life events. “Viewing those with mental disorders as diseased sets them apart and may lead to our perceiving them as physically distinct. Biochemical aberrations make them almost a different species.”

Florida’s Deadliest Rx Drug is Not a Painkiller — Pain News Network

The most deadly prescription drugs in the state are not opioid painkillers, but benzodiazepines – a class of anti-anxiety medication that includes Xanax (alprazolam) and Valium (diazepam).  Xanax alone killed more Floridians last year (813) than oxycodone (723). The medical examiners analyzed toxicology and autopsy results for 11,910 people who died in Florida in 2016, noting not only what drugs were present at the time of death, but which drug actually caused the deaths. The distinction is important and more accurate than the death certificate (ICD) codes often used by the CDC, which merely list the drugs that were present. Critics have long contended that CDC researchers cherry pick ICD data to inflate the number of deaths "involving" or "linked" to opioid medication, in some cases counting the same death twice.

Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial - EBioMedicine

Using truthful or deceiving verbal instructions, we tested how expectancies influence SSRI efficacy in social anxiety disorder. The number of responders was more than three times higher after open administration of escitalopram 20 mg compared to covert administration of the drug presented as “active placebo” in a cover story. Correct vs. incorrect information about the SSRI also yielded different neural changes in brain areas involved in emotion-cognition interactions.

Antidepressants and the Placebo Effect

Many patients in clinical trials realize that they have been given the real drug, rather than the placebo, most likely because of the drug’s side effects. What effect is this likely to have in a clinical trial? We do not have to guess at the answer to this question. Bret Rutherford and his colleagues at Columbia University have provided the answer. They examined the response to antidepressants in studies that did not have a placebo group with those in studies where they did have a placebo group (Rutherford, Sneed, & Roose, 2009). The main difference between these studies is that in the first case, the patients were certain they were getting an active antidepressant, where as in the placebo-controlled trials, they knew that they might be given a placebo. Knowing for sure that they were getting an active drug boosted the effectiveness of the drug significantly. This supports the hypothesis that the relatively small difference between drug and placebo in antidepressant trials are at least in part due to “breaking blind” and discerning that one is in the drug group, because of the side effects produced by the drug.

Antidepressants and the Placebo Effect

The most commonly prescribed antidepressants are SSRIs, drugs that are supposed to selectively target the neurotransmitter serotonin. But there is another antidepressant that has a very different mode of action. It is called tianeptine, and it has been approved for prescription as an antidepressant by the French drug regulatory agency. Tianeptine is an SSRE, a selective serotonin reuptake enhancer. Instead of increasing the amount of serotonin in the brain, it is supposed to decrease it. If the theory that depression is caused by a deficiency of serotonin were correct, we would expect to make depression worse. But it doesn’t. In clinical trials comparing the effects of tianeptine to those of SSRIs and tricyclic antidepressants, 63% of patients show significant improvement (defined as a 50% reduction in symptoms), the same response rate that is found for SSRIs, NDRIs, and tricyclics, in this type of trial (Wagstaff, Ormrod, & Spencer, 2001). It simply does not matter what is in the medication – it might increase serotonin, decrease it, or have no effect on serotonin at all. The effect on depression is the same.

Antidepressants and the Placebo Effect

Yet this 11% figure may overestimate the number of people who benefit from antidepressants. Antidepressants are also prescribed to people who do not qualify for the diagnosis of major depression. My neighbor’s pet dog died; his physician prescribed an antidepressant. A friend in the US was diagnosed with lumbar muscle spasms and was prescribed an antidepressant. I have lost count of the number of people who have told me they were prescribed antidepressants when complaining of insomnia – even though insomnia is a frequently reported side effect of antidepressants. About 20% of patients suffering from insomnia in the United States are given antidepressants as a treatment by their primary care physicians (Simon & VonKorff, 1997), despite the fact that “the popularity of antidepressants in the treatment of insomnia is not supported by a large amount of convincing data, but rather by opinions and beliefs of the prescribing physicians” (Wiegand, 2008, p. 2411).

Antidepressants and the Placebo Effect

More important, in both analyses, the mean difference between drug and placebo was less than two points on the HAM-D. The HAM-D is a 17-item scale on which people can score from 0 to 53 points, depending on how depressed they are. A six-point difference can be obtained just by changes in sleep patterns, with no change in any other symptom of depression. So the 1.8 difference that we found between drug and placebo was very small indeed – small enough to be clinically insignificant. But you don’t have to take my word for how small this difference is. The National Institute for Health and Care Excellence (NICE), which drafts treatment guidelines for the National Health Service in the United Kingdom, has established a three-point difference between drug and placebo on the HAM-D as a criterion of clinical significance (NICE, 2004). Thus, when published and unpublished data are combined, they fail to show a clinically significant advantage for antidepressant medication over inert placebo.

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.”

>50% medical journal editors get money from drug companies

The authors investigated 52 influential U.S.-based journals in 26 physician specialties. In 2014, approximately half the editors of these journals received payments from pharmaceutical or medical device companies. These payments were disclosed by the applicable companies in the U.S.-based Open Payments database a federally run program that requires industry to report information about financial relationships to physicians. These payments were made to the editors personally, rather than for research funding, and were characterized in various ways, including honorariums, patent royalties, food and beverage, travel expenses, and consulting fees. The highest payments went to editors from endocrinology journals, followed by cardiology, gastroenterology, rheumatology and urology. The authors found that, on the whole, journal editors who are also physicians received higher payments from the pharmaceutical and medical device industries than physicians in their same specialty who are not journal editors.

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.