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New study gives the most detailed look yet at the neuroscience of placebo effects -- ScienceDaily

"Our findings demonstrate that the participants who showed the most pain reduction with the placebo also showed the largest reductions in brain areas associated with pain construction," explains co-author Wager, who is also the principal investigator of the Cognitive and Affective Neuroscience Lab at Dartmouth. "We are still learning how the brain constructs pain experiences, but we know it's a mix of brain areas that process input from the body and those involved in motivation and decision-making. Placebo treatment reduced activity in areas involved in early pain signaling from the body, as well as motivational circuits not tied specifically to pain."

Placebo effect may explain reported benefits of psychedelic microdoses -- ScienceDaily

Szigeti and his colleagues designed a citizen science study where individuals who were already microdosing could participate online. First, the 191 participants followed a setup procedure that mixed placebo pills with microdose ones. After the setup, the participants had a set of capsules without knowing which were placebo and which were microdose. The authors call this process 'self-blinding', as participants lost knowledge of which drug they were taking. The setup included barcodes which, when scanned, linked to the study's IT infrastructure and allowed the researchers to track who had taken microdoses or placebos. The participants then filled out surveys about their experiences and completed online cognitive tests, while they took the pills over a four-week period. Participants who were taking the real psychoactive drugs and those unknowingly taking the placebos reported similar psychological benefits. "Our results are mixed: on the one hand, we observed microdosing's benefits in a wide range of psychological measures; on the other hand, equal benefits were seen among participants taking placebos," Szigeti explains. "These findings suggest that the benefits are not due to the drug, but rather due to the placebo-like expectation effects. Many participants who reported that they experienced positive effects while taking the placebo were shocked to learn after the study that they hadn't been taking the real drug."

Patients taking statins experience similar side effects from dummy pills -- ScienceDaily

The team recruited 60 patients aged between 37-79 who were on statins, and had stopped their treatment due to side effects, from June 2016 -- March 2019. During the trial, which took place at Hammersmith Hospital, patients were given four bottles containing a statin, four bottles of a placebo and four empty bottles to take over a course of a year. Patients took identical tablets, blinded to statin or placebo for eight months, and took nothing for four months. The patients took these bottles in a random order and were required to score from 0 -- no symptoms -- to 100 -- worst imaginable symptoms- of any daily side effects they experienced, on a smartphone. Forty-nine of the 60 patients completed the full 12 months of the trial.

Capsule Commentary on Odineal et al., Effect of Mobile Device-Assisted N-of-1 Trial Participation on Analgesic Prescribing for Chronic Pain: Randomized Controlled Trial | SpringerLink

In this study, Odineal and colleagues1 examined changes in prescription analgesic prescribing for approximately 200 patients with chronic pain randomized to either a mobile app–enabled N-of-1 study (tailored, individualized pain-control interventions) or a control group. The app allowed patients to choose two treatment plans to compare over several short trials, selecting from a list of commonly prescribed analgesics or non-pharmaceutical therapies such as yoga or physical therapy. Among intervention patients, the authors found a clinically and statistically significant decrease in NSAID prescriptions relative to controls. Nearly one-quarter of intervention patients stopped NSAIDs during the study period, and the between-group difference was also significant.

Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials | Journal of Neurology, Neurosurgery & Psychiatry

Thirty RCTs with 1610 participants were included in the quantitative analysis. The overall analysis pooling from 26 of the RCTs suggested that anti-inflammatory agents reduced depressive symptoms (SMD −0.55, 95% CI −0.75 to −0.35, I2=71%) compared with placebo. Higher response (RR 1.52, 95% CI 1.30 to 1.79, I2=29%) and remission rates (RR 1.79, 95% CI 1.29 to 2.49, I2=41%) were seen in the group receiving anti-inflammatory agents than in those receiving placebo.

Your healthcare provider's expectations on whether a treatment works may impact its effectiveness -- ScienceDaily

"These findings demonstrate how subtle social interactions can impact clinical outcomes. Even though the study participants were role playing and weren't actual health professionals or patients, you can imagine that in a real clinical context, if the healthcare providers seemed competent, empathetic and confident that a treatment may work, the impact on patient outcomes could be even stronger. Additional research however, is needed to see how this plays out in the real world," explained senior author Luke J. Chang, an assistant professor of psychological and brain sciences and director of the Computational Social Affective Neuroscience Laboratory (Cosan Lab) at Dartmouth.

Light works, Prozac ties placebo

A total of 122 patients were randomized (light monotherapy, 32; fluoxetine monotherapy, 31; combination therapy, 29; placebo, 30). The mean (SD) changes in MADRS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. The combination (effect size [d] = 1.11; 95% CI, 0.54 to 1.64) and light monotherapy (d = 0.80; 95% CI, 0.28 to 1.31) were significantly superior to placebo in the MADRS change score, but fluoxetine monotherapy (d = 0.24; 95% CI, −0.27 to 0.74) was not superior to placebo.

Placebos rarely accurately described in research protocols

Placebo controls are the 'gold' standard against which new treatments are often measured. If a new treatment consistently proves to be better than a placebo treatment, then it is taken to be effective. Otherwise, it isn't. Co-lead author and Director of the Oxford Empathy Programme, Jeremy Howick, said: 'There is a fundamental problem with this "gold" standard. Different placebos have very different effects, which then lead to (sometimes, mistaken) inferences about a new treatment's effects or harms.'

Even psychological placebos have an effect -- ScienceDaily

The researchers used the color green as the placebo in the video experiments, examining it both with and without a psychological narrative ("green is calming because it activates early conditioned emotional schemata"), as well as in the context of a neutral or a friendly relationship. After viewing the videos, the participants assessed their subjective condition with questionnaires over several days. The results showed that the placebo had a positive effect on the participants' well-being when it was prescribed together with a psychological narrative and in the context of a friendly relationship. The observed effect was strongest after administering the placebo but remained evident for up to one week.

Pain can be a self-fulfilling prophecy: New brain imaging research shows that when we expect something to hurt it does, even if the stimulus isn't so painful -- ScienceDaily

Unbeknownst to the subjects, heat intensity was not actually related to the preceding cue. The study found that when subjects expected more heat, brain regions involved in threat and fear were more activated as they waited. Regions involved in the generation of pain were more active when they received the stimulus. Participants reported more pain with high-pain cues, regardless of how much heat they actually got. "This suggests that expectations had a rather deep effect, influencing how the brain processes pain," said Jepma. Surprisingly, their expectations also highly influenced their ability to learn from experience. Many subjects demonstrated high "confirmation bias" -- the tendency to learn from things that reinforce our beliefs and discount those that don't. For instance, if they expected high pain and got it, they might expect even more pain the next time. But if they expected high pain and didn't get it, nothing changed.

What if the Placebo Effect Isn’t a Trick? - The New York Times

Will this work destroy the stuff that actually has to do with wisdom, preciousness, imagination, the things that are actually critical to who we are as human beings?” he asks. His answer: “I don’t know, but I have to believe there is an infinite reserve of wisdom and imagination that will resist being reduced to simple materialistic explanations.”

What if the Placebo Effect Isn’t a Trick? - The New York Times

The subjects were randomly divided into four groups, following standard clinical-trial protocol, and received a daily dose of either vitamin E, aspirin, vitamin E with aspirin or a placebo. A subset also had their DNA sampled — which, Hall realized, offered her a vastly larger genetic database to plumb for markers correlated to placebo response. Analyzing the data amassed during the first 10 years of the study, Hall found that the women with the low-COMT gene variant had significantly higher rates of heart disease than women with the high-COMT variant, and that the risk was reduced for those low-COMT women who received the active treatments but not in those given placebos. Among high-COMT people, the results were the inverse: Women taking placebos had the lowest rates of disease; people in the treatment arms had an increased risk.

What if the Placebo Effect Isn’t a Trick? - The New York Times

A 2015 study published in the journal Pain analyzed 84 clinical trials of pain medication conducted between 1990 and 2013 and found that in some cases the efficacy of placebo had grown sharply, narrowing the gap with the drugs’ effect from 27 percent on average to just 9 percent. The only studies in which this increase was detected were conducted in the United States, which has spawned a variety of theories to explain the phenomenon: that patients in the United States, one of only two countries where medications are allowed to be marketed directly to consumers, have been conditioned to expect greater benefit from drugs; or that the larger and longer-duration trials more common in America have led to their often being farmed out to contract organizations whose nurses’ only job is to conduct the trial, perhaps fostering a more placebo-triggering therapeutic interaction.

What if the Placebo Effect Isn’t a Trick? - The New York Times

The discovery of this genetic correlation to placebo response set Hall off on a continuing effort to identify the biochemical ensemble she calls the placebome — the term reflecting her belief that it will one day take its place among the other important “-omes” of medical science, from the genome to the microbiome. The rs4680 gene snippet is one of a group that governs the production of COMT, and COMT is one of a number of enzymes that determine levels of catecholamines, a group of brain chemicals that includes dopamine and epinephrine. (Low COMT tends to mean higher levels of dopamine, and vice versa.) Hall points out that the catecholamines are associated with stress, as well as with reward and good feeling, which bolsters the possibility that the placebome plays an important role in illness and health, especially in the chronic, stress-related conditions that are most susceptible to placebo effects.

What if the Placebo Effect Isn’t a Trick? - The New York Times

The findings of the I.B.S. study were in keeping with a hypothesis Kaptchuk had formed over the years: that the placebo effect is a biological response to an act of caring; that somehow the encounter itself calls forth healing and that the more intense and focused it is, the more healing it evokes. He elaborated on this idea in a comparative study of conventional medicine, acupuncture and Navajo “chantway rituals,” in which healers lead storytelling ceremonies for the sick. He argued that all three approaches unfold in a space set aside for the purpose and proceed as if according to a script, with prescribed roles for every participant. Each modality, in other words, is its own kind of ritual, and Kaptchuk suggested that the ritual itself is part of what makes the procedure effective, as if the combined experiences of the healer and the patient, reinforced by the special-but-familiar surroundings, evoke a healing response that operates independently of the treatment’s specifics. “Rituals trigger specific neurobiological pathways that specifically modulate bodily sensations, symptoms and emotions,” he wrote. “It seems that if the mind can be persuaded, the body can sometimes act accordingly.”

Sugar pills relieve pain for chronic pain patients: Placebo benefits can be predicted by brain anatomy and psychological traits -- ScienceDaily

About 60 chronic back pain patients were randomized into two arms of the study. In one arm, subjects didn't know if they got the drug or the placebo. Researchers didn't study the people who got the real drug. The other study arm included people who came to the clinic but didn't get a placebo or drug. They were the control group. The individuals whose pain decreased as a result of the sugar pill had a similar brain anatomy and psychological traits. The right side of their emotional brain was larger than the left, and they had a larger cortical sensory area than people who were not responsive to the placebo. The chronic pain placebo responders also were emotionally self-aware, sensitive to painful situations and mindful of their environment. "Clinicians who are treating chronic pain patients should seriously consider that some will get as good a response to a sugar pill as any other drug," Apkarian said. "They should use it and see the outcome. This opens up a whole new field."

Visual illusion proves effective in relieving knee pain for people with osteoarthritis -- ScienceDaily

UniSA researcher and NHMRC Career Development Fellow, Dr Tasha Stanton says the research combined visual illusions and touch, with participants reporting up to a 40 per cent decrease in pain when presented with an illusion of the knee and lower leg elongated. "We also found that the pain reduction was optimal when the illusion was repeated numerous times -- that is, its analgesic effect was cumulative," Dr Stanton says. The small study -- 12 participants -- focused on people over 50 years with knee pain, and a clinical diagnosis of osteoarthritis. Dr Stanton says the research provides "proof of concept" support that visual illusions can play a powerful role in reducing pain.

Lessons learned from placebo groups in antidepressant trials

The analysis of ‘nocebo effects’, e.g. adverse effects in placebo groups of antidepressant trials also confirms the impact of expectations: nocebo symptoms reflected the typical side-effect patterns expected in the drug group, with higher symptoms rates in the placebo groups of tricyclic antidepressant trials compared with placebo groups of trials testing selective serotonin reuptake inhibitors.

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

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.

Even open-label placebos work, if they are explained -- ScienceDaily

For the first time, researchers from the University of Basel, along with colleagues from Harvard Medical School, have compared the effects of administering open-label and deceptive placebos. The team conducted an experimental study with 160 healthy volunteers who were exposed to increasing heat on their forearm via a heating plate. The participants were asked to manually stop the temperature rise as soon as they could no longer stand the heat. After that, they were given a cream to relieve the pain. Some of the participants were deceived during the experiment: they were told that they were given a pain relief cream with the active ingredient lidocaine, although it was actually a placebo. Other participants received a cream that was clearly labeled as a placebo; they were also given fifteen minutes of explanations about the placebo effect, its occurrence and its effect mechanisms. A third group received an open-label placebo without any further explanation. The subjects of the first two groups reported a significant decrease in pain intensity and unpleasantness after the experiment. "The previous assumption that placebos only work when they are administered by deception needs to be reconsidered," says Dr. Cosima Locher, a member of the University of Basel's Faculty of Psychology and first author of the study.

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.

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.