Requesting conflicts of interest declarations from the European Medicines Agency: 3-year follow-up status.

AIMS: We have previously described the European Medicines Agency's (EMA) and the US Food and Drug Administration's guidelines, each for a specific psychiatric indication, on how to design pivotal drug trials used in new drug applications. Here, we report on our efforts over 3 years to retrieve conflicts of interest declarations from EMA. We wanted to assess potential internal industry influence judged as the proportion of guideline committee members with industry conflicts of interest. METHODS: We submitted Freedom of Information requests in February 2020 to access EMA's lists of committee members (and their declared conflicts of interest) involved in drafting the 13 'Clinical efficacy and safety' guidelines available on EMA's website pertaining to psychiatric indications. In our request, we did not specify the exact EMA committees. Here, we describe the received documents and report the proportion of members with industry interests (i.e. defined as any financial industry relationship). It is a follow-up paper to our first report (http://doi.org/10.1017/S2045796021000147). RESULTS: After 2 years and 9 months (November 2022), the EMA sent us member lists and corresponding conflicts of interest declarations from the Committee for Medicinal Products for Human use (CHMP) from 2012, 2013 and 2017. These member lists pertained to 3 of the 13 requested guidelines (schizophrenia, depression and autism spectrum disorder). The 10 remaining guidelines were published before 2011 and EMA stated that they needed to require permission from their expert members (with unknown retrieval rate) and foresaw excessive workload and long wait. Therefore, we withdrew our request. The CHMPs from 2012, 2013 and 2017 had from 34 to 36 members; 39%-44% declared any interests and we judged 14%-18% as having industry interests. For the schizophrenia guideline, we identified two members with industry interests to companies who submitted feedback on the guideline. We did not receive declarations from the Central Nervous System (CNS) Working Party, the CHMP appointed expert group responsible for drafting and incorporating feedback into the guidelines. CONCLUSIONS: After almost 3 years, we received information, which only partly addressed our request. We recommend EMA to improve transparency by publishing the author names and their corresponding conflicts of interest declarations directly in the 'Clinical efficacy and safety' guidelines and to not remove conflicts of interest declarations after 1 year from their website to reduce the risk of stealth corporate influence during the development of these influential guidelines.

Benefits and harms of antipsychotic drugs in drug-naïve patients with psychosis: A systematic review.

OBJECTIVE: To study the benefits and harms of antipsychotics in drug-naïve patients with psychosis. METHODS: This study is a systematic review and meta-analysis of placebo-controlled trials. MAIN OUTCOME MEASURES: Mortality, activities of daily living, quality of life, core psychiatric events, and relapse and recovery rates. DATA SOURCES: PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), two trial registers and references in potentially eligible articles. DATA EXTRACTION: Two researchers extracted data independently. The outcomes were planned to be meta-analysed using Review Manager based on a fixed effect model. RESULTS: Our searches resulted in 493 unique records of which 447 were clearly not eligible. We read the full text of the 46 potentially eligible articles and found one eligible trial in drug-naïve patients, which was unreliable. It was a Chinese trial comparing olanzapine with placebo in 261 patients with first-episode schizophrenia. After 12 weeks, there was an extremely large difference favouring placebo, but the authors reported the opposite, that olanzapine was effective. CONCLUSIONS: The use of antipsychotics cannot be justified based on the evidence we currently have. Withdrawal effects in the placebo groups make existing placebo-controlled trials unreliable.

Long-term harms from previous use of selective serotonin reuptake inhibitors: A systematic review.

BACKGROUND: Millions of people are treated with antidepressants like selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This clinical practice is based on short-term trials that have exaggerated the benefits and underestimated the harms. We also know too little about long-term harms. AIM: To assess harms of SSRIs and SNRIs that persist after end of drug intake. METHODS: Systematic review of placebo-controlled randomised trials of any length in patients with a psychiatric diagnosis and a follow-up of at least six months. Our primary outcomes were mortality, functional outcomes, quality of life and core psychiatric events. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials and checked the references for eligible articles. One researcher extracted data and another checked the data extraction. RESULTS: Our searches returned 9,153 unique records. We included 22 papers for 12 trials on SSRIs. Median intervention and follow-up periods were 15 and 52 weeks, respectively. Median number of randomised participants was 51; only two trials had a drop-out rate below 20%.Outcome reporting was less thorough during follow-up than for the intervention period and only two trials maintained the blind during follow-up. All authors concluded that the drugs were not beneficial in the long term.All trials reported harms outcomes selectively or did not report any. Only two trials reported on any of our primary outcomes (school attendance and number of heavy drinking days). CONCLUSION: The randomised trials currently available cannot be used to investigate persistent harms of antidepressants.

Overestimated lead times in cancer screening has led to substantial underestimation of overdiagnosis.

BACKGROUND: Published lead time estimates in breast cancer screening vary from 1 to 7 years and the percentages of overdiagnosis vary from 0 to 75%. The differences are usually explained as random variations. We study how much can be explained by using different definitions and methods. METHODS: We estimated the clinically relevant lead time based on the observed incidence reduction after attending the last screening round in the Norwegian mammography screening programme. We compared this estimate with estimates based on models that do not take overdiagnosis into account (model-based lead times), for varying levels of overdiagnosis. Finally, we calculated overdiagnosis adjusted for clinical and model-based lead times and compared results. RESULTS: Clinical lead time was about one year based on the reduction in incidence in women previously offered screening. When overdiagnosed tumours were included, the estimates increased to 4-9 years, depending on the age at which screening begins and the level of overdiagnosis. Including all breast cancers detected in women long after the end of the screening programme dilutes the level of overdiagnosis by a factor of 2-3. CONCLUSION: When overdiagnosis is not taken into account, lead time is substantially overestimated. Overdiagnosis adjusted for model-based lead time is a function tending to zero, with no simple interpretation. Furthermore, the estimates are not in general comparable, because they depend on both the duration of screening and duration of follow-up. In contrast, overdiagnosis adjusted for clinically relevant tumours is a point estimate (and interpreted as percentage), which we find is the most reasonable method.

Informed choice requires information about both benefits and harms.

A study found that women participating in mammography screening were content with the programme and the paternalistic invitations that directly encourage participation and include a pre-specified time of appointment. We argue that this merely reflects that the information presented to the invited women is seriously biased in favour of participation. Women are not informed about the major harms of screening, and the decision to attend has already been made for them by a public authority. This short-circuits informed decision-making and the legislation on informed consent, and violates the autonomy of the women. Screening invitations must present both benefits and harms in a balanced fashion, and should offer, not encourage, participation. It should be stated clearly that the choice not to participate is as sensible as the choice to do so. To allow this to happen, the responsibility for the screening programmes must be separated from the responsibility for the information material.

[The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting of observational studies]. / Das Strengthening the Reporting of Observational Studies in Epidemiology (STROBE-) Statement.

Much of biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalizability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. Eighteen items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.

House dust mite control measures for asthma: systematic review.

The major allergen in house dust comes from mites. We performed a systematic review of the randomized trials that had assessed the effects of reducing exposure to house dust mite antigens in the homes of people with mite-sensitive asthma, and had compared active interventions with placebo or no treatment. Fifty-four trials (3002 patients) were included. Thirty-six trials assessed physical methods (26 mattress covers), 10 chemical methods and eight a combination of chemical and physical methods. Despite the fact that many trials were of poor quality and would be expected to exaggerate the reported effect, we did not find an effect of the interventions. For the most frequently reported outcome, peak flow in the morning (1565 patients), the standardized mean difference was 0.00 (95% confidence interval (CI) -0.10 to 0.10). There were no statistically significant differences in number of patients improved (relative risk 1.01, 95% CI 0.80-1.27), asthma symptom scores (standardized mean difference -0.04, 95% CI -0.15 to 0.07) or in medication usage (standardized mean difference -0.06, 95% CI -0.18 to 0.07). Chemical and physical methods aimed at reducing exposure to house dust mite allergens cannot be recommended.

House dust mite control measures for asthma.

Editorial note: This 2011 review predates current reporting standards and methodological expectations for Cochrane Reviews. It should not be used for clinical decision­making. BACKGROUND: The major allergen in house dust comes from mites. Chemical, physical and combined methods of reducing mite allergen levels are intended to reduce asthma symptoms in people who are sensitive to house dust mites. OBJECTIVES: To assess the effects of reducing exposure to house dust mite antigens in the homes of people with mite-sensitive asthma. SEARCH STRATEGY: PubMed and The Cochrane Library (last searches Nov 2007), reference lists. SELECTION CRITERIA: Randomised trials of mite control measures vs placebo or no treatment in people with asthma known to be sensitive to house dust mites. DATA COLLECTION AND ANALYSIS: Two authors applied the trial inclusion criteria and evaluated the data. Trial authors were contacted to clarify information. MAIN RESULTS: Fifty-four trials (3002 patients) were included. Thirty-six trials assessed physical methods (26 mattress encasings), 10 chemical methods, and 8 a combination of chemical and physical methods. Despite the fact that many trials were of poor quality and would be expected to exaggerate the reported effect, we did not find an effect of the interventions. For the most frequently reported outcome, peak flow in the morning (1565 patients), the standardised mean difference was 0.00 (95% confidence interval (CI) -0.10 to 0.10). There were no statistically significant differences either in number of patients improved (relative risk 1.01, 95% CI 0.80 to 1.27), asthma symptom scores (standardised mean difference -0.04, 95% CI -0.15 to 0.07), or in medication usage (standardised mean difference -0.06, 95% CI -0.18 to 0.07). AUTHORS' CONCLUSIONS: Chemical and physical methods aimed at reducing exposure to house dust mite allergens cannot be recommended. It is doubtful whether further studies, similar to the ones in our review, are worthwhile. If other types of studies are considered, they should be methodologically rigorous and use other methods than those used so far, with careful monitoring of mite exposure and relevant clinical outcomes.

Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials.

BACKGROUND: Randomized trials without reported adequate allocation concealment have been shown to overestimate the benefit of experimental interventions. We investigated the robustness of conclusions drawn from meta-analyses to exclusion of such trials. MATERIAL: Random sample of 38 reviews from The Cochrane Library 2003, issue 2 and 32 other reviews from PubMed accessed in 2002. Eligible reviews presented a binary effect estimate from a meta-analysis of randomized controlled trials as the first statistically significant result that supported a conclusion in favour of one of the interventions. METHODS: We assessed the methods sections of the trials in each included meta-analysis for adequacy of allocation concealment. We replicated each meta-analysis using the authors' methods but included only trials that had adequate allocation concealment. Conclusions were defined as not supported if our result was not statistically significant. RESULTS: Thirty-four of the 70 meta-analyses contained a mixture of trials with unclear or inadequate concealment as well as trials with adequate allocation concealment. Four meta-analyses only contained trials with adequate concealment, and 32, only trials with unclear or inadequate concealment. When only trials with adequate concealment were included, 48 of 70 conclusions (69%; 95% confidence interval: 56-79%) lost support. The loss of support mainly reflected loss of power (the total number of patients was reduced by 49%) but also a shift in the point estimate towards a less beneficial effect. CONCLUSION: Two-thirds of conclusions in favour of one of the interventions were no longer supported if only trials with adequate allocation concealment were included.

Screening for breast cancer with mammography.

BACKGROUND: A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. OBJECTIVES: To assess the effect of screening for breast cancer with mammography on mortality and morbidity. SEARCH STRATEGY: We searched PubMed (June 2005). SELECTION CRITERIA: Randomised trials comparing mammographic screening with no mammographic screening. DATA COLLECTION AND ANALYSIS: Both authors independently extracted data. Study authors were contacted for additional information. MAIN RESULTS: Seven completed and eligible trials involving half a million women were identified. We excluded a biased trial from analysis. Two trials with adequate randomisation did not show a significant reduction in breast cancer mortality, relative risk (RR) 0.93 (95% confidence interval 0.80 to 1.09) at 13 years; four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality, RR 0.75 (0.67 to 0.83) (P = 0.02 for difference between the two estimates). RR for all six trials combined was 0.80 (0.73 to 0.88). The two trials with adequate randomisation did not find an effect of screening on cancer mortality, including breast cancer, RR 1.02 (0.95 to 1.10) after 10 years, or on all-cause mortality, RR 1.00 (0.96 to 1.04) after 13 years. We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death. Numbers of lumpectomies and mastectomies were significantly larger in the screened groups, RR 1.31 (1.22 to 1.42) for the two adequately randomised trials; the use of radiotherapy was similarly increased. AUTHORS' CONCLUSIONS: Screening likely reduces breast cancer mortality. Based on all trials, the reduction is 20%, but as the effect is lower in the highest quality trials, a more reasonable estimate is a 15% relative risk reduction. Based on the risk level of women in these trials, the absolute risk reduction was 0.05%. Screening also leads to overdiagnosis and overtreatment, with an estimated 30% increase, or an absolute risk increase of 0.5%. This means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged. In addition, 10 healthy women, who would not have been diagnosed if there had not been screening, will be diagnosed as breast cancer patients and will be treated unnecessarily. It is thus not clear whether screening does more good than harm. Women invited to screening should be fully informed of both benefits and harms.

Laser and photoepilation for unwanted hair growth.

BACKGROUND: Unwanted hair growth is a therapeutic challenge and considerable resources are spent to achieve a hair-free appearance. Epilation with laser devices (alexandrite, diode, neodymium:YAG, and ruby lasers) and intense pulsed light are commonly used although the long-term effect is uncertain. OBJECTIVES: To assess the effects of epilation with lasers and light sources. SEARCH STRATEGY: We searched the Cochrane Skin Group's Specialised Register in February 2004; MEDLINE (from 1966) and EMBASE (from 1980) in April 2005. We searched reference lists of collected trials and contacted trial authors. SELECTION CRITERIA: Randomised controlled trials of laser or photoepilation. DATA COLLECTION AND ANALYSIS: Primary outcomes were objective reduction in hair counts, adverse effects and subjective reduction in hairiness. Secondary outcomes were participants satisfaction and personal observations such as softer, finer, or paler hairs. Two authors independently extracted data and assessed trial quality. MAIN RESULTS: We included eleven randomised controlled trials involving 444 people, none of which were of high methodological quality. A large number of trials were excluded, mainly because of their non-randomised design. The randomisation procedures were either unclear or inadequate, using coin tossing, alternation, drawing lots or cards, or open tables of random numbers. The interventions and outcomes were too heterogeneous to be entered in a meta-analysis. Most trials examined a short-term effect up to six months after final treatment. There appeared to be a short-term effect of approximately 50% hair reduction with alexandrite and diode lasers up to six months after treatment, whereas little evidence was obtained for an effect of intense pulsed light, neodymium:YAG or ruby lasers. Long-term hair removal was not documented with any treatment. Pain, skin redness, swelling, burned hairs and pigmentary changes were infrequently reported adverse effects. AUTHORS' CONCLUSIONS: Some treatments lead to temporary short-term hair removal. High quality research is needed on the effect of laser and photoepilation.

Voriconazole versus amphotericin B in cancer patients with neutropenia.

BACKGROUND: Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy are used both empirically and therapeutically in these patients. OBJECTIVES: To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia. SEARCH STRATEGY: MEDLINE and the Cochrane Library (May 2005). Letters, abstracts and unpublished trials were accepted. Contact to authors and industry. SELECTION CRITERIA: Randomised trials comparing voriconazole with amphotericin B or fluconazole. DATA COLLECTION AND ANALYSIS: Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by two authors independently. MAIN RESULTS: Two trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infections) in neutropenic cancer patients (849 patients, 58 deaths). The other trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from analysis by the authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication and substitution with electrolytes and salt water to avoid handicapping this drug. This choice of comparator resulted in a marked difference in the duration of treatment on trial drugs (77 days with voriconazole versus 10 days with amphotericin B), and precludes meaningful comparisons of the benefits and harms of the two drugs. AUTHORS' CONCLUSIONS: Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions.

Somatostatin analogues for acute bleeding oesophageal varices.

BACKGROUND: Somatostatin and its derivatives are often used for emergency treatment of bleeding oesophageal varices in patients with cirrhosis of the liver. OBJECTIVES: To study whether somatostatin or analogues improve survival or reduce the need for blood transfusions in patients with bleeding oesophageal varices. SEARCH STRATEGY: MEDLINE and The Cochrane Library were searched; last search in Febr 2004. Reference lists of articles, contacted authors. SELECTION CRITERIA: All randomised trials comparing somatostatin or analogues with placebo or no treatment in patients suspected of acute or recent bleeding from oesophageal varices. DATA COLLECTION AND ANALYSIS: The effect variables extracted were: mortality, blood transfusions, use of balloon tamponade, initial haemostasis and rebleeding. Intention-to-treat analyses including all randomised patients were conducted; a random effects analysis was preferred if there was significant heterogeneity between the trials (P < 0.10). The trials were divided in two quality groups; the better trials had concealed allocation of patients and were double-blind. MAIN RESULTS: We included 20 trials (2518 patients). The drugs did not reduce mortality significantly (relative risk 0.96, 95% confidence interval 0.74 to 1.24, for the high-quality trials, and 0.79 for low-quality trials). Units of blood transfused were 0.7 (0.3 to 1.2) less with drugs in the high-quality trials and 1.5 (0.9 to 2.0) less in the low-quality trials. Number of patients failing initial haemostasis was reduced, relative risk 0.67 (0.53 to 0.86). Number of patients with rebleeding was not significantly reduced for the high-quality trials, relative risk 0.82 (0.45 to 1.49) while it was substantially reduced in the low-quality trials, relative risk 0.35 (0.18 to 0.67). Use of balloon tamponade was rarely reported. AUTHORS' CONCLUSIONS: The effect corresponded to one half unit of blood saved per patient. It is doubtful whether this effect is worthwhile. The findings do not suggest a need for further placebo-controlled studies of the type reviewed here. A large placebo controlled trial enrolling thousands of patients is needed if one wishes to rule out the possibility that a worthwhile effect on mortality may have been overlooked.

House dust mite control measures for asthma.

BACKGROUND: The major allergen in house dust comes from mites. Chemical, physical and combined methods of reducing mite allergen levels are intended to reduce asthma symptoms in people who are sensitive to house dust mites. OBJECTIVES: To assess the effects of reducing exposure to house dust mite antigens in the homes of people with mite-sensitive asthma. SEARCH STRATEGY: Cochrane Airways Group trials register, and PubMed and The Cochrane Library (last searches June 2004), reference lists. SELECTION CRITERIA: Randomised trials of mite control measures vs placebo or no treatment in asthmatic people known to be sensitive to house dust mites. DATA COLLECTION AND ANALYSIS: Two reviewers applied the trial inclusion criteria, assessed their quality and extracted the data independently. Study authors were contacted to clarify information. MAIN RESULTS: Forty-nine trials (2733 patients) were included; the number of patients has more than doubled since the last version of this review. Thirty-one trials assessed physical methods, ten assessed chemical methods, and eight a combination of chemical and physical methods. Despite the fact that many trials were of poor quality and would be expected to exaggerate the reported effect, we did not find an effect of the interventions. For the most frequently reported outcome, peak flow in the morning (1339 patients), the standardised mean difference was -0.02 (95% confidence interval (CI) -0.13 to 0.08). There were no statistically significant differences either in number of patients improved (relative risk 1.01, 95% CI 0.80 to 1.27), asthma symptom scores (standardised mean difference -0.01, 95% CI -0.10 to 0.13), or in medication usage (standardised mean difference -0.05, 95% CI -0.18 to 0.09). REVIEWERS' CONCLUSIONS: Chemical and physical methods aimed at reducing exposure to house dust mite allergens cannot be recommended. It is doubtful whether further studies, similar to the ones in our meta-analysis, are worthwhile. If other types of studies are considered, they should be methodologically rigorous and use other methods than those used so far, with careful monitoring of mite exposure and relevant clinical outcomes.

Placebo interventions for all clinical conditions.

BACKGROUND: Placebo interventions are often claimed to improve patient-reported and observer-reported outcomes, but this belief is not based on evidence from randomised trials that compare placebo with no treatment. OBJECTIVES: To assess the effect of placebo interventions. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2002), MEDLINE (1966 to 2002), EMBASE (1980 to 2002), Biological Abstracts (1986 to 2002), and PsycLIT (1887 to 2002). We contacted experts on placebo research, and read references in the included trials. SELECTION CRITERIA: We included randomised placebo trials with a no-treatment control group investigating any health problem. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Outcome data were available in 156 out of 182 included trials, investigating 46 clinical conditions. We found no statistically significant pooled effect of placebo in 38 studies with binary outcomes (4284 patients), relative risk 0.95 (95% confidence interval (CI) 0.89 to 1.01). The pooled relative risk for patient-reported outcomes was 0.95 (95% CI 0.88 to 1.03) and for observer-reported outcomes 0.91 (95% CI 0.81 to 1.03). There was heterogeneity (P=0.01) but the funnel plot was symmetrical. There was no statistically significant effect of placebo interventions in the four clinical conditions investigated in three trials or more: pain, nausea, smoking, and depression, but confidence intervals were wide. We found an overall effect of placebo treatments in 118 trials with continuous outcomes (7453 patients), standardised mean difference (SMD) -0.24 (95% CI -0.31 to -0.17). The SMD for patient-reported outcomes was -0.30 (95% CI -0.38 to -0.21), whereas no statistically significant effect was found for observer-reported outcomes, SMD -0.10 (95% CI -0.20 to -0.01). There was heterogeneity (P<0.001) and large variability in funnel plot results even for big trials. There was an apparent effect of placebo interventions on pain (SMD -0.25 (95% CI -0.35 to-0.16)), and phobia (SMD -0.63 (95% CI -1.17 to -0.08)); but also a substantial risk of bias. There was no statistically significant effect of placebo interventions in eight other clinical conditions investigated in three trials or more: nausea, smoking, depression, overweight, asthma, hypertension, insomnia and anxiety, but confidence intervals were wide. REVIEWERS' CONCLUSIONS: There was no evidence that placebo interventions in general have clinically important effects. A possible small effect on continuous patient-reported outcomes, especially pain, could not be clearly distinguished from bias.