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PubMed2003

A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.

BACKGROUND: Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. METHODS: After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. RESULTS: Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (lamotrigine vs placebo, P =.02; lithium vs placebo, P =.006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode (P =.02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode (P =.006). The most common adverse event reported for lamotrigine was headache. CONCLUSIONS: Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.

Adult↗
PubMed2004

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.

Humans↗
PubMed1995

An empirical evaluation of the placebo run-in.

A prerandomization placebo run-in period is often used in an attempt to exclude potential clinical trial participants who are likely to be poor adheres. It is assumed that potential participants who are poor adherers during the run-in will be less likely to take medication during the trial. This assumption was tested in the Cholesterol Reduction in Seniors Program (CRISP), by prescribing placebo for a 3-week period, but not using the results of the run-in as an entry criterion. The CRISP study was a pilot study designed to compare the effects on lipids and the safety of two doses of lovastatin and placebo in persons 65 years of age and older. After general entry criteria were satisfied, each participant was prescribed placebo for a 3-week period. At the end of the 3-week period, all participants were randomized to one of the three treatment groups, regardless of their adherence to the placebo. Of the 431 participants in the study, 66 (15%) who took less than 80% of the prescribed placebo or who failed to return their unused placebo pills were classified as poor run-in adherers. Poor run-in adherence was associated with lower educational attainment. At 3 and 6 months of follow-up mean adherence was 89.3% and 83.4% among all participants. Exclusion of poor run-in adherers would have increased these means to 90.9% and 85.5%, respectively. Treatment effect as measured by fall in LDL cholesterol would have increased by 2.9 mg/dl in the 40 mg/day dose group at 3 months of follow-up with the addition of a placebo run-in. We conclude that a placebo run-in would have had little effect on the outcome of the CRISP study and would have substantially increased recruitment difficulties. Lower educated persons were more likely to be excluded by a placebo run-in, but the effect of the run-in on follow-up adherence was stronger in less educated participants. More research about the role of a placebo run-in is needed in order to determine the appropriate role of this method in clinical trials.

Aged↗
PubMed1996

The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia.

Discovery of the involvement of endogenous opiates in placebo analgesia represents an important step in understanding the mechanisms underlying placebo response. In the present study, we investigated the effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia in a human model of experimentally induced ischemic pain. First, we found that part of the placebo response was reversed by naloxone, confirming previous studies on the role of opioids in the placebo phenomenon. Second, since it was demonstrated that the action of exogenous and endogenous opiates is potentiated by proglumide, we analysed the effects of this cholecystokinin antagonist on placebo response and found that it enhanced placebo analgesia. The placebo effect can thus be modulated in two opposite directions: it can be partially abolished by naloxone and potentiated by proglumide. The fact that placebo potentiation by proglumide occurred only in placebo responders, but not in non-responders, suggests that activation of an endogenous opiate system is a necessary condition for the action of proglumide. These results suggest an inhibitory role for cholecystokinin in placebo response, although the low affinity of proglumide for cholecystokinin receptors does not rule out the possibility of other mechanisms.

Adult↗
PubMed1997

The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin.

Placebo is a widespread phenomenon in medicine and biology and its mechanisms are understood only partially. Most of our understanding of placebo comes from studies on pain. In particular, placebo analgesia represents a situation where the administration of a substance known to be non-analgesic produces an analgesic response when the subject is told that it is a pain killer. Several theories try to explain this effect by means of anxiety mechanisms, cognitive processes and classical conditioning. However, the placebo response is bidirectional, i.e. analgesic and algesic. In fact, if a subject is told that the ineffective substance is a hyperalgesic drug, a pain increase may occur. The negative effects of placebo are called nocebo and, in extreme cases, they lead to severe pathological conditions. The neurobiology of placebo was born when some authors discovered that placebo analgesia is mediated by endogenous opioids. This claim comes from the observation that the opioid antagonist naloxone can reverse placebo analgesia. On the basis of the discovery of the anti-opioid action of the neuropeptide cholecystokinin, recent studies demonstrate that the blockade of cholecystokinin receptors potentiates the placebo analgesic response, thus suggesting an inhibitory role of cholecystokinin in placebo analgesia. Thus, by antagonizing the anti-opioid action of cholecystokinin during a placebo procedure, a potentiation of the endogenous opioid systems can be obtained.

Analgesia↗
PubMedDate not supplied

Oral sildenafil in the treatment of erectile dysfunction in diabetic men: a randomized double-blind and placebo-controlled study.

PURPOSE: To determine the efficacy and safety of oral sildenafil citrate in the treatment of erectile dysfunction (ED) in diabetic men. MATERIALS AND METHODS: In a randomized, double-blind, placebo-controlled, and fixed-dose study, a total of 282 men (mean age, 46.4 years) with ED (mean duration, 3.6 years) and diabetes (mean duration, 11 years) were randomly assigned to receive 100 mg sildenafil (n=144) or placebo (n=138) approximately 1 h before planned sexual activity, but not more than once daily, for 16 weeks. The efficacy of two treatments was assessed using responses to the International Index of Erectile Function (IIEF) questionnaire. RESULTS: Two hundred sixty-two (93%) of men completed the study (134/144 in the sildenafil group, 128/138 in the placebo group). Positive clinical results were obtained in 68 (51%) of 134 patients in the sildenafil group compared with 14 (11%) of 128 patients in the placebo group (P<.003). Fifty-nine percent of the patients reported at least one successful attempt at sexual intercourse in the sildenafil group as compared with 21% successful attempts for the placebo group (P<.002). Drug-related adverse effects occurred in 32 (22%) of 144 patients taking sildenafil and 4 (3%) of 138 patients receiving placebo. The most common adverse events were headache (20% sildenafil, 2% placebo), flushing (19% sildenafil, 0% placebo), dyspnea (9% sildenafil, 2% placebo), rhinitis (6% sildenafil, 0% placebo), and cardiovascular effects (7% sildenafil, 0% placebo). Of patients taking sildenafil, four (2.7%) developed new chest pains, with documented myocardial infarction in two. CONCLUSION: Oral sildenafil is a moderately effective treatment for ED in men with diabetes. The response rate was lower and cardiovascular events were higher than previously reported in nondiabetic patients.

Adult↗
PubMed1997

Quantification of the placebo response in ulcerative colitis.

BACKGROUND & AIMS: There is consistently a measurable benefit noted among placebo users in treatment trials of ulcerative colitis (UC). The aim of this study was to define the placebo response in active UC and identify study features that influence the placebo response. METHODS: MEDLINE database was searched for placebo-controlled treatment studies of active UC. Data extraction was performed by two reviewers, and one separate investigator reviewed all trials and data extraction before data tabulation. Placebo remission and benefit rates were determined for clinical, endoscopic, and histological outcomes. Synthesis analysis on the weighted proportions from the different studies explored the placebo response as it related to eight study variables. RESULTS: Thirty-eight of 44 studies identified were included in the analysis. The clinical remission rate was 9.1% (confidence interval [CI], 6.6-11.6) and the benefit rate was 26.7% (CI, 24.1-29.2). Similar rates were observed endoscopically and histologically. The number of study visits (< or =3 vs. >3) modified placebo response as assessed by clinical benefit (P = 0.05), endoscopic remission (P = 0.02), and histological remission (P = 0.04). Other study variables were not significant placebo response modifiers. CONCLUSIONS: In trials of active UC, the placebo remission rate is approximately 10% and the placebo benefit rate is approximately 30%. These rates are consistent regardless of assessment end point. The placebo response is greater in trials with more frequent study visits (more than three).

Colitis, Ulcerative↗
PubMed2005

A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease.

BACKGROUND & AIMS: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab' fragment of anti-tumor necrosis factor, CDP870) in Crohn's disease. METHODS: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of > or = 100 points or remission [Crohn's Disease Activity Index < or = 150 points]) in the intent-to-treat population. RESULTS: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. CONCLUSIONS: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.

Adult↗
PubMed1979

Role of pain in placebo analgesia.

The hypothesis that perceived pain intensity can influence placebo analgesia was tested. One hundred and seven subjects rated their pain from from 0 to 10 on a visual analog scale after a standard wisdom tooth extraction. The expected course of such postoperative pain in the absence of therapy or placebo is a steady increase; this was confirmed by blind administration of the placebo. When placebos were given intravenously in view of the patients, some (placebo nonresponders) reported that their pain increased, whereas others (placebo responders) reported that their pain either decreased or remained the same over the next 60 min. A placebo response was more likely to occur if the pain rating 5 min prior to placebo administration (initial pain) was greater than 2.6. Furthermore, placebo responders with initial pain above this 2.6 level reported significantly greater mean analgesia than those with lower initial pain. Indeed, responders with initial pain less than 2.6 reported no change in pain during the 60 min after administration of a placebo. When their initial pain level was greater than 2.6, they reported a steady decline in pain over this period. However, above the 2.6 level there was no obvious relationship between the magnitude of the placebo analgesia and the initial pain.

Analgesia↗
PubMed2000

The long-term effects of non-steroidal anti-inflammatory drugs in osteoarthritis of the knee: a randomized placebo-controlled trial.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat osteoarthritis (OA), though their long-term efficacy is uncertain. We report a comparison of the symptomatic responses to therapy with tiaprofenic acid, indomethacin and placebo over 5 yr. METHODS: A parallel-group, randomized, single-blind trial of patients with knee OA recruited 812 patients from 20 centres; 307 patients received tiaprofenic acid (300 mg b.d.), 202 indomethacin (25 mg t.d.s.) and 303 matching placebo for up to 5 yr. At the end of the parallel-group study, patients receiving tiaprofenic acid or placebo entered a 4-week blinded cross-over study of tiaprofenic acid or placebo, both given for 2 weeks. Assessments were at baseline, 4 weeks, then at 6-month intervals for up to 5 yr in the parallel group study and at 2-week intervals in the cross-over study. They comprised pain scores, duration of morning stiffness, patients' global assessments, paracetamol consumption, adverse reactions, withdrawals and functional outcomes. RESULTS: There were significant falls in overall pain scores in patients receiving NSAIDs compared with placebo at 4 weeks in the parallel-group phase. Thereafter there were no advantages favouring active therapy. In the cross-over phase, pain scores were significantly lower in patients receiving tiaprofenic acid than placebo. Patients who had been receiving long-term tiaprofenic acid showed significant rises in their pain scores when receiving placebo therapy and vice versa. Adverse events were reported by 61% of patients receiving tiaprofenic acid, 63% on indomethacin and 51% on placebo. Potentially severe side-effects were rare; for example, there were only three cases of gastrointestinal bleeding on NSAIDs. The pattern of withdrawal was similar in patients taking NSAIDs and placebo in the parallel-group study; at 48 weeks 53% of the patients remained on tiaprofenic acid, 50% on indomethacin and 54% on placebo. CONCLUSIONS: NSAIDs significantly reduce overall pain over 4 weeks. This short-term responsiveness is retained, and even after several years of therapy with tiaprofenic acid pain scores increased over 2 weeks when it was changed to placebo. Our results do not show long-term benefits from the use of NSAIDs in OA and the majority of patients had persisting pain and disability despite therapy.

Adult↗
PubMed2005

Understanding of placebo controls among older people with schizophrenia.

Research protocols frequently necessitate procedures or design elements that differ from those used in routine clinical care. An example is the inclusion of a placebo arm in many randomized clinical trials. Because there are risks to taking a placebo when one has a chronic disorder such as schizophrenia, ascertaining how well people with severe mental illness understand placebos is an important task for empirical research ethics. We investigated whether schizophrenia patients' understanding of placebo controls could be improved with a brief educational intervention. We randomized 49 middle-aged and older patients with schizophrenia or schizoaffective disorder to receive either (1) a routine explanation of placebos in the context of consent for a hypothetical double-blind placebo-controlled clinical trial, or (2) the consent for the hypothetical trial plus a brief educational module explaining placebos in more depth. Understanding of placebos was assessed with a 12-item questionnaire, and we examined demographic, clinical, neurocognitive, and decision-making correlates of understanding of placebos. Those participants who received the intervention obtained higher scores on the placebo post-test compared to those who received the standard information alone. Performance on the placebo post-test was positively correlated with measures of decisional capacity and neurocognitive abilities and negatively correlated with severity of negative symptoms, but it showed no relationship with positive or general symptoms. Some participants interpreted the common phrase "sugar pill" as relating somehow to diabetes. We conclude that the level of understanding of important research design-related information is not static but may be influenced by how investigators approach the consent process.

Aged↗
PubMedDate not supplied

The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta-analysis.

OBJECTIVE: The placebo response is conventionally asserted to be high in chronic fatigue syndrome (CFS) because of the latter's subjective nature and obscure pathogenesis, but no systematic review of placebo responses has been undertaken. We report such a study. Patient expectation is known to be important in the placebo response. It is also known that CFS patients attending specialist clinics often have strong physical attributions regarding causation and hence skepticism about psychological or psychiatric interventions. If so, the placebo response in CFS may be influenced by the type of intervention according to its perceived rationale. We aimed to estimate the summary placebo response in clinical trials of CFS and to determine whether intervention type influences the placebo response in CFS. METHODS: We searched Medline, Embase, Cochrane Library, PsychInfo, and the references of the identified articles, and contacted experts for controlled trials (randomized or nonrandomized) of any intervention on CFS patients reporting the placebo response as a clinical improvement in physical or general outcomes. Data were extracted from the articles and validity assessment conducted by one reviewer and checked by a second. Meta-analysis and metaregression were performed. RESULTS: The pooled placebo response was 19.6% (95% confidence interval, 15.4-23.7), lower than predicted and lower than in some other medical conditions. The meta-regression revealed that intervention type significantly contributed to the heterogeneity of placebo response (p = .03). CONCLUSION: In contrast with the conventional wisdom, the placebo response in CFS is low. Psychological-psychiatric interventions were shown to have a lower placebo response, perhaps linked to patient expectations.

Adult↗
PubMed2005

The placebo effect in irritable bowel syndrome trials: a meta-analysis.

BACKGROUND: Despite the apparent high placebo response rate in randomized placebo-controlled trials (RCT) of patients with irritable bowel syndrome (IBS), little is known about the variability and predictors of this response. OBJECTIVES: To describe the magnitude of response in placebo arms of IBS clinical trials and to identify which factors predict the variability of the placebo response. METHODS: We performed a meta-analysis of published, English language, RCT with 20 or more IBS patients who were treated for at least 2 weeks. This analysis is limited to studies that assessed global response (improvement in overall symptoms). The variables considered as potential placebo modifiers were study design, study duration, use of a run-in phase, Jadad score, entry criteria, number of office visits, number of office visits/study duration, use of diagnostic testing, gender, age and type of medication studied. FINDINGS: Forty-five placebo-controlled RCTs met the inclusion criteria. The placebo response ranged from 16.0 to 71.4% with a population-weighted average of 40.2%, 95% CI (35.9-44.4). Significant associations with lower placebo response rates were fulfillment of the Rome criteria for study entry (P=0.049) and an increased number of office visits (P=0.026). CONCLUSIONS: Placebo effects in IBS clinical trials measuring a global outcome are highly variable. Entry criteria and number of office visits are significant predictors of the placebo response. More stringent entry criteria and an increased number of office visits appear to independently decrease the placebo response.

Clinical Trials as Topic↗
PubMed1999

Placebo in functional dyspepsia: symptomatic, gastrointestinal motor, and gastric sensorial responses.

OBJECTIVE: Therapeutic trials in functional dyspepsia consistently show a substantial placebo response, but there is no clear explanation for such an effect. Our aim was to evaluate symptomatic, gastrointestinal motor, and gastric sensorial responses to placebo treatment in patients with chronic and severe functional dyspepsia who were part of a therapeutic trial. METHODS: Thirty patients were treated during 8 wk with placebo (white-colored 8-mm tablets containing cellulose) by mouth, 20 min before breakfast, lunch, and dinner. We quantified the symptomatic response to placebo as a change in global health status, and also as a change in the individual and combined (global symptom index) of a five-symptom complex: upper abdominal pain, nausea, vomiting, bloating/fullness, and early satiety. Gastroduodenal motility, during fasting and postprandially, was evaluated by manometry in all patients pretreatment and in 17 patients posttreatment. Gastric sensitivity to distension was evaluated in 18 patients pretreatment and in five patients posttreatment (all of them clinical responders). RESULTS: Placebo treatment produced a striking symptomatic improvement; by 8 wk 80% of the patients reported an improved global health status and their global symptom index markedly decreased (23.9+/-1.3 pretreatment vs 9.1+/-1.2; p < 0.05). Placebo increased the number of gastric phases III starting in the antrum during the fasting period (1.1+/-0.1 vs 1.6+/-0.2; p < 0.05). As a group, no significant changes in postprandial gastroduodenal motility were observed after placebo treatment. However, after placebo a significant improvement in the antral motility index (MI) was observed in the subset of patients with antral hypomotility (MI pretreatment: 7.9+/-1.0; MI posttreatment: 11.7+/-0.4; p < 0.05). Before placebo treatment, patients with functional dyspepsia showed increased sensitivity to stepwise distension of the stomach relative to healthy individuals. After 8 wk of placebo treatment sensitivity to distension remained unchanged, even though patients' clinical status was markedly improved. CONCLUSION: In patients with functional dyspepsia, the symptomatic response to placebo is substantial. Some significant changes were also observed in gastric motility: increase in the gastric phase III number as well as in the postprandial antral motility index in those with hypomotility pretreatment. Remarkably, however, clinical improvement seems to occur independently of detectable changes in gastroduodenal motor activity or gastric hypersensitivity to distension.

Adolescent↗
PubMed2005

The use of placebo in clinical trials on bipolar disorder: a new approach for an old debate.

BACKGROUND: Placebo response is high in bipolar disorder trials. This is a challenge for researchers and an enigma for clinicians. This article will attempt to aid in the comprehension of the ethical questions and methodologies related to the use of placebo in bipolar disorder. METHODS: A systematic review of the main computerized data bases (Medline, Embase, Psychlit, Current Contents) was carried out, using the following key words: placebo, bipolar disorder, mania, depression, clinical trial. RESULTS: Placebo has a very important role in the study of bipolar disorders. From a methodological point of view, and given the limitations of non-inferiority designs, the use of placebo is necessary to evaluate the sensitivity of the study and ensure that the drug under investigation is really effective. For this reason, several procedures may be used to satisfactorily solve the ethical objections. Placebo response in bipolar disorder trials is more likely to occur in patients who are mildly ill, bipolar II, mixed-episode, first-episode, rapid cycling, atypical, non-psychotic, substance abusers and medically ill. The use of concomitant medication such as benzodiazepines, a high frequency of visits, a high number of treatment groups and sites, fixed-dose designs, and the concomitant use of psychotherapy are likely to increase placebo response. CONCLUSION: The subject of the use of placebo in psychiatric clinical trials leads to very relevant ethical, methodological and clinical dilemmas. Many reasons support the use of placebo in acute bipolar studies, whereas in maintenance the length of the treatment with placebo makes the decision more difficult. Ethical concerns can be addressed through operational definitions of outcome measures, add-on and discontinuation designs, early escape strategies, and processes designed to make sure that fully informed consent was fairly obtained. There are a number of clinical and methodological variables that are associated with placebo response.

Attitude↗
PubMed1992

Placebo treatment in congestive heart failure.

In order to evaluate the effect of placebo treatment in congestive heart failure, we retrospectively studied 24 patients with moderately severe congestive heart failure who participated in heart failure treatment trials performed over the past 10 years in the Ohio State University Heart Failure Research Laboratory. Placebo-treated patients from 4 placebo-controlled trials comprised the placebo treatment group (n = 15), while one natural course-controlled trial provided patients for the non-placebo control group (n = 9). Changes in symptoms, left ventricular function and exercise duration were assessed following an 8-week course of therapy. Chronic placebo therapy resulted in an 81-second improvement in exercise duration which was statistically significant when compared to pretreatment baseline and to the duration achieved by the nonplacebo control group. Clinically, functional class improved significantly by 27% above baseline only for the placebo treatment group. Indices of left ventricular function did not change for either group. The salient feature of this study is that the placebo treatment effect, while believed to exist in congestive heart failure, has never been demonstrated in a manner which controlled for the natural course and variability of the disease process. The operative components of the placebo effect remain unknown, and further investigation will be necessary to elucidate the underlying mechanisms involved. However, the importance of this phenomenon lies not only with the response to and effects of placebo therapy but also in the role that the placebo effect plays in what is generally presumed to be the predominant responses, effects and benefits of active drug therapy.

Adult↗
PubMed2002

Changes in brain function of depressed subjects during treatment with placebo.

OBJECTIVE: It has been proposed that 50%-75% of the efficacy of antidepressant medication represents the placebo effect, since many depressed patients improve when treated with either medication or placebo. This study examined brain function in depressed subjects receiving either active medication or placebo and sought to determine whether quantitative electroencephalography (QEEG) could detect differences in brain function between medication and placebo responders. Both QEEG power and cordance, a new measure that reflects cerebral perfusion and is sensitive to the effect of antidepressant medication, were examined. METHOD: Fifty-one subjects with major depression were enrolled in one of two independent, 9-week double-blind, placebo-controlled studies in which either fluoxetine (N=24) or venlafaxine (N=27) was the active medication. Serial QEEG recordings were performed during the course of treatment. After 9 weeks, the blind was broken and subjects were classified as medication responders, placebo responders, medication nonresponders, or placebo nonresponders. RESULTS: No significant pretreatment differences in clinical or QEEG measures were found among the four outcome groups. Placebo responders, however, showed a significant increase in prefrontal cordance starting early in treatment that was not seen in medication responders (who showed decreased cordance) or in medication nonresponders or placebo nonresponders (who showed no significant change). There was no significant change in QEEG power during treatment. CONCLUSIONS: These findings suggest that "effective" placebo treatment induces changes in brain function that are distinct from those associated with antidepressant medication. If these results are confirmed, cordance may be useful for differentiating between medication and placebo responders.

Adult↗
PubMed2003

Meta-analysis of placebo rates in major depressive disorder trials.

BACKGROUND: Placebo effects in major depressive disorder (MDD) have received much interest in the medical literature. However, few quantitative analyses have been done in homogeneous populations. OBJECTIVE: To determine efficacy rates for placebo in patients with MDD; to quantify the correlation between efficacy and publication year, as well as between placebo and drug response rates. DESIGN: Searching MEDLINE (1966-December 2000), EMBASE (1998-February 2001), HealthSTAR (1975-December 2000), and Cochrane (1980-December 2000) databases, randomized, placebo-controlled trials were retrieved including patients with MDD as defined by Diagnostic and Statistical Manual of Mental Disorders, 3rd and 4th editions criteria, Hamilton Rating Scale for Depression score >/=18 or Montgomery-Asberg Depression Rating Scale score >/=16, reporting successes as 50% decreases in scores after 6-8 weeks of treatment. Response rates were summarized using a random effects meta-analysis for per protocol (PP) and intent-to-treat (ITT) results. RESULTS: We included 24 of 134 potential studies examining 4459 patients, 1786 on placebo and 2673 on an antidepressant. Placebo response rates were 45.5% (PP) and 26.9% (ITT). Correlations were significant between year and rates (PP rho 0.448, p = 0.042; ITT rho 0.557; p = 0.006), but not for active drugs. Placebo and drug rates were correlated (PP r 0.397, p = 0.020; ITT r 0.539; p = 0.002). CONCLUSIONS: These placebo rates confirm those reported previously, but were from a homogeneous population. Although statistically significant, the correlation between drug and placebo rates was lower than others reported. During the study period, placebo rates increased linearly; active drugs did not. Correlations between placebo and drug response rates reflected moderate to strong effect sizes. We suggest that current methodology has been unsuccessful in achieving unbiased double-blind conditions not influenced by extra-trial factors, including time.

Antidepressive Agents↗