Lower Placebo Response Rates Research Articles

Controversies in the Pharmacotherapy of Adolescent Depression.

Although fluoxetine and, in the USA, escitalopram are approved for depression in adolescence, substantial concern surrounds antidepressant use in youth. Major controversies regarding the efficacy and safety (increased suicidality) of antidepressants exist. The category of depression is very broad and overinclusive in terms of etiology, the role of psychosocial adversities severity, episodicity, presentation, and relationship with bipolarity. This heterogeneity, not fully considered in Randomized Controlled Trials (RCTs), may account for the disappointing results with respect to both the efficacy and safety. Based on the available literature, we will address the following topics: a) controversies regarding the definition of depression as a unique homogeneous condition with a unique type of pharmacological treatment; b) controversies about the interpretation of data from Randomized Controlled Trials (RCTs) on the efficacy of pharmacological treatments in adolescent depression; c) the interpretation of data regarding the safety of antidepressant treatment in adolescent depression, particularly in terms of increased suicidal risk. According to RCTs, antidepressants are minimally to moderately more effective than placebo, principally based on very high placebo responses, and only fluoxetine shows more evidence of efficacy. These differences in meta-analyses are sometimes statistically but not clinically significant. Depression is a heterogeneous condition in terms of etiology, the role of psychosocial adversities severity, episodicity, presentation, and relationship with bipolarity. This heterogeneity may partly explain the low drug-placebo difference and the high placebo response (possibly related to a high level of natural recovery of adolescent depression). In the National Institute of Mental Health (NIMH)-funded studies, including a lower number of study sites and more reliable enrollment procedures, lower placebo response rates and greater group differences between medication and placebo were found. Robust evidence supports an increased risk of emergent suicidality after starting antidepressants. A clear age effect on suicidal risk after antidepressants is supported by a comprehensive meta-analysis, showing that suicidal risk increases with decreasing age, being markedly greater in subjects aged between 18 and 25 years. However, the term suicidality is too broad, as it includes suicidal ideation, suicidal attempts, and completed suicide, with a wide range of severity and pervasiveness. If emergent suicidality should be actively and carefully explored, empirical evidence, albeit weak, suggests that combined pharmacotherapy (antidepressant and/or lithium) associated with psychotherapy may be helpful in reducing pretreatment suicidal ideation and suicidal risk. Moderate to severe depression should be treated with psychotherapy and/or fluoxetine, the bestsupported medication, and treatment-resistant adolescents should always receive combined treatment with psychotherapy. Suicidal ideation, particularly with a plan, should be actively explored before starting an antidepressant, as a reason for the closest monitoring. Emergent suicidality after starting antidepressants, as well as antidepressant-related activation, should also be closely monitored and may lead to antidepressant discontinuation. Although no response to pharmacotherapy and psychotherapy may occur in up to 40% of depressed adolescents, possible predictors or mediators of poorer response in adolescents are uncertain, and only a few studies support possible treatment strategies. Finally, studies exploring the efficacy of antidepressants in specific depression subtypes, i.e., based on prevalent psychopathological dimensions (apathy, withdrawal, impulsivity), are warranted.

Age Effects on Placebo Response Rates in Clinical Trials of Acute Agents for Migraine: Pooled Analysis of Rizatriptan Trials in Adults

This study examined the effect of age on placebo response rates in rizatriptan trials in adults. Data from eight rizatriptan adult trials involving patients treating moderate/severe migraine attacks with rizatriptan 5 mg (N = 1819), rizatriptan 10 mg (N = 2046) or placebo (N = 1322) were pooled for post hoc analysis. Logistic regression was used to model 2-h pain relief (reduction to mild or none) and 2-h pain freedom rates by treatment groups. Older patients had lower placebo response rates than younger patients; the estimated odds ratio (older vs. younger) for a 10-year age increase was 0.83 for pain relief [95% confidence interval (CI) 0.75, 0.93] and 0.81 for pain freedom (95% CI 0.68, 0.97). The response proportion vs. age trend was flat for rizatriptan 5 mg and slightly increased for rizatriptan 10 mg. The treatment-by-age interaction was significant for pain relief (P < 0.001) and pain freedom (P = 0.001), suggesting an increasing trend of treatment advantage of rizatriptan over placebo as age increased. Age appeared to be an important predictor of placebo response rate in rizatriptan trials, with older patients being less likely to respond to placebo and more likely to respond to rizatriptan.

Depressive Kernsymptome

Core symptoms of depression are a combination of psychological and somatic symptoms, often associated with psychomotor and cognitive disturbances. The diagnostic classifications of depression include the concepts of melancholic, endogenous, or severe depression. All subgroups describe severely depressed patients suffering from most of the core symptoms of depression. In addition these patients exhibit the clinical characteristics of a recurrent unipolar or bipolar course, lower placebo response rates, or higher response rates to ECT, to antidepressant treatments with dually or mixed modes of action, or to lithium augmentation. Higher rates of HPA axis hyperactivity and specific EEG patterns may also occur in this patient group. This suggests a broad overlap of patient subgroups within the diagnostic classification of depression. Because the positive diagnosis of the core symptoms of depression may include clinical consequences, it would be useful to integrate all these concepts into the upcoming new versions of the diagnostic systems DSM-V and ICD-11.

Effects of different antidepressant treatments on the core of depression

Core symptoms of depression are a combination of psychological and somatic symptoms, often combined with psychomotor and cognitive disturbances. Diagnostic classification of depression including the concepts of melancholic, endogenous, or severe depression describe severely depressed patients suffering from most of the core symptoms, together with clinical characteristics of a cyclic unipolar or bipolar course, lower placebo response rates, higher response rates to electroconvulsive therapy, to antidepressant treatments with dually or mixed modes of action, or to lithium augmentation. Higher rates of hypothalamic-pituitary-adrenal axis hyperactivity and specific electroencephalographic patterns have also been shown in this patient group. Summarizing the symptomatology of depression in these patients, a broad overlap between the abovementioned subgroups can be suggested. Because the positive diagnosis of those core symptoms of depression may include clinical consequences, it would be of use to integrate all the mentioned concepts in the upcoming new versions of the diagnostic systems DSM-V and ICD-11.

Flying Almost Blind

Flying Almost Blind

Predictors of the placebo response in functional dyspepsia

Trials in functional dyspepsia report placebo response rates of 30% to 40%. We aimed to identify predictors of the placebo response. Patients from primary, secondary and tertiary practices with functional dyspepsia defined by Rome II criteria were enrolled into one of four clinical trials; 220 patients were randomized to receive placebo. Scintigraphic assessment of gastric emptying at baseline was repeated at the end of the treatment in those with delayed emptying. After a 2 week run-in period, patients were followed for 8 weeks on placebo. Response was assessed on a weekly basis and a responder was defined as satisfactory relief of meal-related symptoms on at least 50% of weeks. The mean age was 44 years (range 18-82) and 74% were female; 76 (35%) were placebo responders. The predominant symptom was an unstable measure over the trial. Independent predictors of a lower placebo response were lower body mass index and a more consistent predominant symptom pattern (both P < 0.05). No association was seen with age, gender, centre type, baseline symptom score, baseline or change in gastric emptying, or baseline quality of life. In functional dyspepsia, a consistent predominant symptom pattern and lower body mass index may be associated with a lower placebo response rate.

This Month in Gastroenterology

This Month in Gastroenterology

The placebo effect in irritable bowel syndrome trials: a meta‐analysis1

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. 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. 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. 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). 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.