Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials

BACKGROUND: The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. METHOD: This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. RESULTS: TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. DISCUSSION: In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. CONCLUSIONS: The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

Rapidly cured out-of-autoclave laminates: understanding and controlling the effect of voids on laminate fracture toughness

Voids are one of the most significant defects found within composites and have been demonstrated to reduce the performance of composite structures. The understanding of the impact of the size and distribution of voids on laminate properties is still limited because voids have proven difficult to deliberately control. This study aims to understand the mechanisms by which voids are generated within out-of-autoclave cured laminates. In this study, a process of prepreg conditioning was developed to control the level of voids within test laminates. Non-conditioned laminates highlighted signs of void growth (1.5%), while conditioned laminates showed consistently low levels of voids (<0.3%). Mass spectrometry indicated higher levels of aqueous and solvent volatiles within the non-conditioned prepreg. Finally, Mode II fracture testing revealed a 21% improvement in toughness for the non-voided laminates. A model on the effect of voids within the Mode II stress state has also been proposed.