In the current study, there was a significant interaction between predictors of the response to placebo and the study intervention. Anxiety at study entry and overall menopausal symptoms at study entry (GCS scores) differed significantly between the two arms as predictors of the response on all three endpoints of flushing, overall menopausal symptoms and depression. Attitude to menopause differed significantly in its predictive ability between the two groups for the response on GCS scores. In terms of the individual arms, there were distinct differences in predictors of outcome observed between the placebo and active groups. Anxiety at study entry predicted placebo response for all the endpoints. In contrast, for flushing and depression in the treatment arm, study entry anxiety significantly predicted a lack of response to treatment, and had no effect on the Greene Climacteric scale scores. None of the other variables that predicted the placebo response was relevant to the treatment response. Improvement during non-treatment run-in predicted subsequent improvement during the treatment phase on GCS and HDI-17 depression scores for the placebo arm. This trend was not mirrored in the active treatment arm. For depression scores, older age at study entry predicted placebo response, as did prior positive experience with phytotherapy. However neither of these variables significantly impacted on outcomes in the active treatment arm. For the Greene Climacteric scale, baseline severity of symptoms was positively correlated with percentage improvement across the treatment phase in the placebo group, but not in the active treatment group.
Previous researchers of a range of other conditions have compared predictors of the responses in placebo and active arms within the same study where effects between the two arms differed [24
]. Severity of symptoms at baseline has been found to differentially predict the placebo and treatment responses, with more severe depression being less responsive to placebo but more responsive to the pharmacological intervention [28
]. Another study on acute bipolar manic episodes found symptom severity, age, number of previous hospitalisations to similarly predict the responses in both arms [25
]. With regard to change in symptom severity during run-in, significant worsening of symptoms was associated with subsequent placebo response, but not "drug response" in an analysis of data from a functional dyspepsia study [29
]. This contrasts with observations from the current study that improvement
during run-in predicted subsequent response to placebo, but not to active treatment. However, to our knowledge, no previous studies have examined data from a RCT where superiority of 'active' treatment over placebo was not established to test the hypothesis that the predictors would be similar in the two arms.
In this study where efficacy of active and placebo were equivalent, the implications of the finding that the predictors of placebo response did not predict the treatment response are intriguing. As mentioned above, it has previously been suggested that the assumption of additivity of effects that underlies the practice of using placebos may not be a logical necessity [1
]. It is possible that psychological mechanisms may operate in the placebo arm only in the absence of pharmacological effects, whereas effective interventions activate pharmacological mechanisms to the exclusion of psychological mechanisms [5
]. Although it is generally accepted that there is a placebo component in the response to the active treatment when participants are blinded, the hypothesis of non-additivity implies that the pharmacological effects of an active intervention could override the psychologically-activated placebo component completely or partially. Essentially, the trial participants would experience either placebo or physiological intervention effects, but not both. If shown to be correct, this would invalidate the assumption that intervention effects are additive to placebo effects.
To our knowledge, no evidence exists from neurobiological studies of differential mechanisms operating in relation to menopausal symptoms, although there is some support for this phenomenon in relation to depression [6
]. As depression, measured on the Hamilton Depression Inventory and the Greene Climacteric subscale, was one of endpoints of the current study, different mechanisms operating in the two arms in the current study cannot entirely be ruled out.
It is interesting to note that higher anxiety at study entry was a significant predictor of the placebo response, but predicted lack
of response to active treatment. This supports the proposition that psychological factors are relevant to the placebo response, at least as moderators, if not mediators. The observation that improvement during non-treatment run-in predicted placebo
response on two of the three endpoints, but did not predict treatment
response, is consistent with the proposal that placebo-induced mechanisms, such as the release of endogenous opioids, may be activated in the anticipatory phase of the placebo response [15
] and hence during therapist-patient or investigator-participant interaction [9
]. The variance in the predictors of placebo and active response observed in the current study is consistent with the hypothesis that different underlying mechanisms may be operating in placebo and treatment arms.
Strengths of the study include the investigation of study entry scores (2 weeks prior to commencement of run-in), in preference to baseline scores, as potential predictors of the placebo response. The effect on psychological mechanisms of enrollment in a clinical trial would be expected to occur from the point of study entry, with the initiation of investigator-participant interaction and other context effects, rather than from initiation of the intervention [9
]. However, because pharmacological effects of the intervention would only be observable from the point of administration of the intervention (see Figure ), baseline
scores were controlled for in the analysis.
A limitation in the interpretation of these findings is that there is no evidence, to our knowledge, supporting this phytotherapeutic combination as an effective treatment for menopausal symptoms. Therefore, a known pharmacological effect for this intervention in the treatment of menopausal symptoms has never been established. This study was a post hoc analysis of data from an RCT and as such, was not designed to explore neurobiological mechanisms. Thus, no definite conclusions can be drawn regarding any different mechanisms of action. Other possible limitations include the relatively small sample size, the use of exclusively subjective outcome measures, and the single scale of measurement for improvement during non-treatment run-in.