The observed treatment effect, i.e. the change from baseline till endpoint, is traditionally thought to be due to four factors: regression towards the mean, natural course of disease, placebo effect i.e. non-specific effects of the therapist and the setting in which therapy takes place, and specific effects of physical or psychological intervention on the target condition 1.

When a specific therapy for a certain disorder exists, we therefore assume that it realizes all these four components through its administration. Cognitive-behavior therapy (CBT) for panic disorder is one such instance, because it has demonstrated its superiority in the rigorously internally calibrated, drug-sensitive 2 group of patients vis-à-vis the pill placebo arm 3 and also against a non-specific psychological intervention 4.

Whether adding pill-placebo to specific psychotherapy enhances its effectiveness is an empirically and theoretically interesting question 5. Some may assume that a specifically effective treatment has already realized all the above-mentioned four components of treatment effect and therefore addition of a pill placebo cannot enhance its effect. On the other hand, some may suspect that addition of pill placebo may subtract from psychological treatment because it may undermine the active commitment of the patient to follow psychological interventions. Or, some may argue that psychotherapy placebo and pharmacotherapy placebo work through different psychological mechanisms and can therefore be additive or synergistic.

While conducting a comprehensive systematic review of randomized controlled trials (RCT) of the combined psychological and drug treatment for panic disorder 67, we had a unique opportunity to compare the psychotherapy alone versus the psychotherapy plus pill placebo arms and would like to repot the results.

The present report represents the first systematic empirical examination of the effect of adding pill placebo to psychotherapy. It found that, for panic disorder with or without agoraphobia, pill placebo may enhance CBT during the acute phase treatment. There was no difference in treatment acceptability between these two treatment arms. The difference in effectiveness, however, seemed to wane in 6–24 months after end of the acute phase treatment.

Twenty-five years ago, Hollon and DeRubeis argued that placebo-psychotherapy combination cannot represent psychotherapy in drug-psychotherapy comparative trials but could not determine from the literature review then whether the former would overestimate or underestimate the latter 5. The current study has assembled newer data and suggests that placebo-psychotherapy combination overestimates the latter and that therefore Hollon and DeRubeis's concerns proved justified.

The fact that pill placebo can add to psychotherapy is intriguing. Theoretical implications of the present findings may be two. Firstly, in contrast to some old claims 16, taking a pill placebo did not undermine the effectiveness of psychological intervention. Secondly, much to the contrary, pill placebo enhanced the effectiveness of CBT. The act of taking an inactive drug can enhance the placebo effect already contained in the effective psychotherapeutic intervention. This is a strong argument against the recently claimed null hypothesis of placebo effect 17.

The observed pill placebo effect over and above the proven psychotherapy may be explainable from both of the main theoretical models of the placebo effect, namely the classical conditioning 18 and expectancy theory 19 In the life of a modern man the beneficial experience of a pill is almost inescapable and this may have contributed to the placebo effect through pill taking in addition to the same through talk therapy. In other words, the pill has become a conditioned stimulus, eliciting a conditioned response which is placebo effect. Or alternatively, according to the expectancy theory, patients expect more from pill and talk therapy so that they respond more to pill and talk therapy. The fact that the benefit of the pill placebo appeared to wane after the treatment termination is compatible with both of these theoretical models. In fact, although they are often presented as competing perspectives, the two theories are not necessarily incompatible with each other 20.

Pragmatic implications of the present findings may not be as straightforward. We have formerly established that antidepressant drug plus CBT was more effective than placebo plus CBT at the end of the acute phase treatment 6. It appears that psychotherapy plus pill placebo would come in-between the two, but in clinical practice prescribing a pill placebo will be very difficult if not unethical. It is important to note, however, that there is some further room to enhance placebo effect when administering CBT to panic disorder.

There are some possible weaknesses to the present study. In the first place, despite our intensive and extensive literature search, we were able to identify only three trials that made a head-to-head comparison between psychotherapy plus placebo against psychotherapy alone. The present findings therefore may lack statistical power and should be regarded exploratory and preliminary. Secondly, in two of the three included studies, the primary outcomes were rated by raters who were not blind to the psychotherapy status but who were blind only to the drug status (active drug vs placebo). However, we must note that the absolute degree of heterogeneity, as expressed by I-squared values and as visually observable in forest plots (Figures 1 and 2), was close to zero among the one blind and two non-blind studies. The open nature of the assessment can therefore not explain away the observed difference. Thirdly, the response rate had to be imputed in one of the three studies 14 based on the panic frequency, which likely not reflect the whole panic disorder psychopathology. Deleting this study, however, did not affect the outcomes (RR = 1.24, 95%CI: 1.00 to 1.54 at the end of acute phase treatment, and RR = 1.28, 95%CI: 0.91 to 1.80 at 6–24 months after treatment discontinuation). We were also unable to conduct detailed meta-analyses of continuous variables presented in the identified studies because each rated some different aspects of panic disorder. For example, one RCT reported frequency of panic attacks, two reported on phobic avoidance, two reported on general anxiety, one reported depression and one reported social dysfunction on various continuous scales. The field would certainly benefit from wider-spread use of a more common metric of overall panic disorder severity, such as the Panic Disorder Severity Scale 11. Lastly, our results concern panic disorder only and generalizability beyond this disorder is not guaranteed. More systematic reviews on this topic in other disorders are warranted.

The act of taking a pill placebo may enhance the placebo effect already contained in the effective psychotherapeutic intervention during the acute phase treatment. There may be some further room for enhancing the psychotherapeutic approach for panic disorder.

The author(s) declare that they have no competing interests.

TAF conceived of the study, and drafted the protocol. All the authors discussed and amended the study protocol. TAF, NW and IMO did the study selection, data extraction and data entry. TAF analyzed the data and wrote the first draft of the manuscript. All the authors discussed and amended the manuscript, and approved the final manuscript.