Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials

Responses to Venkatesh Chandrasekaran and Subramanian Mahadevan:

Thank you for your positive comment on our systematic review.

We endorse updated global systematic reviews of all interventions for patients with attention deficit hyperactivity disorder (ADHD). These should determine which interventions should be used for treatment of patients according to local guidelines. We warn against using two group parallel group trials for assessing drugs for ADHD, if we are not very sure that the drugs offers more benefit or less harm than proper placebo or nocebo.

Responses to Hans-Joachim Kremer:

Thank you for your comments on our systematic review. The term ‘active placebo’ is indeed real and is used in many randomised clinical trials. A problem with many pharmacological trials is that participants in the experimental drug group experience adverse events that compromise the blinding, as fewer adverse events occur in participants in the placebo group. Therefore, some randomised clinical trials use ingredients in the placebo pills that create adverse events similar to the experimental drug, but without having its biological activity. – so-called ‘nocebo effects’.

An active placebo is a placebo tablet that contains a drug that does not have the specific beneficial effects on the disorder being treated as the experimental drug but is designed to mimic some of the other effects of the active substance, thereby creating a ‘nocebo effect’.[1 2] Moncrieff et al.performed a Cochrane review where they investigated ‘active placebo’ versus antidepressant for depression. [1] Their review included 9 trials using active placebos. White et al. argue that in placebo controlled trials it is possible to discriminate between the active drug and placebo on the basis of reported adverse effects alone, and that this raises questions about the true blindness of such trials. [3] In vaccination trials, the vaccine is often boosted by using adjuvants (e.g., aluminum compounds) that create an inflammatory response. Such adjuvants are often used in the placebo vaccine as well in order to blind. Other areas in which nocebo effects have been studied are pain and itch.

We agree with you that nocebo refers to adverse events. [4] Our use of the term nocebo is connected to the use of ‘active placebo tablets’ creating a nocebo effect.

References:
1. Moncrieff J, Wessely S, Hardy R. Active placebos versus antidepressants for depression. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003012. DOI: 10.1002/14651858.CD003012.pub2.
2. Požgain I, Požgain Z, Degmečić D. Placebo and nocebo effect: a mini review. Psychiatria Danubina 2014;26(2):100-7.
3. White K, Kando J, Park T, Waternaux C, Brown WA Side effects and the "blindability" of clinical drug trials. Am J Psychiatry. 1992; 149(12):1730-1.
4. Mitsikostas DD, Mantonakis L, Chalarakis N. Nocebo in clinical trials for depression: a meta-analysis. Psychiatry Research. 2014;215 (1): 82-86.

Responses to Ellen Grant:

Thank you for your comment on our systematic review.

Serious adverse events were recorded in accordance with the International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. (ICH) guidelines. [5] However, when in doubt, we asked the trial authors which classification or definition they had used in their trial. The ICH classification states: “Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) Any untoward medical occurrence that at any dose: - results in death, - is life-threatening, - requires inpatient hospitalization or prolongation of existing hospitalization, - results in persistent or significant disability/incapacity, or - is a congenital anomaly/birth defect." [5] We do not believe that decreased appetite and sleep problems meet the threshold for this definition, but, important as they are, we consider them to belong in the group of more serious ‘non-serious adverse events’.

References:
5. ICH Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice E6(R1). http://bit.ly/1B0jeJg (accessed 4 March 2014).

Ole Jakob Storebø, Psychiatric Research Unit, Psychiatric Department, Region Zealand, Slagelse, Denmark
Department of Psychology, Faculty of Health Science, University of Southern Denmark

Christian Gluud, The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen, Denmark.