Lack of protocols for handling missing sessions of transcranial direct current stimulation (tDCS) in depression trials: what are the risks of neglecting missing sessions?

Transcranial direct current stimulation (tDCS) represents a potential effective treatment for depression and has already shown encouraging results.¹,² Given that tDCS requires the subject’s presence, the probability of missed sessions is high, especially in depressed subjects. However, there is no consensus about the effects of missed sessions on tDCS efficacy.

A recent study reported that 60% of depressive subjects in a tDCS study missed at least one visit out of ten.³ It is also known that the intensity and, probably, the frequency of tDCS sessions significantly increase the effectiveness of tDCS.³ Missing sessions are very frequent, and how to deal with them is an issue of high relevance. Unfortunately, there is a glaring lack of information about missed sessions in tDCS trials for depression, even though this can lead to possible changes in the results and their interpretation. Thus, we can infer that missing sessions is potentially harmful to a complete response by the depressed individual.

We performed a systematic review of the PubMed/MEDLINE database between 2005 and 2015 regarding methods used to handle missing sessions in trials. Of the eight included trials, only three provided some information about missing sessions (Table 1). The two first trials⁴,⁵ mentioned the maximum number of sessions that could be missed (no more than two non-consecutive sessions) before excluding the subject and how they handled such cases. Zanão et al. stated that missing two sessions in the acute treatment phase might not change the final result, although they point out the need for more studies exploring the impact of a higher number of absences on the treatment of depression disorders. The management of this methodological issue is fundamental for scientific development.

Table 1
RCTs characteristics using tDCS for depression

Study	Subjects(n)	Current (mA)	Duration (min)	No. sessions	Anode/Cathode	Dropout	Missing sessions	Positive outcome
Fregni 20066	10	1	20	5	F3/RSO	0	NM	Yes
Boggio 20087	40	2	20	10	F3/RSO	0	NM	Yes
Loo 20108	40	1	20	5(10*)	F3/RSO	6	NM	Yes
Brunoni 20134	120	2	30	12	F3/F4	17	Yes† (>2 sessions)	Yes
Brunoni 20145	37	2	30	10	F3/F4	21	Yes† (>2 sessions)	No
Ho 20149	14	2	20	10	F3/F8 or F8/F3	2	NM	Yes
Segrave 2014	27	2	24	5	F3/F8	1	Yes*	Yes
Bennabi 201510	24	2	30	10	F3/RSO	1	NM	No

• NM= not mentioned; RSO = right supraorbital area; RCT = randomized controlled trial; tDCS = transcranial direct current stimulation.
• ^*
  Previous session result was reported when a patient missed one session.
• ^†
  Participants were allowed to miss two nonconsecutive visits; in such cases, extra tDCS sessions were performed to complete the total number of sessions.

Another question is whether there is a relation between the efficacy and timing of a missing session. Do subjects who missed sessions other than at the beginning of the trial have the same results? What about the lasting effects, are they affected by the timing of missing sessions as well? One study made up for the missed tDCS sessions at the end of the protocol.⁴ This evidently shows concern with the methodological approach but, again, leads us to question whether the results can be interpreted in the same way for these subjects.

Segrave et al.¹¹ considered the last observation carried forward as a way of dealing with the missing data due to missed sessions. This is a conservative method that can minimize the good results of tDCS. Moreover, details about how many subjects missed one or more sessions were not provided. The majority of the available articles made no mention of methodological concerns over this issue.

Considering that depressed individuals have difficulty in performing their daily activities, not only having a well-designed plan to address missing sessions but also building an adaptive protocol requires urgent attention. Therefore, clear definitions about how to address them and well-designed guidelines are needed. A new trial specifically designed to assess tDCS efficacy according to the number of missing sessions would certainly help establish a comprehensive framework for informing how many sessions can be missed without having a major impact on the subject.

References

• ¹
  Brunoni AR, Moffa AH, Fregni F, Palm U, Padberg F, Blumberger DM, et al. Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. Br J Psychiatry. 2016;208:522-31.
• ²
  Valiengo LC, Goulart AC, de Oliveira JF, Benseñor IM, Lotufo PA, Brunoni AR. Transcranial direct current stimulation for the treatment of post-stroke depression: results from a randomised, sham-controlled, double-blinded trial. J Neurol Neurosurg Psychiatry. 2017;88:170-5.
• ³
  Zanão TA, Moffa AH, Shiozawa P, Lotufo PA, Benseñor IM, Brunoni AR. Impact of two or less missing treatment sessions on tDCS clinical efficacy: results from a factorial, randomized, controlled trial in major depression. Neuromodulation. 2014;17:737-42; discussion 742.
• ⁴
  Brunoni AR, Valiengo L, Baccaro A, Zanão TA, de Oliveira JF, Goulart A, et al. The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial. JAMA Psychiatry 2013;70:383-91.
• ⁵
  Brunoni AR, Boggio PS, De Raedt R, Benseñor IM, Lotufo PA, Namur V, et al. Cognitive control therapy and transcranial direct current stimulation for depression: a randomized, double-blinded, controlled trial. J Affect Disord. 2014;162:43-9.
• ⁶
  Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP, Pascual-Leone A. Treatment of major depression with transcranial direct current stimulation. Bipolar Disord. 2006;8:203-4.
• ⁷
  Boggio PS, Rigonatti SP, Ribeiro RB, Myczkowski ML, Nitsche MA, Pascual-Leone A, et al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. Int J Neuropsychopharmacol. 2008;11:249-54.
• ⁸
  Loo CK, Sachdev P, Martin D, Pigot M, Alonzo A, Malhi GS, et al. A double-blind, sham-controlled trial of transcranial direct current stimulation for the treatment of depression. Int J Neuropsychopharmacol. 2010;13:61-9.
• ⁹
  Ho KA, Bai S, Martin D, Alonzo A, Dokos S, Puras P, et al. A pilot study of alternative transcranial direct current stimulation electrode montages for the treatment of major depression. J Affect Disord. 2014;167:251-8.
• ¹⁰
  Bennabi D, Nicolier M, Monnin J, Tio G, Pazart L, Vandel P, et al. Pilot study of feasibility of the effect of treatment with tDCS in patients suffering from treatment-resistant depression treated with escitalopram. Clin Neurophysiol. 2015;126:1185-9.
• ¹¹
  Segrave RA, Arnold S, Hoy K, Fitzgerald PB. Concurrent cognitive control training augments the antidepressant efficacy of tDCS: a pilot study. Brain Stimul. 2014;7:325-31.

Publication Dates

• Publication in this collection
  Dec 2017

History

• Received
  14 Mar 2017
• Accepted
  5 May 2017