CommentaryOpen Access

Commentary: Transcranial direct current stimulation for depression in Alzheimer's disease: study protocol for a randomized controlled trial

Zui Narita1 and Yuma Yokoi1

1Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry Japan 

Dementia is a progressive neurodegenerative disorder that is characterized by a decline in cognition in one or more cognitive domains such as learning and memory, language, executive function, complex attention, perceptual-motor, social cognition1. World Alzheimer Report 2015 reported that 36 million people were living with dementia in 2010, nearly doubling every 20 years to 66 million by 2030 and to 115 million by 20502. Alzheimer’s disease (AD) is the most common form of dementia in the elderly that is increasingly prevalent with advancing age, and the overall burden of it is substantial worldwide3–8. Cognitive dysfunction in AD decreases the quality of life (QOL) of patients and caregivers9. The cholinergic drugs, introduced first in 1997, have been approved worldwide and considered to be the first line pharmacotherapy for mild to severe AD. The mechanism of these drugs is to inhibit the breakdown of acetylcholine, a neurotransmitter associated with memory or cognitive activity, by blocking the enzyme acetylcholinesterase10. Although these drugs can slow the progression of AD, a review study revealed the limited efficacy of these compounds10. Future disease-modifying treatments and therapeutic interventions augmenting current pharmacologic treatments are awaited.

Neuropsychiatric symptoms in patients with AD also compromise their QOL11. Depressive mood is one of the most frequent neuropsychiatric symptoms in AD as well as agitation and apathy12. The prevalence rate of depression in AD is estimated as from 36.7 %13 to 47.8 %12. On the other hand, antidepressant drugs and electroconvulsive therapy (ECT) have not shown significant effect on depression in AD. A meta-analysis revealed that selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors did not show significant effect on depression in AD14. A randomized controlled trial (RCT) with a large sample, also revealed that neither selective serotonin reuptake inhibitors nor noradrenergic and specific serotonergic antidepressants showed superiority to placebo, and concluded that antidepressants should not be used first for depression in AD considering adverse events induced by antidepressants15. Moreover, a recent thorough review, in neither older patients over 65 years nor patients with dementia, verified the effect of ECT16.

Our recent study entitled “Transcranial direct current stimulation for depression in Alzheimer’s disease: study protocol for a randomized controlled trial” was designed to evaluate the safety and effect of transcranial direct current stimulation (tDCS) on depression in patients with AD over 65 years17. tDCS is a simple, cheap, and safe technique of neuromodulation, based on the application of weak, direct electrical current to the brain through relatively large electrodes. Two electrodes are typically placed over the scalp, in which anodal and cathodal stimulation increases and decreases cortical excitability, respectively18. As a novel therapeutic intervention for potentially affecting both cognition and depression, our study may bring a significant impact on these domains in patients with AD, and may be useful to enhance their quality of life. Other than our study, novel studies investigating the effect of tDCS in AD are being explored. For instance, Inagawa, et al. (2016) presented a protocol of the pilot study to assess the safety and efficacy of tDCS during cognitive rehabilitation on cognitive function for patients with major or minor cognitive disorders19.

Seven double-blind RCTs have been so far conducted for AD20–26. Here we review five of them that evaluated multiple-session effects20,22,23,25,26 since a meta-analysis suggests that a larger number of sessions may be more effective27. Two of five controlled trials revealed significant effect on some domains in AD. One study reported a significant improvement in cognitive function after 10 sessions of anodal or cathodal stimulations over left dorsolateral prefrontal cortex (DLPFC) in 34 patients with AD25. In this study, the P300 component of the event-related potential, which is known to be pathologically increased in AD, was also reduced25.The other trial demonstrated significant improvement in visual recognition memory after five sessions of anodal stimulations over left DLPFC in 15 subjects with AD although it did not verify significant effect on neither general cognitive performance measures nor a visual attention measure20.

In remaining three RCTs, tDCS did not show significant improvement in AD. Suemoto, et al. (2014), employing 40 apathetic patients with AD, assessed the effect of six sessions of tDCS in two weeks, and found the lack of a significant benefit on apathy and cognitive outcomes26. This study also reported adverse effects systematically to find that tingling and scalp burning were significantly more frequent in the active tDCS group26. Cotelli, et al. (2014) enrolled 36 subjects with AD, assigning them into three groups, active left DLPFC tDCS plus individualized computerized memory training (ICMT), sham left DLPFC tDCS plus ICMT, and active left DLPFC tDCS plus motor training, with 10 sessions in two weeks23. Active tDCS plus ICMT group did not significantly improve performance across time compared to sham tDCS plus ICMT group, although it revealed significant improvement in a face-name association task compared to active tDCS plus motor training23. Bystad, et al. (2016) included 25 participants with AD to assess the effect of left temporal cortex tDCS with six sessions in 10 days22. Compared with placebo stimulation, active tDCS stimulation did not significantly improve verbal memory function22.

The controlled studies so far provided are largely heterogeneous in methodology and outcomes. Also, a small sample may raise caution in concluding that these results represent effects in the population, which might be an issue of external validity. Moreover, only one RCT has reported adverse effects systematically although they are of concern in trials enrolling elderly participants. Limitations in recruitments should be also noted. Since patients with AD have cognitive dysfunction, they might not be able to decide whether they should give consent. In addition, self report of patients with AD is simply not enough to make an objective assessment of their cognition or QOL. In this context, it is necessary to have caregivers with them; but this might decrease the opportunity of enrollments. Furthermore, as stated above, daily sessions would be preferred to acquire effect; but the long study period might have negative effect on patients’ motivation and increase the dropout rate.

Despite all these potential pitfalls pointed out above, controlled studies investigating tDCS in patients with AD are still advantageous, considering their significant impacts. Further RCTs with larger sample and additional evaluations will be required. Although adverse effects mentioned above were so mild that participants could tolerate them, they must be systematically described to avoid reporting bias. Also, high quality of randomization, allocation concealment, and blinding will be necessary to make trials well-controlled. With more controlled trials, the effect of tDCS in AD should be fully investigated with a systematic review and meta-analysis.

  1. Diagnostic and Statistical Manual of Mental Disorders | DSM Library [Internet]. [cited 2017 Apr 28]. Available from:
  2. World Alzheimer Report 2015: The Global Impact of Dementia | Alzheimer’s Disease International [Internet]. [cited 2017 Apr 28]. Available from:
  3. Ganguli M, Hendrie HC. Screening for cognitive impairment and depression in ethnically diverse older populations. Alzheimer Dis Assoc Disord. 2005 Dec; 19(4): 275–8.
  4. Hebert LE, Weuve J, Scherr PA, et al. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013 May 7; 80(19): 1778–83.
  5. Llibre Rodriguez JJ, Ferri CP, Acosta D, et al. Prevalence of dementia in Latin America, India, and China: a population-based cross-sectional survey. Lancet Lond Engl. 2008 Aug 9; 372(9637): 464–74.
  6. Prince M, Bryce R, Albanese E, et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement J Alzheimers Assoc. 2013 Jan; 9(1): 63–75.e2.
  7. Rocca WA, Petersen RC, Knopman DS, et al. Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States. Alzheimers Dement J Alzheimers Assoc. 2011 Jan; 7(1): 80–93.
  8. Sosa Ortiz AL, Acosta Castillo I, Prince MJ. Epidemiology of dementias and Alzheimer’s disease. Arch Med Res. 2012 Nov; 43(8): 600–8.
  9. León-Salas B, Olazarán J, Muñiz R, et al. Caregivers’ estimation of patients’ quality of life (QoL) in Alzheimer’s disease (AD): an approach using the ADRQL. Arch Gerontol Geriatr. 2011 Aug; 53(1): 13–8.
  10. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006 Jan 25; (1): CD005593.
  11. León Salas B, Olazarán J, Cruz Orduña I, et al. Quality of life (QoL) in community-dwelling and institutionalized Alzheimer’s disease (AD) patients. Arch Gerontol Geriatr. 2013 Dec; 57(3): 257–62.
  12. Acosta Castillo GI, Luisa Sosa A, Orozco R, et al. [Neuropsychiatric symptoms in older adults with dementia and their relationship to disease severity]. Rev Investig Clin Organo Hosp Enfermedades Nutr. 2012 Aug; 64(4): 354–63.
  13. Aalten P, Verhey FRJ, Boziki M, et al. Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord. 2007; 24(6): 457–63.
  14. Nelson JC, Devanand DP. A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc. 2011 Apr; 59(4): 577–85.
  15. Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet Lond Engl. 2011 Jul 30; 378(9789): 403–11.
  16. Oudman E. Is electroconvulsive therapy (ECT) effective and safe for treatment of depression in dementia? A short review. J ECT. 2012 Mar; 28(1): 34–8.
  17. Narita Z, Yokoi Y. Transcranial direct current stimulation for depression in Alzheimer’s disease: study protocol for a randomized controlled trial. Trials. 2017 Jun 19; 18(1): 285.
  18. Brunoni AR, Nitsche MA, Bolognini N, et al. Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimulat. 2012 Jul; 5(3): 175–95.
  19. Inagawa T, Yokoi Y, Okazaki M, et al. COgnitive REhabilitation during transcranial Direct Current Stimulation (CORE-tDCS) for major or mild neurocognitive disorder patients - a protocol of a randomized controlled preliminary research. Brain Stimul Basic Transl Clin Res Neuromodulation. 2017 Mar 1; 10(2): 384.
  20. Boggio PS, Ferrucci R, Mameli F, et al. Prolonged visual memory enhancement after direct current stimulation in Alzheimer’s disease. Brain Stimulat. 2012 Jul; 5(3): 223–30.
  21. Boggio PS, Khoury LP, Martins DCS, et al. Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009 Apr; 80(4): 444–7.
  22. Bystad M, Grønli O, Rasmussen ID, et al. Transcranial direct current stimulation as a memory enhancer in patients with Alzheimer’s disease: a randomized, placebo-controlled trial. Alzheimers Res Ther [Internet]. 2016 Mar 23;8. Available from:
  23. Cotelli M, Manenti R, Brambilla M, et al. Anodal tDCS during face-name associations memory training in Alzheimer’s patients. Front Aging Neurosci [Internet]. 2014 Mar 19; 6. Available from:
  24. Ferrucci R, Mameli F, Guidi I, et al. Transcranial direct current stimulation improves recognition memory in Alzheimer disease. Neurology. 2008 Aug 12; 71(7): 493–8.
  25. Khedr EM, Gamal NFE, El-Fetoh NA, et al. A Double-Blind Randomized Clinical Trial on the Efficacy of Cortical Direct Current Stimulation for the Treatment of Alzheimer’s Disease. Front Aging Neurosci [Internet]. 2014 Oct 9; 6. Available from:
  26. Suemoto CK, Apolinario D, Nakamura Palacios EM, et al. Effects of a non-focal plasticity protocol on apathy in moderate Alzheimer’s disease: a randomized, double-blind, sham-controlled trial. Brain Stimulat. 2014 Apr; 7(2): 308–13.
  27. Shiozawa P, Fregni F, Benseñor IM, et al. Transcranial direct current stimulation for major depression: an updated systematic review and meta-analysis. Int J Neuropsychopharmacol. 2014 Sep; 17(9): 1443–52.

Article Info

Article Notes

  • Published on: August 2, 2017


  • Neurodegenerative
  • Pharmacotherapy
  • Neuropsychiatric


Yuma Yokoi, M.D.
Department of Psychiatry, National Center of Neurology and Psychiatry
4-1-1, Ogawahigashi, Kodaira, Tokyo, Japan
TEL: +81-42-341-2711; FAX: +81-42-346-1944

© 2017 Yokoi Y & Narita Z. This article is distributed under the terms of the Creative Commons Attribution 4.0 International Licens