Home-based transcranial direct current stimulation treatment for major depressive disorder: a fully remote phase 2 randomized sham-controlled trial. Woodham, R.D., Selvaraj, S., Lajmi, N. et al.Nat Med (2024). https://doi.org/10.1038/s41591-024-03305-y
Transcranial direct current stimulation (tDCS) has been proposed as a new treatment in major depressive disorder (MDD). This is a fully remote, multisite, double-blind, placebo-controlled, randomized superiority trial of 10-week home-based tDCS in MDD. Participants were 18 years or older, with MDD in current depressive episode of at least moderate severity as measured using the Hamilton Depression Rating Scale (mean = 19.07 ± 2.73). A total of 174 participants (120 women, 54 men) were randomized to active (n = 87, mean age = 37.09 ± 11.14 years) or sham (n = 87, mean age = 38.32 ± 10.92 years) treatment. tDCS consisted of five sessions per week for 3 weeks then three sessions per week for 7 weeks in a 10-week trial, followed by a 10-week open-label phase. Each session lasted 30 min; the anode was placed over the left dorsolateral prefrontal cortex and the cathode over the right dorsolateral prefrontal cortex (active tDCS 2 mA and sham tDCS 0 mA, with brief ramp up and down to mimic active stimulation). As the primary outcome, depressive symptoms showed significant improvement when measured using the Hamilton Depression Rating Scale: active 9.41 ± 6.25 point improvement (10-week mean = 9.58 ± 6.02) and sham 7.14 ± 6.10 point improvement (10-week mean = 11.66 ± 5.96) (95% confidence interval = 0.51–4.01, P = 0.012). There were no differences in discontinuation rates. In summary, a 10-week home-based tDCS treatment with remote supervision in MDD showed high efficacy, acceptability and safety. ClinicalTrials.gov registration: NCT05202119
MAIN
Major depressive disorder (MDD) is common and it is a leading cause of disability worldwide; it is the most notable precursor in suicide1. MDD is characterized by a prolonged low mood or inability to experience usual feelings of pleasure, which is accompanied by disturbances in sleep, appetite, psychomotor functioning and energy levels, and in cognitive functioning. First-line treatments are antidepressant medications and psychological therapies. However, more than a third of individuals with MDD do not achieve full clinical remission despite full treatment trials2,3.
Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation that applies a weak (0.5–2 mA) direct current via scalp electrodes4. Anodal stimulation shifts membrane potentials toward depolarization and increasing cortical excitability, whereas cathodal stimulation tends to shift membrane potentials toward hyperpolarization, decreasing potential cell firing and inhibiting cortical excitability5. tDCS modulates the resting state potential, thereby modulating cortical tissue excitability, rather than directly triggering an action potential that is in contrast to repetitive transcranial magnetic stimulation6. Neurophysiological effects typically persist beyond the immediate stimulation period7. Anodal tDCS can enhance cortical excitability, which is dependent on the N-methyl-d-aspartate receptor and calcium channel activity, demonstrating a sustained increase in synaptic transmission that is long-term potentiation-like, whereas cathodal tDCS decreases excitability and facilitates long-term depression-like changes8. Neural recordings demonstrate measurables effects on cortical electric fields9. Neurophysiological measures reveal network-level modulatory effects, in which anodal tDCS applied to left dorsolateral prefrontal cortex (DLPFC) is associated with significant changes in connectivity in default mode, self-referential and frontoparietal networks compared with sham tDCS10; it can extend into the deeper limbic brain regions, including the amygdala11, which are key regions in MDD neurocircuitry and reflect potential mechanisms of effect4.
tDCS is applied through a flexible cap or band that is worn over the forehead. The anode electrode is typically placed over the left DLPFC and the cathode is placed over the right DLPFC, in the suborbital or frontotemporal region6. In an individual-patient data meta-analysis, active tDCS relative to sham tDCS was associated with a significantly greater rate of clinical response (30.9% versus 18.9%; number needed to treat (NNT) = 9) and remission (19.9% versus 11.7%; NNT = 13) from 572 participants with MDD in nine studies12. tDCS is safe and well tolerated with no significant differences in attrition rate and adverse events between active and sham stimulation, offering a potential new first-line treatment for MDD4. However, a course of tDCS treatment involves daily sessions for several weeks; most studies have been conducted in a research clinic and have required daily visits6,12.
As it is portable and safe, tDCS can be provided for home use4. We developed a protocol that provides home-based tDCS with real-time remote supervision using videoconferencing13. In MDD, we found significant improvements in depressive symptoms, high acceptability and feasibility13, as also observed in additional open-label trials14,15. However, in our protocol, all participants had both the active tDCS device and real-time visits using videoconferencing, which were associated with meaningful experiences of support and containment16. Three randomized controlled trials (RCTs) of home-based tDCS in MDD have taken place17,18,19; however, none were fully remote because all included in-person study appointments, two trials were probably underpowered because of small sample sizes (n = 11 (ref. 18) and n = 58 (ref. 19)), and all were limited to a 6-week duration; they found no significant effects of active relative to sham tDCS17,18,19. However, the recent meta-analysis by Nikolin et al.20 reported that the active tDCS effects continue to increase for up to 10 weeks compared to sham stimulation.
In the present study, we sought to investigate the clinical efficacy and safety of a 10-week course of home-based tDCS for MDD in a large, double-blind, randomized superiority trial conducted in both the UK and USA. All participants had MDD as determined by a structured diagnostic interview; all were in a current depressive episode of at least moderate severity. Participants in our study might be taking stable antidepressant medication for at least 6 weeks, might be in psychotherapy for at least 6 weeks or might be treatment-free, reflecting the range of forms of MDD from first-episode and recurrent MDD to treatment-resistant depression. All study visits were remote and we were able to monitor participants’ tDCS use in real time. The primary objective was to investigate clinical efficacy at the 10-week end point of treatment between active and sham tDCS treatment arms.
- Received14 February 2024
- Accepted17 September 2024
- Published21 October 2024
Transcranial direct current stimulation (tDCS) has been proposed as a new treatment in major depressive disorder (MDD). This is a fully remote, multisite, double-blind, placebo-controlled, randomized superiority trial of 10-week home-based tDCS in MDD. Participants were 18 years or older, with MDD in current depressive episode of at least moderate severity as measured using the Hamilton Depression Rating Scale (mean = 19.07 ± 2.73). A total of 174 participants (120 women, 54 men) were randomized to active (n = 87, mean age = 37.09 ± 11.14 years) or sham (n = 87, mean age = 38.32 ± 10.92 years) treatment. tDCS consisted of five sessions per week for 3 weeks then three sessions per week for 7 weeks in a 10-week trial, followed by a 10-week open-label phase. Each session lasted 30 min; the anode was placed over the left dorsolateral prefrontal cortex and the cathode over the right dorsolateral prefrontal cortex (active tDCS 2 mA and sham tDCS 0 mA, with brief ramp up and down to mimic active stimulation). As the primary outcome, depressive symptoms showed significant improvement when measured using the Hamilton Depression Rating Scale: active 9.41 ± 6.25 point improvement (10-week mean = 9.58 ± 6.02) and sham 7.14 ± 6.10 point improvement (10-week mean = 11.66 ± 5.96) (95% confidence interval = 0.51–4.01, P = 0.012). There were no differences in discontinuation rates. In summary, a 10-week home-based tDCS treatment with remote supervision in MDD showed high efficacy, acceptability and safety. ClinicalTrials.gov registration: NCT05202119
MAIN
Major depressive disorder (MDD) is common and it is a leading cause of disability worldwide; it is the most notable precursor in suicide1. MDD is characterized by a prolonged low mood or inability to experience usual feelings of pleasure, which is accompanied by disturbances in sleep, appetite, psychomotor functioning and energy levels, and in cognitive functioning. First-line treatments are antidepressant medications and psychological therapies. However, more than a third of individuals with MDD do not achieve full clinical remission despite full treatment trials2,3.
Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation that applies a weak (0.5–2 mA) direct current via scalp electrodes4. Anodal stimulation shifts membrane potentials toward depolarization and increasing cortical excitability, whereas cathodal stimulation tends to shift membrane potentials toward hyperpolarization, decreasing potential cell firing and inhibiting cortical excitability5. tDCS modulates the resting state potential, thereby modulating cortical tissue excitability, rather than directly triggering an action potential that is in contrast to repetitive transcranial magnetic stimulation6. Neurophysiological effects typically persist beyond the immediate stimulation period7. Anodal tDCS can enhance cortical excitability, which is dependent on the N-methyl-d-aspartate receptor and calcium channel activity, demonstrating a sustained increase in synaptic transmission that is long-term potentiation-like, whereas cathodal tDCS decreases excitability and facilitates long-term depression-like changes8. Neural recordings demonstrate measurables effects on cortical electric fields9. Neurophysiological measures reveal network-level modulatory effects, in which anodal tDCS applied to left dorsolateral prefrontal cortex (DLPFC) is associated with significant changes in connectivity in default mode, self-referential and frontoparietal networks compared with sham tDCS10; it can extend into the deeper limbic brain regions, including the amygdala11, which are key regions in MDD neurocircuitry and reflect potential mechanisms of effect4.
tDCS is applied through a flexible cap or band that is worn over the forehead. The anode electrode is typically placed over the left DLPFC and the cathode is placed over the right DLPFC, in the suborbital or frontotemporal region6. In an individual-patient data meta-analysis, active tDCS relative to sham tDCS was associated with a significantly greater rate of clinical response (30.9% versus 18.9%; number needed to treat (NNT) = 9) and remission (19.9% versus 11.7%; NNT = 13) from 572 participants with MDD in nine studies12. tDCS is safe and well tolerated with no significant differences in attrition rate and adverse events between active and sham stimulation, offering a potential new first-line treatment for MDD4. However, a course of tDCS treatment involves daily sessions for several weeks; most studies have been conducted in a research clinic and have required daily visits6,12.
As it is portable and safe, tDCS can be provided for home use4. We developed a protocol that provides home-based tDCS with real-time remote supervision using videoconferencing13. In MDD, we found significant improvements in depressive symptoms, high acceptability and feasibility13, as also observed in additional open-label trials14,15. However, in our protocol, all participants had both the active tDCS device and real-time visits using videoconferencing, which were associated with meaningful experiences of support and containment16. Three randomized controlled trials (RCTs) of home-based tDCS in MDD have taken place17,18,19; however, none were fully remote because all included in-person study appointments, two trials were probably underpowered because of small sample sizes (n = 11 (ref. 18) and n = 58 (ref. 19)), and all were limited to a 6-week duration; they found no significant effects of active relative to sham tDCS17,18,19. However, the recent meta-analysis by Nikolin et al.20 reported that the active tDCS effects continue to increase for up to 10 weeks compared to sham stimulation.
In the present study, we sought to investigate the clinical efficacy and safety of a 10-week course of home-based tDCS for MDD in a large, double-blind, randomized superiority trial conducted in both the UK and USA. All participants had MDD as determined by a structured diagnostic interview; all were in a current depressive episode of at least moderate severity. Participants in our study might be taking stable antidepressant medication for at least 6 weeks, might be in psychotherapy for at least 6 weeks or might be treatment-free, reflecting the range of forms of MDD from first-episode and recurrent MDD to treatment-resistant depression. All study visits were remote and we were able to monitor participants’ tDCS use in real time. The primary objective was to investigate clinical efficacy at the 10-week end point of treatment between active and sham tDCS treatment arms.
