Transcranial direct current stimulation as early augmentation in adolescent obsessive compulsive disorder: A pilot proof-of-concept randomized control trial

Abstract

BACKGROUND

Transcranial direct current stimulation (tDCS) is proven to be safe in treating various neurological conditions in children and adolescents. It is also an effective method in the treatment of OCD in adults.

AIM

To assess the safety and efficacy of tDCS as an add-on therapy in drug-naive adolescents with OCD.

METHODS

We studied drug-naïve adolescents with OCD, using a Children’s Yale-Brown obsessive-compulsive scale (CY-BOCS) scale to assess their condition. Both active and sham groups were given fluoxetine, and we applied cathode and anode over the supplementary motor area and deltoid for 20 min in 10 sessions. Reassessment occurred at 2, 6, and 12 wk using CY-BOCS.

RESULTS

Eighteen adolescents completed the study (10-active, 8-sham group). CY-BOCS scores from baseline to 12 wk reduced significantly in both groups but change at baseline to 2 wk was significant in the active group only. The mean change at 2 wk was more in the active group (11.8 ± 7.77 vs 5.25 ± 2.22, P = 0.056). Adverse effects between the groups were comparable.

CONCLUSION

tDCS is safe and well tolerated for the treatment of OCD in adolescents. However, there is a need for further studies with a larger sample population to confirm the effectiveness of tDCS as early augmentation in OCD in this population.

Key Words: Adolescents, Early augmentation, Obsessive compulsive disorder, Safety, Transcranial direct current stimulation

Core Tip: Transcranial direct current stimulation (tDCS) is a safe treatment modality in the management of obsessive compulsive disorder (OCD) in adolescents. Cathodal stimulation over the supplementary motor area produces insignificant improvement in severity of OCD than sham controls. The improvement following 10 sessions of tDCS is mostly short-lasting and usually goes off by 6 wk.

INTRODUCTION

Obsessive compulsive disorder (OCD) is among the most common psychiatric disorders, with a mean age of onset of 19 years and almost a quarter of patients developing the disorder by the age of 10 years[1]. Transcranial direct current stimulation (tDCS) stimulates the brain with electrodes on the scalp. It's safe, affordable, and can activate or suppress cortical activity. Research on its effectiveness in treating OCD is limited to a few studies on adults who are treatment-resistant[2,3]. Even in such patients, it has shown promising results. There is significant heterogeneity between the studies. The electrode placement sites include the supplementary motor area (SMA), orbitofrontal cortex (OFC), and right and left dorsolateral prefrontal cortex (DLPFC)[2,4]. A systemic review of three meta-analyses of tDCS in OCD suggested cathode placement at pre-SMA and anode placement at the extra-cephalic sites as the site with better results. Pre-SMA has been shown to be an effective site for neuromodulation in OCD in repetitive transcranial magnetic stimulation (rTMS) studies as well[4]. By keeping the anode at extracephalic sites the chance of short-circuiting the current flow is reduced. Extra-cephalic sites that have previously been studied include the occipital region, neck, and deltoid. Theoretically, when using deltoid as the extracephalic site, the current will traverse through a pathway involving the striatum, which is a major brain area involved in OCD. The choice of right deltoid was made to save the cardiac electrical conduction from the ill effects of tDCS current. This electrode placement results in modulation of the majority of areas (cortical and sub-cortical) implicated in OCD[5].

tDCS use as early augmentation can lead to an earlier response in OCD with functional recovery. The aim of this randomized controlled trial (RCT) was to assess the efficacy of tDCS as an add-on therapy in drug-naive adolescents with OCD. We hypothesized that utilizing tDCS as an additional therapy with fluoxetine would result in an earlier reduction in obsessive-compulsive symptoms than using fluoxetine with sham tDCS.

MATERIALS AND METHODS

Study design

This was a randomized, single-blind, sham-controlled trial conducted at a tertiary care centre in India. Adolescents between 10 and 18 years of age attending Outpatient services at King George’s Medical University, Lucknow and diagnosed with moderate OCD based on DSM-5 criteria who were drug naïve (for at least 1 month) were included[6,7]. The diagnosis of OCD and comorbidities was made using the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. The Children’s Yale-Brown obsessive-compulsive scale (CY-BOCS) was used to assess the severity of OCD, and cases with a score ≥ 13 were included. Individuals with medical comorbidities requiring priority management, any other psychiatric conditions except major depressive disorder (MDD), intellectual disability, or any contraindication to tDCS were excluded. Revised Child Anxiety and Depression Scale-Hindi adaptation (RCADS-H) was applied to assess anxiety and depressive symptoms. Ethical approval was obtained from the Institutional Ethics Committee (107^th ECM II B-Thesis/P16). Written informed consent from the parent/guardian and assent of the adolescent was obtained. The study was registered prospectively with the Clinical Trials Registry of India (CTRI/2021/12/039002). After which recruitment was done between January 2022 and January 2023 with follow up completed by April 2023.

Randomization and blinding

The sample size was calculated through Priori analysis using “G Power: Statistical Power analyses 3.1.9.7” application[8]. Considering an effect size of 0.25, power of 80%, and drop out rate of 20%, the sample size calculated was 30. Participants attending child and adolescent psychiatry outpatient department on specified days of the week were enrolled in the study by investigators (Agarwal V, Kar SK, Arya A). Adolescents who met the inclusion criteria were enrolled in the study by the principal investigator (Agrawal A). Randomization was done using a computer-generated random number table which was generated by the co-investigator (Agarwal V) method in a 1:1 manner in true and sham groups. Blinding of allocation was ensured by giving a sham stimulation as described below. The investigator was aware of the allocation.

tDCS protocol

Stimulation was provided with tDCS device-Neurostim by Neurosoft, Russia. Two electrodes (size: 5 cm × 5 cm) were placed in the sponge (7 cm × 5 cm) to deliver current after being secured with rubber bands. The cathode was placed on the left SMA, corresponding to FC1 as per the international 10-20 EEG system[9]. During the tDCS session, a current of 2 mA was applied for 20 min with an anode on the right deltoid. The procedure was performed once daily until 10 sessions were completed, with no more than two consecutive days skipped. Adolescents were started on 20 mg of fluoxetine daily, with the dose increased to 40 mg/d after 1 wk. The treating psychiatrist adjusted the dose of fluoxetine during the follow-up period. Adolescents in the sham group were also provided with a brief stimulation after applying electrodes at the same site. Sham stimulation consisted of ramp-up and ramp-down periods of 20 s each during the start and end of the session. During the intervening 20 min, no current was passed. Such stimulation provides somatosensory effects and is recognized as the ‘gold standard’ sham tDCS method[10,11].

Clinical assessments of study variables

We gathered information from adolescents on their demographics and illness. We measured clinical symptoms, CY-BOCS, and RCADS-H scores at different intervals. CY-BOCS is an adapted version of the Yale-Brown Obsessive compulsive scale (Y-BOCS) for use in children and adolescents. Y-BOCS is the gold standard assessment scale for obsessive compulsive symptoms and is widely used in research as well as clinical practice. It has high reliability (α = 0.87) and good validity (r = 0.62)[12]. RCADS-H is the Hindi adaptation of RCADS done by Mishra et al[13]. The original scale has high reliability and moderate validity scores in all subscales except for OCD subscale[14]. To check for side effects, we used a checklist developed from a study done by Eryilmaz et al[15]. Due to coronavirus disease 2019 (COVID-19), assessments were in-person or over the phone. Any minor adverse effects were treated conservatively. We took all COVID-19 precautions.

Statistical data analysis

We used IBM SPSS version 25.0 to analyze data. Descriptive statistics were performed on demographic and clinical variables. We checked for normalcy with the Shapiro-Wilk test. We compared baseline characteristics using the Fisher's exact test for categorical data and the Mann-Whitney U test for numeric variables. Repeated measures ANOVA assessed outcome measure changes. We used Hedges' g for effect size and considered P-values < 0.05 statistically significant.

RESULTS

The trial was conducted in 2022 after the clinical trial registry was completed. A total of 72 adolescents with OCD were screened, out of which 51 were excluded. Finally, 21 adolescents were enrolled and randomized; 18 completed the intervention, and 9 followed up till 12 wk (Figure 1). Baseline clinical and demographic characteristics of the groups were comparable (Table 1). Among the active group, the majority had contamination-related obsessions (n = 7, 70%), washing/cleaning compulsions (n = 6, 60%). In the sham group, the majority had aggression-related obsessions (n = 6, 75%) and washing/cleaning compulsions (n = 5, 62.5%).

Figure 1 Consolidated Standards of Reporting Trials 2010 flow diagram for the study.

Table 1 Sociodemographic and clinical variables among the groups, mean ± SD, n (%).

	Active tDCS (n = 10)	Sham tDCS (n = 8)	P value
Age, yr	14.4 ± 2.4	14.3 ± 2.5	0.96
Age at onset, yr	12.7 ± 3.6	12.0 ± 1.9	0.69
Duration of symptoms, months	19.8 ± 19.5	28.3 ± 29.2	0.68
Gender, male	5 (50)	6 (75)	0.28
Religion, Hindu	8 (80)	7 (87.5)	0.67
Education
Up to high school	8 (80)	6 (75)	0.8
Up to intermediate	2 (20)	2 (25)
Domicile, urban	6 (60)	4 (50)	0.67
Type of family, nuclear	5 (50)	5 (62.5)	0.59
Number of family members
≤ 5	4 (40)	5 (62.5)	0.34
> 5	6 (60)	3 (37.5)
Family income in Rs/month
≤ 20000	4 (40)	3 (37.5)	0.91
> 20000	6 (60)	5 (62.5)
Developmental delay	2 (20)	-
Past history
Hypothyroidism	1 (10)	-
OCD	2 (20)	-
Depressive episode	-	1 (12.5)
Family history of psychiatric illness, present	2 (20)	-
Co-morbidities
Excoriation	1 (10)	-
Subnormal intelligence	1 (10)	-
Major depressive disorder	-	1 (12.5)
Hospitalization	2 (20)	-

tDCS: Transcranial direct current stimulation; OCD: Obsessive compulsive disorder.

Outcome measures

Patients who completed the entire protocol till 12 wk were included in the per protocol (PP) analysis (n = 9, active-6, sham-3). Intention to treat (ITT) analysis was done, with missing data handled using the Last Observation Carried Forward method (n = 18, active-10, sham-8). Total CY-BOCS score in ITT analyses is shown in Figure 2. The total CY-BOCS score was higher in active tDCS (M = 26.83, SD = 6.01) as compared to sham tDCS (M = 22.67, SD = 4.51) but the difference was not statistically significant. (U = 18, P = 0.056). Intergroup differences were not observed in CY-BOCS or RCADS-H scores at any point of assessment. The repeated-measures ANOVA for the CY-BOCS obsession subscale scores and total scores revealed a significant reduction with time in both groups in ITT but only in the active group in PP analysis (Table 2). Significant reduction in CY-BOCS compulsions subscale over time was present in both groups (in ITT and PP analyses).

Figure 2 Children’s Yale-Brown obsessive-compulsive scale total score in between the group across time. CY-BOCS: Children’s Yale-Brown obsessive-compulsive scale.

Table 2 Repeated measures ANOVA test for within group and between groups in both intention to treat and per protocol analysis, mean ± SD.

Clinical variables	Active tDCS group	Sham tDCS group	Time group interaction (F; P value)
CY-BOCS obsession score (0-20)
Baseline
ITT	13.60 (3.06)	11.38 (3.20)
PP	15.16 (2.92)	11.67 (3.51)
2 wk
ITT	7.40 (3.20)	9.0 (3.21)
PP	6.17 (3.54)	9.00 (3.60)
6 wk
ITT	7.60 (2.84)	6.50 (2.39)
PP	6.33 (2.73)	7.67 (2.08)
12 wk
ITT	6.20 (3.29)	5.75 (2.19)
PP	4.00 (1.67)	5.67 (2.08)
Within the group (F; P value)
ITT	13.42; < 0.0011	39.34; < 0.001	2.20; 0.1291
PP	29.52; 0.0011	9.12; 0.091	3.77; 0.0511
CY-BOCS compulsion score (0-20)
Baseline
ITT	11.50 (2.99)	9.0 (3.82)
PP	11.67 (3.93)	11.0 (1.00)
2 wk
ITT	5.90 (4.09)	6.12 (3.00)
PP	4.0 (4.19)	7.0 (2.64)
6 wk
ITT	5.90 (3.63)	4.50 (2.92)
PP	3.83 (2.71)	6.67 (2.51)
12 wk
ITT	5.10 (4.07)	3.38 (2.06)
PP	2.50 (2.42)	3.67 (1.52)
Within the group (F; P value)
ITT	17.10; < 0.0011	17.83; < 0.001	1.44; 0.2471
PP	34.58; < 0.001	16.05; 0.0151	2.22; 0.115
CY-BOCS total score (0-40)
Baseline
ITT	25.10 (5.06)	20.38 (4.21)
PP	26.83 (6.01)	22.67 (4.51)
2 wk
ITT	13.30 (6.92)	15.12 (4.39)
PP	10.17 (7.19)	16.00 (6.00)
6 wk
ITT	13.50 (5.87)	11.0 (4.57)
PP	10.17 (4.26)	14.33 (4.16)
12 wk
ITT	11.30 (7.18)	9.12 (3.44)
PP	6.50 (3.62)	9.33 (3.51)
Within the group (F; P value)
ITT	16.55; < 0.0011	40.91; < 0.001	2.13; 0.1371
PP	43.76; < 0.001	14.82; 0.0511	3.91; 0.061

¹Greenhouse-Geisser correction. CY-BOCS: Children’s Yale-Brown obsessive-compulsive scale; ITT: Intention to treat; PP: Per protocol.

RCADS-H subscale and total scores showed group time interaction to be significant in the MDD subscale [F (3) = 3.55, P = 0.50]. The mean reduction in CY-BOCS subscales and total scores was compared between both groups during the initial 2 wk (Table 3). Response rates at 2 wk were not significantly different [8 out of 10 in the active vs 3 out of 8 in the sham group, Fischer's exact test P = 0.145, number needed to treat = 2.35, 95%CI: (1.2, 127.2)].

Table 3 Comparison of mean reduction in Children’s Yale-Brown obsessive-compulsive scale total score between 2 groups across different follow-up periods, mean ± SD.

Change in C-YBOCS scores	Active tDCS (n = 10)	Sham tDCS (n = 8)	U value	P value
Baseline vs 2 wk
Obsessions	6.2 ± 4.26	2.37 ± 0.99	18	0.056
Compulsions	5.6 ± 3.75	2.87 ± 1.76	22	0.121
Total	11.8 ± 7.77	5.25 ± 2.22	18	0.056
Baseline vs 6 wk
Obsessions	7.0 ± 3.90	4.87 ± 1.53	22.5	0.131
Compulsions	6.5 ± 3.75	4.5 ± 2.64	25	0.312
Total	11.6 ± 6.93	9.37 ± 2.87	28	0.307
Baseline vs 12 wk
Obsessions	11.2 ± 1.66	9.0 ± 4.0	27.5	0.285
Compulsions	10.0 ± 2.0	7.5 ± 3.2	19	0.069
Total	13.8 ± 8.68	11.25 ± 3.34	29.5	0.373

tDCS: Transcranial direct current stimulation; CY-BOCS: Children’s Yale-Brown obsessive-compulsive scale.

Safety measures

No major adverse effects were recorded, and tDCS stimulation was well tolerated. 8 of 10 adolescents in active and 7 of 9 in sham group reported at least one side effect (relative risk = 1.03, number needed to harm = 45.0). For an individual session, 53.3% of active stimulations and 51.4% of sham stimulations resulted in a side effect. The maximum relative risk was for headache (2.14 for per session incidence and 1.56 for per individual incidence). Other side effects commonly reported were numbness, itching, pain at the stimulation site and sedation.

Medications

The average dose of fluoxetine and clonazepam was similar in both groups across all assessments. Adjunct medications were Risperidone 0.5 mg/d (2 in the active group, started after completion of tDCS sessions), Melatonin 3 mg (1 in the active group), and Propranolol 20 mg/d (1 in the sham group).

DISCUSSION

To the best of our knowledge, this is the first study worldwide that: (1) Has utilized tDCS as an early intervention strategy and (2) has studied tDCS in adolescents with OCD[16]. There was a significant reduction in CY-BOCS scores in both groups across the time frame assessed. Despite having a small sample size and single blinding, we did not find any significant intergroup differences in various statistical methods. A number of reasons could explain these findings, including early onset is a known risk factor for poor prognosis, biological differences in early onset OCD could be one of the key reasons. Stimulation parameters that showed positive results had tried twice-daily sessions and longer sessions of up to 30 min. Whether such changes in stimulation parameters could affect response in OCD is yet to be studied. An RCT targeting left OFC with cathodal stimulation also found non-significant changes between active and sham groups, which were controlled for single drug[17]. Another RCT with left DLPFC anodal and right OFC cathodal stimulation along with fluoxetine found non-significant differences with active and sham tDCS[18].

There were no comparator studies available for the adolescent age group. Among studies in adults with OCD, a trial by Silva et al[19] using cathodal SMA stimulation and anodal stimulation over the right supraorbital area showed a significant difference on repeated measures-ANOVA, group time interaction. However, the change in YBOCS scores was noticed in the period between 6 and 12 wk. The authors suggested a delayed effect of tDCS through neuroplasticity. Since we lost a number of patients during this period, we could have missed the delayed effects of tDCS. Multiple studies, including 3 RCTs, however, support the contrary hypothesis of acute effects of tDCS[3,17,20].

Stimulation sites on SMA have shown positive results in a number of studies other than one by Silva et al[19]. An open-label trial using cathodal tDCS over SMA and anodal stimulation over the right supraorbital area in treatment-resistant OCD reported a 26% decrease in Y-BOCS scores[20]. Even anodal stimulation at SMA has reported comparable findings in 25 adults with treatment-resistant OCD[3]. These differences arise from the use of medications, the level of resistance in patients included in the study, and other methodological issues.

A significant difference between groups was observed in the change in depressive symptoms. Comorbid depressive symptoms are common in OCD, and one RCT has reported such a change in depressive symptoms, while another one reported a non-significant reduction in depressive and anxiety symptoms[19,20].

Response in OCD is defined as ≥ 35% reduction in CY-BOCS scores and remission as CY-BOCS ≤ 12 score[21]. Our study found a high response rate of 80% at 2 wk, although the difference with the sham group was not significant. Larger trials have found lower response rates ranging between 15% and 19%[19,20]. The high response rate can be attributed to the selection of drug naïve adolescents and the exclusion of treatment-resistant cases and those with comorbidities. A trial by Yoosefee et al[18], which excluded treatment-resistant cases and used fluoxetine, reported similar response rates in active and sham groups. But they used a lower frequency of sessions (3/wk) and did not target SMA[5]. 5 of 10 adolescents in the active group attained remission, which was sustained till 12 wk. No other studies reported remission in study participants.

One of the reasons for finding no significant difference between the groups could be due to the placebo effect, which has been observed highly in studies of rTMS and tDCS[22]. Participants receive considerable information during the recruitment phase and speculate about its effects[23]. The placebo effect through caregiving, change of environment, and its neurobiological component have been seen in OCD patients as well[24]. The placebo effect in tDCS has been less in treatment-resistant cases[25]. Since the majority of the previous studies have been in such patient populations, the difference in response rates and comparable effects in sham and true groups can be explained by placebo response. Placebo and expectation effects can also change with the wording used to explain participants[26].

Another aspect is that tDCS affects long-term neuroplasticity, which takes several weeks to show its effects. This is particularly important in OCD, as a measurable response can take 8 to 12 wk[27,28]. Meanwhile, the long-term effects of tDCS, particularly on developing brains have not been studied thoroughly. Data from tDCS use in children with neurodevelopmental and motor disorders does not show any serious long-term adverse effects[29]. But long-term follow-up studies in mood and anxiety disorders in children are lacking.

Strengths and limitations

Our study found that tDCS is a safe modality of treatment in adolescents with OCD. tDCS was not found to be effective in this study. Limitations of our study include a small sample size, single blinding, and not conducting twice daily or extended protocols. This highlights the need for further research with robust methodology, controlled drug use, and a larger sample size. The study was also limited by a short follow-up period; therefore, we may have missed out on the long-term effects of tDCS on adolescents, particularly in terms of development. This is another area of research in future studies.

CONCLUSION

tDCS as a modality for the treatment of OCD in the adolescent age group is safe and well tolerated. However, early intervention with tDCS, may not be effective in adolescents with OCD.