TDCS is a non-invasive brain stimulation technique that modulates cortical excitability and spontaneous brain activity in a safe, economic, and well-tolerated manner. Since BD is a common and complicated disorder that sometimes causes long-term use of psychiatric medications, the use of new alternative therapies such as TDCS can be effective in improving the performance of BD patients. To the best of our knowledge, this is the first clinical trial that investigates the effect of tDCS combined with medication therapy on depression and inhibitory control of patients with BD. The findings of our study revealed the effectiveness of right anode/left cathode tDCS (2 mA, 20 min) combined with medication in reducing depression of adults with BD compared to those received medication only. Some studies have examined the effect of tDCS on the depression of BD patients. In a clinical trial by Sampaio-Junior et al. (24), patients with bipolar depression received left prefrontal anodal stimulation as an add-on treatment to their pharmacological therapy. Patients receiving active stimulation had a more significant symptom reduction as compared to those treated with sham tDCS. Dondé et al. (25) in a meta-analysis showed that tDCS could improve depressive symptoms in patients with bipolar depression, particularly after 1 week of treatment. Herrera-Melendez et al. (26) in a review study also found out that tDCS potentially improves depressive symptoms in patients with bipolar depression. Aparicio et al. (27) and Martin et al. (28) also concluded that tDCS can reduce depressive symptoms. McClintock et al.(29), in a controlled clinical trial, concluded that tDCS could have positive neurocognitive effects in patients with unipolar and bipolar depression. There is one published case report on the combination of tDCS with pharmacological treatment in a male patient with an acute episode of mania (30) where the authors performed anodal tDCS over the right DLPFC combined with a pharmacological intervention and reported an improvement of manic symptoms that lasted until 72 h after stimulation. These findings are consistent with our results. In our study, the use of medication alone (mood stabilizers) also reduced depression of BD patients which is consistent with the results of Sachs et al. (31), Pacchiarotti et al. (32), who reported the effect of antidepressant drugs in BD.
DLPFC has been linked to depression due to decreased left DLPFC performance and increased right DLPFC performance (33). During the depression, there is a possibility of dysfunction along with decreased regional blood flow or glucose metabolism in left DLPFC (34) and hyperactivity of the right DLPFC (according to the theory of prefrontal asymmetry), The right anode/left cathode tDCS can therefore help reduce depressive symptoms (33). On the other hand, although mood stabilizers have been approved by the FDA for treating patients with BD, they are not enough because some patients are resistant to these medications or high doses of these medications can reduce the patients’ daily performance. The use of tDCS can facilitate the effects of medication therapy. It can modulate synaptic transmission by regulating the dose of transmitters, including serotonin (35). Hence, it is suggested that tDCS can be a useful method for treating depression of BD patients combined with medication. The effect of combined therapy in our study was not stable for 3 months after stimulation. This may be because of the low number of sessions and duration (10 sessions each for 20 min). The use of high number and longer sessions may affect the stability of its effect.
The findings of our study showed the effectiveness of combining tDCS with medication in reducing commission error of BD patients under a go/no-go task compared to the medication therapy alone, indicating its impact on the improvement of their response inhibition ability. Some studies have reported the effict of tDCS on inhibitory control such as Hogeveen eta al. (18), Cunillera et al. (36), and Wynn et al. (37), indicating that the placement of electrodes in different areas of the brain causes different efficiencies over time. For justifying the results, it can be said that the frontal-lateral region, as one of the important regions of the prefrontal cortex which was simulated in our study, is responsible for identifying and determining actions, evaluating and predicting the consequences of current behavior, social control, and response inhibition. Moreover, based on the Barkley’s inhibition model, it is assumed that the proper executive functioning depends on the proper functioning of inhibition in the frontal and prefrontal cortex (38). Furthermore, it has been reported that the F3 region in the prefrontal cortex plays an important role in inhibiting inappropriate behavioral responses(39). Therefore, stimulation of this area could improve the management of impulsive behaviors and response inhibition in BD patients by regulating the activity of frontal, prefrontal lobes, and anterior cingulate cortex. As mentioned above, tDCS modulates synaptic transmission by regulating the dose of transmitters. Hence, it can be said that TDCS is a complementary therapy and can accelerate and improve the mechanism of medication therapy.
In our study, gains in response inhibition ability were not maintained at 3-month follow-up. Stable results may be achieved if the number and duration of tDCS sessions increases or the stimulated area is changed. Since BD is one of the most severe psychiatric disorders and, on the other hand, response inhibition is severely impaired in these patients and is associated with other behavioral consequences, other interventions such as emotion regulation strategies, cognitive rehabilitation are required along with tDCS to be able to stabilize this effectiveness. Medication therapy alone (use of mood stabilizers) did not improve response inhibition ability of patients in our study. This is consistent with the results of Pavuluri et al. (40) who showed that treatment with either risperidone or divalproex failed to dampen disordered amygdala connectivity in the occipital-limbic network during a response inhibition fMRI task, but is against the results of Pavuluri et al. (41) who showed that treatment with second-generation antipsychotics followed by lamotrigine monotherapy enhanced prefrontal and temporal lobe activity during a go/no-go task.
Some of the limitations of the present study were the use of a purposive sampling method, small sample size, and not examining different TDCS protocols. Therefore, it is suggested that further studies be performed using a larger sample size and objective tools such as electroencephalography and functional magnetic resonance imaging. Moreover, it is recommended that the effect of combining medication therapy with other novel therapies such as neurofeedback or repetitive transcranial magnetic stimulation be investigated.