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Electrical Brain Stimulation for Depression: What's Working and What's Still "On the Way"
Last reviewed: 18.08.2025
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Transcranial electrical stimulation (tES)—the umbrella term for tDCS, tACS, and tRNS—is back in the spotlight. A major systematic review and meta-analysis by Mayo Clinic and colleagues pooled 88 randomized trials (5,522 participants) and broke down where, how, and for whom these techniques actually work. The big news: tACS showed robust effects in major depression, tDCS showed measurable improvement in patients with depression associated with other psychiatric/physical illnesses, and tDCS + drug combination enhanced response compared with drug therapy alone. Side effects were generally mild to moderate.
The meta-analysis covered publications up to September 17, 2024, and assessed several outcomes at once: the severity of depressive symptoms, response and remission rates, and safety. The authors separately analyzed three stimulation formats and three clinical "contexts": major depression (MDD), depression with psychiatric comorbidities (DPC), and depression with somatic comorbidities (DMC). This design made it possible to see that "electricity" is not a monolith, but a set of tools for different tasks.
Background
Depression remains one of the main causes of lost years of life with disability: even with the right therapy, a third of patients do not achieve a response, and remission is achieved steadily even less often. Antidepressants have a moderate effect and often have side effects; psychotherapy is effective, but requires time and accessibility. Hence the interest in non-drug neuromodulation methods.
The map of interventions has long included ECT (high efficiency, but limitations in terms of tolerability/stigma) and TMS (proven effect, but equipment and time are expensive). In comparison, transcranial electrical stimulation (tES) is a more accessible class of methods: compact devices, simple protocols, prospects for home use under the supervision of a clinic. Under the tES umbrella are three techniques with different physiology:
- tDCS (direct current) - gently shifts cortical excitability; most often targets the left dorsolateral prefrontal cortex (DLPFC), which is hypoactive in depression.
- tACS (alternating current) - attempts to entrain abnormal oscillations in networks associated with mood, attention, and self-reference.
- tRNS (random noise) - through stochastic resonance increases the signal-to-noise ratio in networks, but the database is still small.
The theoretical goal is the same for all of them: to normalize the work of frontolimbic networks (DLPFC ↔ cingulate cortex ↔ amygdala) and the balance between the frontoparietal control network and the default network. However, the clinical literature has been heterogeneous until recently: small RCTs, different currents, duration, electrode locations; populations were mixed - "pure" major depression and depression against the background of comorbidities (pain, post-stroke conditions, anxiety disorders, etc.). Add to this the variability of control (sham does not always perfectly "blind" due to tingling under the electrodes) and inconsistency in outcomes (total score, response, remission, duration of effect) - and it becomes clear why the results of individual studies diverged.
Therefore, the next logical step is a large systematic review and meta-analysis that:
- will decompose the effect by methods (tDCS, tACS, tRNS) and clinical contexts (MDD, depression with psychiatric and somatic comorbidities);
- assess whether the combination with pharmacotherapy/psychotherapy enhances the clinical response;
- compare the safety of methods and standardize adverse event reporting;
- will provide guidelines for stimulation parameters (goal, polarity, number of sessions) in order to move away from the “art of protocols” to reproducible schemes.
These are the questions that the latest meta-analysis addresses: it helps to understand who should be offered what type of tES first, where the evidence is already sufficient for practice, and where head-to-head testing and personalization based on neurophysiological markers are still needed.
Key Results
- tACS (alternating current)
- Significant improvement in symptoms in MDD: SMD -0.58 (95% CI -0.96…-0.20);
- Increase in response rate: OR 2.07 (1.34-3.19);
- Quality of evidence - high. - tDCS (direct current)
- Greatest benefit in depression with comorbidities:
• DMC: SMD −1.05 (−1.67…−0.43);
• DPC: SMD −0.78 (−1.27…−0.29);
- For “pure” MDD, the effect is smaller and statistically borderline;
- The combination of tDCS + medication enhances the effect: SMD −0.51 and OR of response 2.25;
- tDCS + psychotherapy did not show any additive effects;
- The best protocol is the anode over the left dorsolateral prefrontal cortex. - tRNS (random noise)
- There is little data yet, so no conclusions can be made about the benefits. - Safety
- Adverse events are more common in tES groups but are mild/moderate (burning, tingling, headache). Serious events are rare.
Why is it important to differentiate the clinical context? In depression with somatic or psychiatric comorbidities (pain, stroke, anxiety disorders, etc.), the brain networks of depression can be “reconfigured” so that soft current modulation gives a more noticeable clinical benefit. And in classical MDD, tACS (rhythmic tuning of networks) can work better than the “fine” polarization of tDCS. These differences are not statistical nitpicks, but a hint for stimulation personalization.
What does this mean for practice now?
- Who should consider tES:
- Patients with MDD where medications are poorly tolerated/not working - tACS as a high-evidence option;
- Patients with depression and somatic/psychiatric comorbidities - tDCS, especially in addition to medication. - How to select a protocol:
- For tDCS - the anode is on the left above the DLPFC, the cathode is contralateral/orbital (the specialist will specify the details);
- Plan a course (usually 10-20 sessions) and monitor tolerance;
- Consider that tRNS is still “under study”. - What not to expect:
- An immediate “ketamine-like” effect;
- A universal response: some patients do not respond, stratification and adjustment of parameters are needed.
Despite the positive picture, the authors are cautious: the overall quality of evidence for most outcomes is low/moderate (exception: tACS in MDD). The reasons are typical for the field: heterogeneity of protocols (currents, electrodes, duration), variability of populations, different outcome scales. That is, the course towards standardization and “fine tuning” remains a priority.
What to add to the research
- Make a head-to-head: tACS vs tDCS in “pure” MDD and in subtypes (melancholic, atypical, etc.);
- Individualize EEG/neuroimaging parameters (frequencies, electrode placement, current doses);
- To record “hard” outcomes (remission, durability of response, functional recovery) and safety during long-term observation;
- Standardize reporting of adverse events to enable fair comparisons of methods and their combinations.
Context: Where is tES on the map of non-drug interventions
In the treatment of depression, “nerve” technologies are often compared to TMS (magnetic stimulation) and ECT. tES has a different niche: fewer hardware requirements, lower entry threshold, the possibility of a home format under clinical supervision (within an evidence-based framework), potential synergy with drugs and cognitive training. The new report does not “crown” tES as a panacea, but clearly shows that the method has taken its place in the arsenal, especially as an adjuvant.
Restrictions
- Irregularity of stimulation parameters between RCTs;
- Heterogeneity of samples and scales;
- For tRNS, there are too few studies to make clinical recommendations;
- The effects of "tDCS monotherapy" on MDD appear modest - the combination with pharmacotherapy is important.
Conclusion
TES is no longer a “fashionable gadget”, but a working tool with evidence: tACS helps with major depression, tDCS - with depression with comorbidities and in combination with drugs; safety is acceptable, and the next task is to standardize protocols and learn to adjust the current to the patient, and not vice versa.
Source: Ren C. et al. Transcranial Electrical Stimulation in the Treatment of Depression: A Systematic Review and Meta-Analysis. JAMA Network Open, 2025 Jun 18; 8(6):e2516459. doi:10.1001/jamanetworkopen.2025.16459