Psychiatry is entering a new era—one where medications and electricity converge to reshape the brain’s plasticity. Among the most exciting pairings being explored is ketamine with transcranial direct current stimulation (tDCS). Both treatments have independent antidepressant effects, but together they might open a new chapter in treating resistant depression.

1. Two distinct routes to the same goal: synaptic renewal

• Ketamine is a rapid-acting NMDA receptor antagonist that increases glutamate transmission, activates AMPA receptors, and triggers downstream BDNF and mTOR cascades—pathways linked to neuroplasticity and mood improvement.
• tDCS delivers a low-intensity electrical current (1–2 mA) through scalp electrodes to modulate cortical excitability. When the anode is placed over the left dorsolateral prefrontal cortex (DLPFC), it enhances activity in brain regions underactive in depression.

Both interventions boost plasticity—ketamine chemically, tDCS electrically. When combined, the hypothesis is that tDCS can guide or stabilize the neural rewiring triggered by ketamine.

2. What research currently tells us

Preclinical evidence: promising signals

In a foundational experiment by Lahogue & Pinault (2021), anodal tDCS applied over frontoparietal regions reduced the abnormal cortical oscillations (so-called oscillopathies) induced by ketamine in rats. This suggests that electrical stimulation can modulate ketamine’s electrophysiological footprint, supporting the idea that one can steer the brain’s “plasticity window.”

Clinical landscape: early but expanding

• A systematic review by Ren et al. (2025) synthesised transcranial electrical stimulation (tES—including tDCS) trials in major depressive disorder and confirmed antidepressant benefits with good tolerability.
• Tham et al. (2022) reported robust response rates using repeated subcutaneous (SC) ketamine twice weekly for treatment-resistant depression, while Pereira et al. (2023) extended this to SC esketamine, showing maintained efficacy.
• In contrast, home-based tDCS trials (Nature Medicine, 2025) found mixed results—reminding us that stimulation parameters and supervision matter as much as dose.

Though no large human study yet combines ketamine and tDCS directly, related data from TMS + ketamine protocols offer analogical optimism. Meta-analyses (Arubuolawe et al., 2024; Dębowska et al., 2023) show that concurrent TMS enhances and prolongs ketamine’s antidepressant effects, hinting that combining pharmacologic and electrical neuromodulation could yield synergy.

3. Why the combination makes mechanistic sense

• Ketamine opens the gate. Within hours of dosing, ketamine creates a state of increased synaptic receptivity—a “plasticity window.”
• tDCS provides direction. By biasing excitatory–inhibitory balance across prefrontal networks, tDCS can theoretically consolidate adaptive connectivity patterns.

In essence, ketamine loosens the knots; tDCS helps tie them differently.

This rationale resonates with the concept of metaplasticity—how one form of stimulation alters the brain’s responsiveness to another. Sequential application may amplify antidepressant durability while minimizing total ketamine exposure.

4. Translating theory into clinical design

Until evidence matures, any ketamine + tDCS protocol should remain within research or advanced clinical innovation frameworks. A pragmatic, safety-focused outline could look like this:

Phase	Approach	Parameters (illustrative)
Induction	tDCS before ketamine to “prime” cortex	1–2 mA × 20–30 min; anode L-DLPFC, cathode R-supraorbital
Ketamine administration	SC or IV 0.25–0.5 mg/kg	Once or twice weekly for 4–6 sessions
Consolidation	Optional tDCS immediately post-infusion	Same montage; may enhance retention
Maintenance	Gradual spacing of both modalities	Based on symptom recurrence and tolerability

Monitor vitals, mood, dissociation, BP, and cognitive change at each visit. Exclude patients with seizures, metallic cranial implants, or unstable cardiovascular status. Institutional ethics approval and detailed informed consent are essential, as ketamine remains off-label for psychiatric use outside esketamine formulations.

5. A balanced view: opportunity with caution

While the neurobiological logic is compelling, caution is warranted:

• Evidence gaps: No randomized human trials yet prove additive benefit or define sequencing.
• Safety overlap: Both interventions alter excitability; rare risk of overstimulation or mania requires monitoring.
• Variability: Dose-response in tDCS follows a non-linear curve (Sabé et al., 2024); more is not always better.

Still, the low cost, portability, and non-invasiveness of tDCS make it a realistic adjunct for clinicians already using ketamine under supervision.

6. The future: precision neuromodulation

The next step is personalised protocols guided by biomarkers—EEG or QEEG oscillatory signatures, HRV indices, or fNIRS-derived prefrontal activity. As our ability to see and shape the brain improves, combinations like ketamine + tDCS may move from experimental curiosity to precision therapy.

For now, think of them as two instruments in the same orchestra: ketamine provides the melody of rapid relief; tDCS adds rhythm and stability.

Author:
Dr. Srinivas Rajkumar T, MD (AIIMS Delhi), DNB, MBA (BITS Pilani)
Consultant Psychiatrist, Mind & Memory Clinic
Apollo Clinic Velachery (opposite Phoenix MarketCity), Chennai
📞 +91 85951 55808 | 🌐 srinivasaiims.com