At this very moment, a quiet revolution is transforming treatment for depression. At the forefront is a group of therapies known collectively as "neuromodulation," defined as “the alteration of nerve activity through targeted delivery of a stimulus to specific neurological sites.” Translated into plain English, this means applying electricity selectively and in specific patterns to change the activity of brain cells.
Several neuromodulation technologies are under development; a couple has already been approved by the FDA and are in widespread use for depression. These are vagal nerve stimulation using electrodes implanted in the body and repetitive transcranial magnetic stimulation (TMS). TMS takes advantage of one of the fundamental laws of physics (Ampere’s Law) linking electricity to magnetism. TMS harnesses Ampere’s Law to generate weak electrical currents deep within brain tissue using externally-placed electromagnets — it stimulates nerve cells electrically without the need for surgery, electrodes, or any other implanted brain hardware.
It’s important to note that patients receiving neuromodulation therapy for depression do not feel better instantly. That’s because it’s not the electrical stimulation itself, nor the activity driven directly by electrical stimulation, that relieves depression. Instead, it is a delayed change occurring in brain cells after the stimulation is over that improves mood. That is where the term "neuromodulation" comes from. How does neuromodulation work, exactly?
All forms of neuromodulation rely on the "plasticity" of the brain. Plasticity (more technically "neuroplasticity") refers to the property of the mature brain allowing it to change over time, including in response to its own activity. Brain cells (neurons) process information electrochemically, exchanging information at specialized cell junctions called synapses.
Short-term activity changes at synapses can lead to long-term changes in a neuron’s properties. Among the properties that can change is the likelihood that the neuron will "fire" in the future, thereby transmitting information to other neurons. Other properties that can change include the physical structure of a neuron’s synapses and other aspects of its "wiring diagram" (neural architecture). Even the elimination or creation of synapses and of whole new brain cells (synaptic pruning, synaptogenesis, and neurogenesis) can be affected in this way.
Together, all these aspects of neuroplasticity add up to changes in brain circuitry and brain activity, but this takes weeks or even months to transpire. That is why neuromodulation takes weeks or months to improve mood — it takes that long for neuroplasticity to do its job. To summarize, it is not direct stimulation of nerve or brain cell activity that makes depressed people feel better; it is the long-term effects this has on brain circuitry and brain activity that ultimately lift mood and change behavior.
How different is this from how antidepressant pills work? Patients often come to me with the idea that depression is caused by a "chemical imbalance" in their brains. This concept has gained traction over the past half-century, during the same period that antidepressant medications have come into widespread use.
The first antidepressant pills were invented in the 1950s and their use expanded tremendously with the advent of low side-effect versions in the 1980s. All antidepressant pills work by elevating a small subset of brain chemicals (neurotransmitters) in the brain, so the notion that depression is caused by an imbalance in these chemicals sounds perfectly reasonable: You get depressed from a "serotonin deficiency." This can be corrected by taking a "selective serotonin reuptake inhibitor" (SSRI, e.g. Prozac, Lexapro, etc) that raises serotonin levels back to normal and makes you feel better. If you’re severely depressed that’s because you have a deficiency in a second neurotransmitter, norepinephrine. In that case, you should take a stronger pill called a "Serotonin and Norepinephrine Reuptake Inhibitor" (SNRI, e.g. Effexor, Cymbalta, etc) that fixes both chemical imbalances at the same time. If your depression is a bit unusual, it may be because you suffer from a "chemical imbalance" in a third neurotransmitter, dopamine. We have a pill just for that too (Wellbutrin, which increases dopamine and norepinephrine); it works for depressed patients who suffer from combined "dopamine and norepinephrine deficiency."
This sounds straightforward, but is it really true that depression is caused by "serotonin deficiency," "norepinephrine deficiency" or "dopamine deficiency?"
There is a big problem with this idea: Just like the neuromodulation therapies discussed earlier, antidepressant medications take weeks or even months to work. This doesn’t make sense if the pills cure depression by fixing a chemical imbalance. Within minutes of taking an antidepressant medication, levels of serotonin, norepinephrine and/or dopamine begin to change at synapses in a person’s brain. If your depression were caused by a chemical imbalance that could be corrected by antidepressant medication, you should start to feel better within minutes of taking your first pill. And you should be completely cured of depression within a week of taking an antidepressant pill regularly because that is how long it takes for the medication to peak and stabilize in your system. Instead, the positive effects of the pills on mood can take months to occur.
The most plausible explanation for why antidepressant medications take so long to work is that, just like neuromodulation therapies, they rely on neuroplasticity. Prozac doesn’t improve mood by instantly fixing a "serotonin deficiency." Instead, it and all other antidepressant pills work by slowly changing brain circuitry and patterns of brain activity — in other words, they also work by neuromodulation.
This is plausible because, as already mentioned, the brain is both electrical and chemical — it is an electrochemical machine. The difference between the newer "neuromodulation" therapies and the more traditional antidepressant pills is just in the way that neuromodulation is achieved: electrode- and magnet-based stimulators change electrical currents in the brain, whereas antidepressant pills change chemicals in the brain, but both rely on neuroplasticity to improve mood. Because of neuroplasticity, short-term changes in brain cell activity — regardless of whether it is achieved by a drug, an electrode, an electromagnet, (or by talking to a talented therapist) — lead to long-term changes in brain circuitry and activity patterns. It is this process that ultimately lifts a person out of depression, and it takes weeks, if not months, to happen.
Or does it? Recently a new antidepressant medication has emerged that works much faster than pills, nerve stimulators, or TMS. Astute physicians noticed that some patients anesthetized with a drug called ketamine emerged from anesthesia in a much better mood than before they went under. Interestingly, this mood improvement could last for weeks or even months after the anesthetic agent had worn off. A version of ketamine ("esketamine") delivered by nasal spray has recently been approved by the FDA as a rapid-acting antidepressant, but nobody yet understands how it works.
The pharmacology of ketamine is extremely complex: It binds to a wide range of brain receptors that are completely different from the targets of antidepressant pills. Moreover, there are some differences in the brain targets of the nasal spray version (esketamine) versus the intravenous anesthetic version (ketamine), and some of these differences could be important for antidepressant response. For now, the only thing clear about ketamine/esketamine is that its mechanism of action is different from antidepressant pills. Given how rapidly it works, it must also act differently than neuromodulation therapies like TMS or nerve stimulation.
I’m just thankful no patients have walked into my office yet saying they’re depressed because of a "ketamine imbalance." I hope scientists figure out how ketamine works before that begins to happen!
 Yang, C., Yang, J., Luo, A. et al. Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites. Transl Psychiatry 9, 280 (2019). https://doi.org/10.1038/s41398-019-0624-1