For many people living with major depressive disorder, the path to recovery is rarely a straight line. Even when a prescribed antidepressant begins to work, there is often a frustrating plateau known as a partial response. Here’s the gap between feeling “better” and feeling “well”—a state where symptoms have improved, but the patient has not reached full remission.
The danger of settling for a partial response is that residual symptoms can act as a bridge back to a full depressive episode. According to Nissa Keyashian, MD, a psychiatrist in San Jose, California, evidence suggests that any remaining symptoms of depression can increase the likelihood of a relapse, even after significant initial improvement.
When traditional medications like selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants provide only modest relief, patients and providers must decide when to pivot. For those seeking depression treatment: when to consider TMS or ketamine for partial response, the decision often hinges on the severity of remaining symptoms and the patient’s tolerance for the side effects of their current regimen.
While adjusting dosages or adding psychotherapy are common first steps, emerging interventional treatments offer a different biological approach to “rewiring” the brain’s response to depression.
The Biological Shift: How Ketamine and Esketamine Work
Most traditional antidepressants focus on modulating neurotransmitters like serotonin, dopamine, and norepinephrine to regulate mood. Ketamine and its derivative, esketamine, operate on a different chemical pathway entirely. Instead of targeting serotonin, they block N-methyl-D-aspartate (NMDA) receptors, which in turn regulates glutamate—a neurotransmitter closely linked to the pathology of depression.
This mechanism does more than just shift chemistry; it promotes structural change. Alex Dimitriu, MD, a psychiatrist and founder of Menlo Park Psychiatry and Sleep Medicine, notes that unlike traditional antidepressants, ketamine increases synaptic plasticity. “Essentially helping the brain rewire and form recent connections quickly,” Dr. Dimitriu says. For a patient who has stopped responding to standard meds, this ability to facilitate new neural connections can be a critical turning point.
There are two primary ways these medications are administered, each with different regulatory statuses and delivery methods:
- Ketamine Infusions: Administered via IV in a clinic or hospital setting. While widely used off-label for depression, ketamine is not FDA-approved for this specific indication.
- Esketamine (Spravato): An FDA-approved nasal spray specifically for treatment-resistant depression. It is typically reserved for those who have failed at least two antidepressants and must be administered under medical supervision.
The experience of esketamine is highly structured. Patients typically begin with two sessions per week for the first month before transitioning to weekly or biweekly doses. Because the drug can cause dissociation—a feeling of mental disconnect—as well as spikes in blood pressure or extreme sleepiness, patients are required to be monitored for at least two hours following each treatment.
Magnetic Stimulation: A Non-Invasive Alternative
For patients who prefer a non-pharmacological approach or who cannot tolerate the side effects of medication, Transcranial Magnetic Stimulation (TMS), or rTMS, provides an option. Rather than introducing a chemical agent into the bloodstream, TMS uses magnetic pulses to stimulate electrical activity in specific regions of the brain.
The treatment specifically targets the dorsolateral prefrontal cortex, an area of the brain associated with the negative thought loops and dwelling common in depression. A magnetic coil, housed in a special cap, delivers these pulses in sessions lasting between 3 and 30 minutes.
TMS is generally well-tolerated and non-invasive, meaning no sedation is required and patients can drive themselves home immediately. But, it is a significant time commitment. A typical course requires clinic visits five days a week for at least a month. While rare, the treatment carries a low risk of triggering seizures and can cause temporary side effects such as facial muscle twitching, headaches, or ringing in the ears.
Comparing Interventional Options
| Treatment | Mechanism | Delivery Method | Key Consideration |
|---|---|---|---|
| TMS | Magnetic pulses to prefrontal cortex | In-clinic magnetic coil | Time-intensive (daily visits) |
| Ketamine | NMDA receptor block/Glutamate | IV Infusion (Off-label) | Requires clinic-based IV |
| Esketamine | NMDA receptor block/Glutamate | Supervised nasal spray | FDA-approved for treatment-resistance |
Navigating the Path to Remission
Moving from a partial response to full remission requires a candid dialogue with a healthcare provider. Naomi Torres-Mackie, PhD, a clinical psychologist at Northwell Lenox Hill Hospital, emphasizes that patients should first establish a clear understanding of how well their current treatment is actually working.
Dr. Torres-Mackie suggests that when discussing options with a provider, patients should ask for a plural list of alternatives. This allows them to weigh the pros and cons of different strategies—such as adjusting dosages, adding a second medication, or pursuing interventional treatments like TMS—rather than feeling locked into a single path.
The transition to these advanced treatments is often complicated by the “insurance hurdle.” Because TMS and esketamine are specialized, many insurers require extensive documentation proving that at least two other antidepressants were tried and failed before they will grant coverage. Generic ketamine infusions, being off-label, are frequently an out-of-pocket expense, though they may be easier to access administratively.
For those exploring these options, the Mayo Clinic and the National Institute of Mental Health provide authoritative guidelines on the criteria for treatment-resistant depression and the safety profiles of interventional psychiatry.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.
If you or a loved one are in crisis, please contact the 988 Suicide & Crisis Lifeline by calling or texting 988 in the US and Canada, or calling 111 in the UK.
As clinical research continues to evolve, the next major checkpoint for patients and providers will be the continued integration of these therapies into standard care guidelines and the potential expansion of insurance coverage for off-label ketamine use. Ongoing trials into the long-term durability of TMS and esketamine will likely dictate how these treatments are phased into the standard depression care timeline.
We invite you to share your experiences with treatment-resistant depression or ask questions about these therapies in the comments below.
