Treatment-Resistant Depression · Hayward, CA

By the time most patients ask me about TMS, they have already tried two, three, sometimes five antidepressants. They did the SSRI. They did the SNRI. They added bupropion, then maybe lithium, then switched again. Some got partial relief. Some got side effects that were worse than the depression. Most are tired of waiting eight weeks for the next medication to maybe work.

So when they sit down in my Hayward office and ask, TMS or medication?, the question underneath is usually different. It is: which pathway have we not tried yet, which side effects are tolerable, and which treatment can I actually finish.

The real question after two failed antidepressants

Treatment-resistant depression is not a label most patients give themselves. A 2022 Delphi consensus of international experts defines it as depression that has not responded to at least two antidepressants given at adequate dose and duration during the current episode.^[1] That is the working definition I use in clinic, and it matters because of what comes next in the algorithm.

The STAR*D trial, the largest sequenced-treatment study of depression ever run, followed more than 4,000 patients through up to four medication steps. The original 2006 report gave step-by-step remission rates of 36.8%, 30.6%, 13.7%, and 13.0%. Cumulatively, 67% of patients eventually remitted.^[2] A 2023 reanalysis of patient-level STAR*D data using the protocol-specified outcome measure put the true cumulative remission closer to 35%.^[3]

However you read those numbers, the pattern is the same. Each medication trial after the first one has a smaller chance of working. By trial three or four, the odds of full remission on another pill are roughly one in seven. That is the moment when the question stops being which antidepressant next and becomes are we still solving the same problem with the same tool.

What medication actually means

Medication is not one thing. It is a set of chemical pathways you are choosing to influence.

SSRIs — sertraline, fluoxetine, escitalopram, citalopram — primarily act on serotonin. SNRIs like venlafaxine and duloxetine act on serotonin plus norepinephrine. Bupropion (Wellbutrin) is different. It works on dopamine and norepinephrine, which is why it tends to be more activating and less likely to cause sexual side effects or weight gain.^[4]

Newer mechanisms have entered the picture. Auvelity (dextromethorphan-bupropion) was FDA-approved on August 18, 2022 as the first oral NMDA receptor antagonist for major depressive disorder.^[5] In the GEMINI Phase 3 trial of 327 adults with MDD, Auvelity reduced MADRS depression scores by 15.9 points at week 6 versus 12.0 for placebo. Remission was 39.5% on Auvelity versus 17.3% on placebo, with separation from placebo by week one.^[6] Important caveat: GEMINI studied MDD broadly, not specifically TRD, so the data does not yet tell us how Auvelity performs in patients who have already failed multiple antidepressants.

Lithium augmentation remains one of the most evidence-supported strategies when an antidepressant has helped only partially. Bauer’s systematic review of acute trials found roughly 45% response with adjunctive lithium versus 18% on placebo.^[7] Lithium requires blood-level monitoring and labs, but the response data is sturdy.

Where medication starts to feel like waiting

Medication asks you to be patient. You start a new SSRI. You wait four to six weeks. You titrate. You wait again. You might get partial relief and a side effect: nausea, sexual dysfunction, weight gain, emotional blunting, sleep disruption, sweating. Some of those fade. Some do not. Some get worse with dose increases that were supposed to help.

If you have done this two or three times, you are not failing the system. You are revealing what the system can and cannot do. Medication targets neurotransmitter pathways through the bloodstream. When the bloodstream-and-receptor model has been tried thoroughly and the depression has not budged, the question becomes whether the circuits themselves need a different kind of input.

How TMS works on the brain differently

Transcranial magnetic stimulation does not travel through the bloodstream. It uses focused magnetic pulses to stimulate specific brain regions from the outside of the scalp. For depression, the target is most often the left dorsolateral prefrontal cortex, an area underactive in depressed patients and central to the circuits that regulate mood, motivation, and rumination.^[8]

The mechanism is closer to circuit retraining than chemistry. Each session delivers thousands of pulses that drive activity in the target region and the networks connected to it. Over a course of treatment, this changes how those networks fire, a phenomenon called long-term potentiation that supports neuroplasticity.^[9] In simple terms: TMS uses repeated stimulation to help the brain build new patterns out of the old depressive loops.

That is a different mode of action from any oral antidepressant. It is why TMS often helps patients who did not respond to medication, and why it can be used while continuing the antidepressants you already take.

Where TMS asks something different of you

TMS is not painless and it is not casual. A standard depression course is five days a week for four to six weeks, typically 30 to 36 sessions.^[8] The treatment is delivered in a clinic chair. Sessions run about 20 minutes for iTBS up to 40 minutes for standard 10-Hz protocols. You can drive yourself, go to work, pick up your kids afterward.

What the brochures undersell is the sensation. The pulses feel like rapid tapping against the scalp at the treatment site. Most patients describe it as uncomfortable for the first few sessions and then increasingly tolerable. Some report headache, scalp soreness, or facial twitching during stimulation. In a meta-analysis of 93 placebo-controlled trials, active TMS adverse events were reported by 29.3% of patients versus 13.6% on sham, but discontinuation rates were nearly identical between the two (2.5% versus 2.7%).^[15] Most side effects are short-lived, and most patients finish the course.

Side effects: where the burden actually lives

The honest comparison is not which treatment has side effects. It is where the side effects show up and how long they last.

Medication side effects are systemic because the drug circulates through the body. Sexual dysfunction, weight changes, sleep changes, sweating, GI upset, emotional flattening, drug-drug interactions: these are the ones I hear about most. They tend to last as long as you take the medication, and they often outlast the depression itself if the antidepressant only helped halfway.

TMS side effects are mostly local and time-limited. They show up during sessions or shortly after, and they are usually resolved by the time you walk out the next day. Scalp discomfort and headache are the most common, and both typically respond to coil repositioning, intensity adjustment, or a regular dose of acetaminophen before sessions.^[15]

Two safety considerations deserve direct attention. Seizure with rTMS is rare. A 2022 transdiagnostic analysis of 43,873 accelerated TMS sessions reported a seizure rate of roughly 1 in 44,000 sessions, about 0.0023%.^[16] For standard once-daily protocols the historical rate is on the order of 7 per 100,000 sessions. Risk is concentrated in patients with personal or family seizure history, certain medications that lower seizure threshold, or alcohol withdrawal.

Manic or hypomanic switch is the second consideration, particularly for patients with bipolar history. A 2024 network meta-analysis of theta-burst stimulation found no significant increase in manic switch incidence with active TBS versus sham, but every TMS clinic should screen for bipolar history and monitor for early signs: sudden surge in energy, decreased sleep without fatigue, racing thoughts, irritability, impulsivity.^[17] If any of those show up during treatment, the plan needs to be adjusted, not pushed through.

Which one should come first

If you have not yet had a careful, sequenced medication trial, meaning two different antidepressants, each at an adequate dose for an adequate duration, ideally guided by your symptom pattern, that is usually the place to start. Medication is easier to begin, often covered up front by insurance, and adjustments are relatively quick. If your symptom pattern points to a specific pathway (low energy and motivation suggest something dopaminergic like bupropion; severe insomnia or anxiety suggest a different conversation), that should drive the medication choice.

TMS becomes the right next step when one or more of these is true: you have failed two or more well-dosed antidepressants in this episode, medication side effects have made adherence impossible, you cannot tolerate further weight gain or sexual dysfunction, you are pregnant or planning pregnancy and want to avoid systemic exposure, or you simply do not want to add another daily pill.

Many patients do both. TMS is typically delivered while continuing whichever antidepressant has been most helpful, and the two strategies are not mutually exclusive. The decision is rarely medication or TMS in isolation. It is what does the next 90 days look like, and which combination gives you the best chance of getting your life back.

What happens after TMS works

One of the questions patients ask most often: does it last. The data here is honest. In a systematic review of TMS responders followed over a year, roughly 67% remained in response at 3 months, 53% at 6 months, and 46% at 12 months without further treatment.^[18] Real-world data from accelerated Deep TMS protocols shows similar or better durability when maintenance is structured.

What that tells me clinically: TMS response is durable for many patients, but not all. Relapse risk is real, and the plan should include a maintenance strategy from day one. That can mean a continued antidepressant, brief TMS booster sessions if symptoms creep back, ongoing therapy, behavioral activation, sleep regulation, reduced alcohol and cannabis, and addressing whatever life patterns are still feeding the depression.

The rest of the plan still matters

Medication and TMS reduce the force of the depression. They make it easier to act. They do not, by themselves, rewrite the patterns that have been running for years.

The patients who do best long-term are the ones who use the treatment window to do the other work. Therapy that targets the specific patterns: rumination, avoidance, self-criticism, trauma. Behavioral activation that gets them back into the activities depression had quietly amputated. Sleep that becomes regular again. Movement, even small amounts, that nudges the brain in a different direction. Honest conversations about alcohol and cannabis. Connection with people they had stopped reaching out to.

This is what recovery actually looks like: it gets easier to interrupt the spiral, answer the message, keep the appointment, challenge the thought, restart the day. That is what we are aiming for at Exxceed Wellness. Not the absence of bad days. The ability to act outside the old depressive pattern with less force than it used to take.

The bottom line

Medication targets specific neurotransmitter pathways: serotonin, norepinephrine, dopamine, NMDA activity, lithium-based augmentation. TMS uses focused magnetic pulses to stimulate the mood circuits in the prefrontal cortex and the networks connected to them. The two strategies are different in mechanism, different in side-effect profile, and different in what they ask of you to complete.

If you have not yet had a thoughtful medication trial, that is usually the right next step. If you have, and you are still not where you want to be, TMS is among the most evidence-supported neuromodulation options for treatment-resistant depression available in California today. The right answer depends on your treatment history, your symptom pattern, your tolerance for side effects, your schedule, your insurance, and your willingness to commit to a course you can actually finish.

If you are in Hayward or anywhere in the Bay Area and you are weighing the next step, that is what a consultation is for. We look at what has been tried, what has worked and what has not, and we build a plan around the treatment that gives you the best chance of feeling like yourself again.

Nefretiri Abat, JD, PMHNP-BC — Founder, Exxceed Wellness. Exxceed Wellness is a psychiatric practice based in Hayward, CA offering medication management, TMS therapy, SPRAVATO, and ketamine treatment for treatment-resistant depression, ADHD, anxiety, and related conditions. This article is for educational purposes and does not constitute medical advice. If you are in the Bay Area and considering your next step, schedule a consultation at exxceedwellness.com.