When depression hasn't lifted with the first treatment — or the second — the questions change. People stop asking "will anything work?" and start asking "what are my actual options, and how do I choose between them?" Three of the most talked-about are antidepressant medication, TMS (transcranial magnetic stimulation), and ketamine.

These three are often presented as rivals. They're better understood as different tools for different situations. They work through completely different mechanisms, they act on very different timescales, and the right choice depends on your history, how urgent things are, and what you've already tried. For many people the answer isn't one of them — it's a sequence, or a combination.

This is a psychiatrist's honest comparison: how each works, what the evidence supports, the trade-offs, and how we actually decide.

The short version

Medication changes brain chemistry over weeks. It's the most established, most studied, and most accessible option — and for most people it's the right first step. The trade-offs are the wait for an effect and the trial-and-error of finding the right drug.

TMS uses magnetic pulses to stimulate a specific brain region. It has strong, regulator-approved evidence for depression, no systemic drug side effects, and is a leading option when medication hasn't worked. The main ask is time: a course of sessions over several weeks.

Ketamine works through a different chemical system entirely and can lift depression — including some severe, treatment-resistant depression — remarkably fast, sometimes within hours to days. It's powerful and genuinely different, but it's given under supervision, its benefits need a plan to maintain, and it's not a casual or standalone fix.

No single one of these is a miracle, and anyone marketing one as a guaranteed cure is overstating it. Here's the detail.

How each one works

Medication

Antidepressants work by gradually shifting the chemical signalling between neurons — most commonly the availability of serotonin, noradrenaline and dopamine. They act broadly across the brain and typically take a few weeks to reach full effect.

Medication is the foundation of depression treatment for good reason: it's been studied in enormous numbers of patients, it's widely available and affordable, and it works well for a great many people. The downsides are the waiting period before you know if a particular drug suits you, side effects that vary by medication, and the reality that finding the right one (or right combination) can take some trial and error.

TMS[Transcranial magnetic stimulation]

 uses a magnetic coil held against the scalp to deliver focused pulses to a specific brain region — most often the left dorsolateral prefrontal cortex, an area that's underactive in depression. Those pulses induce small electrical currents that gradually change the activity of the targeted circuit. Because it's focal and doesn't circulate through the body, it avoids the systemic side effects medication can cause.

TMS is given as a course of sessions (typically over several weeks). You're awake throughout, and you go straight back to your day afterwards. It has regulatory approval and solid trial evidence for depression, including treatment-resistant depression.

Ketamine

Ketamine works on a different system from standard antidepressants — primarily the brain's glutamate signalling and the NMDA receptor — and appears to rapidly promote new connections between neurons. That different mechanism is why it can act so much faster, and why it can sometimes help people who haven't responded to conventional medication. 

In practice it's delivered in controlled, supervised ways — for example intravenous infusions or intranasal esketamine — in a clinical setting, with monitoring during and after. Sessions can produce short-lived, unusual perceptual experiences while the medicine is active, which is one reason supervision matters. 

The key distinction: medication and ketamine both work on chemistry, but different chemistry and on very different timescales, while TMS stimulates a circuit directly. Three genuinely different routes to the same goal.

Speed: one of the biggest practical differencesThis is where these options separate most clearly, and it matters a lot in real life.

  • Medication usually takes several weeks to show its full effect.
  • TMS builds over a course of weeks, with many people noticing change part-way through.
  • Ketamine can work fast — sometimes within hours to days — which is part of why it's drawn so much interest, particularly for severe depression and for distress that needs a quicker response.

That speed is a genuine advantage of ketamine, but it comes with an important caveat: a single ketamine treatment's benefit can fade, so it's used as part of a planned course with a strategy to maintain the gains, not as a one-off. Fast relief and lasting relief are not the same thing, and good treatment plans for both.

What the evidence actually shows

Patients deserve straight talk here, because these three aren't on identical footing.Medication has the deepest evidence base of the three — decades of large, controlled trials across many forms of depression. It's the most reliable starting point for most people.

TMS has strong, regulator-approved evidence for depression, including when several medications haven't worked. It is not an experimental fringe treatment; the data behind it are genuinely good.

Ketamine and esketamine have a strong and growing evidence base for rapid reduction of depressive symptoms, including in treatment-resistant depression and in situations involving acute suicidal distress. The honest nuances are around durability (the need for a maintenance plan), the importance of supervised, structured delivery, and the fact that long-term use is still being studied. Used properly — in the right patient, in a monitored setting — it's a powerful and legitimate tool, not a recreational shortcut.

I'd always rather you start with realistic expectations and be pleasantly surprised than be sold certainty that the evidence doesn't support.

Side effects and what each one asks of you

Medication

Side effects depend on the drug — things like nausea, sleep or appetite changes, sexual side effects, or emotional blunting are possible, and most settle or can be managed by adjusting the medication. The main commitment is taking it consistently and reviewing it; the trade-off is the trial-and-error of finding the right fit.

TMS

Generally very well tolerated. The most common side effects are mild and short-lived — some scalp discomfort at the stimulation site and headache, usually easing over the first sessions. It's non-systemic and non-sedating, with no downtime. The main ask is time: a course of sessions means regular clinic visits over several weeks.

Ketamine

Given in a supervised setting precisely because it needs monitoring. During treatment people may feel temporary effects like dissociation (a floaty, detached feeling), changes in perception, a rise in blood pressure, or nausea; these are transient and settle as the medicine wears off, which is why you're observed and don't drive yourself home. Used in a structured clinical programme with proper screening, it has a reassuring safety profile — and misuse concerns relate to unsupervised use, not monitored treatment. The ask is a planned course plus the time for in-clinic, observed sessions.

How we actually choose

We don't pick a treatment because it's in the news. We start from your diagnosis, your history, how severe and urgent things are, and what you've already tried. 

A few of the principles:

Usually, medication and therapy come first. For most people with depression, an antidepressant and/or psychotherapy is the sensible first step, simply because the evidence is broad and it's accessible.

When the first treatments don't work, that's the turning point. If you've genuinely tried adequate courses of medication without enough benefit — treatment-resistant depression, anxiety or OCD, TMS and ketamine come into their own. Which one we lean toward depends on the details.

Urgency matters. When someone is severely unwell or in acute distress and we need movement quickly, ketamine's speed can be decisive. When there's more time and the priority is a durable, low-side-effect option, TMS is often a natural fit.

Your circumstances and preferences count. 

Tolerance of side effects, ability to attend repeated sessions, feelings about medication, and practical factors all legitimately shape the plan — weighed honestly against the evidence, never used to dress up a weaker option as a stronger one.

It's often a sequence or a combination, not a single pick

The "medication vs TMS vs ketamine" framing helps you understand the options, but real treatment rarely forces a single choice.

People often move through a sequence — starting with medication, then adding or switching to TMS or ketamine if needed. And these approaches can be combined: many people continue an antidepressant while having a course of TMS or ketamine, because the mechanisms are different and can complement each other. The skill of good treatment is sequencing and combining these tools for the individual — not crowning one winner.

Frequently asked questions

Which works fastest?

 Ketamine is typically the fastest — sometimes within hours to days — which is part of why it's used for severe or urgent depression. Medication and TMS build over weeks.

Should I try TMS or ketamine if medication hasn't worked? 

Both are strong options for treatment-resistant depression. Which one fits depends on urgency, your history, side-effect considerations, and practicalities — that's what an assessment is for.

Is ketamine safe?

 In a supervised, properly screened clinical programme it has a reassuring safety profile. Its temporary effects (like dissociation) are why it's monitored, and concerns about misuse relate to unsupervised use rather than structured treatment.

Can these be combined? 

Yes. People often continue medication alongside a course of TMS or ketamine, because the mechanisms differ and can work together.

How do I choose? 

You don't have to choose alone. An assessment looks at your diagnosis, history, urgency and preferences, and we give you an honest view of what each option can and can't do for you.

The bottom line

Medication, TMS and ketamine aren't three versions of the same thing — they're three different tools working through different mechanisms on different timescales. Medication is the broad, well-evidenced first step; TMS is a strong, low-side-effect option especially when medication hasn't worked; and ketamine offers rapid relief for severe or resistant depression, used in a supervised, planned way. For many people the best answer is a thoughtful sequence or combination, matched to their situation.

If your depression hasn't responded to what you've tried so far, the most useful next step is an assessment — where we can look honestly at your history and tell you which of these options, or which combination, makes sense for you.