The short answer
Treatment-resistant depression usually means depression that hasn't improved enough after at least two antidepressants, each taken at an adequate dose for long enough. It's common, affecting an estimated 30% or more of people with depression. Before using the label, a GP checks the diagnosis, adherence, dose and other contributors like bipolar disorder, alcohol, thyroid problems and medicines. Many options remain, including switching or adding medicines, psychological therapy, and specialist treatments such as rTMS, ECT and esketamine, which involve a psychiatrist.
On this page
What is treatment-resistant depression?
Treatment-resistant depression (TRD) is depression that hasn't improved enough despite proper treatment. There's no single agreed definition, but the most widely used one, adopted by regulators in the US and Europe, is an inadequate response to at least two antidepressants, where each was taken at an adequate dose, for long enough, and consistently [1].
Australian funding rules use a similar bar. To qualify for Medicare-funded rTMS, for example, you need to have not improved after adequate trials of at least two classes of antidepressant, each at the recommended dose for at least three weeks, with adherence formally checked and psychological therapy tried where appropriate [2]. The PBS listing for esketamine requires depression that has been inadequately responsive to at least two oral antidepressants [3].
The term can feel discouraging. Some Australian guidance for GPs talks about "treatment failure" instead [4], which keeps the focus on how particular treatments worked rather than on the person. Either way, it doesn't mean your depression can't be treated.
How common is treatment-resistant depression?
It's estimated that at least 30% of people with depression meet the two-antidepressant definition [1].
The best-known evidence comes from STAR*D, a large US study in which 3,671 outpatients started treatment and could move through up to four treatment steps if they didn't recover [5]. The original investigators reported remission rates of 36.8% at the first step, 30.6% at the second, then 13.7% and 13.0% at the third and fourth, with a cumulative remission rate of 67% [5].
That headline figure has been challenged. A 2023 reanalysis of the patient-level data, using the outcome measure specified in the study's original protocol and excluding people who already scored as remitted when they started a treatment step, put the cumulative remission rate at 35% [6]. The two analyses measure things differently, and researchers still debate them. What both show is that many people need more than one attempt, and that the chance of remission drops with each additional step [5][6].
Is it really treatment-resistant? What gets checked first
A significant share of people labelled with TRD are "pseudo-resistant". Their earlier treatment trials weren't adequate, or the medicine wasn't taken consistently [1]. So the first job is a careful review. Australian guidance for GPs covers these areas [4][7]:
- The diagnosis. Is this depression, or could it be bipolar disorder, a primary anxiety disorder, a personality disorder or another psychiatric condition [4][7]?
- Physical health. Conditions such as hypothyroidism, Parkinson's disease and some forms of dementia can cause or worsen depression [7].
- Other medicines. Some prescription medicines can contribute to low mood [7].
- Adherence and side effects. Was the antidepressant taken regularly? Did side effects get in the way? [4]
- Dose and duration. Was each medicine given at a therapeutic dose for long enough to judge it? [1][2] See how long antidepressants take to work.
- Alcohol and other drugs. Substance use disorders are a common contributor that needs to be addressed [4][7]. Our guide to antidepressants and alcohol covers this.
- Life circumstances. Psychological, social and lifestyle factors need attention too [4].
What are the treatment options for treatment-resistant depression?
Here's an overview, followed by more detail on each.
| Option | What it involves | Who's usually involved |
|---|---|---|
| Optimising or switching medicine | Adjusting the dose or changing to a different antidepressant | GP, sometimes with psychiatrist advice |
| Augmentation | Adding a second medicine, such as an antipsychotic or lithium | GP and/or psychiatrist |
| Psychological therapy | Adding therapy such as CBT to medication | Psychologist |
| rTMS | Magnetic stimulation of the brain, as an outpatient | Psychiatrist-led service |
| ECT | Brief, controlled seizure under general anaesthetic | Psychiatrist, hospital |
| Esketamine nasal spray | Supervised doses at an accredited centre | Psychiatrist |
| Ketamine (off-label) | Specialist-supervised treatment | Psychiatrist |
Optimising or switching antidepressants
The first steps are often to increase the dose, switch to a different medicine in the same class, or switch to a different class [4]. Switching class is worth considering when depression hasn't started to improve significantly [4]. Options include mirtazapine, tricyclics and MAOIs, which are PBS-listed, and newer medicines such as agomelatine and vortioxetine, which are TGA-approved but not PBS-listed [4]. The evidence for simply extending a trial, switching or combining antidepressants is mixed [1]. Our guide to antidepressants in Australia explains the main types.
Adding a second medicine (augmentation)
Augmentation means adding a medicine to boost the antidepressant's effect. Common choices are an atypical antipsychotic such as aripiprazole, or lithium [4]. A Cochrane review found that adding quetiapine, cariprazine, ziprasidone or olanzapine improved symptoms compared with continuing the antidepressant alone, although the certainty of evidence varied [8]. Adding mirtazapine made little difference [8].
These medicines have their own side effects and monitoring. For example, kidney and thyroid function are checked before starting lithium [7]. That's one reason a psychiatrist is often involved.
Adding psychological therapy
Psychological therapy is a real option, not a fallback. A Cochrane review of six trials (698 people) found that adding psychotherapy, mostly CBT, to antidepressants improved symptoms and nearly doubled the chance of remission in the short term compared with medication alone [9]. Therapy on its own isn't established as effective in TRD, but it offers significant relief when added to medication [1]. Your usual GP can refer you to a psychologist under a mental health care plan.
Seeing a psychiatrist
If depression still isn't responding after trying other options, Australian guidance recommends referral for specialist review [4]. A psychiatrist can reassess the diagnosis in depth and offer treatments that GPs don't provide.
Repetitive transcranial magnetic stimulation (rTMS)
rTMS uses magnetic pulses applied to the head to stimulate brain areas involved in mood. It's done as an outpatient, without an anaesthetic. A network meta-analysis of 113 trials found standard high-frequency rTMS roughly tripled the odds of response compared with sham treatment, and was as acceptable to patients as sham [10].
Medicare has funded rTMS since 1 November 2021 for adults with a major depressive episode who haven't responded to at least two classes of antidepressant and have never had TMS before [2]. A psychiatrist trained in rTMS must prescribe and plan the treatment, and either a GP or psychiatrist can refer [2].
Electroconvulsive therapy (ECT)
ECT is among the most effective treatments for depression [10][11]. A major review found real ECT was significantly more effective than simulated ECT and probably more effective than medication [11]. It's given under general anaesthetic, usually in hospital, by a psychiatrist-led team.
Memory and thinking side effects are the main concern. A meta-analysis of 84 studies found measurable drops in thinking skills were mostly limited to the first three days after treatment, with function recovering after that [12]. The authors noted that standard tests for memory of past events weren't available in the studies they reviewed [12], so it's worth discussing memory effects in detail with the treating team.
Esketamine nasal spray
Esketamine is a form of ketamine given as a nasal spray alongside an oral antidepressant. It's established as effective for TRD [1]. In Australia, it's PBS-listed for treatment-resistant major depression that has been inadequately responsive to at least two oral antidepressants. It must be prescribed by the treating psychiatrist, and each dose is given under supervision at an accredited treatment centre [3].
Side effects include nausea, dissociation (feeling detached or unreal), dizziness, vertigo, raised blood pressure and sleepiness, and they're more common at higher doses [13]. In trials, people on esketamine were about twice as likely to stop treatment because of side effects [13].
Ketamine
Ketamine is approved in Australia as an anaesthetic, so using it for depression is off-label [14]. The RANZCP says there's sufficient evidence only for treatment-resistant depression, and it isn't a first-line treatment [14]. Effects come on quickly but usually fade within about a week after a single dose [14]. The College says it should be prescribed by a psychiatrist, or a doctor supervised by one, with blood pressure monitoring and a structured safety framework, especially for repeated doses [14]. It isn't subsidised and carries risks including bladder and thinking problems with repeated use, as well as misuse [14].
Psilocybin
Since 1 July 2023, psychiatrists approved under the TGA's Authorised Prescriber scheme can prescribe psilocybin and MDMA for specific conditions, including treatment-resistant depression [15]. The RANZCP stresses this should only happen under rigorous conditions, with ongoing psychotherapy as an essential part of treatment [15]. Access is limited and it remains an emerging treatment.
A consultation doesn't guarantee a prescription. Your GP decides what's clinically appropriate.
What does a GP do, and when is a psychiatrist involved?
Many treatments for TRD involve specialist care. The GP's role is to assess, optimise and refer, and to stay involved throughout.
| A GP can | A psychiatrist can |
|---|---|
| Review your history and check the diagnosis [7] | Reassess complex or uncertain diagnoses |
| Check for physical causes and contributing medicines [7] | Guide more complex medicine combinations [4] |
| Review adherence, side effects, dose and duration [4] | Prescribe and plan rTMS [2] |
| Switch or adjust antidepressants [4] | Provide ECT |
| Arrange psychological therapy | Prescribe esketamine [3] |
| Refer you to a psychiatrist [4] | Offer ketamine where appropriate [14] |
| Coordinate ongoing care and follow-up | Apply to prescribe psilocybin as an Authorised Prescriber [15] |
When should you see a GP?
See a GP if you've tried two or more antidepressants without enough improvement, if side effects are making treatment hard to stick with, or if your depression is getting worse. Don't stop or change an antidepressant on your own. Talk it through with your doctor first.
If you'd like to talk to a GP about how you've been feeling, you can request an appointment. A GP can review your history and past treatments, and refer you to a psychiatrist when specialist care is needed. Learn more about depression.
If you're in crisis or thinking about suicide, call Lifeline on 13 11 14 or 000 in an emergency. See our urgent help page for more options.
This page is general information, not medical advice.
Common questions
What is considered treatment-resistant depression?
The most widely used definition is an inadequate response to at least two antidepressants, despite adequate dose, duration and adherence [1]. There's no single agreed definition, which makes research and care less consistent [1]. Australian Medicare and PBS rules for rTMS and esketamine use a similar two-antidepressant threshold [2][3].
How many people have treatment-resistant depression?
Is esketamine on the PBS?
Does Medicare cover rTMS for depression?
Can a GP treat treatment-resistant depression?
A GP plays a big part: reviewing the diagnosis, checking for medical and other contributors, optimising or switching medicines, arranging psychological therapy and referring to a psychiatrist [4][7]. Specialist treatments such as rTMS, ECT, esketamine and ketamine are provided by or under psychiatrists [2][3][14].
Does treatment-resistant depression ever get better?
Yes, for many people. In the large STAR*D study, about 31% of people who hadn't remitted on their first antidepressant did remit at the second treatment step, although the odds fell with later steps [5]. A later reanalysis suggests the original figures were optimistic, but it agrees that some people do respond to a later treatment [6]. Having two treatments not work doesn't mean nothing will.
References
- McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394-412. pubmed.ncbi.nlm.nih.gov/37713549
- Australian Government Department of Health, Disability and Ageing. MBS Online: Item 14216 (rTMS treatment mapping) and explanatory note TN.1.28. Accessed November 2026. www9.health.gov.au/mbs/fullDisplay.cfm?type=item&q=14216&qt=item
- Pharmaceutical Benefits Scheme. Esketamine nasal spray (item 14786F), treatment resistant major depression, authority required. Schedule effective 1 November 2026. pbs.gov.au/medicine/item/14786F
- Mitchell PB. What to do when SSRI and SNRI antidepressants don't work: a guide for GPs. Medicine Today. 2024;25(12):18-21. medicinetoday.com.au/system/files/pdf/MT2024-12-018-MITCHELL_1.pdf
- Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-17. pubmed.ncbi.nlm.nih.gov/17074942
- Pigott HE, Kim T, Xu C, Kirsch I, Amsterdam J. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study's patient-level data with fidelity to the original research protocol. BMJ Open. 2023;13(7):e063095. pubmed.ncbi.nlm.nih.gov/37491091
- Mitchell PB. Management of treatment-resistant depression: a guide for GPs. Medicine Today. November 2018. medicinetoday.com.au/mt/2018/november/feature-article/management-treat
- Davies P, Ijaz S, Williams CJ, Kessler D, Lewis G, Wiles N. Pharmacological interventions for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2019;12(12):CD010557. pubmed.ncbi.nlm.nih.gov/31846068
- Ijaz S, Davies P, Williams CJ, Kessler D, Lewis G, Wiles N. Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2018;5(5):CD010558. pubmed.ncbi.nlm.nih.gov/29761488
- Mutz J, Vipulananthan V, Carter B, et al. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019;364:l1079. pubmed.ncbi.nlm.nih.gov/30917990
- UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361(9360):799-808. pubmed.ncbi.nlm.nih.gov/12642045
- Semkovska M, McLoughlin DM. Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol Psychiatry. 2010;68(6):568-77. pubmed.ncbi.nlm.nih.gov/20673880
- Qu Y, Li S, Tian L, Tian X, Wu Y. Dose-dependent adverse events of esketamine in treatment-resistant depression: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2026;17:1792570. pubmed.ncbi.nlm.nih.gov/42292802
- Hussain S, Gale C, Sarma S, et al. Royal Australian and New Zealand College of Psychiatrists professional practice guidelines for the use of ketamine in psychiatric practice (PPG 24). Aust N Z J Psychiatry. 2025. Accessed November 2026. ranzcp.org/getmedia/952ea6ad-68ca-4623-96bb-8dc4ae9f3c14/PPG-24-Use-of
- Royal Australian and New Zealand College of Psychiatrists. Change to classification of psilocybin and MDMA. Accessed November 2026. ranzcp.org/news-analysis/change-to-classification-of-psilocybin-and-md
Published by Mental Health Clinic. Last updated 6 November 2026. This page is general information only and isn’t a substitute for advice about your own situation. If you or someone else is in danger, call 000.