A ketamine vial, a person running up stairs, and fresh vegetables and fruit

Treatment-resistant depression: what helps beyond antidepressants, from exercise and diet to esketamine

Ruslan Dorfman, PhD, MBA3 Nov 2026

Depression is one of the most common health conditions, and most people who seek treatment are offered psychotherapy, medication or both. But only about one in three people reaches remission with their first antidepressant. When depression does not improve after two or more adequate trials of antidepressants, it is called treatment-resistant depression. This does not mean that nothing will work. It means it is time to look more closely at the reasons and to consider other options. Here is what research shows for lifestyle approaches, brain stimulation treatments, ketamine and esketamine, and how pharmacogenetic testing fits in.

Why might depression not respond to treatment?

Before deciding that depression is treatment-resistant, your health care team will usually check:

Whether the dose was high enough and taken long enough, usually at least four to six weeks.
Whether the medication was taken regularly, or stopped because of side effects.
Whether your body breaks the medication down too quickly or too slowly because of your genes.
Whether other medications, alcohol or cannabis are interfering.
Whether another condition is involved, such as an anxiety disorder, thyroid problems, chronic pain, sleep problems or bipolar disorder.

Combining psychotherapy, such as cognitive behavioural therapy (CBT), with medication is more effective than either one alone, and adding CBT is also recommended when medication alone has not been enough.

Can exercise help with depression?

Yes. Exercise is one of the best-studied non-drug treatments for depression. In a 2024 review of 218 clinical trials with more than 14,000 people, walking or jogging, yoga and strength training gave moderate reductions in depression, and the benefit grew with the intensity of the exercise. An earlier analysis of resistance (strength) training trials found that for about every four people who did strength training, one more person had a meaningful improvement in depressive symptoms.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 guidelines recommend supervised exercise as a treatment on its own for mild depression and as an add-on to other treatments for more severe depression. A typical program is 30 to 40 minutes of exercise, three to four times a week, for at least nine weeks. Exercise may work in several ways, including raising brain-derived neurotrophic factor (BDNF), a protein that supports brain cells, and improving sleep, energy and a sense of accomplishment.

Exercise may also help prevent depression. A study using genetic data from large populations found that people who were more physically active had a lower risk of developing major depression. Sticking with regular exercise can be hard when depression drains energy and motivation, so start small, choose something you enjoy, and ask family members or a health care provider to support you.

Do diet and weight management help?

Obesity and depression are linked in both directions: obesity increases the risk of developing depression, and depression increases the risk of developing obesity. A diet high in processed foods, refined carbohydrates and saturated fat has been linked with more depressive symptoms.

The SMILES trial. Adults with major depression who received seven sessions of dietary support from a dietitian, focused on a Mediterranean-style diet, improved more than those who received social support. After 12 weeks, 32% of the diet group reached remission, compared with 8% of the social support group. The trial was small, with 67 participants.
The RAINBOW trial. In 409 adults with obesity and depression, a program that combined behavioural weight loss, problem-solving therapy and, when needed, antidepressants improved both weight and depression after 12 months, though the effects were modest.

Because the evidence is still limited, CANMAT considers a Mediterranean-type diet a third-line option. A healthy diet and weight management are best used alongside other depression treatments, not instead of them. The same is true for supplements.

What about brain stimulation treatments?

Repetitive transcranial magnetic stimulation (rTMS) uses magnetic pulses applied to the scalp to stimulate areas of the brain involved in mood. It does not need anaesthesia and does not affect memory. Treatment is usually given in daily sessions, five days a week, for four to six weeks. About 40% to 50% of people with difficult-to-treat depression respond. CANMAT recommends rTMS for people whose depression has not improved with first-line psychotherapy and medication.
Electroconvulsive therapy (ECT) remains one of the most effective treatments for treatment-resistant depression, with response rates of 65% to 75%. It is given under general anaesthesia. Memory side effects are the main concern, although modern techniques have reduced them. ECT is the first choice for the most severe and life-threatening depression.

How are ketamine and esketamine used?

Ketamine is an anaesthetic that, at low doses, can reduce depressive symptoms and suicidal thoughts within hours to days. The effect of a single dose usually lasts up to about a week, so treatment is repeated, with maintenance doses usually given every one to four weeks.

Esketamine is a nasal spray containing a closely related form of ketamine. In 2020, Health Canada approved it, together with an SSRI or SNRI antidepressant, for adults with major depression who have not responded to several earlier treatments. In a large trial in people with treatment-resistant depression, 27% of people treated with esketamine reached remission after eight weeks, compared with 18% of people treated with quetiapine, an add-on medication.
Intravenous ketamine is used off-label in some specialized clinics.

CANMAT recommends ketamine and esketamine as second-line add-on treatments. Both can cause dissociation (feeling detached or unreal), dizziness and a rise in blood pressure, so each treatment is given in a clinic with monitoring for at least two hours afterward. Ketamine can be misused, and long-term use can cause bladder problems. Treatment is costly, and coverage varies between provinces and insurance plans.

What other treatments are being studied?

Anti-inflammatory medications. Some people with depression have signs of inflammation. A review of 36 trials found that anti-inflammatory medications, including NSAIDs such as celecoxib, statins and minocycline, improved depressive symptoms, especially when added to antidepressants, but all the studies had a high risk of bias. NSAIDs taken with SSRIs or SNRIs also increase the risk of stomach bleeding. Read more about whether ibuprofen and celecoxib can help treat depression.
Psilocybin-assisted psychotherapy. Early trials in treatment-resistant depression are promising, but CANMAT still considers it investigational because of problems with study design and a lack of long-term safety data.
Treatments for postpartum depression. Zuranolone, a pill taken once a day for 14 days, was approved by Health Canada in 2025 for moderate or severe postpartum depression. Read more about treating postpartum depression.

How can pharmacogenetic testing help?

Pharmacogenetic testing can help at several points on the way to finding treatment that works:

Before calling a medication a failure. Poor metabolizers can have high drug levels and side effects that make them stop, while ultrarapid metabolizers may clear the drug before it can work. Your genetic results help tell a medication that does not suit you from a dose that does not suit your body.
Choosing the next antidepressant. The Clinical Pharmacogenetics Implementation Consortium (CPIC) gives dosing advice based on CYP2C19, CYP2D6 and CYP2B6 for many SSRIs and SNRIs, and on CYP2D6 and CYP2C19 for tricyclic antidepressants, which CANMAT notes still have an important role in treatment-resistant depression.
Add-on medications. Aripiprazole and brexpiprazole, common add-on medications, have CYP2D6-based dosing advice in their product labels.

Esketamine and ketamine are broken down mainly by the CYP2B6 and CYP3A4 enzymes, but there is no pharmacogenetic dosing guideline for them yet. A pharmacist can still check for interactions with your other medications.

A Pillcheck test reports CYP2D6, CYP2C19, CYP2B6, CYP3A4 and other genes that affect antidepressants, add-on medications and many other drugs. A pharmacist reviews your results together with all your medications, and your report can be shared with your doctor and psychiatrist. Read more about how DNA testing can help find the best anxiety and depression medication and what to do when antidepressants are not working.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Summary

Treatment-resistant depression means depression that has not improved after two or more adequate antidepressant trials. Many effective options remain.
Check the dose, duration, side effects, interactions, other conditions and how your body breaks down the medication.
Exercise, especially walking or jogging, yoga and strength training, reduces depression and can be used alone for mild depression or added to other treatments.
A healthy diet and weight management can help modestly alongside other treatments.
rTMS and ECT are effective brain stimulation treatments for depression that has not responded to medication.
Esketamine and ketamine work quickly and are second-line add-on treatments that need clinic monitoring.
Pharmacogenetic testing helps choose antidepressants, tricyclics and add-on medications, and their doses.

Frequently asked questions

How many antidepressants should I try before it is called treatment-resistant?

Depression is usually called treatment-resistant when it has not improved after at least two different antidepressants, each taken at an adequate dose for an adequate time.

Can exercise replace my antidepressant?

For mild depression, supervised exercise can be a treatment on its own. For moderate or severe depression, it works best added to other treatments. Do not stop a medication without talking to your doctor.

Is esketamine available in Canada?

Yes. Health Canada approved esketamine nasal spray in 2020 for adults with major depression who have not responded to several earlier treatments. It is given in a certified clinic under supervision.

Can a genetic test tell me whether ketamine will work?

No. There is no pharmacogenetic guideline for ketamine or esketamine yet. Genetic testing is most useful for choosing antidepressants and add-on medications and their doses.