What Is Treatment-Resistant Depression? Symptoms, Causes, Treatments, and More

Those people have what is known as treatment-resistant depression (TRD).

“There is no consensus on what constitutes treatment-resistant depression, but a conventional definition is the lack of response to two or more treatments of adequate dose and duration,” says Charles DeBattista, MD, director of the Depression Research Clinic at Stanford University School of Medicine in California.

In other words, if you’ve tried at least two types of antidepressants — for example, a selective serotonin reuptake inhibitor and a tricyclic antidepressant — and you don’t feel a whole lot better, you may have this challenging form of depression.

“Treatment-resistant depression is different from other forms of depression in that patients are more likely to have persisting symptoms and to relapse to depression even after [responding well] to treatment,” explains John Krystal, MD, the Robert L. McNeil, Jr. professor and chair of psychiatry at Yale School of Medicine in New Haven, Connecticut.

But even though it’s called treatment-resistant, this type of depression is not totally untreatable, thanks to newer approaches that have been shown to help alleviate symptoms and improve the quality of life of people with TRD.

TRD generally has the same symptoms as other forms of depression, such as major depressive disorder (MDD), but with the added problem of not getting enough relief from typical treatments, explains Dr. Krystal.

• Depressed or anxious mood that won’t go away
• Loss of interest or pleasure in activities you once enjoyed
• Feelings of hopelessness or worthlessness
• Irritability or restlessness
• Low energy or fatigue
• Disruptions in sleep, appetite, or libido
• Difficulty concentrating and remembering things
• Aches or pains
• Digestive issues
• Suicidal thoughts or behaviors

Additionally, people with TRD may have especially high levels of anxiety and feel depressed for a longer period of time than others, says Krystal.

That said, a common misconception about TRD is that it’s always a very serious form of depression. Not so, Dr. DeBattista says. “Some treatment-resistant depression cases are mild but chronic,” he explains.

Researchers are still trying to figure out exactly why standard depression treatments don’t work for some people.

“The causes of treatment-resistant depression versus MDD are not well understood,” says Krystal. “Depression has many complex causes, including major life stress, genetic risk, maladaptive personality and coping traits, and lack of social support.” Factors such as lifestyle habits or underlying medical conditions that cause inflammation may also play a role, he adds.

• Skipping doses of prescribed antidepressants
• Stopping taking their antidepressant too soon, as it can take 6 to 12 weeks or longer for the full benefits to kick in
• Taking other medication that can cause negative drug interactions
• Misusing alcohol or other drugs
• Having been misdiagnosed with the wrong mental health condition
• Having another medical or psychiatric condition along with depression

“Treatment-resistant depression, relative to MDD, is diagnosed based purely on the response to treatment,” Krystal says.

• Other forms of depression, such as bipolar depression or psychotic depression
• Endocrine disorders, such as hypothyroidism, or an underactive thyroid
• Neurological illnesses, including Parkinson’s disease and epilepsy
• Metabolic issues, such as hypercalcemia (too much calcium in the blood)
• Infections, including syphilis and HIV

Though people with TRD may not find relief with standard antidepressant medications and therapies, “any notion that this type of depression can’t be treated is false,” DeBattista says, insisting that “many patients with treatment-resistant depression will ultimately find a treatment that is effective.”

Krystal agrees: “Don’t give up. Purely and simply, don’t give up. The fact that past treatments have not worked does not mean that all treatments will not work.”

If it turns out that you have TRD, your doctor may recommend one or more of the following options.

Medication Strategies

• Suggest that you give your original medications more time to work: Some people take longer to respond to antidepressants than others.
• Increase the dose of your current treatment: Upping your dosage may improve your symptoms.
• Switch your medications: Some people try several antidepressants before they find one that works.
• Add another antidepressant: Two medicines from different drug classes used at the same time can help target a wider range of the brain chemicals associated with mood regulation.
• Try augmentation therapy: This involves adding an additional medication typically used for another mental or physical health issue, such as mood stabilizers, antipsychotics, anti-anxiety drugs, or thyroid hormones.

An important note: Never make any changes to your medication regimen or stop taking your medication without consulting your doctor. Doing so may cause withdrawal symptoms, increase your depressive symptoms, or trigger the return of symptoms that had been reduced.

Psychotherapy

Transcranial Magnetic Stimulation

If other treatments haven’t been effective, your doctor may recommend transcranial magnetic stimulation (TMS), a noninvasive treatment approved by the U.S. Food and Drug Administration (FDA) that uses magnetic waves to stimulate nerve cells in the brain.

This procedure involves placing an electromagnetic coil on the scalp that directs currents to stimulate nerve cells in an area of the brain involved in depression and mood regulation.

TMS is typically delivered daily, five times a week, over four to six weeks. How long each session lasts will depend on the type of stimulation pattern used, and most people are able to resume their normal daily activities afterward.

• Headaches
• Lightheadedness
• Scalp discomfort, especially at the site of stimulation
• Spasms, tingling, or twitching of the muscles in your face

Electroconvulsive Therapy

ECT is very effective for major depression, relieving symptoms in about 80 percent of people who undergo the procedure.

• Confusion
• Headache
• Jaw pain
• Muscle aches
• Memory loss, which usually improves within a couple months after treatment ends
• Nausea
• Other medical complications, particularly if you have serious heart problems

Vagus Nerve Stimulation

VNS involves surgically implanting a device in the chest that connects a wire to the vagus nerve, a nerve that travels into areas of the brain thought to be involved in mood regulation. The wire delivers electrical signals to the nerve, which transmits them to the brain, potentially improving depressive symptoms.

• Cough
• Difficulty swallowing
• Headaches
• Hoarseness
• Insomnia
• Skin tingling or prickling
• Shortness of breath
• Throat pain
• Voice changes
• Worsened sleep apnea

Deep Brain Stimulation

DBS involves the surgical implantation of electrodes into areas of the brain that are triggering depression. Doctors use brain scans to identify the most appropriate places to implant the electrodes.

Newer Medicines

Some newer medicines may also help TRD.

• Ketamine This is an anesthetic that’s delivered intravenously in a doctor’s office or clinical setting. Unlike other medications for depression, which can take weeks or even months to fully kick in, ketamine produces rapid relief, especially among people with suicidal thoughts, according to one study. In fact, the study found that ketamine was effective within 24 hours among people with depression who had suicidal thoughts.

  [18]

   Ketamine also appears to work at least as well as ECT among people with TRD without psychosis, according to another study.

  [19]

• Esketamine (Spravato) In March 2019, the FDA approved this ketamine derivative for use in conjunction with an oral antidepressant for TRD. In January 2025, the FDA approved esketamine for use on its own (without an oral antidepressant) for TRD. Esketamine is given as a fast-acting nasal spray in a doctor’s office or clinic setting.

  [20]

Botox

Clinical Trials and Novel Treatments

Researchers are currently studying innovative therapies for TRD.

Investigators are also examining newer classes of antidepressants, as well as ways to make TMS treatments more efficient, according to DeBattista.

Certain lifestyle strategies can improve symptoms in some people with persistent depression, notes Krystal.

• Fill up on plant foods and lean proteins. Sticking to a diet rich in fruits, vegetables, whole grains, fish, olive oil, low-fat dairy, and antioxidants is associated with a lower risk of depression, according to frequently cited research. For maximum benefit, you should also limit your intake of red or processed meats, sweets, high-fat dairy products, butter, potatoes, and high-fat gravy, all of which were linked to a higher risk of depression in the same analysis.

  [24]

• Aim to exercise on most days. Getting your heart pumping can significantly reduce depressive symptoms. The U.S. Department of Health and Human Services recommends that healthy adults try to get at least 150 minutes weekly of moderate aerobic activity or at least 75 minutes weekly of vigorous activity. Any physical activity you enjoy — from walking to jogging to gardening — counts as exercise.

  [25]

• Keep in touch with friends and family. Isolation can worsen depression, which is why it’s important to reach out to people close to you when you’re struggling with your symptoms.
• Establish a regular sleep routine. Sleep disturbances are common among people with depression, and not getting enough sleep — or getting poor-quality sleep — can worsen your symptoms. Going to bed and waking up at the same time each day helps stabilize your sleep schedule.

• Poor quality of life
• Social and workplace problems
• Financial instability

• Alzheimer’s disease
• Chronic pain
• Diabetes
• Heart disease
• Stroke