11 Evidence-Based Treatments for Treatment-Resistant Depression

It's common to feel stuck or defeated when you learn you have treatment-resistant depression. (TRD). It means you tried at least two types of antidepressants at the prescribed dose for the recommended amount of time, but your symptoms didn't get better. 

You're far from out of options, though. Other research-backed treatments are available to help you take charge of depression. These include powerful prescription medications, various kinds of talk therapy, and cutting-edge procedures. Here's what you need to know about each, so you can feel prepared to talk with your doctor about which options might be right for you. 

Your doctor might start by suggesting one or more of these tactics:

• Stay on your medication. Sometimes, antidepressants take longer than the usual four to eight weeks to start working.
• Increase the dose. You may benefit from a higher-than-typical amount of the medicine.
• Switch antidepressants. Trying a different class of antidepressant, which works in a different way, may help — e.g. switching from a selective serotonin reuptake inhibitor (SSRI) to a serotonin-norepinephrine reuptake inhibitor (SNRI).

To stay safe, never make changes to your medication unless your doctor tells you to. 

What it is: A psychiatrist, psychologist, or other mental health care professional teaches you ways to manage TRD. Most often, you get talk therapy and take an antidepressant. But therapy without medication is an option too, especially if you've been getting serious side effects. 

How it works: You can choose from various types of talk therapy, including cognitive behavioral therapy, family or marital therapy, and group therapy.   

What to expect: It may take around 12 to 16 sessions to get the most out of talk therapy. Also, getting therapy twice a week may be better than getting it once a week. 

What it is: Your doctor may prescribe two classes of antidepressants instead of one. 

How it works: Taking two classes of antidepressants together could affect a greater range of brain chemicals (neurotransmitters) tied to mood. These chemicals include dopamine, serotonin, and norepinephrine.

What to expect: Research shows that taking two antidepressants works better for TRD than taking one — but the improvement may be small. Still, taking two antidepressants may cause fewer side effects and create the need for fewer follow-up tests than taking an antidepressant with another drug, such as an antipsychotic or lithium. 

What it is: It's a drug that's taken along with an antidepressant to treat TRD. When taken by itself, an antipsychotic mainly treats symptoms and conditions linked to psychosis (losing touch with reality). But you don't have to have psychosis to benefit from this medication.  

How it works: It helps change the balance of certain brain chemicals, called neurotransmitters, that affect how you feel and act.

What to expect: Adding a second-generation antipsychotic to an antidepressant may strike a better balance between effectiveness and manageable side effects compared with other drugs that can be added on, such as lithium and thyroid medication.

What it is: It's a mood stabilizer that's taken along with an antidepressant to treat TRD. When taken by itself, lithium mainly treats bouts of mania in bipolar disorder. 

How it works: Lithium acts on your brain to help you better control emotions. Exactly how it does that isn't clear. 

What to expect: In studies, people with TRD who took an antidepressant plus lithium were more likely to get relief than people who took an antidepressant with a sham treatment called a placebo. If your doctor prescribes lithium, you'll need routine tests to check the level of it in your blood. 

What it is: This lab-made version of thyroid hormones can be taken along with an antidepressant to treat TRD. Taken by itself, it mainly treats low levels of the hormone (hypothyroidism).

How it works: One explanation is that low thyroid levels can cause depression symptoms. Raising those levels may boost mood in some people. 

What to expect: In small studies, twice as many people with TRD who took an antidepressant plus thyroid medicine had good responses compared with those who took an antidepressant plus placebo. Also, the side effects of thyroid meds may be easier to handle than those of antipsychotics and lithium.

What it is: It's a prescription drug that's taken along with an antidepressant to treat TRD. When taken by itself, a stimulant is a common treatment for ADHD.

How it works: Stimulants boost certain brain chemicals, which can lift mood when taken with an antidepressant.

What to expect: The combo of an antidepressant and a stimulant may be extra helpful for depression that brings tiredness, daytime sleepiness, low motivation, trouble feeling joy or pleasure, or worse memory and concentration.

What it is: Ketamine is a powerful anesthetic that's given into a vein (IV). Eskatamine (Spravato) is a nasal spray that's made from ketamine. Either drug is typically used along with an antidepressant to treat severe TRD. 

How it works: Ketamine and esketamine affect a different system in your brain than antidepressants do. They may help connections between neurons regrow.

What to expect: Your depression symptoms may get better within hours, and the effects may last up to weeks. A health care professional gives you ketamine or esketamine in a doctor's office or clinic and watches you closely for side effects afterward. 

What it is: This treatment uses a device outside your body that gives off magnetic fields, which stimulate nerve cells in your brain. People who get rTMS for treatment-resistant depression also typically take antidepressants.

How it works: A health care professional places an electromagnetic coil against your scalp. The device gives off currents that affect nerve cells in the part of your brain linked with mood control.

What to expect: You typically need several sessions of rTMS. The sessions may take up to 30 minutes. One review of research found that rTMS worked better than a sham treatment in people with treatment-resistant depression. 

What it is: Health care professionals send a mild electric current through your brain while you sleep. Your doctor may suggest ECT if other treatments don't help. 

How it works: ECT causes a seizure that might lead to changes in your brain chemistry. These changes may relieve depression symptoms fast. 

What to expect: You might need a series of these treatments to get relief from depression. You may feel confused or have some memory loss after getting ECT, but these side effects tend to be temporary. 

What it is: Health care professionals do surgery to place a device in your chest. The device sends mild electrical signals to your brainstem through the vagus nerve in your neck. Your doctor may suggest VNS if options like rTMS and ECT don't help. 

How it works: The electrical impulses of VNS may relieve depression symptoms by affecting your brain's mood centers. 

What to expect: There's little research on how effective VNS is for treatment-resistant depression. In studies of more than 200 people, 20% to 30% said their depression symptoms improved a year after getting VNS. Others said their symptoms didn't improve or became worse.