Feeling sad or hopeless from time to time is a normal and natural part of life. It happens to everyone. For people with depression, these feelings can become intense and long-lasting. This can lead to problems at work, home, or school.

Depression is usually treated with a combination of antidepressant medication and certain types of therapy, including psychotherapy. For some, antidepressants provide enough relief on their own.

While antidepressants work well for many people, they don’t improve symptoms for 10–15 percent of people with depression. In addition, 30–40 percent notice only a partial improvement in their symptoms.

Depression that doesn’t respond to two trials of medications from different classes of antidepressants is known as treatment-resistant depression. Some also refer to it as treatment-refractory depression.

Read on to learn more about treatment-resistant depression, including treatment approaches that can help.

There’s no standard diagnostic criteria for treatment-resistant depression, but doctors generally make this diagnosis if someone has tried at least two different types of antidepressant medication from different classes without any improvement.

If you think you have treatment-resistant depression, it’s important to get a diagnosis from a doctor. While you might have treatment-resistant depression, they’ll want to double-check a few things first, such as:

  • Was your depression correctly diagnosed in the first place?
  • Are there other conditions that could be causing or worsening symptoms?
  • Was the antidepressant used in the right dose?
  • Was the antidepressant taken correctly?
  • Was the antidepressant tried for a long enough time?

Antidepressants don’t work quickly. They usually need to be taken for six to eight weeks in appropriate doses to see the full effect. It’s important that the medications are tried for a long enough time before deciding that they aren’t working.

However, some research shows that people who show some improvement within a couple weeks of starting an antidepressant are more likely to eventually have a full improvement in their symptoms.

Those who don’t have any response early in treatment are less likely to have full improvement, even after several weeks.

Experts aren’t sure why some people don’t respond to antidepressants, but there are several theories.

Some of the most popular ones include:

Incorrect diagnosis

One of the most common theories is that people who don’t respond to treatment don’t actually have major depressive disorder. They may have symptoms similar to those of depression, but actually have bipolar disorder or other conditions with similar symptoms.

Genetic factors

One or more genetic factors likely have a role in treatment-resistant depression.

Certain genetic variations may increase how the body breaks down antidepressants, which could make them less effective. Other genetic variants might change how the body responds to antidepressants.

While a lot more research is needed in this area, doctors can now order a genetic test that may help to determine which antidepressants will work best for you.

Metabolic disorder

Another theory is that people who don’t respond to treatment may process certain nutrients differently. One study found that some people who don’t respond to antidepressant treatment have low levels of folate in the fluid around the brain and spinal cord (cerebrospinal fluid).

Still, no one’s sure what causes this low level of folate or how it’s related to treatment-resistant depression.

Despite its name, treatment-resistant depression can be treated. It just might take some time to find the right plan.

Antidepressants

Antidepressant medications are the first choice for treating depression. If you’ve tried antidepressants without much success, your doctor will likely start by suggesting an antidepressant in a different drug class.

A drug class is a group of medications that work in a similar way. The different drug classes of antidepressants include:

If the first antidepressant you tried was a selective serotonin reuptake inhibitor, your doctor might recommend either a different antidepressant in this class or an antidepressant in a different class.

If taking a single antidepressant doesn’t improve your symptoms, your doctor may also prescribe two antidepressants to be taken at the same time. For some people, the combination may work better than taking one medication by itself.

Other medications

If an antidepressant alone doesn’t improve your symptoms, your doctor might prescribe a different type of medication to take with it.

Combining other medications with an antidepressant sometimes works better than the antidepressant by itself. These other therapies are often called augmentation treatments.

Other medications that are commonly used with antidepressants include:

Other medications that your doctor might recommend include:

Nutritional supplements may also help, especially if you have a deficiency. Some of these may include:

Psychotherapy

Sometimes, people who don’t have much success taking antidepressants find that psychotherapy or cognitive behavioral therapy (CBT) is more effective. But your doctor will likely advise you to continue taking medication.

In addition, some research shows that CBT improves symptoms in people who don’t improve after taking antidepressants. Again, most of these studies involve people simultaneously taking medication and doing CBT.

Procedures

If medications and therapy still don’t seem to be doing the trick, there are a few procedures that may help.

Two of the main procedures used for treatment-resistant depression include:

  • Vagus nerve stimulation. Vagus nerve stimulation uses an implanted device to send a mild electrical impulse into your body’s nervous system, which may help to improve depression symptoms.
  • Electroconvulsive therapy. This treatment has been around since the 1930s and was originally known as electroshock therapy. ECT is a safe and effective treatment for clinical depression, but is used as a last resort due to cost and the fact that it is an invasive treatment.

There are also a variety of alternative treatments that some people try for treatment-resistant depression. There isn’t much research to back up the effectiveness of these treatments, but they may be worth trying in addition to other treatments.

Some of these include:

In recent years, there’s a lot of interest in using stimulant drugs along with antidepressants to improve treatment-resistant depression.

Stimulants that are sometimes used with antidepressants include:

But so far, the research surrounding the use of stimulants for treating depression is inconclusive.

For example, in one study, using methylphenidate with antidepressants didn’t improve overall symptoms of depression.

Similar results were found in another study that looked at the use of methylphenidate with antidepressants and one that evaluated using modafinil with antidepressants.

Even though these studies found no overall benefit, they did show some improvement in symptoms, such as fatigue and tiredness.

Thus, stimulants may be an option if you have fatigue or excessive tiredness that doesn’t improve with antidepressants alone. They might also be an option if you have attention deficit hyperactivity disorder as well as depression.

Lisdexamfetamine is one of the best-studied stimulants used for treatment-resistant depression. Although some studies have found improved symptoms when combined with antidepressants, other research has found no benefit.

An analysis of four studies of lisdexamfetamine and antidepressants found that the combination was no more beneficial than taking antidepressants alone.

Managing treatment-resistant depression can be difficult, but it’s not impossible. With a little time and patience, you and your doctor can develop a treatment plan that improves your symptoms.

In the meantime, consider connecting with others facing similar challenges for support and information about what’s worked for them.

The National Alliance on Mental Illness offers a program called Peer to Peer that involves 10 free educational sessions that break down everything from talking to your doctor to staying current on the latest research.