Treatment-Resistant Depression

What is treatment-resistant depression?

Treatment-resistant depression (TRD) is a type of major depressive disorder (MDD). It happens when at least two different first-line antidepressants aren’t enough to manage the condition during a depressive episode. The two treatments must be of adequate dosage and duration (at least six to eight weeks) before a healthcare provider can diagnose TRD.

First-line antidepressants for the treatment of MDD are usually SSRIs (selective serotonin reuptake inhibitors) or SNRIs (serotonin and norepinephrine reuptake inhibitors). This is because they generally have fewer and less severe side effects compared to other antidepressants. TRD can develop in people who were previously responsive to antidepressant medications.

Despite its name, there are treatment options available for TRD, but it may take time to find the right one for you.

How common is treatment-resistant depression?

Approximately 30% of people who’ve been diagnosed with MDD and who’ve tried medications for MDD have treatment-resistant depression. MDD is one of the most common mental health conditions. It affects 5% to 17% of people at some point in their lives.

What are the symptoms of treatment-resistant depression?

People with treatment-resistant depression (TRD) have the same symptoms as people with major depressive disorder, like depressed mood, sleep disturbances and appetite changes. But people with TRD are more likely to have:

• More severe symptoms.
• Depressive episodes that last longer.
• Anhedonia (reduced ability to experience pleasure).
• A higher number of lifetime depressive episodes.
• Anxiety.
• Suicidal ideation and behavior.

If you or a loved one are thinking about suicide, dial 988 on your phone to reach the Suicide and Crisis Lifeline. Someone is available to help you 24/7.

What causes treatment-resistant depression?

Researchers don’t know the exact cause of TRD. As depression has many contributing factors — like genetics and brain chemistry — so does treatment-resistant depression.

They think that chronic stress may contribute to TRD by changing the function of your hypothalamic-pituitary-adrenal (HPA) axis. Your HPA axis is an important bodily process that’s responsible for stress adaptation. Chronic stress can worsen depression, which makes it more difficult to treat.

What are the risk factors for treatment-resistant depression?

Studies show that compared to people who have MDD that isn’t treatment-resistant, people with treatment-resistant depression are more likely to have physical health conditions, including:

• Autoimmune diseases.
• Thyroid disease.
• Heart disease.
• Cerebrovascular disease.

How is treatment-resistant depression diagnosed?

The diagnosis of treatment-resistant depression isn’t clearly defined. But most healthcare providers diagnose TRD if your depression symptoms haven’t improved after trying at least two first-line antidepressant medications. Most providers consider the following to be first-line depression medications:

• SSRIs
• SNRIs.
• Bupropion.
• Mirtazapine.

You generally have to take an antidepressant for at least six to eight weeks to see if it improves your symptoms.

If you don’t notice a change in your symptoms after trying two antidepressants, your healthcare provider may refer you to a psychiatrist. They’ll assess your medical and mental health history, including:

• Reviewing all of the medications you’re taking, including prescriptions, over-the-counter medications, herbal supplements and nonmedical drugs. Certain medications may interfere with the effectiveness of antidepressants or make depression worse.
• Discussing whether you’re taking your antidepressant and other medications as prescribed.
• Reviewing your experience with psychotherapy (talk therapy) and if it has helped manage depression.
• Assessing physical health conditions that can sometimes cause or worsen depression, like thyroid disease and chronic pain.
• Assessing issues like substance use problems.
• Considering if a different mental health condition more accurately describes your symptoms, like bipolar disorder or a personality disorder.

After this conversation, your provider may diagnose you with treatment-resistant depression. They’ll then work with you to find the best treatment option.

How is treatment-resistant depression treated?

There are several strategies to manage treatment-resistant depression. It could take a while to find the right strategy for you. Try not to lose hope.

To start, your psychiatrist may:

• Give your current antidepressant more time to see if it works.
• Increase the dose of a first-line antidepressant.
• Add a different class of antidepressant so you’re taking two different types.
• Encourage you to see a psychologist for psychotherapy. It may take time to find a therapist you “click” with. There are also several different types of psychotherapy.

If these strategies don’t work, your psychiatrist will likely recommend a different kind — or combination — of medications or treatments.

Currently, the U.S. Food and Drug Administration (FDA) approves five medications for the treatment of TRD:

• Aripiprazole (Abilify®) and brexpiprazole (Rexulti®): These are third-generation antipsychotic medications. They may improve depression symptoms by affecting your levels of serotonin and norepinephrine.
• Quetiapine (Seroquel®) and olanzapine (Zyprexa®): These are second-generation antipsychotic medications. Quetiapine is approved as an adjunctive (secondary) treatment to antidepressants for TRD. Olanzapine is approved when combined with fluoxetine (Prozac®). They may improve depression symptoms by affecting your dopamine levels. These medications also have sedative effects.
• Esketamine nasal spray (Spravato®): This is a derivative of ketamine. The FDA approved esketamine in 2019 as an adjunct treatment for adults with TRD, in combination with an oral antidepressant. Esketamine can lead to rapid remission of depressive symptoms within two hours of taking it. Due to serious risks of sedation and dissociation, as well as a potential for misuse, you have to receive esketamine in a clinical setting where a healthcare provider can monitor you for at least two hours after taking it.

The FDA has also approved the following treatments for TRD:

• Electroconvulsive therapy (ECT): ECT is a medical procedure that involves passing a mild electric current through your brain, causing a short seizure. This can stimulate nerve cells and produce brain changes that improve your mood.
• Repetitive transcranial magnetic stimulation (rTMS): This is a noninvasive treatment that involves using a magnetic coil to influence your brain’s natural electrical activity. It may change specific areas of your brain that affect your mood.

Other TRD treatments

Other treatment options for TRD include:

• Deep brain stimulation (DBS): DBS is a medical procedure that involves a mild electrical current delivered to a specific part of your brain. The electricity in that current stimulates the brain cells in that area, which can help several conditions, including TRD.
• Lithium (Eskalith®): Research shows that taking lithium in addition to an antidepressant (like citalopram) can help improve TRD.
• MAOIs (monoamine oxidase inhibitors): MAOIs were the first type of antidepressant invented. Due to several dietary restrictions, side effects and safety concerns, providers typically only prescribe them if all other classes of antidepressants haven’t improved depression symptoms.
• Pramipexole (Mirapex®): Pramipexole is a medication that’s FDA-approved for the treatment of Parkinson's disease. Studies show that it can relieve depressive symptoms in Parkinson's disease. It may help people with TRD.
• Vagus nerve stimulation (VNS): VNS involves implanting a device that sends regular, mild pulses of electrical energy to your brainstem through the vagus nerve in your neck. It can alter the level of specific neurotransmitters in your brain that play a role in regulating mood.

Researchers are also studying psilocybin as a potential treatment for TRD. Psilocybin is a psychedelic compound isolated from hallucinogenic mushrooms.

Side effects of TRD treatment

Medications and treatments for TRD generally have more side effects than first-line antidepressants. And they can vary widely. Your healthcare provider will discuss the possible side effects or complications of each treatment option. Don’t hesitate to ask questions.

Can treatment-resistant depression be prevented?

As scientists don’t know the exact cause of TRD, it’s generally unpreventable. But chronic stress likely plays a role, and there are steps you can take to manage your stress, including:

• Exercise regularly. Even a short walk can boost your mood.
• Get quality sleep. This is essential to overall health.
• Try relaxation activities, such as meditation, yoga, breathing exercises and muscle relaxation.
• Set goals for your day, week and month. Narrowing your view will help you feel more in control of the moment and long-term tasks.
• Practice mindfulness and gratitude, acknowledging the good parts of your day or life.
• Learn to say “no” to additional responsibilities when you’re too busy or stressed.
• Stay connected with people who keep you calm, provide emotional support and help you with practical things.
• Consider talking to a therapist or your healthcare provider about stress.

What can I do if I have treatment-resistant depression?

Aside from seeking professional, medical help for treatment-resistant depression (TRD), there are some things you can do at home that may help improve your symptoms, including:

• Getting regular exercise.
• Getting quality sleep (not too little, not too much).
• Eating a healthy diet.
• Avoiding alcohol, which is a depressant, as well as nonmedical drugs.
• Spending time with people you care about.

When should I see my healthcare provider about treatment-resistant depression?

You should have regular appointments with your healthcare provider while finding an effective treatment plan for TRD to assess how it’s working.

Otherwise, talk to your provider in the following situations:

• If you develop bothersome side effects.
• If your symptoms aren’t improving or if they’ve gotten worse.
• If you’re thinking of stopping the medication.

A note from Cleveland Clinic

If you have treatment-resistant depression (TRD), know that you’re not alone. About 30% of people with major depressive disorder have it. There are several treatment options for TRD, but it’ll likely take time to find the best one for you. Your healthcare provider and/or psychiatrist will support you through the process.