Treatment-resistant depression: what are my options?

If you have depression and have tried courses of antidepressant medications one or more times without success, it’s easy to get discouraged. Will you feel this way forever? 

Thankfully, there are many effective options for treating depression, even in resistant cases. Read on to learn about the options available to you.

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There’s no clear definition of treatment-resistant depression (TRD), also called refractory depression. It’s usually defined as at least two antidepressant treatment failures when an adequate dose has been given for a long-enough time (Gaynes, 2020).

Depression is a very common mental illness, with approximately 12% of people experiencing it at least once during their lifetime. Women are about twice as likely to have depression as men. Although depression usually first occurs during midlife, it’s becoming more common in younger people due to alcohol and substance abuse (Bains, 2020)

Most cases of depression can be treated successfully. The main treatment for depression is with antidepressant medication. But 10–15% of people treated with antidepressants don’t respond to treatment, and 30–40% have some, but not complete, relief from the symptoms of depression (Tundo, 2015).

People with TRD can have depressive symptoms like feelings of powerlessness and suicidal thoughts. The depression they’re experiencing can harm how they function at work and in their social and family lives. Their physical health may also be impacted (Tundo, 2015).

If you have depression, you’ve probably first been diagnosed and treated by a primary care provider (PCP), who will likely have prescribed an antidepressant medication. If that didn’t work to relieve the depression, your provider may have changed your dose or prescribed another medication. 

If you’re still experiencing symptoms of depression after these changes, it may be time to see a psychiatrist. Psychiatrists are medical doctors who are knowledgeable about different types of mental conditions and the types of treatment available for them. 

A psychiatrist will check to see if (Pandarakalam, 2018):

• The diagnosis of depression is correct—Depression can be confused with other mood disorders, such as bipolar disorder, or with substance abuse and other conditions that may be treated differently.

• The appropriate medication has been prescribed

• The medication has been taken long enough to have an effect (usually 6–12 weeks), the dosage is correct, and you’re taking it correctly

• Other physical conditions are present, such as viral infections or vitamin deficiencies

• Other mental conditions are present, such as anxiety disorder or eating disorders

Pharmacological treatment is usually prescribed first for depression. There are many different types, or classes, of antidepressant medications (Bains, 2020):

• SSRIs (selective serotonin reuptake inhibitors), such as fluoxetine (see Important Safety Information), sertraline (see Important Safety Information), paroxetine (see Important Safety Information), and citalopram. SSRIs are usually the first type of antidepressant a healthcare provider will prescribe for depression.

• SNRIs (serotonin norepinephrine reuptake inhibitors), such as venlafaxine (see Important Safety Information), duloxetine (see Important Safety Information), and desvenlafaxine

• Serotonin modulators, including trazodone (see Important Safety Information), vilazodone, and vortioxetine

• Atypical antidepressants, including bupropion (see Important Safety Information) and mirtazapine (see Important Safety Information). These are often prescribed for patients who develop unwanted side effects from SSRIs or SNRIs.

• Atypical antipsychotics, such as olanzapine

• TCAs (tricyclic antidepressants), such as amitriptyline, doxepin, and nortriptyline

• MAOIs (monoamine oxidase inhibitors), including tranylcypromine, phenelzine, selegiline, and isocarboxazid

TCAs and MAOIs aren’t frequently prescribed because they can have negative side effects and because overdoses can be fatal, but there may be situations in which a healthcare provider determines that one of these is best for you.

What if you don’t respond to antidepressants?

If you don’t respond to typical antidepressant therapy, your provider may increase the dosage of the medication. You may be switched from one antidepressant to a different antidepressant, either in the same class or a different class––for instance, from one SSRI to another SSRI, or from an SSRI to an SNRI. Your current medication may even be combined with another antidepressant, usually from another class, to have more impact (Tundo, 2015).

Another approach is augmentation, in which you combine your current treatment with another substance that isn’t itself an antidepressant. This additional substance could be lithium, thyroid hormone, omega-3 fatty acids, antipsychotics, dopamine agonists (used to treat Parkinson’s syndrome), or many others that have been shown to work well when combined with typical antidepressant therapy (Tundo, 2015).

If you don’t respond to any of these approaches, your healthcare provider or psychiatrist may diagnose you with treatment-resistant depression.  

Medications aren’t the only treatments you can try for resistant depression. There are many other things that can help:

• Psychotherapy (talk therapy can be combined with antidepressant medication. Studies show this works better than medication alone or psychotherapy alone. There are many different types of psychotherapy, including cognitive behavioral therapy (CBT), interpersonal therapy (IPT), problem-solving therapy (PST), and others (Kamenov, 2017).

• Electroconvulsive therapy (ECT) can be very effective for treatment-resistant depression. Some psychiatrists think it should be considered sooner than it usually is for depression that hasn’t responded to other treatments (Pandarakalam, 2018).

• Transcranial magnetic stimulation (TMS) uses electromagnetic energy to alter brain activity. There’s a great deal of research that shows TMS is effective for some people with treatment-resistant depression, either alone or in combination with medication (Somani, 2019).

• Vagus nerve stimulation (VNS) is another form of brain stimulation. Like TMS, VNS uses electromagnetic energy to alter brain activity. There’s less evidence for its effectiveness than there is for TMS (Pandarakalam, 2018).

• Complementary therapies are nontraditional therapies done in combination with conventional treatments (medication and/or psychotherapy). They include hypnotherapy, reflexology, aromatherapy, reiki, osteopathy, broad-spectrum light therapy, and acupuncture. Some people with treatment-resistant depression have had good results with complementary therapies (Pandarakalam, 2018).

• Physical activity/exercise is an effective but often-overlooked therapy for depression. Studies have found that exercise alone is as effective as medication for some people with depression and can also heighten the benefits of medications (Kvam, 2016).

• Ketamine an anesthetic, can provide quick relief from depression, but the effects may not last long. It can be especially helpful for people with thoughts of suicide (Corriger, 2019). The FDA recently approved a form of ketamine called esketamine, used as a nasal spray, for TRD (FDA, 2019).

• Neurosurgery can be done for severe depression if all other approaches have been unsuccessful (Pandarakalam, 2018)

If you have TRD, don’t give up hope. As you can see, many different types of treatment are available. If you keep looking, the chances are good you’ll find an effective treatment that works for you. Speak with your healthcare provider about your options and before making any changes in your treatment. 

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Current version

April 15, 2021

Written by

Alison Dalton

Fact checked by

Steve Silvestro, MD

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About the medical reviewer

Steve Silvestro, MD, Ro

Dr. Steve Silvestro is a board-certified pediatrician and Associate Director, Clinical Content & Education at Ro.