Psychotherapy, also known as talk therapy, can be used alone or in combination with medications for TRD to help you identify underlying issues that may be contributing to your depression. It can also teach you coping behaviors to help manage your symptoms and deal effectively with life stressors.
Adding a form of psychotherapy called cognitive behavioral therapy to standard medication treatment has been linked to better short-term, mid-term, and long-term outlooks for people with TRD than drug treatment alone, according to one frequently-cited systematic review and meta-analysis.
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.
Approximately 50 to 60 percent of people with treatment-resistant depression experience meaningful symptom improvement with TMS, and one-third of them experience a full remission of symptoms.
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.
Though TMS is generally safe and well tolerated, it can cause side effects such as:
Headaches
Lightheadedness
Scalp discomfort, especially at the site of stimulation
Spasms, tingling, or twitching of the muscles in your face
Electroconvulsive Therapy
Electroconvulsive therapy (ECT) — in which doctors purposely trigger a seizure by delivering electrical currents through the brain while the patient is asleep under general anesthesia — is sometimes used to treat people with TRD. ECT is thought to help change the brain’s chemistry in a way that may lessen symptoms of TRD.
ECT is very effective for major depression, relieving symptoms in about 80 percent of people who undergo the procedure.
An ECT session induces a seizure that lasts about a minute, and patients wake up about 5 to 10 minutes later. In the United States, ECT sessions are usually given two or three times per week for a total of 6 to 12 treatments, depending on how severe your depression is and how quickly your symptoms respond to treatment.
ECT is much safer today than in the past, when treatments were administered using high doses of electricity without anesthesia and caused serious adverse effects. Although modern-day ECT is generally safe, it can cause some side effects:
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
Vagus nerve stimulation (VNS), an FDA-approved surgical treatment for TRD, is usually offered only to individuals who’ve tried at least four medications, ECT, or both without experiencing a significant improvement in their symptoms.
Adding VNS to standard depression treatments is more effective for TRD than standard treatments alone and led to a significantly higher remission rate in one five-year study.
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.
Potential side effects of VNS include:
Deep Brain Stimulation
Deep brain stimulation (DBS) is an experimental therapy that is only used in people with severe depression whose symptoms haven’t improved after trying medication, psychotherapy, or ECT.
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.
During surgery, doctors implant the electrodes in the brain. The electrodes are connected to a neurostimulator implanted under the skin near the collarbone, similar to a pacemaker. The neurostimulator is used to send electrical currents to the brain to ease depressive symptoms.
After the procedure, you and your healthcare team work together to determine which settings on the neurostimulator work best at relieving your depressive symptoms.
Although not yet an FDA-approved treatment, DBS is a promising option for TRD, according to one systematic review and meta-analysis. Future research is needed to confirm its effectiveness.
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. Ketamine also appears to work at least as well as ECT among people with TRD without psychosis, according to another study.
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.
Botox
Botulinum toxin (Botox) injections may improve depressive symptoms, according to research. However, the FDA hasn’t yet approved Botox for treating depression. Researchers are still studying why Botox might help with depression.
Clinical Trials and Novel Treatments
Researchers are currently studying innovative therapies for TRD.
One receiving a lot of media attention involves the use of psilocybin, a mind-altering psychedelic chemical found in certain mushrooms. According to a study, combining psilocybin with psychotherapy provided a “substantial and rapid” decrease in symptoms for up to a year in patients with major depressive disorder.
Other research suggests that anti-inflammatory medications such as cyclooxygenase-2 inhibitors (COX-2 inhibitors) may help treat persistent depression by targeting inflammation in the body, which is thought to play a role in TRD. COX-2 inhibitors include celecoxib (Celebrex), the only version currently available in the United States, which is approved to treat certain forms of arthritis and related conditions. Additional research is needed to determine whether these medications are helpful for people with TRD.
Investigators are also examining newer classes of antidepressants, as well as ways to make TMS treatments more efficient, according to DeBattista.
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