“There is no consensus on what constitutes treatment-resistant depression, but a conventional definition is the lack of response to two or more treatments of adequate dose and duration,” says Charles DeBattista, MD, the director of the Depression Research Clinic at Stanford University School of Medicine in California. In other words, if you’ve tried at least two types of antidepressants — for example, a selective serotonin reuptake inhibitor and a tricyclic antidepressant — and you don’t feel a whole lot better, you may have this unique form of depression. “Treatment-resistant depression is different from other forms of depression in that patients are more likely to have persisting symptoms and to relapse to depression even after [responding well] to treatment,” explains John Krystal, MD, the Robert L. McNeil, Jr., professor and chair of psychiatry at Yale School of Medicine in New Haven, Connecticut. But even though it’s called treatment-resistant, this type of depression isn’t untreatable, thanks to newer treatments shown to help alleviate symptoms and improve the quality of life for people with TRD. Symptoms of depression, according to the National Institute of Mental Health (NIMH), include:
Depressed or anxious mood that won’t go awayLoss of interest or pleasure in activities you once enjoyedFeelings of hopelessness or worthlessnessIrritability or restlessnessLow energy or fatigueDisruptions in sleep, appetite, or libidoConfusion or difficulty concentrating and remembering thingsAches or painsDigestive issuesSuicidal thoughts or behaviors
Additionally, people with TRD may have especially high levels of anxiety and feel depressed for a longer period of time than others, says Krystal. That said, a common misconception about TRD is that it’s always a very serious form of depression. Not so, Dr. DeBattista says. “Some treatment-resistant depression cases are mild but chronic,” he explains. Your doctor will ask questions about how well your depression responded to any medications you’ve already tried, including when, how often, and how long you took those medications, according to the Cleveland Clinic. Your doctor may also perform a thorough psychiatric and medical evaluation to rule out other potential causes of treatment resistance, such as:
Other forms of depression, such as bipolar depression or psychotic depressionHypothyroidism, or an underactive thyroidCushing’s disease, which occurs when your body is exposed to too much of the hormone cortisolObstructive sleep apneaAnemia
“The causes of treatment-resistant depression versus MDD are not well understood,” says Krystal. “Depression has many complex causes, including major life stress, genetic risk, maladaptive personality and coping traits, and lack of social support.” Factors such as lifestyle habits or underlying medical conditions that cause inflammation may also play a role, he adds. Some scientists think that depression is caused by low levels of mood-regulating brain chemicals like serotonin and norepinephrine. However, a systematic review published in July 2022 in the journal Molecular Psychiatry found little evidence to support that idea. Other research, published in June 2019 in the journal Molecular Psychiatry, suggests that TRD may be linked to differences in brain structure. And additional studies, including one review published in Patient Preference and Adherence, indicates that people with depression are less likely to respond to standard therapies if they:
Skip doses of prescribed antidepressants or don’t take them regularlyStop taking their antidepressant too soon, as it can take 6 to 12 weeks or longer for the full benefits to kick inTake other medicines that can cause negative drug interactionsMisuse alcohol or drugsAre misdiagnosed with the wrong mental health conditionHave another medical or psychiatric condition along with depression
Poor quality of lifeSocial and workplace problemsFinancial instability
People with depression also have an increased risk of certain health conditions, according to NIMH experts, including:
Alzheimer’s diseaseChronic painDiabetesHeart diseaseStroke
One of the most serious consequences of untreated depression is suicide risk. According to a review published in Psychiatric Services, 17 percent of people with TRD have attempted suicide. People with TRD also have a 23 percent higher risk of death by any cause than people with MDD who have not had any episodes of TRD, according to a study published in December 2022 in JAMA Psychiatry. Krystal agrees: “Don’t give up. Purely and simply, don’t give up. The fact that past treatments have not worked does not mean that all treatments will not work.” If it turns out that you have TRD, your doctor may recommend one or more of the following options.
Medication Strategies
If standard antidepressant medications don’t improve your symptoms, your doctor may first try optimizing your current medication regimen, according to the Mayo Clinic. They may:
Suggest you give your original medications more time to work. Some people take longer to respond to antidepressants than others.Increase the dose of your current treatment. Upping your dosage may improve your symptoms.Switch medications. Some people try several antidepressants before they find one that works.Add another antidepressant. Two medicines from different drug classes used at the same time can help target a wider range of the brain chemicals associated with mood regulation.Try augmentation therapy. This involves adding an additional medication typically used for another mental or physical health issue, such as mood stabilizers, antipsychotics, anti-anxiety drugs, or thyroid medicines.
An important note: Never make any changes to your medication regimen or stop taking your medication without consulting your doctor. Doing so may cause withdrawal symptoms, increase your depressive symptoms, or trigger the return of symptoms that have been reduced, partially or fully.
Psychotherapy
Psychotherapy, also known as talk therapy, can be used alone or in combination with medications for TRD to help you identify unhelpful thought patterns and replace them with more constructive ones. It can also teach you coping behaviors to help manage your symptoms and deal effectively with life stressors, say Mayo Clinic experts. Adding the psychotherapy called cognitive behavioral therapy to standard medication treatment has been linked to a better short-term, mid-term, and long-term outlook for people with TRD than drug treatment alone, according to a systematic review and meta-analysis published in October 2018 in the journal Psychiatry Research.
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, according to Harvard Health Publishing. This painless procedure involves placing an electromagnetic coil on the scalp that creates currents to stimulate an area of the brain involved in depression and mood regulation, explain Mayo Clinic experts. TMS is typically delivered in 30 sessions, over four to six weeks, according to the Cleveland Clinic. Each session lasts about 40 minutes, 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:
HeadacheLightheadednessScalp discomfort, especially at the site of stimulationSpasms, 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, especially if they’re having suicidal thoughts, say Mayo Clinic experts. ECT is thought to help rewire the brain 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, according to the American Psychiatric Association. An ECT session usually lasts about 5 to 10 minutes. In the United States, ECT sessions usually are given two or three times a week over three to four weeks. ECT is much safer today than in the past, when treatments were administered in high doses without anesthesia and caused serious side effects, according to the Mayo Clinic. Although modern-day ECT is generally safe, it can cause some side effects:
ConfusionHeadacheJaw painMuscle achesMemory loss, which usually improves within a couple months after treatment endsNauseaSerious heart problems in rare cases
Vagus Nerve Stimulation
Vagus nerve stimulation (VNS), an FDA-approved surgical treatment for TRD, is usually offered only to individuals who’ve tried ECT or TMS without experiencing a significant improvement in their symptoms, according to the Mayo Clinic. Adding VNS to standard depression treatments is more effective for TRD than standard treatments alone, according to a five-year study published in July 2017 in The American Journal of Psychiatry. VNS involves implantation of 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:
CoughDifficulty swallowingHeadachesHoarsenessInsomniaSkin tingling or pricklingShortness of breathThroat painVoice changesWorsened sleep apnea
Deep Brain Stimulation
Deep brain stimulation (DBS) is an experimental therapy used only for people with severe depression whose symptoms haven’t improved after trying medication, psychotherapy, or ECT, say researchers at NYU Langone Health in New York City. DBS involves the surgical implantation of electrodes into areas of the brain that are triggering depression, according to Mount Sinai in New York City. Doctors use brain scans to identify the most appropriate places to implant the electrodes. During a first surgery, doctors implant the electrodes in the brain. In a second surgery the next day, the electrodes are connected to a neurostimulator implanted under the skin near the collarbone, similar to a pacemaker. Doctors then use the neurostimulator to send electrical currents to the brain to ease your depressive symptoms. After the procedure, you and your doctor 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 a systematic review and meta-analysis of 17 studies published in April 2021 in Frontiers in Neuroscience. Future research is needed to confirm its effectiveness.
Newer Medicines
Some newer medicines may 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 a study published in November 2021 in The Journal of Clinical Psychiatry. In fact, the study found that ketamine was effective within 24 hours among people with depression who had suicidal thoughts.Esketamine (Spravato) In March 2019, the FDA approved this ketamine derivative for use in conjunction with 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 published in July 2020 in Scientific Reports. However, the FDA hasn’t yet approved Botox for treating depression. Researchers are still studying why Botox might help depression.
Lifestyle Measures
Certain lifestyle strategies can improve symptoms for some people with persistent depression, notes Krystal.
Fill up on plant foods and lean proteins. Sticking to a diet rich in fruits, vegetables, whole grains, fish, olive oil, low-fat dairy, and antioxidants is associated with a lower risk for depression, according to research published in July 2017 in Psychiatry Research. For maximum benefit, you should also limit your intake of red or processed meats, sweets, high-fat dairy products, butter, potatoes, and high-fat gravy, all of which were linked to a higher risk of depression in the same analysis.Aim to exercise for 30 minutes, most days. Getting your heart pumping for a half-hour a day, three to five times weekly, can significantly reduce depressive symptoms, say Mayo Clinic experts. Any physical activity you enjoy — from walking to jogging to gardening — counts as exercise.Keep in touch with friends and family. Isolation can worsen depression, which is why it’s important to reach out to people close to you when you’re struggling with your symptoms.Establish a regular sleep routine. Sleep disturbances are common among people with depression, and not getting enough sleep — or getting poor-quality sleep — can worsen your symptoms. Going to bed and waking up at the same time each day helps stabilize your sleep schedule.
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 published in February 2022 in the Journal of Psychopharmacology, combining psilocybin with psychotherapy provided a “substantial and rapid” decrease in symptoms for up to a year in patients with major depression. Research published in Neuropsychiatric Disease and Treatment suggests that anti-inflammatory medications such as cyclooxygenase-2 inhibitors (COX-2 inhibitors) also help treat persistent depression by targeting inflammation in the body, which is thought to play a role in TRD. Commonly used COX-2 inhibitors include celecoxib (Celebrex) and infliximab (Remicade), medications approved to treat certain forms of arthritis and related conditions. Additional research is needed to determine if these medications are helpful for people with TRD. Investigators are also examining newer classes of antidepressants, as well as ways to make TMS more efficient, according to DeBattista. Here are some of Everyday Health’s top resources for people with TRD. National Alliance on Mental Illness Peer-to-Peer This program provides eight free educational sessions for adults with mental health conditions who want to better understand their condition and recovery options. The sessions are taught by trainers with lived experience with mental health conditions. Mental Health America Support Community This virtual mental health support group and community connects patients, caregivers, and loved ones with similar struggles. Substance Abuse and Mental Health Services Administration (SAMHSA) The SAMHSA offers a free, 24/7 treatment referral and information service in English and Spanish for people dealing with mental health or substance use disorders. You can reach its national help line at 800-662-HELP (4357). Anxiety & Depression Association of America (ADAA) The ADAA website offers a Find a Therapist directory and provides credible educational information about depression.
