Treatment-Resistant Depression

How well is your depression treatment working? Does it help a bit, but you still don't feel as if the darkness has lifted? Perhaps you feel the treatment isn't working at all. If so, you could have treatment-resistant depression, also called refractory depression.

Unfortunately, depression treatments don't always work. As many as two-thirds of people with depression aren't helped by the first antidepressant they try. Up to a third don't respond to several attempts at treatment.

Treatment-resistant depression (TRD) can leave you feeling hopeless and discouraged. Months or even years can go by without any relief. And after the effort it took to get help, it can be demoralizing when you're just not getting better.

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But if your depression treatment isn't working, don't give up. Many people can get their treatment-resistant depression under control. You and your doctor just need to find the right approach. This might include different drugs, therapy, and other treatments. If you're still struggling with depression despite treatment, here's what you need to know.

Understanding Treatment-Resistant Depression

What is treatment-resistant depression? Surprisingly, that can be hard to answer. Experts still disagree on what exactly the term means.

Some researchers define TRD as a case of depression that doesn't respond to two different antidepressants from different classes. Other experts say that a person needs to try at least four different treatments before depression can be truly considered treatment-resistant.

Of course for you, the exact definition doesn't matter. You just need to ask yourself some basic questions.

  • Has your treatment failed to make you feel better?
  • Has your treatment helped a bit, but you still don’t feel like your old self?
  • Have the side effects of your medication been hard to handle?

If the answer is yes to any of these, you need to see your doctor. Whether or not you actually have treatment-resistant depression, you need expert help.

Treatment-Resistant Depression: Getting Help

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Although a primary care doctor can treat depression (research suggests that 60%-65% of antidepressants are prescribed by primary care physicians), it may be best to see a specialist, like a psychiatrist, if you think you may have treatment-resistant depression. It's a good idea to also work with a therapist, like a psychologist or social worker, because the best treatment is often a combination of medicine and therapy.

Treatment-resistant depression can be hard to diagnose. Sometimes, other conditions or problems can cause similar symptoms. So when you meet with your doctor, they will want to:

  • Confirm the diagnosis. Some people who apparently have treatment-resistant depression were misdiagnosed. They never had only depression in the first place. Instead, they have conditions like bipolar disorder (where antidepressants may be less effective than in unipolar depression), or problems with drugs or alcohol that can cause or worsen depression, or a medical condition (such as hypothyroidism) that can cause symptoms of depression, and may have been getting the wrong treatment. When major depressive disorder is accompanied by other medical or psychiatric disorders (such as anxiety disorders, eating disorders, or personality disorders), the depression often is harder to treat, particularly if the additional disorders that are present don't receive their own independent treatment.
  • Make sure you've been using your medicine correctly. Up to half of all people who get prescribed drugs for depression don't take them as recommended. They miss doses or stop taking them because of side effects. Some give up too soon - it can take 4-12 weeks for a medicine to take effect. Sometimes taking a medicine at too low a dose also explains an inadequate response.
  • Check for other causes. Other issues - ranging from thyroid problems to substance abuse - can worsen or cause depression. So can many medicines used to treat common medical problems. Sometimes, switching medicines or treating an underlying condition can resolve a hard-to-treat depression.

You may wonder why some people do so well with the first medication they try, while you continue to suffer. Experts don't know for sure, but we do know that not all depressions are the same across every sufferer. Evidence also suggests that people who have especially severe depression or long-term depression may be harder to treat.

Medications for Treatment-Resistant Depression

Different antidepressants work in different ways to affect specific chemicals (neurotransmitters) that transmit information along brain circuits that regulate mood. If your current medicine isn't helping - or isn't helping enough - other drugs might. There are two basic approaches:

  • Switching medicines. There are a number of different classes of antidepressants, including SSRIs (such as citalopram [Celexa], escitalopram [Lexapro], fluoxetine [Prozac], fluvoxamine [Luvox], paroxetine [Paxil], and sertraline [Zoloft]) and SNRIs (such as desvenlafaxine [Khedezla or Pristiq], duloxetine [Cymbalta], levomilnacipran [Fetzima], and or venlafaxine [Effexor]). Newer antidepressant medicines that affect many different serotonin receptors in the brain include vilazodone (Viibryd) and vortioxetine (Trintellix, formerly called Brintellix). Older classes of antidepressants include tricyclics like doxepin (Adapin), amitriptyline (Elavil), imipramine (Tofranil), and nortriptyline (Pamelor, Aventyl); tetracyclics like amoxapine (Asendin), maprotiline (Ludiomil,) mazindol (Mazanor); and mirtazapine (Remeron). Some antidepressants, such as bupropion (Wellbutrin) or mirtazapine (Remeron), are thought to affect the brain chemicals dopamine and norepinephrine through unique mechanisms, and are often combined with other antidepressants in order to take advantage of their combined effects. Another older class of antidepressants, called MAO inhibitors (such as isocarboxazid [Marplan], phenelzine [Nardil], selegiline [Emsam], and tranylcypromine [Parnate]) affect a special enzyme inside brain cells that can increase the functioning of several different neurotransmitters. Sometimes, switching from one class of antidepressant to another can make a difference. Another option is to switch from one drug to another in the same class. A person who wasn't helped by one SSRI could still benefit from a different one. In addition, l-methylfolate (Deplin) has shown success in for treating treatment resistant depression. L-methylfolate is a prescriptionstrength form of the B- vitamin,folate, and helps regulate the neurotransmitters in the brain that control moods.
  • Adding a medicine. In other cases, your doctor might try adding a new medicine to the antidepressant you're already using. This can be especially helpful if your current drug is partly helping, but not completely relieving your symptoms. This can be called adjunct therapy or augmenting treatment with another medicine. What medicines might they try? One option is to add a second antidepressant from a different class. This is called combination therapy. Another approach is called augmentation therapy: adding a medicine not typically used to treat depression, like lithium, an anticonvulsant, or an antipsychotic. Aripiprazole (Abilify), brexpiprazole (Rexulti) or quetiapine (Seroquel XR) are FDA-approved as add-on therapies to an antidepressant for treatment-resistant depression. Olanzapine-Fluoxetine (Symbyax) is a combination drug that contains the active ingredients in fluoxetine (Prozac) and olanzapine (Zyprexa) together in one tablet and is approved for the acute treatment of treatment-resistant depression. Spravato (esketamine) nasal spray may be used in conjunction with an oral antidepressant for the treatment of depression in adults who have tried other antidepressant medicines but have not benefited from them. One drawback to this approach is that the more medicines you take, the greater potential for side effects or drug interactions.. People have different reactions to the drugs used for treatment-resistant depression. The medicine that works best for one person might have no benefit for you. And unfortunately, it's hard for your doctor to know beforehand what drug or combination of drugs will work best. Arriving at the right treatment can take patience.

Other Treatments for Treatment-Resistant Depression

Drugs aren't the only approach used in treatment-resistant depression. Some other methods included in the treatment of TRD are:

  • Talk therapy. Approaches like cognitive behavioral therapy - which focuses on concrete goals and how your own thoughts and behaviors contribute to your depression -- can really help people with depression. There’s some evidence it works especially well with treatment-resistant depression. If you've tried therapy in the past and it hasn't helped, you could try again. Think about seeing a new therapist. Or look into a different therapeutic approach. For instance, if one-on-one therapy didn't do much for you, ask your doctor if group therapy or a different approach might be more worth a try.
  • ECT (electroconvulsive therapy.) ECT is typically used in people with serious or life-threatening depression that can’t be resolved by other treatments, or in significant depressive episodes that have not gotten better after several medication trials. It uses electric impulses to trigger controlled seizures in the brain. A series of ECT treatments (usually 6-12 over a few weeks) can often rapidly relieve depression, although some form of continued therapy (either a medicine or else periodic ECT "booster" treatments are usually necessary to prevent relapse.
  • VNS (vagus nerve stimulation.) This approach is also used in people with serious depression that just hasn't responded to other treatments. Like ECT, it uses electrical stimulation to relieve the symptoms of depression. The difference is that the device is surgically implanted in your body. VNS is FDA-approved for the long-term (not acute) depression of chronic depression that does not respond to at least two antidepressant trials. Its effects may take up to 9 months to appear and studies have shown that a meaningful response seems to occur only in about 1 in 3 people.
  • TMS (transcranial magnetic stimulation.) This is a non- invasive approach that's been approved for treatment-resistant depression. Like VNS and ECT, it uses electrical stimulation to treat depression. Unlike those procedures, TMS poses few side effects. It may be best for seriously depressed people who are mildly resistant to drug therapy. Treatment is done on an outpatient basis four to five days a week for four or more weeks. It is considered safe, but appears to be not as effective as ECT.
  • Experimental techniques. Experts are researching new techniques to tackle treatment-resistant depression, like deep brain stimulation and MST (magnetic seizure therapy.) Although some studies have been promising, more research needs to be done. But if you're interested in trying them, talk to your doctor about joining a clinical trial.

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Sometimes, a doctor might recommend hospitalization for treatment-resistant depression. It could be the best option if your depression is severe and you're at risk of hurting yourself. A stay in the hospital also offers a way for you to recover from your depression in a safe and stable environment. You’ll get a break from some of the daily stresses that might contribute to your condition. Your doctors will also get a chance to collaborate and come up with a good treatment plan.

Living With Treatment-Resistant Depression

Life with depression is hard, but treatment-resistant depression can be especially brutal. When one treatment after another doesn't help, you can lose hope that you'll ever feel better. All your efforts -- the doctor's visits, the medication trials, the therapy sessions -- might seem like a waste.

But they haven't been a waste. Arriving at the right treatment for depression can take time. It can take some trial and error. Look at it this way: if you try a particular treatment and it doesn’t help, you're that much closer to finding the one that will make you feel better.

Whatever you do, don't settle. Don't give up and accept the symptoms of depression. Remember, the longer a depression goes on, the harder it may be to treat. Go back to your doctor and see if there's something else you can try. There are so many good treatments for depression out there. You just need to find the right one for you.

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