If you’ve been diagnosed with treatment-resistant depression, you might be wondering what happens next. You’ve already tried some medications. Maybe you’ve already tried talk therapy, too. They haven’t helped. So what now?

“Having treatment-resistant depression is a terrible burden for people,” says Ian A. Cook, MD, director of the Depression Research Program at the University of California Los Angeles. “But they really should hold on to some optimism.” Success might not come overnight. But with some patience and effort, you and your doctor can find an approach that will help.

Unfortunately, there’s no simple step-by-step plan to tackle treatment-resistant depression. Every case is different. But this article will give you an idea of how your doctor and therapist might think about your treatment. There are three basic approaches for treatment-resistant depression: medications, psychotherapy, and brain stimulation treatments. Here’s a guide to the options.

Medications for Treatment-Resistant Depression

If you have treatment-resistant depression, you’ve already tried some medications. Nonetheless, your doctor — preferably an expert at treating the condition — will likely recommend that you try again with a new approach.

You might be skeptical about going onto yet another medication. But keep in mind that there are lots of different drugs available and they work in different ways. Often it takes time — and trial and error — to find the right drug at the right dose or in the right combination, says Dean F. MacKinnon, MD, associate professor of psychiatry at the Johns Hopkins Hospital in Baltimore.

Here are your drug options for treatment-resistant depression:

Newer antidepressants. These include SSRIs — like Prozac, Celexa, and Zoloft — as well as drugs from other classes, like Effexor, Cymbalta, Wellbutrin, and Remeron. Generally, doctors are likely to start with these drugs.

Another new antidepressant, Symbyax, combines the active ingredient in Prozac with an antipsychotic, the active ingredient in Zyprexa. This combination medicine is the first drug approved by the FDA to specifically treat acute treatment-resistant depression.

Older antidepressants. These include tricyclic antidepressants or TCAs (like Elavil and Pamelor) and Monoamine Oxidase Inhibitors or MAOIs (like Nardil and Parnate.) While these drugs can help with treatment-resistant depression, many doctors only turn to them when other antidepressants have failed. They tend to have more severe side effects. MAOIs can cause dangerous interactions with other drugs and foods.

Add-on medications. Antidepressants aren’t the only type of drug for treatment-resistant depression. Sometimes using an antidepressant and then adding a different type of medicine can help. This is called add-on or augmentation therapy. Some of these drugs include lithium, antianxiety drugs, anticonvulsants, and antipsychotics. Abilify, Seroquel, and Zyprexa have been FDA approved as add-on therapy in treatment-resistant depression. Symbyax is a combination drug that contains the active ingredients in Zyprexa and Prozac together in one tablet and is approved for the treatment of treatment-resistant depression. One drawback to this approach is that the more medicines you take, the greater potential for side effects.

While not truly a drug, Deplin — a prescription medicinal food that contains folate — is also used to enhance the effect of an antidepressant.

Where will your doctor start? It really depends on the person. Here are some of the things that your doctor will consider when deciding what drug treatment to try next.

What drugs haven’t worked? If you have treatment-resistant depression, your doctor is unlikely to suggest that you go back on a medicine that didn’t help. In fact, he or she might suggest shifting to a different class of medication, which might work in a completely different way in the brain.

What drugs have helped a bit, but not enough? If a particular medication has helped ease your treatment-resistant depression symptoms at least a little, your doctor might suggest that you stick with it. Then to boost the effect, you could add on a second antidepressant or a different kind of drug.

If any close relatives had depression, what medication worked for them? There might be a genetic component to how well a person responds to a medication.So something that worked for your father or sister might be more likely for work for you.

What are the side effects? Your doctor will consider how the possible side effects might affect you specifically to get a good match. For instance, some antidepressants can increase the risk of weight gain. For some, that might be unacceptable or even dangerous. But for others — like people who have lost weight during a depression — it could actually be a good idea.

Of course, one of the things your doctor might need to do is get you off some of the medications you’re on now. If you’ve been struggling with treatment-resistant depression for a long time, you might have accumulated a lot of different prescriptions over the years. Some of those drugs might not have any purpose. Others might be interacting with each other, or even worsening your symptoms.

When you’re trying a new drug for treatment-resistant depression, make sure to give it a fair chance. Cook says that many people who think they are treatment-resistant — because they’ve tried a number of antidepressants without success — might not be. Instead, they just weren’t on the medicine long enough to know one way or another. Side effects are often the reason.

“One of the drawbacks to virtually all of the antidepressants is that the benefits come late and the side effects come immediately,” Cook tells WebMD. However, he says that if you can stick with a medication for a couple of weeks, those side effects often resolve themselves.

Psychotherapy for Treatment-Resistant Depression

Along with medications, talk therapy — like cognitive-behavioral, psychodynamic, and interpersonal therapy — is one of the first approaches that a person with treatment-resistant depression might try.

Research has shown that therapy can help with treatment-resistant depression specifically. The best evidence is with cognitive-behavioral therapy (CBT), which encourages people to see how their own thoughts and behaviors contribute to their depression. One study looked at people who didn’t get better using an antidepressant. Researchers found that switching to CBT improved symptoms by 50%. Talk therapy took longer to have an effect, but in the long run was just as effective as trying a different medication.

MacKinnon believes that the concrete focus of cognitive-behavioral therapy can be especially helpful for people struggling with treatment-resistant depression. Approaches that delve into your past and deeper emotional issues might not work as well right now, he says.

“When you’re in the middle of a depression, it’s really hard to look back at your life and learn from it,” MacKinnon says. “Your depression will so distort your perspective that you might come up with the wrong lessons.” It might be more productive to engage in that sort of therapy once the depression has lifted, he says.

However, the best therapeutic approach for treatment-resistant depression really depends on what feels right. Keep in mind that many therapists use a combination of approaches. Perhaps the most important thing is to find a therapist whom you like and trust. Having a good partnership is likely to boost your chances of success.

Brain Stimulation for Treatment-Resistant Depression

There’s another very different approach to tackling treatment-resistant depression: electrical stimulation of the brain. Doctors have long known that using electrical impulses can sometimes relieve the symptoms of depression.

Some of these approaches have been around for decades, such as ECT, which was once called electroshock therapy. Others are cutting-edge and only in clinical trials now. Here’s a rundown of the various approaches for treatment-resistant depression.

ECT (electroconvulsive therapy). ECT uses electrical impulses to trigger a controlled seizure in the brain. It’s generally reserved for severe or life-threatening cases of depression where nothing else has helped. But it works well and takes effect much faster than medication.

If you’re considering ECT, Cook advises that you go to a specialty center if possible. ECT can result in memory loss and confusion, which may take a few weeks or months to clear up. You might get better results with health care professionals who do the procedure regularly.

TMS (transcranial magnetic stimulation). This approach was approved by the FDA in 2008 for treatment-resistant depression in people with severe depression. Using an electromagnet, your doctor sends bursts of energy to specific parts of the brain.

TMS has some advantages over other electrical stimulation treatments. It’s done on an outpatient basis — usually four to five sessions a week for four weeks. You could get it right in the doctor’s office; the doctor just holds a small device against your scalp. It’s painless, doesn’t require surgery, and has few side effects and risks. Some insurance plans will cover TMS treatments if a person is diagnosed with severe major depressive disorder, and Medicare programs in some eastern and southern states recently began covering the therapy.

What are the disadvantages? While studies show that TMS can help, it has not been proven to be as effective as ECT in controlling depression. Researchers are still trying to sort out who might be most likely to benefit from it. As of now, they believe that TMS might work best in people with moderate symptoms who have only had one unsuccessful round of treatment with an antidepressant.

VNS (vagus nerve stimulation). This approach began as a treatment for epilepsy, but it’s since become an approved treatment for resistant depression. A surgeon implants a small device — like a pacemaker — in your chest. It’s connected to some wires that run under the skin and up to the vagus nerve in the neck. Once switched on, the device sends regular pulses of electricity to the nerve.

While there was a lot of initial excitement about VNS for treatment-resistant depression, Cook says the enthusiasm has faded. VNS requires surgery, which always poses some risks. And while studies have shown that it can help, it seems to work only in a minority of people. As of now, insurance companies generally don’t cover VNS therapy unless it is used to treat seizures.

Experimental treatments. Researchers are looking at other methods of using electrical stimulation for treatment-resistant depression. Deep brain stimulation has shown promising results in early studies, but it requires surgically implanting electrodes in the brain. MST (magnetic seizure therapy) triggers a controlled seizure in the brain. The hope is that it will have some of the benefits of ECT but with fewer side effects.

These treatments have not been approved for treatment-resistant depression. If you’re interested in trying them, talk to your doctor about joining a clinical trial.

Recovering From Treatment-Resistant Depression

By definition, treatment-resistant depression is hard to control. And the more treatments you try that don’t help, the more you might despair. You might have seen other people — relatives, friends, or co-workers — go through a depression and snap back after a couple of months. Why is it so different for you?

But experts say that while you might have a tough case, lots of other people do, too.

“People who don’t respond to an antidepressant sometimes jump to the conclusion that they’re doomed,” says Cook. “But that’s not true at all, and their depression is coloring their outlook.” In fact, the majority of people who are depressed don’t get better with the first prescription. The key is to stick with treatment and to keep trying.

“When I see new patients with treatment-resistant depression, I tell them that if they want to borrow some of my optimism, they’re welcome to it,” says Cook. While they might have lost hope, Cook says that he’s seen many people who were just as depressed recover.

“Despite how it feels, lots of people have been through this,” says Cook, “and lots of people get better.”