Drug strategies for treatment-resistant depression


If you have treatment-resistant depression, you have tried antidepressants in the past without much success. But you shouldn’t give up. Finding the right medicine, dose, or mixture of medicines for you can take time.

“There are more than two dozen safe and effective antidepressants,” says Jonathan E. Alpert, MD, PhD, chair of the American Psychiatric Association Research Council and professor of psychiatry at Montefiore Medical Center.

The problem is, doctors can’t predict exactly how people will react to each drug. “Many different factors contribute to depression, such as genetics and life stressors,” says psychiatrist Walter Dunn, MD, PhD, assistant clinical professor of health sciences at UCLA Health. Until there is a better understanding of the disease, finding the right treatment is a matter of trial and error.

In search of the best approach

You and your doctor can discuss these drug strategies for treatment-resistant depression:

Make sure you are taking your medicine as prescribed. Three in four people do not take their medication as recommended by their doctor. Some people skip a day every now and then or stop taking medication when they start to feel better. But these measures can prevent an antidepressant from working well, says James W. Murrough, MD, PhD, director of the Depression and Anxiety Center at the Icahn School of Medicine at Mount Sinai. Talk to your doctor before changing the way you take your medications.

Give your current medication more time. Antidepressants usually don’t start working right away. Typically, it takes them 6 to 8 weeks to reach their maximum effect, says Murrough. For some people, the process can take even longer.

Your body must also adjust to the medicine. When you take a new antidepressant, you may have side effects, such as a dry mouth, headache, fatigue, or an upset stomach. But these symptoms often go away after a few weeks.

Change the dose of your medicine. People respond to antidepressants differently. You may need more or less medicine than the standard amount. If you don’t feel any different after 2 to 4 weeks, your doctor may increase your dose, says Alpert.

Switch to another antidepressant. If your medicine does not work, your doctor may suggest that you switch to another medicine. It’s usual. Research shows that only about a third of people find relief from their depression with the first antidepressant they take.

Most antidepressants affect chemicals in the brain called neurotransmitters, such as serotonin, norepinephrine, and dopamine. Each type of antidepressant affects these chemicals in a different way:

  • Selective Serotonin Reuptake Inhibitors (SSRIs). These are often the first antidepressants prescribed because they are less likely to cause side effects. They include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and escitalopram (Lexapro).
  • Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs). Examples of SNRI are duloxetine (Cymbalta), venlafaxine (Effexor XR), levomilnacipran (Fetzima), and desvenlafaxine (Pristiq).
  • Atypical antidepressants. These drugs do not fit into the other main categories. Examples include mirtazapine (Remeron), vortioxetine (Trintellix), and bupropion (Wellbutrin SR).
  • Tricyclic antidepressants. An older class, these antidepressants cause more side effects. They include mipramine (Tofranil), nortriptyline (Pamelor), amitriptyline, and doxepin.
  • Monoamine oxidase inhibitors (MAOIs). If you are taking these medicines, such as tranylcypromine (Parnate), phenelzine (Nardil), and isocarboxazid (Marplan), you will need to follow a strict diet as they can cause dangerous interactions.

Your doctor may want to try a medicine from the same class or from a different class. “Research shows that if you don’t respond to one SSRI, another may work,” says Dunn.

Add another medicine to your current antidepressant. Your doctor may want to add another medicine to the one you are already taking called augmentation. “If you’re feeling better and your symptoms have improved by 30-50%, we’ll try to add something more to make up the difference,” Dunn said.

Your doctor may also prescribe medications for other problems, such as anxiolytics, antipsychotics, mood stabilizers, and thyroid hormones.

Consider pharmacogenetic testing. With these tests, scientists study a sample of your saliva or blood. They check your DNA for genes that control certain enzymes or cell receptors. Most of these tests look at how your body metabolizes or breaks down drugs. If you metabolize a drug too quickly, you may need a higher dose of the antidepressant, says Dunn. On the other hand, if it takes longer for your body to metabolize a drug, it can build up and cause side effects.

Pharmacogenetic tests will not show which drugs work best. But they can offer clues about the dose you might need or your risk for side effects, says Alpert.

Everyone’s depression is different. You may need to try several medications and doses before you find the right one for you. Study shows that 67% of people found relief with the fourth drug. The process can be frustrating, but it’s important to keep trying, Dunn says.

“These drugs are not permanent,” he says, “so we have the luxury of trying one and stopping it if you don’t like it.” With time, patience, and communication with your doctor, it’s very likely that you will find the right treatment for your treatment-resistant depression.


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