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When the First Treatment for Depression Doesn’t Work

When the First Treatment for Depression Doesn't WorkWhen the first treatment you try for your depression doesn’t work, it can feel utterly painful. As it is, depression makes you feel hopeless and helpless. An ineffective intervention might feel like the final straw.

But it’s actually not uncommon for the first treatment to be unsuccessful. In fact, about 40 to 50 percent of people don’t respond to the first antidepressant they’re prescribed, according to Jonathan E. Alpert, M.D., Ph.D, the associate director of the Massachusetts General Hospital Depression Clinical and Research Program and co-founder and co-director of the Depression and Anxiety Group Practice.

Still, the people who stick with treatment do get better. So there is hope – real, tangible hope. Below, you’ll learn why treatment might not work, along with what you can do and how you can advocate for yourself.

Why the First Treatment Doesn’t Work

There are many reasons why the initial treatment doesn’t take. Here’s a selection.

Incorrect diagnosis. The treatment might be ineffective because the person doesn’t have depression in the first place. For instance, medical illnesses such as hypothyroidism can look like depression. Hypothyroidism produces significant fatigue, lack of motivation and difficulty concentrating, Dr. Alpert said.

A person might have another psychiatric disorder such as bipolar disorder. “On average bipolar disorder takes 7 years to diagnose,” said Kelli Hyland, M.D., a psychiatrist in outpatient private practice in Salt Lake City, Utah. Or an individual might have a personality disorder, which doesn’t respond to medication, she said. (In fact, “medication is often contraindicated.”)

Even if the diagnosis is correct, medical conditions can blunt the effect of antidepressants, Alpert said.

Stressors. Sometimes, the person is “living in an untenable situation,” Alpert said. So it doesn’t matter how well the antidepressant is working because the individual is still surrounded by stress – either at home or at work – that needs to be addressed, he said.

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Adherence. Some people might stop taking their medication because they’re concerned that it’s habit-forming, addictive or a crutch, Alpert said. Other individuals might stop because they actually feel better. But, as he said, “Once someone responds, they need to stay on medication for a minimum of 6 to 9 months to ensure they don’t have a rapid relapse.”

Another reason people stop taking their medication is side effects, such as nausea, diarrhea, sexual dysfunction or weight gain, he said. (“Many of these side effects can be addressed by switching to a lower dosage or a different antidepressant or sometimes by prescribing a second medication that helps alleviate the side effect.”)

Alcohol or drug use. “Alcohol and drugs interfere with antidepressant response,” Alpert said. Even having a beer or glass of wine at night can mess with your medication, Hyland said.

Other medications. Hyland noted that other medications, such as steroids and hormones, can interfere with antidepressants. (Being perimenopausal or menopausal also can affect efficacy, she said.)

Sleep problems. “I tell my patients that if you’re not sleeping, we can take medication ‘til the cows come home,” Hyland said. “Insomnia exacerbates mood, anxiety and coping.” Treating an underlying sleep disorder or trauma is important, she said.

Severity of illness. With moderate to severe depression, people often do best with medication and therapy, Hyland said. And sometimes two or three medications aren’t enough, she said.

The Next Steps

If your first ineffective treatment was medication, there are several ways physicians proceed. Alpert begins by examining the reasons the medication didn’t work. If he can eliminate the above as culprits, he might increase the dose of the medication. He also might switch the patient to another antidepressant within the same class (such as switching from one selective serotonin reuptake inhibitor, or SSRI, to another). He then might choose a medication from another class.

Another technique is to add a medication to augment the effects of the initial antidepressant, “especially if there is some evidence of a partial response,” Alpert said. In other words, if a person thinks they’re about 20 percent better and they’re tolerating the medication well, the doctor may prescribe a second antidepressant that works on a different mechanism of the brain, he said. An example is combining an SSRI, which targets serotonin, with Wellbutrin, which works on dopamine and norepinephrine.

Physicians also might prescribe an atypical antipsychotic, such as Abilify or Seroquel, to bolster the effects of the original antidepressant, Alpert said.

Psychotherapy, including cognitive-behavioral therapy and interpersonal therapy, is highly effective for treating depression. Therapists help clients learn about their illness, cope with stressors in their lives, identify and change dysfunctional thinking, and take action to get better.

If you’re only taking medication, seeing a therapist can be tremendously helpful. (If you’re solely working with a therapist, it’s also possible that you might need medication.)

When the First Treatment for Depression Doesn’t Work

Margarita Tartakovsky, M.S.

Margarita Tartakovsky, M.S. is an Associate Editor and regular contributor at Psych Central. Her Master's degree is in clinical psychology from Texas A&M University. In addition to writing about mental disorders, she blogs regularly about body and self-image issues on her Psych Central blog, Weightless.

APA Reference
Tartakovsky, M. (2018). When the First Treatment for Depression Doesn’t Work. Psych Central. Retrieved on October 31, 2020, from
Scientifically Reviewed
Last updated: 8 Oct 2018 (Originally: 17 May 2016)
Last reviewed: By a member of our scientific advisory board on 8 Oct 2018
Published on Psych All rights reserved.