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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.)

What You Can Do

According to Alpert, you can enhance your treatment by participating in healthy habits, such as exercising, eating nutrient-rich foods and keeping a consistent sleep-wake cycle. (Here’s more on doing things when you’re depressed.)

However, it’s important not to set high expectations, create a long list or be critical. If patients can do one thing, Hyland said, it’s to practice mindfulness. “That’s one of the best things I can help patients do.” This doesn’t mean meditating (unless you’d like to). Simply practice being an observer, she said. Observe your thoughts and feelings without judgment. Be patient and compassionate with yourself.

Hyland also suggested getting more support. “A doctor is rarely enough.” This could be asking your friend to accompany you to a doctor’s appointment or attending a support group, she said.

If you have a hard time remembering to take your medication, incorporate it into your routine, Alpert said. For instance, “take your medication when you brush your teeth in the morning or at night.” Keep the medication in the same place on the bathroom counter, or use a pillbox, he said.

Hyland creates a treatment plan for all her patients. She recommended individuals do the same for themselves. For instance, on your plan, you might write that if your energy doesn’t increase in four weeks, you’ll make a follow-up appointment; if you start having suicidal thoughts, you’ll see your practitioner immediately; when you’re feeling upset, you’ll talk to your pastor. This way, when you’re having an especially tough time, you don’t have to rely on your brain to make a wise decision. It’s already been made for you.

It’s also important to remember that if a treatment doesn’t work it’s not your fault. According to Alpert, “people will think they’ve failed, aren’t a good patient or their depression can’t be treated. The reality is that our medications are limited. Antidepressants don’t work nearly as well as we wish they did.” A person may need to try three medications before finding the right one.

Communication is Key

The other key factor in making the most of your treatment is to communicate regularly with your providers. Many people view doctors as all-knowing authorities, and they’re afraid to speak up, ask questions or voice their concerns.

But you’re more likely to get the best treatment when you keep the communication lines open. Be honest with your prescribing physician, and ask questions. Both Alpert and Hyland suggested several critical questions to ask.

  • What symptoms are we targeting with this medication? Knowing what symptoms the medication is supposed to improve will help you keep track of your progress, Hyland said.
  • When can I expect to improve? Similarly, she suggested asking your doctor about the time frame.
  • Should I keep a mood or sleep diary? This helps you keep track of your symptoms and stressors, spot patterns and gives you a better idea of whether the medication is working, Hyland said. “Many medications work really slowly.”
  • What other habits do you suggest I work on? If I notice improvement, how can I build on that? Hyland always asks her patients to engage in one behavior – something they love or loved to do – to bolster the treatment. For instance, she might ask a patient to walk their dog for 10 minutes two or three times a week. If you’re just starting out, ask your practitioner, “What can I do that will give me the most bang for my buck?” she said.
  • Can I see you in 2 to 4 weeks for 10 minutes? Many doctors, Hyland said, will schedule your next appointment in 6 to 8 weeks. But you need to check in and let the doctor know how you’re feeling and if you’re experiencing troublesome side effects.
  • Am I taking an optimal dose of this antidepressant? It’s common to start a patient on a low dose. (It might be a fourth of the max dose, Alpert said.) So if your first treatment doesn’t work, you might need a higher dose. It’s important to know what dose you’re taking, whether it’s the maximum and what the plans are for increasing the dose, Alpert said.
  • What can be done about my side effects? While side effects come with all medications, you can minimize them. This might mean adjusting the dose, switching medications, adding another medication or taking the medication at a different time, among other techniques. Again, this is why it’s crucial to be candid with your doctor.
  • Do I need other tests? According to Alpert, physicians may order additional tests when the patient has the textbook definition of depression but hasn’t responded to the first or second treatment. Depending on the particular symptoms, they might check a person’s thyroid, blood sugar, calcium, vitamin B12 or D or folate levels; evaluate the person for anemia, or refer them for a sleep study, he said.

Also, if a particular medication has been helpful for a relative, mention it to your doctor, Hyland said. “A lot of times a medication that works for a family member will work for the patient.”

It takes time and effort to find an effective treatment. “Perseverance is key,” Alpert said. He acknowledged that it’s tough to have hope when you’re already depressed and pessimistic. “The reality is that our treatments don’t work well enough for the first [intervention] to be effective.” But, as the research shows, people who stick with treatment improve and can even fully recover.

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 July 9, 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.