Why Antidepressants Don’t Always Work and What You Can Do About It

When Prozac was first introduced in 1987, it generated a wave of excitement – finally, there seemed to be a new antidepressant medication with fewer side effects that worked well. Over the years, there has been a shift towards disappointments – efficacy of antidepressants seems low, side effects seem high, and placebo effects may be larger than we first thought.

To date, we do not have a good explanation for why antidepressants work for some people and not others. Perhaps our best data comes from a government study called STAR-D (Sequenced Treatment Alternatives to Relieve Depression)*. This study showed that about the first antidepressant medication eliminated depression in about one-third of patients and improved depression in about one-half of patients. In the next level, some patients had a medication switch, and depression was eliminated in another one-quarter of these patients. Other patients tried to add on another medication and about one-third of these patients became symptom-free. There were an addition third and fourth level switch available. Over the course of the total four levels, about 70% of patients became symptoms free.

So what does this mean? Even in a controlled study, there were 30% of patients who did not become symptom-free, even after 4 different medication changes! Clearly, medication does not work for everyone.

So what can you do? Here are some options you can consider:

  1. Keep trying! There is some evidence that eventually you will find a good medication, and there are certainly plenty of antidepressants on the market.
  2. Try psychotherapy. There are different types of psychotherapy and all can be helpful for the treatment of depression. The most important factor is the relationship between you and your therapist – so when you are starting aim for a good fit rather than a certain type of therapy.
  3. Use genetic testing. If you have tried several antidepressants and nothing is working, it is possible that you have atypical metabolism of those medications. There are several genetic tests on the market that your doctor can use to help guide the choice of an antidepressant.
  4. Consider neuromodulation therapy. The two main FDA-approved neuromodulation therapy for treatment-resistant depression are TMS (Transcranial Magnetic Stimulation) and ECT (Electroconvulsive Therapy). Please see our other blogs and videos for more information about TMS.


Live mentally healthy,
Dr. Jennie Byrne

Dr. Jennie Byrne, M.D., PhD. With over 15 years of medical expertise, Jennie Byrne, MD, PhD, is a board-certified psychiatrist with experience treating mental health conditions in adults, including dementia, attention-deficit hyperactivity disorder, anxiety, and depression. After practicing in New York City for 12 years, Dr. Byrne relocated to North Carolina in 2008; she currently cares for patients in Chapel Hill, North Carolina, at Cognitive Psychiatry of Chapel Hill. Dr. Byrne earned her bachelor’s degree at the University of Pennsylvania in Philadelphia. She then received her doctorate from New York University Department of Neurophysiology. She also has a doctorate of medicine from New York University School of Medicine. Dr. Byrne went on to complete a psychiatry residency at Mt. Sinai School of Medicine in New York. In addition to her work as a psychiatrist, Dr. Byrne has performed extensive research on attention, memory, and depression. As a board-certified adult psychiatrist, Dr. Byrne focuses on the needs of each patient to pro

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