I've taken different antidepressants over the years, and now my body seems to reject medications that helped before. Any suggestions?

We certainly know that antidepressant medications sometimes seem to stop working. Clinicians started to describe the “Prozac poop out” more than a decade ago, and it seems that the same thing can happen with any antidepressant. For some type of medications (like narcotic pain medication or benzodiazepine anxiety medications) we understand the chemistry of tolerance. For those drugs, long term use causes brain cells to adapt so that the same amount of medication has less and less effect over time. That tolerance and dependence process is pretty similar from person to person. Developing a “tolerance” to antidepressant drugs is very unpredictable from person to person, and we haven’t found any chemical change that explains it.

But the more we study this problem, the better we understand that we don’t really understand it. For example, we used to believe that whenever one antidepressant medication seemed to stop working, it was best to try switching to a medication of a different chemical type or class. We now know that the chemical type of class isn’t a useful guide. If one medication stops working, it’d definitely worth trying a different one—but the odds of success seem about equal if the new medication is similar to or different from the one that’s no longer helping.

Even if we don’t have a lot of science to guide us, we can still come up with some practical advice. If your antidepressant medication doesn’t seem to be helping:

  • Consider whether other substances (alcohol, street drugs, or changes in prescription medication) might be making depression worse.
  • Ask whether the dose of the medication is at the most effective level.
  • If it’s time to try something different, changing to a different medication or adding a second “booster” medication seem about equally likely to help.
  • How you respond to one medication doesn’t really predict how you will respond to a different one (even a different medication from the same family).
  • When trying a different medication, it’s important to be patient enough (sticking with it long enough to know if it will really help) but not too patient (sticking with it past the point of futility). Be sure to ask your doctor how and when you will assess whether any new treatment is right for you.

About the Doc

About the Doc

Greg Simon, MD, MPH, is a psychiatrist and researcher at  Kaiser Permanente Washington Health Research Institute in Seattle. His research focuses on improving the quality and availability of mental health services for people living with mood disorders, and he has a specific interest in activating consumers to expect and demand more effective mental health care.

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