Ask Dr. Pat

Antidepressants: What Are Your Options When Your Medication Isn’t Helping?

Dr. Pat Consults:

Dr. Patricia Yarberry Allen is a collaborative physician who writes a weekly Medical Monday” column for Women’s Voices for Change.  (Search our archives for her posts, calling on the expertise of medical specialists, on topics from angiography to vulvar melanoma.)

This week, Dr. Pat has asked Megan Riddle, M.D./Ph.D., a psychiatry resident at the University of Washington and a graduate of the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, to address the concerns of a woman whose depression is sapping her of energy and enthusiasm and who is not responding to the antidepressant medication prescribed for her.

3134063173_e05b16f9fb_zImage by Ashley Rose via Flickr (Creative Commons License)


Dear Dr. Pat:

I have been struggling with depression for about the past year and a half. It came on gradually, slowly sapping me of my energy and typical enthusiasm. I can’t concentrate at work; all I want to do is sleep all day, and nothing in life is enjoyable any more. I am 62 and had a similar episode in my 20s. I kept pushing the whole issue aside and trudging through my days, but my husband encouraged me to go see my primary care doctor, who referred me to a psychiatrist, who prescribed an antidepressant. I have been on that for about three months now, but it’s just not making much of a difference. Maybe I’m a little bit better, but I’m just feeling hopeless and just don’t know what to do. I have friends who have been on antidepressants and say it just takes time and I should stick with it, but this really isn’t working for me. What are my options? I’m going to see my psychiatrist later this month, but want to have an idea about what’s out there.



Dr. Riddle Responds:

Dear Sharon:

I am sorry to hear that your depression has only partially improved. Unfortunately, this is not uncommon. Only about one in three people respond fully to the first antidepressant they try. Numerous attempts have been made to predict who will respond to which antidepressants.   Depression is a complex disease that can look different in different individuals, and while there has been some thought that different subtypes of depression may respond better to particular medications, a recent large study found no differences in remission rates with different antidepressants.

Looking at differences on a genetic level is just beginning to bear fruit. For example, we do know that individuals metabolize drugs at different rates due to specific variations in their genes, meaning that giving the same dose to two people can actually result in very different blood levels. Those who are super-fast metabolizers, clearing the drug quickly from their body, will actually require much higher doses of their antidepressant in order to reach therapeutic levels.   While we are slowly integrating this genetic information into our practices, it is still not routine; it may become more so in the future, since insurance companies are beginning to cover the costs of these genetic tests. Let’s hope that someday we will be better able to guide prescribing practices based on an individual’s genetics; at this time, though, we must rely on a collaborative process between physician and patient to explore options and determine the best treatment.

Have you been on the medication long enough? First, let your psychiatrist know that your current antidepressant isn’t working for you. The good news is that there are a number of options for where to go next, and a number of studies have been done to help guide treatment. You and your doctor have already taken the first step, which is to make sure you have been on your first medication for a sufficient time—6 to 12 weeks on a therapeutic dose. This can seem like a long time when you are feeling terrible, but many individuals don’t feel the full effect of the antidepressant until they’ve taken it for at least 6 weeks—and some can continue to improve for months, so it is important to give your first medication a long-enough time to take effect. Your friends are right that it can take time; however, after three months you should explore making a change.

Switching to another medication. One option is to switch to a different type of antidepressant. Antidepressants are categorized by our understanding of their mechanism of action. Probably the most well-known class, and what we often start with, are the selective serotonin reuptake inhibitors (SSRIs). These include many drugs you’ve likely heard of, such as fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa), to name a few. These medications block the clearance of serotonin from the synapse where it is active; this means that you have more serotonin able to interact with your receptors. However, exactly how SSRIs alleviate depression is more complicated than just increasing the level of serotonin at your receptors, because, while the increase in serotonin happens over a very short period of time after starting the medication, the clinical effects—as we’ve discussed—can take weeks. Research suggests that the true effects may be occurring farther downstream of this serotonin increase, possibly by effects on brain plasticity—increasing your brain’s flexibility and helping you to get out of your mental rut.

When an SSRI proves ineffective we often switch to serotonin–norepinephrine reuptake inhibitors (SNRIs), which, as the name implies, affect norepinephrine in addition to serotonin. These medications include venlafaxine (Effexor), desvenlafaxine (Pristiq), and duloxetine (Cymbalta), among others. Other options to switch to include atypical antidepressants, such as bupropion (Wellbutrin), which affects the neurotransmitter dopamine, and mirtazapine (Remeron) which acts on both norepinephrine and serotonin. Sometimes, people opt to try older classes of antidepressants, such as the tricyclics or MAOIs. Each group comes with its own set of side effects, and discussing these with your psychiatrist can help guide the decision process. In a large-scale study, about half of patients achieved remission of their depression by the end of trying two different antidepressant medications.

Next page: Adding a second medication; adding psychotherapy to the mix; behavioral activation; electroconvulsive therapy.

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