UNDERSTANDING HOW SSRIs WORK: An Interview with Pharmacist, Dr. Margaret Tsopanarias

Dr. Margaret Tsopanarias is a clinical pharmacist with over a decade of experience in myriad pharmaceutical environments, including clinical, research and retail venues. She kindly agreed to be interviewed about the pharmacological and neurophysiological mechanisms of SSRIs (Selective Serotonin Reuptake Inhibitors) such as Prozac, Zoloft and Lexapro, for treatment of depression and anxiety.

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JGC: - John G. Cottone, PhD

MT: - Margaret Tsopanarias, PharmD

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JGC: Margaret, thank you so much for your time. I think your knowledge and expertise in pharmacology and neurophysiology can help inform psychologists, like myself, as well as the patients that we treat, about how SSRIs actually work; why they usually take so long to start working; and why they sometimes lead to patients feeling worse before they feel better.

MT: It is my pleasure to answer any questions you have regarding SSRIs. Before I get into the nitty gritty, I wanted to mention something that I feel is important. When I counsel patients on their medications (for all different disease states), once I zero-in on their antidepressant treatment, I routinely ask "Is this working for you?" I often hear "I guess it does but then again, I don't really feel any different." That is the answer I usually get from people that have been on their antidepressant medication for a year or more.

In some regard, I think that is a good answer to hear, instead of hearing "sad," "depressed," "unmotivated" or "tired," because some of us expect these medications cause an exaggerated euphoric effect when this is simply not the case. We need to train ourselves to understand that these medications are, at best, going to make people feel well enough to begin implementing the structural life changes recommended by their therapists. Therefore if you are not singing in the rain or sliding down rainbows, it doesn't mean that the medication is not working. We have to keep our expectations realistic.

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JGC: So let's start with some basics: What are SSRIs, and how do they work to increase serotonin in the brain?

MT: Selective Serotonin Reuptake Inhibitors, or SSRIs, are medications that amplify the neurotransmitter serotonin in the brain with the hope of alleviating symptoms of depression and anxiety. They are traditionally a first-line choice for doctors to prescribe for these symptoms, based on their safety and efficacy profile. Serotonin is believed to be responsible for well-being and mood, among other things.

In our brain, there are sending cells and receiving cells. The space in between is called a synapse. In depression, there is a deficiency in serotonin being sent to the receiving cell. Sometimes, the sending cell reabsorbs the serotonin before it even makes it to the receiving cell. It's as if the sending cell had a change of heart. SSRIs work by blocking those areas where serotonin can be reabsorbed in the sending cell, therefore increasing the amount of serotonin in the gap (synapse), which can keep moving along to the receptor of the receiving cell.

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JGC: When patients that I see with severe depression or anxiety finally decide to try medication and are prescribed an SSRI, like Lexapro or Zoloft, they are often discouraged upon learning from their psychiatrist that it will take upwards of a month to start working. Can you explain why that is and why some patients actually feel worse - more depressed or more anxious - before they start to feel better?

MT: In depression, the receiving cell is so hungry for serotonin we see an increase in receptors reaching out for serotonin. This is called upregulation. When this happens, not only do we see an increase in the overall number of serotonin receptors but we also see an increase in the variety of serotonin receptors present. Though some of the receptor types that are added are related to mood, others are related to sleep, appetite and sexual function, among other things. This is why we don't want to start with a high dosage of SSRIs too quickly. If we give too much too fast, we will see a flooding of serotonin to all receptors types, including those involved in functions unrelated to mood, which can lead to a dramatic increase in side effects.

When we start patients with depression on SSRIs, we go low and slow to avoid side effects as much as possible, but they still occur to some extent. That's because there still is an increase of serotonin that meets the overabundance of serotonin receptors present from upregulation. Then, over the course of a few weeks, we start to see downregulation, a reduction of these serotonin receptors (of all types). At this point we start to see both the positive effects as well as the side effects diminishing. Downregulation occurs over the course of the first two to four weeks after starting an SSRI, which is why there is often a delay in efficacy of SSRIs for two to four weeks. After the downregulation process evens out, we usually see a more consistent positive effect of SSRIs on mood and more limited side effects, if any.

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JGC: As far as you know, do individuals develop tolerance to SSRIs as with some other psychiatric medications?

MT: My experience with medication therapy management, and my communication with hundreds of patients through the years, leads me to believe that tolerance of SSRIs can occur but not to the same degree as other medications or at the same schedule. When this happens, psychiatrists will start to use combination therapy, whereby combinations of medications in different classes are used.

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JGC: I have also heard some patients talking about something called "SSRI poop-out" whereby their medication just stops working. Is that a real phenomenon, as far as you know, or is it more likely that these individuals had other physiological or psychological changes that intensified their symptoms?

MT: I have come across that but not often. There is a lot of trial and error that goes into the pharmacological treatment of depression. When one fails, fortunately we have options for alternatives and add-ons.

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JGC: Finally, the ultimate goal for most of my patients taking SSRIs is to eventually come off of them. However, I know it can be dangerous for individuals taking SSRIs to just stop taking them cold turkey, without tapering off. Can you explain why this is?

MT: Neurons get used to a certain level of serotonin. When individuals taking SSRIs discontinue too quickly, this can lead to negative side effects, such as depression, anxiety, and flu-like symptoms.

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JGC: Are there any other recommendations in this area that you think could be helpful, either to psychiatrists, psychologists, or the patients that we treat?

MT: It's very important to stay adherent to your medications to see positive results. If you miss a dose of your medication, take it as soon as you remember. If it's close to the next dose, skip the missed dose and resume as normal. Do not double up on your medication. Keep all doctors informed of all the medications you are taking. It's important to make sure you are not taking other medications that may increase serotonin without your psychiatrist's awareness.

Sometimes medications that are not prescribed by psychiatrists (like Tramadol, which is used for pain, as well as certain medications used to treat migraines), can cause serotonin syndrome if taken in combination with an antidepressant. Serotonin syndrome, which is a cluster of symptoms that sometimes occurs after starting an SSRI, is not common but if you experience symptoms such as agitation, dilated pupils, muscle weakness or rigidity, loss of coordination or rapid heart rate, seek medical attention.

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John G. Cottone, PhD, is a licensed psychologist in private practice and the author of "Who Are You? Essential Questions for Hitchhikers on the Road of Truth."