Is stopping a cold SSRI turkey dangerous?

A better understanding of SSRI antidepressants

Source: Lisa Cottone / Quixotic Publishing; used with permission

Selective Serotonin Reuptake Inhibitors (SSRIs) were introduced in 1987 with the release of Prozac and have since become the most common type of antidepressant used by Americans. According to Olfson and Marcus (2009), nearly 67 percent of respondents take antidepressants in the United States are treated with SSRIs. Over the past three decades, SSRIs have emerged as the primary treatment for depression, preferred over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) because they tend to have fewer side effects and are less dangerous if accidentally overdosed (Santarsieri & Schwartz, 2017). Still, many of the patients I work with and would refer to as such biological depressionare resistant to SSRIs because they don't understand why it can take up to a month to start working and why they may feel worse before they feel better.

To help those considering SSRIs better understand how these drugs work, I asked a clinical pharmacist, Dr. Margaret Tsopanarias, asked to explain the pharmacological and neurophysiological mechanisms of SSRIs. Dr. Tsopanarias has over 15 years of pharmacy experience including clinical, research and retail stores. He currently works at Paramount Specialty Pharmacy in New York.

John G. Cottone and Margaret Tsopanarias
Source: Lisa Cottone / Quixotic Publishing


JGC: John G. Cottone, Ph.D.

MT: Margaret Tsopanarias, PharmD, AAHIVP


JGC:Margaret, thank you very much for your time. I think your expertise can help educate psychologists like me and the patients we treat about how SSRIs actually work. why they usually take so long to work; and why people sometimes feel worse before they start to feel better when they start ingesting it.

MT:I am happy to answer your questions about SSRIs. Before I get into the basics, I wanted to mention something that I think is important. When I counsel patients about their antidepressant drug I routinely ask, "Will this work for you?" and in response I often hear: "I think it is, but then again, I don't really feel any different."

All in all, that's not a bad answer for me as some people expect these drugs to produce an overly euphoric response, but it just isn't. We need to train ourselves to understand that these drugs make people feel good at best, so that they can begin making the structural life changes recommended by their therapists. Therefore, if you and you are not taking any of these drugs sing in the rain or Slide down the rainbowdoes not mean the drug is not working. We have to keep our expectations realistic.

JGC: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 (SSRIs) are drugs that increase the neurotransmitter serotonin (5-HT) in the brain in hopes of relieving symptoms of depression and anxiety. They have traditionally been a first choice for doctors to prescribe these symptoms because of their safety and efficacy profile. Serotonin is said to be responsible for well-being and mood, among other things.

In our brain there are sending and receiving cells, and the space between them is called the synapse. In depression, there is a lack of serotonin, which is sent to the receiving cell. Sometimes the sending cell reabsorbs the serotonin before it even reaches the receiving cell: it is as if the sending cell has a change of heart.

SSRI resume blocking
Source: Lisa A. Cottone / Quixotic Publishing

SSRIs block the areas where serotonin can be reabsorbed in the sending cell, thus increasing the amount of serotonin in the gap (synapse) that can move on to the receptor of the receiving cell. The exact mechanism is not fully understood, but it is believed that SSRIs bind to serotonin transporters (also known as SERTs), and this action blocks the reuptake of serotonin back into the "sending" cell it came from (Lutz, 2013) .

JGC:When patients I see with major depression or anxiety finally decide to try medication and are prescribed an SSRI like Lexapro or Zoloft, they often get discouraged when their psychiatrist tells them it's more than a month will take time to start working. Can you explain why this is and why some patients actually feel worse - more depressed or more anxious - before they feel better?

Source: Lisa Cottone / Quixotic Publishing

MT: What we often see in depression is that the receiving cell is so hungry for serotonin that it increases the number of receptors that reach for it. This is known as upregulation. When this happens, it doesn't just increase the overall value number of serotonin receptors, but also an increase in diversity of existing serotonin receptors. Although some of the types of receptors added are mood related, others are sleep related. Appetite and sexual function among others. Because of this, we don't want to start too quickly with a high dose of SSRIs: giving too high a dose too quickly will flood all types of receptors with serotonin, including those involved in functions unrelated to it have mood, and this can lead to a dramatic increase in side effects.

When patients with depression are started on SSRIs, psychiatrists leave low and slow however, to avoid side effects as much as possible, they do occur to a certain extent. This is because there is still an increase in serotonin, which is due to the overabundance of serotonin receptors from the upregulation phase caused by depression. Then, over the course of a few weeks, we notice a decrease in serotonin receptors (of all kinds) in response to the frequency of serotonin in the synapse: this is called Down regulation. At this point, both of the positive effects are and The side effects of the drug begin to decrease.

Down-regulation occurs in the first two to four weeks after starting an SSRI, which is why the effectiveness of SSRIs is often delayed by two to four weeks. After the downregulation process has stabilized, psychiatrists usually slowly increase the dose of the SSRI, and then we see a more consistent, positive effect of the drug on mood and limited side effects, if any.

JGC:How do you know, like others, do individuals develop a tolerance to SSRIs from psychiatric drugs?

MT:My experience with drug therapy management and my communication with hundreds of patients over the years leads me to believe that tolerance to SSRIs can occur, but not to the same extent as with other drugs or on the same schedule. In this case, psychiatrists begin combination therapy, using combinations of drugs in different classes.

JGC:I've also heard some patients talk about something called "SSRI poop-out" where their drugs just stop working. As far as you know, is this a real phenomenon, or is it more likely that these people had other physiological or psychological changes that made their symptoms worse?

MT:I've come across "SSRI Poop-Out", but not often. There are many trials and errors going into the pharmacological treatment of depression. Fortunately, if one fails, we have options for alternatives and add-ons.

JGC:After all, the ultimate goal for most of my patients who take SSRIs is that they eventually break away from them. However, I know that it can be dangerous for people taking SSRIs to stop taking cold turkey without rejuvenating. Can you explain why that is?

MT:Neurons get used to a certain level of serotonin. If people who take SSRIs stop taking SSRIs too quickly, it can lead to negative side effects like depression, anxiety, and flu-like symptoms.

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

Source: Freepik (used with permission)

MT:It is very important that you adhere to your medication for positive results. If you forget a dose of your medication, take it as soon as you remember. If it is close to the next dose, skip the missed dose and continue as normal.

Don't duplicate your medication. Keep all doctors informed of all medications you are taking. It's important to make sure you're not taking other medications that may increase serotonin levels without your psychiatrist noticing.

Sometimes drugs that are not prescribed by psychiatrists (such as tramadol, which is used for pain and certain drugs used to treat migraines) can cause this Serotonin Syndrome in combination with an antidepressant. Serotonin syndrome, which is a group of symptoms that sometimes appear after starting an SSRI, is not common. However, if symptoms such as agitation, dilated pupils, muscle weakness or stiffness, loss of coordination, or rapid heart rate occur, seek medical attention.


Olfson M, Marcus SC. National Patterns in the Treatment of Antidepressants. Arch Gen Psychiatry. 2009; 66 (8): 848- 856.

Santarsieri D & Schwartz T. (2015). Antidepressant Effectiveness and Exposure to Side Effects: A Quick Guide for Physicians. Drug context. 2015; 4: 212290

Lutz, P. (2013). Multiple Serotonergic Pathways to Antidepressant Efficacy. Journal of Neurophysiology, 109 (9): 2245--22; 2249