Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs)

The Full Story

Antidepressants are medications primarily used to treat depression, clinically referred to as "major depressive disorder" or MDD. They are also regularly used to treat many other conditions, such as panic disorder, anxiety, Posttraumatic Stress Disorder (PTSD), Obsessive-Compulsive Disorder (OCD), Premenstrual Dysphoric Disorder (PMDD), social phobia, fibromyalgia, night eating syndrome and menopause.

Most scientists believe that depression is caused by an imbalance of neurotransmitters. Humans are constantly releasing, breaking down, and recycling hormones and neurotransmitters that allow us feel emotion. Antidepressants interact with specific neurotransmitters associated with mood balance: serotonin, dopamine and norepinephrine.

The use of "mood lifters" has been described since antiquity. Flowers and herbs, such as St. John's Wort were noted to calm people after being applied to wounds. They were subsequently made into teas and tinctures for people to drink. Alcohol, amphetamines, cocaine and opioids also have been historically used to treat depression; they are not recommended today for a variety of reasons, including legal issues and ultimate worsening of depression symptoms. 

The first antidepressant drugs were introduced in the 1950s. One was a tricyclic antidepressant (TCA) and the other was a monoamine oxidase inhibitor (MAOI). Their discovery opened the field for exploration of how medications can actually change the behavior of depressed patients, and not just make them feel good momentarily.

Selective serotonin reuptake inhibitors (SSRIs) are typically the first line agent prescribed for depression. In clinical trials, it was shown that SSRIs are just as effective as the TCAs, while having fewer and less severe side effects.

Serotonin is produced in our brains and intestines. It is released into our bodies in response to pleasurable activities, such as being rewarded for work, laughing and eating. Quickly after the serotonin acts on the neuron, and delivers the "feel good" message, it is taken back up into where it was released. Some of the serotonin will be sent right out to work again, some will be broken up into building blocks that will be rebuilt at a later time, and some is discarded. As the name implies, serotonin reuptake inhibitors block the reabsorption of the serotonin so that it remains out in its working form. The theory is that if the serotonin stays out longer, it will make us feel good for longer.

Of course, the system is much more complicated than that. For example, it appears that with an excess of serotonin around, our bodies can become less sensitive to the serotonin signal. Also, serotonin does more than just contribute to how we feel. The serotonin made in the brain only works there, but the serotonin made in the intestines travels around and plays a part in many daily functions of living, from blood clotting to digestion. Sometimes patients who take SSRIs will have unusual effects in other systems because of this, such as easy bruising, sexual dysfunction, or constipation.

Although antidepressants have been in use for several decades now, there are no good predictors for which antidepressant will work best for a person or which side effects they will experience. There is likely an individual chemical and genetic variance that contributes to who does better on which drug. Often, a physician will start by prescribing one SSRI, then try another if needed.

Overall, the SSRIs are quite safe compared to other drugs used for depression in the past. The TCAs can cause serious cardiac rhythm and conduction issues, liver damage and seizures. Before SSRIs were introduced, the TCAs were a leading cause of death by drug overdose.

The most common side effects of SSRIs are nausea, vomiting, diarrhea, dry mouth, jitteriness, drowsiness, weight gain, weight loss, decreased sexual desire, and sexual dysfunction.

One of the potential side effects of SSRIs is Serotonin Syndrome (SS). This potentially life-threatening condition is caused by too much serotonin in the body. The symptoms of SS overlap with some of the common side effects of SSRIs and also symptoms of anxiety.

SS most often occurs when there is more than one drug being used that affects the release or uptake of serotonin in the body. Often a patient presenting with SS will have recently added another antidepressant to their regimen, and that precipitates SS. However, other common contributors to SS are illicit drugs, such as cocaine and ecstasy, which have serotonin reuptake inhibition properties. Even dextromethorphan, the active ingredient in many over the counter cough syrups, and tramadol, used for pain, have serotonin reuptake inhibitor activity and can contribute to serotonin toxicity.

SS will typically occur within several hours of starting the new medication. Most often, the medication suspected to be causing the problem will be stopped, reduced or changed.

The early symptoms of SS are nausea, vomiting, diarrhea, sweating, agitation, confusion, muscle rigidity, dilated pupils, shivers, and goose bumps. In serious cases, the symptoms will progress to very high temperature, seizures, irregular heartbeat, and coma.

Although SS is potentially life-threatening, it can be treated in a hospital. Someone who may be experiencing SS should not take any more medicine. He or she should call the doctor or go to the emergency room right away. 

The treatment for SS is mostly supportive care. For example, if the patient develops high temperatures, cooling will be attempted in the ER. IV fluids are typically administered, and a class of medications, called benzodiazepines, will be used to calm brain and muscle activity as needed. An antihistamine called cyproheptadine can attach to serotonin receptors and block them from being activated by the serotonin.

Even though SSRIs are generally well tolerated with regular use and even in overdose, two SSRIs, citalopram and escitalopram, have some unique and dangerous side effects and issues in overdose. These drugs are known to cause seizures and a potentially serious heart conduction issue, referred to as QT prolongation. These medications should not be used in people with a history of seizures or QT prolongation. 

Some people will only need to be on antidepressants for a short period of time, to address a situational depression. Others may need antidepressants for years. It is very important to take them as they are prescribed. SSRIs typically take about 2 weeks before the positive effects start to be felt. For example, with sertraline (Zoloft^®), some results should be felt within about 2 weeks of starting the medication, but the peak response does not occur until approximately 6 weeks.

Just as the SSRIs take time to start, time should also be given to stop them. Suddenly stopping the drugs can cause withdrawal symptoms. A healthcare provider can develop a schedule to discontinue the medication and taper down. Each medication has its own unique chemical profile and a specific plan should be made accordingly. 

In 2013, the CDC released "Health, United States, 2013, with Special Feature on Prescription Drugs".  This report looked at prescription use by medication class and age group. For ages 18-64, the use of antidepressants increased from 2.2% of people in 1988-1994, to 10.6% of people in 2007-2010. For age 65 and over the use for the same time period increased from 3.0% to 13.7%. To put that into perspective, it is estimated that approximately 1 in 10 Americans takes an antidepressant. 

There has been some controversy on antidepressant use and potential overuse. In January of 2010, The Journal of the American Medical Association released a large review of almost 30 years of medical literature examining the effectiveness of antidepressants in treating depression. They found that people with mild or moderate symptoms of depression have a response equal to that of a placebo, meaning they were no better off taking an antidepressant versus nothing at all. However, people with severe symptoms of depression seemed to have been helped by the drugs.

Overall, SSRIs may help many people with a variety of issues. The SSRIs do have side effects, but they are generally well tolerated in comparison to antidepressants used in the past.

If you think someone may have taken an overdose of SSRIs (or any drug), call Poison Control at 1-800-222-1222 right away or log onto webPOISONCONTROL^®. Whether you call or log on, expert assistance is available 24 hours a day.     

Pela Soto, PharmD, BSHS, BS
Certified Specialist in Poison Information