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Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressant medication prescribed for treatment of a range of psychiatric disorders. They are most often used for depression but are also widely prescribed to help manage symptoms of anxiety and anxiety-related disorders, including generalized anxiety, social anxiety, obsessive-compulsive disorder and post-traumatic stress disorder (PTSD). The prototype drug in this group is fluoxetine, best known by its trade name, Prozac.

What Are SSRIs?

SSRI is short for selective serotonin reuptake inhibitor. The SSRIs are a group of related chemical compounds that increase the amount of the neurotransmitter serotonin in the brain. Neurotransmitters ferry signals from one nerve cell to the next across a juncture known as the synapse. After relaying a message across the synapse, a neurotransmitter generally gets reabsorbed by the nerve cells, a process known as “reuptake.” SSRIs inhibit the absorption process, resulting in higher serotonin levels. The increased availability of serotonin at synapses facilitates the transmission of nerve signals involved in regulating mood, appetite, biorhythms, and overall well-being.

The first major SSRI to be introduced to the general public was fluoxetine, widely known by its trade name, Prozac, in 1987. More than three decades later, Prozac remains one of the most popular SSRIs and is the 19th most prescribed drug in America. Other SSRIs include sertraline (Zoloft), citalopram (Celexa), paroxetine (Paxil, Brisdelle, Pexeva), escitalopram (Lexapro), fluvoxamine (Luvox), and vilazodone (Viibryd). They differ from Prozac slightly in chemical structure and therefore in the specific symptoms they target and their possible side effects; for example, the SSRI bupropion (Wellbutrin) is sometimes used to help people stop smoking.

Drugs like penicillin changed the course of human history, providing a cure for infections that ravaged populations around the globe, but Prozac may be the first drug to ever become a cultural celebrity. In 1993, psychiatrist Peter Kramer wrote Listening to Prozac, claiming that the drug didn’t just cure depression but changed personality. The book became a blockbuster bestseller and inspired many other books about the drug and its uses, but its most enduring contribution may have been to widen the public discussion of mental health conditions and reduce the stigma attached to them.

What conditions do SSRIs treat?

Although SSRIs are primarily used to treat depression, they are commonly prescribed for the treatment of  anxiety and related conditions. They have also been used to treat impulse-related disorders like trichotillomania (hair-pulling disorder), although evidence of their efficacy for such conditions is mixed, and they are generally not a first-line treatment. They are also used to treat eating disorders, including anorexia.

What are common SSRIs and their uses?

Popular SSRI antidepressants include sertraline (Zoloft), fluoxetine (Prozac, Sarafem), citalopram (Celexa), paroxetine (Paxil, Brisdelle, Pexeva), escitalopram (Lexapro), fluvoxamine (Luvox), and vilazodone (Viibryd). In addition to depression, the SSRIs are frequently prescribed to treat panic attacks, PTSD, OCD, and social anxiety.

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How Do SSRIs Work?

Exactly how the SSRIs counter depression has never been clear. Despite all the books and attention that SSRIs get, the drugs fully relieve depression in only a third of patients. SSRIs do not work at all in a full third of patients and provide only partial relief of symptoms in another third of patients.

Does depression result from a chemical imbalance of the brain?

The belief that depression is a chemical imbalance caused by low serotonin levels has become widely accepted, despite there being no evidence for it. The increase in neurotransmitter levels attributed to SSRIs may contribute to depression relief, but it is not considered the main source of improvement. One reason is that the neurotransmitter changes happen immediately, but the drugs can take six weeks or more to provide relief of symptoms. Researchers believe that the time lag is due to the development of new nerve cell connections—neuroplasticity—which pave the way for mental and behavioral flexibility.

What is the rationale for using drugs that affect serotonin?

The monoamine theory of depression has long been influential. It holds that depression results from a deficit of one or more neurotransmitters in the brain. It links the neurotransmitters to specific groups of symptoms. For example, serotonin-dependent signals affect sleep, digestion, mood, and behavior regulation; norepinephrine drives the fight-flight-freeze response; and dopamine has been linked to motivation, movement, and the capacity for pleasure. However, the notion that a chemical imbalance in the brain generates depression has given way to newer ideas that reflect a greater understanding of how the brain works.

How Effective Are SSRIs?

Depression is an extraordinarily complex condition involving multiple brain and body functions and basic appetite for life itself. Due to changes in the activity level of various emotional signaling centers, the brain becomes extremely biased toward negative thoughts and feelings and easily overwhelmed by them. The ability to enjoy life vanishes. Motivation flees with it. Physical movement becomes difficult. Sleep is disturbed. It is a notoriously difficult illness to treat. Talk therapy not only provides symptomatic relief but improves brain function as well. Yet it is not always enough—or fast enough.

From the beginning, there have been questions about the effectiveness of SSRIs. A large meta-analysis recently published in The Lancet found that, overall, all SSRIs and SNRIs were more effective than placebo in treating adults with major depression. However, many well-known SSRIs are ineffective for as many as 30 percent of people who try them.

The successful treatment of depression is important. The longer that depression episodes last and the more episodes that occur, the more that depression changes the brain and becomes a chronic condition and a source of psychic pain. Patients who are prescribed an SSRI that doesn’t manage their symptoms well often feel discouraged or unwilling to try another option, further complicating their treatment prospects.

What is the clinical efficacy of SSRIs?

According to a six-year meta-analysis, SSRIs were more efficacious than placebos in adults with depression when judged by two criteria: efficacy (response rate) and acceptability (measured by whether treatment was discontinued for any reason). The efficacy of a given SSRI across thousands of studies varies significantly, ranging anywhere from about one-third as effective to twice as effective as a placebo, but the effect sizes were generally modest. Studies consistently show that antidepressants work best in conjunction with therapies like cognitive-behavioral therapy (CBT).   

How long does it take to start feeling better?

Approximately four to six weeks after treatment begins, patients who are responding to SSRIs notice that they have more energy, are less anxious, and feel less hopeless about the future. If a patient has not shown such improvement after six weeks, it’s likely that their doctor will recommend trying another antidepressant.

Risks and Side Effects
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Although the class of drugs was developed in the hopes of eliminating some of the unpleasant (and dangerous) side effects of earlier types of antidepressants, side effects nevertheless accompany SSRI usage. Some, like an increased risk of suicidal ideation in children and adolescents or cardiac arrest in adults, are very serious, while others, like dry mouth or sexual dysfunction, can be troublesome but not life-threatening. Because of their side effects, however—as well as their inconsistent results in treating depression—they continue to generate controversy. Like most antidepressants, SSRIs appear to be most effective when used in combination with cognitive-behavioral therapy or other forms of therapy.

Can SSRIs cause personality changes?

When used correctly, SSRIs can help relieve depression and anxiety, but don’t cause massive personality shifts. If someone feels emotionally flat or not like themselves on an antidepressant, this is considered an adverse side effect, and they may want to consult their physician about switching medications. When SSRIs work properly, patients report a decrease in negative rumination and better overall functioning. Patients might experience temporary withdrawal symptoms, such as increased depression, anxiety, and anger, when stopping an SSRI that should be discussed with their overseeing physician.

Do SSRIs cause sexual dysfunction?

Approximately 70 percent of people taking SSRIs experience some form of sexual dysfunction, including the loss of orgasm. Even as SSRIs increase serotonin levels, they have a dampening effect on the neurotransmitter dopamine, which is associated with the elation of falling in love. Patients should be aware of the potential for some SSRIs to cause problems with sexual desire and performance. In some cases, these issues can be addressed by changing antidepressants, lowering the dosage, or taking a brief, physician-directed medication hiatus

Controversies About SSRIs

Despite their popularity, SSRIs have been the subject of controversy from the beginning. Many people are skeptical about how effective they truly are and how much they cost. Concerns have arisen about serious side effects, like an increase in suicidal thoughts or the potential for causing harm to the fetus during pregnancy.

Are SSRIs really any more effective than a placebo?

When all the results of drug trials are examined in aggregate, SSRIs prove to be modestly more effective than a placebo for approximately one-third of the individuals who try them. Plus, it often takes experimenting with a few different types of SSRIs before finding the one that alleviates symptoms.

Are they safe for children?

Despite the rapid rise in use of SSRIs, their use in young people has raised many questions. After examining the results of a 2004 study, the FDA mandated that drug manufacturers include a black box warning that the antidepressants can increase suicidal thoughts and behavior in children and teens. Critics of the black box warning argue that it scares parents and youths away from potentially helpful treatments. In fact, not enough is known about the way the drugs affect children’s bodies versus adults’ to make them a first-choice treatment. Some experts also worry about the overprescribing of SSRIs when normal sadness gets mistaken for depression.

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