As the National Alliance for Research on Schizophrenia & Depression in Great Neck, N.Y., pointed out, mood disorders are caused by a flaw in chemistry, not character. That’s why medications that alter brain chemistry play a large role in psychiatric treatment.

There are now five prescription drugs in the class known as selective serotonin reuptake inhibitors (SSRIs) approved in the United States for the treatment of depression, obsessive-compulsive disorders, bulimia nervosa, anxiety, panic disorder and other medical conditions such as PMS.

This raises the question: Does any member of the class provide better symptom relief or reduce serious or long-lasting side effects in treating these conditions?

James’ ExperienceJames L. Smith, a 40-year-old high school teacher in Pontiac, Mich., has experienced bouts of depression since he completed college in the mid-1980s. His family doctor initially prescribed a tricyclic antidepressant for him, but he found its side effects troublesome. “The medication made me tired and I had a difficult time sleeping,” he said. “Basically, I just stopped taking it after about three months. I decided I’d rather live with the depression.”

By the time James sought help a second time, SSRIs had become available. “The psychiatrist I saw explained there was a whole new group of medications that were very good,” Smith said. “If one didn’t help after several months, he would prescribe another one. I assumed that meant they weren’t identical; that one might work better than another for me. But that wasn’t necessary. The first SSRI prescribed has worked well for more than five years.”

How Do Antidepressants Work?

According to the Encyclopedia Britannica, serotonin — also known as 5-Hydroxytryptamine or 5-HT — is a chemical that naturally occurs in the human brain, intestines, blood platelets and mast cells. Interestingly, it is also a component of many toxic venoms, including those of the wasp and some poisonous toads.

The chemical is derived from tryptophan, a natural amino acid. As a neurotransmitter, one of serotonin’s most important functions is the transmission of impulses across synapses, the space between neurons or nerve cells.

Typically serotonin is concentrated in two specific areas of the brain: the midbrain and the hypothalamus. These areas are responsible for regulating mood, hunger, sleep and aggression. Changes in the concentration of serotonin in these areas are linked to a variety of mood disorders, particularly depression.

Serotonin levels are thought to be reduced to below optimal levels when it is returned (or taken up) too quickly or in too great a quantity by neurons after the chemical has transmitted an impulse across a synapse.

All SSRI medications function by prolonging (or inhibiting) the process by which serotonin is taken up by neurons (the process referred to as “reuptake”). All SSRIs are designed to prolong the reuptake process only for serotonin. To differentiate between serotonin and a host of other chemicals in the brain, they must be highly selective.

That’s how the class came to be known as “selective serotonin reuptake inhibitors” — they prevent (inhibit) serotonin (and only serotonin) from experiencing too much or too long of a reuptake process. This makes more serotonin available in the brain. According to Sheldon H. Preskorn, M.D., professor and chair of the department of medicine and behavioral sciences at University of Kansas School of Medicine, Wichita, and author of Applied Clinical Psychopharmacology, SSRIs are effective for a significant number of individuals who use them as directed for this purpose.

The SSRIs’ Pedigree

SSRIs weren’t the first prescription antidepressants. That distinction goes to iproniazid, a member of the antidepressant class known as monoamine oxidase inhibitors (MAOIs).

Iproniazid was discovered accidentally in the early 1950s when the tuberculosis patients for whom it was prescribed experienced not only improvements in their tuberculosis, but also in their mood and activity levels. Later in the decade, the first antidepressant in the tricyclic class, Imipramine (Tofranil), was found to have good results for depression, although it had been originally developed as a treatment for schizophrenia.

It took almost 30 years for researchers to unravel enough of the brain’s functioning to understand that MAOIs and tricyclics probably work by promoting increases in the levels of certain brain chemicals, such as serotonin and norepinephrine. Then the search was on for medications that could do this selectively, that is, increase one of the chemicals responsible for improved mood, but not all of them at the same time.

The first SSRI to be approved by the U.S. Food and Drug Administration was Prozac in 1987; the most recent was Celexa in 1998. The five SSRIs presently approved for use in the United States are:

  • fluvoxamine maleate (Luvox) manufactured by Solvay
  • paroxetine (Paxil) manufactured by Smith Kline Beecham
  • sertraline (Zoloft) manufactured by Pfizer
  • citalopram (Celexa) manufactured by Forest Laboratories
  • fluoxetine (Prozac) manufactured by Eli Lilly

Comparison of SSRIs’ Use, Efficacy and Side Effects

The condition or conditions for which a medication is prescribed is termed its indications or use. How well it does what it is supposed to do is termed efficacy; and how well it avoids causing other symptoms is determined by the number and severity of its side effects. Because each of the SSRIs has a unique molecular structure, it is possible to compare them with one another for these characteristics.

In terms of use, all SSRIs except Luvox (fluvoxamine) are FDA-approved for treatment of depression. Luvox is approved in the U.S. only for treating obsessive-compulsive disorders, although it is used internationally for depression, too.

As Preskorn pointed out, rigorous studies of the SSRIs to one another would be ideal and useful in comparing efficacy and side effects, but no such study exists or is likely to be undertaken. However, that doesn’t mean these drugs’ outcomes can’t be compared.

In his opinion, there’s a lot that can be determined based on the large number of SSRI studies that have been done. For example, he noted, the following features have generally been reported as similar across the class:

  • Flat-dose antidepressant-response curves — or the ability to produce the same average response rate at each dose above the effective, minimum dose over the dosing range;
  • Equivalent antidepressant action at their usually effective therapeutic dose (however, data for fluvoxamine was not available for comparison);
  • Similar efficacy when used on a maintenance basis to prevent relapse;
  • The usually effective minimum dose of each produces 60 percent to 80 percent inhibition of serotonin uptake;
  • All have benign adverse side effects when compared to drugs in the tricyclic class.

All Work Equally Well for ManyMichael Messer, medical director of ThedaCare Behavioral Health in Appleton, Wis., said that the marked similarity of the five SSRIs means that all are generally appropriate for a wide range of individuals. “For a physically healthy person between 20 to 50 years of age not taking any other medications, any of the SSRIs will probably work equally well, with a comparable number and type of side effects, generally dependent on the dose,” he explained.

Messer noted side effects, when they do occur, are also similar and range in severity from mild to severe. They include interruptions in sexual performance, headaches, anorexia, diarrhea, nervousness, tremors and insomnia. According to Messer, the SSRIs’ effect on sexual performance is often the most pronounced undesirable outcome. “In patients who experience this side effect, interest in sex, as well as orgasmic response can be affected,” he said. “However, since recovery of sexual performance occurs after SSRIs are discontinued, many patients will tolerate these effects to gain the medications’ overall beneficial impact.”

Differences in Efficacy, Side Effects Do ExistBoth Messer and Preskorn pointed out that for older individuals, patients with medical conditions in addition to the one for which the SSRI is prescribed, or those taking other medications at the same time, some SSRIs may be less appropriate than others. This has to do with their pharmacokinetic characteristics, which Preskorn describes as “clinically different” from one another.

These differences include how each of them bind proteins; which of several specific enzymes in the body each one depends upon for chemical transformation; how long each persists in the body; and which metabolites or chemical byproducts each one produces.

Physician-Patient Collaboration KeyThe experts agreed there’s no single SSRI that’s universally best for all patients. The choice of the best SSRI for individuals older than 50, or those who have other medical conditions or medication needs is one that requires careful consideration of both the characteristics of the patient as well as the distinct chemical features of each specific drug.