The most significant class of antidepressants marketed in recent years is the selective serotonin reuptake inhibitors (SSRIs). The six SSRIs available in the United States are citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). The primary uses for the SSRIs include unipolar and bipolar major depression and all of the anxiety disorders. However, controlled trials also support the use of SSRIs in the treatment of other psychiatric disorders including dysthymia, premenstrual dysphoria, bulimia nervosa, obesity, borderline personality disorder, alcoholism, rheumatic pain, and migraine headache.

Among the SSRIs, there are more similarities than differences. Although all SSRI drugs have the same the mechanism of action, each SSRI has a slightly different pharmacological and pharmacokinetic characteristics. This leads to differences among the SSRIs in their half-lives, clinical activity, side effects, and drug interactions. There are differences between SSRIs that could be clinically significant.

The first drug in the SSRI class was Prozac (Fluoxetine), which hit the United States market in 1987. Prozac was FDA approved on December 29, 1987. It is manufactured by Eli Lilly and Company.

Zoloft (Sertraline hydrochloride) was the second SSRI to come to market in the United States, and it was approved by the FDA on December 30, 1991. Zoloft is manufactured by Pfizer Inc.

Paxil (Paroxetine hydrochloride) was the third SSRI to come to market in the United States and was approved by the FDA on December 29, 1992. Paxil is manufactured by GlaxoSmithKline.

Luvox (Fluvoxamine maleate) was the next SSRI FDA approved on December 05, 1994. However, now its marketing status is "Discontinued".

Celexa (Citalopram hydrobromide) was approved by the FDA on July 17, 1998. Celexa is manufactured by Forest Pharmaceuticals, Inc.

Lexapro (Escitalopram oxalate) is the newest and most selective of the SSRIs approved by the FDA on August 14, 2002. Lexapro is manufactured by Forest Pharmaceuticals, Inc. Lexapro is a cleaner, improved version of Celexa.

Mechanism of action

The brain communicates with itself through the use of special chemicals called neurotransmitters, such as serotonin and norepinephrine. Neurotransmitters carry signals from one nerve cell to another. Low levels of serotonin and norepinephrine have not been proven to cause depression but it widely believed that elevation of these chemicals is associated with improvement in mood in depressed people.

All SSRIs have the same general mechanism of action. SSRIs seem to relieve symptoms of depression by blocking the reabsorption (reuptake) of serotonin by certain nerve cells in the brain. This leaves more serotonin available, which enhances neurotransmission (sending of nerve impulses) and improves mood. In due course, the levels of natural serotonin will rise again, and in some instances the SSRI can be reduced and withdrawn.

Approved indications and uses

SSRIs have been primarily used for the treatment of depression and have been studied for several indications outside of depression.

Celexa (Citalopram) is indicated for the treatment of:

• depression

Lexapro (Escitalopram) is indicated for the treatment of:

• major depressive disorder

• generalized anxiety disorder (GAD)

Paxil (Paroxetine) is indicated for the treatment of:

• major depressive disorder

• obsessive compulsive disorder (OCD)

• panic disorder

• social anxiety disorder

• generalized anxiety disorder

• posttraumatic stress disorder (PTSD)

Prozac (Fluoxetine) is indicated for the treatment of:

• major depressive disorder

• obsessive-compulsive disorder

• moderate to severe bulimia nervosa

• panic disorder

• in January 2003, Prozac was approved by the FDA for the treatment of depression and OCD in children and adolescents who are 7 to 17 years of age.

Zoloft (Sertraline) is indicated for the treatment of:

• major depressive disorder

• obsessive-compulsive disorder

• panic disorder

• posttraumatic stress disorder

• premenstrual dysphoric disorder (PMDD) in adults (newest indication)

• social anxiety disorder

Efficacy

Clinical trials comparing an SSRI with another SSRI indicate that drugs in this class are equally efficacious. Each SSRI produces approximately a 60% overall response rate (ie, at least a 50% reduction in symptoms as a result of treatment).

Adverse reactions & side effects

While SSRIs do not appear to differ in overall tolerability, the reported incidences of specific adverse effects vary. Adverse effects that patients experience are usually mild to moderate and do not require dose reductions or discontinuation. SSRIs possess the following adverse effects:

• Nausea. The most coomon side effect accociated with use of SSRIs is nausea. Paroxetine and sertraline have been associated with slightly more cases of nausea.

• Sexual dysfunction. Depression itself may cause sexual dysfunction and all SSRIs have been associated with sexual dysfunction during therapy in men and women. There may be lesser detrimental effect on sexual function by fluoxetine compared to other agents. Citalopram has been associated with loss of libido. Paroxetine appears to cause the highest rate of sexual dysfunction.

• Anticholinergic effects. Paroxetine causes a higher rate of anticholinergic effects, such as dry mouth, constipation, and cognitive disruption, compared with other SSRIs. These effects may be particularly difficult to tolerate for elderly or concomitantly medically ill patients.

• Weight. The SSRIs vary in their effect on the weight. Sertraline is generally associated with a small degree of weight loss in the acute phase of treatment, whereas paroxetine can cause weight gain after long-term treatment. Fluoxetine has the most potent appetite-suppressing effects in the short term and produces a greater degree of weight loss than paroxetine, sertraline, citalopram, or escitalopram.

• Diarrhea. Sertraline and fluoxetine are more frequently associated with diarrhea, paroxetine has a lower incidence.

• Anxiety, agitation, insomnia. Fluoxetine has been associated with highest rate of anxiety and agitation. Escitalopram and paroxatine are less likely to cause insomnia than fluoxetine and sertraline.

• Dry mouth. Citalopram and paroxetine are more likely to cause dry mouth than escitalopram and fluoxetine.

• Drowsiness, fatigue. Paroxetine has been associated with highest rate of drowsiness, somnolence than other SSRIs.

• Headache. Sertraline and fluoxetine are associated with higher level of headache.

In some cases, antidepressants may be associated with worsening symptoms of depression or suicidal thoughts or behavior, particularly early in treatment or when you change your dosage. Be sure to talk to your doctor about any changes in your symptoms. You may need more careful monitoring at the beginning of treatment or upon a change in treatment, or you may need to stop the medication if your symptoms worsen.

Pharmacokinetics

Some of the key differences among SSRIs are due to differences in their pharmacokinetic properties. The only pharmacokinetic parameters shared by all the SSRIs is that they are relatively slowly, but completely, absorbed from the gut. They differ with regard to their protein binding, metabolism, half-lives, whether they have linear or nonlinear pharmacokinetics, whether they have active metabolites.

Half-life

The half-life of a drug is the time required to achieve steady-state plasma concentrations (i.e., to metabolize half the dose and lower blood concentrations by 50%). Half-life can be used to estimate how long it will take to clear a drug from the body after treatment is discontinued.

Fluoxetine is unique because of its long half-life and the long half-life of its active metabolite norfluoxetine. Fluoxetine has a half-life of 4-6 days and its active metabolite, norfluoxetine, has a half-life of 4-16 days. In comparison, citalopram, escitalopram, paroxetine, and sertraline have shorter half-lives in the range of 20-35 hours, and steady-state concentrations (and therapeutic effect) are reached much more rapidly. The long half-life of fluoxetine may blunt the effects of missed doses or treatment discontinuation and makes it easier to discontinue than any of the other SSRIs. On the other hand, fluoxetine requires a much longer washout period than the other SSRIs (several weeks), particularly when switching to monoamine oxidase inhibitors (MAOIs) or TCA.

Antidepressants with relatively short half-lives are desirable for people with multiple comorbidities and complex, multiple-drug regimens because they allow for once-daily dosing. A short half-life enables physicians to switch more rapidly and safely to an alternative antidepressant if treatment fails or if unfavorable drug reactions occur.

Linear and nonlinear pharmacokinetic.

One of the important differences to note among the SSRIs is whether their pharmacokinetic properties are linear or nonlinear.

Citalopram, escitalopram and sertraline show linear and dose-proportional pharmacokinetics. Plasma concentrations of these drugs are proportional to the daily dose administered and, therefore, predictable. In contrast, fluvoxamine, fluoxetine and paroxetine have nonlinear pharmacokinetics. Higher doses may produce much greater increases in plasma drug concentrations than would otherwise be expected. Thus, increasing the dose of paroxetine or fluoxetine can result in disproportionate and unpredictable increases in plasma levels, half-lives, and adverse effects. Titration of fluoxetine and paroxetine doses may therefore be more difficult than with citalopram, escitalopram and sertraline.

Drug Interactions

The interaction between monoamine oxidase inhibitors (MAOIs) and SSRIs is the most important drug interaction limiting SSRI use. This combination may lead to the development of a hyperserotonergic syndrome consisting of excitement, diaphoresis, rigidity, hyperthermia, tachycardia, hypertension, and possibly death. The severity of this interaction necessitates at least 5 week washout when switching a patient from fluoxetine to an MAOI to allow complete elimination of the fluoxetine. At least 14 days should be allowed after stopping citalopram, escitalopram, paroxetine or sertraline before starting an MAOI. This difference in washout time between fluoxetine and citalopram, escitalopram, paroxetine and sertraline when switching from an SSRI to an MAOI is one of the key differences between SSRIs.

Citalopram, escitalopram and sertraline have the lowest potential for drug interactions among the SSRIs. Citalopram should be avoided in patients likely to take overdoses. Sertraline would be preferable for cardiac patients taking beta blockers or type IC antiarrhythmic agents.

Taking thioridazine with paroxetine or fluoxetine may cause serious heart problems.