Review of Selective Serotonin Reuptake Inhibitors

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.

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 (at least a 50% reduction in symptoms as a result of treatment).

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 side 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.

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.

Taking thioridazine with paroxetine or fluoxetine may cause serious heart problems. Citalopram, escitalopram and sertraline have the lowest potential for drug interactions among the SSRIs.