Selective Serotonin Reuptake Inhibitors

Abstract

The selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) are the most widely prescribed class of antidepressants in the United States and a number of other countries. All the SSRIs except fluvoxamine have an indication for major depressive disorder (MDD) in the United States. The SSRIs were the first rationally developed class of psychiatric medications and thus share many similarities: equivalent acute and maintenance antidepressant efficacy, flat dose-response curve for antidepressant efficacy, ascending dose-response curve for adverse effects, adverse effect profile consistent with excessive serotonin agonism, 60%–80% inhibition of serotonin uptake at their lowest, usually effective antidepressant dose, and efficacy for both depressive and anxiety disorders. The SSRIs have good tolerability and do not cause severe side effects seen with certain other antidepressants (e.g., intracardiac conduction delays, seizures, postural hypotension). Because of their wide therapeutic index, the SSRIs have demonstrated good safety in overdose and there is no evidence of long-term safety problems. However, the different SSRIs do differ considerably in pharmacokinetics and effects on cytochrome P450 enzymes. Three of the SSRIs—fluoxetine, fluvoxamine, and paroxetine—inhibit one or more CYP enzymes to a substantial degree and have the potential to cause clinically meaningful drug-drug interactions. There is some debate about the efficacy of SSRIs in patients with more severe depression. If a patient has not been able to tolerate one SSRI, many clinicians will try a second SSRI; however, most psychiatrists prefer to switch to a drug with a different mechanism of action if a patient has had an inadequate response to an adequate trial of one SSRI, since there is no compelling evidence showing that nonresponders to one SSRI will respond to a trial of a different SSRI. All the SSRIs have a flat dose-response curve, so that there is usually no advantage in using doses above the usually effective minimum dose.