A significant difference among the SSRIs is their broad range of serum half-lives. Fluoxetine has the longest half-life: 4 to 6 days; its active metabolite has a half-life of 7 to 9 days. The half-life of sertraline is 26 hours, and its less active metabolite has a half-life of 3 to 5 days. The half-lives of the other three, which do not have metabolites with significant pharmacologic activity, are 35 hours for citalopram, 27 to 32 hours for escitalopram, 21 hours for paroxetine, and 15 hours for fluvoxamine. As a rule, the SSRIs are well absorbed after oral administration and have their peak effects in the range of 3 to 8 hours. Absorption of sertraline may be slightly enhanced by food.

There are also differences in plasma protein binding percentages among the SSRIs, with sertraline, fluoxetine, and paroxetine being the most highly bound and escitalopram being the least bound.

All SSRIs are metabolized in the liver by the cytochrome P450 (CYP) enzymes. Because the SSRIs have such a wide therapeutic index, it is rare that other drugs produce problematic increases in SSRI concentrations. The most important drug–drug interactions involving the SSRIs occur as a result of the SSRIs inhibiting the metabolism of the coadministered medication. Each of the SSRIs possesses a potential for slowing or blocking the metabolism of many drugs (Table 27-2). Fluvoxamine is the most problematic of the drugs in this respect. It has a marked effect on several of the CYP enzymes. Examples of clinically significant interactions include fluvoxamine and theophylline (Theo-Dur) through CYP 1A2 interaction; fluvoxamine and clozapine (Clozaril) through CYP 1A2 inhibition; and fluvoxamine with alprazolam (Xanax) or clonazepam (Klonopin) through CYP 3A4 inhibition. Fluoxetine and paroxetine also possess significant effects on the CYP 2D6 isozyme, which may interfere with the efficacy of opiate analogs, such as codeine and hydrocodone, by blocking the conversion of these agents to their active form. Thus, coadministration of fluoxetine and paroxetine with an opiate interferes with its analgesic effects. Sertraline, citalopram, and escitalopram are least likely to complicate treatment because of interactions.

The SSRIs are believed to exert their therapeutic effects through serotonin reuptake inhibition. They derive their name because they have little effect on reuptake of norepinephrine or dopamine. Often, adequate clinical activity and saturation of the 5-HT transporters are achieved at starting dosages. As a rule, higher dosages do not increase antidepressant efficacy but may increase the risk of adverse effects.

Citalopram and escitalopram are the most selective inhibitors of serotonin reuptake, with very little inhibition of norepinephrine or dopamine reuptake and very low affinities for histamine H₁, γ-aminobutyric acid (GABA), or benzodiazepine receptors. The other SSRIs have a similar profile except that fluoxetine weakly inhibits norepinephrine reuptake and binds to 5-HT_2C receptors, sertraline weakly inhibits norepinephrine and dopamine reuptake, and paroxetine has significant anticholinergic activity at higher dosages and binds to nitric oxide syn-thase.

A pharmacodynamic interaction appears to underlie the antidepressant effects of combined fluoxetine–olanzapine. When taken together, these drugs increase brain concentrations of norepinephrine. Concomitant use of SSRIs and drugs in the triptan class (sumatriptan [Imitrex], naratriptan [Amerge], rizatriptan [Maxalt], and zolmitriptan [Zomig]) may result in a serious pharmacodynamic interaction—the development of a serotonin syndrome (see Precautions and Adverse Reactions). However, many people use triptans while taking low doses of an SSRI for headache prophylaxis without adverse reaction. A similar reaction may occur when SSRIs are combined with tramadol (Ultram).

In the United States, all SSRIs other than fluvoxamine have been approved by the FDA for treatment of depression. Several studies have found that antidepressants with serotonin–norepinephrine activity—drugs such as the MAOIs, TCAs, venlafaxine, and mirtazapine produce higher rates of remission than SSRIs in head-to-head studies. The continued role of SSRIs as first-line treatments thus reflects their simplicity of use, safety, and broad spectrum of action.

Direct comparisons of individual SSRIs have not revealed any to be consistently superior to another. There nevertheless can be considerable diversity in response to the various SSRIs among individuals. For example, more than 50% of people who respond poorly to one SSRI will respond favorably to another. Thus, before shifting to non-SSRI antidepressants, it is most reasonable to try other agents in the SSRI class for persons who did not respond to the first SSRI.

Some clinicians have attempted to select a particular SSRI for a specific person on the basis of the drug’s unique adverse effect profile. For example, thinking that fluoxetine is an activating and stimulating SSRI, they may assume it is a better choice for an abulic person than paroxetine, which is presumed to be a sedating SSRI. These differences, however, usually vary from person to person. Analyses of clinical trial data shows that the SSRIs are more effective in patients with more severe symptoms of major depression than those with milder symptoms.