SSRIs

Editor's Notes

• #14: Owens and colleagues have assayed the relative potency of escitalopram and other SSRIs in the inhibition of the neuronal uptake of the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE) and dopamine (DA). A lower inhibitory constant (K i ) indicates that the compound produces inhibition at a lower concentration (represented in nanomoles per liter), i.e., it is more potent. Escitalopram and the other SSRIs are potent and selective serotonin reuptake inhibitors, but the serotonin selectivity ratio (comparing the extent of serotonin reuptake inhibition to the extent of inhibition of norepinephrine reuptake) indicates that escitalopram is the most selective inhibitor of serotonin reuptake studied to date. Both serotonergic and noradrenergic systems are thought to play a role in depression and in its treatment, and the selectivity of a compound to inhibit one transporter over another has not been associated with greater clinical efficacy. However, some of the CNS-related adverse effects associated with antidepressant therapy such as agitation, anxiety, nervousness, insomnia, and even tremor may be due to an increase in noradrenergic tone. Thus, treatment with an agent that has minimal effect on the noradrenergic system may result in a lower incidence of these side effects. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350.
• #20: The relative selectivity of an SSRI can be expressed as a ratio of the compound’s affinity for the serotonin transporter compared with its affinity for other monoamine transporters. These studies were carried out using cloned human monoamine transporters and compared the uptake inhibition by escitalopram to each of the commercially available SSRIs. In comparing affinities for the serotonin and norepinephrine transporter, Owens and colleagues found that escitalopram is the most selective serotonin reuptake inhibitor studied to date — even more selective than citalopram, which itself is more selective than other SSRIs. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350.
• #28: Escitalopram lacks affinity for the histamine-1 receptor, having much less (i.e., an order of magnitude) affinity compared with citalopram and R -citalopram. The weak affinity of citalopram for the histamine receptor (an inhibitory constant (Ki) below 1000 nanomoles (nM) may be physiologically relevant) is attributable to R-citalopram. This suggests that escitalopram may be less likely than citalopram to produce antihistaminic effects such as sedation. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350.
• #41: Despite sharing a similar mechanism of action, the SSRIs are a heterogeneous group of compounds, which can be distinguished from one another pharmacokinetically, as shown on this slide. Drugs with longer half-lives, such as fluoxetine, citalopram, and escitalopram are likely to have fewer discontinuation symptoms if doses are missed or therapy is abruptly discontinued. Fluoxetine and norfluoxetine, its active metabolite, both contribute to the very prolonged half-life observed for fluoxetine. Fluoxetine, paroxetine, and sertraline are highly protein bound (  94%), whereas the protein binding of escitalopram (56%) is considerably less. The absolute bioavailability of escitalopram, citalopram, fluoxetine, and paroxetine is not affected by food in the stomach. However, food does alter the pharmacokinetics of sertraline. Paroxetine and fluoxetine have nonlinear pharmacokinetics over their usual dosing range, whereas those for escitalopram, citalopram and sertraline are linear. As a rule, nonlinear pharmacokinetics result when a drug induces or inhibits its own CYP450 metabolism and the patient can develop disproportionate increases in plasma levels with dose increases, which may result in increased risk of adverse effects. In drugs that demonstrate linear pharmacokinetics, a change in dose will produce a proportional change in plasma drug concentration. The usual dose ranges for treatment of major depressive disorder (expressed as mg per day) are shown for the SSRIs. References 1. van Harten JV. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet. 1993;24:203-220. 2. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(suppl 1):1-21. 3. Preskorn SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry. 1993;54(suppl 9):14-34. 4. Physicians’ Desk Reference . 56 th ed. Montvale, NJ: Medical Economics Company; 2002. 5. Data on file, Forest Laboratories, Inc., 2002