EDITORIALS Antidepressant Selection in the Postgenomic Era

The term selective serotonin reuptake inhibitors (SSRIs) implies a common mechanism of action for these agents; hence, the assumption by pharmacy managers and health care planners that they are all clinically equivalent. Extensive clinical case report data belie this assumption, however, as individuals may have differing responses to the different SSRIs, and the average profile of response in terms of symptoms and side effects may differ between agents; however, there are little empirical data bearing on this issue, as few studies have directly contrasted SSRIs in empirical clinical trials. In this issue, Stahl and colleagues compare sertraline and citalopram in a well-designed, double-blind, controlled trial. They employed a range of assessment instruments including the Hamilton Depression Rating Scale, the Montgomery–Asberg Depression Rating Scale, and the Clinical Global Impressions Scale. They noted a significant improvement with sertraline at week 12, whereas improvement with citalopram began at weeks 2 to 4. Also, a significant anxiolytic effect of the citalopram, but not the sertraline, was demonstrated in comparison to a placebo. As investigators note, there have been quite variable results in previous comparisons of SSRIs. In a previous double-blind, multicenter study comparing sertraline and citalopram with 308 patient completers, but without a placebo trial, there were no statistically significant differences in rate of side effects between the two agents, although there was an absolute increase in citalopraminduced sexual dysfunctional symptoms that did not reach statistical significance. In this study, the patients in the sertraline groups used significantly more sedatives and hypnotics than those in the citalopram group, whereas there was a slight but nonsignificant increase in response in the citalopram group as well as a higher dosage of citalopram employed (Ekselius et al 1997). In a comparison of citalopram and fluoxetine, citalopram also showed a significantly better response at 2 weeks, demonstrating an earlier onset of recovery (Patris et al 1996), whereas another report from this group suggested greater reduction of anxiety symptoms with citalopram, as compared to fluoxetine (Bougerol et al 1997). Given the discrepant or variable results between different multicenter trials regarding comparisons between SSRIs, the investigators interpret these results in the context of different populations responding differentially to one SSRI as compared with another. A number of studies suggest that patients who were intolerant of (Brown and Harrison 1995; Thase et al 1997; Zarate et al 1996) or failed to respond to (Joffe et al 1996; Thase et al 1997) an initial SSRI trial may respond to a second trial with a different SSRI. Thus, the investigators are probably right in stating that these results support a differential response to SSRIs in different populations rather than the conclusion that one SSRI is clearly superior to another in a generalizable fashion. This conclusion, although not directly inferable from this study, has important practical and research implications. A trend for pharmacies or health care organizations to restrict SSRIs to one or two agents, under the assumption that they are all equivalently efficacious, may not be valid and would prevent access of patients to medications that might be effective for them when the SSRI chosen by the pharmacy is not. When cost control issues become paramount in clinical care, definitive empirical data that can correct these assumptions of equal efficacy for the SSRIs in all populations are clearly called for. There are many reasons, of course, why antidepressants may differ in their efficacy. Differences in pharmacokinetics, including drug metabolism; differences in pharmacologic effects; and differences in nontarget pharmacologic mechanisms that contribute to side effects and tolerability can contribute to differential responses. Thus, for example, agents that enhance dopaminergic activities, such as buproprion, would be expected to have a different profile of efficacy than the SSRIs. Similarly, mixed noradrenergic/serotonergic reuptake blockers such as venlafaxine would be expected to have some properties of the SSRIs with additional effects that more nearly mimic the actions of the tricyclics at higher doses, where noradrenergic effects are more prominent. A better understanding of differential efficacy of the antidepressants and the populations that are best served by the individual agents could have important implications for treatment interventions. If this conclusion is true, however, it remains elusive as to how to define population differences that are relevant for treatment response. Up until now, demographic or clinical characteristic approaches to defining homogeneous populations that will respond to one rather than another antidepressant have been largely disappointing. But with the advent of new techniques of mapping the genotype permitting the identification of single nucleotide pairs that vary between individuals, the door is opened to identifying genetic differences in individuals that are relevant for medication responses. Indeed, this has resulted in a new field of “pharmacogenomics.” By identifying genetic differences between populations of responders to a particular medication and those who are nonresponders, the possibility of identifying those who would most benefit from a particular medication and those