In this study of adolescents with treatment-resistant depression, no association was found between mean plasma concentration at 6 weeks and response rates at 12 weeks. However, adolescents treated with citalopram whose plasma concentration was equal to or greater than the GM showed a higher response rate compared to those treated with citalopram whose plasma concentration was less than the GM. A similar but nonsignificant trend was found in youth treated with fluoxetine. In addition, a dose increase that resulted in an increase in exposure from less than the GM at 6 weeks to exposure equal to or greater than the GM at 12 weeks was also associated with a greater likelihood of response in those treated with either citalopram or fluoxetine. Taken together, these observations suggest the possibility of a threshold for optimal clinical benefit in some adolescents treated with either citalopram or fluoxetine. Drug concentration was not a strong determinant of adverse events, although higher venlafaxine plus ODV levels were associated with cardiovascular and other adverse effects. We first review the limitations and strengths of this study, place the findings placed in the context of the extant literature, and discuss clinical and research implications.
The major limitation of this study is that the measurement of drug exposure was added onto this clinical trial, which was not itself designed to assess the relationship between drug exposure and outcome. The ideal study examining the relationship between drug exposure and clinical response or adverse events would obtain multiple levels at several fixed doses of medication. We did not consistently note the time of the last drug dose, which could substantially influence exposure. This may have contributed to the considerable variation in drug concentration and also limited our ability to analyze these data using a population pharmacokinetics approach.23,24
Our use of a 6-week measure of exposure to predict 12-week outcome assumes that 6-week exposure is representative of the overall exposure across the treatment period. Although levels obtained at 6 and 12 weeks were highly correlated, there certainly was evidence of variability. Participants were not genotyped for common genetic variations in cytochrome P450 enzymes, so we cannot determine to what extent the variability in drug exposure was because of how quickly participants metabolized medications. Finally, we might have biased estimates of the relationships between drug level and both response and adverse events, as those who did not respond, who had serious adverse events, or who left the study before 6 weeks were much less likely to have had a drug level obtained.
Despite these limitations, this study is the first to examine the relationships between the drug concentration of SSRIs and SRNIs and the outcome in treatment-resistant depressed adolescents, and provides empirical support for the selective use of a dose increase for treatment nonresponders to either citalopram or fluoxetine.
In those treated with citalopram, higher plasma concentration assessed at 6 weeks predicted response at 12 weeks, with similar nonsignificant trend for those treated with fluoxetine. This finding has unclear predictive validity, insofar as there was no drug concentration cut point that sharply discriminated between responders and nonresponders. More specific effects were found among those who were nonresponders at 6 weeks and had a low drug concentration. For these youth, a dose increase in either citalopram or fluoxetine at 6 weeks was much more likely to result in response at 12 weeks if drug concentration moved from less than the GM at 6 weeks to equal to or greater than the GM by 12 weeks. In this sample, the GM for both citalopram and fluoxetine were lower than the concentrations estimated to achieve either 80% occupancy of the serotonin transporter in striatum or 80% serotonin reuptake inhibition, both of which are associated with clinical response.16,25
Our finding that there was a greater likelihood of response in those participants whose levels of either citalopram or fluoxetine were greater than the GM is consistent with these observations.
We did not find a clear relationship between outcome and drug exposure for either paroxetine or venlafaxine. Because the GM of paroxetine and venlafaxine were higher than the minimum concentration reported by Meyer et al16
to be associated with at 80% serotonin transporter binding, it is not surprising that further increases in dose and concentration were not beneficial. Although there is evidence in adults that higher doses of venlafaxine (ranging from 75 to 375 mg) result in greater efficacy, 10,26
our findings suggest that more is not necessarily better for depressed adolescents.
The results of this study provide preliminary evidence that clinical response to citalopram and fluoxetine in adolescent depression is related to exposure. Assessment of plasma levels may be particularly helpful for identifying youth who would benefit from a dose increase, namely, nonresponders to fluoxetine or citalopram who also have low drug concentration. Whereas it is true that current practice guidelines already recommend a dose increase of an SSRI if the patient does not respond to the initial dose of an antidepressant (1), these data suggest that an increase will be much more likely to be beneficial if current drug exposure is suboptimal. For those with adequate concentration, the clinician may do better to switch or augment than to increase the dose further. Future work that ties measures of drug concentration to biomarkers of response such as serotonin reuptake inhibition or changes in gene expression may help to identify a plasma concentration of fluoxetine or citalopram above which clinical response is likely. Such work could lead to empirically guided therapeutic monitoring strategies that personalize antidepressant dosing and substantially improve treatment response and clinical outcomes for depressed adolescents.