Imaging studies have shown that serum concentrations of the selective serotonin reuptake inhibitor citalopram correlate with serotonin transporter (5-HTT) occupancy in vivo. In patients with major depressive disorders treated with citalopram, 80% 5-HTT occupancy was considered to be necessary for maximal therapeutic effects, which requires citalopram serum concentrations of at least 50 ng/mL. The aim of this study was to compare treatment outcome in patients with citalopram serum concentrations greater than and less than 50 ng/mL after 7 days of treatment. This study included inpatients with acute major depressive disorder according to International Classification of Disease, 10th Revision who were treated with citalopram. In weekly intervals, the severity of depression was assessed with the 17-item Hamilton Depression Rating Scale (HAMD-17), and serum concentrations of citalopram were measured from baseline until week 5. Fifty-five patients were eligible for this analysis. After 7 days of treatment, 19 patients showed citalopram serum concentrations of 50 ng/mL or greater; 36 patients had lower concentrations. Patients at greater than the 50-ng/mL threshold had (i) lower mean HAMD-17 sum scores from day 7 to end point (P e 0.018 for each analysis); (ii) a more pronounced HAMD-17 decrease (P e 0.019 for each analysis), and (iii) 23 days' shorter duration of hospitalization (P = 0.033) than patients with levels of citalopram less than 50 ng/mL. As regards adverse effects, both patient groups were not significantly different. Despite therapeutic doses, a significant number of patients had serum concentrations less than 50 ng/mL, and these were associated with an unfavorable treatment outcome; therapeutic drug monitoring is recommended to optimize dosing citalopram in the early phase of treatment.
The aim of antidepressant drug treatment is to produce remission without causing adverse effects during the acute phase of the illness and to prevent relapses or recurrences during continuation or maintenance therapy. To achieve these goals, drug choice and dosage must be optimized for each patient individually. Therapeutic drug monitoring (TDM), which is based on the assumption that clinical effects correlate better with blood levels than doses, can be helpful. When using tricyclic antidepressant drugs TDM enhances safety and efficacy. For newer antidepressant drugs, however, it is a matter of debate to which extend TDM can have beneficial effects. For many antidepressants there exist carefully designed studies concerning the relationship between plasma concentration and clinical effects that allow the definition of recommended therapeutic ranges of the plasma concentration. In some drugs however, concentration-effect studies are lacking so far, but target ranges resulting from clinically relevant plasma concentrations or from pharmacokinetic studies could be provided. During the last years, knowledge on therapeutic references ranges in blood towards TDM guided treatment has markedly improved for new antidepressant drugs, and many specific indications have been defined for useful TDM. Recently published guidelines describe the best practice of TDM for neuropsychiatric drugs. The aim of this review is to summarize the current status of TDM for antidepressant drugs and discuss the literature with regard to response optimization, pharmacovigilance and economic benefits and with regard to needs for further research.
It is concluded that treatment with citalopram should be guided by symptom rating at baseline and on day 14 and serum concentration determination on day 7.
: We describe a female patient who was an extensive metabolizer of cytochrome P450 isoenzyme (CYP) 2D6 and an intermediate metabolizer of CYP2C19 (genotype: CYP2C19 *1/*2). She exhibited high serum concentrations of venlafaxine and O-desmethylvenlafaxine and developed severe tremor after comedication with cotrimoxazole (sulfamethazole/trimethoprim). Venlafaxine is mainly metabolized by O- and N-demethylation. O-demethylation is catalyzed by the highly polymorphic CYP2D6 and N-demethylation by several enzymes, CYP2C19, CYP2C9, and CYP3A4. The observed overall pharmacokinetic effect was most probably the result of decreased N-demethylation of venlafaxine by (1) reduced expression of CYP2C19 due to a genetic deficit and (2) inhibition of CYP2C9 by cotrimoxazole.
The data taken together indicate that TDM-guided dosing of citalopram has the potential to be cost effective by reducing the length of hospitalization.
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