Paroxetine in Major Depression: Correlating Plasma Concentrations and Clinical Response

Background: In analogy to tricyclic antidepressants, serum concentrations of selective serotonin reuptake inhibitors (SSRIs) are frequently measured in order to optimize treatment results. However, clinical evidence for this approach is sparse. Methods: Forty patients with major depression were treated with paroxetine 20 mg/day for 14 days and with 40 mg/day for further 49 days. Treatment response measured by Hamilton depression rating scales (HAMD) was correlated with paroxetine plasma concentrations. Results: There was a significant difference between paroxetine plasma levels at 20 and 40 mg/day, respectively [20 mg/d: median 24 (range 4-358); 40 mg/d: 92 (30-398)]. However, the interindividual variance was very large. 18 out of 40 patients responded to paroxetine treatment. Conclusions: Receiver operated characteristic (ROC) analysis suggested no upper or lower limit of response. Responder had significantly higher paroxetine levels at day 7 [responder: 33 (4-107); non-responder: 13 (3-77)] but not at the end of the study [responder 93 (30-361); non-responder: 94 (59-398)]. Furthermore, plasma levels were not related to adverse events, age, body weight or severity of depression. These findings do not support any need for a routine screening of paroxetine plasma concentrations in clinical practice.

References

• 1 Alvan G, Bechtel P, Iselius L, Gundert-Remy U. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations.  Eur J Clin Pharmacol. 1990;  39 533-537
• 2 Bolo N R, Hode Y, Nedelec J F, Laine E, Wagner G, Macher J P. Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by flourine magnetic resonance spectroscopy.  Neuropsychopharmacology. 2000;  23 428-438
• 3 Danish University Antidepressant G roup. Paroxetine: A selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study.  J Affect Disord. 1990;  18 289-299
• 4 Karson C N, Newton J E, Livingston R, Jolly J B, Cooper T, Spring J, Komoroski R A. Human brain fluoxetine concentrations.  J Neuropsychiatry Clin Neurosci. 1993;  5 322-329
• 5 Kaye C M, Haddock R E, Langley P F, Mellows G, Tasker T C, Zussman B D, Greb W H. A review of the metabolism and pharmacokinetics of paroxetine in man.  Acta Psychiatr Scand. 1989;  350 60-75
• 6 Kuhs H, Schlake H P, Rolf L H, Rudolf G A. Relationship between parameters of serotonin transport and antidepressant plasma levels or therapeutic response in depressive patients treated with paroxetine and amitriptyline.  Acta Psychiatr Scand. 1992;  85 364-369
• 7 Laursen A L, Mikkelsen P L, Rasmussen S, le-Fevre H P. Paroxetine in the treatment of depression - a randomized comparison with amitriptyline.  Acta Psychiatr Scand. 1985;  71 249-255
• 8 Mossman D, Somoza E. ROC curves, test accuracy, and the description of diagnostic tests.  J Neuropsychiatry Clin Neurosci. 1991;  3 330-333
• 9 Müller M J, Dragicevic A, Fric M, Gaertner I, Grasmader K, Hartter S, Hermann E, Kuss H J, Laux G, Oehl W, Rao M L, Rollmann N, Weigmann H, Weber-Labonte M, Hiemke C. Therapeutic drug monitoring of tricyclic antidepressants: how does it work under clinical conditions?.  Pharmacopsychiatry. 2003;  36 98-104
• 10 Normann C, Hummel B, Schärer L O, Hörn M, Grunze H, Walden J. Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double blind study.  J Clin Psychiatry. 2002;  63 337-344
• 11 Rasmussen B B, Brosen K. Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of selective serotonin reuptake inhibitors.  Ther Drug Monit. 2000;  22 143-154
• 12 Sindrup S H, Brosen K, Gram L F. Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: nonlinearity and relation to the spartein oxidation polymorphism.  Clin Pharmacol Ther. 1992;  51 288-295
• 13 Tasker T C, Kaye C M, Zussman B D, Link C G. Paroxetine plasma levels: lack of correlation with efficacy or adverse events.  Acta Psychiatr Scand. 1989;  350(suppl) 152-155