Duloxetine Serum Concentrations and Clinical Effects. Data from a Therapeutic Drug Monitoring (TDM) Survey

Abstract

Introduction: The aim of this study was to relate drug concentrations in serum and clinical effects in patients treated with the new antidepressant duloxetine.

Methods: Data were obtained from a newly established therapeutic drug monitoring (TDM) survey. Duloxetine was measured using HPLC with UV detection and clinical effects by the clinical global impressions (CGI) scale for improvement.

Results: The study included 103 depressed inpatients (69% female). Patients under duloxetine monotherapy who were very much improved according to CGI had significantly (p<0.05) higher serum levels than patients with moderate, minimal or lacking improvement (mean±SD and range, 93±53 ng/mL and 30–182 ng/mL and 47±39 ng/mL and 5–178 ng/mL, respectively). Daily doses were similar in the two groups (76±27 vs. 83±27 mg/d). Receiver operating characteristics (ROC) curve analysis revealed significant predictive properties of duloxetine serum levels (p=0.011) for improvement with a lower threshold concentration of duloxetine of 58 ng/mL.

Discussion: The findings indicate that therapeutic drug monitoring of duloxetine and titration to steady state serum concentrations above 58 ng/mL is useful for treatment optimization.

References

• 1 Adli M, Pilhatsch M, Bauer M. et al . Safety of high-intensity treatment with irreversible monoamine oxidase inhibitor tranylcypromine in patients with treatment-resistant depression.  Pharmacopsychiatry. 2008;  41 252-257
• 2 Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability.  J Affect Disord. 2000;  58 19-36
• 3 Baumann P, Hiemke C, Ulrich S. et al . The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.  Pharmacopsychiatry. 2004;  37 243-265
• 4 Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG. et al . Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.  Neuropsychopharmacology. 2002;  25 871-880
• 5 Chan C, Yeo KP, Pan AX. et al . Duloxetine pharmacokinetics are similar in Japanese and Caucasian subjects.  Br J Clin Pharmacol. 2007;  63 310-314
• 6 Detke MJ, Lu Y, Goldstein DJ. et al . Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial.  J Clin Psychiatry. 2002;  63 308-315
• 7 Detke MJ, Wiltse CG, Mallinckrodt CH. et al . Duloxetine in the acute and long-term treatment of major depressive isorder: a placebo- and paroxetine- controlled trial.  Eur Neuropsychopharmacol. 2004;  4 457-470
• 8 Everitt B, Rabe-Hesketh S. Linear mixed models I. In Analysing Medical Data Using S-PLUS. New York: Springer 2001: p 243-268
• 9 Fava M, Mallinckrodt CH, Detke MJ. et al . The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates?.  J Clin Psychiatry. 2004;  65 521-530
• 10 Fric M, Pfuhlmann B, Laux G. et al . The influence of smoking on the serum level of duloxetine.  Pharmacopsychiatry. 2008;  41 151-155
• 11 Gillmann PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated.  Br J Pharmacol. 2007;  151 737-748
• 12 Goldstein DJ, Lu Y, Detke MJ. et al . Duloxetine in the treatment of depression. A double-blind placebo-controlled comparison with paroxetine.  J Clin Psychiatry. 2004;  24 389-399
• 13 Guy W. Early Clinical Drug Evaluation Unit (ECDEU) assessment manual for psychopharmacology. Revised. NIMH publication (DHEW publ No ADM 76-338). Bethesda MD: National Institute of Mental Health 1976: p 217-222
• 14 Hanley JA, McNeil BJ. The meaning and the use of the area under a receiver operating characteristic (ROC) curve.  Radiology. 1982;  143 29-36
• 15 Hansen RA, Gartlehner G, Lohr KN. et al . Efficacy and safety of second-generation antidepressant in the treatment of major depressive disorder.  Ann Intern Med. 2005;  143 415-426
• 16 Hirschfeld RM. Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs.  J Clin Psychiatry. 1999;  60 326-335
• 17 Hirschfeld RM, Montgomery SA, Keller MB. et al . Social functioning in depression: a review.  J Clin Psychiatry. 2000;  61 268-275
• 18 Lantz RJ, Gillespie TA, Rash TJ. et al . Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects.  Drug Metab Dispos. 2003;  31 1142-1150
• 19 Lee WC, Hsiao CK. Alternative summary indices for the receiver operating characteristic curve.  Epidemiology. 1996;  7 605-611
• 20 Lindell M, Karlsson MO, Lennernas H. et al . Variable expression of CYP and Pgp genes in human small intestine.  Eur J Clin Invest. 2003;  33 493-499
• 21 Lingjaerde O, Ahlfors UG, Bech P. et al . The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients.  Acta Psychiatr Scand Suppl. 1987;  334 1-100
• 22 Lobo ED, Bergstrom RF, Reddy S. et al . In vitro and in vivo evaluations of cytochrome P450 1A2 interactions with duloxetine.  Clin Pharmacokinet. 2008;  47 191-202
• 23 Lopez AD, Mathers CD, Ezzati M. et al . Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data.  Lancet. 2006;  367 1747-1757
• 24 Lopez-Munoz F, Alamo C, Rubio G. et al . Reboxetine combination in treatment-resistant depression to selective serotonin reuptake inhibitors.  Pharmacopsychiatry. 2007;  40 14-19
• 25 Mace S, Taylor D. Selective Serotonin reuptake inhibitors: a review of efficacy and tolerability in depression.  Expert Opin Pharmacother. 2000;  1 917-933
• 26 MacGillivray S, Arroll B, Hatcher S. et al . Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta analysis.  BMJ. 2003;  326 1014
• 27 Mann K, Hiemke C, Schmidt LG. et al . Appropriateness of therapeutic drug monitoring for antidepressants in routine psychiatric inpatient care.  Ther Drug Monit. 2006;  28 83-88
• 28 Montgomery SA, Baldwin DS, Blier P. et al . Which antidepressants have demonstrated superior efficacy? A review of the evidence.  Int Clin Psychopharmacol. 2007;  22 323-329
• 29 Müller MJ, Dragicevic A, Fric M. et al . Therapeutic Drug Monitoring of tricyclic antidepressants: how does it work under clinical conditions.  Pharmacopsychiatry. 2003;  36 98-104
• 30 Nierenberg AA. The treatment of severe depression: is there an efficacy gap between SSRI and TCA antidepressant generation?.  J Clin Psychiatry. 1994;  55 ((Suppl A)) 55-59 , discussion 60–61, 98–100
• 31 Olver JS, Burrows GD, Norman TR. Third-generation antidepressants: do they offer advantages over the SSRIs?.  CNS Drugs. 2001;  15 941-954
• 32 Papakostas GI, Fava M, Thase ME. Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches.  Biol Psychiatry. 2008;  63 699-704
• 33 Papakostas GI, Homberger CH, Fava M. A meta-analysis of clinical trial comparing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder.  J Psychopharmacol. 2008;  , Feb 28. [Epub ahead of print]
• 34 Pjrek E, Willeit M, Praschak-Rieder N. et al . Treatment of seasonal affective disorder with duloxetine: an open-label study.  Pharmacopsychiatry. 2008;  41 100-105
• 35 Preskorn SH, Greenblatt DJ, Flockhardt D. et al . Comparison of duloxetine, escitalopram and sertraline effects on cytochrome P450 2D6 function in healthy volunteers.  J Clin Psychopharmacol. 2007;  27 28-34
• 36 Raskin J, Goldstein DJ, Mallinckrodt CH. et al . Duloxetine in the long-term treatment of major depression disorder.  J Clin Psychiatry. 2003;  64 1237-1244
• 37 Skinner MH, Kuan HY, Pan A. et al . Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers.  Clin Pharmacol Ther. 2003;  73 170-177
• 38 Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning:cardiovascular toxicity.  Toxicol Rev. 2005;  24 205-214
• 39 Ulrich S, Hiemke C, Laux G. et al . Value and actuality of the prescription information for therapeutic drug monitoring of psychopharmaceuticals: a comparison with the medico-scientific evidence.  Pharmacopsychiatry. 2007;  40 121-127
• 40 Waldschmitt C, Vogel F, Maurer C. et al . Measurement of duloxetine in blood using high-performance liquid chromatography with spectrophotometric detection and column switching.  Ther Drug Monit. 2007;  29 767-772
• 41 Warrington SJ. Clinical implications of the pharmacology of serotonin reuptake inhibitors.  Int Clin Psychopharmacol. 1992;  7 ((Suppl. 2)) 13-19

Correspondence