Pharmacopsychiatry 2013; 46(07): 261-266
DOI: 10.1055/s-0033-1354370
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Early Improvement and Serum Concentrations of Citalopram to Predict Antidepressant Drug Response of Patients with Major Depression

E. Ostad Haji
1   Department of Psychiatry & Psychotherapy, University Medical Center Mainz, Mainz, Germany
A. Tadic
1   Department of Psychiatry & Psychotherapy, University Medical Center Mainz, Mainz, Germany
S. Wagner
1   Department of Psychiatry & Psychotherapy, University Medical Center Mainz, Mainz, Germany
A. Dragivevic
1   Department of Psychiatry & Psychotherapy, University Medical Center Mainz, Mainz, Germany
M. J. Müller
2   Department of Psychiatry, Clinic for Psychiatry, Giessen, Germany
K. Boland
3   Department of Psychiatry & Psychotherapy, University Med. Center of Bonn, Bonn, Germany
M. L. Rao
4   Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
M. Fric
5   Department of Psychiatry & Psychotherapy, Inn Salzach Klinikum, ­Wasserburg, Germany
G. Laux
6   Department of Psychiatry, Inn-Salzach Hospital, Wasserburg, Germany
C. Hiemke
1   Department of Psychiatry & Psychotherapy, University Medical Center Mainz, Mainz, Germany
› Author Affiliations
Further Information

Publication History

received 04 February 2013
revised 25 July 2013

accepted 31 July 2013

Publication Date:
24 September 2013 (online)



Post hoc analyses of clinical trials have shown that early improvement around day 14 is highly predictive for later response. More­over, evidence has been given that sufficiently high concentrations of antidepressant drugs in blood are required to attain response. In this study, we determined cut-off levels for citalopram serum concentrations and clinical improvement during the early phase of treatment to predict later response and the predictive power of these measures either alone or in combination.


Inpatients with depressive disorder according to ICD-10 who received citalopram were included. Psychopathology was assessed by the 17-item Hamilton Depression (HAMD-17) rating scale, and serum concentrations of citalopram were measured in weekly intervals.


The analysis included 55 inpatients. Receiver operating characteristics analysis revealed for citalopram a serum concentration of 53 ng/ml on day 7 and a clinical improvement of 24% on the HAMD-17 scale on day 14 as significant cut-off values to predict response after 5 weeks of treatment. Both measures taken together predicted response on week 5 with 73% sensitivity and 85% specificity with an odds ratio of 14.6.


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.

  • References

  • 1 Bauer M, Bschor T, Pfennig A et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry 2007; 8: 67-104
  • 2 Baghai TC, Blier P, Baldwin DS et al. Executive summary of the report by the WPA section on pharmacopsychiatry on general and comparative efficacy and effectiveness of antidepressants in the acute treatment of depressive disorders. Eur Arch Psychiatry Clin Neurosci 2012; 262: 13-22
  • 3 Serretti A, Chiesa A, Calati R et al. Influence of family history of major depression, bipolar disorder, and suicide on clinical features in patients with major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci 2012; [Epub ahead of print]
  • 4 Quitkin FM, Mc Grath PJ, Stewart JW et al. Can the effects of antidepressants be observed in the first two weeks of treatment?. Neuropsychopharmacology 1996; 15: 390-394
  • 5 Stassen HH, Angst J, Delini-Stula A. Fluoxetine versus moclobemide: Cross-comparison between the time courses of improvement. Pharmacopsychiatry 1999; 32: 56-60
  • 6 Stassen HH, Angst J, Hell D et al. Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. J Clin Psychiatry 2007; 68: 1195-1205
  • 7 Stassen H, Anghelescu IG, Angst J et al. Predicting response to psycho­pharmacological treatment: survey of recent results. Pharmacopsychiatry 2011; 44: 263-272
  • 8 Nierenberg AA, McLean NE, Alpert JE et al. Early non-response to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry 1995; 152: 1500-1503
  • 9 Szegedi A, Müller MJ, Anghelescu I et al. Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. J Clin Psychiatry 2003; 64: 413-420
  • 10 Henkel V, Seemüller F, Obermeier M et al. Does early improvement triggered by antidepressants predict response/remission? Analysis of data from a naturalistic study on a large sample of inpatients with major depression. J Affect Disord 2009; 115: 439-449
  • 11 Tadić A, Helmreich I, Mergl R et al. Early Improvement is a predictor of treatment outcome in patients with mild major, minor or subsyndromal depression. J Affect Disord 2010; 120: 86-93
  • 12 Szegedi A, Jansen WT, Van Willigenburg AP et al. Early Improvement in the first two weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry 2009; 70: 344-353
  • 13 Glotzbach PK, Preskorn SH. Brain concentrations of tricyclic antidepressants: single-dose kinetics and relationship to plasma concentrations in chronically dosed rats. Psychopharmacology 1982; 78: 25-27
  • 14 Hiemke C, Baumann P, Bergemann N et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 2011; 44: 195-235
  • 15 Ǻsberg M, Cronholm B, Sjoqvist F et al. Relationship between plasma level and therapeutic effect of nortriptylin. Br Med J 1971; 3: 331-334
  • 16 Perry PJ, Zeilmann C, Arndt S. Tricyclic antidepressants in plasma: An estimate of their sensitivity and specificity as a predictor of response. J Clin Psychopharmacol 1994; 14: 230-240
  • 17 Preskorn SH, Burke MJ, Fast GH. Therapeutic drug monitoring. Principles and practice. Psychiatr Clin North Am 1993; 16: 611-645
  • 18 Preskorn SH, Dorey RC, Jerkovich GS. Therapeutic drug monitoring of tricyclic antidepressants. Clin Chem 1988; 34: 822-828
  • 19 Burke MJ, Preskorn SH. Therapeutic drug monitoring of antidepressants. Cost implications and relevance to clinical practice. Clin Pharmacokinet 1999; 37: 147-165
  • 20 Preskorn SH, Fast GA. Therapeutic drug monitoring for antidepressants: efficacy, safety, and cost effectiveness. J Clin Psychiatry 1991; 52: 23-33 Review. Erratum in: J Clin Psychiatry 1992; 52: 353
  • 21 Lundmark J, Bengtsson F, Nordin C et al. Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients. Acta Psychiatr Scand 2000; 101: 354-359
  • 22 Ruhe HG, Booij J, vWeert HC et al. Evidence why paroxetine dose escalation is not effective in major depressive disorder: A randomized controlled trial with assessment of serotonin transporter occupancy. Neuropsychopharmacology 2009; 34: 999-1010
  • 23 Eggart V, Hiemke C, Zernig G. “There is no dose-response relationship in psychopharmacotherapy” vs. “pharmacotherapy in psychiatry is based on ligand-receptor interaction”: a unifying hypothesis and the need for plasmaconcentration based clinical trials. Psychopharmacology 2011; 217: 297-300
  • 24 Ostad Haji E, Tadić A, Wagner S et al. Association between citalopram serum levels and clinical improvement of patients with major depression. J Clin Psychopharmacol 2011; 31: 281-286
  • 25 Reis M, Lundmark J, Bengtsson F. Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992–1997. Ther Drug Monit 2003; 25: 183-191
  • 26 Tanum L, Strand LP, Refsum H. Serum concentrations of citalopram-dose-dependent variation in R- and S-enantiomer ratios. Pharmacopsychiatry 2010; 43: 190-193
  • 27 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56-62
  • 28 Helmreich I, Wagner S, Mergl R et al. Sensitivity to changes during antidepressant treatment: a comparison of unidimensional subscales of the Inventory of Depressive Symptomatology (IDS-C) and the Hamilton Depression Rating Scale (HAMD) in patients with mild major, minor or subsyndromal depression. Eur Arch Psychiatry Clin Neurosci 2012; 262: 291-304
  • 29 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
  • 30 Frahnert C, Rao ML, Grasmäder K. Analysis of eighteen antidepressants, four atypical antipsychotics and active metabolites in serum by liquid chromatography: a simple tool for therapeutic drug monitoring. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 794: 35-47
  • 31 Greiner C, Hiemke C, Bader W et al. Determination of citalopram and escitalopram together with their active main metabolites desmethyl (es-) citalopram in human serum by column-switching high performance liquid chromatography (HPLC) and spectrophotometric detection. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 848: 391-394
  • 32 Zweig MH, Campbell G. Receiver-operating characteristics (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993; 39: 561-577 Review. Erratum in: Clin Chem 1993; 39: 1589
  • 33 Le Bloc’h Y, Woggon B, Weissenrieder H et al. Routine therapeutic drug monitoring in patients treated with 10–360 mg/day citalopram. Ther Drug Monit 2003; 25: 600-608
  • 34 Leinonen E, Lepola U, Koponen H et al. The effect of age and concomitant treatment with other psychoactive drugs on serum concentrations of citalopram measured with a nonenantioselective method. Ther Drug Monit 1996; 18: 111-117
  • 35 Meyer JH, Wilson AA, Sagrati S et al. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C] DASB positron emission tomography study. Am J Psychiatry 2004; 161: 826-835
  • 36 Unterecker S, Warrings B, Deckert J et al. Correlation of QTc interval prolongation and serum level of citalopram after intoxication – a case report. Pharmacopsychiatry 2012; 45: 30-34
  • 37 Nierenberg AA, Farabaugh AH, Alpert JE et al. Timing of onset of action of antidepressant response with fluoxetine treatment. Am J Psychiatry 2000; 157: 1423-1428
  • 38 Posternark MA, Zimmermann M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005; 66: 148-158
  • 39 Mitchel AJ. Two-week delay in onset of action of antidepressants: New evidence. Br J Psychiatry 2006; 188: 105-106
  • 40 Papakostas GI, Petersen T, Sklarsky KG et al. Timing of clinical improvement and symptom resolution in the treatment of major depressive disorder. Psychiatry Res 2007; 149: 195-200
  • 41 Papakostas GI, Perlis RH, Scalia MJ et al. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006; 26: 56-60
  • 42 Taylor MJ, Freemantle N, Geddes JR et al. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry 2006; 63: 1217-1223
  • 43 Gex-Fabry M, Balant-Gorgia AE, Balant LP. Clomipramine concentration as a predictor of delayed response: a naturalistic study. Eur J Clin Pharmacol 1999; 54: 895-902
  • 44 Gex-Fabry M, Balant-Gorgia AE, Balant LP et al. Time course of clinical response to venlafaxine: relevance of plasma level and chirality. Eur J Clin Pharmacol 2004; 59: 883-891
  • 45 Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905-1917
  • 46 Adli M, Baethge C, Heinz A et al. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005; 255: 387-400