Skip to main content Accessibility help

Effect of antidepressant switching between nortriptyline and escitalopram after a failed first antidepressant treatment among patients with major depressive disorder

  • Ole Köhler-Forsberg (a1), Erik Roj Larsen (a2), Henriette N. Buttenschøn (a3), Marcella Rietschel (a4), Joanna Hauser (a5), Daniel Souery (a6), Wolfgang Maier (a7), Anne Farmer (a8), Peter McGuffin (a8), Katherine J. Aitchison (a9), Rudolf Uher (a10) and Ole Mors (a11)...



For patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).


To compare the switch between the TCA nortriptyline and the SSRI escitalopram.


Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 ( and ISRCTN No.03693000 ( Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery–Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting β-coefficients with 95% CIs.


Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, β = −0.38, 95% CI −0.51 to −0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, β = −0.34, 95% CI −0.41 to −0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions.


These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.

Declarations of interest

K.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.


Corresponding author

Correspondence: Ole Köhler-Forsberg, Psychosis Research Unit, Aarhus University Hospital, Risskov, Skovagervej 2, DK-8240 Risskov, Denmark. Email:


Hide All

These authors contributed equally to this work.



Hide All
1Bayes, AJ, Parker, GB. Comparison of guidelines for the treatment of unipolar depression: a focus on pharmacotherapy and neurostimulation. Acta Psychiatr Scand 2018; 137: 459–71.10.1111/acps.12878
2Cipriani, A, Furukawa, TA, Salanti, G, Chaimani, A, Atkinson, LZ, Ogawa, Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; 391: 1357–66.
3Pereira, VS, Hiroaki-Sato, VA. A brief history of antidepressant drug development: from tricyclics to beyond ketamine. Acta Neuropsychiatr 2018; 30: 307–22.10.1017/neu.2017.39
4Trivedi, MH, Rush, AJ, Wisniewski, SR, Nierenberg, AA, Warden, D, Ritz, L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 2840.10.1176/appi.ajp.163.1.28
5Bose, A, Tsai, J, Li, D. Early non-response in patients with severe depression: escitalopram up-titration versus switch to duloxetine. Clin Drug Investig 2012; 32: 373–85.10.2165/11631890-000000000-00000
6Nierenberg, AA, Fava, M, Trivedi, MH, Wisniewski, SR, Thase, ME, McGrath, PJ, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006; 163: 1519–30.10.1176/ajp.2006.163.9.1519
7Thase, ME, Rush, AJ, Howland, RH, Kornstein, SG, Kocsis, JH, Gelenberg, AJ, et al. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry 2002; 59: 233–9.10.1001/archpsyc.59.3.233
8Rush, AJ, Trivedi, MH, Wisniewski, SR, Stewart, JW, Nierenberg, AA, Thase, ME, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354: 1231–42.10.1056/NEJMoa052963
9Bschor, T, Baethge, C. No evidence for switching the antidepressant: systematic review and meta-analysis of RCTs of a common therapeutic strategy. Acta Psychiatr Scand 2010; 121: 174–9.10.1111/j.1600-0447.2009.01458.x
10Bschor, T, Kern, H, Henssler, J, Baethge, C. Switching the antidepressant after nonresponse in adults with major depression: a systematic literature search and meta-analysis. J Clin Psychiatry 2018; 79: 10.10.4088/JCP.16r10749
11Souery, D, Serretti, A, Calati, R, Oswald, P, Massat, I, Konstantinidis, A, et al. Citalopram versus desipramine in treatment resistant depression: effect of continuation or switching strategies: a randomized open study. World J Biol Psychiatry 2011; 12: 364–75.10.3109/15622975.2011.590225
12Mohamed, S, Johnson, GR, Chen, P, Hicks, PB, Davis, LL, Yoon, J, et al. Effect of antidepressant switching v. augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA 2017; 318: 132–45.10.1001/jama.2017.8036
13Brignone, M, Diamand, F, Painchault, C, Takyar, S. Efficacy and tolerability of switching therapy to vortioxetine versus other antidepressants in patients with major depressive disorder. Curr Med Res Opin 2016; 32: 351–66.10.1185/03007995.2015.1128404
14Shelton, RC, Williamson, DJ, Corya, SA, Sanger, TM, Van Campen, LE, Case, M, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005; 66: 1289–97.10.4088/JCP.v66n1012
15Connolly, KR, Thase, ME. If at first you don't succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 2011; 71: 4364.10.2165/11587620-000000000-00000
16Nakajima, S, Uchida, H, Suzuki, T, Watanabe, K, Hirano, J, Yagihashi, T, et al. Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?: a randomized open-label trial. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1983–9.10.1016/j.pnpbp.2011.08.008
17Uher, R, Farmer, A, Maier, W, Rietschel, M, Hauser, J, Marusic, A, et al. Measuring depression: comparison and integration of three scales in the GENDEP study. Psychol Med 2008; 38: 289300.10.1017/S0033291707001730
18Wing, J, Sartorius, N, Üstun, T. WHO Diagnosis and Clinical Measurement in Psychiatry. A Reference Manual for SCAN. Cambridge University Press, 1998.10.1017/CBO9780511666445
19Uher, R, Maier, W, Hauser, J, Marusic, A, Schmael, C, Mors, O, et al. Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression. Br J Psychiatry 2009; 194: 252–9.10.1192/bjp.bp.108.057554
20Lingjaerde, O, Ahlfors, UG, Bech, P, Dencker, SJ, Elgen, K. 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 1987; Suppl 334: 1100.10.1111/j.1600-0447.1987.tb10566.x
21Montgomery, SA, Åsberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9.10.1192/bjp.134.4.382
22Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 5662.10.1136/jnnp.23.1.56
23Beck, AT, Ward, CH, Mendelson, M, Mock, J, Erbaugh, J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4: 561–71.10.1001/archpsyc.1961.01710120031004
24Lane, P. Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharm Stat 2008; 7: 93106.10.1002/pst.267
25Papakostas, GI, Fava, M, Thase, ME. Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches. Biol Psychiatry 2008; 63: 699704.10.1016/j.biopsych.2007.08.010
26Uher, R, Mors, O, Rietschel, M, Rajewska-Rager, A, Petrovic, A, Zobel, A, et al. Early and delayed onset of response to antidepressants in individual trajectories of change during treatment of major depression: a secondary analysis of data from the genome-based therapeutic drugs for depression (GENDEP) study. J Clin Psychiatry 2011; 72: 1478–84.10.4088/JCP.10m06419
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary materials

Köhler-Forsberg et al. supplementary material
Table S1

 Word (21 KB)
21 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Effect of antidepressant switching between nortriptyline and escitalopram after a failed first antidepressant treatment among patients with major depressive disorder

  • Ole Köhler-Forsberg (a1), Erik Roj Larsen (a2), Henriette N. Buttenschøn (a3), Marcella Rietschel (a4), Joanna Hauser (a5), Daniel Souery (a6), Wolfgang Maier (a7), Anne Farmer (a8), Peter McGuffin (a8), Katherine J. Aitchison (a9), Rudolf Uher (a10) and Ole Mors (a11)...
Submit a response


No eLetters have been published for this article.


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *