, Volume 235, Issue 11, pp 3201–3209 | Cite as

The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose

  • E. M. McGlashan
  • L. S. Nandam
  • P. Vidafar
  • D. R. Mansfield
  • S. M. W. Rajaratnam
  • S. W. CainEmail author
Original Investigation



Disturbances of the circadian system are common in depression. Though they typically subside when depression is treated with antidepressants, the mechanism by which this occurs is unknown. Despite being the most commonly prescribed class of antidepressants, the effect of selective serotonin reuptake inhibitors (SSRIs) on the human circadian clock is not well understood.


To examine the effect of the SSRI citalopram (30 mg) on the sensitivity of the human circadian system to light.


This study used a double-blind, placebo-controlled, within-subjects, crossover design. Participants completed two melatonin suppression assessments in room level light (~ 100 lx), taking either a single dose of citalopram 30 mg or a placebo at the beginning of each light exposure. Melatonin suppression was calculated by comparing placebo and citalopram light exposure conditions to a dim light baseline.


A 47% increase in melatonin suppression was observed after administration of an acute dose of citalopram, with all participants showing more suppression after citalopram administration (large effect, d = 1.54). Further, melatonin onset occurred later under normal room light with citalopram compared to placebo.


Increased sensitivity of the circadian system to light could assist in explaining some of the inter-individual variability in antidepressant treatment responses, as it is likely to assist in recovery in some patients, while causing further disruption for others.


Light sensitivity Circadian rhythms Depression Antidepressants Melatonin suppression Light at night Sleep 



We would like to thank Mr. Michael Cummins, Mr. Arnold Moss and Mr. Frank Suss of the Monash University Campus Pharmacy for their assistance in coordinating this trial, in particular Mr. Michael Cummins for performing and maintaining the randomisation and blinding. We would like to additionally thank and acknowledge Dr. Hamni Sahi for her assistance conducting medical screening of participants for the study. Lastly, we would like to acknowledge the contribution of the staff and students of the Monash University Sleep and Circadian Medicine Laboratory for their assistance in running the project.

Funding information

EM McGlashan receives financial support from the Australian Government through a Research Training Program (RTP) Scholarship. P Vidafar receives a PhD scholarship from the National Health and Medicine Research Council (NHMRC), via the Neurosleep Centre for Research Excellence (CRE).

Compliance with ethical standards

Conflicts of interest

EM McGlashan, P Vidafar, LS Nandam, DR Mansfield and SW Cain report no conflicts of interest. SMW Rajaratnam reports no conflicts or funding in direct relation to this work, but that he has served as a consultant through his institution to Vanda Pharmaceuticals, Philips Respironics, EdanSafe, The Australian Workers’ Union, National Transport Commission, Transport Accident Commission, New South Wales Department of Education and Communities, and has through his institution received research grants and/or unrestricted educational grants from Vanda Pharmaceuticals, Shell, Teva Pharmaceuticals, Rio Tinto, Seeing Machines, Takeda Pharmaceuticals North America, Philips Lighting, Philips Respironics, Cephalon, and ResMed Foundation, and reimbursements for conference travel expenses from Vanda Pharmaceuticals. His institution has received equipment donations or other support from OptalertTM, Compumedics, and Tyco Healthcare. He has served as an expert witness and/or consultant to shift work organisations. SMW Rajaratnam also serves as a Program Leader in the Cooperative Research Centre for Alertness, Safety and Productivity.


  1. American Psychiatric Association (2013) DSM 5. American Psychiatric Association, Washington, DCGoogle Scholar
  2. Anderson JL, Glod CA, Dai J, Cao Y, Lockley SW (2009) Lux vs. wavelength in light treatment of Seasonal Affective Disorder. Acta Psychiatr Scand 120:203–212CrossRefGoogle Scholar
  3. Aoki H, Ozeki Y, Yamada N (2001) Hypersensitivity of melatonin suppression in response to light in patients with delayed sleep phase syndrome. Chronobiol Int 18:263–271CrossRefGoogle Scholar
  4. Argyropoulos SV, Wilson SJ (2005) Sleep disturbances in depression and the effects of antidepressants. Int Rev Psychiatry 17:237–245CrossRefGoogle Scholar
  5. Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita M, Smeraldi E (2003) Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. J Clin Psychiatry 64:648–653CrossRefGoogle Scholar
  6. Bezchlibnyk-Butler K, Aleksic I, Kennedy SH (2000) Citalopram--a review of pharmacological and clinical effects. J Psychiatry Neurosci 25:241PubMedPubMedCentralGoogle Scholar
  7. Brainard G, Hanifin J, Greeson J, Byrne B, Glickman G, Gerner E, Rollag M (2001) Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 21:6405–6412CrossRefGoogle Scholar
  8. Bramley J, Sollars P, Pickard G, Dudek F (2005) 5-HT1B receptor-mediated presynaptic inhibition of GABA release in the suprachiasmatic nucleus. J Neurophysiol 93:3157–3164CrossRefGoogle Scholar
  9. Breslau N, Roth T, Rosenthal L, Andreski P (1996) Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 39:411–418CrossRefGoogle Scholar
  10. Buysse DJ, Reynolds C, Monk T, Berman S, Kupfer DJ (1989) The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 28:193–213CrossRefGoogle Scholar
  11. Carvalho L, Gorenstein C, Moreno R, Pariante C, Markus R (2009) Effect of antidepressants on melatonin metabolite in depressed patients. J Psychopharmacol 23:315–321CrossRefGoogle Scholar
  12. Chellappa SL, Steiner R, Oelhafen P, Lang D, Gotz T, Krebs J, Cajochen C (2013) Acute exposure to evening blue-enriched light impacts on human sleep. J Sleep Res 22:573–580CrossRefGoogle Scholar
  13. Cuesta M, Mendoza J, Clesse D, Pévet P, Challet E (2008) Serotonergic activation potentiates light resetting of the main circadian clock and alters clock gene expression in a diurnal rodent. Exp Neurol 210:501–513CrossRefGoogle Scholar
  14. Cuesta M, Clesse D, Pévet P, Challet E (2009) New light on the serotonergic paradox in the rat circadian system. J Neurochem 110:231–243CrossRefGoogle Scholar
  15. Cunningham JEA, Shapiro CM (2018) Cognitive Behavioural Therapy for Insomnia (CBT-I) to treat depression: a systematic review. J Psychosom Res 106:1–12CrossRefGoogle Scholar
  16. Czeisler CA, Weitzman ED, Moore-Ede MC, Zimmerman JC, Knauer RS (1980) Human sleep: its duration and organization depend on its circadian phase. Science 210:1264–1267CrossRefGoogle Scholar
  17. Dijk D-J, Czeisler CA (1995) Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 15:3526–3538CrossRefGoogle Scholar
  18. Emens J, Lewy AJ, Mark J, Arntz D, Rough J (2009) Circadian misalignment in major depressive disorder. Psychiatry Res 168:259–261CrossRefGoogle Scholar
  19. Even C, Schröder CM, Friedman S, Rouillon F (2008) Efficacy of light therapy in nonseasonal depression: a systematic review. J Affect Disord 108:11–23CrossRefGoogle Scholar
  20. Gannon RL, Millan MJ (2007) Evaluation of serotonin, noradrenaline and dopamine reuptake inhibitors on light-induced phase advances in hamster circadian activity rhythms. Psychopharmacology 195:325–332CrossRefGoogle Scholar
  21. Gooley JJ, Mien IH, Hilaire MAS, Yeo S-C, Chua EC-P, Van Reen E, Hanley CJ, Hull JT, Czeisler CA, Lockley SW (2012) Melanopsin and rod–cone photoreceptors play different roles in mediating pupillary light responses during exposure to continuous light in humans. J Neurosci 32:14242–14253CrossRefGoogle Scholar
  22. Gwirtsman HE, Halaris AE, Wolf AW, DeMet E, Piletz JE, Marler M (1989) Apparent phase advance in diurnal MHPG rhythm in depression. Am J Psychiatry 146:1427CrossRefGoogle Scholar
  23. Hallam KT, Olver JS, Horgan JE, McGrath C, Norman TR (2005a) Low doses of lithium carbonate reduce melatonin light sensitivity in healthy volunteers. Int J Neuropsychopharmacol 8:255–259CrossRefGoogle Scholar
  24. Hallam KT, Olver JS, Norman TR (2005b) Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers. Neuropsychopharmacology 30:1400–1404CrossRefGoogle Scholar
  25. Hallam K, Begg D, Olver J, Norman TR (2009) Abnormal dose-response melatonin suppression by light in bipolar type I patients compared with healthy adult subjects. Acta Neuropsychiatrica 21:246–255CrossRefGoogle Scholar
  26. Hensler JG (2003) Regulation of 5-HT 1A receptor function in brain following agonist or antidepressant administration. Life Sci 72:1665–1682CrossRefGoogle Scholar
  27. Hickie IB, Naismith SL, Robillard R, Scott EM, Hermens DF (2013) Manipulating the sleep-wake cycle and circadian rhythms to improve clinical management of major depression. BMC Med 11:79CrossRefGoogle Scholar
  28. Johns M (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14:540–545CrossRefGoogle Scholar
  29. Lam RW, Levitt AJ, Levitan RD, Michalak EE, Cheung AH, Morehouse R, Ramasubbu R, Yatham LN, Tam EM (2016) Efficacy of bright light treatment, fluoxetine, and the combination in patients with nonseasonal major depressive disorder: a randomized clinical trial. JAMA Psychiatry 73:56–63CrossRefGoogle Scholar
  30. Li S-X, Liu L-J, Xu L-Z, Gao L, Wang X-F, Zhang J-T, Lu L (2013) Diurnal alterations in circadian genes and peptides in major depressive disorder before and after escitalopram treatment. Psychoneuroendocrinology 38:2789–2799CrossRefGoogle Scholar
  31. Linkowski P (2003) Neuroendocrine profiles in mood disorders. Int J Neuropsychopharmacol 6:191–197CrossRefGoogle Scholar
  32. Linkowski P, Mendlewicz J, Kerkhofs M, Leclercq R, Golstein J, Brasseur M, Copinschi G, Van Cauter E (1987) 24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment. J Clin Endocrinol Metab 65:141–152CrossRefGoogle Scholar
  33. Lockley SW, Brainard GC, Czeisler CA (2003) High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light. J Clin Endocrinol Metab 88:4502–4505CrossRefGoogle Scholar
  34. Lucas RJ, Peirson SN, Berson DM, Brown TM, Cooper HM, Czeisler CA, Figueiro MG, Gamlin PD, Lockley SW, O’Hagan JB, Price LLA, Provencio I, Skene DJ, Brainard GC (2014) Measuring and using light in the melanopsin age. Trends Neurosci 37:1–9CrossRefGoogle Scholar
  35. Mayers AG, Baldwin DS (2005) Antidepressants and their effect on sleep. Hum Psychopharmacol Clin Exp 20:533–559CrossRefGoogle Scholar
  36. McGlashan EM, Drummond SPA, Cain SW (2018) Evening types demonstrate reduced SSRI treatment efficacy. Chronobiol Int:1–4Google Scholar
  37. Meesters Y, Dekker V, Schlangen LJM, Bos EH, Ruiter MJ (2011) Low-intensity blue-enriched white light (750 lux) and standard bright light (10 000 lux) are equally effective in treating SAD. A randomized controlled study. BMC Psychiatry 11:17CrossRefGoogle Scholar
  38. Moore RY, Card JP (1985) Visual pathways and the entrainment of circadian rhythms. Ann N Y Acad Sci 453:123–133CrossRefGoogle Scholar
  39. Moore RY, Speh JC (2004) Serotonin innervation of the primate suprachiasmatic nucleus. Brain Res 1010:169–173CrossRefGoogle Scholar
  40. Morawetz D (2003) Insomnia and depression: which comes first? Sleep Research Online 5:77–81Google Scholar
  41. Nathan PJ, Burrows GD, Norman TR (1999) Melatonin sensitivity to dim white light in affective disorders. Neuropsychopharmacology 21:408–413CrossRefGoogle Scholar
  42. Noehr-Jensen L, Zwisler ST, Larsen F, Sindrup SH, Damkier P, Nielsen F, Brosen K (2009) Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker. Eur J Clin Pharmacol 65:887–894CrossRefGoogle Scholar
  43. Olfson M, Marcus SC (2009) National patterns in antidepressant medication treatment. Arch Gen Psychiatry 66:848–856CrossRefGoogle Scholar
  44. Pickard GE, Rea MA (1997) Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms. Biol Cell 89:513–523CrossRefGoogle Scholar
  45. Pickard G, Smith B, Belenky M, Rea M, Dudek F, Sollars P (1999) 5-HT1B receptor-mediated presynaptic inhibition of retinal input to the suprachiasmatic nucleus. J Neurosci 19:4034–4045CrossRefGoogle Scholar
  46. Rahman SA, Flynn-Evans EE, Aeschbach D, Brainard GC, Czeisler CA, Lockley SW (2014) Diurnal spectral sensitivity of the acute alerting effects of light. Sleep 37:271–281CrossRefGoogle Scholar
  47. Ralph MR, Foster RG, Davis FC, Menaker M (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247:975–978CrossRefGoogle Scholar
  48. Rea MA, Glass JD, Colwell CS (1994) Serotonin modulates photic responses suprachiasmatic nuclei in the hamster. J Neurosci 74:3635–3642CrossRefGoogle Scholar
  49. Schmitt JA, Riedel WJ, Vuurman EF, Kruizinga M, Ramaekers JG (2002) Modulation of the critical flicker fusion effects of serotonin reuptake inhibitors by concomitant pupillary changes. Psychopharmacology 160:381–386CrossRefGoogle Scholar
  50. Sletten TL, Vincenzi S, Redman JR, Lockley SW, Rajaratnam SMW (2010) Timing of sleep and its relationship with the endogenous melatonin rhythm. Front Neurol 1:137CrossRefGoogle Scholar
  51. Sollars P, Ogilvie M, Rea M, Pickard G (2002) 5-HT1B receptor knockout mice exhibit an enhanced response to constant light. J Biol Rhythm 17:428–437CrossRefGoogle Scholar
  52. Thapan K, Arendt J, Skene DJ (2001) An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans. J Physiol 535:261–267CrossRefGoogle Scholar
  53. Tutek J, Molzof HE, Lichstein KL (2017) Multilevel modeling of chronotype and weekdays versus weekends to predict nonrestorative sleep. Chronobiol Int 34:1401–1412CrossRefGoogle Scholar
  54. Urrila AS, Karlsson L, Kiviruusu O, Pelkonen M, Strandholm T, Marttunen M (2012) Sleep complaints among adolescent outpatients with major depressive disorder. Sleep Med 13:816–823CrossRefGoogle Scholar
  55. Von Bahr C, Ursing C, Yasui N, Tybring G, Bertilsson L, Röjdmark S (2000) Fluvoxamine but not citalopram increases serum melatonin in healthy subjects–an indication that cytochrome P 450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol 56:123–127CrossRefGoogle Scholar
  56. Weber ET, Gannon RL, Ma R (1998) Local administration of serotonin agonists blocks light-induced phase advances of the circadian activity rhythm in the hamster. J Biol Rhythm 13:209–218CrossRefGoogle Scholar
  57. Wehr TA, Muscettola G, Goodwin FK (1980) Urinary 3-methoxy-4-hydroxyphenylglycol circadian rhythm: early timing (phase-advance) in manic-depressives compared with normal subjects. Arch Gen Psychiatry 37:257–263CrossRefGoogle Scholar
  58. Wilson SJ, Bailey JE, Rich aS, Adrover M, Potokar J, Nutt DJ (2004) Using sleep to evaluate comparative serotonergic effects of paroxetine and citalopram. Eur Neuropsychopharmacol 14:367–372CrossRefGoogle Scholar
  59. World Health Organisation (2004) The global burden of disease: 2004 update. WHO Press, SwitzerlandGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological SciencesMonash UniversityClaytonAustralia
  2. 2.Queensland Brain InstituteThe University of QueenslandBrisbaneAustralia
  3. 3.Monash Lung and Sleep, Monash HealthClaytonAustralia

Personalised recommendations