Skip to main content
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

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.

Objective

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

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • American Psychiatric Association (2013) DSM 5. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Anderson JL, Glod CA, Dai J, Cao Y, Lockley SW (2009) Lux vs. wavelength in light treatment of Seasonal Affective Disorder. Acta Psychiatr Scand 120:203–212

    Article  CAS  Google Scholar 

  • Aoki H, Ozeki Y, Yamada N (2001) Hypersensitivity of melatonin suppression in response to light in patients with delayed sleep phase syndrome. Chronobiol Int 18:263–271

    Article  CAS  Google Scholar 

  • Argyropoulos SV, Wilson SJ (2005) Sleep disturbances in depression and the effects of antidepressants. Int Rev Psychiatry 17:237–245

    Article  Google Scholar 

  • 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 64:648–653

    Article  CAS  Google Scholar 

  • Bezchlibnyk-Butler K, Aleksic I, Kennedy SH (2000) Citalopram--a review of pharmacological and clinical effects. J Psychiatry Neurosci 25:241

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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 21:6405–6412

    Article  CAS  Google Scholar 

  • Bramley J, Sollars P, Pickard G, Dudek F (2005) 5-HT1B receptor-mediated presynaptic inhibition of GABA release in the suprachiasmatic nucleus. J Neurophysiol 93:3157–3164

    Article  CAS  Google Scholar 

  • Breslau N, Roth T, Rosenthal L, Andreski P (1996) Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 39:411–418

    Article  CAS  Google Scholar 

  • 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 28:193–213

    Article  CAS  Google Scholar 

  • Carvalho L, Gorenstein C, Moreno R, Pariante C, Markus R (2009) Effect of antidepressants on melatonin metabolite in depressed patients. J Psychopharmacol 23:315–321

    Article  CAS  Google Scholar 

  • 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 22:573–580

    Article  Google Scholar 

  • 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 210:501–513

    Article  CAS  Google Scholar 

  • Cuesta M, Clesse D, Pévet P, Challet E (2009) New light on the serotonergic paradox in the rat circadian system. J Neurochem 110:231–243

    Article  CAS  Google Scholar 

  • Cunningham JEA, Shapiro CM (2018) Cognitive Behavioural Therapy for Insomnia (CBT-I) to treat depression: a systematic review. J Psychosom Res 106:1–12

    Article  Google Scholar 

  • Czeisler CA, Weitzman ED, Moore-Ede MC, Zimmerman JC, Knauer RS (1980) Human sleep: its duration and organization depend on its circadian phase. Science 210:1264–1267

    Article  CAS  Google Scholar 

  • 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 15:3526–3538

    Article  CAS  Google Scholar 

  • Emens J, Lewy AJ, Mark J, Arntz D, Rough J (2009) Circadian misalignment in major depressive disorder. Psychiatry Res 168:259–261

    Article  Google Scholar 

  • Even C, Schröder CM, Friedman S, Rouillon F (2008) Efficacy of light therapy in nonseasonal depression: a systematic review. J Affect Disord 108:11–23

    Article  Google Scholar 

  • Gannon RL, Millan MJ (2007) Evaluation of serotonin, noradrenaline and dopamine reuptake inhibitors on light-induced phase advances in hamster circadian activity rhythms. Psychopharmacology 195:325–332

    Article  CAS  Google Scholar 

  • 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 32:14242–14253

    Article  CAS  Google Scholar 

  • 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 146:1427

    Article  CAS  Google Scholar 

  • 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 8:255–259

    Article  CAS  Google Scholar 

  • Hallam KT, Olver JS, Norman TR (2005b) Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers. Neuropsychopharmacology 30:1400–1404

    Article  CAS  Google Scholar 

  • 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 21:246–255

    Article  Google Scholar 

  • Hensler JG (2003) Regulation of 5-HT 1A receptor function in brain following agonist or antidepressant administration. Life Sci 72:1665–1682

    Article  CAS  Google Scholar 

  • 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 11:79

    Article  Google Scholar 

  • Johns M (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14:540–545

    Article  CAS  Google Scholar 

  • 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 73:56–63

    Article  Google Scholar 

  • 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 38:2789–2799

    Article  CAS  Google Scholar 

  • Linkowski P (2003) Neuroendocrine profiles in mood disorders. Int J Neuropsychopharmacol 6:191–197

    Article  CAS  Google Scholar 

  • 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 65:141–152

    Article  CAS  Google Scholar 

  • 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 88:4502–4505

    Article  CAS  Google Scholar 

  • 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 37:1–9

    Article  CAS  Google Scholar 

  • Mayers AG, Baldwin DS (2005) Antidepressants and their effect on sleep. Hum Psychopharmacol Clin Exp 20:533–559

    Article  CAS  Google Scholar 

  • McGlashan EM, Drummond SPA, Cain SW (2018) Evening types demonstrate reduced SSRI treatment efficacy. Chronobiol Int:1–4

  • 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 11:17

    Article  Google Scholar 

  • Moore RY, Card JP (1985) Visual pathways and the entrainment of circadian rhythms. Ann N Y Acad Sci 453:123–133

    Article  CAS  Google Scholar 

  • Moore RY, Speh JC (2004) Serotonin innervation of the primate suprachiasmatic nucleus. Brain Res 1010:169–173

    Article  CAS  Google Scholar 

  • Morawetz D (2003) Insomnia and depression: which comes first? Sleep Research Online 5:77–81

    Google Scholar 

  • Nathan PJ, Burrows GD, Norman TR (1999) Melatonin sensitivity to dim white light in affective disorders. Neuropsychopharmacology 21:408–413

    Article  CAS  Google Scholar 

  • 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 65:887–894

    Article  CAS  Google Scholar 

  • Olfson M, Marcus SC (2009) National patterns in antidepressant medication treatment. Arch Gen Psychiatry 66:848–856

    Article  Google Scholar 

  • Pickard GE, Rea MA (1997) Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms. Biol Cell 89:513–523

    Article  CAS  Google Scholar 

  • 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 19:4034–4045

    Article  CAS  Google Scholar 

  • 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 37:271–281

    Article  Google Scholar 

  • Ralph MR, Foster RG, Davis FC, Menaker M (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247:975–978

    Article  CAS  Google Scholar 

  • Rea MA, Glass JD, Colwell CS (1994) Serotonin modulates photic responses suprachiasmatic nuclei in the hamster. J Neurosci 74:3635–3642

    Article  Google Scholar 

  • 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 160:381–386

    Article  CAS  Google Scholar 

  • Sletten TL, Vincenzi S, Redman JR, Lockley SW, Rajaratnam SMW (2010) Timing of sleep and its relationship with the endogenous melatonin rhythm. Front Neurol 1:137

    Article  CAS  Google Scholar 

  • Sollars P, Ogilvie M, Rea M, Pickard G (2002) 5-HT1B receptor knockout mice exhibit an enhanced response to constant light. J Biol Rhythm 17:428–437

    Article  CAS  Google Scholar 

  • 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 535:261–267

    Article  CAS  Google Scholar 

  • Tutek J, Molzof HE, Lichstein KL (2017) Multilevel modeling of chronotype and weekdays versus weekends to predict nonrestorative sleep. Chronobiol Int 34:1401–1412

    Article  Google Scholar 

  • Urrila AS, Karlsson L, Kiviruusu O, Pelkonen M, Strandholm T, Marttunen M (2012) Sleep complaints among adolescent outpatients with major depressive disorder. Sleep Med 13:816–823

    Article  Google Scholar 

  • 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 56:123–127

    Article  Google Scholar 

  • 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 13:209–218

    Article  CAS  Google Scholar 

  • 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 37:257–263

    Article  CAS  Google Scholar 

  • 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 14:367–372

    Article  CAS  Google Scholar 

  • World Health Organisation (2004) The global burden of disease: 2004 update. WHO Press, Switzerland

    Google Scholar 

Download references

Acknowledgements

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

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).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S. W. Cain.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McGlashan, E.M., Nandam, L.S., Vidafar, P. et al. The SSRI citalopram increases the sensitivity of the human circadian system to light in an acute dose. Psychopharmacology 235, 3201–3209 (2018). https://doi.org/10.1007/s00213-018-5019-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-018-5019-0

Keywords

Navigation