Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial

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Background:
Patients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short-term usage. Melatonin, a naturally occurring nocturnal hormone, has the potential to stabilize disrupted circadian rhythmicity. Our aim was to investigate how prolonged-release melatonin affects rest-activity patterns in medicated patients with severe mental illness and if benzodiazepine dose reduction is associated with changes in circadian rhythm parameters.

Method:
Data were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage was gradually tapered. Here we report the results of 72 h of actigraphic assessment of activity-rest cycles performed pre and post tapering. Changes in rest-activity rhythm parameters between the melatonin and placebo group were analyzed using the univariate general linear model. Change in activity counts per 6 h, from baseline to follow-up, in the whole sample was analyzed using paired samples t-test.

Results:
A subsample of 48 patients participated in the actigraphic assessment: 20 in the melatonin group and 28 in the placebo group. Rest-activity cycles varied from regular to highly disrupted. Melatonin significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre tapering, but differences did not reach statistical significance.

Conclusion:
Our data suggest melatonin as an aid during benzodiazepine withdrawal for patients distressed by disrupted circadian rest-activity cycles. Benzodiazepine tapering might result in diminished sedentary behavior but further research is needed.

Trial registration:
ClinicalTrials NCT01431092, clinicaltrials.gov. Registered 31 August 2011.

Keywords:
Schizophrenia, Bipolar disorder, Circadian rhythms, Benzodiazepines, Discontinuation, Withdrawal, Circadian rhythm, Randomized clinical trial

Autoři: Lone Baandrup ^1*; Ole Bernt Fasmer ^2,3; Birte Yding Glenthøj ¹; Poul Jørgen Jennum ⁴
Působiště autorů: Center for Neuropsychiatric Schizophrenia Research (CNSR) & Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Copenhagen University Hospital, Mental Health Center Glostrup, Mental Health Services-Capital Region of Denmar ¹; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway. ²; Department of Clinical Medicine, Section for Psychiatry, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway. ³; Rigshospitalet, Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Center for Healthy Ageing, Faculty of Health Sciences, University of Copenhagen, DK 2600 Glostrup, Denmark. ⁴
Vyšlo v časopise: BMC Psychiatry 2016, 16:348
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1186/s12888-016-1062-8

© 2016 The Author(s).

Open access
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The electronic version of this article is the complete one and can be found online at: http://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-016-1062-8

Souhrn

Trial registration:
ClinicalTrials NCT01431092, clinicaltrials.gov. Registered 31 August 2011.

Keywords:
Schizophrenia, Bipolar disorder, Circadian rhythms, Benzodiazepines, Discontinuation, Withdrawal, Circadian rhythm, Randomized clinical trial

Zdroje

1. Tahmasian M, Khazaie H, Golshani S, Avis KT. Clinical application of actigraphy in psychotic disorders: a systematic review. Curr Psychiatry Rep. 2013;15:359–0359.

2. Ancoli-Israel S, Cole R, Alessi C, Chambers M, Moorcroft W, Pollak CP. The role of actigraphy in the study of sleep and circadian rhythms. Sleep. 2003;26:342–92.

3. Morgenthaler T, Alessi C, Friedman L, Owens J, Kapur V, Boehlecke B, et al. Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. Sleep. 2007;30:519–29.

4. Bromundt V, Koster M, Georgiev-Kill A, Opwis K, Wirz-Justice A, Stoppe G, et al. Sleep-wake cycles and cognitive functioning in schizophrenia. Br J Psychiatry. 2011;198:269–76.

5. Berle JO, Hauge ER, Oedegaard KJ, Holsten F, Fasmer OB. Actigraphic registration of motor activity reveals a more structured behavioural pattern in schizophrenia than in major depression. BMC Res Notes. 2010;3:149. doi:10.1186/1756-0500-3-149.:149-3.

6. Martin JL, Jeste DV, Ancoli-Israel S. Older schizophrenia patients have more disrupted sleep and circadian rhythms than age-matched comparison subjects. J Psychiatr Res. 2005;39:251–9.

7. Wulff K, Dijk DJ, Middleton B, Foster RG, Joyce EM. Sleep and circadian rhythm disruption in schizophrenia. Br J Psychiatry. 2012;200:308–16.

8. Wirz-Justice A, Haug HJ, Cajochen C. Disturbed circadian rest-activity cycles in schizophrenia patients: an effect of drugs? Schizophr Bull. 2001;27:497–502.

9. Monti JM, BaHammam AS, Pandi-Perumal SR, Bromundt V, Spence DW, Cardinali DP, et al. Sleep and circadian rhythm dysregulation in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:209–16.

10. Baldwin DS, Aitchison K, Bateson A, Curran HV, Davies S, Leonard B, et al. Benzodiazepines: risks and benefits. A reconsideration. J Psychopharmacol. 2013;27:967–71.

11. NICE technology appraisal. Guidance on the use of zalepon, zolpidem and zopiclone for the short-term management of insomnia. London: National Institute for Clinical Excellence; 2004.

12. Clay E, Falissard B, Moore N, Toumi M. Contribution of prolonged-release melatonin and anti-benzodiazepine campaigns to the reduction of benzodiazepine and Z-drugs consumption in nine European countries. Eur J Clin Pharmacol. 2013;69:1–10.

13. Kunz D, Bineau S, Maman K, Milea D, Toumi M. Benzodiazepine discontinuation with prolonged-release melatonin: hints from a German longitudinal prescription database. Expert Opin Pharmacother. 2012;13:9–16.

14. Baandrup L, Lindschou J, Winkel P, Gluud C, Glenthoj BY. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: A randomised, placebo-controlled, blinded trial. World J Biol Psychiatry. 2016;17(7):514–24.

15. Baandrup L, Fagerlund B, Jennum P, Lublin H, Hansen JL, Winkel P, et al. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial-the SMART trial protocol. BMC Psychiatry. 2011;11:160. doi:10.1186/1471-244X-11-160.:160-11.

16. Littner M, Kushida CA, Anderson WM, Bailey D, Berry RB, Davila DG, et al. Practice parameters for the role of actigraphy in the study of sleep and circadian rhythms: an update for 2002. Sleep. 2003;26:337–41.

17. Van Someren EJ, Swaab DF, Colenda CC, Cohen W, McCall WV, Rosenquist PB. Bright light therapy: improved sensitivity to its effects on rest-activity rhythms in Alzheimer patients by application of nonparametric methods. Chronobiol Int. 1999;16:505–18.

18. Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry. 2000;61:373–7.

19. Suresh Kumar PN, Andrade C, Bhakta SG, Singh NM. Melatonin in schizophrenic outpatients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:237–41.

20. Norris ER, Karen B, Correll JR, Zemanek KJ, Lerman J, Primelo RA, et al. A double-blind, randomized, placebo-controlled trial of adjunctive ramelteon for the treatment of insomnia and mood stability in patients with euthymic bipolar disorder. J Affect Disord. 2013;144:141–7.

21. Afonso P, Figueira ML, Paiva T. Sleep-promoting action of the endogenous melatonin in schizophrenia compared to healthy controls. Int J Psychiatry Clin Pract. 2011;15:311–5.

22. Martin J, Jeste DV, Caliguiri MP, Patterson T, Heaton R, Ancoli-Israel S. Actigraphic estimates of circadian rhythms and sleep/wake in older schizophrenia patients. Schizophr Res. 2001;47:77–86.

23. Harvey AG. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry. 2008;165:820–9.

24. Jagannath A, Peirson SN, Foster RG. Sleep and circadian rhythm disruption in neuropsychiatric illness. Curr Opin Neurobiol. 2013;23:888–94.

25. Pritchett D, Wulff K, Oliver PL, Bannerman DM, Davies KE, Harrison PJ, et al. Evaluating the links between schizophrenia and sleep and circadian rhythm disruption. J Neural Transm. 2012;119:1061–75.

26. Apiquian R, Frésan A, Munos-Delgado J, Kiang M, Ulloa RE, Kapur S. Variations of rest-activity rhythms and sleep-wake in schizophrenic patients versus healthy subjects: An actigraphic comparative study. In: Biological Rhythm Research, vol. 39. 2008. p. 69–78.

27. Cohrs S. Sleep disturbances in patients with schizophrenia: impact and effect of antipsychotics. CNS Drugs. 2008;22:939–62.

28. Krystal AD, Goforth HW, Roth T. Effects of antipsychotic medications on sleep in schizophrenia. Int Clin Psychopharmacol. 2008;23:150–60.