Opinion Editorial
REFERENCES 1. Sarrazin S, Poupon C, Linke J, et al. A multicenter tractography study of deep white matter tracts in bipolar I disorder: psychotic features and interhemispheric disconnectivity [published online February 12, 2014]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2013.4513.
4. Linke J, King AV, Poupon C, Hennerici MG, Gass A, Wessa M. Impaired anatomical connectivity and related executive functions: differentiating vulnerability and disease marker in bipolar disorder. Biol Psychiatry. 2013;74(12):908-916.
2. Mahon K, Burdick KE, Ikuta T, et al. Abnormal temporal lobe white matter as a biomarker for genetic risk of bipolar disorder. Biol Psychiatry. 2013;73(2):177-182.
5. Versace A, Andreazza AC, Young LT, et al. Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder [published online January 29, 2013]. Mol Psychiatry. doi:10.1038/mp.2012.188.
3. Pettigrew JD, Miller SMA. A ‘sticky’ interhemispheric switch in bipolar disorder? Proc Biol Sci. 1998;265(1411):2141-2148.
6. Braskie MN, Kohannim O, Jahanshad N, et al. Relation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in
healthy young adults. Neuroimage. 2013;82:146-153. 7. Bhatia KD, Henderson L, Ramsey-Stewart G, May J. Diffusion tensor imaging to aid subgenual cingulum target selection for deep brain stimulation in depression. Stereotact Funct Neurosurg. 2012;90(4):225-232.
Melatonin Prophylaxis in Delirium Panacea or Paradigm Shift? Sophia E. de Rooij, MD, PhD; Barbara C. van Munster, MD, PhD; Annemarieke de Jonghe, MD
Delirium is a common neuropsychiatric syndrome, especially in patients with preexistent cognitive impairment. Delirium is often precipitated by an acute infection, an operation, or an intensive care unit (ICU) stay and is Related article page 397 associated with premorbid conditions, such as cerebral infarction, dementia, and genetic predisposition. The syndrome manifests itself in up to 50% of elderly hospitalized inpatients, with higher frequencies reported for ICU patients. Delirium is independently associated with increased mortality, impaired physical and cognitive recovery, and increased hospital costs. Although patients usually recover from delirium after resolution of the underlying condition, delirium seems to be an important risk factor for dementia, even in persons w ithout prior cognitive impairment.1 Despite these adverse sequelae, the pathogenesis of delirium is still incompletely understood, although both stress hormones and proinflammatory cytokines have been shown to affect aspects of mental function, such as attention, memory, and perception.2,3 The diagnostic criteria for delirium described in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the International Classification of Diseases, 10th Revision include the core features of disturbance of consciousness, change in cognition or perceptual disturbance, onset ranging from hours to days, and a tendency for symptoms to fluctuate; this fluctuation is often accompanied by a disturbance in the circadian day-night rhythm.4 Management of delirium begins with treatment of the underlying illness. To control symptoms such as agitation and hallucination, antipsychotic medication, with sedative effects, are often used. However, antipsychotics can lead to prolonged QT intervals and extrapyramidal symptoms and an increased risk of fatal cardiovascular incidents, especially in patients with dementia. In addition, the disturbed circadian rhythm itself is unresponsive to antipsychotics. 364
Melatonin, a pineal gland hormone, secreted in response to evening darkness, promotes the onset of sleep. Along with the superchiasmatic nucleus, melatonin synchronizes the circadian rhythm that regulates the sleep-wake cycle. The pineal gland is located centrally in the brain but outside the blood-brain barrier. Thus, peripheral influences, such as infections, cytokines, or drugs, may disrupt its function. Low melatonin concentrations have been found in diverse conditions associated with delirium, including surgery and sleep deprivation in ICU patients.5,6 These findings suggest a relationship between abnormal melatonin secretion and postoperative delirium. Although it has been hypothesized that exogenous administration of melatonin might treat delirium, clinical evidence linking melatonin treatment with reduced severity of delirium symptoms in elderly patients is limited. In a small randomized clinical trial, melatonin supplementation seemed effective in restoring normal circadian rhythms in ICU patients.7 A systematic review,4 which included 4 randomized clinical trials and 5 case series comprising 330 patients with dementia, showed that 7 of 9 studies found a clear reduction in circadian disturbances in patients receiving melatonin. Given the severity of the sequelae of delirium, strategies are needed to prevent the development of delirium in vulnerable patients. Two recent clinical trials have shown that lowdose melatonin administered nightly to medical or elective surgical patients was effective in decreasing the incidence of delirium.8,9 Moreover, melatonin was well tolerated in these populations of acutely ill patients with multiple comorbid conditions. These 2 trials were the first randomized trials with findings suggesting that a pharmacologic intervention may decrease the incidence of delirium.8,9 Melatonin is categorized by the US Food and Drug Administration as a dietary supplement, not as a drug. A prescriptiononly, timed-release melatonin product (Circadin) was approved for use by the European Medicines Agency in 2007. Interestingly, melatonin supplements are associated with large
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Copyright 2014 American Medical Association. All rights reserved.
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Editorial Opinion
variations in effective doses and serum concentrations (S. E. d. R, B. C. v. M., and A. d. J., unpublished data, 2013). This partly has to do with the fact that melatonin is not a regulated drug but a natural product, which can vary in purity and integrity. For example, melatonin doses of 3, 5 and 10 mg, respectively, were administered in the studies by Bourne et al,7 Al-Aama et al,8 and Sultan.9 During the past decade, many strategies for preventing delirium in ICU patients have been investigated, including antipsychotics, benzodiazepines, and cholinesterase inhibitors, all with varying results. However, the study by Hatta et al10 reported in this issue is the first to show a significant prophylactic effect on the incidence of delirium in elderly ICU patients treated with ramelteon. A melatonin receptor agonist, ramelteon was approved by the US Food and Drug Administration in 2005 for treatment of insomnia in adults, characterized as difficulty in falling asleep. Ramelteon activates 2 of the ARTICLE INFORMATION Author Affiliations: Section of Geriatrics, Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands (de Rooij, van Munster, de Jonghe); Department of Geriatrics, Gelre Hospitals, Apeldoorn, the Netherlands (van Munster). Corresponding Author: Sophia E. de Rooij, MD, PhD, Section of Geriatrics, Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, PO Box 22660, Room F4-159, 1100 DD Amsterdam, the Netherlands ([email protected]). Published Online: February 19, 2014. doi:10.1001/jamapsychiatry.2013.4532. Conflict of Interest Disclosures: None reported. REFERENCES 1. Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367(1):30-39.
3 melatonin receptors, melatonin receptors 1 and 2, and causes numerous physiologic processes, similar to the effects of melatonin. To our knowledge, no published studies have demonstrated whether ramelteon in humans is more or less safe or effective than melatonin. Thus, melatonin and ramelteon prevent delirium in acutely ill medical, elective surgical, and ICU patients.8-10 It remains to be demonstrated whether this strategy is effective in other high-risk populations, such as patients with dementia or elderly patients undergoing hip surgery. Nevertheless, additional randomized clinical trials with more participants, using more physiologic doses of melatonin and controlling such environmental variables as light and noise, are required. Other issues that remain to be addressed are the pathophysiologic mechanisms responsible for the development of delirium and the effects of melatonin and/or melatonin receptor agonists on the long-term sequelae of delirium.
2. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res. 2008;65(3):229-238. 3. Cunningham C, Campion S, Lunnon K, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry. 2009;65(4):304-312. 4. de Jonghe A, Korevaar JC, van Munster BC, de Rooij SE. Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia: are there implications for delirium? a systematic review. Int J Geriatr Psychiatry. 2010;25(12):1201-1208. 5. Shilo L, Dagan Y, Smorjik Y, et al. Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int. 2000;17(1):71-76. 6. Cronin AJ, Keifer JC, Davies MF, King TS, Bixler EO. Melatonin secretion after surgery. Lancet. 2000;356(9237):1244-1245.
jamapsychiatry.com
7. Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care. 2008;12(2):R52. doi:10.1186/cc6871. 8. Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011;26(7):687-694. 9. Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010;4(3):169-173. 10. Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial [published online February 19, 2014]. JAMA Psychiatry. doi:10.1001 /jamapsychiatry.2013.3320.
JAMA Psychiatry April 2014 Volume 71, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Auckland User on 05/16/2015
365
REFERENCES 1. Sarrazin S, Poupon C, Linke J, et al. A multicenter tractography study of deep white matter tracts in bipolar I disorder: psychotic features and interhemispheric disconnectivity [published online February 12, 2014]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2013.4513.
4. Linke J, King AV, Poupon C, Hennerici MG, Gass A, Wessa M. Impaired anatomical connectivity and related executive functions: differentiating vulnerability and disease marker in bipolar disorder. Biol Psychiatry. 2013;74(12):908-916.
2. Mahon K, Burdick KE, Ikuta T, et al. Abnormal temporal lobe white matter as a biomarker for genetic risk of bipolar disorder. Biol Psychiatry. 2013;73(2):177-182.
5. Versace A, Andreazza AC, Young LT, et al. Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder [published online January 29, 2013]. Mol Psychiatry. doi:10.1038/mp.2012.188.
3. Pettigrew JD, Miller SMA. A ‘sticky’ interhemispheric switch in bipolar disorder? Proc Biol Sci. 1998;265(1411):2141-2148.
6. Braskie MN, Kohannim O, Jahanshad N, et al. Relation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in
healthy young adults. Neuroimage. 2013;82:146-153. 7. Bhatia KD, Henderson L, Ramsey-Stewart G, May J. Diffusion tensor imaging to aid subgenual cingulum target selection for deep brain stimulation in depression. Stereotact Funct Neurosurg. 2012;90(4):225-232.
Melatonin Prophylaxis in Delirium Panacea or Paradigm Shift? Sophia E. de Rooij, MD, PhD; Barbara C. van Munster, MD, PhD; Annemarieke de Jonghe, MD
Delirium is a common neuropsychiatric syndrome, especially in patients with preexistent cognitive impairment. Delirium is often precipitated by an acute infection, an operation, or an intensive care unit (ICU) stay and is Related article page 397 associated with premorbid conditions, such as cerebral infarction, dementia, and genetic predisposition. The syndrome manifests itself in up to 50% of elderly hospitalized inpatients, with higher frequencies reported for ICU patients. Delirium is independently associated with increased mortality, impaired physical and cognitive recovery, and increased hospital costs. Although patients usually recover from delirium after resolution of the underlying condition, delirium seems to be an important risk factor for dementia, even in persons w ithout prior cognitive impairment.1 Despite these adverse sequelae, the pathogenesis of delirium is still incompletely understood, although both stress hormones and proinflammatory cytokines have been shown to affect aspects of mental function, such as attention, memory, and perception.2,3 The diagnostic criteria for delirium described in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the International Classification of Diseases, 10th Revision include the core features of disturbance of consciousness, change in cognition or perceptual disturbance, onset ranging from hours to days, and a tendency for symptoms to fluctuate; this fluctuation is often accompanied by a disturbance in the circadian day-night rhythm.4 Management of delirium begins with treatment of the underlying illness. To control symptoms such as agitation and hallucination, antipsychotic medication, with sedative effects, are often used. However, antipsychotics can lead to prolonged QT intervals and extrapyramidal symptoms and an increased risk of fatal cardiovascular incidents, especially in patients with dementia. In addition, the disturbed circadian rhythm itself is unresponsive to antipsychotics. 364
Melatonin, a pineal gland hormone, secreted in response to evening darkness, promotes the onset of sleep. Along with the superchiasmatic nucleus, melatonin synchronizes the circadian rhythm that regulates the sleep-wake cycle. The pineal gland is located centrally in the brain but outside the blood-brain barrier. Thus, peripheral influences, such as infections, cytokines, or drugs, may disrupt its function. Low melatonin concentrations have been found in diverse conditions associated with delirium, including surgery and sleep deprivation in ICU patients.5,6 These findings suggest a relationship between abnormal melatonin secretion and postoperative delirium. Although it has been hypothesized that exogenous administration of melatonin might treat delirium, clinical evidence linking melatonin treatment with reduced severity of delirium symptoms in elderly patients is limited. In a small randomized clinical trial, melatonin supplementation seemed effective in restoring normal circadian rhythms in ICU patients.7 A systematic review,4 which included 4 randomized clinical trials and 5 case series comprising 330 patients with dementia, showed that 7 of 9 studies found a clear reduction in circadian disturbances in patients receiving melatonin. Given the severity of the sequelae of delirium, strategies are needed to prevent the development of delirium in vulnerable patients. Two recent clinical trials have shown that lowdose melatonin administered nightly to medical or elective surgical patients was effective in decreasing the incidence of delirium.8,9 Moreover, melatonin was well tolerated in these populations of acutely ill patients with multiple comorbid conditions. These 2 trials were the first randomized trials with findings suggesting that a pharmacologic intervention may decrease the incidence of delirium.8,9 Melatonin is categorized by the US Food and Drug Administration as a dietary supplement, not as a drug. A prescriptiononly, timed-release melatonin product (Circadin) was approved for use by the European Medicines Agency in 2007. Interestingly, melatonin supplements are associated with large
JAMA Psychiatry April 2014 Volume 71, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Auckland User on 05/16/2015
jamapsychiatry.com
Editorial Opinion
variations in effective doses and serum concentrations (S. E. d. R, B. C. v. M., and A. d. J., unpublished data, 2013). This partly has to do with the fact that melatonin is not a regulated drug but a natural product, which can vary in purity and integrity. For example, melatonin doses of 3, 5 and 10 mg, respectively, were administered in the studies by Bourne et al,7 Al-Aama et al,8 and Sultan.9 During the past decade, many strategies for preventing delirium in ICU patients have been investigated, including antipsychotics, benzodiazepines, and cholinesterase inhibitors, all with varying results. However, the study by Hatta et al10 reported in this issue is the first to show a significant prophylactic effect on the incidence of delirium in elderly ICU patients treated with ramelteon. A melatonin receptor agonist, ramelteon was approved by the US Food and Drug Administration in 2005 for treatment of insomnia in adults, characterized as difficulty in falling asleep. Ramelteon activates 2 of the ARTICLE INFORMATION Author Affiliations: Section of Geriatrics, Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands (de Rooij, van Munster, de Jonghe); Department of Geriatrics, Gelre Hospitals, Apeldoorn, the Netherlands (van Munster). Corresponding Author: Sophia E. de Rooij, MD, PhD, Section of Geriatrics, Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, PO Box 22660, Room F4-159, 1100 DD Amsterdam, the Netherlands ([email protected]). Published Online: February 19, 2014. doi:10.1001/jamapsychiatry.2013.4532. Conflict of Interest Disclosures: None reported. REFERENCES 1. Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367(1):30-39.
3 melatonin receptors, melatonin receptors 1 and 2, and causes numerous physiologic processes, similar to the effects of melatonin. To our knowledge, no published studies have demonstrated whether ramelteon in humans is more or less safe or effective than melatonin. Thus, melatonin and ramelteon prevent delirium in acutely ill medical, elective surgical, and ICU patients.8-10 It remains to be demonstrated whether this strategy is effective in other high-risk populations, such as patients with dementia or elderly patients undergoing hip surgery. Nevertheless, additional randomized clinical trials with more participants, using more physiologic doses of melatonin and controlling such environmental variables as light and noise, are required. Other issues that remain to be addressed are the pathophysiologic mechanisms responsible for the development of delirium and the effects of melatonin and/or melatonin receptor agonists on the long-term sequelae of delirium.
2. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res. 2008;65(3):229-238. 3. Cunningham C, Campion S, Lunnon K, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry. 2009;65(4):304-312. 4. de Jonghe A, Korevaar JC, van Munster BC, de Rooij SE. Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia: are there implications for delirium? a systematic review. Int J Geriatr Psychiatry. 2010;25(12):1201-1208. 5. Shilo L, Dagan Y, Smorjik Y, et al. Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int. 2000;17(1):71-76. 6. Cronin AJ, Keifer JC, Davies MF, King TS, Bixler EO. Melatonin secretion after surgery. Lancet. 2000;356(9237):1244-1245.
jamapsychiatry.com
7. Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care. 2008;12(2):R52. doi:10.1186/cc6871. 8. Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011;26(7):687-694. 9. Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010;4(3):169-173. 10. Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial [published online February 19, 2014]. JAMA Psychiatry. doi:10.1001 /jamapsychiatry.2013.3320.
JAMA Psychiatry April 2014 Volume 71, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Auckland User on 05/16/2015
365
