|DR. AK KALA AWARD PAPER
|Year : 2019 | Volume
| Issue : 2 | Page : 78-84
Effectiveness of melatonin in the management of delirium: A retrospective study
Sandeep Grover, Devakshi Dua, Swapnajeet Sahoo, Subho Chakrabarti, Ajit Avasthi
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||22-Jul-2020|
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Background: Melatonin, a naturally occurring endogenous hormone, primarily secreted by the pineal gland plays a key role in managing multiple bodily functions which are affected among patients with delirium. In view of the same, exogenous melatonin has been evaluated in the prevention and management of delirium. Compared to the data on role of melatonin in prevention of delirium, data on the management of delirium are limited. Aim: To evaluate the effectiveness of melatonin in patients with delirium and to compare the same with haloperidol and quetiapine. Materials and Methods: Using retrospective study design, data of patients diagnosed with delirium as per the Diagnostic and Statistical Manual, 5th Revision criteria, and rated on Delirium Rating Scale-Revised 98 version at the baseline and 6 consecutive days. Results: The study included 108 patients, of whom 34 were on melatonin, 31 were on quetiapine, and 43 were on haloperidol. Findings of the present study show that melatonin is as effective as haloperidol and quetiapine in the management of delirium. Patients required 1.5–6 mg/day of melatonin, administered during the evening time. Melatonin was mostly used in patients who had prolonged QTc interval, which precluded the use of antipsychotics. Conclusion: The present study suggests that melatonin may be another pharmacological treatment option for the management of delirium, especially among patients with prolonged QTc interval.
Keywords: Delirium, effectiveness, melatonin
|How to cite this article:|
Grover S, Dua D, Sahoo S, Chakrabarti S, Avasthi A. Effectiveness of melatonin in the management of delirium: A retrospective study. J Mental Health Hum Behav 2019;24:78-84
|How to cite this URL:|
Grover S, Dua D, Sahoo S, Chakrabarti S, Avasthi A. Effectiveness of melatonin in the management of delirium: A retrospective study. J Mental Health Hum Behav [serial online] 2019 [cited 2022 Sep 25];24:78-84. Available from: https://www.jmhhb.org/text.asp?2019/24/2/78/290520
| Introduction|| |
One of the important complications of severe physical illnesses includes delirium, which is understood as an acute-onset neuropsychiatric condition, is often considered to have a fluctuating course, and is reversible and short-lasting. It is known to be associated with increased mortality,, longer duration of hospital stay,, poor functionality, higher treatment cost,,, cognitive decline and increased risk of developing dementia, significant distress due to symptoms of delirium among patients after recovery,, significant distress and features of posttraumatic stress disorder after symptom resolution, significant distress among the caregivers taking care of the patients during the experience of delirium, and increased postdischarge sleep disturbances. Besides the cognitive and noncognitive symptoms, sleep disturbance is considered as an important symptom of delirium. Further, sleep disturbance is also understood as a precipitating factor for delirium. Sleep disturbances in delirium include sleep fragmentation with poor nighttime sleep with frequent short naps during the day and overall poor quality of sleep. Accordingly, it can be said that sleep disturbance is a precipitating factor, symptom, and outcome of delirium.
The co-occurrence of sleep disturbance and delirium in hospitalized patients, especially those admitted to intensive care units (ICUs), is often attributed to common pathophysiological pathways and a potential cause–effect relationship. Among the various etiological models/hypotheses of delirium, diurnal dysregulation or melatonin dysregulation is one of the important hypotheses, which is based on alteration in the sleep physiology among the medically ill patients as a cause of delirium. Accordingly, to this hypothesis, among the medically ill patients, 24-h circadian rhythm cycle is disrupted along with the alteration in the various stages of sleep. As a result of this, normal sleep integrity and physiological sleep architecture are disturbed. Various factors that have been linked with poor sleep in medically ill patients include severity of the critical illness, ambient noise, exposure to artificial light, pain, use of multiple medications, and use of mechanical ventilation.,,, Studies that have evaluated melatonin levels among patients with delirium suggest that there is alteration in melatonin secretion among patients undergoing surgeries.,,,
|Figure 1: Significant difference between haloperidol and melatonin (P < 0.05)|
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From the sleep perspective, earlier, it was believed that sedation was beneficial in preventing delirium. However, with time, it has been realized that not only total sleep duration is important, but the preservation of sleep architecture is also important from the perspective of prevention and management of delirium. Accordingly, it is hypothesized that melatonin, which has an important role in regulating circadian rhythm, may be of some benefit in preventing and managing delirium. Further, melatonin is considered to have a benign side effect profile and is considered to have no influence on QTc interval. Due to this, it can be considered as a safer option among patients with prolonged QTc interval.
Available data are inconclusive for the role of melatonin in the prevention of delirium, with some of the studies reporting no therapeutic benefit with melatonin, when compared to placebo,,, whereas others suggest that it may be of some benefit.,,, Few studies, which have evaluated the efficacy/effectiveness of melatonin and ramelteon in the management of delirium, suggest that the use of these agents is associated with reduction in severity of delirium and reduction in agitation. However, all the available studies are limited to small sample size and there are no randomized controlled trials (RCTs), which have evaluated the role of melatonin in the management of delirium. Accordingly, there is a need to expand this literature. In this background, this retrospective study aimed to evaluate the effectiveness of exogenous melatonin in the management of delirium. Additional aim of the study was to compare the effectiveness of melatonin with haloperidol and quetiapine and evaluate the differential effect of melatonin in adult and elderly patients.
| Materials and Methods|| |
This retrospective study was conducted at a tertiary care multispecialty hospital where there are a lot of cross-referrals to the Consultation-Liaison Psychiatry (CLP) team from various medical and surgical wards and ICUs. Delirium forms the most common psychiatric diagnosis among all the referrals received. In the CLP setting, the diagnosis of delirium is made on the basis of Diagnostic and Statistical Manual, 5th Revision (DSM-5). Initially, any patient referred to CLP team is evaluated by a trainee psychiatry resident, under the supervision of a senior resident (a trained psychiatrist, equivalent of the registrar). After the detailed workup, the case is discussed with the consultant in-charge and the final diagnosis is made. All the patients diagnosed with delirium are usually followed up on a daily basis and are rated on Delirium Rating Scale-Revised-98 (DRS-R98) version and Mini-Mental State Examination (MMSE) for about a week, or longer if delirium does not resolve during this time frame. Besides the use of pharmacological agents, the management of patients with delirium involves providing support and orientation, providing unambiguous environment, measures at maintaining competence and providing other supportive measures. Data of all the patients are entered into the CLP register, and the data are verified once weekly for the accuracy.
For this retrospective study, CLP register was screened for all the patients diagnosed with delirium, during the study period of October 2017–March 2019 for starting of melatonin. Treatment records of all the patients diagnosed with delirium and started on melatonin, for whom rating for DRS-98 and MMSE for baseline and 6 consecutive days was available, were selected. In addition, for the control group, age, gender, and baseline severity of delirium matched patients treated with haloperidol and quetiapine were also selected if the data for DRS-98 and MMSE for baseline and 6 consecutive days were available. Demographic data, clinical data, scores on DRS-98, and MMSE for baseline and 6 consecutive days were also extracted.
Data were analyzed using SPSS-14. Mean, standard deviation (SD), frequency, and percentages were calculated. Comparisons were done using unpaired t-test, Chi-square test, paired t-test, and one-way ANOVA. Besides using paired t-test, repeated-measure ANOVA was used to evaluate the effectiveness of each pharmacological agent.
| Results|| |
The study included 108 patients, of whom 34 were managed with melatonin, 31 were managed with quetiapine only, and 43 patients received haloperidol [Table 1]. The mean age of all the three groups was slightly more than 50 years, and the majority of the patients were of nonelderly (<65) age. In all three groups, close to two-thirds of the subjects were males. There was no significant difference between the three groups in terms of age, proportion of patients in the elderly age group, and gender [Table 1]. In terms of clinical variables, compared to haloperidol group, significantly higher proportion of the patients in the melatonin and quetiapine group had hospital emergent delirium [Table 1]. Further, in terms of duration of delirium, before baseline assessment, compared to those managed with quetiapine, the duration of delirium was significantly longer among those who were managed with melatonin. The mean dose of haloperidol used for the management of delirium was 0.64 (SD: 0.35; range: 0.25–1.25) mg/day, whereas the same for quetiapine was 23.38 (SD: 8.38; range: 12.5–37.5) mg/day and 3.57 (1.43; range: 1.5–6) mg/day for melatonin.
|Table 1: Comparison of demographic, clinical, Delirium Rating Scale-revised-98, and mini-mental state examination profile|
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It was seen that melatonin was mostly used in patients who had prolonged QTc interval.
The mean DRS-R-98 total score at the baseline was slightly more than 30 in all the three groups, and there was no significant difference between the three groups in terms of DRS-R-98 severity score from baseline to all the 6 consecutive days, except for the significant difference in the DRS-R-98 severity scores, between haloperidol and melatonin group for day 2, 4, and 5, with all the scores, significantly higher for the haloperidol group [Table 1]. In terms of clinical remission, as indicated by DRS-R-98 severity score of <10, there was no significant difference in number of patients in all the three groups from baseline to day 6, except for the fact that on day 5 and 6, significantly higher proportion of patients in the quetiapine group achieved remission. In terms of total MMSE scores, all the three groups did not differ significantly at the baseline assessment and assessments on all the 6 days [Table 1].
Effectiveness of all three agents was evaluated by comparing the rating of baseline, with rating on subsequent 6 days, using paired t-test and repeated-measure ANOVA test. As is evident from [Table 2], with respect to t-test values, for both DRS-R-98 and MMSE, there was significant improvement in all the three groups from day 1 itself, and the same persisted till the day 6. There was significant improvement in symptoms from day 3 to day 6 also [Table 2].
Efficacy was also evaluated separately for the adult and elderly patients (i.e., age ≥ 65 years). All the three medications led to significant improvement in the DRS-R-98 and MMSE scores in the adult and elderly group, except for lack of significant improvement in DRS-R-98 from baseline to day 1 in the melatonin group among the elderly, MMSE scores from baseline to day 1 in the quetiapine group among the elderly, and MMSE scores from baseline to day 1 in the quetiapine group among the elderly from baseline to day 1 to through day 4.
When repeated-measure ANOVA was used to analyze the data, Mauchly's test was significant for all three groups (P < 0.001), indicating that there was violation of sphericity. As the eta values were more than 0.75, Huynh-Feldt correction was used. After the correction, the F-value was still significant for all the three groups for reduction in the DRS-R-98 scores. Similarly, for the MMSE scores too, Mauchly's test was significant for all the three groups (P < 0.001). For the haloperidol group, the eta values were <0.75, whereas the same was more than 0.75, for the other two groups. As a result, for haloperidol group, Greenhouse–Geisser correction was used, and for the other two groups, Huynh-Feldt correction was used. The F values for all the three groups were significant after the required corrections [Table 2].
Further, to evaluate the effect of covariates, we included age, gender, duration of delirium before starting of medication, onset of delirium (hospital emergent/onset before admission), and the dose of medication used as between-subject factor. It was seen that in the haloperidol group, all the variables had significant impact on the effectiveness both in terms of MMSE score and DRS-R-98 scores, except for the fact that gender had no influence on DRS-R-98 scores. However, in the quetiapine group, none of these variables had any significant effect on MMSE and DRS-R-98 scores, except for significant influence of onset of delirium (hospital emergent/onset before admission) on DRS-R-98 score.
In the melatonin group, age and gender did not have any significant effect, whereas duration of delirium before starting of medication, onset of delirium (hospital emergent/onset before admission), and the dose of medication had significant influence on the effectiveness both in terms of DRS-R-98 and MMSE score.
| Discussion|| |
At present, although there are reasonable amount of data evaluating the role of melatonin and ramelteon in the prevention of delirium, there is limited information on the role of melatonin in the management of delirium. Another review of literature published in 2015 included three case reports evaluating the role of melatonin in patients with delirium. A review published in 2018 concluded that there is no RCT, evaluating the role of melatonin in established delirium. In their review, the authors reported only one case report in which use of slow-release formulation of melatonin in the dose of 2 mg led to improvement in delirium. Hence, there is a need to expand this literature. Accordingly, it can be said that the present study, although not an RCT, still expands the available literature on effectiveness of melatonin in patients with established delirium.
This retrospective study attempted to compare the effectiveness of melatonin with haloperidol and quetiapine among patients diagnosed with delirium as per the DSM-5 criteria, seen in the CLP setting. The effectiveness was evaluated using standard scales for evaluating the effectiveness of medications in patients with delirium. The three groups did not differ significantly in terms of age, gender, duration of delirium before baseline assessment, and baseline DRS-98 total and severity score, suggesting that any difference in effectiveness seen between the groups in the present study cannot be attributed to these variables. Compared to haloperidol group, significantly higher proportion of the patients in the other two groups had hospital emergent delirium. Further, the demographic and clinical profile of the study participants is similar to the participants in previous RCTs, which evaluated the effectiveness of atypical antipsychotics from this center., The doses of haloperidol and quetiapine used in the present study were also similar to the doses used in previous RCTs from this center. These findings suggest that the study sample included in the present study was representative of the patients of delirium, seen in CLP setting.
Findings of the present study suggest that melatonin is as effective as haloperidol and quetiapine in the management of delirium. When the data were separately analyzed for adult and elderly groups, all the three medications led to significant improvement in the DRS-R-98 scores in both the adult and the elderly patients. Significant improvement was seen in the MMSE in adult patients in all the three medication groups, but in the elderly, significant improvement was noted only in the quetiapine and the haloperidol group. In the melatonin group, significant improvement in the MMSE score was observed only by day 4.
Antipsychotics are considered as the preferred pharmacological agents in patients with delirium. However, a major concern with use of antipsychotics in patients with delirium is QTc prolongation. Melatonin is a naturally occurring hormone, which is not known to be associated with QTc prolongation. Equal effectiveness of melatonin and antipsychotics, as seen in the present study, suggests that melatonin may be a good alternative for the management of delirium.
Equal effectiveness of haloperidol and quetiapine in the present study lends support to the existing literature, which indicates that quetiapine is efficacious in the management of delirium.,,,,,,,,,,
Findings of the present study must be interpreted in light of its limitations. The limitations of the present study include retrospective study design, small sample size, evaluation of data of mixed adult and elderly patient group, and use of heterogeneous study sample referred to CLP team, rather than taking sample from one treatment setting. Further, the present study did not evaluate the side effects of medications. Future studies must attempt to carry out an RCT, with larger sample size.
| Conclusion|| |
The present study suggests that melatonin is as effective as haloperidol and quetiapine in the management of delirium.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mattoo SK, Grover S, Gupta N. Delirium in general practice. Indian J Med Res 2010;131:387-98.
] [Full text]
Grover S, Ghormode D, Ghosh A, Avasthi A, Chakrabarti S, Mattoo SK, et al
. Risk factors for delirium and inpatient mortality with delirium. J Postgrad Med 2013;59:263-70.
] [Full text]
Sharma A, Malhotra S, Grover S, Jindal SK. Incidence, prevalence, risk factor and outcome of delirium in intensive care unit: A study from India. Gen Hosp Psychiatry 2012;34:639-46.
van den Boogaard M, Schoonhoven L, van der Hoeven JG, van Achterberg T, Pickkers P. Incidence and short-term consequences of delirium in critically ill patients: A prospective observational cohort study. Int J Nurs Stud 2012;49:775-83.
Maldonado JR. Acute brain failure: Pathophysiology, diagnosis, management, and sequelae of delirium. Crit Care Clin 2017;33:461-519.
Leslie DL, Inouye SK. The importance of delirium: Economic and societal costs. J Am Geriatr Soc 2011;59 Suppl 2:S241-3.
Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: A meta-analysis. JAMA 2010;304:443-51.
Grover S, Shah R. Distress due to delirium experience. Gen Hosp Psychiatry 2011;33:637-9.
Grover S, Ghosh A, Ghormode D. Experience in delirium: Is it distressing? J Neuropsychiatry Clin Neurosci 2015;27:139-46.
O'Malley G, Leonard M, Meagher D, O'Keeffe ST. The delirium experience: A review. J Psychosom Res 2008;65:223-8.
Altman MT, Knauert MP, Murphy TE, Ahasic AM, Chauhan Z, Pisani MA. Association of intensive care unit delirium with sleep disturbance and functional disability after critical illness: An observational cohort study. Ann Intensive Care 2018;8:63.
Figueroa-Ramos MI, Arroyo-Novoa CM, Lee KA, Padilla G, Puntillo KA. Sleep and delirium in ICU patients: A review of mechanisms and manifestations. Intensive Care Med 2009;35:781-95.
Weinhouse GL, Schwab RJ, Watson PL, Patil N, Vaccaro B, Pandharipande P, et al
. Bench-to-bedside review: Delirium in ICU patients – Importance of sleep deprivation. Crit Care 2009;13:234.
Freedman NS, Gazendam J, Levan L, Pack AI, Schwab RJ. Abnormal sleep/wake cycles and the effect of environmental noise on sleep disruption in the intensive care unit. Am J Respir Crit Care Med 2001;163:451-7.
Maldonado JR. Neuropathogenesis of delirium: Review of current etiologic theories and common pathways. Am J Geriatr Psychiatry 2013;21:1190-222.
Parthasarathy S, Tobin MJ. Effect of ventilator mode on sleep quality in critically ill patients. Am J Respir Crit Care Med 2002;166:1423-9.
Delisle S, Ouellet P, Bellemare P, Tétrault JP, Arsenault P. Sleep quality in mechanically ventilated patients: Comparison between NAVA and PSV modes. Ann Intensive Care 2011;1:42.
Bihari S, Doug McEvoy R, Matheson E, Kim S, Woodman RJ, Bersten AD. Factors affecting sleep quality of patients in intensive care unit. J Clin Sleep Med 2012;8:301-7.
Alexopoulou C, Kondili E, Plataki M, Georgopoulos D. Patient-ventilator synchrony and sleep quality with proportional assist and pressure support ventilation. Intensive Care Med 2013;39:1040-7.
Monteleone P, Forziati D, Orazzo C, Maj M. Preliminary observations on the suppression of nocturnal plasma melatonin levels by short-term administration of diazepam in humans. J Pineal Res 1989;6:253-8.
Cronin AJ, Keifer JC, Davies MF, King TS, Bixler EO. Melatonin secretion after surgery. Lancet 2000;356:1244-5.
Guo X, Kuzumi E, Charman SC, Vuylsteke A. Perioperative melatonin secretion in patients undergoing coronary artery bypass grafting. Anesth Analg 2002;94:1085-91, table of contents.
Derenzo J, Macknight B, DiVittore NA, Bonafide CP, Cronin AJ. Postoperative elevated cortisol excretion is not associated with suppression of 6-sulfatoxymelatonin excretion. Acta Anaesthesiol Scand 2005;49:52-7.
Abbasi S, Farsaei S, Ghasemi D, Mansourian M. Potential role of exogenous melatonin supplement in delirium prevention in critically ill patients: A double-blind randomized pilot study. Iran J Pharm Res 2018;17:1571-80.
de Jonghe A, van Munster BC, Goslings JC, Kloen P, van Rees C, Wolvius R, et al
. Effect of melatonin on incidence of delirium among patients with hip fracture: A multicentre, double-blind randomized controlled trial. CMAJ 2014;186:E547-56.
Jaiswal SJ, McCarthy TJ, Wineinger NE, Kang DY, Song J, Garcia S, et al
. Melatonin and sleep in preventing hospitalized delirium: A randomized clinical trial. Am J Med 2018;131:1110-7.e4.
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;4:169-73.
] [Full text]
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;26:687-94.
Artemiou P, Bily B, Bilecova-Rabajdova M, Sabol F, Torok P, Kolarcik P, et al
. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients. Kardiochir Torakochirurgia Pol 2015;12:126-33.
Hanania M, Kitain E. Melatonin for treatment and prevention of postoperative delirium. Anesth Analg 2002;94:338-9.
Choy SW, Yeoh AC, Lee ZZ, Srikanth V, Moran C. Melatonin and the prevention and management of delirium: A scoping study. Front Med (Lausanne) 2017;4:242.
Grover S, Subodh BN, Avasthi A, Chakrabarti S, Kumar S, Sharan P, et al
. Prevalence and clinical profile of delirium: A study from a tertiary-care hospital in North India. Gen Hosp Psychiatry 2009;31:25-9.
Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the Delirium Rating Scale-revised-98: Comparison with the Delirium Rating Scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci 2001;13:229-42.
Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98.
Chakraborti D, Tampi DJ, Tampi RR. Melatonin and melatonin agonist for delirium in the elderly patients. Am J Alzheimers Dis Other Demen 2015;30:119-29.
Grover S, Kumar V, Chakrabarti S. Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium. J Psychosom Res 2011;71:277-81.
Grover S, Mahajan S, Chakrabarti S, Avasthi A. Comparative effectiveness of quetiapine and haloperidol in delirium: A single blind randomized controlled study. World J Psychiatry 2016;6:365-71.
Devlin JW, Roberts RJ, Fong JJ, Skrobik Y, Riker RR, Hill NS, et al
. Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 2010;38:419-27.
Devlin JW, Skrobik Y, Riker RR, Hinderleider E, Roberts RJ, Fong JJ, et al
. Impact of quetiapine on resolution of individual delirium symptoms in critically ill patients with delirium: A post-hoc
analysis of a double-blind, randomized, placebo-controlled study. Crit Care 2011;15:R215.
Kim KY, Bader GM, Kotlyar V, Gropper D. Treatment of delirium in older adults with quetiapine. J Geriatr Psychiatry Neurol 2003;16:29-31.
Lee KU, Won WY, Lee HK, Kweon YS, Lee CT, Pae CU, et al
. Amisulpride versus quetiapine for the treatment of delirium: A randomized, open prospective study. Int Clin Psychopharmacol 2005;20:311-4.
Maneeton B, Maneeton N, Srisurapanont M. An open-label study of quetiapine for delirium. J Med Assoc Thai 2007;90:2158-63.
Omura K, Amano N. Clinical experience of quetiapine in 24 elderly patients with delirium. Psychogeriatrics 2003;3:69-72.
Tahir TA, Eeles E, Karapareddy V, Muthuvelu P, Chapple S, Phillips B, et al
. A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. J Psychosom Res 2010;69:485-90.
Pae CU, Lee SJ, Lee CU, Lee C, Paik IH. A pilot trial of quetiapine for the treatment of patients with delirium. Hum Psychopharmacol 2004;19:125-7.
Sasaki Y, Matsuyama T, Inoue S, Sunami T, Inoue T, Denda K, et al
. A prospective, open-label, flexible-dose study of quetiapine in the treatment of delirium. J Clin Psychiatry 2003;64:1316-21.
Shinno H, Matsuoka T, Yamamoto O, Noma Y, Hikasa S, Takebayashi M, et al
. Successful treatment with quetiapine for delirium in terminally ill cancer patients. Psychogeriatrics 2007;7:64-8.
[Table 1], [Table 2]