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 Table of Contents  
DR. AK KALA AWARD PAPER
Year : 2019  |  Volume : 24  |  Issue : 2  |  Page : 78-84

Effectiveness of melatonin in the management of delirium: A retrospective study


Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication22-Jul-2020

Correspondence Address:
Sandeep Grover
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmhhb.jmhhb_56_19

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  Abstract 


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 2020 Sep 26];24:78-84. Available from: http://www.jmhhb.org/text.asp?2019/24/2/78/290520




  Introduction Top


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.[1] It is known to be associated with increased mortality,[2],[3] longer duration of hospital stay,[4],[5] poor functionality,[5] higher treatment cost,[4],[5],[6] cognitive decline and increased risk of developing dementia,[7] significant distress due to symptoms of delirium among patients after recovery,[8],[9] significant distress and features of posttraumatic stress disorder after symptom resolution,[10] significant distress among the caregivers taking care of the patients during the experience of delirium,[10] and increased postdischarge sleep disturbances.[11] Besides the cognitive and noncognitive symptoms, sleep disturbance is considered as an important symptom of delirium.[12] Further, sleep disturbance is also understood as a precipitating factor for delirium.[13] Sleep disturbances in delirium include sleep fragmentation with poor nighttime sleep with frequent short naps during the day and overall poor quality of sleep.[14] 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.[15] 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.[16],[17],[18],[19] Studies that have evaluated melatonin levels among patients with delirium suggest that there is alteration in melatonin secretion among patients undergoing surgeries.[20],[21],[22],[23]
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,[24],[25],[26] whereas others suggest that it may be of some benefit.[27],[28],[29],[30] 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.[31] 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 Top


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.[32] 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)[33] version and Mini-Mental State Examination (MMSE)[34] 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.

Analysis

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 Top


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].
Table 2: Efficacy of haloperidol, quetiapine, and melatonin

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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 Top


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.[31] Another review of literature published in 2015 included three case reports evaluating the role of melatonin in patients with delirium.[35] A review published in 2018 concluded that there is no RCT, evaluating the role of melatonin in established delirium.[31] 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.[30] 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.[36],[37] 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.[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47]

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 Top


The present study suggests that melatonin is as effective as haloperidol and quetiapine in the management of delirium.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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