Exploring psychotherapeutic issues and agents in clinical practice
Delirium is a complex neurobehavioral syndrome caused by dysregulation of baseline brain activity secondary to systemic disturbances (Maldonado, 2013). It is characterized by an alteration in the level of attention and awareness that develops over a short period of time and is seen as a change from the patient’s baseline. Nonpharmacological approaches are important for the prevention and management of delirium (Tabet & Howard, 2009). Pharmacotherapy has a role, but is more successful for preventing delirium than treating it (Friedman, Soleimani, McGonigle, Egol, & Silverstein, 2014). In this article, I will first briefly describe delirium and then discuss the use of melatonergic drugs for preventing delirium.
What Is Delirium?
The Confusion Assessment Method (CAM) is a simple and practical means for identifying delirium (Inouye et al., 1990). The diagnosis of delirium using the CAM requires evidence of (a) an acute onset and fluctuating course, (b) inattention, and either (c) disorganized thinking or (d) an altered level of consciousness. Delirium is most commonly seen in hospitalized older patients with pre-existing cognitive impairment (Inouye, Westendorp, & Saczynski, 2014), and it can be caused by a wide variety of medical and neurological factors (usually more than one factor is present). Many types of medications (including prescription and over-the-counter drugs) and treatment with multiple drugs are associated with a high risk of delirium. Delirium is more likely to be encountered in medical settings, such as nursing homes, emergency departments, and hospitals (especially postoperatively and in intensive care units), but can certainly occur in psychiatric settings. Dementia, depression, substance abuse, substance withdrawal, and psychotropic drug use are examples of known risk factors for delirium of which psychiatric nurses should be made aware. Patients with delirium have a worse prognosis, an increased risk of developing long-term cognitive and functional decline, and an elevated mortality rate. Awareness of delirium is important because it can be easily missed, and it may be better to prevent delirium than to treat it.
Melatonin and Delirium
The central internal (endogenous) circadian rhythm pacemaker (regulating such 24-hour biological cycles as endocrine function, body temperature, and sleep-wake cycle) is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light influences SCN function via a neural pathway from the retina to the SCN. A pathway also runs from the SCN to the pineal gland, where the synthesis and release of the hormone melatonin occurs. Carbohydrate intake stimulates the influx of the amino acid tryptophan into the brain relative to other amino acids. Tryptophan is synthesized into the neurotransmitter serotonin in the brain, and melatonin is synthesized from serotonin in the pineal gland. Melatonin secretion is regulated internally by the normal autonomous activity of the SCN and regulated externally by light exposure on the retina. Melatonin is effective for treating circadian rhythm sleep disturbances (e.g., associated with jet lag), but it is only modestly effective in the treatment of insomnia unrelated to circadian rhythm sleep disturbances (Pandi-Perumal, Srinivasan, Spence, & Cardinali, 2007).
Maldonado (2013) reviewed seven theories that have been proposed to explain the processes leading to the development of delirium. One theory is referred to as the diurnal dysregulation or melatonin dysregulation hypothesis, which suggests that disruptions to the 24-hour circadian cycle (including melatonin secretion and/or activity) and sleep stages may lead to direct and indirect physiological disturbances associated with delirium. The abnormal tryptophan metabolism model of delirium emphasizes the role of tryptophan as a precursor for serotonin and melatonin (Fitzgerald et al., 2013). Based on these physiological mechanisms, two controlled treatment studies have investigated the use of melatonin for preventing delirium (Al-Aama et al., 2011; Sultan, 2010). A third randomized, double-blind, placebo-controlled study is being conducted, but no results have been published (de Jonghe et al., 2011).
Sultan (2010) investigated the effect of three drugs, including melatonin, on the incidence of postoperative delirium after scheduled hip arthroplasty surgery in 222 older adults ages 65 and older. This randomized, double-blind, controlled study compared four premedication treatment groups: (a) no premedication drug (control); (b) melatonin 5 mg; (c) midazolam 7.5 mg; and (d) clonidine 100 μg. For each treatment group, the study drug was given once at bedtime (night before surgery) and a second dose was given 90 minutes prior to surgery. All patients received spinal anesthesia. The main outcome measure was the incidence of postoperative delirium during 3 days of follow-up assessment. Melatonin was associated with a significantly lower risk of delirium (10%) compared with control (33%), mid-azolam (44%), and clonidine (37%). The 62 patients who developed delirium (across all four groups) were then treated openly with melatonin, but the number of doses given to these patients was not reported. Of these 62 patients, 36 (58%) responded to melatonin.
Al-Aama et al. (2010) investigated the use of low-dose melatonin on the risk of delirium in a randomized, double-blind, placebo-controlled trial of patients admitted through the emergency department to a medical unit in a tertiary care hospital. The patients were 65 and older. The 145 patients were randomized to receive melatonin (0.5 mg per day) or placebo at night for 2 weeks or until discharge. The main outcome measure was the occurrence of delirium during the hospital stay. Melatonin was associated with a significantly lower risk of delirium (12%) compared with placebo (31%). At time of enrollment, five patients in the melatonin group and nine in the placebo group had pre-existing delirium. After excluding these 14 patients, melatonin was still associated with a significantly lower risk of delirium (4%) compared with placebo (19%). Melatonin was more effective than placebo even after controlling for associated risk factors. There were no differences between melatonin and placebo on measures of sleep.
Ramelteon and the Prevention of Delirium
Ramelteon (Rozerem®) is a synthetic analog of melatonin (Rajaratnam, Cohen, & Rogers, 2009). It is a melatonin MT1 and MT2 receptor agonist drug currently approved for the treatment of insomnia characterized by difficulty falling asleep. It is structurally unrelated to benzodiazepine drugs and does not bind to gamma-aminobutyric acid receptors or serotonin receptors. Ramelteon is effective (8 mg at bedtime) for sleep initiation, but its effectiveness for sleep maintenance is unclear. According to the product label for ramelteon, its major active metabolite is M-II, which has approximately one tenth and one fifth the binding affinity of ramelteon for human MT1 and MT2 receptors, respectively. Unlike ramelteon, M-II has weak affinity for the serotonin 5-HT2B receptor. Although the MT1 and MT2 receptor potency of M-II is lower than ramelteon, M-II circulates at substantially higher concentrations than ramelteon (producing a 20-fold to 100-fold greater mean systemic exposure compared to ramelteon).
Hatta et al. (2014) recently investigated the use of ramelteon for the prevention of delirium in a multicenter, rater-blinded, randomized, placebo-controlled trial conducted in intensive care units and regular acute wards of four university hospitals and one general hospital. Eligible patients were ages 65 to 89, newly admitted because of serious medical problems, and able to take medicine orally. Patients were excluded from the study if they had an expected hospital stay or life expectancy of less than 48 hours. The 67 patients were randomized to receive ramelteon (8 mg) or placebo at night for 1 week. The main outcome measure was the incidence of delirium during the 7 days. Ramelteon was associated with a significantly lower risk of delirium (3%) compared with placebo (32%), even after controlling for risk factors, and a significantly longer time to development of delirium compared with placebo. Curiously, there were no apparent differences between ramelteon and placebo on any sleep measures.
Hatta et al. (2014) suggested that the prophylactic effect of ramelteon might be mediated by its action on MT1 and MT2 receptors, directly regulating activity of the SCN. This is plausible, as circadian dysregulation is associated with cognitive and neuropsychiatric disturbances that occur in delirium, whereas delirium itself dysregulates circadian integrity by interfering with its links to environmental regulators (Fitzgerald et al., 2013). Two other potential mechanisms are also possible.
Pathologically sustained high levels of cortisol occurring with acute stress can precipitate and/or sustain delirium (Maclullich, Ferguson, Miller, de Rooij, & Cunningham, 2008). The pars tuberalis (PT) is the rostral part of the anterior pituitary gland (Yasuo & Korf, 2011). Most pituitary gland hormones, including the adrenocorticotropic hormone (ACTH) and follicle-stimulating hormone (FSH), are produced in the pars distalis (PD) of the anterior pituitary. Endocannabinoids are rapidly acting immune-modulatory lipid-signaling molecules important for adaptation to stressful and aversive situations. Cannabinoid receptors (CB1 and CB2) are part of the endocannabinoid system, but they are also binding sites for exogenous cannabinoids (i.e., cannabis or related synthetic compounds). Endocannabinoid signaling molecules have been detected in the human PT. The CB1 receptor has been detected in the human PD, localized mainly on ACTH-secreting and FSH-secreting cells. ACTH stimulates the secretion of glucocorticoid steroid hormones (e.g., cortisol) from the adrenal gland. Mammalian PT contains high levels of MT1 receptors. Endocannabinoid signaling is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis (Hill & Tasker, 2012). Low endocannabinoid levels have been associated with an increased risk for delirium (Hauer et al., 2012). Ramelteon MT1 receptor binding might regulate pituitary endocannabinoid signaling and CB1 receptor-mediated ACTH release, thereby attenuating an aberrant HPA axis stress response that could trigger delirium in high-risk patients.
Vasopressin is a peptide hormone released from the posterior pituitary that has a regulatory role on homeostasis via effects in the kidney, cardiovascular system, and central nervous system. One effect is to stimulate the secretion of ACTH and facilitate the effect of corticotropin-releasing hormone (released from the hypothalamus) on ACTH secretion. Vasopressin therefore modulates the release of corticosteroids from the adrenal gland in response to stress. Delirium is associated with elevated cerebrospinal fluid levels of serotonin metabolites (Hall, Shenkin, & Maclullich, 2011). Central serotonin 5-HT2B receptors regulate serotonin release via the serotonin transporter, and released vasopressin has been shown to activate 5-HT2B receptors indirectly (Knowles & Ramage, 1999). The ramelteon metabolite M-II might interact with 5-HT2B receptor signaling, influencing central serotonergic transmission and/or regulating the effects of vasopressin in such a way that reduces the risk of developing delirium in high-risk patients.
Delirium is an important clinical syndrome for nurses to recognize and become knowledgeable about its management. Nonpharmacological treatment approaches largely depend on nursing measures and should be a standard practice for all patients in the prevention and management of delirium (Tabet & Howard, 2009). Nurses should also be familiar with the use of various drug therapies, including melatonergic drugs. Melatonin and ramelteon are promising approaches for the prevention of delirium that deserve further study.
- Al-Aama, T., Brymer, C., Gutmanis, I., Woolmore-Goodwin, S.M., Esbaugh, J. & Dasgupta, M. (2011). Melatonin decreases delirium in elderly patients: A randomized, placebo-controlled trial. International Journal of Geriatric Psychiatry, 26, 687–694. doi:10.1002/gps.2582 [CrossRef]
- de Jonghe, A., van Munster, B.C., van Oosten, H.E., Goslings, J.C., Kloen, P., van Rees, C. & de Rooij, S.E. (2011). The effects of melatonin versus placebo on delirium in hip fracture patients: Study protocol of a randomised, placebo-controlled, double-blind trial. BMC Geriatrics, 11, 34. doi:10.1186/1471-2318-11-34 [CrossRef]
- Fitzgerald, J.M., Adamis, D., Trzepacz, P.T., O’Regan, N., Timmons, S., Dunne, C. & Meagher, D.J. (2013). Delirium: A disturbance of circadian integrity?Medical Hypotheses, 81, 568–576. doi:10.1016/j.mehy.2013.06.032 [CrossRef]
- Friedman, J.I., Soleimani, L., McGonigle, D.P., Egol, C. & Silverstein, J.H. (2014). Pharmacological treatments of non-substance-withdrawal delirium: A systematic review of prospective trials. American Journal of Psychiatry, 171, 151–159. doi:10.1176/appi.ajp.2013.13040458 [CrossRef]
- Hall, R.J., Shenkin, S.D. & Maclullich, A.M. (2011). A systematic literature review of cerebrospinal fluid biomarkers in delirium. Dementia and Geriatric Cognitive Disorders, 32, 79–93. doi:10.1159/000330757 [CrossRef]
- Hatta, K., Kishi, Y., Wada, K., Takeuchi, T., Odawara, T., Usui, C. & Nakamura, H. (2014). Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial. Journal of the American Medical Association Psychiatry, 71, 397–403. doi:10.1001/jamapsychiatry.2013.3320 [CrossRef]
- Hauer, D., Weis, F., Campolongo, P., Schopp, M., Beiras-Fernandez, A., Strewe, C. & Schelling, G. (2012). Glucocorticoid-endocannabinoid interaction in cardiac surgical patients: Relationship to early cognitive dysfunction and late depression. Reviews in the Neurosciences, 23, 681–690. doi:10.1515/revneuro-2012-0058 [CrossRef]
- Hill, M.N. & Tasker, J.G. (2012). Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience, 204, 5–16. doi:10.1016/j.neuroscience.2011.12.030 [CrossRef]
- Inouye, S.K., van Dyck, C.H., Alessi, C.A., Balkin, S., Siegal, A.P. & Horwitz, R.I. (1990). Clarifying confusion: The Confusion Assessment Method. A new method for detection of delirium. Annals of Internal Medicine, 113, 941–948. doi:10.7326/0003-4819-113-12-941 [CrossRef]
- Inouye, S.K., Westendorp, R.G. & Saczynski, J.S. (2014). Delirium in elderly people. Lancet, 383, 911–922. doi:10.1016/S0140-6736(13)60688-1 [CrossRef]
- Knowles, I.D. & Ramage, A.G. (1999). Evidence for a role for central 5-HT2B as well as 5-HT2A receptors in cardiovascular regulation in anaesthetized rats. British Journal of Pharmacology, 128, 530–542. doi:10.1038/sj.bjp.0702822 [CrossRef]
- Maclullich, A.M., Ferguson, K.J., Miller, T., de Rooij, S.E. & Cunningham, C. (2008). Unravelling the pathophysiology of delirium: A focus on the role of aberrant stress responses. Journal of Psychosomatic Research, 65, 229–238. doi:10.1016/j.jpsychores.2008.05.019 [CrossRef]
- Maldonado, J.R. (2013). Neuropathogenesis of delirium: Review of current etiologic theories and common pathways. American Journal of Geriatric Psychiatry, 21, 1190–1222. doi:10.1016/j.jagp.2013.09.005 [CrossRef]
- Pandi-Perumal, S.R., Srinivasan, V., Spence, D.W. & Cardinali, D.P. (2007). Role of the melatonin system in the control of sleep: Therapeutic implications. CNS Drugs, 21, 995–1018. doi:10.2165/00023210-200721120-00004 [CrossRef]
- Rajaratnam, S.M.W., Cohen, D.A. & Rogers, N.L. (2009). Melatonin and melatonin analogues. Sleep Medicine Clinics, 4, 179–193. doi:10.1016/j.jsmc.2009.02.007 [CrossRef]
- Sultan, S.S. (2010). Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi Journal of Anaesthesia, 4, 169–173. doi:10.4103/1658-354X.71132 [CrossRef]
- Tabet, N. & Howard, R. (2009). Nonpharmacological interventions in the prevention of delirium. Age and Ageing, 38, 374–379. doi:10.1093/ageing/afp039 [CrossRef]
- Yasuo, S. & Korf, H.W. (2011). The hypophysial pars tuberalis transduces photoperiodic signals via multiple pathways and messenger molecules. General and Comparative Endocrinology, 172, 15–22. doi:10.1016/j.ygcen.2010.11.006 [CrossRef]