Melatonin disorders

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

However, despite its enormous importance to human physiology, no pharmacological compounds targeting the components of the circadian clock system have been identified to date. There are, nevertheless, two therapeutic approaches that are currently used for treatment of circadian-related disorders - full-spectrum and bright light therapy and melatonin therapy. Melatonin is a hormone that is produced by the pineal gland in... 

Melatonin secretion is synchronized to the light/dark (LD) cycle, with a nocturnal maximum (in young humans, about 200 pg/ml plasma) and low diurnal baseline levels (about 10 pg/ml plasma). Studies have supported the value of the exogenous administration of melatonin in circadian rhythm sleep disorders, insomnia, cancer, neurodegenerative diseases, disorders of the immune function, and oxidative damage (Karasek et al. 2002 Pandi-Perumal et al. 2005, 2006 Srinivasan et al. 2005a,b, 2006 Hardeland et al. 2006). 

A reduced endogenous melatonin production seems to be a prerequisite for effective exogenous melatonin treatment of sleep disorders. A recent metaanalysis of the effects of melatonin in sleep disturbances, including all age... 

Melatonin receptor agonists in the treatment of sleep disorders... 

Buscemi, N., Vandermeer, B., Hooton, N. et al. (2006). Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction meta-analysis. Br. Med. J. 332, 385-93. 

Srinivasan, V., Smits, M., Spence, W. et al. (2006). Melatonin in mood disorders. World J. Biol. Psychiatry, in press. 

Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed in Ann. Rep. Med. Chem., volume 39 [29]. Since then, ramelteon has been approved, representing an important milestone for the proof of concept of this target, and has opened new possibilities for research. 

Robertson, J.M., and Tanguay, P.E. (1997) Case study the use of melatonin in a boy with refractory bipolar disorder. J Am Acad Child Adolesc Psychiatry 36 822-825. 

Antihistamines such as diphenhydramine, a mainstay of OTC sleep preparations, are also used widely by parents for their children at doses of 1 mg/kg. Most of the reports of the use of clonidine for sleep disorders are clinical and anecdotal case reports of use in children with ADFFD (Wilens et ah, 1994 Prince et ah, 1996). There are some safety concerns about using clonidine once a day at bedtime, especially in patients who take a daytime stimulant. Melatonin was studied using a double-blind, placebo-controlled, crossover design (Jan et ah, 1994) on a mixed group of 15 children with sleep disturbances, with some improvement reported. However, caution is warranted in using this agent because melatonin is unregulated, and there are concerns about the purity and safety of some commercially available preparations (Werry and Aman, 1999). 

Most attempts of using hormones as psychotropic medications were conducted with gonadal or with thyroid hormones, mainly because of the apparent mood changes associated with physiological or disorder-associated changes in levels or activity of these hormones. However, as shown in Table 17-1, current applications are broader and involve several hormones and systems. It is anticipated that, with acquired knowledge on mood effects of several other hormones, that list will continue to expand. Here, I focus on psychotropic effects of gonadal and thyroid hormones. Cortisol and melatonin are only briefly discussed. 

Ravindran AV, Bialik RJ, Lapierre YD Primary early onset dysthymia, biochemical correlates of the therapeutic response to fluoxetine, 11 urinary metabolites of serotonin, norepinephrine and melatonin. J Affect Disord 31 119-123, 1994d Razani J, White KL, White J, et al The safety and efficacy of combined amitryptiline and tranylcypromine antidepressant treatment—a controlled trial. Arch Gen Psychiatry 40 657-661, 1983... 

Rosenthal NE, Jacobsen FM, Sack DA, et al. Atenolol in seasonal affective disorder a test of the melatonin hypothesis. Am J Psychiatry 1988 145 52-56. 

Chase JF, Gidal BE. Melatonin therapeutic use in sleep disorders. Ann Pharmacother 1997 10 1218-1226. 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid-eye-movement (REM) sleep. These observations have been applied to the development of ramel-teon, a prescription hypnotic, which is an agonist at melatonin receptors (see Chapter 22). 

Clinical studies in patients with sleep disorders have shown that oral melatonin supplementation may alter sleep architecture. Subjective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. However, the significance of these findings is impaired by many study limitations. 

Another recognized type of depression is seasonal affective disorder (SAD). People in far northern or southern latitudes develop this condition in the winter, apparently from lack of sunshine needed to lower the melatonin level in the morning (see Section 13). Light therapy is beneficial.1110 Persons with the SAD syndrome also tend to crave carbohydrates and to stay in bed for 9-10 hours. 

Timing is critical for melatonin to be effective if it is given at the wrong time for sleep disorders or jet lag, it can cause increased daytime sleepiness (5,7) and worsened mental performance (8). Drowsiness and a small fall in body temperature are commonly reported effects (9), particularly after daytime administration, when endogenous concentrations of melatonin are low. 

Four of six children with pre-existing severe neurological disorders had increased seizure activity within 2 weeks of starting oral melatonin 5 mg at bedtime (12). Seizure frequency returned to baseline after treatment was stopped, and increased again after rechallenge with melatonin 1 mg. A convulsion during melatonin treatment, which recurred when medication was continued, has been reported to the WHO database but not published (5). Headache, which recovered after melatonin was withdrawn, has also been reported in a few cases (5). 

There was suppression of endogenous melatonin secretion in two of five patients with bipolar disorder after 12 weeks of treatment with high-dose melatonin (10 mg/day)... 

There was suppression of endogenous melatonin secretion in two of five patients with bipolar disorder after 12 weeks of treatment with high-dose melatonin (10 mg/day) (19). One woman developed an unentrained sleep-wake cycle after melatonin was withdrawn (not previously a feature of her illness), which persisted for several months. 

A 14-year-old girl with major depressive disorder had drowsiness, dizziness, blurred vision, and confusion after taking an overdose of melatonin (24-36 mg) (31). 

Giladi N, Shabtai H. Melatonin-induced withdrawal emergent dyskinesia and akathisia. Mov Disord 1999 14(2) 381-2. 

Paavonen EJ, Nieminen-von Wendt T, Vanhala R, Aronen ET, Von Wendt L. Effectiveness of melatonin in the treatment of sleep disturbances in children with Asperger disorder. J Child Adolesc Psychopharmacol 2003 13 83-95. 

---