The Therapeutic Potential of Melatonin: A Review of the Science

Samir Malhotra, MD; Girish Sawhney, MD; Promila Pandhi, MD

Disclosures
In This Article

Brain Function, Neuropsychiatry, and Behavior

Seizures

The pineal, acting primarily but not exclusively through melatonin, is proposed to be a "tranquilizing organ" that promotes homeostatic equilibrium.[7] Melatonin stabilizes the electrical activity of the central nervous system and causes rapid synchronization of the electroencephalogram.[9] By contrast, pinealectomy predisposes animals to seizures.[9] Recent evidence from experimental work suggests that melatonin provides anticonvulsant activity in various models of epilepsy. In mice, intracerebroventricular administration of melatonin protected against seizures induced by kainate, glutamate, and N-methyl-D-aspartate;[56] however, it was ineffective against pentylenetertrazol-induced seizures, thereby suggesting a potential role in grand mal epilepsy. Similarly, melatonin antagonized the seizure-producing effects of cyanide[57] and ferric chloride.[58] The anticonvulsant effect of melatonin has also been demonstrated in amygdala-kindled rats.[59]

Some of these experimental data have been corroborated by clinical studies in patients with epilepsy. Bazil and colleagues[60] found melatonin levels to be reduced in patients with intractable epilepsy. In a study of 6 children with intractable seizures, administration of 3 mg of oral melatonin 30 minutes before bedtime in addition to the antiepileptic regimen led to clinical improvement in seizure activity in 5 of the children, by parent report.[61] However, because of the paucity of well-controlled studies, melatonin cannot, as yet, be recommended in any form of epilepsy, although it may have some role as an adjuvant therapy for children with intractable seizures.

Depression

Nocturnal melatonin levels are low in subjects with major depressive disorder and panic disorder.[62,63] This is particularly marked in subjects with abnormal pituitary-adrenal responses to exogenous corticoids (abnormal dexamethasone suppression)[27] who also have disturbed corticoid-secretion patterns. Healthy individuals with a dysthymic disposition (mild or episodic depression) also had lower-than-normal nocturnal melatonin levels[27] as did subjects with melancholic depression.[64] By contrast, higher-than-normal melatonin levels have been observed in manic subjects during the manic phase.[64] More significant than changes in the absolute melatonin level at any given time is the amplitude of the circadian melatonin rhythm, which is blunted in patients with depression and becomes normal on recovery.[65]

The link among melatonin levels, pineal function, and mood disorders is strengthened by epidemiologic and chronobiological evidence. Both seasonal affective disorder (SAD) and classic "nonseasonal" depressions demonstrate a marked seasonal incidence with peaks in the fall and spring, respectively.[66,67] This coincides with the troughs of the circannual melatonin rhythm.[68]

The requirement of intact beta-receptor function for melatonin synthesis and the stimulatory effect of norepinephrine on melatonin synthesis and release[7] point toward a theoretic relation of melatonin to depression. Several of the tricyclic antidepressants dramatically increase melatonin synthesis in humans.[69,70] In one study, 8 weeks of clomipramine treatment resulted in a lowering of melatonin levels at 12 am, 2 am and 4 am as well as an elevation of melatonin levels at 8 am, 2 pm, and 8 pm.[70] Thus, it is possible that the relation of norepinephrine action to affective disorders is mediated in part by effects on melatonin synthesis. Tricyclics often exert sedative effects and for this reason are often administered at night -- an appropriate time to enhance melatonin rhythm amplitude. Furthermore, beta-receptor blockers depress melatonin secretion[8] and can cause neuropsychiatric problems, such as nightmares, insomnia, lassitude, dizziness, and depression.[71]

Brain serotonin levels rise after melatonin administration,[72] which may be significant because serotonin has been linked with an array of neuropsychiatric phenomena.[73,74,75,76,77] Diminished central serotonin, as indicated by low levels of the serotonin marker 5-hydroxy indole acetic acid (5-HIAA) in cerebrospinal fluid, is associated with impulsiveness, aggression and autoaggression,[73,74,75] alcoholism,[76] compulsive gambling, overeating, and other obsessive-compulsive behaviors.[77] Support of the serotonin system with serotonergic nutrients or drugs can elevate mood, reduce aggression, increase the pain threshold, reduce anxiety, relieve insomnia, improve impulse control, and ameliorate obsessive-compulsive syndromes.[77,78,79]

Endogenous Depression

Classic endogenous or "nonseasonal" depression is characterized by insomnia (especially early-morning awakening), appetite suppression and weight loss, and advanced onset of nocturnal melatonin release; these individuals are probably phase-advanced ("morning people"), although not very effectively.[80] Classic depression typically begins in the spring and persists through the summer,[67] the period of light-phase lengthening. This group may benefit from an induced phase delay (and light-phase shortening) effected by bright light exposure in the evening,[81] later rising with avoidance of bright light in the morning and melatonin administration (especially delayed-release melatonin) in the late evening or immediately before bed. Melatonin administration that prolongs the nocturnal melatonin rise may exacerbate SAD[82] and bipolar and classic depression.[83] In this latter study,[83] large quantities (> 1 g/day) of melatonin were taken in divided doses throughout the day, thus abolishing the normal, daily melatonin rhythm.

The use of large doses of melatonin in the morning and early afternoon represents exceedingly poor design for a study examining the hormone's effects on depression (or any other condition), especially when one considers the clear evidence that blunted amplitude and disturbed melatonin rhythm play a role in depression, rather than low absolute levels at any given time.[65,84] Thus, melatonin should be used only with caution in patients with depression and should always be appropriately timed and in conjunction with light therapy and sleep-phase change. Disruption of normal circadian rhythm by poorly timed melatonin administration can logically worsen depression.

In a recent study of postmenopausal women, melatonin administration led to a significant mitigation of depression.[85] In a large-dose-range trial, agomelatine, a melatoninergic agonist, was found to alleviate depression as well as anxiety.[86] However, another study found that the addition of melatonin to ongoing fluoxetine treatment had no beneficial effect on the 3-month outcome, postelectroconvulsive therapy.[87]

Seasonal Affective Disorder

SAD is characterized by late sleep, morning hypersomnia, increased appetite, and retarded onset of nocturnal melatonin release. SAD subjects are probably phase-delayed ("night people").[74,75] SAD typically begins in the fall and persists through the winter,[67] during the period of light-phase shortening. SAD sufferers may benefit from induced-phase advance (and light-phase lengthening), effected by bright light exposure in the morning (especially predawn), early rising (to the point of partial morning sleep deprivation, eg, rising at 3-4 am), and melatonin administration before bed, which should be early in the evening.[88]

The relationship between depression and light deprivation has been reviewed.[89,90] Phototherapy as an adjuvant in depression may accelerate responses to antidepressants among patients with depression.[91] Moreover, melatonin secretion has been shown to be wavelength-dependent as exposure to monochromatic light at 460 nm produced a 2-fold greater circadian phase delay.[92]

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