Measurement of serum or urinary melatonin may be a useful neuroendocrine indicator of affective disorders. Its clinical applicability has not yet been demonstrated but, as this review shows, melatonin is a sensitive marker for biological rhythms and a major link between the external environment's light-dark cycles and the body's internal neurohormonal regulation. Melatonin production reflects the presence of daily and seasonal rhythms of light exposure and may well express pathological changes in adrenergic sensitivity in depression.
MELATONIN PRODUCTION AND ADMINISTRATION
Melatonin is produced exclusively by the pineal gland. Animals and humans who have undergone pinealectomy (following tumor resection or irradiation) do not have detectable levels of melatonin.1'3 Melatonin is derived from serotonin under the control of postganglionic noradrenergic neurons (from the superior cervical ganglion acting on pineal beta-adrenergic receptors) which stimulate the synthesis of n-acetylserotonin from serotonin. This is the rate-limiting step.4 N-acetylserotonin is methylated to form melatonin.5 Natural photoperiod and laboratory manipulation of the lightdark cycle demonstrate that bright light influences melatonin production in man as well as animals.5-8
Animal investigations have given important clues to the relationship between the external environment and the production of melatonin. Rats exposed to constant dark produce the greatest amount of melatonin. Similarly, there is a light-dark and season-related rhythm in the daily levels of n-acetyltransferase in the rat pineal gland that can be manipulated by changes in the lightdark cycle.6 Mice with no melatonin production lack the two necessary synthetic enzymes, n-acetyltransferase and HIOMT.9
* Control Systems for Melatonin Secretion
Control of melatonin production is primarily via beta-adrenergic pineal receptors which are outside of the blood-brain barrier and receive visual sensory input primarily via the suprachiasmatic nucleus and superior cervical ganglia. Alpha-adrenergic control is secondary.10 Perturbations of the normal cycle of melatonin production, which is high during the dark period of normal sleep and minimal during the day, may occur by exposure to bright light in both animals and humans. This melatonin cycle parallels the serotonin cycle in the CSF of monkeys, with both melatonin and serotonin being high during the night and low during the day." This melatonin cycle has been found to be ''freerunning," that is, unrelated to lightdark changes in blind individuals and those in constant darkness, but daytime darkness does not turn on melatonin secretion.12 Melatonin production and timing may be disrupted by the administration of betablockers or the presynaptic alphaadrenergic agonist Clonidine.1515 The daily cycle of melatonin production is altered in aging with the melatonin peak advanced in time.16,17 This alteration has been proposed as an index of brain aging.18 There is a very significant negative correlation between age and 24-hour melatonin secretion, peak plasma melatonin level, and lag in time from sunset to the onset of significant elevation of plasma melatonin over daytime values.18 Senile dementia, however, does not affect melatonin levels independent of aging.19 The normal human circadian and seasonal melatonin rhythm is illustrated in the Figure.
Season affects morning melatonin levels, with lower 6 to 8 am values during the bright months of April through July than during the dark months of November through January, but no seasonal effects on maximal nighttime melatonin peaks have been observed.20
* Melatonin Administration in Humans
Melatonin is readily absorbed when given orally with a rapid peak and elimination over a few hours.22"25 Melatonin concentrations in saliva, plasma, and urine are higher than the normal physiologic baseline following oral doses of 2 to 240 mg. Melatonin is psychoactive; sleepiness is its most consistent principal effect.13,24,27 Chronic oral administration of melatonin (2 mg daily) for one month to normal volunteers has no effect on most endocrine measures.15
The potential importance of melatonin as a marker and perhaps a pacer of circadian rhythms is sug- gested by a study involving double- blind administration of 5 mg of mela- tonin orally for a few days before and after flights between London and San Francisco. Jet lag is believed to be a disorder of circadian rhythms. Subjective benefit in jet lag was observed when melatonin was compared with placebo, although a short-acting hypnotic comparison group was not part of the study design.28
Serum Melatonin v Time of Day During Winter and Summer20
A causal role of melatonin in seasonal affective disorder has been challenged by the lack of clinical effect of oral melatonin given to depressed patients for one week, although in another study melatonin partially reversed the therapeutic effects of bright artificial light.29,30 Patients reported more fatigue, less energy, and more need for sleep while receiving melatonin than while receiving placebo, but total Hamilton depression rating scores were not significantly different.
* Melatonin in Human Blood and Urine
Although urinary studies are useful in reflecting the total production of melatonin metabolites over the collection period, usually the hours of normal dark and sleep, they fail to demonstrate the time of onset, peak levels, or time of offset of melatonin secretion. Frequent plasma measurements can better reflect the shape of the melatonin circadian curve and its alteration in response to experimental manipulation of the light-dark cycle. Lewy has also suggested that the dim light melatonin onset (DLMO) is a useful index of circadian rhythm phase (see Dr. Lewy's article, "Treating Chronobiologic Sleep and Mood Disorders with Bright Light," in this issue).
DISTURBANCES IN MELATONIN PRODUCTION
Dim light can rapidly suppress melatonin production in animals. However, Lewy has demonstrated that bright light, of 1 500 to 2500 lux, is required to evoke the same response in humans.8 This intensity is brighter than average room light, and 2500 lux approximates the light level from a window on a clear spring day. Melatonin production rapidly resumes when the bright light exposure is ended.
Atenolol and propranolol are both capable of lowering nighttime melatonin production acutely by blocking the pineal beta-adrenergic receptors involved in regulating melatonin production.13,14,31 The effect of atenolol suggests a bela-1-adrenorcceptor on the pineal cells is involved.14 Atenolol, which penetrates the blood-brain barrier poorly, is active on the pineal because the pineal gland is outside of the bloodbrain barrier.
If depression were caused by too much melatonin, then beta blockers should be effective antidepressants. This is not the case for most seasonal and nonseasonal depressed patients. Rosenthal, however, did successfully treat three seasonal affective disorder patients with atenolol.32
Intravenous Clonidine given to normal sleeping volunteers lowers melatonin production during sleep, suggesting that there is also alpha-2adrenergic regulation of melatonin production.15 Presynaptic alpha-2autoreeeptors on the sympathetic neurons innervating the pineal ol the rat have been demonstrated.31
* Pathologic Factors
There is a trough in the circannual rhythm of melatonin that is associated with the highest incidence of peptic ulcer disease and hospital admissions for depression.33
The relationship between depression and alterations in Cortisol regulation, with loss of suppression in response to dexamethasone, has been repeatedly demonstrated, although the relevance to the pathophysiology of depression and the specificity of the finding remain controversial. Interestingly, low nocturnal melatonin is found in both depression and some Cushing's syndrome patients.34 Low nocturnal melatonin is also found in patients with cluster headaches, but without associated Cortisol hypersecretion.55 A group of eight anorexia nervosa patients had higher melatonin levels than did depressives.30 Sympatholytic diseases, such as Shy-Drager syndrome and idiopathic orthostatic hypotension, also cause disruption in melatonin secretion.31
In one study comparing healthy subjects in the United States and lapan, urinary melatonin levels were related to the risks of developing breast cancer, depression, and cardiovascular disease based on family history questionnaires and an abbreviated MMPI.37 In a study of depressives, three of eight melancholies did not show the expected nighttime rise in 6-sulphatoxymelatonin.38 In another study, four DSM-III major depressives had a lower group mean overnight 6-OHmelatonin than did age adjusted normals.17
The rebound production of melatonin when lights are turned off is very rapid in humans compared to animals. Melatonin rebound is slower in some depressive patients than in normal controls.39 Sensitivity to light suppression during both acute illness and remission is greater in those with bipolar disorder than in normal controls, suggesting that this may be a useful trait marker of bipolar affective disorder, although its specificity has not yet been studied.40 Drug-free euthymic bipolar patients demonstrated suppression of nocturnal melatonin production in response to 500 lux of fluorescent light, whereas matched normal volunteers did not.
Melancholic patients have a lower nocturnal plasma melatonin maximum when compared with both nonmelancholic depressive patients and normal controls.41,42 There is contradictory evidence concerning the possible phase change of the melatonin nighttime peak. One group claimed that the melatonin night peak occurred earlier in six endogenous depressive patients than in normal controls,45 while another group reported that the melatonin rhythm in 11 patients with primary affective disorders was not phase advanced compared with normal controls.44
Low nighttime melatonin maximum levels are found in both unipolar and bipolar depressive patients, and these levels are stable from acute illness through remission, suggesting that this is a trait marker for depressive disorders.20,34,45
The existence of a low melatonin depression syndrome has been proposed, with characteristics including a low peak plasma melatonin nocturnal secretion, escape on the standard 1 mg dexamethasone suppression test, and alterations in the Cortisol production cycle, as well as some daily and annual cyclic variation in depressive symptomatology. 58,45,40 Early parental loss, before age 17, may be associated with this syndrome.45,46 Maximal melatonin levels at night tend to be correlated with retardation symptoms on psychopathological ratings. The dexamethasone suppression test abnormalities may be explained by melatonin inhibiting CRF in depression. Decreased melatonin levels in response to dexamethasone have been reported in unipolar, bipolar, and healthy control subjects.46,47
Low melatonin is not associated with abnormalities in the TRH-TSH stimulation lest as there is no correlation between the TRH-stimulatcd change in TSH and the maximal serum melatonin at night.48
The effects of antidepressant treatment on melatonin have not been studied sufficiently to draw any major conclusions. Several preliminary studies have indicated an effect consistent with antidepressant alteration of adrenergic receptor sensitivity.
Desipramine. Seven male depressive patients who received four weeks of desipramine did not show change in melatonin before or after lights were turned off, but plasma drug concentrations averaged only 70 ng/mL (the lower end of the therapeutic range) and so may have been too low to demonstrate any effect.41,49 In contrast, others have reported that desipramine given to depressed patients and normal controls increased plasma melatonin at three weeks in patients but not in normal controls who were given the drug and achieved therapeutic plasma levels.50 The authors commented that this increase occurred in the patients at a time when beta-adrenergic down-regulation would be expected, with an attendant reduction in melatonin production. The net effect of desipramine appeared to be an increase in noradrenergic neurotransmission at the pineal rather than a decrease. The inclusion of a control group of normal volunteers who achieved comparable plasma levels of desipramine without comparable melatonin changes helps to support the concept that melatonin changes are related to the drug's normalizing or antidepressant effects. A supporting study of four DSM-III major depressive patients given desipramine showed an increase in overnight urinary 6OH-melatonin at weeks 1, 2, and 3 relative to baseline.17
Amitriptyline. Amitriptyline given to female inpatients with primary affective disorders did not alter melatonin rhythms but was effective in normalizing Cortisol rhythm both during acute illness and when the patients had clinically recovered.51
MAOIs. Murphy has reported that during the course of treating 27 depressed patients with monoamine oxidase inhibitors, the 8 am plasma melatonin increased from baseline to day 21 to 24 in patients receiving tranylcypromine (a nonselective MAOI) and clorgyline (a selective MAO type A inhibitor) but not in those receiving deprenyl (a selective MAO type B inhibitor).52 Many of the patients treated with tranylcypromine and clorgyline had elevated platelet serotonin content. Serotonin is a substrate for MAO type A and should increase with tranylcypromine and clorgyline but not deprenyl. A companion study of rhesus monkeys demonstrated increased CSF melatonin, n-acetyl serotonin, and serotonin during both the day and night with clorgyline treatment.
Lithium does not alter the nighttime secretion of melatonin in normal volunteers receiving therapeutic doses for three weeks, although lithium-stabilized bipolar affective disorder patients demonstrated a trend toward reduced melatonin secretion.16
* Light Effects in Treating Depression
The application of bright artificial light in treating seasonal affective disorders (SAD) was originally based on the analogy of hibernation in animals, which is governed largely by photoperiod. The original intent of using lights was to extend the photoperiod artificially (in the morning and evening) and thus create a photoperiod similar to that in summer. Photoperiod, as rellected by latitude. is highly correlated with the greater prevalence of self-reported symptoms of SAD in northern latitudes of the United States than in the southern part of the country.55 Bright light is a powerful influence on the biological clock as reflected by alterations in body temperature and Cortisol rhythms.54 Lewy et al suggest that sleep and mood disorders should be phase typed based on whether the circadian rhythms are advanced or delayed so that specific timing of lights in the morning or evening could be recommended.55-57 Plasma, urine, and dim light melatonin onset measures are useful markers of circadian rhythm abnormalities.
Melatonin production appears to be under the control of numerous factors, including the light-dark cycle and the autonomic nervous system. Urine and plasma melatonin may be useful markers of depression. Low nocturnal maximum values are found in the plasma of some depressed individuals. Both light treatment, which successfully improves seasonal depressive patients, and beta blockers, which have no acute effect on most depressed patients, lower nocturnal melatonin levels. Oral melatonin administration has been shown to partially reverse the therapeutic effect of light in depression.30 Desipramine and some MAO inhibitors appear to increase melatonin in depressed patients. These mixed results argue against alterations in melatonin levels being an etiologic factor in most cases of depression, although melatonin levels can be used to phase type circadian rhythm, and perhaps used as a marker for depression.
Bipolar affective disorder patients appear to be unusually sensitive to light-induced suppression of melatonin production both when acutely ill and in remission. The development of these markers for clinical application will probably have to await the development of a highly standardized protocol for blood sampling, the standardization of the overnight urine collection methodology, or the refinement of dim light melatonin onset. Like all potential markers in psychiatry, these will require further study to evaluate their sensitivity and specificity for major affective disorders.
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