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Case-control study of evening melatonin concentration in primary insomnia

^a University Department of Psychiatry, Littlemore Hospital, Oxford, OX4 4XN

Correspondence to: Dr Cowen.

The function of melatonin is not fully established, but recent studies suggest that it plays a role in the regulation of sleep. Thus, physiological doses of melatonin given to healthy volunteers decreased the time taken to fall asleep,¹ and the incidence of insomnia in the population rises during middle and old age,² when serum concentrations of melatonin decline.³ Haimov et al found that elderly patients with insomnia had lower than normal peak urinary concentrations of the melatonin metabolite 6-sulphatoxy melatonin and a delayed onset to peak secretion.⁴ We investigated evening plasma melatonin concentrations in subjects with primary insomnia and matched controls and predicted that the subjects with insomnia would have lower melatonin concentrations.

Subjects, methods, and results

Cases and controls were recruited predominantly by advertisement, but two cases were referrals from general practice. The 10 men and 10 women with insomnia had a mean age of 53.9 years (range 40-68), and the 20 controls matched for sex and age (within five years) had a mean age of 54.7 (40-69). The cases and controls were recruited continuously over two years, and all but three of the controls were studied within three months of their matched case. We used a supplemented structured interview to ensure that the cases met criteria for primary insomnia according to Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R). Their mean duration of insomnia was 18 years (range 2-50), and they had no other current axis 1 disorder according to DSM-III-R. The controls had no current axis 1 disorder. None of the subjects had taken psychotropic drugs or ß adrenoceptor antagonists for at least one month, and all gave their informed consent to the study, which was approved by the local ethics committee.

Subjects came to the laboratory at 6 pm, when we inserted an indwelling venous cannula under dim light conditions (<100 lux). Sampling for plasma melatonin began at 6 30 pm and continued at 30 minute intervals until 11 pm. We measured melatonin concentration by means of a radioimmunoassay with a limit of detection of 1.3 pg/ml (intra-assay and interassay coefficients of variation, 8% and 13% respectively). We log transformed the melatonin concentrations to achieve a normal distribution and analysed them with a matched pairs analysis of variance with time and diagnosis as the main factors.

Figure 1 shows the plasma melatonin concentrations. The analysis showed significant differences for diagnosis (F=5.65, df=1.19, P=0.028) and time (F=113.56, df=9.171, P=0.001) but no interaction of diagnosis by time (F=0.24, df=9.171, P=0.987). For all the time points considered together, the geometric mean paired difference in melatonin secretion between cases and controls was 11.6 pg/ml (95% confidence interval 0.06 to 23.2, t=2.1, df=19, P<0.05).

View larger version (13K): [in this window] [in a new window]   Fig 1--Geometric mean (SD) plasma melatonin concentrations in 20 cases with primary insomnia and 20 matched controls. Cases had significantly lower concentrations than controls (P=0.028, analysis of variance of log transformed data)

Comment

Our findings add to data suggesting that some patients with insomnia have decreased melatonin secretion.⁴ We did not sample the subjects up to the usual time of peak melatonin secretion (about 3 am) and therefore cannot tell whether those with insomnia had a phase shift in melatonin secretion with a delayed peak or an overall lowering of melatonin output.

Two further caveats are important. Firstly, people with primary insomnia often experience anxiety and depression; accordingly, lowered plasma melatonin could be associated with the presence of minor psychiatric symptoms rather than insomnia itself. Secondly, it would have been preferable to study the cases and controls simultaneously because this would have avoided possible bias due to seasonal variation in melatonin secretion. Nevertheless, our findings support the possibility that some patients with insomnia may benefit from treatment with exogenous melatonin,⁵ but controlled studies are needed to assess the nature and durability of such an effect.

Funding: Glaxo Pharmaceuticals.

Conflict of interest: None.

1. Zhdanova IV, Wurtman RJ, Lynch HJ, Ives JR, Dollins AB, Morabito C, et al. Sleep inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 1995;57:552-8. [Medline]
2. Dement WC, Laughton EM, Carskadon MA. White paper on sleep and ageing. J Am Geriatr Soc 1982;30:25-50. [Medline]
3. Iguch H, Kato K, Ibayashi H. Age dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metab 1982;55:27. [Medline]
4. Haimov I, Laudon M, Zisapel N, Souroujon M, Nof D, Shlitner A, et al. Sleep disorders and melatonin rhythms in elderly people. BMJ 1994;309:167. [Free Full Text]
5. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995;346:541-3. [Medline]

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