The association of nocturnal serum melatonin levels with major depression in patients with acute multiple sclerosis

doi:10.1016/j.psychres.2007.11.022

Psychiatry Research

Volume 161, Issue 2, 30 November 2008, Pages 253-257

https://doi.org/10.1016/j.psychres.2007.11.022 Get rights and content

Abstract

The association of nocturnal serum melatonin levels was investigated in acute multiple sclerosis (MS) patients with major depression (MD). The sample comprised 13 patients with MD and 12 with no psychiatric disorders admitted to our clinic due to acute MS attacks. Psychiatric evaluation was performed with the Structured Clinical Interview for DSM-IV (SCD-I). The level of depressive symptoms was assessed with the Beck Depression Scale (BDS). Blood samples were taken from the patients to determine melatonin level at 03.30h and 10.00h before steroid treatment started. Melatonin levels were determined using the ELISA test. Nocturnal serum melatonin levels (21.2 ± 17.1 pg/ml) of the patients with MD were significantly lower than those (51.5 ± 18.3 pg/ml) of the patients without MD. A significant negative correlation was found between BDS scores and nocturnal serum melatonin levels. These findings suggest that a melatonin deficiency may be among the factors involved in the occurence of depression in MS patients.

Introduction

Multiple sclerosis (MS), a chronic disease that leads to motor, sensorial, affective and cognitive deficits, usually has its onset young adulthood. It is a disease characterized by inflammation, demyelination and glial scarring in the pathological examination of central nervous system tissues (Sandyk and Awerbuch, 1993a, Miller, 2000).

The causal relationships between MS and affective disorders have yet to be determined, although mood disorders in MS were first described by Jean Marie Charcot in 1877 (Sandyk and Awerbuch, 1993b). In MS the rate of depression is higher than in other chronic neurological diseases. The concomitant occurrence of depression and abnormal levels of melatonin has also been reported (Miles and Philbrick, 1988).

Melatonin is synthesized by the pineal gland (Arendt, 1995). l-tryptophan is converted into 5-hydroxy-tryptophan in pinealocytes by tryptophan hydroxylase (Chokroverty, 2000). Serotonin is produced via decarboxylation. Serotonin is converted by sequential activities of two enzymes, serotonin-N-acetyl transferase and hydroxyindole-O-methyl transferase (Claustrat et al., 2005). Melatonin is metabolized in liver and its principal metabolite is 6-hydroxy-melatonin (Miles and Philbrick, 1988, Sandyk and Awerbuch, 1993b, Chokroverty, 2000).

The biosynthesis and secretion of melatonin is controlled to a large extent by a nonadrenergic system (Lewy et al., 1981, Rabe-Jablonska and Szymanska, 2001). The suprachiasmatic nucleus of the hypothalamus causes inhibition of melatonin secretion, leading to the gamma-aminobutyric acid. Therefore, decreased melatonin levels may reflect hypothalamic dysfunction in the regulation of oscillatory melatonin secretion. Hypothalamic and periventricular lesions are often encountered in MS. At the same time, decreased melatonin levels may also reveal serotonin function disorders, as serotonin is the precursor of melatonin (Sandyk and Awerbuch, 1993b).

Melatonin is secreted nocturnally, and the nocturnal serum melatonin level is 25–85 pg/ml in adults (Sandyk and Awerbuch, 1993a, Sandyk and Awerbuch, 1993b). The melatonin level reaches its peak between 04.00h and 06.00h, and levels decline between 07.00h and 09.00h. Although melatonin levels show a constant rhythmic amplitude in each individual, there are large differences among individuals (Arendt, 1988).

Since the nocturnal melatonin secretion may be reduced in patients with depression, it is likely that decreased melatonin secretion is also associated with the depressive symptoms of MS. Lower levels of production may contribute to depression due to evidence of pineal gland calcification and hypothalamic dysfunction commonly seen in MS (Sandyk and Awerbuch, 1993b).

The aim of the present study was to investigate the association of nocturnal serum melatonin levels in acute MS patients with concomitant MD.

Section snippets

Subjects

The sample consisted of 25 patients (9 male, 16 female) previously diagnosed with MS according to McDonald criteria (Polman et al., 2005). Because of acute MS attacks, the patients were hospitalized at the Neurology Clinic of Meram Medical School of Selcuk University. None of the patients had any autoimmune disease.

Mean disease duration (± S.D.) was 7.2 ± 7.7 years. Thirteen patients (52%) had MD, and 12 patients (48%) had no psychiatric disorders. Mean age was 40.0 ± 10.7 (22–63) years for women

Results

The average EDSS and BDS scores of the patients were 2.0 ± 1.5 (0.5–5.0), and 16.28 ± 11.00 (1–37), respectively. The average disease duration and number of episodes were 7.2 ± 7.7 (1–32) years and 4.0 ± 2.3 (1–9), respectively.

There was no difference between the patients with and without MD in terms of age (P = 0.629), gender (χ² = 0.322, P = 0.571), disease duration (P = 0.904), EDSS (P = 0.283), and number of attacks (P = 0.668) (Table 1).

Since morning melatonin levels did not differ (7.03 ± 8.69 and 7.86 ±

Discussion

Disturbance in the melatonin circadian profile in depression has already been reported (Crasson et al., 2004). The studies (Crasson et al., 2004, Boyce, 1985, McIntyre et al., 1986, Cavallo, 1987) described abnormalities of secretion rhythms with advanced phases and/or decrease in nocturnal amplitude of melatonin rhythm in depression. Wetterberg (1982) also reported low nocturnal melatonin secretion in patients with depression. Beck-Friis et al. (1984) categorized hypomelatoninemia in

References (25)

Beck-FriisJ. et al.
Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects
Psychoneuroendocrinology
(1984)
CavalloA. et al.
Melatonin circadian rhythm in childhood depression
Journal of the American Academy Child and Adolescent Psychiatry
(1987)
ClaustratB. et al.
The basic physiology and pathophysiology of melatonin
Sleep Medicine Reviews
(2005)
CrassonM. et al.
Serum melatonin and urinary 6-sulfatoxymelatonin in major depression
Psychoneuroendocrinology
(2004)
FangetF. et al.
Nocturnal plasma melatonin levels in schizophrenic patients
Biological Psychiatry
(1989)
LewyA.J. et al.
Manic-depressive patients may be supersensitive to light
Lancet
(1981)
MilesA. et al.
Melatonin and psychiatry
Biological Psychiatry
(1988)
NairN.P. et al.
Circadian rhythm of plasma melatonin in endogenous depression
Progress in Neuro-Psychopharmacology & Biological Psychiatry
(1984)
SekulaL.K. et al.
Neuroendocrine aspects of primary endogenous depression. XV: mathematical modeling of nocturnal melatonin secretion in major depressives and normal controls
Psychiatry Research
(1997)
SouêtreE. et al.
Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality
Psychiatry Research
(1989)

ArendtJ.

Melatonin

Clinical Endocrinology

(1988)

ArendtJ.

Pineal gland: basic physiology and clinical implications

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Brief reportThe association of nocturnal serum melatonin levels with major depression in patients with acute multiple sclerosis

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Psychoneuroendocrinology

Journal of the American Academy Child and Adolescent Psychiatry

Sleep Medicine Reviews

Psychoneuroendocrinology

Biological Psychiatry

Lancet

Biological Psychiatry

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Psychiatry Research

Psychiatry Research

Melatonin

Clinical Endocrinology

Pineal gland: basic physiology and clinical implications

Brief report
The association of nocturnal serum melatonin levels with major depression in patients with acute multiple sclerosis