Barbara L. Parry

Melatonin in mood disorders

The cyclic nature of depressive illness, the diurnal variations in its symptomatology and the existence of disturbed sleep–wake and core body temperature rhythms, all suggest that dysfunction of the circadian time keeping system may underlie the pathophysiology of depression. As a rhythm-regulating factor, the study of melatonin in various depressive illnesses has gained attention. Melatonin can be both a ‘state marker’ and a ‘trait marker’ of mood disorders. Measurement of melatonin either in saliva or plasma, or of its main metabolite 6-sulfatoxymelatonin in urine, have documented significant alterations in melatonin secretion in depressive patients during the acute phase of illness. Not only the levels but also the timing of melatonin secretion is altered in bipolar affective disorder and in patients with seasonal affective disorder (SAD). A phase delay of melatonin secretion takes place in SAD, as well as changes in the onset, duration and offset of melatonin secretion. Bright light treatment, that suppresses melatonin production, is effective in treating bipolar affective disorder and SAD, winter type. This review discusses the role of melatonin in the pathophysiology of bipolar disorder and SAD.

Seasonal Affective Disorder and Phototherapy

Recognition that the timing of depressive episodes is related to the seasons goes back at least to Hippocrates (circa 400 B.C.),’ who noted that “melancholia occurs in the spring.” In the last 150 years many researchers have noted seasonal variations in affective episodes and in suicide, an indirect reflection of the incidence of depression. The suicide data, well reviewed by Kevan2 and A ~ c h o f f , ~ show a peak incidence in late spring and early summer. The incidence of depressive episodes is highest in spring and fall, whereas mania seems to occur most frequently in late summer.‘ Several authors have correkted the incidence of these occurrences with climatic variables such as sunshine and temperature and have shown statistically significant relationship^.^*^-^ Such survey studies, however, cannot establish a causal link between environmental influences and psychopathology. In order to probe the mechanisms by means of which these seasonal rhythms might be mediated, we have adopted a different strategy. We have recruited and studied a population of patients who have a history of extreme seasonal vulnerability to changes in mood and behavior. In this paper we summarize our experience with these patients and their condition, and discuss our interventions in their seasonal rhythms, and the extensive animal literature on which these interventions were patterned.

Longitudinal sleep EEG, temperature, and activity measurements across the menstrual cycle in patients with premenstrual depression and in age-matched controls

After a 2-month evaluation period, eight women with moderate to severe premenstrual depression and eight age- and sex-matched controls underwent sleep electroencephalographic (EEG) and temperature recordings 2 nights a week over the course of one menstrual cycle. Overall, patients had more Stage 2 (%) sleep and less rapid eye movement (REM) sleep (% and minutes) than normal controls. Stage 3 sleep and number of intermittent awakenings varied with phases of the menstrual cycle. Temperature minima were earlier in patients compared with controls, but this difference was not statistically significant, and there was no significant effect of menstrual cycle phase on the timing of temperature minima. Wrist motor activity did not change during the menstrual cycle in patients or controls. Thus, in this sample of women with premenstrual depression, we did not find sleep EEG alterations similar to those reported in some patients with major depressive disorder. In light of the small number of subjects and the large individual variability, the absence of marked changes with the menstrual cycle may be a function of a Type II error.

Chronobiological Basis of Female-Specific Mood Disorders

Women have twice the incidence of major depression compared with men. They are prone to develop episodes of depression during times of reproductive hormonal change at puberty, with use of oral contraceptives, during the premenstrual phase of the menstrual cycle, postpartum and during the perimenopause (see review: Parry 1995a). Wirz-Justice (1995) describes the variety of disturbances in biological rhythms observed in mood disorders. In this report, we describe the chronobiological disturbances observed in female-specific mood disorders, namely, premenstrual dysphoric disorder, pregnancy and postpartum depression and menopause. We hypothesize that changing reproductive hormones, by affecting the synchrony or coherence between components of the circadian system, may alter amplitude or phase (timing) relationships and thereby contribute to the development of mood disorders in predisposed individuals.

Can critically timed sleep deprivation be useful in pregnancy and postpartum depressions

BACKGROUND The aim of this study was to test the efficacy of critically timed sleep deprivation in major mood disorders (MMD) occurring during pregnancy and postpartum. METHODS Nine women who met DSM-IV criteria for a MMD with onset during pregnancy or within 1 year postpartum underwent a trial of either early-night sleep deprivation (ESD), in which they were sleep deprived in the early part of one night and slept from 03:00-07:00 h, or late-night sleep deprivation (LSD), in which they were deprived of sleep in the latter part of one night and slept from 21:00-01:00 h. Mood was assessed before the night of sleep deprivation, after the night of sleep deprivation, and after a night of recovery sleep (sleep 22:30-06:30 h) by trained clinicians, blind to treatment condition, using standardized scales. RESULTS More patients responded to LSD (nine of 11 trials: 82%) compared with ESD (two of six trials: 33%) and they responded more after a night of recovery sleep (nine of 11 nights: 82%) than after a night of sleep deprivation (six of 11 nights: 55%). Pregnant women were the only responders to ESD and the only nonresponders to LSD. LIMITATIONS The small and heterogeneous sample size prevents us from making more definitive conclusions based on statistical analyses. CONCLUSIONS Although the findings are preliminary, the results suggest that with further study, critically timed sleep deprivation interventions may benefit women with pregnancy or postpartum major mood disorders and potentially provide a viable alternative treatment modality for those women who are not candidates for pharmacologic or psychotherapeutic interventions. Such interventions are needed to help prevent the devastating effects of depression during pregnancy and the postpartum period on the mother, infant, her family and society.

Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and normal control subjects

In this study of 23 patients with premenstrual dysphoric disorder (PMDD) and 18 normal comparison (NC) subjects, we examined sleep EEG measures during baseline midfollicular (MF) and late luteal (LL) menstrual cycle phases and after early sleep deprivation (ESD), in which subjects slept from 03.00 to 07.00 h, and late sleep deprivation (LSD), in which subjects slept from 21.00 to 01.00 h. Each sleep deprivation night was followed by a night of recovery sleep (ESD-R, LSD-R) (sleep 22.30-06.30 h) and was administered in the late luteal phase of separate menstrual cycles. During baseline studies, sleep EEG measures differed significantly by menstrual cycle phase, but not group. Both PMDD and NC groups showed longer REM latencies and less REM sleep (minutes and percent) during the luteal compared with the follicular menstrual cycle phase. PMDD subjects, however, did not show sleep architecture changes similar to those of patients with major depressive disorders. Sleep quality was better during recovery nights of sleep in PMDD compared with NC subjects. REM sleep measures changed in association with clinical improvement in responders to sleep deprivation. Both early and late sleep deprivation may help to correct underlying circadian rhythm disturbances during sleep in PMDD, although differential sleep changes during ESD vs. LSD did not correlate with clinical response. Further sleep studies addressing additional circadian variables may serve to elucidate mechanisms mediating the therapeutic effects of sleep deprivation in PMDD.

Plasma Melatonin Circadian Rhythm Disturbances During Pregnancy and Postpartum in Depressed Women and Women With Personal or Family Histories of Depression

OBJECTIVE The purpose of this study was to test the hypothesis that disturbances in levels of plasma melatonin differentiate pregnant and postpartum women with major depression from matched pregnant and postpartum healthy comparison women. METHOD Participants were 25 pregnant women (10 with major depression, 15 healthy) and 24 postpartum women (13 with major depression, 11 healthy). Healthy comparison women were matched on the number of weeks pregnant or postpartum. Plasma melatonin levels for each subject were measured every 30 minutes, in dim light (<30 lux), from 6:00 p.m. to 11:00 a.m. The values of plasma melatonin levels were log-transformed, and calculations were determined for the following measures: baseline and synthesis onset and offset times, duration, peak concentration, and area under the curve. Groups were compared by analyses of covariance, with age, number of weeks pregnant or postpartum, breast-feeding status, and body mass index as covariates. RESULTS Morning melatonin levels from 2:00 a.m. to 11:00 a.m. were significantly lower in pregnant women with major depression relative to healthy pregnant women. However, these levels were significantly higher in postpartum women with major depression across time intervals relative to postpartum healthy women. Pregnant but not postpartum women with a personal or family history of depression, regardless of their current diagnosis, had significantly earlier melatonin synthesis and baseline offset times relative to women without a family history of depression. In pregnant healthy women but not pregnant women with major depression, melatonin levels increased during the course of pregnancy. This association was not found among postpartum women with major depression or postpartum healthy women. CONCLUSIONS Plasma nocturnal melatonin concentrations, particularly during morning hours, were lower in depressed pregnant women but elevated in depressed postpartum women relative to matched healthy comparison women. In addition, melatonin timing measures were advanced in pregnant women with a personal or family history of depression. These findings implicate disturbances in the regulation of the melatonin generating system in pregnancy and postpartum depression.

Blunted Phase-Shift Responses to Morning Bright Light in Premenstrual Dysphoric Disorder

Patients with premenstrual dysphoric disorder (PMDD) respond therapeutically to sleep deprivation and light therapy. They have blunted circadian rhythms of melatonin. The authors sought to test the hypothesis that these disturbances are a reflection of a disturbance in the underlying circadian pacemaker or, alternatively, that they reflect a disturbance in the input pathways to the clock. To test these hypotheses, after a 2-month diagnostic evaluation, 8 patients who met DSM-IV criteria for PMDD and 5 normal control (NC) subjects underwent two studies to determine whether PMDD subjects showed (1) altered melatonin sensitivity to light suppression (Study 1) and (2) altered phase-shift responses to morning light as a measure of the functional capacity of the underlying pacemaker (Study 2). In both studies, measurements were made during asymptomatic follicular and symptomatic luteal menstrual cycle phases in PMDD patients. The results of Study 1 showed no significant effect of group or menstrual cycle phase on the amount or percentage of suppression of melatonin by light. The results of Study 2 showed that with respect to the variable of offset time, PMDD subjects, when symptomatic, showed a reduced and directionally altered melatonin phase-shift response to a morning bright light stimulus ; in 4 of 5 NC subjects, melatonin offset was advanced by bright morning light, whereas in PMDD subjects, it was delayed (3 subjects) or not shifted (5 subjects) (group effect, p = .045). Study 2 also revealed that area under the curve also changed differentially in PMDD versus NC subjects. In summary, the primary findings from this pilot study suggest that in PMDD there is a maladaptive (directionally altered and blunted) response to light in the symptomatic luteal phase. Because the suppressive effects of light were similar in PMDD and NC subjects, the previously observed low melatonin levels in this disorder do not likely represent a disturbance in pineal reactivity to suprachiasmatic nucleus efferents. Instead, the findings support a possible disturbance in PMDD in the clock itself or its coupling mechanisms.

Electrophysiological findings during the menstrual cycle in women with and without late luteal phase dysphoric disorder: relationship to risk for alcoholism?

This study evaluated electrophysiological (EEG, ERGs), and cognitive (neuropsychological testing) responses in patients with late luteal phase dysphoric disorder (LLPDD, DSM-III-R) and controls over the menstrual cycle. In both groups, the frequency and stability of electroencephalogram (EEG) alpha activity significantly differed over the menstrual cycle. The latency of the P3 components of the auditory event-related potentials (ERPs) did not vary as a function of the menstrual cycle, but the P3 latency was found to be later in LLPDD subjects as a group. When the LLPDD subjects were assessed based on family history of alcoholism, it was found that those with alcoholic relatives had more high-frequency alpha (9-12 Hz) in their EEG, lower P3 component amplitudes, and longer P3 component latencies when compared to LLPDD subjects without alcoholic relatives or controls. These data suggest that LLPDD may have persistent neurophysiological correlates, some of which are also in common with risk for alcoholism.

The role of central serotonergic dysfunction in the aetiology of premenstrual dysphoric disorder: Therapeutic implications

Premenstrual dysphoric disorder (PMDD), as defined in DSM-IV, is a mood disorder. One of the leading theories for the pathogenesis of mood disorders is dysfunction of the serotonergic system. An increasing database suggests that serotonergic dysfunction also characterises PMDD. Evidence that treatments which enhance serotonergic function are beneficial in reducing the symptoms of PMDD support this hypothesis. Indeed, most of the evidence from baseline studies suggests predominantly a serotonergic rather than a noradrenergic or dopaminergic dysfunction. Challenge studies further support this hypothesis. These findings of neurotransmitter dysfunction are more consistent than those of other neuroendocrine abnormalities for example. Based on treatment studies, a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, fluoxetine, has been approved for use in PMDD by the US Food and Drug Administration.