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It has been established that 4.4 to 20% of the general population suffers from a major depressive disorder (MDD), which is frequently associated with a dysregulation of normal sleep-wake mechanisms. Disturbances of circadian rhythms are a cardinal feature of psychiatric dysfunctions, including MDD, which tends to indicate that biological clocks may play a role in their pathophysiology. Thus, episodes of depression and mania or hypomania can arise as a consequence of the disruption of zeitgebers (time cues). In addition, the habit of sleeping at a time that is out of phase with the body's other biological rhythms is a common finding in depressed patients. In this review, we have covered a vast area, emerging from human and animal studies, which supports the link between sleep and depression. In doing so, this paper covers a broad range of distinct mechanisms that may underlie the link between sleep and depression. This review further highlights the mechanisms that may underlie such link (e.g. circadian rhythm alterations, melatonin, and neuroinflammatory dysregulation), as well as evidence for a link between sleep and depression (e.g. objective findings of sleep during depressive episodes, effects of pharmacotherapy, chronotherapy, comorbidity of obstructive sleep apnea and depression), are presented., Competing Interests: Declaration of Competing Interests The authors have read the journal's policy and have the following potential conflicts: SRP is a stockholder and the President and Chief Executive Officer of Somnogen Canada Inc., a Canadian corporation. He declares that he has no competing interests that might be perceived to influence the content of this article. This does not alter the authors’ adherence to all the journal policies. All remaining authors declare that they have no proprietary, financial, professional, nor any other personal interest of any nature or kind in any product or services and/or company that could be construed or considered to be a potential conflict of interest that might have influenced the views expressed in this manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Immortalized SCN2.2 cells retain most biochemical and biophysical characteristics of the native rat SCN including the expression of clock genes and circadian regulatory proteins, and its distinctive pacemaker function. This study assessed the expression and signaling of MT(1) and MT(2) melatonin receptors in SCN2.2 cells. SCN2.2 cells express MT(1) and MT(2) receptors mRNA as detected by RT-PCR. In situ hybridization with digoxigenin-labeled probes demonstrated that mRNA for MT(1) and MT(2) melatonin receptors is expressed mostly in cells with neuronal-like morphology, representing 10.8+/-2.2% and 9.8+/-0.2%, respectively, of the SCN2.2 cell population. MT(1) and MT(2) melatonin receptor proteins are expressed in both rat SCN2.2 cells and rat SCN tissue as demonstrated by Western blot analysis with specific receptor antiserum. Melatonin (0.1-100 nM) inhibited forskolin (20 microM)-stimulated cAMP formation in a dose-dependent manner and this effect was blocked by the competitive melatonin receptor antagonist luzindole (100-1000 nM). Furthermore, melatonin (1 nM) stimulated protein kinase C (PKC) activity by approximately 2-fold. The selective MT(2) receptor antagonist 4P-PDOT (100 nM) blocked this effect, indicating that the melatonin-mediated increase in PKC activity occurs through activation of MT(2) melatonin receptors. We conclude that SCN2.2 cells express functional melatonin receptors, providing an in vitro model to unveil the melatonin signaling pathway(s) involved in the regulation of circadian rhythms.

It is unclear whether the functional changes found in panic disorder reflect disturbed physiology of particular neurotransmitters. One method of investigating altered neurotransmission is to assess regional brain activations in response to agonist challenges. D-Fenfluramine is a medication that induces neuronal release of serotonin. Using ¿15OH(2)O and positron emission tomography (PET), measurements of regional cerebral blood flow (rCBF) were done at t=-20, -5, +20 and +35 relative to the IV D-fenfluramine injection (t=0) in nine panic-disordered and 18 healthy subjects. Subjects were otherwise healthy, right-handed, non-smoking and not taking psychotropic medication. ¿15OH(2)O PET scans were assessed with Statistical Parametric Mapping using individual global cerebral blood flow as a covariate. Comparisons of the (baseline) first two scans between healthy and panic-disordered subjects showed a decreased rCBF in the left posterior parietal-superior temporal cortex in the patient group. Fenfluramine-induced increases as defined by the last two scans minus the first two scans were compared between groups and a significantly greater increase in the same left posterior parietal-superior temporal region was found in panic-disordered subjects. Consistent with this finding, differences between the last two scans (post-fenfluramine) of the healthy and panic-disordered subjects showed an increased rCBF in the left superior temporal cortex in panic-disordered subjects. Functional pathology in the left parietal-superior temporal cortex in panic disorder may be related to abnormal modulation by serotonin.

Nine bipolar patients (2 men and 7 women) and 12 healthy control subjects completed overnight sampling for serum melatonin (MT) and urinary 6-sulphatoxymelatonin (aMT6s). The patients were investigated during manic, depressed, and/or euthymic states. Although serum MT levels did not differ significantly across the bipolar groups, in all cases serum MT levels were significantly lower than in control subjects. Differences in MT levels were also present between bipolar patients who were in a depressed phase and control subjects. There were no statistically significant differences in urinary aMT6s levels among the patients and control subjects, although in all cases nocturnal aMT6s levels were significantly higher than daytime levels. This study provides tentative evidence for decreased serum MT as a trait but not a state marker in bipolar affective disorder.

The present study investigated pre- and post-treatment 24-h urinary metabolites of monoamines and melatonin as a function of response to treatment in primary early onset dysthymic patients. The main finding was that treatment responders had lower urinary 5-hydroxyindoleacetic acid (5-HIAA) levels prior to treatment. Following treatment, urinary 5-HIAA tended to be decreased in nonresponders and increased in responders. As well, metanephrine levels were lower and 6-sulphatoxymelatonin levels were higher in responders prior to treatment. These data support the view that there is a biological substrate for certain subgroups of dysthymia, part of which may involve serotonergic systems.

This study investigates the effect of a serotonergic agent, fenfluramine, on neuronal activity, as measured using [18F]fluorodeoxyglucose (FDG) uptake with positron emission tomography (PET) in humans. Eleven subjects each received oral fenfluramine and placebo, on two different occasions, followed by FDG PET scans. Our study shows that fenfluramine modulates ongoing neuronal activity in a regionally specific fashion with a relative increase in metabolism in the prefrontal cortex and a relative decrease in the occipital-temporal regions.

Output of melatonin or its main metabolite, 6-sulphatoxy melatonin, provides an index of noradrenergic activity in the pineal gland, which is of interest in major depression and during its treatment with antidepressants. Fifteen female depressed outpatients did not differ in levels of 24-hour urinary 6-sulphatoxy melatonin compared with 13 female control subjects. However, a subgroup of the depressed patients (n = 9) who were treated with desipramine showed a significant elevation of 6-sulphatoxy melatonin levels after 1 week of treatment and a return to baseline levels after 6 weeks. There was also a significant negative correlation between 6-sulphatoxy melatonin levels and symptom severity as measured by the Hamilton Rating Scale for Depression after 3 weeks of treatment with desipramine. The other subgroup of depressed patients (n = 6) were treated with adinazolam, a benzodiazepine with antidepressant properties. Despite comparable antidepressant effects to those achieved with desipramine, adinazolam was not associated with any apparent change in 6-sulphatoxy melatonin output during 6 weeks of treatment. There was also no correlation between 6-sulphatoxy melatonin levels and symptom severity.

A relationship of urinary catecholamines and of urinary free cortisol with violent suicide attempts has been reported. We have reexamined this issue in patients within 24 hours of hospital admission. Suicide attempters had significantly higher norepinephrine (NE: mean +/- SD = 58.3 +/- 27.0 micrograms/24 hours; n = 27) than did control patients with suicidal ideation (mean +/- SD = 37.1 +/- 21.3; n = 10). Among suicide attempters, those who used physical means had the highest NE levels (mean +/- SD = 69.7 +/- 21.3) and those who took overdoses of antidepressants (mean +/- SD = 51.9 +/- 17.3; n = 6), benzodiazepines (mean +/- SD = 65.1 +/- 29.7; n = 5), or miscellaneous drugs (mean +/- SD = 59.1 +/- 36.5; n = 11) had lower NE values. In contrast to NE, urinary dopamine (mean +/- SD = 402.6 +/- 392 micrograms/24 hours, epinephrine (EPI: mean +/- SD = 14.3 +/- 4.0 micrograms/24 hours), the NE/EPI ratio (mean +/- SD = 8.3 +/- 0.9), urinary free cortisol (mean +/- SD = 157.9 +/- 11.5 micrograms/24 hours) and serum cortisol (mean +/- SD = 35.0 +/- 13.1 nM/l) did not differ between groups. There were no group differences in age (mean +/- SD = 36.3 +/- 16.5 years), Beck Depression Inventory score (mean +/- SD = 26.3 +/- 12.9), Beck Hopelessness Scale score (mean +/- SD = 10.0 +/- 5.6), Beck Scale for Suicidal Ideation score (mean +/- SD = 13.6 +/- 9.3), or Hamilton Rating Scale for Depression score (mean +/- SD = 19.5 +/- 9.8). In the four parasuicide groups, there was no difference in suicide intent (mean +/- SD = 13.3 +/- 7.9). These findings indicate that there is increased NE output shortly after suicide attempts. Previous reports of a low NE/EPI ratio in suicidal patients may reflect adaptive changes rather than the acute state of the patient at the time of the attempt.

Since neuroleptic treatment produces a significant increase in striatal metabolism relative to cortical metabolism, we wished to determine whether the dopamine agonist apomorphine (APO) might have the opposite effect, and whether it would discriminate schizophrenic patients from healthy controls. Eleven neuroleptic-naive schizophrenic patients (diagnosed according to DSM-III) and eight normal subjects were compared with respect to cerebral accumulation of 18F-fluorodeoxyglucose measured by positron emission tomography following APO, 0.75 mg/70 kg (weight adjusted), or saline. Relative striatal glucose metabolism decreased significantly after APO in schizophrenic patients but not in control subjects. Post hoc analysis of data in 12 other regions revealed that relative superior temporal metabolism decreased very slightly, but significantly, in schizophrenic patients but not in control subjects after APO, and that the posterior frontal region increased in control subjects but not in the patient group.

Urinary excretion of the principal melatonin metabolite, sulphatoxy melatonin (aMT6s), was assessed both during the day and during the night in 38 female eating disorder patients (anorexia nervosa, n = 17; bulimia nervosa, n = 12; anorexia nervosa + bulimia nervosa, n = 9) and 14 female control subjects. Correlations between nocturnal serum melatonin and urinary aMT6s were also obtained. All patient groups and the controls showed a preservation of diurnal rhythm with elevated nocturnal urinary aMT6s values and no significant difference in amplitude between groups. However, patients with concurrent major depression had significantly lower levels of daytime and nighttime urinary aMT6s than the nondepressed group. Weight did not influence these findings. Correlations between nocturnal serum melatonin levels and urinary aMT6s were high for control subjects (r = 0.77) and moderate for the patient groups (r = 0.31). This may reflect differences in the rate of excretion of melatonin between patients and controls.

The objective of the study was to determine dose-response relationships of growth hormone, vasopressin, blood pressure, heart rate, and behavioral responses to clonidine. Ten healthy male volunteers were tested with each of three doses of clonidine (0.7, 1.4, and 2.1 micrograms/kg) with at least 1 week between tests. All doses gave a significant growth hormone response with a peak at 50 min. The high dose gave a significantly higher response than either the medium dose or the low dose, which did not differ from each other. Within individual subjects, there was a consistency of response to the different doses; thus, three of the volunteers had responses of 5 ng/ml or higher to the low dose. Those three subjects had higher growth hormone peaks after the highest dose than did six other subjects. Vasopressin showed a drop following clonidine after the two higher doses. Systolic blood pressure dropped following clonidine, showing a significantly greater drop for the medium and high doses than for the low dose. Diastolic blood pressure also showed a drop, but responsiveness did not differ between doses. There was significant dryness of mouth produced by clonidine, but no difference between doses. There was a significant sedative effect following clonidine which was greater for the high dose than for the medium or low dose. The finding that some subjects had a growth hormone peak of 5 ng/ml or greater after the low dose supports the hypothesis that use of a low dose strategy may be useful in confirming supersensitivity in conditions where increased responsiveness is suspected. The lack of difference between blood pressure responses to the medium and high doses of clonidine--doses that have different effects on growth hormone--supports the hypothesis that differences in responsiveness of presynaptic and postsynaptic alpha 2-adrenergic receptors exist.

Increasing evidence implicates altered dopamine function in major affective illness. In the present study, growth hormone responses to the dopamine agonist apomorphine were not different for 14 male depressed patients and 16 healthy male volunteers. Baseline and post-apomorphine prolactin levels were lower for the depressed patients than the control subjects, but the percent decrease following apomorphine was not different for the two groups. Neuroendocrine responses were not significantly altered during chronic treatment with the dopamine agonist piribedil. These neuroendocrine results suggest that decreased baseline prolactin levels in depressed patients do not reflect altered postsynaptic receptor sensitivity in the tuberoinfundibular dopamine system.

The mode of action of lithium in the treatment of bipolar affective disorder is unknown. Among its actions are effects on release and response to catecholamines in experimental animals. We have therefore examined its effect on peripheral catecholamines in man. After 3 weeks of administration of therapeutic doses of lithium carbonate, healthy volunteers showed a differential response of catecholamines to insulin stimulation. Although the response of plasma norepinephrine remained unchanged, epinephrine response was dramatically reduced. These findings provide additional evidence for the separate neural regulation of the adrenal medulla and sympathetic nerve endings. Further studies are necessary to determine whether these effects on peripheral epinephrine are paralleled by changes in central epinephrine.

As part of an ongoing longitudinal study of drug-free schizophrenic patients, we serially sampled resting early morning prolactin levels in 10 subjects. In a preliminary analysis, these levels were compared to those found in matched normal control subjects over a 4-year period. Both control and schizophrenic subjects showed a marked annual variation in prolactin levels. Six schizophrenic patients sampled in each quarter of the year showed a significant annual rhythm, with prolactin highest in the spring (March-May). In seven schizophrenic patients and nine controls sampled at two seasons in the year, prolactin was significantly higher in spring-summer (March-August) than in fall-winter (September-February), with no difference between patients and control subjects.

This study investigated whether the indices of dopaminergic function, yawning and growth hormone release induced by apomorphine, as well as the drug-induced nausea and hyperthermia, show sensitization or tolerance to repeated injections. Five normal volunteers received 12 injections of apomorphine hydrochloride (0.75 mg/70 kg) every 2 weeks. Yawning, as measured by the latency of onset and the time of peak activity, showed sensitization. The growth hormone response showed no change. Feelings of nausea and hyperthermia showed tolerance to repeated injections. These findings suggest that yawning may be a suitable index of dopaminergic function in studies of schizophrenia.

Using two different antisera, one binding only melatonin (M) and the other binding both M and N-acetylserotonin (NAS), brain tissue and the Harderian gland were investigated using fluorescence and peroxidase labeled double antibody immunohistology. M has been identified in the outer nuclear layer of the retina, in the optic nerves, chiasma and the tracts, suprachiasmatic nucleus and the Harderian gland. NAS, but not M, was found in the granule layer of the cerebellum, spinal tract of the trigeminal roots and the pontal and spinal reticular formation. The possible relationship of cerebellar and brain stem NAS to brain excitability as well as localization of M in the visual pathway, suprachiasmatic nucleus and the Harderian gland in the relation to the regulation of light dependent circadian periodicity is discussed.

Plasma prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and cortisol were repeatedly measured during the morning over a 4-hour period in patients who received single or chronic doses of desipramine (DMI) or zimelidine (ZIM). Preclinical studies had suggested that DMI, an uptake inhibitor specific for norepinephrine, would have different effects than ZIM, a selective serotinin uptake inhibitor. The GH response to DMI was blunted in the depressed patients. Neither DMI nor ZIM produced changes in LH or cortisol. DMI acutely increased plasma PRL, whereas ZIM had an effect only after chronic pretreatment. Chronic DMI but not ZIM increased baseline PRL. The patterns and magnitude of responses raise questions concerning the role of serotonin and norepinephrine in PRL release in man and the applicability of current preclinical models.

Frontal and parietal lobe metabolism was measured by [18F] fluorodeoxyglucose positron emission tomography in 8 never-medicated DSM-III schizophrenic patients and in 10 control subjects. Patients were in a psychotic episode at the time of this scan. Seven of eight had been ill less than 2 years and had only mild neurocognitive impairment. Frontal lobe glucose metabolism was significantly greater in schizophrenic patients than in controls. This finding differs from that of hypofrontality reported in chronic patients previously treated with neuroleptics. Relative glucose metabolism in the interior parietal lobe was significantly lower in schizophrenic patients than in controls. The frontal/parietal ratios were significantly greater in patients than in controls.

The growth hormone (GH) response to apomorphine hydrochloride (APO) was examined monthly in 12 schizophrenic patients on drug holiday for up to 22 months and compared with age- and sex-matched controls. There was more variability in the response of patients than controls on the first trial and on several subsequent challenges. Patients' and controls' GH responses to an APO challenge did not distinguish them from each other on the first trial. However, longitudinal data revealed that in a subgroup of five schizophrenic patients and five controls, studied for 12 consecutive trials, the GH response averaged over the 12 trials was significantly lower in the patients than in the controls. Moreover, when schizophrenics' responses on each successive trial were compared, responses decreased over time, but were significantly different from controls only in the later trials. Three of the patients were followed for more than 12 trials, and their GH responsivity increased in the later trials. GH response to APO was significantly correlated with positive symptom scores in three patients but not in four others. There was a trend toward an association between the occurrence of relapse and GH increment induced by APO. A significant association between change in body weight and change in GH response to APO was discovered, suggesting that a changing body weight may contribute to the variability in subjects' response to APO.