Circadian Dysregulation

Sleep Disturbances. Abnormal sleep is a core symptom of major depressive disorder, with sleep disruption seen at all stages in the sleep cycle (Benca, 1994). Symptoms include difficulty falling asleep, or staying asleep, as well as early-morning awakening. Hypersomnia is also described. Electroencephalography (EEG) abnormalities in depressed patients include prolonged sleep latency, decreased slow-wave sleep, and reduced rapid eye movement (REM) latency with disturbances in the relative time spent in both REM (increased) and non-REM sleep (decreased slow-wave sleep).

Reduced REM latency probably is the best studied and most reproducible sleep-related EEG finding in depressed patients, and this abnormality is reversed by most antidepressants. Sleep deprivation, particularly if instituted in the second half of the night, has a similar effect, although the rapid, dramatic improvement in depressive symptoms is short lived (Wu et al., 1999). Changes in nocturnal body temperature and attenuation of the normal fluctuations in core body temperature during sleep further suggest a more generalized dysregulation of normal circadian rhythms in patients with depression. To date, however, none of these markers have proven to be specific to depression.

Endocrine Disturbances. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most reproducible biomarkers of major depressive disorder (reviewed in Holsboer, 2000). Increases in urinary cortisol production, levels of corticotropin-releasing hormone (CRH) in spinal fluid (Nemeroff, 1996), and a general disturbance in the normal pattern of cortisol secretion have been identified (Carroll et al., 1981). Blunted suppression of morning cortisol levels following oral dexam-ethasone administration, the so-called dexamethasone suppression test (DST), was previously considered a specific marker of depressive illness. It is now recognized as an abnormality in only some subsets of depressed patients, notably psychotic depressives. Also reported is blunted adrenocorticotrophic hormone (ACTH) response to exogenous CRH. More sensitive to detect HPA dysregulation is the combined use of the DST and the CRH stimulation test. In the setting of an abnormal HPA axis test, clinical response appears to best correlate with normalization of the neuroendocrine abnormality. Elevated plasma cortisol following dexamethasone (DEX) predicts a protracted clinical course. The combined DEX/CRH test appears to be a useful predictor of increased relapse risk. Recent reports of alterations in cortisol regulation in women with a history of early life trauma or abuse further suggest that HPA axis dysregulation may be an important marker of vulnerability to various types of affective disorders in later life, paralleling studies in rodents and primates (Heim et al., 2000).

Thyroid markers have also been examined in patients with affective disorder (Nemeroff, 1989). Even with normal levels of circulating thyroid hormone, elevated levels of thyroid antibodies have been demonstrated in patients with depression but without overt thyroid dysfunction. A blunted response of thyroid-stimulating hormone to exogenous thyroid-releasing hormone (thyroid stimulation test) has also been described.

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