84,85 BPD patients also show persistent dysregulation of other rhythmic autonomic functions as well (notably, reduced heart-rate variability) independent

of drug treatments.86 Sleep monitoring (polysomnography) has shown shortened latency from onset of sleep to the first rapid eyemovement (REM) phase in both major depression and mania, greater inter-night variability of sleep duration and increased nocturnal time awake, with delayed sleep onset and longer sleep duration in remitted BPD outpatients compared with matched, healthy controls,84 as well as impaired sleep Androgen Receptor high throughput screening efficiency and disruption of circadian activity patterns in euthymic BPD patients versus controls with or without Inhibitors,research,lifescience,medical insomnia.62,82,87 Such abnormalities may be associated with the emerging evidence, that longevity is reduced among BPD patients (reflected Inhibitors,research,lifescience,medical as a huge excess of deaths owing to suicide or other violence in the young, and a moderate, but important increase in mortality due to cardiovascular, pulmonary, and other medical illnesses in older patients).88,89 Such findings suggest that some physiological characteristics may be relatively enduring “trait-makers,” diagnostic features, or potential endophenotypes, and not merely nonspecific abnormalities associated with emotional distress, acute illness, or treatment effects. Notably, systematic abnormalities in acrophase-timing, with sustained phase-advances, support Inhibitors,research,lifescience,medical the hypothesis that circadian

rhythms of BPD patients cycle somewhat faster than once every 24 hours.90 Mood-stabilizing treatment with lithium can Inhibitors,research,lifescience,medical slow circadian motility rhythms and promote more nearly normal 24-hour cycles.91 In SAD patients, bright-light therapy may normalize circadian rhythms, and dawn-simulation can facilitate awakening, consistent with phase-delay hypothesis for seasonal mood disturbances.66 Also, melatonin, regulated by the environmental light/dark cycle, can act as an

endogenous synchronizer, either in stabilizing or reinforcing bodily rhythms. Inhibitors,research,lifescience,medical It is therefore called a “chronobiotic” molecule or zeitgeber involved in signaling the time of day and time of year.92 Phase-shifting by melatonin has been attributed to actions on brain melatonin MT2 receptors present in the hypothalamic suprachiasmatic nucleus (SCN) that directly influence Ketanserin the electrical and metabolic activity of this critical nucleus.92 In addition to its phase-shifting effect, melatonin acts directly on the amplitude of daily oscillations in activity and other rhythms. Of interest, reduced or blunted amplitude of melatonin secretion was found in depressive BPD patients during clinical recovery, and low melatonin levels may represent a trait marker for depression.93 In an attempt to take advantage of the therapeutic opportunities available through the central melatonin system, researchers have developed several melatonin agonists with improved properties over those of melatonin itself.