Given that depression is associated with perturbations of most endocrine and neurotransmitter systems, it is not surprising that depression alters physiologic function. The neurobiology of depression needs to account for these. In addition, it is apparent that the location of the insults in the particular individual can account for the specific symptoms of that individual and that the specific treatments used for restoring normal mood would influence the impact of those therapies on specific physiologic functions.
Diurnal, nocturnal, and seasonal effects are generated by an endogenous circadian pacemaker, entrained by environmental cues, particularly light/dark cycles. These circadian effects of sleep, temperature, and neuroendocrine secretion are mediated by periodic gene expression originating in the hypothalamic suprachiasmatic nuclei (186). Mutations in clock genes accelerate and delay circadian cycles (187). Serotonergic neurons project to the suprachiasmatic nucleus in the hypothalamus help regulate circadian sleep-wake cycles, temperature, and the HPA axis.
As part of circadian effects, there are normal 24-h fluctuations in neuroendocrine secretion, especially cortisol, growth hormone, TSH, and melatonin, as already noted above. These hormonal systems are often disrupted in depression thought to be due to heightened arousal. With shorter daylight hours, some individuals who experience the aforementioned have recurring autumn and winter depression (seasonal affective disorder, SAD) thought to be related to phase delay in the sleep-wake cycle (186, 188).
Sleep is often disturbed in depression. Imaging studies using [18(F)] 2-fluoro-2-deoxy-D-glucose PET have noted changes in oxygen utilization consistent with abnormal arousal in depressed patients associated with increased glucose utilization in ventromedial prefrontal cortex (189) and blunted response in anterior paralimbic regions during REM sleep (190). Hyper-aroused patients demonstrate loss of delta sleep, loss of sleep continuity, and increased core body temperature during sleep. Changes in quantitative perfusion MRI have been noted in treatment responders (191).
Since sleep is related to endocrine function and depression, it is interesting that deep sleep has an inhibitory influence on the HPA axis. Activation of the HPA axis or administration of glucocorticoids can lead to arousal and sleeplessness. A 24-h increase of ACTH and cortisol secretion can result in insomnia, consistent with a disorder of CNS hyper-arousal (192). In addition, elevated CRF in depressed patients can cause a hyper-arousal in some brain regions that can be observed by evaluating brain glucose utilization, consistent with the imaging findings. Sleep deprivation can produce temporary remission of depression in many patients with major depression, perhaps through effects on the HPA axis.
Sleep also is influenced by neurotransmitters. 5-HT neurons project from the dorsal raphe nuclei to the cholinergic cells of the pons to tonically inhibit rapid eye movement (REM) sleep. Depletion of 5-HT duplicates the findings of increased REM
sleep time, decreased time to onset of first REM sleep (REM latency), and decreased amount of slow wave sleep that are seen in nearly 50% of depressed patients and 10% of controls. Depletion of 5-HT and NE shortens REM latency and increases REM sleep. REM rebound is an aspect of antidepressant rebound (193).
Painful physical symptoms are also common complaints in depression (194). This may in part be related to the shared 5-HT and NE pathways in depression and pain (195) since 5-HT and NE modulate pain through the descending pain pathways. Serotonergic projections descend through the rostral ventral medulla and the pontine raphe into the spinal cord where they modulate pain. Norepinephrine neurons also project through the dorsolateral pons, locus coeruleus, medial and lateral parabrachial nuclei, and associated areas into the spinal cord to modulate pain. The effects of 5-HT and NE are synergistic in this system. Thus, dual reuptake inhibitors are effective in relieving the physical symptoms associated with depression (196). Recent functional imaging studies indicate that the presence of anxiety may accentuate pain perception (197).
Depressed patients also frequently complain about altered appetite. Both the endocrine systems and neurotransmitters are involved in appetite control. The mono-amines that are often perturbed during depression also have effects on appetite. DA modulates sensory feedback and appetite (198, 199). NE in the hypothalamus increases meal size and stimulates carbohydrate intake through a2-adrenergic receptors (200). This effect shows rapid tolerance. Corticosterone upregulates a2-adrenoreceptors. 5-HT acts through the 5-HT2C receptor to affect eating rate and through the 5-HT1B receptor to affect meal size (198). CRF is a potent anorectic when injected in cerebral ventricles or paraventricular nucleus. Thus, when present, elevated CRF associated with depression may contribute to anorexia.
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