Sleep Cycle

Dr. Philip Grossi
Sunday, 29 June 2014

Disturbances of the sleep cycle are among the most common disturbances associated with psychiatric disorders. The most common sleep disturbance is insomnia but oversleeping can also be an issue.  Insomnia can involve falling asleep (initial insomnia), staying asleep (middle insomnia), or early morning awakening (delayed insomnia). Usually people with this problem do not feel rested when awakened and usually experience irritability, anxiety, fatigue and reduced productivity the following day. I intend to set out the current understanding of the sleep/wake cycle in this blog.

Sleep is a regularly occurring state of unconsciousness resulting from two competing internal processes. Those processes are designated homeostatic which controls the amount of sleep and circadian which controls the timing of sleep. In the homeostatic process the longer one is awake the stronger the drive to sleep. So, as a normal day progresses the homeostatic drive increases and abates when one sleeps. If one is sleep deprived, then the homeostatic process increases to become overwhelming.  The circadian process is a synchronization of many bodily processes which starts with an area called the suprachiasmatic nucleus in the hypothalamus. Signals from that nucleus influence the sleep/wake cycle, hormone release, body temperature, and other physiological systems. It is the opposition of these two systems that consolidates sleep and wakefulness into discrete periods. The opposition can be thought of as similar to a teeter totter. When weight is added to one end that end falls, when weight is added to the other end or weight is taken from the original end, then the balance shifts. So the wake promoting and sleep promoting work to inhibit one another. If wake promoting activity is higher then sleep promoting is inhibited and one is awake. I sleep promoting activity is greater, then wake promoting is inhibited and one is asleep.

The neurobiology and neurophysiology underlying these competing systems is far from clear and established.  It would appear sleep promoting involves GABA, galanin, and melatonin whereas wake promoting involves orexin (hypocretin), norepinephrine, histamine, serotonin, and acetylcholine. GABA is the main inhibitory neurotransmitter in the human brain. Orexin is a peptide produced by neurons in the lateral hypothalamus and tilts the balance toward wakefulness. This discovery was made in narcoleptics who are orexin deficient. GABA is driven by the homeostatic process whereas orexin is driven by the circadian process.

Since the 1960s with the advent of the benzodiazepines the clinical treatment of sleep has focused on the sleep promoting side of the equation. The drugs thus used include all the household names. Doxepin was the first agent aimed to block wakefulness rather than promote sleep. Histamine levels increase during the night which is the likely explanation for H blockers promoting sleep maintenance. With the discovery of the orexin system and its wakefulness promoting actions, a whole new approach has opened for sleep therapeutics. Antagonists that block the orexin receptors inhibit excitatory input to arousal systems and create the conditions for sleep.  Such drugs are on the horizon and should be in the marketplace soon. One such drug, Suvorexant, has demonstrated efficacy at all doses and tolerability. It should be with us in months.





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