Sleep represents a dramatic change in physiologic state — one that occurs nightly. Sleep results from alterations in the balance of major neurotransmitter systems in the brain. Serotonin, norepinephrine, histamine, dopamine, melatonin, γ-aminobutyric acid and acetylcholine are all major players in the coordination of sleep and wake behaviours.3,4
Sleep can be defined and quantified with polysomnography (a basic type of sleep study), which collects physiologic information by various methods, including electroencephalography (EEG), electro-oculography and electromyography, and plots these variables against time. Additional physiologic measures including cardiac and respiratory function are commonly measured at the same time.
Not all time spent asleep is equal. Classically, sleep is characterized by an orderly progression of 4 non–rapid eye movement sleep states (numbered 1–4) followed by rapid eye movement (REM) sleep. This cycle generally takes about 90 minutes and repeats itself 4 or 5 times throughout the night, with an increasing amount of REM sleep in each successive cycle. A general summary of sleep stage characteristics is provided in .
Stage 1 is typically thought of as a transitional sleep state, and excessive stage 1 sleep is a marker of poor-quality sleep. If something interrupts sleep (such as a baby crying), the person typically rises to wakefulness and then re-enters transitional stage 1 sleep. Stage 1 represents less than 5% of total sleep during the night, whereas stage 2 represents about 50%. Stage 2 sleep has a characteristic electroencephalographic signature, the K-complex, which consists of high-voltage negative and then positive discharges with a trailing spindle (high-frequency, low-voltage discharge of approximately 0.5 seconds).
Stages 3 and 4 are biologically similar and are sometimes referred to collectively as slow-wave sleep or delta sleep. They represent homeostatic or restorative sleep. For example, when someone is sleep deprived and has the opportunity to “pay back” sleep, he or she typically enters this stage readily.5
As the neurochemical content of the brain changes over the course of the night, slow-wave sleep is characterized by a reduction in amines such as norepinephrine and serotonin and an even greater relative reduction in acetylcholine.6
People tend to feel most rested after having ample slow-wave sleep.7
REM sleep is a distinct state associated with vivid dreaming. It is not the most restorative sleep state and is, in fact, physiologically unstable. Breathing tends to become more irregular in REM sleep, and cardiac arrhythmias may be more common. REM sleep is characterized by significant reductions in norepinephrine and serotonin and lesser decreases in acetylcholine in the brain relative to wakefulness, such that REM sleep is more cholinergic than slow-wave sleep. The REM sleep state most closely resembles wakefulness according to EEG and neurochemical criteria. Consequently, people often find it easier to waken out of REM sleep than other sleep states.8
Despite some similarities to wakefulness, however, significant regional differences in brain function occur in this state, with marked increases in limbic activity (“the emotional brain”) and reductions in activity in the prefrontal cortex (“the rational brain”), which might account for some features of dreams.9
Circadian (time-of-day) factors are also important for the expression of REM sleep. Thus, the sleep obtained in a daytime nap may not necessarily be of the same restorative value as sleep obtained at night. It is unusual to have REM sleep during daytime naps, for example, although this can occur in cases of significant sleep deprivation and in narcolepsy.10
Many of the major neurotransmitter systems involved in the regulation of sleep are responsible for multiple functions in the brain, including functions relevant to psychiatric disorders. It is therefore not surprising that significant interactions could occur between sleep and psychiatric disorders. As reviewed by Buysse et al,11
several notable research findings support such interactions, including the following:
- Symptoms of insomnia are associated with significant risk for new-onset depression and anxiety disorders.
- Sleep disturbances are among the most common symptoms of psychiatric disorders.
- Manipulations of sleep and circadian rhythms are useful treatments for mood disorders.
Objective assessment of the characteristics of sleep in patients with depression, by polysomnographic methods, has revealed consistent differences from control populations in a number of sleep variables. One of the most robust findings has been that this disorder is characterized by a short REM latency (the time it takes to enter REM sleep from sleep onset).12
All antidepressant therapies, including psychotherapy, pharmacotherapy and electroconvulsive therapy, have demonstrated an improvement in depression associated with an increase in REM latency. Other characteristics of sleep that have been observed in patients with depression include difficulties initiating sleep, decreased sleep continuity (i.e., increased number of awakenings), decreased slow-wave sleep (i.e., decreased percentage of stage 3 or 4 sleep) and enhanced REM sleep.11
Sex differences in sleep physiology and behaviour have been identified, both in humans and in other species. In particular, higher amplitude of slow-wave activity and slower age-related decline in slow-wave activity have been reported in women.13
In addition, sleep is associated with hormonal changes.14
For example, thyroid-stimulating hormone is suppressed by sleep, whereas growth hormone is expressed during slow-wave sleep, and sleep deprivation blunts peaks in secretion of the latter. Cortisol follows a complex circadian rhythm, with increasing concentrations toward the end of the night. In contrast, prolactin generally peaks during sleep, but this peak can be reduced by remaining awake. Prolactin has also been noted to increase REM sleep in animals.14
Oxytocin appears to have dual function in sleep, at least in nonhuman animals. Under stress-free conditions, basal oxytocin may promote sleep, whereas under stress, oxytocin may increase wakefulness.15
Our understanding of hormonal influences on sleep regulation remains limited. The available data have been reviewed recently.13
It is notable that progesterone and its 5α-reduced metabolites, including allopregnanolone, have significant sedative properties.16
Estrogen, on the other hand, has generally excitatory effects in the nervous system and has been associated with a decrease in the expression of REM sleep.17
Concentrations of estrogen, progesterone and the 5α-reduced progesterone metabolites increase several-fold during pregnancy and drop to prepregnancy levels within a few days after childbirth;18
these changes could therefore be implicated in the fatigue and insomnia that have been observed in healthy pregnant women during the third trimester of pregnancy.19
Conflicting data about the role of sex hormones in sleep has likely resulted from differences in methodologic techniques. For example, some studies have assessed effects of pharmacologic hormonal therapy (e.g., with pregnenolone) on sleep in men;20
this is obviously much different from studying sleep on the basis of physiologic changes in the menstrual cycle in women.21,22
Similarly, the effect of exogenous administration of high doses of estrogen in the form of synthetic compounds may be very different from that of lower doses of naturally occurring compounds. In addition, it has been difficult to interpret the effects of estrogen in the context of progesterone co-administration in typical hormone therapy regimens.