By Alexandra Cotoi
Insomnia is a sleep disorder that manifests through symptoms of deteriorated sleep quality, increased difficulty in initiating and maintaining sleep, frequently followed by fatigue during the day1. A large number of effectors including social, psychiatric2 and genetic factors participate in the manifestations of insomnia, causing a variety of symptoms expressed through numerous degrees of seminology and severity. The genetic component has recently been studied on insomniac Drosophila models, resulting in the finding of several homologous gene categories associated with human behavior, neuronal and sensory system activity3. However, the major biological contributors to the symptoms of insomnia fall under several defective neurobiological pathways. Insomnia is highly heterogeneous in its malfunctioning circuits and frequently these pathways combine and contribute to an aberrant sleeping pattern that can later proliferate in a symptom of a more serious health issue or disease. Treatments are readily available in a variety of forms including medicinal drugs, non pharmaceutical treatments as well as cognitive therapies. In addition to examining and creating more efficient drugs, current research is also found to be occupied with treatments such as electroacupuncture as a form of non-invasive therapy4. Recognizing and treating the symptoms and causes of insomnia is essential to improving sleep hygiene and preventing the development of closely associated psychological and psychiatric disorders. ( I like your intro - very concise and to the point: Erin N)
Keywords: sleep/wake switch, thalamic filter, GABA-A receptor, HPA axis, non-benzodiazepine, eszopiclone
Outline:
1. Neurologic and Physiologic Pathways of Insomnia
1.1. Inappropriate Sleep/Wake Switch
1.2. Malfunctioning Thalamic Filter
1.3. Hyperactivity in the HPA axis
2. Types of Insomnia
2.1. Degree of Seminology
2.1.1. Onset, Intermittent, Terminal
2.2. Degree of Severity
2.2.1. Mild
2.2.2. Moderate
2.2.3. Severe
3. Causes of Insomnia
4. Treatments
4.1. GABA-A Modulator Therapy with Non-benzodiazepines (Eszopiclone)
5. References
1. Neurologic and Physiologic Pathways of Insomnia
The basis of insomnia is found to be highly correlated with defects in several neurobiological and physiological circuits. In the majority of insomnia cases, these neuro-physiologic pathways do not generally function independently of each other. This sleep disorder is often characterized as a heterogeneous combination of defective pathways that contribute to an aberrant sleeping behavior.
1.1. Inappropriate Sleep/Wake Switch
One such circuit that drives the instigation of insomniac behaviour is an inconsistent and inappropriate “on” switch of the “wake” network in the circadian sleep/wake circuit during the night1. In cases where this occurs, the suprachiasmatic nucleus (SCN) excites the orexin neurons in the dorsal hypothalamus, which successively activate the tuberomamillary nucleus (TMN). This leads to the gamma-aminobutyric acid (GABA) interactive inhibition at the ventrolateral preoptic nucleus (VLPO) and activation of the forebrain and the cortex using cholinergic and histaminergic projections during normal periods of sleep. Histamine release can also actively inhibit the sleep centre in patients with insomnia, triggering a reduced input to the VLPO1. Studies using positron emission tomography (PET) show that under stages of insomnia, there is an increase in glucose metabolism across the cerebral regions of the brain, indicating the inability to deactivate the “wake” state5. The “sleep/wake” switch is highly inconsistent with the phases of an ordinary circadian “sleep/wake” pattern, causing abnormal states of arousal during the night, even though the circuit itself is not necessarily malfunctioning.
1.2. Malfunctioning Thalamic Filter
Sleep neurological pathways in insomniacs can also include a defective cortico-striatal-thalamic-cortical circuit1, where the thalamus fails to filter incoming sensory information causing the individual to be hypersensitive to external stimuli during sleep states. This occurs when the pyramidal cells of the prefrontal cortex send excitatory glutaminergic projections to the striatum, which consecutively activate GABA neurons. These directly inhibit selective sensory information coming into the thalamus creating a filter that under normal conditions blocks the discriminatory activation of the glutaminergic neurons from projecting back to the frontal cortex1. However, during insomnia, the thalamic filter is malfunctioning thus reducing the ability of GABA neurons to block part of the incoming sensory information. This reactivates the frontal cortex causing increased periods of arousal. Generally, this occurs because of low GABAergic neurotransmission circulating in the sleep network, especially at the output level of the striatum and the input level of the thalamus 1.
1.3. Hyperactivity in the HPA axis
Another neurophysiologic pathway that is often overlooked but can play an underlying role in the instigation of insomniac behavior is the hyperactivation of the hypothalamus- pituitary- adrenal axis (HPA axis). Under daily circumstances and periods of stress, the hypothalamus will secrete corticotrophin releasing hormone (CRH) that will circulate to the anterior pituitary and stimulate the production and release of adrenocorticotrophic hormone (ACTH). ACTH is then transported through the circulatory system to the adrenal cortex where it will promote the biosynthesis of cortisol. Elevated levels of systemic cortisol contribute to a hyperaroused central nervous system that could ultimately induce states of insomnia6, 7/sup>. Although this hypothesis shows various consistencies across research, hyperarousal due to heightened cortisol level has been linked to increases in metabolic use of oxygen throughout the entire systemic and central nervous system8.
2. Types of Insomnia
There are a number of different types of categorized insomniac behaviours and most can be characterized depending on their seminology or severity.
2.1. Degree of Seminology
2.1.1. Onset, Intermittent, Terminal
Insomniac behaviour that is experienced at the beginning of early sleep phases is considered onset insomnia, while irregular and discontinuous sleep is associated with intermittent insomnia2. Lastly, terminal insomnia is found to occur during the early morning stages of arousal and awakening2.
2.2. span>Degree of Severity
2.2.1. Mild Insomnia
Mild insomnia is generally experienced due to inadequate amounts of sleep and is sometimes associated with the feeling of fatigue, irritability and complaints of obstructed nightly sleep episodes. This usually leads to little or no psychomotor retardation or impairment of habitual functioning9.
2.2.2. Moderate Insomnia
Moderate insomnia is always experienced due to insufficient sleep and increased restlessness, fatigue and irritability following a regular sleep episode. This sleep disturbance consistently results in psychomotor retardation or impairment of occupational and habitual functioning9.
2.2.3. Severe Insomnia
Severe insomnia is related to occurrences of increased complaints of substantially disturbed night sleep, anxiety and frequent fatigue during the day. This dramatically retards psychomotor functioning and severely impairs habitual activities9.
3. Causes of Insomnia
Insomnia can be associated with a large family of causal factors, which include social determinants, physiologic and medical determinants as well as a number of comorbid psychiatric disorders2. Social effectors are sometimes part of the habitual activities that cause a disruption in the “sleep/wake” switch; these rely partially on dramatically altering the circadian pattern by changing the sleeping phases significantly and inconsistently. In adolescents and adults this can be due to erratic phase delay10 caused by overnight activities and night jobs that desynchronize the sleep/wake phase shift2. A number of other social components also contribute to insomnia by inappropriately activating the HPA axis through the occurrence of everyday chronic stressors. These include issues relating to divorce, low family income and unemployment2 as well as substance abuse. Physiologic causes are related partially to genetics, heredity and family history that predispose younger generations to this disorder11, as well as influencing the onset of medical dyspnea and pain13. On the other hand, a number of pharmaceutical products have also been found to induce insomniac behaviour2, including antidepressant drugs such as fluoxetine (Prozac) and sertraline (Zoloft or Lustral)12. Frequently, these medicinal compounds are prescribed to patients that are mainly experiencing depression, or in combination with other mood stabilizers and atypical antipsychotics in disorders such as manic depression. In these bipolar psychiatric conditions, a combination of drugs is crucially necessary in normalizing both the depressive and manic symptoms. When prescribing only one set of dugs such as antidepressants (fluoxetine or sertraline), this causes a decomposition between depressive and manic symptoms. Treating only one side of the symptoms only exacerbates the other polarity. Therefore, antidepressants are combined along with mood stabilizers and anticonvulsants, in treating manic depression. However, insomnia frequently acts as a comorbid disorder depicting a reflection and a result of these psychiatric disorders14. In general, a melange of these factors will trigger or exacerbate the symptoms of insomnia.
4. Treatments
A number of treatments involve the use of non-pharmaceutical compounds to reduce insomnia, as well cognitive therapies and electroacupuncture. Pharmacological treatments however, are the most commonly used in forms of hypnotics, benzodiazepines and non-benzodiazepines.
4.1. GABA-A Modulator Therapy with Non-benzodiazepines (Eszopiclone)
Non-benzodiazepines have recently been found to reduce symptoms associated with insomnia lacking the side effects from other previously prescribed benzodiazepine medication1, 13. Specifically, eszopiclone (Lunesta), the S-enantiomer of R,S-zopiclone, is a GABA-A positive allosteric modulator that binds to sites on α1, α2, α3 and α5 receptors subunits of the GABA-A receptor1. Essentially, the binding of these modulators at the corresponding receptor sites causes the GABA-A channel to open more frequently and remain open for a longer time, allowing for a greater flow of negative charge (Cl -) to move inside neuron. This is especially important in the thalamic filter where it allows for the systematic blocking of the selective incoming sensory information, by substituting for the lack of GABAergic neurotrasmittion in the thalamus. Behaviourally, binding of the compound corresponds to the initiation of sedating behaviours and anxiolitic, anti-convulsant actions1, 15. Unlike other drugs in the benzodiazepine classes, eszopiclone is found to be rapidly absorbed and does not accumulate in the system to produce the hangover effects of psychomotor retardation and daytime sleepiness16. Moreover, because binding of the compound on the particular subunits of the GABA-A receptors does not induce conformational change, it reduces the effects of developing withdrawal, dependence, tolerance and side effects commonly found in other benzodiazepine medications1. The diminished effect of acquired tolerance allows the drug to be taken over long term periods of treatment, while sustaining its efficacy when administered correctly in recommended doses of 2-3 mg/night for adults and 1-2 mg/night in elderly16. Moreover, there is little reported evidence of a rebound effect when discontinuing the non-benzodiazepine treatment16. Eszopiclone is only one of several non-benzodiazepines that modulate insomniac behaviour by targeting the defective neurobiological GABA circuits, however, there are also a number of other drugs that target other circuits differently and reduce the behavioural effects of insomnia.
These studies do not always coincide with research looking at comorbid disorders, since for the purposes of examining insomnia as a separate disorder, specific drugs are administered and investigated. Treatment of comorbid disorders (for example schizophrenia and insomnia) requires a set of drugs including conventional and atypical antipsychotics to treat psychotic symptoms as well medication prescribed for insomniac symptoms. In cases of administering a cocktail of drugs, the medications themselves can ultimately trigger or exacerbate lingering symptoms. For individuals who discontinue their prescribed medication for their comorbid disorders, insomnia may or may not linger depending on whether it initiated as a result of the medication or if it was primarily a clinical case of an insomniac disorder. Research is now focused on finding drugs that target the sources of symptoms as well as reducing the side effects and increasing tolerance.
alexandra, i thought your neurowiki was well written and quite complete. my only suggestion, is to consider using an alternative method of formatting your references, such that the superscripts appear in consecutive order throughout the text. (hma)
(I don't really know what you mean by that, the references go in order and so do the citations in the superscripts. If you could explain what you mean by that I would gladly change them) --cotoiale
Erin Nuro: Very infomrative wiki! My only suggestion would be the possible use of any pictures to reflect the neuroogic and physiologic pathways of insomnia.
thank you for the suggestion; I will post some pictures momentarily
5. References
1. Stahl, S.M. (2008). Stahl's Essential Psychopharmacology. (3rd ed).Cambridge: Cambridge University Press.
2. Dollander, M. (2002). Etiology of adult insomnia. Encephale Revue de Psychiatrie Clinique Biologique et Therapeutique, 28, 493-502.
3. Seugnet, L., Suzuki, Y., Thimgan, M., Donlea, J., Gimbel, S.I., Gottschalk, L., Duntley, S.P., and Shaw, P.J. (2009). Identifying sleep regulatory genes using a Drosophila model of insomnia. Journal of Neuroscience, 29, 7184-7157.
4. Jing-wen, R., Chu-huai, W., Xin-xue, L., Ying-shuo, Y., Yue-hua, H., Zhong-dong, R., Ming, W., Xiao-xiang., and Xin-sheng, L. (2009). Electroacupuncture treatment of chronic insomniacs. Chinese Medical Journal, 122, 2869-2873.
5. Schwartz, J. R. L., and Roth, T. (2008). Neurophysiology of sleep and wakefulness: basic science and clinical implications. Current Neuropharmacology, 6, 367-378.
6. Vgontzas, A. N., Bixler, E. O., Lin, H. M., Prolo, P., Mastorakos, G., Vela-Bueno, A., Kales, A., and Chrousos, G. P. (2001). Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. The Journal of Clinical Endocrinology & Metabolism, 86 (8), 3787-3794.
7. Rodenbeck, A., and Hajak, G. (2001). Neuroendocrine dysregulation in primary insomnia. Revue Neurologie, 157 (11), S57-S61.
span style="font-family: Calibri;">8. Bonnet, M. H., and Arand, D. L. (1995). 24-hour metabolic rate in insomniacs and matched normal sleepers. Sleep, 18 (7), 581-588.
9. American Academy of Sleep Medicine. (2001). The International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Westchester: American Academy of Sleep Medicine.
10. Liu, X. C., and Buysse, D. J. (2006). Sleep and youth suicidal behavior: a neglected field. Current Opinion in Psychiatry, 19 (3), 288-293.
11. Bastien, C. H., and Morin, C. M. (2000). Familial incidence of insomnia. Journal of Sleep Research, 19 (1), 49-54.
12. Cook, M. D., and Conner, J. (2995). Retrospective review of hypnotic use in combination with fluoxetine or sertraline. Clinical Drug Investigation, 9 (4), 212-216.
13. Drake, C. L., Roehrs, T., and Roth, T. (2003). Insomnia causes, consequences and therapeutics: an overview. Depression and Anxiety, 18, 163-176.
14. Johnson, E. O., Roth, T., Schultz, L., and Breslau, N. (2006). Epidemiology of DSM-IV insomnia in adolescence: lifetime prevalence, chronicity, and an emergent gender difference. Pediatrics, 117, e247-e356.
15. Hair, P. I., McCormack, A., and Curran, M. P. (2008). Eszopiclone: a review of its use in the treatment of insomnia. Adis Drug Evaluation, 68 (10), 1415-1434.
16. Morin, A. K., and Willett, K. (2009). The role of eszopiclone in the treatment of insomnia. Advances in Therapy, 26 (5), 500-518.
Insomnia (last edited 2011-09-14 14:50:18 by Chris)