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First Published Sunday, 9 November 2008

Insomnia

Study the first to show a specific neurochemical difference in the brains of adults with primary insomnia


A study in the Nov. 1 issue of the journal Sleep is the first demonstration of a specific neurochemical abnormality in adults with primary insomnia, providing greater insight to the limited understanding of the condition’s pathology.


Results indicate that gamma-aminobutyric acid (GABA), the most common inhibitory transmitter in the brain, is reduced by nearly 30 percent in individuals who have been suffering from primary insomnia for more than six months. These findings suggest that primary insomnia is a manifestation of a neurobiological state of hyperarousal, which is present during both waking and sleep at physiological and cognitive levels.


GABA is reduced in the brain of individuals with insomnia, suggesting overactivity is present not only at the level of excessive thoughts and emotions, but can also be detected at the level of the nervous system,” said principal investigator Dr John Winkelman of Brigham and Women’s Hospital, which is a teaching affiliate of Harvard Medical School in Boston, Mass.


GABA decreases overall activity in many brain areas, helping the brain to “shut down.” Having a “racing mind” and an inability to shut down at night is a common complaint of people with primary insomnia.


Chronic insomnia, or symptoms that last for at least a month, affects about 10 percent of all adults in industrialized countries and is the most common sleep disorder. Most often insomnia is a “comorbid” disorder, present with another medical illness, mental disorder or sleep disorder, or associated with certain medications or substances. Approximately 25 percent of people suffering from insomnia are considered to have primary insomnia, which is defined as a difficulty falling asleep or maintaining sleep in the absence of coexisting conditions.


According to Winkelman, the recognition that primary insomnia is associated with a specific neurochemical deficiency helps validate the often misunderstood complaint of insomnia.


Recognition that insomnia has manifestations in the brain may increase the legitimacy of those who have insomnia and report substantial daytime consequences,” he said. “Insomnia is not just a phenomenon observed at night, but has daytime consequences for energy, concentration and mood.


This preliminary study included 16 participants (eight men and eight women) who were screened to be free of medical and sleep disorders, as well as anxiety and mood disorders, and who were not taking prescription medication. Ages ranged from 25 to 55 years. Researchers recruited people who had difficulty initiating or maintaining sleep with resulting daytime distress or dysfunction for a period of at least six months. The average duration of participants’ symptoms was 10 years. Objective data were collected by actigraphy and overnight polysomnography. Proton magnetic resonance spectroscopy (1H-MRS) was used to non-invasively determine GABA levels. For statistical comparison the study included a well-matched control group consisting of seven women and nine men.


Significant correlations were found between GABA levels and both subjective and objective sleep measures after adjusting for age, body mass index (BMI) and gender. In subjects with primary insomnia, sleep continuity, as measured by minutes of wake after sleep onset (WASO) on sleep study, was strongly associated with GABA levels.


According to the study, reductions in brain GABA levels also have been observed with 1H-MRS in major depressive disorder (MDD) and anxiety disorders. Primary insomnia shares many features with anxiety and depressive disorders, including sleep disturbance, elevation in anxiety, and impairments in concentration and energy. In addition, primary insomnia is an important risk factor for incident mood and anxiety disorders. The study raises the possibility that GABA deficiencies seen in people with mood and anxiety disorders may be based on disturbances in sleep.


The study also reports that many of the hypnotic medications that are most effective in treating insomnia are benzodiazepine receptor antagonists (BzRAs), which increase activity at the GABA neurons. According to a new clinical guideline for the evaluation and management of chronic insomnia in adults, which was published by the American Academy of Sleep Medicine in the Journal of Clinical Sleep Medicine, hypnotic treatment should be supplemented with behavioral and cognitive therapies whenever possible.


Another sleepless night


Winkelman JW, Buxton OM, Jensen JE, et al. Reduced Brain GABA in Primary Insomnia: Preliminary Data from 4T Proton Magnetic Resonance Spectroscopy (1H-MRS). SLEEP 2008 Nov 1;31(11):1499-1506   [Abstract]

Comment:
An observed neurotransmitter deficiency associated with a disorder does not necessarily mean the deficiency causes the disorder. It may be an effect of the disorder. ‘Chemical-imbalance’ theories have been postulated for many disorders in the past but they rarely survive the test of time (see below)

Serotonin

Serotonin:  The ‘chemical imbalance’ myth

The chemical hypothesis of anxiety and depression proposes that these disorders are caused by too little of a neurotransmitter, usually serotonin, in the brain, which is corrected by antidepressant drugs.


Its been known for more than a decade that the ‘chemical imbalance/low serotonin’ theory was deeply flawed, yet it continues to be promoted in the media and even medical journals.


Serotonergic antidepressants do increase serotonin levels both in synapses and the brain overall within about 30 minutes of the first dose, and levels may remain higher for some weeks. But they drop back to baseline or below at about the time patients begin to feel an improvement in anxiety or depression, usually some 4 to 12 weeks after beginning treatment.1


The fact that the boost in serotonin doesn’t immediately alleviate anxiety and depression is the first clue that there is more to these disorders than just a lack of serotonin.


Perhaps, the best indicator that increasing serotonin levels isn’t the factor responsible for the therapeutic effect of antidepressants is the French drug tianeptine (Stablon®), a Selective Serotonin Re-Uptake Enhancer/Accelerator. That is, it speeds up the removal of serotonin from the synapses. Yet, it is as effective as Selective Serotonin Re-uptake Inhibitors such as Prozac®, which delay removal of the neurotransmitter.


Further evidence against the hypothesis comes from rat models of depression. Rats bred to have a high genetic predisposition for depression have up to 8 times more serotonin in brain regions associated with anxiety disorders and clinical depression – the nucleus accumbens, prefrontal cortex, hippocampus, and hypothalamus – than controls.2 Chronic antidepressant treatment reduces serotonin to levels found in normal rats.


How antidepressants work is still a matter of debate. The most likely current theory is that they do so by stimulating neurogenesis – the formation of new neurons, especially in the hippocampus, and encouraging increased nerve-fiber innervation between limbic structures and the forebrain.


It shouldn’t matter how antidepressants work, just as long as they do, except that the ‘chemical imbalance’ theory is used to promote sales of the serotonin precursors L-Tryptophan and 5-HTP which not only can’t work as advertised, but which, at least in the case of L-Tryptophan, may cause harm because of a contaminate, Peak-X. Peak-X is thought to trigger the immune system disorder Eosinophilia-myalgia syndrome (EMS). L-Tryptophan linked EMS caused the deaths of 37 people in the late 1980s and permanently damaged the health of another 1,500+.


Despite claims that Peak-X contamination was confined to a few batched produced by one manufacturer, Simat et al found markers for Peak-X in pharmaceutical grade L-Tryptophan on sale in Germany in 1998. A 2001 U.S. Food and Drug Administration (FDA) Information Paper on L-tryptophan and 5-hydroxy-L-tryptophan (5-HTP) contains more information on the current thinking about these supplements.



See also: Abstract+: The media and the chemical imbalance theory
of depression


The “Chemical Imbalance” Explanation for Depression: Origins,
Lay Endorsement, and Clinical Implications
(PDF format)



References: (Note 5-HT = serotonin)

  • Bianchi M, Moser C, Lazzarini C, Vecchiato E, Crespi F. (2002)
    Forced swimming test and fluoxetine treatment: in vivo evidence that peripheral 5-HT in rat platelet-rich plasma mirrors cerebral extracellular 5-HT levels, whilst 5-HT in isolated platelets mirrors neuronal 5-HT changes.
    Exp Brain Res. 2002 Mar;143(2):191-7. [Abstract]

  • Stenfors C, Yu H, Ross SB. (2001)
    Pharmacological characterisation of the decrease in 5-HT synthesis in the mouse brain evoked by the selective serotonin re-uptake inhibitor citalopram.
    Naunyn Schmiedebergs Arch Pharmacol, vol 363(2):p 222-32 [Abstract]

  • Alvarez JC, Sanceaume M, Advenier C, et al. (1999)
    Differential changes in brain and platelet 5-HT concentrations after steady-state achievement and repeated administration of antidepressant drugs in mice.
    Eur Neuropsychopharmacol, vol 10(1):p 31-6 [Abstract]

  • Moret C, Briley M.
    Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis.
    J Neural Transm. 1997;104(2-3):147-60. [Abstract]

  • Trouvin JH, Gardier AM, Chanut E, et al. (1993)
    Time course of brain serotonin metabolism after cessation of long-term fluoxetine treatment in the rat.
    Life Sci, vol 52(18):p PL187-92 [Abstract]

  • Caccia S, Anelli M, Codegoni AM, Fracasso C, Garattini S. (1993)
    The effects of single and repeated anorectic doses of 5-hydroxytryptamine uptake inhibitors on indole levels in rat brain.
    Br J Pharmacol. 1993 Sep;110(1):355-9. [Abstract]

  • Caccia S, Fracasso C, Garattini S, Guiso G, Sarati S. (1992)
    Effects of short- and long-term administration of fluoxetine on the monoamine content of rat brain.
    Neuropharmacology. 1992 Apr;31(4):343-7. [Abstract]

  • Leonard BE. (1988)
    Pharmacological effects of serotonin reuptake inhibitors.
    J Clin Psychiatry. 1988 Aug;49 Suppl:12-7. [Abstract]

  • Zangen A, Overstreet DH, Yadid G. (1997)
    High serotonin and 5-hydroxyindoleacetic acid levels in limbic brain regions in a rat model of depression: normalization by chronic antidepressant treatment.
  • J Neurochem, vol 69(6):p 2477-83 [Abstract]


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