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Etanercept for Sleep in Patients with Alcohol Use Disorder—Mechanisms Need to be Elucidated
CORRESPONDENCE Etanercept for Sleep in Patients with Alcohol Use Disorder—Mechanisms Need to be Elucidated
brain in humans, even if the primary pathology is in the brain?
To the Editor: read with interest the article titled “Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence” by Irwin et al. (1). I would like to put forward two queries regarding the scientific basis behind the methodology of the study.
The effect of proinflammatory cytokines on sleep is far from being clarified. The newfound use of TNF alpha blockers in brain disorders has put forward more questions than answers. More translational research is needed to elucidate the mechanisms by which proinflammatory cytokines modulate brain function and behavior.
1. Etanercept is a fusion protein comprising domains from a tumor necrosis factor (TNF) receptor fused to the Fc portion of immunoglobulin G1 (IgG1). It has a molecular weight of 150,000 Da and hence does not cross the blood-brain barrier (BBB) when administered systemically (2). Alcohol dependence and rapid eye movement (REM) sleep disturbance are traditionally considered to be disorders with primary pathology in the brain. In the present study, assuming that etanercept was administered subcutaneously in the study population, can we suppose that neutralization of peripheral TNF alone (by etanercept) would account for its effect on the brain (and hence sleep)? As a corollary, if the primary inflammatory pathology in alcohol dependence and REM sleep disturbance is assumed to be in the brain, that would continue to exist even if the peripheral TNF is blocked. In this context, at least one previous study found no effect of systemic etanercept on cognition in patients with dementia of the Alzheimer’s type (3). The possible reason for the absence of efficacy was attributed to the fact that etanercept does not cross the blood-brain barrier. 2. Peripheral cytokines are known to signal inflammation in the brain. Interleukin-1 beta (IL-1) and TNF alpha (TNF-␣) are now considered sleep regulatory substances. Do peripheral cytokine levels correlate with cytokine levels in the
Dr. Krishnadas reports no biomedical financial interests or potential conflicts of interest. Rajeev Krishnadas
I
0006-3223/10/$36.00
University of Glasgow Southern General Hospital Govan Road Glasgow United Kingdom E-mail: [email protected] 1. Irwin MR, Olmstead R, Valladares EM, Breen EC, Ehlers CL (2009): Tumor necrosis factor antagonism normalizes rapid eye movement sleep in alcohol dependence. Biol Psychiatry 66:191–195. 2. Banks WA, Plotkin SR, Kastin AJ (1995): Permeability of the blood-brain barrier to soluble cytokine receptors. Neuroimmunomodulation 2:161– 165. 3. Bohac D, Burke W, Cotter R, Jillian Z, Potter J, Gendelman H (2002): A 24-week randomized, double-blind, placebo-controlled study of the efficacy and tolerability of TNFR: FC (etanercept) in the treatment of dementia of the Alzheimer type. Proceedings of the 8th International Conference on Alzheimer’s Disease and Related Disorders. Neurobiol Aging 23(suppl 1):S83.
doi:10.1016/j.biopsych.2009.06.019
BIOL PSYCHIATRY 2010;67:e1 © 2010 Society of Biological Psychiatry
brain in humans, even if the primary pathology is in the brain?
To the Editor: read with interest the article titled “Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence” by Irwin et al. (1). I would like to put forward two queries regarding the scientific basis behind the methodology of the study.
The effect of proinflammatory cytokines on sleep is far from being clarified. The newfound use of TNF alpha blockers in brain disorders has put forward more questions than answers. More translational research is needed to elucidate the mechanisms by which proinflammatory cytokines modulate brain function and behavior.
1. Etanercept is a fusion protein comprising domains from a tumor necrosis factor (TNF) receptor fused to the Fc portion of immunoglobulin G1 (IgG1). It has a molecular weight of 150,000 Da and hence does not cross the blood-brain barrier (BBB) when administered systemically (2). Alcohol dependence and rapid eye movement (REM) sleep disturbance are traditionally considered to be disorders with primary pathology in the brain. In the present study, assuming that etanercept was administered subcutaneously in the study population, can we suppose that neutralization of peripheral TNF alone (by etanercept) would account for its effect on the brain (and hence sleep)? As a corollary, if the primary inflammatory pathology in alcohol dependence and REM sleep disturbance is assumed to be in the brain, that would continue to exist even if the peripheral TNF is blocked. In this context, at least one previous study found no effect of systemic etanercept on cognition in patients with dementia of the Alzheimer’s type (3). The possible reason for the absence of efficacy was attributed to the fact that etanercept does not cross the blood-brain barrier. 2. Peripheral cytokines are known to signal inflammation in the brain. Interleukin-1 beta (IL-1) and TNF alpha (TNF-␣) are now considered sleep regulatory substances. Do peripheral cytokine levels correlate with cytokine levels in the
Dr. Krishnadas reports no biomedical financial interests or potential conflicts of interest. Rajeev Krishnadas
I
0006-3223/10/$36.00
University of Glasgow Southern General Hospital Govan Road Glasgow United Kingdom E-mail: [email protected] 1. Irwin MR, Olmstead R, Valladares EM, Breen EC, Ehlers CL (2009): Tumor necrosis factor antagonism normalizes rapid eye movement sleep in alcohol dependence. Biol Psychiatry 66:191–195. 2. Banks WA, Plotkin SR, Kastin AJ (1995): Permeability of the blood-brain barrier to soluble cytokine receptors. Neuroimmunomodulation 2:161– 165. 3. Bohac D, Burke W, Cotter R, Jillian Z, Potter J, Gendelman H (2002): A 24-week randomized, double-blind, placebo-controlled study of the efficacy and tolerability of TNFR: FC (etanercept) in the treatment of dementia of the Alzheimer type. Proceedings of the 8th International Conference on Alzheimer’s Disease and Related Disorders. Neurobiol Aging 23(suppl 1):S83.
doi:10.1016/j.biopsych.2009.06.019
BIOL PSYCHIATRY 2010;67:e1 © 2010 Society of Biological Psychiatry