Posted by Phillipa on November 18, 2010, at 21:44:02
Maybe some of the new meds that target the circadian rhythm will work better than current treatments. But fits with a lot that is posted here. Phillipa
Depression Linked to Altered Activity of Circadian Rhythm Gene
Jacquelyn K. Beals, PhDNovember 18, 2010 Disturbance of the biochemical mechanisms that regulate circadian rhythm may be associated with depression, according to research findings recently published in the October issue of the Journal of Affective Disorders.
The study, led by scientists at The Ohio State University, investigated whether the expression levels of 4 genes already associated with the biological clock differed between healthy adults with and without a history of depression.
The 4 "circadian clock genes" selected for the study were Clock, Period1, Period2, and Bmal1; their expression levels were determined by measuring levels of their respective messenger RNAs (mRNAs) in peripheral blood leukocytes (PBLs).
"The 4 genes were selected based on past studies on stress, depression, and circadian gene expression," first study author Jean-Philippe Gouin, MA, MPs, clinical psychology PhD candidate, Department of Psychology, The Ohio State University, Columbus, told Medscape Medical News.
"We chose to study Clock and Bmal1 because they are the major regulators of circadian rhythm genes, senior study author Ning Quan, PhD, assistant professor, Division of Oral Biology, College of Dentistry, Department of Molecular Virology, Immunology and Medical Genetics, and the Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, told Medscape Medical News.
"Period1 and Period2 were selected because these genes have been shown to express their proteins in vivo with circadian rhythmicity and they are regulated by the Clock-Bmal1 complex. In addition, they inhibit Clock-Bmal1 activity, closing the feedback loop," Dr. Quan added.
Chronic Stress Alters Clock Gene Expression
The circadian clock genes are active in the hypothalamic suprachiasmatic nucleus, the "internal clock" that regulates several body systems to a cycle approximately 24-hours long; they are also expressed in the heart, kidneys, lungs, liver, eyes, skeletal muscles, and PBLs.
As noted above, the present study measured expression levels of circadian clock gene expression by assessing mRNA levels in PBLs. All blood samples were drawn between 9 and 11 am.
Study participants were 60 adults (mean age, 71 years). Half the participants (n = 30) had a history of depression: 16 with a single episode of major depression, 13 with recurrent episodes, and 1 with "depressive disorder not otherwise specified."
Only 4 of this group were depressed during the study. The 30 other participants had no history of clinical depression.
All participants were drawn from a larger study of caregivers for family members with progressive dementia and noncaregiver controls. Animal studies have shown that chronic stress can alter clock gene expression, and dementia caregiving is a source of chronic stress. The present study included 25 caregivers and 35 noncaregivers, but these categories were not found to influence clock gene expression.
However, individuals with a history of depression differed significantly from those with no such history in the mRNA expression of Clock (P = .05), Period1 (P = .02), and BMal1 (P = .04).
Briefly, low levels of Clock mRNA were more common among participants with no history of depression, but high levels of Clock mRNA were more common in participants with a history of depression. The same high/low depression/nondepression pattern was also found for Period 1 and Bmal1 mRNA expression.
In a simultaneous analysis of all 4 circadian genes, only Clock mRNA expression was "an independent predictor of history of depression" (P = .05). None of the other 3 circadian genes predicted a history of depression, but the association with Clock as a predictor remained stable even after adjustments for age, sex, caregiving, and confounding health variables, such as body mass index, use of alcohol and tobacco, exercise, medical conditions, and medications.
Predictor for Depression?
Dr. Quan noted that gene expression in this system is complex and specific to cell type and tissue. "I do not know whether the stronger association between depression and the Clock is logical. At least, I dont think we understand the logic at this point," he said.
"There are many confounding factors. If we can design a study to take blood samples at different times of the day, then we can think about whether Clock may be used as a predictor for depression," said Dr. Quan. "For now it is premature to think that."
The current study showed that the pattern of higher expression of circadian genes differs between people with a history of (unipolar) depression and those without such a history and that Clock constituted a predictor of a history of depression.
However, in light of inconsistent findings in the literature on clock genes, the study authors suggest several possibilities: involvement of several interacting genes with redundant feedback loops, the need for several polymorphisms to actually disrupt the circadian clock system, or an indirect effect due to the impact of these genes on sleep disturbances a recognized risk factor for depression.
"All the circadian genes are part of regulatory feedback loops," said Mr. Gouin. "Clock expression is the end result of one of the regulatory feedback loops; that is, it can be inhibited or not by other circadian genes."
Treatments Target Clock Genes
Medscape Medical News also asked Francesco Benedetti, MD, Department of Neuropsychiatric Sciences, Scientific Institute and University Vita Salute San Raffaele, Milan, Italy, to comment on the study.
Asked if Clock might ever become a molecular target for therapies to prevent depression or relieve depressive symptoms, Dr. Benedetti indicated a figure from one of his own papers.
"It already is," he said. The figure shows pathways by which lithium, valproic acid, and antipsychotics, as well as selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and even light therapy, influence Clock and Bmal1. "All the known treatments for mood disorders target the clock genes," said Dr. Benedetti.
Mr. Gouin, Dr. Quan, and Dr. Benedetti have disclosed no relevant financial relationships.
J Affect Disord. 2010;126:161-166.
poster:Phillipa
thread:970722
URL: http://www.dr-bob.org/babble/20101117/msgs/970722.html