Perlis醫師接受來自AstraZeneca、Bristol-Myers Squibb、Eli Lilly、Elan/Eisai、GlaxoSmithKline、Pfizer和U.S. Pharmaceuticals Group的研究支持、顧問費用、發言費用或獎金,擁有Concordant Rater Systems LL的股票和專利。Uher博士宣告沒有相關財務關係。
Am J Psychiatry. 線上發表於2010年4月1日。
Genetic Abnormality in Huntington's Disease More Frequent in Those With Depression
By Jacquelyn K. Beals, PhD
Medscape Medical News
April 15, 2010 — An increased number of CAG repeats — the genetic abnormality causing Huntington’s disease (HD) — is more frequent among patients with major depressive disorder than in the general population, according to a recent study published online April 1 in the American Journal of Psychiatry.
Depression, as well as problems with impulse control, cognitive symptoms, and irritability, occurs more often in patients who will eventually develop HD, but the associated CAG repeat had not previously been studied in patients with major depressive disorder.
HD results from a mutation in HTT (the Huntingtin gene) and is an autosomal dominant disorder, requiring only 1 mutant allele for clinical symptoms to be expressed. The mutation consists of an expanded "trinucleotide repeat," a sequence of the 3 nucleotides C, A, and G, that encode the amino acid glutamine in the Huntingtin protein.
People with 6 to 34 repeats of the CAG sequence are clinically normal, those with 36 to 39 repeats are somewhat likely to develop symptoms, and 40 or more repeats cause HD. The number of repeats tends to increase each time the gene is inherited. Maternal inheritance usually involves increases (or, less often, decreases) of up to 5 repeats; paternal inheritance typically involves increases averaging 10 repeats.
A further characteristic of HD is that symptoms appear between the ages of 30 and 50 years, with age at onset varying inversely with the number of CAG repeats. HD is a "prototypical CAG repeat disorder," said first study author Roy H. Perlis, MD, MSc, assistant professor of psychiatry, Harvard Medical School, and Depression Clinical and Research Program, Massachusetts General Hospital, Boston, in his email to Medscape.
Asked why HD symptoms do not appear until middle age, Dr. Perlis explained, "It may be a cumulative effect...Part of the motivation for the study, as we point out in the paper, is that depressive symptoms and irritability may be present a decade or more before the characteristic movement symptoms in Huntington’s."
The expanded CAG repeats probably interfere with phosphorylation of adenosine diphosphate in the mitochondria. "Mitochondrial phosphorylation is the engine producing energy for each cell," Rudolf Uher, PhD, MRCPsych, clinical lecturer in affective disorders at the Institute of Psychiatry, King’s College London, United Kingdom, told Medscape Psychiatry.
"When [phosphorylation] is blocked, the cell function deteriorates. And this is even more so for neural cells [that] will have high energy demands." Dr. Uher added, "The fact that it takes more than 30 years for [HD] to manifest itself is a testimony to how great the reserves of our brains are."
This case-control study investigated associations between the number of CAG repeats in a group with major depressive disorder (n = 34) and a healthy group matched by sex, age, education, and ethnicity (n = 74). Two persons in the case group had CAG repeats of 36 and 37, but no repeats above the normal range were found in the control group (Fisher’s exact test, P = .098).
In a second "discovery cohort," DNA was obtained from 1493 white patients (self-reported) from the multicenter Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The control DNA source was the chromosome with the shorter repeat, from 4007 HD patients. Among the STAR*D patients, DNA analysis found 4 variants with 36, 37, 38, and 42 CAG repeats. None of the control group had repeats outside the normal range (Fisher’s exact test, P = .006).
Replication was performed in patients (n = 601) diagnosed as having depression from a German inpatient unit. The control group (n = 1339) had been recruited from the same region as a comparison group for neuropsychiatric studies. A single expanded repeat (38 copies of CAG) was found among depression patients but none of the control group (Fisher’s exact test, P = .31). Combining the 3 cohorts yielded 7 repeats outside the normal range among depression cohorts and none in the comparison groups (Fisher’s exact test, P = .001).
The results show a higher than expected occurrence of "low-end" HD-associated alleles among patients with major depressive disorders. One interpretation is that the depression is an early presentation of later-developing HD. Another possibility leads to greater understanding of "borderline" or "incompletely penetrant" alleles (36 to 39 CAG repeats) for which no clinical characteristics have been defined. These alleles may cause depression but not lead to HD.
In either case, the results suggest that clinicians should ask patients with major depressive disorders about their family history of movement disorders, as well as doing a thorough neurological examination.
"This rare genetic variant still accounts for only a very small amount of the overall risk for depression," said Dr. Perlis. "I would emphasize that we are not suggesting genetic testing in people with depression, which would be extremely premature.
"Rather, we wanted to point out that many other neurologic disorders present with depressive symptoms and that clinical assessment of the patient presenting with depression includes consideration of neurologic symptoms. So we’re arguing for closer clinical assessment and emphatically not genetic testing," Dr. Perlis concluded.
Dr. Perlis has received research support, advisory or consulting fees, or speaking fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Elan/Eisai, GlaxoSmithKline, Pfizer, and U.S. Pharmaceuticals Group and has equity holdings in and patents for Concordant Rater Systems LLC. Dr. Uher has disclosed no relevant financial relationships.