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Studies Give Boost to Therapies for Depression
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Studies Give Boost to Therapies For Depression
It is easy to forget, with the protracted debate about the increased risk of suicide for children on antidepressants, that those same drugs have substantially improved and refined the treatment of depression.
For people taking antidepressants, low folate levels in the blood may mean a higher chance of relapse after treatment, according to a study led by George Papakostas. (Photo by Graham Ramsay)
"In that way, we've been lucky," said George Papakostas, HMS instructor in psychiatry at Massachusetts General Hospital. "For those of us who treat depression, the treatments developed during the '80s and '90s are relatively effective and tolerable, and quite safe."
In other ways, psychiatrists feel stuck. About one quarter to one half of people diagnosed with major depressive disorder will find only partial relief or none at all from the most commonly prescribed antidepressants, such as venlafaxine (Effexor), bupropion (Wellbutrin), duloxetine (Cymbalta), or the selective serotonin reuptake inhibitors (SSRIs).
"We have yet to develop or discover any biomarkers that can reliably and consistently predict outcome," Papakostas said. If psychiatrists knew in advance which antidepressants were more or less likely to work and for which patients, they could devise more tailored treatments and avoid exposing patients to ineffective drugs and unnecessary side effects. Ideally, such markers would be efficient, inexpensive, convenient, and scientifically validated, and perhaps they would suggest opportunities for intervention.
Folate and its metabolic products may be shaping up to become these markers. Two new research papers by Papakostas and his colleagues suggest that low folate levels may help guide clinicians at two critical junctures: what to do when fluoxetine (Prozac) or other SSRIs are not working and whom to watch more closely for relapse if the SSRIs do help.
Double Dip: Folate and Mood
The relationship between folate and depression has been studied for more than 40 years, though folic acid may be better known for preventing other medical conditions, such as neural tube defects and cardiovascular disease. Several studies have linked lower folate concentrations with depression. Seven years ago, Maurizio Fava, director of the hospital's Depression Clinical and Research Program and senior author on the new papers, found that people who had low blood folate levels before treatment for major depressive disorder were less likely to find relief in fluoxetine.
| "Our primary objective is to expand, if possible, the armamentarium of the clinician when called to treat someone with treatment-resistant depression." |
In his new analysis, Papakostas found that the higher doses or additional medications helped nearly half of the people with normal folate levels whose depression had resisted eight weeks of fluoxetine, but made a difference for only 7 percent of people with low folate levels.
In a companion paper in the same issue, people whose moods were restored by fluoxetine, but possessed low folate levels before treatment, were much more likely to relapse, despite the extra 28 weeks of fluoxetine. The relapse rate was 43 percent compared to 3 percent for people with normal folate levels. The results were published in the August Journal of Clinical Psychiatry.
The studies are too small to readily translate into clinical recommendations, but "if the results are consistently replicated, folate could be one of the potential markers clinicians may use to stratify patients by prognosis," said Papakostas.
If low folate levels predict treatment failure, would supplements of folic acid or the metabolic end product of folate boost the effectiveness of antidepressants? That is the next question Papakostas and his colleagues want to answer. In January, they began a five-year interventional trial sponsored by the National Institute of Mental Health. They want to enroll men and women aged 18 to 80 on SSRIs or venlafaxine, a serotonin and norepinephrine reuptake inhibitor, who are experiencing symptoms of depression despite the medications. For more information on the study, contact Papakostas at 617-726-6697.
Predisposition for Low Folate
The low folate levels measured in these studies are not the same as folate deficiency. In fact, there is some evidence from Tufts University researchers that the Food and Drug Administration mandate to require folic-acid fortification of all enriched grain products by 1998 may have nearly eradicated extremely low serum folate levels.Yet vitamins alone may not solve a genetic predisposition for low folate. Other researchers have found that a significant number of severely depressed patients possess a genotype, the C677T allele of the MTHFR gene, related to the poor conversion of folic acid to the end product needed by the body to donate methyl groups required in the synthesis of neuronal messengers and membranes. Another co-author on the Papakostas papers, David Mischoulon, HMS assistant professor of psychiatry at MGH, is investigating how the MTHFR genotype affects response to treatment.
Interestingly, the end product of this pathway, s-adenosyl methionine (SAMe), may be an effective medicine in its own right. SAMe has been marketed for more than 25 years in Europe as an antidepressant, but was released in the United States as an over-the-counter dietary supplement under the Dietary Health and Supplement Act in 1999. SAMe breaks down only a few months after being manufactured, especially when exposed to high or low temperatures, so the unregulated product found in this country may contain unreliable doses, Papakostas said.
In addition to the five-year supplement study, the MGH group is conducting what may be the first U.S. double-blind, placebo-controlled trial of SAMe used as a single therapy. They are comparing its efficacy with escitalopram oxalate (Lexapro), one of the newest SSRIs.
"Our primary objective is to expand, if possible, the armamentarium of the clinician when called to treat someone with treatment-resistant depression," Papakostas said. That job is only growing. In an influential paper last year, Fava, HMS professor of psychiatry at MGH, raised the bar by urging his colleagues to expand the traditional definition of treatment-resistant depression, which has been an absolute lack of improvement following eight to 12 weeks of antidepressants. He argued that it should encompass patients who show some improvement, but may have residual symptoms, including fatigue, sleep disturbance, lack of interest, and low motivation.
"For some patients," Papakostas said, "it may be difficult to get to the point where the mood is fully restored, but that should not prevent us from setting as our ultimate goal to fully treat the disorder."
--Carol Cruzan Morton