The results of a major review of published research that examined the relationship between depression and level of omega-3 fatty acids in the diet suggest that omega-3 fatty acids have antidepressant effects.

However, the researchers point out that the quality of the studies means it's still too soon to say definitively that omega-3s can treat depression or bipolar disorder.

More studies are also needed to determine the appropriate dosage and the best composition of omega-3 supplements, as well as the patients who are most likely to benefit from the therapy, Drs. Pao-Yen Lin of Chang Gung University College of Medicine in Kaohsiung and Kuan-Pin Su of China Medical University Hospital in Taichung, both in Taiwan, conclude.

Fish and fish oil, as well as flax seed oil, are rich sources of omega-3 polyunsaturated fatty acids (PUFAs). Because areas in which there is high omega-3 PUFA consumption have a lower prevalence of depression, much interest has been generated in their use as antidepressants, the researchers note in the Journal of Clinical Psychiatry.

Interest has been particularly strong in using omega-3s for treatment-resistant depression, childhood depression, and postpartum depression. But studies to date have had mixed results.

Lin and Su reviewed 10 clinical trials, lasting 4 weeks or longer, which used two omega-3 PUFAs -- eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) -- to treat depression or bipolar disorder.

When the researchers pooled the data from all of the trials, they found a significant antidepressant effect of omega-3s.

However, because the trials used different methods to analyze the data, the researchers say, the findings must be interpreted with caution. There is also evidence for publication bias, they add, meaning studies that didn't find a benefit of omega-3s were less likely to have been published than those with positive results.

Because omega-3s are safe and have many other health benefits, the nutrients could be particularly beneficial to patients with depression and heart disease or diabetes, or women who are pregnant or breast-feeding, Lin and Su note.

Nevertheless, they conclude, "more large-scale, well-controlled studies are warranted to find out the favorable target subjects, the optimal composition and the dosage of EPA and DHA, and the long-term efficacy of omega-3 fatty acids in treating depression."

SOURCE: Journal of Clinical Psychiatry, July 2007.

A variation in a gene called GRIK4 appears to make people with depression more likely to respond to the medication citalopram (Celexa) than are people without the variation, a study by the National Institute of Mental Health (NIMH), part of the National Institutes of Health, has found.

The increased likelihood was small, but when people had both this variation and one in a different gene shown to have a similarly small effect in an earlier study, they were 23 percent more likely to respond to citalopram than were people with neither variation.

The finding addresses a key issue in mental health research: the differences in people’s responses to antidepressant medications, thought to be based partly on differences in their genes. Some patients respond to the first antidepressant they attempt, but many don’t. Each medication takes weeks to exert its full effects, and patients’ depression may worsen while they search for a medication that helps. Genetic studies, such as the one described here, may lead to a better understanding of which treatments are likely to work for each patient.

Results of the study are in the August issue of the American Journal of Psychiatry, reported by lead researcher Francis J. McMahon, MD, Silvia Paddock, PhD, of NIMH, and colleagues. Scientists from the National Human Genome Research Institute, the National Institute on Alcohol Abuse and Alcoholism, Mount Sinai School of Medicine, and University of Texas Southwestern Medical Center also contributed to the research.

“We’re moving steadily closer to being able to personalize treatments based on patients’ genetic variations. This is a crucial need for the millions of Americans who suffer from depression,” said NIMH Director Thomas R. Insel, MD. “New techniques have led to advances that would have been inconceivable a few years ago and are making individualized treatment an achievable goal.”

The researchers studied DNA provided earlier by patients participating in a recently completed NIMH clinical trial, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The trial showed that depressed patients who don’t benefit from the first medication they try have a fair chance of being helped by others.

After the trial, researchers spelled out the DNA codes contained in 68 genes suspected of being involved in depression, collected from 1,297 of the patients who had participated in STAR*D. The genetic material included the occasional variations that occur from person to person. Comparing the DNA codes of those who had responded to citalopram and those who hadn’t, the scientists found that responders were more likely to have a variation in a gene called HTR2A. Results of that study were published in May 2006.

In the newest study, researchers examined the genetic material of more of the patients who had participated in STAR*D, for a total of 1,816 samples, and repeated the comparison of DNA from citalopram responders and nonresponders. They discovered that people with the variation in the GRIK4 gene had a higher likelihood of response, and again found that the variation in the HTR2A gene also made people more likely to respond. The results were reproduced, strengthening their validity.

The protein produced by HTR2A acts as a receptor on brain cells for the chemical messenger serotonin, one of several neurotransmitters that enable the cells to communicate with each other. The discovery that a variation in a serotonin-related gene could affect response to citalopram was not entirely surprising, since the serotonin system is known to be involved in depression. Citalopram targets this system.

But GRIK4 makes a protein that acts as a receptor in a different neurotransmitter system, the glutamate system. Recent studies suggest that the glutamate system also is involved in depression, an assertion supported by the new finding.

“We know that a number of biological mechanisms underlie depression and affect treatment. Findings like this one are building a picture of what they are and how they interact, and can reveal potential molecular targets for faster-acting and more effective medications,” said McMahon. Both of the genes consist of two copies each. The 23 percent increase in likelihood of response to citalopram occurred in people who carried the favorable variations in both copies of both of the genes. People with fewer of the favorable variations didn’t have as high a response rate, but still were more likely to respond than were people with none of the favorable variations.

By using a recent technique called “SNP tags,” the researchers used fewer resources, in less time, than usually required for these kinds of studies. SNP tags eliminated the need to compare all of the millions of structural units that comprise even a tiny segment of DNA – a resource- and time-intensive process – by organizing the units into more manageable blocks of information.-NIH/National Institute of Mental Health

It's one of the most missed diagnoses in psychiatry. Bipolar disorder, involving moods that swing between the highs of mania and the lows of depression, is typically confused with everything from unipolar depression to schizophrenia to substance abuse, to borderline personality disorder, with just about all stops in between. Patients themselves often resist diagnosis, because they may not see as pathologic the surge in energy that accompanies the mania or hypomania that distinguishes the condition.

But on a few points consensus is emerging. Bipolar disorder is a chronically recurring illness. And the age of onset is dropping—in less than one generation it has gone from age 32 to 19. Whether there is a genuine increase in prevalence of the disorder is a matter of some debate, but there does seem to be a genuine increase among the young.

What's more, the depression of manic-depression is emerging as a particularly thorny problem for both patients and their doctors.

"Depression is the bane of treatment of bipolar disorder," says Robert M.A. Hirschfeld, M.D., head of psychiatry at the University of Texas Medical Branch in Galveston.

It's what is most likely to motivate patients to accept care. People spend more time in the depression phase of the disorder. And unlike unipolar depression, the depression of bipolar illness tends to be treatment-resistant.

"Antidepressants don't work very well in bipolar depression," says Dr. Hirschfeld. "They are underwhelming in their ability to treat the depression." In fact, a shift away from antidepressants is formally recognized in new treatment guidelines for bipolar disorder just released by the American Psychiatric Association.

As physicians gain experience in treating the disorder, they are discovering that antidepressants have two negative effects on the course of the disorder. Used by themselves, antidepressants can induce manic episodes. And over time they can accelerate mood cycling, increasing the frequency of episodes of depression or of mania followed by depression.

Instead, research points to the value of drugs that work as mood stabilizers for the depression of bipolar disorder, either alone or in combination with antidepressants. If antidepressants have any use at all in bipolar disorder, it may be as acute treatment for bouts of severe depression before mood stabilizers are added or substituted.

Even in cases of severe depression, the new guidelines favor increasing the dosage of mood stabilizers over other strategies.

Not so long ago, mood stabilizers could be summed up in a single word—lithium, in use since the 1960s to tame mania. But research has additionally demonstrated the effectiveness of divalproex sodium (Depakote) and lamotrigine (Lamictal), drugs that were initially developed for use as anticonvulsants in seizure disorders. Divalproex sodium has been approved for use as a mood stabilizer in bipolar disorder for several years, while lamotrigine is undergoing clinical trials for such an application.

"Optimizing the dose of lithium or divalproex has good antidepressant effects," reports Dr. Hirschfeld. "We also now know that divalproex and lamotrigine are very good for preventing recurrence in bipolar patients." A study showed that lamotrigine not only delays the time to any mood events but is notably effective against the depressive lows of bipolar illness.

No one knows for sure exactly how anticonvulsants work in bipolar disorder. For that matter, the condition has been described since the time of Hippocrates, but it is still not clear what goes awry in manic-depression.

Despite the unknowns, medications for treating the disorder are proliferating. In contrast to downplaying antidepressants in the depressive phase of the disorder, clinical research is ramping up the value of antipsychotic drugs for combating the manic phase, albeit a new generation of such drugs, collectively called atypical antipsychotics. Chief among them are olanzapine (Zyprexa) and risperidone (Risperdal). They are now considered a first-line approach to acute mania, and adjuncts for long-term therapy along with mood stabilizers.

In the long term, however, observes Nassir Ghaemi, M.D., assistant professor of psychiatry at Harvard and head of bipolar research at Cambridge Hospital, medication goes only so far. "Drugs are not effective enough. It may have to do with the overuse of antidepressants; they interfere with the benefits of mood stabilizers.

"Medications don't take you to the finish line." There seem to be residual symptoms of depression that don't clear. Even when patients stabilize into a normal, or euthymic, mood state, he says, some troubling signs can appear.

"Sometimes we see in euthymic patients cognitive dysfunction that we didn't expect in the past—word-finding difficulties, trouble maintaining concentration," Dr. Ghaemi explains. "Cumulative cognitive impairment seems to emerge with time. It may be related to findings of decreased size of the hippocampus, a brain structure that serves memory. We are on the verge of recognizing long-term cognitive impairment as a result of bipolar disorder."

He believes there is a role for aggressive psychotherapy for keeping patients well, for keeping everyday ups and downs from becoming full-blown episodes. At the very least, he finds, psychotherapy can help patients resolve the work and relationship problems that often outlast symptoms.

In addition, psychotherapy can help patients learn new coping styles and interpersonal habits. "Many of the ways patients deal with their illness are not relevant when they are well," explains Dr. Ghaemi.

For example, he says, many people develop the habit of staying up late as a way of coping with the manic symptoms. "What they couldn't change before because of the illness needs to be changed after treatment if, for example, it bothers a spouse. People have to learn to change. But the longer one is ill, the harder it is to become completely well, because the harder it is to change the habits of one's life."

And for young people diagnosed with bipolar illness, he considers psychotherapy essential. "The younger patients are, the less convinced they are that they have bipolar disorder," he says. "They have impaired insight. They're especially concerned about the need to take medications. They should be in psychotherapy to get educated about the illness and medication."

He also stresses the value of support groups, especially for young people. "It's another, important layer of validation."

THE QUESTION People with depression often take an antidepressant that blocks a particular protein from distributing serotonin in the body. Scientists recently discovered the same protein in bone.

By suppressing this protein, might such an antidepressant (known as a selective serotonin-reuptake inhibitor, or SSRI) have a negative effect on bones?

THIS STUDY analyzed data on 5,995 older men (average age, 74); 160 of them took an SSRI, and 151 took another type of antidepressant.

Bone density scans revealed that men who took SSRIs had about four per cent lower density in the hip and six per cent lower in the spine than did men who did not take antidepressants. There was virtually no difference in bone density between those who took other types of antidepressants and those who took none.

A companion study of 2,722 women who averaged 78 years old (198 taking SSRIs, 118 another type of antidepressant) measured bone density changes in the hip over five years, finding a greater decrease among SSRI users compared with non-users and no difference between women who took another antidepressant and those who took none.

WHO MAY BE AFFECTED? Older people. Bone loss often begins as early as the mid-30s (usually later for men), making bones thinner and weaker, and accelerates as people age.

CAVEATS A relatively small number of people in both studies took antidepressants. The studies did not determine how dose or duration of use might affect the results.

Some experts believe that depression itself contributes to loss of bone density.

FIND THIS STUDY June 25 issue of Archives of Internal Medicine.

LEARN MORE ABOUT loss of bone density, leading to osteoporosis, at www.rheumatology.org/public/factsheets and www.niams.nih.gov/bone.

Soon depression sufferers may not have to wait weeks or months their antidepressant medication to kick in.

Scientists are closer to understanding how to develop fast-acting antidepressant medications after doing two studies on both humans and mice using the human and veterinary medication, ketamine.

Ketamine, which in recent years has been abused as an illegal “party drug,” probably won’t be used as antidepressant because it has too many side effects, researchers said.

The drug, however, relieves symptoms of depression within hours, rather than the weeks or months that it takes current antidepressants to work, and has given scientists a clue on how to develop medications that get to the biological root of depression.

The most recent study, from the National Institute of Mental Health (NIMH), backed up a previous study that showed ketamine blocks a receptor called NMDA on brain cells. But unlike the previous study, researchers this time learned that blocking this receptor increases the activity of another receptor, AMPA, which is crucial for ketamine’s rapid antidepressant actions.

“This new finding is a major step toward learning how to improve treatment for the millions of Americans with this debilitating disorder (and) toward eliminating the weeks of suffering and uncertainty they have to endure while they wait for their medications to work,” said NIH Director Elias Zerhouni, M.D., in a statement.

NMDA and AMPA are receptors for the neurotransmitter, glutamate, one of the chemical messengers that enable brain cells to communicate with each other. Glutamate has only recently been eyed as a factor in depression, according to the study, which was reported online in Biological Psychiatry on July 23. .

Researchers added that focusing on NMDA, AMPA and glutamate may allow for the development of drugs that quickly attack the root of depression, rather than taking the round-about approach that the currently available SSRI, monoamine oxidase inhibitor, and tricyclic antidepressants take.