The combined administration of olanzapine (Zyprexa) and fluoxetine (Prozac) significantly reduced the symptoms of treatment-resistant depression and depression with psychotic features, compared to either agent as monotherapy. Treatment-resistant depression, defined as the failure of two or more adequate trials of two different classes of antidepressant treatments, is a significant public health concern.

Duloxetine, an investi-gational antidepressant agent, called a dual reuptake inhibitor, was shown to be superior to placebo in reducing the severity of depressive symptoms. The Phase II data came from a multisite trial of 173 patients with major depression who randomly received either duloxetine, fluoxetine or placebo for eight weeks. The drug was well-tolerated.

Over the past 10 to 15 years, scientists have found and studied an unusual kind of steroid, which is similar to sex hormones, but unusual in that it’s produced in the brain, rather than in sex glands. Researchers found that a hormone, called allopregnanolone, is related to mood changes in premenstrual dysphoric disorder, a form of premenstrual syndrome (PMS) in which women experience severe depression and anxiety. The neurosteroid also turned out to be related to alcohol dependence and withdrawal.

Other research showed that some antidepressants raise the level of allopregnanolone in the brain. Since allopregnanolone had already been linked to depression and anxiety, these findings led scientists to look for direct relationships between the medications and the neurosteroid. The current study looked specifically at how three SSRIs affected allopregnanolone in the laboratory.

The researchers started by cloning human and animal DNA that is needed to synthesize allopregnanolone from progesterone. Then they looked at what happened when the antidepressants were added. They found that the SSRI medications led to more production of allopregnanolone. Another antidepressant from a different family of drugs had no effect.

Because the three SSRI antidepressants had such a strong direct effect on the levels of allopregnanolone, the researchers believe that the medications probably work not just by changing the availability of serotonin, but also by changing the availability of allopregnanolone, a completely different process.

Writing in the Proceedings of the National Academy of Sciences, the authors explain that understanding the role played by allopregnanolone in depression and anxiety and how antidepressant medications affect that role, can help scientists develop better treatments for these affective disorders. More knowledge will also help clarify the causes of anxiety and depression in PMS. The researchers hope that, in time, their findings will be useful in developing new ways of treating these mood disorders.

Researchers at Oxford University in Oxford, England, studied 151 patients who enrolled in a 12-week treatment program for depression. All patients were referred by their primary physician, and none required hospitalization. The 116 women and 35 men had an average age of 35 years. About half reported having been treated for depression in the past, and about half reported a family history of the illness.

Patients were randomly assigned to four groups. One group got six training sessions in problem-solving techniques, administered by a trained general practitioner, while another got the same training administered by a trained nurse. A third group received antidepressant medication and visited their doctors every two weeks. The final group got both training and medication.

The patients completed ratings of their symptoms before the treatment and at 6, 12, and 52 weeks after it began. Their physicians completed similar ratings at the same intervals.

At both 12 and 52 weeks, the 116 patients who completed the study all showed significant improvement. There were no significant differences between the medication group and the therapy groups, and the combination of medication and therapy wasn’t any more effective than one or the other.

Writing in the January 1st issue of the British Medical Journal, the Oxford researchers report that over half the patients showed significant improvement after 12 weeks, with up to two-thirds showing improvement after 52 weeks.

The researchers concluded that training in problem solving, which focuses on identifying difficulties, choosing goals, and practicing solutions, is neither more nor less effective than taking medication. Nor did it matter who delivered the training.

Given these results, the researchers suggest that problem solving therapy should be offered to patients who prefer non-drug treatment. This training can be completed in primary care when appropriately trained personnel are available. They suggest that the training is most suitable for patients with moderate symptoms.

Like the currently popular antidepressants — Prozac, Paxil, and Zoloft, the new drug, called reboxetine, affects pathways in the brain involving brain chemicals called neurotransmitters. But while the leading drugs work on a neurotransmitter called serotonin, the new medication takes a different approach, targeting a transmitter called norepinephrine. Research results from a number of countries suggest that this approach is at least as effective, and for some patients, more so.

According to Dr. Gerd Laux of Germany, reboxetine has proved “highly significant” in reducing depression in studies that included over 5,000 hospitalized and outpatient participants. The number of patients who stop taking the drug due to side effects, most commonly dry mouth, agitation, and urinary hesitancy, was similar to the number that stop taking other antidepressants — a little less than 10 percent.

In Spain, reports Dr. Jose Carrasco, reboxetine has been used with patients who don’t respond to other antidepressants, as well as in combination with other drugs. “However, it is progressively becoming a first-line treatment,” he stated, noting that between 10 and 20 percent of Spanish psychiatrists now prefer to start treatment with reboxetine.

Carrasco said that among more than 2,500 patients with major depressive disorder, 78 percent had no symptoms after eight weeks of treatment. He also pointed out that although 28 percent reported side effects such as dry mouth, constipation, and sleepiness during the first week, this number dropped to 10 percent by the eighth week, suggesting that side effects may clear up after a short period of time.

All of the researchers emphasized the positive effects of reboxetine on social function in depressed patients. “There is a strong sense that most of the patients who use this [drug] have improvements in social function,” noted Dr. Carlos Berlanga of Mexico. He reports that many patients returned to their pre-depression levels of social functioning. Laux of Germany, Carrasco of Spain, Dr. Roger Montenegro of Argentina, and Dr. Koen Demyttenaere of Belgium all reported significant improvements in this area in patients taking the drug.

Reboxetine may be particularly helpful for depressed patients who haven’t responded to other therapies, and for those whose condition is severe, noted several of the researchers. Demyttenaere of Belgium noted that for these patients reboxetine may be more effective than medications that target serotonin.

Demyttenaere explained that because reboxetine targets norepinephrine, it seems to work on different aspects of depression from the drugs that target serotonin. Drugs like Prozac and Paxil appear to be more effective against symptoms of anxiety and agitation, while reboxetine may improve motivation and drive, he said. He noted that some patients taking serotonin-targeting drugs complain of feeling detached, and reboxetine may alleviate this feeling.

Montenegro of Argentina, who is Secretary of Education for the World Psychiatry Association, said that reboxetine also appears safe and effective in patients over age 65. “We experienced a very good profile of action with very low side effects, and also rapid function, with a very good relief of symptoms after the first or second week.” Demyttenaere also noted that reboxetine appears to take effect faster than other antidepressants, and researchers from the United States suggest that the drug may be more effective than current antidepressants for elderly patients.

A common complaint among patients taking drugs that target serotonin is sexual dysfunction. Both Demyttenaere and Montenegro reported that reboxetine does not appear to have this side effect.

According to Gerri Schwartz of Upjohn, the company that hopes to market reboxetine in the United States, the company is doing two large additional studies in this country that they hope to complete by fall. When these are finished, the FDA is likely to approve the drug. So far, reboxetine is the only drug of its kind in this new class of antidepressants.

Editorial Commentary: The release of Prozac in the late 1980′s marked the beginning of a new era of antidepressants. Previous antidepressants were just as effective, but had more side-effects, and most importantly, were much more dangerous in an overdose. The earlier antidepressants were like shotguns, binding to many sites within the brain. Prozac seems to bind primarily to sites associated with serotonin, one of the actions of the older antidepressants. Reboxetine binds to another site affected by the older antidepressants, one associated with norepinephrine. Acquiring more specific compounds such as reboxetine provides more choices for patients suffering from depression. Like taste in movies and food allergies, there is wide individual variations in response and tolerance to antidepressants, and the more choices, the more likelihood of finding a good fit. In addition, it is probable that like most other psychiatric medications, reboxetine will prove to be effective in other conditions beyond depression.