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.

A study has found that paroxetine (Paxil/ SmithKline Beecham) effectively reduced depression in patients without affecting cardiac function. The patients in the study were administered either paroxetine, an SSRI, nortriptyline or placebo. Of the 41 patients taking nortriptyline, heart rates increased by 11% and 7 of the patients dropped out of the study because of potentially serious cardiovascular side effects, such as angina and sinus tachycardia. There is evidence that because depression can increase the risk for myocardial infarction and death effective relief of depression may improve outcomes in cardiac patients.

Although the link between depression and diabetes is well known, the order of the association was thought to be the same as for other chronic illnesses. Once a chronic illness begins to have a negative impact on people’s lives, they are more prone to depression. This holds true for diabetes, heart disease, multiple sclerosis, or any other disease.

In the course of trying to measure the quality-of-life for a diabetic who is also depressed, these research teams discovered that in as many as 90 percent of cases, depression begins first and up to 10 years before the diabetes develops. Reactive depression — depression that begins as a reaction to having diabetes — actually only accounts for a small number of depressed patients.

Physicians have serious concerns regarding the role depression plays in the development of Type II diabetes and even graver concerns that depression in many diabetics is undiagnosed and, therefore, untreated.

For a diabetic, being depressed carries additional risks. Depressed diabetics have poor glucose control and more diabetic complications. The good news is that treating the depression improves both the depression and the diabetes.

The researchers urge health-care providers, especially primary-care practitioners, to look for and treat depression in diabetic patients.

If you have Type II diabetes, you should be aware of your increased risk for depression and should report any depressive symptoms you may experience to your health-care provider. Because untreated, depression not only takes the joy of your life, it shortens it by making your diabetes worse.

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.

“Somatization is a normal, daily experience. It’s highly situational, [with] marked individual differences and marked cultural differences, and associated clearly with psychosocial stress,” stated Normal Jensen, M.D., a professor at the University of Wisconsin in Madison. Jensen addressed an audience of physicians at the annual meeting of the American College of Physicians/American Society of Internal Medicine in Philadelphia last week.

Although “full blown” somatization disorder is fairly rare — less than two percent of Americans are diagnosed with it — Jensen explained that features of the disorder are common. “In primary care, anywhere up to three quarters of our patients have medically unexplained symptoms,” he reported. “The impact on health care services is HUGE.”

Physicians who see patients with complaints that can’t be explained are often distressed and frustrated, noted Jensen. And that frustration is shared by patients, who often consult a long series of physicians and specialists who fail to identify what’s wrong. Some doctors, Jensen said, may turn their frustration on the patient, telling them “it’s all in their head.”

But somatization, he emphasized, is real. Our understanding of pain and other somatic complaints has evolved in recent decades to reveal that sensations are affected by thoughts, emotions, and prior experience. In addition, new discoveries about the role of opioid receptors in the nervous system have provided increasing evidence for a physical basis for somatic complaints.

“Patients appreciate knowing that there are possible molecular and neurophysiological reasons for why their sensations vary from [those of] others, and within themselves from day to day,” Jensen explained.

Patients with these kinds of symptoms shouldn’t be told that there’s no physical reason for their complaints, said Jensen. “I tell them that in fact there is a good physiological reason for their symptoms. I tell them that ‘you’ve either acquired, or were born with, an abnormal nervous system.’ I tell them that ‘your nervous system is allowing you to feel sensations that normal people, or you when you are normal, don’t feel.’

“The nervous system quite naturally filters out unnecessary, confusing, distracting information,” Jensen continued. “Think how it would be if I was constantly aware of my clothes, and my watch, and my jewelry. If I had to process all that information all the time, what else would I be able to do? I wouldn’t even be able to read a book!”

One of the difficulties in treating patients with somatic symptoms is that many patients have an additional illness. “It’s not just somatization. It’s somatization with an anxiety disorder, or with a bad mood disorder, or a thought disorder, or a personality disorder,” said Jensen. He noted that he refers patients to psychiatrists when he wants “to be sure that there isn’t a comorbid condition… or when I want help with treating one of these disorders.”

Another concern, according to Jensen, is that one patient may consult a number of doctors, and specialists may diagnose serious medical conditions based on a patient’s complaints. “These people can get in trouble, because if you look closely enough at any of us, you’re going to find something wrong that could be treated,” he explained.

“What that means is that [generalists] and [their] sub-specialty colleagues have to learn to work together with our patients,” stated Jensen.

Right now, there are no medications that modify sensory perception by targeting opioid receptors, and none specifically for somatization symptoms, noted Jensen. In his own practice, he reported, he looks for symptoms of depression and/or anxiety, and tries antidepressant or anti-anxiety medications if the patient has such symptoms, even if they don’t meet the diagnostic criteria for one of these disorders.

Cognitive behavior therapy has proven helpful for patients with somatic symptoms, too. This therapy, which can be delivered by a trained general practitioner or by a mental health professional, focuses on the relationship between variability of a patient’s symptoms and changes in mood and life events.

As for the future, Jensen reports that there has been some recent evidence that gabapentin (neurontin), an anti-epileptic medication used to prevent seizures, may affect the body’s opioid receptors and thus alter sensory perceptions.

It’s important to remember that somatic symptoms can also mask emotional distress, said Jensen. Patients who have been taught or conditioned not to express emotions, particularly negative ones, may not even realize they’re depressed, anxious, fearful, or grief-stricken. “I do believe that there is a sort of transformation of psychological distress into physical symptoms,” he stated.

Of more than 1,200 study participants followed, 15 percent had marriages or live-in relationships that fit the classification of moderately to highly stressful, based on an assessment using the Pearlin and Schooler nine-item scale of perceived marital stress test. Participants were asked to describe their feelings on a scale of one to four, with four being the most negative, when they thought about the pleasures and problems that go into daily life with a spouse or significant other. Individuals with a score of 23 or greater were classified as having a stressful relationship.

The rate of type 2 diabetes among individuals in unhappy relationships was greatest for Hispanics and those with a family history of diabetes, both of which are risk factors for this disease. Mexican Americans with or without a family history of diabetes and non-Mexican Americans with a family history of the disease who reported stressful relationships were the most likely to be affected, notes lead study author Susan P. Fowler, MPH. Even after adjusting for known diabetes risk factors like age, obesity and hypertension, as well as socio-economic and cultural differences that may also influence disease development, the higher rate of diabetes occurrence in people with stressful relationships held true across-the-board, she adds.

None of the study participants were diagnosed with diabetes when the study began. A two-hour glucose tolerance test revealed, however, that those in unhappy relationships had elevated blood plasma levels, compared with people in happier relationships. Follow-up seven to eight years later revealed that 18 percent of those in stressful relationships had developed diabetes, while only nine percent of those in less stressful relationships had developed the disease.

"The study suggests that individuals susceptible to developing diabetes will be the most hard hit by marital stress," says Fowler. She notes that previous studies on the relationship between stress and diabetes indicate that stress may cause an exaggerated response in tissue to stimulate the sympathetic nervous system to develop insulin resistance. So Fowler hypothesizes that possibly, when stress in a relationship triggers onset of diabetes it "may just be a bigger reaction to ‘fight or flight response’ stimuli in those most susceptible to diabetes."

But don’t leave your lover in hopes of saving your health, warns Fowler. The same study found a higher rate of diabetes among those who had later divorced or separated or had been widowed. Overall, the rate of diabetes was 34 percent greater in this group, but occurrence of diabetes in non-Hispanics who had let a stressful relationship was more than twice that of individuals who had stayed with their partners.

Fowler, therefore, suggests that people in stressful relationships, especially those at risk for developing diabetes, do whatever is necessary to heal their relationships and stay physically and emotionally healthy. "Seek marriage counseling; eat a healthy diet, practice stress management techniques like exercise or mediation, or go church or find some other spiritual activity," she concludes.

Editorial Commentary: Stress of varying kinds has been shown to elevate blood sugar levels. Marital stress can be particularly troubling. Stress can increase blood sugar levels by increasing stress hormones but it can also lead to less healthy behaviors, such as increased eating and less exercise. It is important that people who are at risk for developing diabetes get tested yearly or more often if they develop symptoms of diabetes whether or not they are under unusual stress. Risk factors for diabetes include being overweight, having a family history of diabetes, a personal history of having gestational diabetes or having a baby weighing greater than nine pounds, or being from a high risk ethnic group such as African Americans, Hispanic Americans or American Indians. Symptoms of diabetes include excessive thirst or hunger, frequent urination, especially at night, unintentional weight loss or recurrent yeast infections (in women).

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.