FDA Approves Duloxetine for Maintenance Treatment of Major Depressive Disorder

The United States Food and Drug Administration approved duloxetine (Cymbalta, Eli Lilly and Company) for the maintenance treatment of major depressive disorder (MDD) in adults ≥18 years of age. Duloxetine was previously approved for the acute treatment of MDD, management of diabetic peripheral neuropathic pain, and treatment of generalized anxiety disorder in adults.

In a double-blind, placebo-controlled trial of 533 MDD patients, duloxetine 60 mg/day was given to each patient. After 12 weeks, 278 patients who qualified for the 6-month continuation phase were randomly assigned to either duloxetine 60 mg/day dose or placebo. The trial demonstrated that patients who continued treatment with duloxetine experienced a longer time to relapse (ie, the reappearance of depressive symptoms) than did placebo-treated patients.

Nausea was the most frequently reported side effect during the acute phase; however, neither duloxetine nor placebo showed significant differences in reported side effects during the continuation phase.

For more information, please consult the medication’s full prescribing information (www.cymbalta.com). –ML


Fluoxetine and CBT Combination Therapy for Adolescent Depression

The Treatment for Adolescents With Depression Study (TADS) was a 26-week trial that evaluated the efficacy of fluoxetine monotherapy versus combination therapy in depressed adolescents. The $17 million study was conducted in 13 sites in the United States.

The initial cohort consisted of 439 adolescents between 12 and 17 years of age with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. Primary outcome measures included the total score and response rate of the Children’s Depression Rating Scale-Revised, defined as a much or very much improved score according to the Clinical Global Impressions-Improvement scale.

At study onset, subjects randomly received one of three active treatments—fluoxetine 10 mg/day monotherapy, cognitive-behavioral therapy (CBT) monotherapy, and fluoxetine 10mg/day plus CBT combination therapy—or placebo. All treatments, including placebo, were double-blind for the first 12 weeks. After that period, all treatments were unmasked except for CBT. Subjects taking placebo were then offered active treatment and subjects initially randomized to active treatment were asked to participate for the remaining duration of the study. Out of the initial 439 subjects, 327 participated from some point on after the 12-week mark and 243 (74.3%) completed the study.

Dosing was adjusted depending on periodic response rates and to reduce adverse effects. Subjects receiving CBT attended 15 studies during the first 12 weeks; thereafter, sessions were scheduled in accordance to treatment response.

TADS investigator, John S. March, MD, MPH, from Duke University, reported that the CBT techniques in this study included a blend of “cognitive restructuring, behavioral activation, and conflict resolution, with sessions for teen (subject) and teen plus parent.” CBT sessions embraced a hybrid of required, structural targets for subjects combined with more flexible, subject-driven targets.

Response rates were measured at weeks 12, 18, and 36. At week 12, response rates were 73% for combination therapy, 62% for fluoxetine, and 48% for CBT. Response rates at week 18 were 85% for combination therapy, 69% for fluoxetine, and 65% for CBT. Week 36 results were 86% for combination therapy, 81% for fluoxetine, and 81% for CBT.

The authors noted that fluoxetine accelerates recovery from depression at treatment outset, but the CBT catches up. That is, response rates for both fluoxetine and CBT reached 81% by week 36. Combination therapy results in the best early improvement across all domains of outcome.

The TADS researchers monitored all subjects for suicidal ideation throughout the study. Among patients receiving fluoxetine monotherapy, 14.7% were involved in “suicidal events” compared to 8.4% of the combination therapy group and 6.3% of the CBT monotherapy group. CBT protected against suicidal events in patients taking fluoxetine. The reason for this is unclear; nor is it clear why fluoxetine was associated with higher rates of suicidal events.

Funding for this study was provided by the National Institute of Mental Health; fluoxetine and placebo were provided by Eli Lilly. (Arch Gen Psychiatry. 2007;64(10):1132-1143.) —LS


Anorexia Risk: Greater for Males with Female Twins?

No evidence has yet explained decisively why anorexia nervosa is 10 times more common in females than in males. Underreporting of anorexia in males could be one explanation, and some believe that anorexia in males is a separate disease than anorexia in females. The etiologic hypothesis seemingly favored most by existing evidence, however, is that females and males with anorexia share very similar characteristics, but that the males who develop anorexia still hold unique traits that predispose them to anorexia.

A recent study by Marco Procopio, MD, MRCPsych, at the Medical School University of Sussex, Brighton, and colleagues, posited that the neurodevelopment of fetuses is affected by the hormonal environment in utero, in turn, contributing to the diversity in the risk of developing anorexia between the two genders. The authors explained that the methodology used to test this hypothesis is a “comparison of the prevalence of anorexia in members of monozygotic and dizygotic twin pairs, stratified by the possible different sex permutations.”

“The extraordinary difference in the prevalence of anorexia between the two sexes has always intrigued me,” Dr. Procopio said. “The phenomenon is so dramatic that I have always thought that if we understood it we could also understand some of the factors involved in the illness’s etiology.”

After reading a study discussing the importance of position in the womb on the characteristics of female and male mice, Dr. Procopio decided that studying mixed gender twins could provide valuable insight into the gender differences in anorexia.
The study population included every member of the Swedish Twin Registry born between January 1, 1935 and December 31, 1958 who agreed to participate in a telephone interview. Seventy-six percent participated.

Prevalence of anorexia between males and females was measured using broad diagnostic criteria and narrow diagnostic criteria. “Broad criteria” is defined as a full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), anorexia diagnosis at time of interview; “narrow criteria” is a subgroup of the broad criteria group that, in addition to DSM-IV anorexia, included amenorrhea.

Overall, the study confirmed that prevalence of anorexia is much higher among females than males but that this tendency disappeared for males with a dizygotic female twin. Using broad criteria, the prevalence of anorexia among dizygotic female twins was 1.12 (0.85–1.47, 95% CI), and 0.02 (0.001–0.16, 95% CI) for male dizygotic twins. Among dizygotic opposite-sex dizygotic twins, however, anorexia prevalence was 0.71 (0.50–1.02, 95% CI) for females and 0.60 (0.41–0.89, 95% CI) for males. Although males with a female twin are more likely to develop anorexia than male twin pairs, females with a male twin are no more likely than other females to develop anorexia.

“We were extremely pleased that the results of this study fitted so neatly with our hypothesis,” Dr. Procopio said. “It is another demonstration of the importance of the neurodevelopment in the genesis of mental illness.” (Arch Gen Psychiatry. 2007;64(12):1402-1408). –LS


Abnormal Visual Information Processing in Body Dysmorphic Disorder May Lead to Distorted Perception of Self and Others

Body dysmorphic disorder (BDD) affects 1.7% of the American population. It is characterized by the excessive preoccupation with real or imagined defects in physical appearance. A recent study by Jamie D. Feusner, MD, of the University of California-Los Angeles, and colleagues, suggests that abnormal visual information processing may cause individuals with BDD to see themselves, in addition to others, as ugly and deformed.

This study involved 12 right-handed, treatment-free patients with BDD and 13 control subjects matched by age, sex, and educational achievement. Participants were shown three types of black-and-white photographs of others’ faces that were altered to include high (detailed), low (blurry), or normal (unaltered) spatial frequency information. With each facial stimuli, functional magnetic resonance imaging (ie, the best method to visualize functional brain processes with a good tradeoff between resolution on the time and spatial scales) showed changes in the participants’ blood-oxygen-level resonance. The study concluded that visual processing for BDD patients in the left hemisphere of the brain was greater for all face types. The control group used left hemisphere processing only for the high spatial frequency faces.

That these findings occurred while subjects viewed faces other than their own suggests that BDD patients view faces in a very detailed, piecemeal manner rather than a global, holistic manner. However, it is important to note that these abnormalities may have been conditioned by certain factors, including a bias for detail processing over global processing of faces, abnormal activation of the amygdalae for high and low spatial frequency tasks, and the assumption that the other subjects are as detail-biased as the participant in the perception of his or her own appearance. In addition, the study was limited due to its small sample size and restricted range of severity of the body-image disorder, possibly not allowing enough variance to establish a correlation between symptom severity and brain activation.

Researchers said that future studies need to both record emotional ratings for each spatial frequency task and have larger samples with patients ranging from mild symptoms to severe body-image distortion. In addition, future studies should test for abnormalities while a patient processes his or her own face. However, the information this study has found about the underlying pathophysiology may help primary care physicians better understand BDD and better identify it in their practices.

“It is important to screen for BDD and, if identified, refer [the patient] to psychiatric treatment rather than surgical or dermatologic treatment,” Dr. Feusner said. “Their problems are in the brain, not in their appearance.”

Funding for this research was provided by grants from the National Center for Research Resources at the National Institutes of Health, the National Institute of Mental Health, and the Saban Family Foundation; and a donation from Neysa Jane Body Dysmorphic Disorder Fund, Inc. (Arch Gen Psych. 2007;64(12):1417-1425.) –ML


Depression Treatment Reduces Mortality Risk for Older Patients With MDD and Diabetes

Diabetes and depressive disorders, including major depressive disorder (MDD), are two of the most common conditions presented by patients in primary care settings. Both conditions often occur comorbidly; depression is a risk factor for diabetes, and risk of depression is increased in patients with diabetes. Depression can also affect a patient’s adherence to a diabetes treatment regimen and dietary restrictions. For older adults and the elderly, both conditions can significantly contribute to diminished quality of life and increased risk of mortality. Nevertheless, there have been no studies examining the effect of MDD treatment in older patients with both conditions.

Hillary R. Bogner, MD, MSCE, of the Department of Family Medicine and Community Health at the University of Pennsylvania in Philadelphia, and colleagues, studied 584 patients between 60 and 94 years of age to determine if older patients with diabetes and MDD who received treatment for depressive symptoms had a reduced risk of mortality when compared to depressed patients with diabetes who received no treatment for MDD.

Patient data were gathered from the multi-site, randomized trial, Prevention of Suicide in Primary Care Elderly: Collaborative Trial with additional data gathered from the National Death Index Plus. For inclusion in the study, patients had either a Centers for Epidemiologic Studies Depression scale score of >20 or were positive responders to supplemental questions from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Structured Clinical Interview about mood, past symptoms, or treatment of MDD. Depression severity was also assessed with the Hamilton Rating Scale for Depression. Presence of diabetes or past symptoms of diabetes was determined by self report.

Of 584 participants included in the study, 123 patients reported history of diabetes. Patients were then randomly assigned to either usual care, which did not include any treatment for MDD, or a depression care management intervention. For the intervention group, depression care managers worked with primary care physicians (PCPs) at 20 practices located in several United States metropolitan areas to recommend MDD treatment and assist with maintaining treatment adherence. Patients were monitored for 2 years following assignment and received follow-up evaluation after 5 years.

Bogner and colleagues found that at the end of the study period, 110 patients had died. The authors found that patients receiving depression care management were less likely to have died at the end of the 5-year follow-up period than patients receiving usual care. Patients with MDD and diabetes in the intervention group had a mortality rate of 68.2/1,000 people per year; however, depressed patients with diabetes in usual care experienced a mortality rate of 103.4/1,000 people per year. After adjusting for baseline patient characteristics including age, presence of additional illnesses, and others, the authors concluded that depression care management reduced risk of mortality for patients with MDD and diabetes.

“The importance is that this is the first known study to look whether a depression care intervention in primary care can influence mortality among older depressed adults with diabetes,” Dr. Bogner said. “The study results indicate that more resources to treat depression in primary care can influence mortality.”

The authors stated that these findings support the integration of depression evaluation and treatment with diabetes management in primary care. Study limitations included selecting primary care practices in primarily metropolitan areas, which may not reflect a PCP’s experience in other areas of the United States, and a diabetes diagnosis based on self report alone.

Bogner and colleagues stated that ongoing studies are examining mediators to mortality risk including medication adherence and improvement in depression symptoms.

Funding for this research was provided by the National Institute of Mental Health. (Diabetes Care. 2007;30(12):3005-3010.) –CP

Dispatches is written by Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.