Military-related post-traumatic stress disorder (PTSD) showed no response to risperidone (Risperdal) for antidepressant-resistant symptoms, data from a multicenter Veterans Affairs study showed. Risperidone-treated patients had about a four-point greater improvement on a PTSD scale than did those who received placebo, but the difference did not achieve statistical significance. Detailed analysis showed no significant difference between groups at any point during the six months of follow-up, John H. Krystal, MD, of the VA Connecticut Healthcare system in West Haven, and co-authors reported in the Aug. 3 issue of JAMA. nor did the groups differ significantly with respect to anxiety, depression, or health-related quality of life. Action Points  

• Antidepressants are the predominant pharmacotherapy for PTSD, but second-generation antipsychotics are commonly used for PTSD symptoms resistant to serotonin reuptake inhibitors.
• Point out that in this study of patients with PTSD symptoms resistant to at least two adequate treatments with SSRIs, risperidone had no significant beneficial effects upon depression symptoms and was associated with a higher rate of adverse effects than a placebo.

“Overall, the data do not provide strong support for the current widespread prescription of risperidone to patients with chronic serotonin reuptake inhibitor [SRI]-resistant military-related PTSD symptoms, and these findings should stimulate careful review of the benefits of these medications in patients with chronic PTSD,” the authors wrote in conclusion.

Second-generation antipsychotics, such as risperidone, have become a widely used adjunctive therapy for patients with SSRI-resistant PTSD symptoms. Yet, the practice has limited supporting evidence, the authors noted in their introduction.

In 2009 almost 87,000 veterans with PTSD received prescriptions for an antipsychotic, and in 94% of cases, the prescription was for a second-generation agent. Risks associated with the drugs are not inconsequential and include weight gain and extrapyramidal motor symptoms, the authors continued.

To assess the benefits of adjunctive risperidone in SSRI-resistant, military-related PTSD, Krystal’s team of investigators at 23 VA hospitals enrolled patients who had experience in a military combat theater and met diagnostic criteria for military-related PTSD.

Eligible patients had a Clinician-Administered PTSD Scale (CAPS) score greater than 50, a history of intolerance or lack of response to at least two antidepressants, and an inadequate response to two SSRI treatments of at least four weeks’ duration. Ongoing drug therapy for PTSD could be continued.

Investigators randomized and treated 267 patients with either risperidone or placebo for six months. the primary endpoint was change in CAPS score from baseline to six months.

Most of the patients (72.3%) had long-standing military-related PTSD dating back to the Vietnam War or earlier, and their symptoms were judged to be principally related to direct participation in combat.

Additionally, 70% of the patients had a lifetime history of major depression, and 62% had a history of drug or alcohol abuse.

The results showed that the mean CAPS score declined by 16.3 points in the risperidone group and by 12.5 points in the placebo group (P=0.11).

Analysis of secondary outcomes showed no significant differences between groups with respect to changes in scores for depression (P=0.11), anxiety (P=0.09), or quality of life (P=0.79 to P=0.13).

The change in patient-rated Clinical Global Impression (CGI) also did not achieve statistical significance, nor did the adjusted mean difference in observer-rated CGI.

Adverse events occurred more often in the risperidone arm, including weight gain (15.3% versus 2.3%), fatigue (13.7% versus 0.0%), somnolence (9.9% versus 1.5%), and hypersalivation (9.9% versus 0.8%).

“Compared with placebo, risperidone produced only a 3.74-point greater reduction from baseline in the CAPS total score,” the authors wrote. “Thus, it is unlikely that clinicians could detect the magnitude of the risperidone effect over placebo that was observed in this study.”

The study was supported by the Department of Veterans Affairs. Risperidone and matching placebo were provided by Ortho-McNeil Janssen.

Krystal disclosed relationships with Aisling Capital, AstraZeneca, Brintnall and Nicolini, Bristol-Myers Squibb, Easton and Associates, Eli Lilly, F. Hoffman-La Roche, Forest Laboratories, Gilead Sciences, GlaxoSmithKline, Janssen, Lundbeck Research, Medivation, Merz Pharmaceuticals, MK Medical Communications, Naurex, Pfizer, SK Holdings, Sunovion Pharmaceuticals, Takeda Industries, Tetragenex, Teva Pharmaceutical, Eisai, Lohocla Research, Mnemosyne, and Shire, as well as several patent interests.

Coauthor Rosenheck disclosed relationships wwith Eli Lilly, Janssen, AstraZeneca, Wyeth, GlaxoSmithKline, Bristol-Myers Squibb, Organon, and Otsuka, as well as participation as an expert witness in legal proceedings.

Press Release Source: Abbott On Friday March 4, 2011, 9:00 am EST

ABBOTT PARK, Ill., March 4, 2011 /PRNewswire/ — Results from a Phase 2, 8-week dose-ranging study using low doses of atrasentan in patients with diabetic kidney disease were published this week in the Journal of the American Society of Nephrology. The published study results suggest that atrasentan, used in conjunction with renin-angiotensin system (RAS) inhibitors, may reduce albuminuria (presence of protein in urine) for patients with type 2 diabetes.

Atrasentan is a highly selective endothelin-A receptor (ETAR) antagonist under investigation as a potential treatment for diabetic kidney disease.

Key findings from the 8-week study of three doses of atrasentan (0.25 mg, n=22; 0.75 mg, n=22; 1.75 mg, n=22) vs. placebo (n=23) were:

• Atrasentan significantly reduced urine albumin-to-creatinine ratio (UACR) in the 0.75 mg and 1.75 mg groups vs. placebo (P=0.001 and P=0.011 by repeated measures, respectively). The 0.25 mg dose had no significant effect
• Reduction from baseline to final UACR was 21%, 42%, and 35% in the 0.25 mg, 0.75 mg and 1.75 mg groups vs. 11% in placebo (P=0.291, P=0.023 and P=0.073, respectively).
• A significantly larger proportion of subjects achieved >40% reduction in UACR from baseline in the 0.75 mg group vs. placebo (50% vs 17% respectively, P=0.029). The proportion of patients in the 0.25 mg and 1.75 mg groups (30% and 38% respectively) did not reach statistical significance.
• Peripheral edema was the most common adverse event (14%, 18% and 46% for 0.25, 0.75 and 1.75 mg with P=0.007 for 1.75 mg vs. 9% in placebo). other adverse events that occurred in >5% of patients and at a rate >5% vs. placebo included dizziness, urinary tract infection, headache and hypoglycemia. due to the small numbers of patients in each treatment group and the low event rates, the significance of these other adverse events is unknown.

“Current standard of care modestly slows the progression of the disease and previous studies with standard of care have shown an association with albuminuria reduction and a slowing of disease progression,” said Donald E. Kohan, M.D., Ph.D., Professor of Medicine, Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah and lead investigator for the study. “These early study results suggest that atrasentan may have an additional therapeutic role for albuminuria reduction when added to the current standard of care for patients with type 2 diabetes.”

“Chronic kidney disease and diabetic kidney disease are growing healthcare issues. New treatments that could potentially alter the progression of the disease are needed,” said James Stolzenbach, Ph.D., divisional vice president, Dyslipidemia and Renal, Abbott. “Abbott looks forward to continued study of atrasentan in longer, outcome-driven clinical trials.”

Study Objectives and Design

The study was a double-blind, dose-ranging, placebo-controlled study of 89 diabetic subjects with nephropathy on stable doses of renin-angiotensin system (RAS) inhibitors for >2 months with urinary albumin-to-creatinine ratio (UACR) of 100-3000 mg/g, eGFR >20 mL/min/1.73m2, and NT-pro-BNP