CHICAGO, June 3 -- Unless cancer patients have major depression, antidepressants don't seem to do anything for them, Australian researchers have found.Sertraline (Zoloft) did not lead to less depression, anxiety, or fatigue, or to a better overall quality of life than did placebo for those with advanced cancer, reported Martin R. Stockler, M.B.B.S., M.Sc., of the University of Sydney in Australia, and colleagues.
These findings of the randomized clinical trial were unexpected and disappointing, Dr. Stockler said at the American Society of Clinical Oncology meeting here.
"Treatment with a selective serotonin reuptake inhibitor should be reserved for those with a proven indication," he and colleagues concluded in the study, which was also published simultaneously online in The Lancet Oncology.
Previous studies have shown antidepressants to be effective for patients with cancer in treating major depression associated with cancer, preventing major depression during treatment with high-dose interferon, and treating hot flushes, they noted
"Our results should not affect the use of antidepressants for these indications," they said.
The researchers started the Zoloft's Effects on Symptoms and Survival Time (ZEST) Trial in July 2001 and by February 2006 had recruited 189 patients with metastatic disease, They were being given palliation and scored at least 4 of 10 for depression, anxiety, fatigue or low energy.
Patients were randomized to once-daily sertraline at a dose of 50 mg or to placebo, to be continued indefinitely.
The study excluded patients with major depression at baseline. Those who developed major depression during the study discontinued treatment and were started on antidepressant treatment under a psychiatrist's care.
However, in February 2006 study recruitment was stopped early when the safety and data-monitoring committee found shorter survival with sertraline than placebo at the first interim analysis (adjusted hazard ratio 1.62 P=0.02).
In the final analysis of 189 patients with a median follow-up of 19 months, the researchers found a trend for lower unadjusted overall survival with sertraline (HR 1.35, P=0.09) but the difference disappeared after adjusting for baseline prognostic factors (HR 1.27, P=0.20).
"Apparent effects on survival were exaggerated in our trial," Dr. Stockler said.
While the initial survival difference was unexpected, a further surprise was that "a clinically important benefit was excluded for all major outcomes," he said.
Among the findings comparing sertraline and placebo, the investigators reported:
No difference for the primary endpoint, depression as defined by theCenter for Epidemiologic Studies Depression scale (23.3 versus 23.7, P=0.8).
No difference in the anxiety portion of the Hospital Anxiety and Depression Scales (23.9 versus 25.8, P=0.3).
No difference in fatigue on the Functional Assessment of Cancer Therapy fatigue scale (56.8 versus 57.1, P=0.9).
No difference in overall physical or emotional wellbeing scores on the Functional Assessment of Cancer Therapy general scale (71.9 versus 70.2, P=0.2).
No difference in clinician-rated quality of life on the Spizter's Quality of Life Index (76.5 versus 74.5, P=0.5).
Two previous trials had shown a benefit to for depression symptoms in cancer patients for fluoxetine (Prozac) and paroxetine (Paxil), but those studies included patients with major depression and those without it.
Dr. Stockler said he would be "very surprised if the results were any different" for cancer patients without major depression with these other antidepressants.
Adverse event frequency and severity were similar between groups. No suicides were documented or reported, he added.
The main limitation of the study was the subjective definition of the study population, he said.
"Diagnosis of major depression was our main exclusion criterion, but this judgment was arbitrary and left to the responsible oncologist," the investigators wrote. "Individuals will differ in their thresholds for recognition, diagnosis, and treatment of depression."
But they noted, "this situation highlights the reality of clinical practice, and it strengthens our conclusion that sertraline should not be used indiscriminately in patients with advanced cancer who do not have major depression."
Overall, "it was a very disappointing result," Dr. Stockler said. "The aim of the trial was to help people feel better…but I think the upside is that it means that we can focus on things that are beneficial such as psychological therapies and exercise."
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