London, UK—Pharmacists, who regularly fill prescriptions for Zoloft and its generic equivalents, might be surprised by new research suggesting the early effects may be different from what has been commonly assumed.

A study in The Lancet Psychiatry found that taking sertraline leads to an early reduction in anxiety symptoms, commonly found in depression, several weeks before any improvement in depressive symptoms.

The University College of London–led clinical trial is touted as the largest-ever placebo-controlled trial of an antidepressant that was not funded by the pharmaceutical industry. The study also included a wide range of patients, including those with mild-to-moderate symptoms.

Essentially, the study found that sertraline did not appear to improve depressive symptoms, which include low mood, loss of pleasure, and poor concentration, within 6 weeks, although weak evidence indicated those results by 12 weeks. In fact, participants who took sertraline were twice as likely as those who took a placebo to say their mental health had improved.

Overall, researchers say the results support the continued prescribing of sertraline and other similar antidepressants for people experiencing depressive symptoms. “It appears that people taking the drug are feeling less anxious, so they feel better overall, even if their depressive symptoms were less affected,” said lead author Gemma Lewis, PhD. “We hope that we have cast new light on how antidepressants work, as they may be primarily affecting anxiety symptoms such as nervousness, worry and tension, and taking longer to affect depressive symptoms.”

For the study, patients received one capsule of sertraline 50 mg or placebo daily for 1 week, then 2 capsules daily for up to 11 weeks, consistent with evidence on optimal dosages for efficacy and acceptability. Patients were recruited between January 1, 2015, and August 31, 2017, and randomly assigned to the selective serotonin reuptake inhibitor or placebo. Primary-outcome analyses were of 550 patients (266 in the sertraline group and 284 in the placebo group; 85% follow-up that did not differ by treatment allocation).

Defined as the primary outcome were depressive symptoms 6 weeks after randomization; that was measured by using the Patient Health Questionnaire, 9-item version (PHQ-9) scores. Researchers tracked depressive symptoms and remission at 2, 6, and 12 weeks—as well as generalized anxiety symptoms, mental and physical health–related quality of life, and self-reported improvement—as secondary outcomes.

“We found no evidence that sertraline led to a clinically meaningful reduction in depressive symptoms at 6 weeks,” the authors report. “The mean 6-week PHQ-9 score was 7·98 (SD 5·63) in the sertraline group and 8·76 (5·86) in the placebo group (adjusted proportional difference 0·95, 95% CI 0·85–1·07; P = 0·41). However, for secondary outcomes, we found evidence that sertraline led to reduced anxiety symptoms, better mental (but not physical) health-related quality of life, and self-reported improvements in mental health. We observed weak evidence that depressive symptoms were reduced by sertraline at 12 weeks.”

The authors also point out that most past studies for antidepressants were conducted many years ago in regulatory trials for new drugs, and often include only patients who see specialists, although, more recently, most antidepressants are prescribed in primary care to a broader group of patients, including those with milder symptoms.

“Antidepressants are one of the most commonly prescribed medications in the UK and prescription rates have risen dramatically over the last decade in high income countries. However, we are still developing our understanding of exactly how they work,” Lewis said.

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