A reanalysis of a pivotal antidepressant trial suggested that the selective serotonin reuptake inhibitor (SSRI) sertraline may ease key symptoms of depression and anxiety within 2 weeks of treatment — effects that the primary analysis missed.

The secondary analysis of the landmark Prescribing ANtiDepressants Appropriately (PANDA) trial, which examined the impact of treatment on individual symptoms rather than total depression scores, revealed modest early improvements in sadness, self-loathing, and anxiety among people taking sertraline, even as some physical symptoms, such as sleep and libido, temporarily worsened.

“Our analysis found that sertraline had a beneficial impact on low mood and suicidal thinking as soon as 2 weeks into treatment, with improvements sustained over the 12 weeks of the trial,” lead author Giulia Piazza, PhD, research fellow in the Division of Psychiatry at the University College London (UCL), London, England, told Medscape Medical News.

“By studying each symptom on its own, we could see that sertraline acts faster on mood and anxiety than traditional total scores suggest,” she added, emphasizing that early benefits can be masked by side effects that are themselves counted as depression symptoms.

The study was published on October 30 in Nature Mental Health.

PANDA Revisited

The PANDA trial is a randomized, placebo-controlled study that included 653 adults with depressive symptoms from primary care practices across England.

Published in The Lancet in 2019, the study showed that sertraline did not significantly outperform placebo on total depression scores at 6 weeks, as measured by the nine-item Patient Health Questionnaire and the Generalized Anxiety Disorder 7 scale.

Additional symptom data from the Beck Depression Inventory II were also included. However, participants taking sertraline reported less anxiety and better overall mental health.

Because the earlier findings contrasted with real-world experience and fueled debate over whether SSRIs are effective for mild depression, the investigators decided to take a second look.

Piazza, who was not part of the original PANDA research group, led the new analysis with several of the original investigators. They applied a network approach, an innovative statistical method that maps how individual symptoms of depression and anxiety influence one another. The model shows how improvement in one domain, such as mood or anxiety, can cascade through related symptoms over time.

Among 571 participants with complete data, sertraline produced small, but statistically significant, early benefits. At 2 weeks, those taking the drug reported lower levels of sadness, restlessness, and self-dislike compared with placebo. By 6 weeks, reductions extended to anxiety, worry, and indecisiveness.

Effect sizes were modest (-0.03 to -0.10) but consistent across measures. The most substantial improvements were seen for self-critical thinking and loss of pleasure (η² = 0.017-0.019; FDR-corrected P < .001).

Some physical symptoms, notably poor sleep and reduced libido, worsened temporarily, with small opposite-direction effect sizes of about 0.04 to 0.06. Because these somatic items can reflect both medication effects and the illness itself, they may have obscured early emotional gains when total scores were averaged.

Global Context

Antidepressant use is widespread worldwide. The World Health Organization estimates that about 10% of adults take an antidepressant, with rates near 15% in the US and the UK. Sertraline (Zoloft) remains one of the most prescribed antidepressants globally.

Researchers said the new analysis helps explain sertraline’s enduring popularity. Many patients experience early relief in mood and anxiety, even when overall depression scores appear unchanged, they noted.

By distinguishing emotional from physical symptom domains, the study offers a clearer view of how antidepressant effects unfold, and how short-term side effects can temporarily obscure progress.

“This knowledge can help doctors and patients better understand how antidepressants work, and which symptoms are likely to change first,” Piazza said.

While the current analysis does not provide an overall estimate of benefit, the researchers noted that in the original PANDA trial, 59% of participants receiving sertraline reported feeling better after 12 weeks compared with 42% on placebo. Piazza said those figures are consistent with the level of improvement typically seen with antidepressant treatment.

The authors emphasized that the observed changes were modest and that the work was exploratory. They said the findings should be confirmed in future studies but could help shape how antidepressant trials are designed and interpreted.

“Our findings provide robust evidence that continues to support the prescription of sertraline for people experiencing depressive and anxiety symptoms,” co-author Glyn Lewis, MD, professor of epidemiological psychiatry at UCL and the PANDA trial lead said in a press release. “These findings will help patients and clinicians make more informed decisions about treatment.”

Mixed Reaction

Commenting on the study in a press release from the Science Media Centre, Atheeshaan Arumuham, MD, academic clinical fellow at the Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, England, said the analysis helps explain why antidepressants sometimes appear ineffective in trials or public debate.

He noted that shared decision-making processes that emphasize preparing patients for early side effects, combined with focused monitoring to provide timely support, can sustain treatment long enough for therapeutic benefits to emerge.

Joanna Moncrieff, MD, professor of critical and social psychiatry at UCL, took a different view. She told Medscape Medical News that the reanalysis “does not contradict the PANDA trial’s main conclusion” that overall depressive symptoms did not differ significantly between sertraline and placebo at 6 weeks.

“The differences across individual symptoms are small,” Moncrieff said. “Where there are differences, they likely reflect the emotional-numbing properties of antidepressants or expectancy effects rather than true antidepressant efficacy.”

She added that none of the individual symptoms were validated as outcome measures and argued that “it seems unlikely these small effects would outweigh the adverse effects associated with sertraline, such as sexual dysfunction, dependence, and withdrawal.”

The study was supported by the Wellcome Trust, and the PANDA trial was funded by the National Institute for Health Research (NIHR) and the NIHR University College London Hospitals Biomedical Research Centre. Piazza is the recipient of a Wellcome Trust PhD studentship, and Lewis disclosed having potential conflicts as detailed in the published paper. Moncrieff and other coauthors reported having no competing interests. Arumuham reported receiving funds from the NIHR and serving as a trustee for Gaming the Mind, a mental health charity.