Surprising Mechanism Behind Sertraline’s Short-Term Benefit

When there is clinical uncertainty about whether antidepressants should be prescribed in primary care settings, the presence of anxiety symptoms may indicate an increased chance of benefit, a randomized trial found.

In a group of 550 primary care patients with mild to severe depressive symptoms, sertraline (Zoloft) did not reduce depressive symptoms at six weeks compared to placebo as measured through the 9-Item Patient Health Questionnaire (adjusted proportional difference 0.95, 95% CI 0.85-1.07, P=0.41), reported Gemma Lewis, PhD, of University College London in England, and colleagues.

However, there were mild improvements in depressive symptoms at 12 weeks, with a 13% reduction in PHQ-9 scores (difference 0.87, 95% CI 0.79-0.97) as a secondary outcome, the authors wrote in Lancet Psychiatry.

Secondary analyses also found that sertraline was associated with reduced anxiety symptoms at 6 weeks and 12 weeks compared to placebo, as well as improved functioning and self-reported mental health, they noted.

“Our findings support the prescription of SSRI antidepressants in a wider group of participants than previously thought, including those with mild to moderate symptoms who do not meet diagnostic criteria for depression or [generalized] anxiety disorder, especially when anxiety symptoms such as worry and restlessness are present,” Lewis told MedPage Today in an email.

Zoloft, or sertraline hydrochloride, is a selective serotonin reuptake inhibitor (SSRI), approved by the FDA in the 1990s to treat depression, obsessive-compulsive disorder, and social anxiety disorder, among other conditions. However, the majority of studies supporting its use involve patients in outpatient — and not primary care — settings.

This trial, which takes a “scattergun approach,” suggests a broader and more vaguely defined primary care population could benefit from antidepressants, which is important considering primary care is the largest treatment setting for depression and anxiety, wrote Brenda Penninx, PhD, of Vrije Universiteit in Amsterdam, in an accompanying editorial.

Penninx cautioned against overprescribing antidepressants, however, particularly since the overall effect sizes found in this trial were small and researchers did not examine the long-term effects of sertraline. The findings do not mean clinicians should bypass alternatives to pharmacological treatment like psychotherapy either, she added.

Long-term use of antidepressants, which many patients continue for several months or even years after remission, has been associated with “disturbing side-effects,” like sexual dysfunction, weight gain, and metabolic dysregulation, which providers should take into account when considering prescribing SSRIs, she noted.

“In the process of pharmacotherapy, antidepressant discontinuation deserves as much clinical attention as antidepressant initiation,” Penninx wrote.

The so-called “PANDA trial” by Lewis and colleagues enrolled adult patients from 179 primary care centers across four cities in England who had any level of depressive symptoms within the past two years, and who had been uncertain (along with their providers) about the potential benefit of using antidepressants. Notably, some participants were recruited through clinical record reviews and were not therefore current patients or treatment seekers. The remainder were referred through their general practitioners.

The PHQ-9 was the primary measure for depression, the 7-Item Generalized Anxiety Disorder Assessment was used for anxiety, and functionality and mental health were self-reported through the 12-Item Short-Form Health Survey.

Patients were assigned to either 50 mg oral sertraline or placebo administered daily for one week and then twice daily for up to 11 weeks. Patients could increase doses to three times daily after six weeks if they had consulted with their clinicians, though more than 90% of patients remained on 100 mg doses, Lewis said.

Overall, patients were a mean age of 40 and 59% were women. Within the cohort, 54% met criteria for depression, 46% met criteria for anxiety, and 30% met criteria for both. Some patients (15%) did not meet criteria for any condition. The vast majority (80%) of patients self-reported prior depression.

There was no association between baseline depression duration and depressive symptoms at six weeks (difference 1.08, 95% CI 0.96-1.22, P=0.19), and there was no evidence indicating responses to treatment were affected by depression severity or duration, although these analyses lacked statistical power, the authors reported.

There were two adverse events in the placebo group and three in the sertraline arm, one of which involved suicidal ideation and was classified as “possibly related to the study medication,” Lewis said.

Although using clinical uncertainty as an entry criterion creates a population similar to the one currently receiving antidepressants, it’s also possible that patients with few depressive symptoms were less likely to respond to antidepressants, reducing the treatment effect, the authors reported. It may also mean patients with severe depression are underrepresented in the trial, they added. They also used self-reported measures for mental health symptoms instead of observer-rated scales like the Hamilton Depression Scale. Finally, sertraline may have had an effect on depression too small to be detected in a trial of this size.

Lewis received personal fees from Fortitude Law outside this work.

Penninx reported receiving grants from the Dutch Ministry of Health/NWO, Boehringer Ingelheim, and Jansen Research regarding this editorial.

The study was funded by the National Institute for Health Research.

Primary Source

Lancet Psychiatry

Source Reference: Lewis G, et al “The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial” Lancet Psychiatry 2019; DOI: 10.1016/S2215-0366(19)30366-9.

Secondary Source

Lancet Psychiatry

Source Reference: Penninx B “Examining the antidepressant scattergun approach” Lancet Psychiatry 2019; DOI: 10.1016/S2215-0366(19)30366-9.