Researchers Propose Strategies to Minimize Adverse Events Associated With SSRIs in Youth

In a paper published in the journal Translational Psychiatry, researchers from Johns Hopkins University proposed two SSRI-treatment strategies for depression in children and adolescents that they believe may be able to reduce the destabilization that often accompanies acute antidepressant initiation in this patient population.

The researchers, led by Adam Kaplin, M.D., Ph.D., an assistant professor of psychiatry and neurology at Johns Hopkins University School of Medicine, examined data from a 2004 report by the Food and Drug Administration—the same report that led the agency’s decision to issue the black-box warning and guidelines on pediatric SSRI treatment—to determine the relationship between the half-life of six antidepressants (fluoxetine, citalopram, venlafaxine, sertraline, paroxetine, and fluvoxamine) and the rate of suicide-related events (SREs) in pediatric patients. The researchers found a significant positive correlation between the two factors, indicating that the faster the loading rate of an SSRI, the higher the chances of an SRE occurring (P<0.05).

Based on these findings, the team used a computer-generated dosing simulation to develop novel treatment regimens for citalopram, venlafaxine, sertraline, paroxetine, and fluvoxamine that mimic the pharmacological profile of fluoxetine—the antidepressant with the longest half-life and lowest relative risk of SREs in pediatric populations.

The researchers also looked for ways to reverse the acute negative behavioral effects of antidepressants in a rodent model. They found that co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, but not reboxetine, suggesting the involvement of 5-HT1AR in mediating the negative consequences of acute SSRI treatment.

“The combination drug-treatment strategy of a 5-HT1AR antagonist administered in combination with an SSRI reversed the acute anxiogenic effects of an SSRI alone in rodents,” the authors wrote. “We are hopeful that this treatment strategy can be developed and tested for future use in humans.”

“I think the construct that there could be an agent that could help with the destabilizing process at beginning of SSRI treatment is a worthwhile concept worthy of more research,” Louis Kraus, M.D., a professor of child and adolescent psychiatry at Rush University Medical Center, told Psychiatric News. “But, even now we have safe and effective ways of treating depression using therapy and medication management that has shown time and time again to help depression and save lives.”

“My concern is for children and adolescents with depression who are not taking SSRIs when indicated, leading to an increased risk of suicide and worsening depression,” Kraus added.

For more information on efforts to treat depression in children and adolescents, see the Psychiatric News article “Are FDA Antidepressant Warnings Linked to Rise in Youth Suicides?”

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