May 20, 2015
Phased SSRI Dosages Could Mitigate Suicide Risks
in Youngsters

Baltimore—Carefully stepping up the dosage of selective serotonin reuptake inhibitors (SSRIs) might be a method to use a wider range of the depression medications in children without increasing suicide risks, according to a new study.

Background information in the report, published recently in the journal Translational Psychiatry, noted that unintended consequences appeared to have occurred because of a black box warning, required by the FDA in 2004 because the drugs increased suicidal thoughts and actions by 3% to 4%.

Study authors from Johns Hopkins University suggest that, with 10% of all children and adolescents in the United States suffering from depression, the suicide rate has gone up because of hesitancy to prescribed SSRIs, even though the suicide risk of untreated major depressive disorder is greater than the drugs’ side effects.

“These medications have to be dosed in a careful way,” said senior investigator Adam Kaplin, MD, PhD, an assistant professor of psychiatry and neurology at the Johns Hopkins University School of Medicine. He pointed out that is “exactly what psychiatrists have been doing for a long time in adults” to mitigate the adverse effects of SSRIs.

The complication, however, is that for children and adolescents, treatment regimens have tended to be more intense because “it is excruciatingly painful to wait for kids to respond when they are often already at the end of their ropes before meeting with a medical professional,” Kaplin said. Unlike adults, he pointed out, young people rarely seek treatment on their own and usually must wait for parents to become aware of the problem and take them for professional care.

The researchers sought to determine how to mitigate suicidality risks which occur shortly after initiating SSRIs. The first step was analyzing the same data the FDA used in 2004 to issue its black box warning. The study found that while SSRIs made young patients more impulsive, particularly during the first month of treatment, they really do not create suicidal thoughts where there were none before.

A computer simulation was then performed to find optimal pediatric dosing for the faster-acting SSRIs—paroxetine, citalopram, sertraline, venlafaxine and fluvoxamine—so that they would act in a similar way to fluoxetine, the slowest-acting SSRI and the only one that is FDA-approved for children aged 8 to 12 years.

It can take several weeks or months for fluoxetine to reach therapeutic levels in the blood and begin to have an effect.

The model generated the same kinds of dosing regimens psychiatrists use for medicating adults experiencing SSRIs’ negative effects, such as starting with half the normal initial dose and slowly increasing it to achieve therapeutic levels, the researchers explain.

The newly proposed dosing guidelines likely would improve safety, but they would also slow how long it takes before patients receive relief, even from the faster-acting SSRIs.

In a second part of the study, the researchers worked with mice to determine that the molecule WAY-100635—previously used in adult human research studies—produced “a synergistic effect when given with an SSRI,” explained Kristen Rahn, PhD, a Johns Hopkins instructor of psychiatry and behavioral sciences and of neurology. “And it completely alleviated the anxiety the animals had.”

Given by itself, though, WAY-100635 had no significant effect on anxiety levels but, combined with SSRI treatment, it eliminated the start-stop effect on serotonin levels and created a smoother transition, according to the study.

U.S. Pharmacist Social Connect