Smarter SSRI Dosing Could Decrease Suicide Risk in Depressed Youth

Meghan Ross, Associate Editor

New research offers novel strategies to reduce suicide risk among depressed children and adolescents prescribed selective serotonin reuptake inhibitors (SSRIs).

Since SSRIs have been shown to increase suicidal thoughts and actions in pediatric and adolescent populations, the FDA issued a black box warning describing this risk in 2004. However, a recent study published in Translational Psychiatry noted the suicide rate among youth with major depressive disorder has increased since then—seemingly because clinicians hesitate to prescribe SSRIs, even though leaving depression untreated increases suicide risk to a greater extent.

One of the problems with SSRIs is they can cause an initial drop in serotonin and then slowly increase it, causing a potential delay in antidepressant effects. In order to treat depression in youth quickly, early SSRI dosing has tended to be more intense, the study authors explained.

Presently, fluoxetine (Prozac) is the only FDA-approved SSRI for children aged 8 to 12 years, and it is the slowest-acting one. In fact, it can take weeks or months for the drug’s therapeutic effects begin to kick in.

“One of the hardest parts of our jobs is to get people through that delayed period of time where we all wish our medicines worked faster,” said senior study investigator Adam Kaplin, MD, PhD, an assistant professor of psychiatry and neurology at Johns Hopkins University School of Medicine, in a press release. “…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.”

Thus, the researchers sought to pinpoint optimal dosing for faster-acting SSRIs in children that could closely mimic Prozac. Using computer simulations, they determined an ideal dosing strategy for paroxetine, citalopram, sertraline, venlafaxine, and fluvoxamine would start at half the normal initial dose, and then slowly increase to achieve therapeutic results.

Noting this new dosing regimen would improve safety, yet delay depression relief even from fast-acting SSRIs, the researchers considered methods to prevent the negative behavioral effects potentially caused by the initial drop in serotonin levels.

“…Because pediatric populations have increased rates of suicidal ideation and impulsivity during the first month of SSRI treatment, it is plausible that the acute negative effects of SSRIs could be a result of the 5-HT1AR-mediated decrease in serotonergic output during acute treatment,” the authors wrote. “If (this) accounts for the increased suicidal ideation, then antidepressants that lead to a more moderate activation of 5-HT1ARs should have a lower rate of suicidal ideation in children and adolescents.”

While testing their theory, the researchers found combining acute SSRI treatment with WAY-100635, a 5-HT1AR antagonist used in adult research studies, reversed the negative behavioral effects. In other words, co-administering WAY-100635 could decrease the odds of children experiencing anxiety and impulsivity during SSRI treatment, which could lower their risk of suicidal thoughts and actions.

“Until a selective 5-HT1AR antagonist is approved for use in children, the novel and specific dosing strategies for existing SSRIs that are proposed here provide immediate potential for decreasing the frequency of suicide-related events in pediatric patients with major depressive disorder, while maximizing the speed of therapeutic effects,” the researchers concluded.