A new approach for treating children with depression could reduce an elevated suicide risk linked with the early stage of antidepressant treatment regimens.
In 2003 and 2004, European and US medicines regulators warned about the possible increased risk of suicide and suicidal thoughts among children and adolescents treated with selective serotonin reuptake inhibitors (SSRIs). They advised that only fluoxetine was proven to be effective at treating depression among children.
Researchers at Johns Hopkins University in Baltimore, Maryland, reviewed these recommendations and the data on which they were based, pointing out that acute antidepressant exposure increases the frequency of impulsive behaviour in young people with major depressive disorder (MDD) but that long-term treatment is beneficial. Their findings were published in Translational Psychiatry
on 5 May 2015.
The researchers say that improving strategies in paediatric MDD is essential, as a recent decline in antidepressant use has coincided with increased suicidal behaviour in young adults.
They aimed to determine whether the negative effects seen shortly after starting SSRIs could be mitigated through careful dosing of SSRIs or by using combination treatments.
The researchers used computer simulation to find the optimal paediatric dosing for the faster-acting SSRIs (paroxetine, citalopram, sertraline, venlafaxine and fluvoxamine) so that they would match the daily blood concentrations of fluoxetine, the slowest-acting SSRI.
They found that their optimal dosing model (see table) matched the dosing regimens psychiatrists traditionally use for adults with depression who are experiencing SSRIs’ negative effects. They suggest this dosing strategy could be used until an improved pharmacological treatment is developed.
The team also tested a combination of treatments in order to completely block the early negative effects of SSRIs.
Acute SSRI exposure activates the 5-HT1A receptor, which decreases serotonergic neuron output, explain the researchers. They hypothesised that blocking the 5-HT1A receptor would lead to a decrease in the acute negative effects of SSRI treatment and tested a 5-HT1A receptor antagonist, WAY-100635, in a mouse model of MDD.
Given on its own, WAY-100635 had no significant effect on anxiety levels, but combined with a SSRI, the molecule reversed the acute anxiogenic effects of the SSRI.
“We are hopeful that this treatment strategy can be developed and tested for future use in humans,” the researchers say.
- This article was amended on 20 May 2015 to clarify that the proposed dosing model for children matched regimens used for adults experiencing negative effects of SSRIs.
 Rahn KA, Cao Y-J, Hendrix CW et al. The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression. Translational Psychiatry 2015;5:e563. doi:10.1038/tp.2015.57.