Two new strategies have been developed by Johns Hopkins researchers to treat depression in young patients using serotonin reuptake inhibitors (SSRIs) while mitigating the risks and potential negative effects such as increased suicidal thoughts. The strategies are published in Translational Psychiatry.

In 2004, the Food and Drug Administration (FDA) issued a black box warning for SSRIs after a summary examination of all drug company sponsored studies showed the drugs increased suicidal thoughts and actions by 2–4% vs. placebo during the initial weeks after starting treatment. However, the black box warning may have possibly contributed to an increased rate of suicide because clinicians may have been hesitant to prescribe SSRIs.

In the study, researchers include a new understanding of how to mitigate suicide risk while receiving SSRI treatment. They assessed whether the early negative effects shortly after treatment initiation could be mitigated by either careful dosing done in adults with anxiety disorders or by combining SSRIs with another drug previously shown to speed up the effects of SSRIs in adults.

The researchers analyzed the same data reviewed by the FDA in 2004 that led to the issuing of the black box warning. They found that SSRIs made young patients more impulsive but did not create suicidal thoughts where there were previously none. Using a computer simulation, the team found optimal dosing for the faster-acting SSRIs (eg, paroxetine, citalopram, sertraline, venlafaxine, and fluvoxamine) in children so that these other SSRIs would act similar to fluoxetine, the only SSRI approved for children ages 8–12; fluoxetine (Prozac) is the slowest-acting SSRI.

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Their computer simulation model created the same kinds of dosing regimens psychiatrists use for dosing adults experiencing negative effects from SSRIs. The dosing regimens usually start with half the normal initial dose and slowly titrate it to achieve therapeutic levels. The new proposed guidelines would improve safety but also slow how long it takes before patients experience relief.

In addition, researchers found that adding WAY-100635, a molecule used in adult human research, produced a synergistic effect when given with an SSRI and relieved anxiety in mice. WAY-100635 given alone had no significant effect on anxiety levels. The molecule works by helping the brain get serotonin, which is the goal for long-term SSRI treatment. Initial exposure to SSRIs reduces serotonin, however, and this is what researchers believe causes adult anxiety and impulsivity in children. Pairing SSRI treatment with WAY-100635 may remove the “stop-start” mechanism and help smooth the transition. .

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