Antidepressants for Children and Teens

New Strategies May Reduce Suicide Risk

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Jonathan Nourok

A team of researchers at Johns Hopkins University have been investigating two new treatment strategies which they believe will help reduce the risk for suicide in children and teens using selective serotonin reuptake inhibitor (SSRI) antidepressants.

The increased risk for suicidal thoughts and urges was first revealed when a meta analysis was conducted using 24 smaller studies of children and teenagers who were using either antidepressants or placebo pills.

  When the data was analyzed, it was found that those young people who were using SSRIs had double the risk for attempting suicide as those who were taking only an inactive sugar pill.  In 2004, based upon these results, the U.S. Food and Drug Administration (FDA) chose to issue a black box warning regarding the increased risk for suicidal thoughts and behaviors in children and teens using these antidepressants.  Later, in 2006, the warning was extended to include young adults under the age of 25.

While the warning was intended to reduce suicide among children and teens, it may have, unfortunately, had the opposite effect.  The rate of suicide attempts appears to have risen, perhaps, speculates study author Dr. Adam Kaplin, because doctors now shy away from using these medications for their patients.  He points out, however, that untreated depression also puts young people at risk for suicide; and, when children in need of treatment go without, increased suicide rates may be the unintended consequence.

Dr. Kaplin and his colleague's study, which was published in the May 5, 2015 issue of Translational Medicine, sought to mitigate this problem by studying two possible methods of dealing with the suicidality which can emerge early in the treatment process.  The two strategies examined included performing very careful dosing – which is already often done with other conditions, such as high blood pressure, diabetes and anxiety disorders – and combining the antidepressant with a molecule that affects serotonin called WAY-100635, which has previously been studied to try and speed up the therapeutic effect of SSRIs in adults.

The team first took a closer look at the data used by the FDA in 2004 that led to the black box warning.  What they found was that even though patients on SSRIs tended to become more impulsive during their first month in treatment, and thus more likely to act upon their suicidal urges, the drugs themselves weren't actually creating suicidal thoughts where they didn't already exist.

Next, because fluoxetine (brand name Prozac), an SSRI with a very long half-life, is the only SSRI which is currently FDA-approved for treating children between the ages of 8 to 12, they did a computer simulation to determine what the optimal dosing would be in other SSRIs with quicker metabolism in order to mimic the effects of fluoxetine.  Basically, what happened when they did this is that it created dosing regimens where children would be started on lower doses and then slowly increased to a therapeutic level.

Unfortunately, this type of dosing regimen, while probably safer, does not deliver the fast results that are often desired when a child is suffering from depression.

  Because of this, the researchers also looked at the possibility of using a molecule called WAY-100635 in addition to an SSRI to help prevent the anxiety and impulsivity that may increase during the initial phase of treatment..  Although WAY-100635 does nothing to help anxiety by itself, when combined with an SSRI, it alleviates this symptom.

The reason it may help patients to respond more quickly to SSRIs is that when patients initially begin using an SSRI it can actually reduce the brain's output of serotonin, a substance which is believed to be in short supply in individuals with depression.  Eventually, the antidepressant does begin to increase serotonin, and thus relieve depression, but the initial reduction and subsequent rise in serotonin creates a rough transition into treatment and may possibly cause the symptoms of anxiety and impulsivity that lead to young people being more likely to act upon their suicidal urges.

"Now that we have uncovered this effect and worked out this mechanism," notes Kaplin, "we are in the process of communicating with pharmaceutical companies to see which of them might have tested a drug similar to WAY-100635 that didn't do anything by itself and therefore was abandoned."  If Kaplin and his team can find an existing drug already using this molecule, they would be one step closer to developing a much safer treatment strategy for children and teens who might otherwise not be getting the treatment that they need.

Sources:

"FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications."  U.S. Food and Drug Administration.  U.S. Department of Health and Human Services.  Updated:  April 10, 2013.  Accessed:  May 29, 2015.

Friedman, Richard A.  "Antidepressants' Black-Box Warning — 10 Years Later."  New England Journal of Medicine. 371 (2014):1666-1668.

Rah, K.A., Y.J. Cao, C.W. Hendrix and A.I. Kaplin.  "The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression."  Translational Psychiatry.  5 (2015): e563.

 

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