The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression.

K A Rahn,Y-J Cao,A I Kaplin,C W Hendrix

doi:10.1038/tp.2015.57

Abstract

Acute antidepressant exposure elevates the frequency of impulsive behavior and suicidal thoughts in children and adolescents with major depressive disorder (MDD). Long-term antidepressant treatment, however, is beneficial for pediatric MDD, so it is necessary to explore novel treatments that prevent the potentially dangerous consequences of acute antidepressant initiation. In the present study, a treatment strategy designed to reverse the acute negative behavioral effects of antidepressants was tested in rodents. Co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, a serotonin reuptake inhibitor, but not reboxetine, a norepinephrine reuptake inhibitor, supporting the involvement of 5-HT1AR in mediating the negative consequences of acute selective serotonin reuptake inhibitor (SSRI) treatment. No 5-HT1AR antagonists are currently approved for use in pediatric populations, so alternative strategies should be explored. One such strategy was suggested based on the hypothesis that the rate of 5-HT1AR activation and the subsequent inhibition of serotonergic neuron activity caused by acute SSRI administration is proportional to the loading rate of an antidepressant. Existing pharmacological data were examined, and significant correlations were observed between the half-life of antidepressants and the rate of suicide-related events (SREs). Specifically, antidepressants with longer half-lives have lower rates of SREs. On the basis of these data, novel dosing strategies were developed for five antidepressants to mimic the pharmacological profile of the antidepressant with the longest half-life, fluoxetine. These dosing strategies could be used to decrease the rate of SREs associated with acute antidepressant treatment in pediatric MDD until an improved pharmacological treatment is developed.

Highlights

Major depressive disorder (MDD) occurs in ~ 8% of all children and adolescents[1] and can negatively impact social, cognitive and emotional development
Treatment of MDD with an selective serotonin reuptake inhibitor (SSRI) causes a small but significant elevated risk of suicidal behavior in children and adolescents[5,6] The present study was designed to better understand the mechanisms by which acute SSRI administration in children and adolescents results in increased suicide-related events (SREs), and from this knowledge develop novel treatment strategies to combat this elevated risk of suicidal thoughts and actions
We hypothesized that blockade of 5-HT1A receptor (5-HT1AR) would lead to a decrease in the acute negative effects of SSRI treatment, which has implications for the increased rates of suicidal ideation in the initial weeks of antidepressant treatment through inhibition of the feedback loop and prevention of decreased serotonergic output

Summary

Introduction

Major depressive disorder (MDD) occurs in ~ 8% of all children and adolescents[1] and can negatively impact social, cognitive and emotional development. In October 2004, the FDA conducted a meta-analysis of 24 double-blind placebo-controlled trials of pediatric SSRI treatment and found an increased risk of suicidal thoughts and behaviors in children and adolescents initiating SSRI treatment (four, versus 2% in placebo controls).[4,5,6] On the basis of these findings, the FDA issued a black box warning and guidelines that include the requirement for weekly examinations to monitor suicidal thoughts and behaviors during the first month of pediatric antidepressant treatment. This warning was extended to include young adults (18–24 years) in 2007.7 More recent behavioral data collected from 15–99-year-old subjects treated with SSRIs revealed a 2.6%

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