The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression.
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.
1] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA [2] Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
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Rahn
Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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Cao
Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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Hendrix
1] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA [2] Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
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Kaplin
D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects; D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects*; D001007:Anxiety / Q000139:chemically induced*; D001522:Behavior, Animal / Q000187:drug effects*; D002648:Child; D003865:Major Depressive Disorder / Q000188:drug therapy*; D005473:Fluoxetine / Q000009:adverse effects; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000009:adverse effects; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D000077593:Reboxetine; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects; D059020:Suicidal Ideation; D013405:Suicide
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D005473:Fluoxetine; D009025:Morpholines; D010879:Piperazines; D011725:Pyridines; D000077593:Reboxetine; D044282:Receptor, Serotonin, 5-HT1A; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide