New Insights into How Serotonin Selective Reuptake Inhibitors Shape the Developing Brain

Abstract

Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system (CNS) development, such sensitive periods shape the formation of neuro-circuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint, as well as the environmental context. While allowing for adaptation, such sensitive periods are also windows of vulnerability during which external and internal factors can confer risk to brain disorders by derailing adaptive developmental programs. Our group has been particularly interested in developmental periods that are sensitive to serotonin (5-HT) signaling, and impact behavior and cognition relevant to psychiatry. Specifically, we review a 5-HT-sensitive period that impacts fronto-limbic system development, resulting in cognitive, anxiety, and depression-related behaviors. We discuss preclinical data to establish biological plausibility and mechanistic insights. We also summarize epidemiological findings that underscore the potential public health implications resulting from the current practice of prescribing 5-HT reuptake inhibiting antidepressants during pregnancy. These medications enter the fetal circulation, likely perturb 5-HT signaling in the brain, and may be affecting circuit maturation in ways that parallel our findings in the developing rodent brain. More research is needed to better disambiguate the dual effects of maternal symptoms on fetal and child development from the effects of 5-HT reuptake inhibitors on clinical outcomes in the offspring. Birth Defects Research 109:924-932, 2017. © 2017 Wiley Periodicals, Inc.

Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies

“…The neurodevelopmental pattern of the serotonin system is remarkably conserved across species 29, 32, 33 . Therefore, rodent studies of early SSRI exposure can yield important insights and circumvent some of the difficulties of studying this phenomenon in humans.…”

“…The first few postnatal weeks in rodents are instrumental in the maturation of both the serotonin system and cortical circuit wiring, and also show the highest levels of serotonin and its metabolites in the brain 29 . In terms of brain development, this period is approximately equivalent to the third trimester of human gestation 37 .…”

“…Animal experiments have several other advantages, such as the ability to study the developmental effects of SSRI treatment during a healthy pregnancy and a high degree of control over drug dosing and period of exposure. The last decade especially has witnessed a major surge in animal studies examining various neurobiological outcomes of perinatal SSRI exposure, which have been described in numerous narrative reviews 14, 29–34 . To maximize the translational value of animal studies, and in line with efforts to reduce the use of animals in research, it is imperative to comprehensively bundle all available preclinical evidence.…”

BDNF, 5-HT, and Anxiety: Identification of a Critical Periadolescent Developmental Period

“…In addition, treatment of children or adolescents with selective serotonin reuptake inhibitors (SSRIs), the first line of pharmacological intervention for anxiety and depression, has been associated with suicidality. This has led to preclinical studies demonstrating that SSRI administration during early postnatal and preadolescent periods can cause long-lasting anxiety behaviors, even into adulthood, in animal models (2). Mechanistic studies in adult animals have demonstrated a link between anxiety, 5-HT, and brain-derived neurotrophic factor (BDNF), a major neurotrophic factor that undergoes elevated expression during the periadolescent period (3–5).…”

Maternal antioxidant treatment prevents behavioural and neural changes in offspring exposed to prenatal social stress

“…However in the prenatally stressed juveniles, protein levels in the frontal cortex had returned to levels equivalent to those observed in non-stressed offspring. The serotonin system plays a critical role during neurodevelopment, in particular in the development of the limbic system (including the amygdala, hippocampus and prefrontal cortex), which is important for processing emotional behaviours 70 . Therefore, this transient dysregulation of gene expression in prenatally stressed foetal brains could temporarily affect crucial neurodevelopmental processes at a period of high vulnerability, in line with the concept of the foetal origins of adulthood disease 71,72 , potentially leading to long-term alterations in the offspring brains.…”