Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence

Abstract

Selective serotonin reuptake inhibitor (SSRI) antidepressants are frequently used in the management of antenatal maternal mood disturbances. SSRIs readily cross the placenta and increase central serotonergic tone in the fetus. Given serotonin's key neurodevelopmental role, such prenatal exposure raises concerns about its impact on child development. Preclinical studies report enduring molecular, physiological, and behavioral consequences of developmental SSRI exposure. In humans, sustained developmental outcomes remain largely unstudied, and distinguishing between the effects of prenatal SSRI exposure and the impact of maternal mental illness remains a key challenge.

Figure 1

Molecular serotonin system components, effects of selective serotonin reuptake inhibitor (SSRI) exposure, and outcomes related to antenatal SSRI exposure. Pre- and postsynaptic components of the serotonin system with key molecules that regulate serotonin synthesis, release, reuptake, and degradation are shown under normal conditions (left) and under SSRI exposure (right). Blockade of the serotonin transporter leads to an increase in serotonergic tone. 5-HT, serotonin; 5-HTT, serotonin transporter; MAO-A, monoamine oxidase A; TPH, tryptophan hydroxylase.

Figure 2

Comparison of preclinical and clinical findings associated with prenatal exposure to stress and selective serotonin reuptake inhibitor (SSRI) medications. (a) Preclinical and (b) clinical findings related to the consequences of exposure to stress or to SSRIs are summarized. Red vertical lines mark the time of exposure. In (a) the stress-exposed preclinical summary, light red represents the period of exposure in rhesus macaques and dark red represents the period of exposure in rats. 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, serotonin; 5-HTT, serotonin transporter; ADHD, attention-deficit hyperactivity disorder; DA, dopamine; DHPG, dihydroxyphenylglycol; EEG, electroencephalography; FHRV, fetal heart rate variability; GR, glucocorticoid receptor; HPA, hypothalamic–pituitary–adrenal; IGF-1, insulin-like growth factor-1; MCA, middle cerebral artery; S100B, S100 calcium-binding protein B; TPH, tryptophan hydroxylase; trp, tryptophan; TSH, thyrotropin.

Figure 3

Long-term consequences of altered serotonergic tone. (a) Pre- and postsynaptic components of the serotonin system with key molecules that regulate serotonin synthesis, release, reuptake, and degradation are shown under normal conditions (left), SSRI exposure during development (middle), and in later life after developmental exposure to SSRIs. Although SSRI exposure during development leads to acute increases in serotonergic tone, it inhibits the development of the serotonin system and leads to reduced serotonin tone later in life. 5-HT, serotonin; 5-HTT, serotonin transporter; MAO-A, monoamine oxidase A; TPH, tryptophan hydroxylase. (b) Schematic representation of genetic, environmental, and pharmacological factors that collectively alter serotonergic tone during development. Examples of consequences of pathologically high or low serotonergic tone during development are listed. 5-ht, serotonin; 5-htt, serotonin transporter gene; mao-a, monoamine oxidase A gene; tph1, tryptophan hydroxylase 1 gene; tph2, tryptophan hydroxylase 2 gene.