Impact of SSRIs on Early Development

Introduction

While much of the discussion on the long-term adverse effects of SSRIs may seem speculative or overly reliant on indirect evidence, there is, in fact, a substantial body of research highlighting the potentially lasting effects of SSRIs. [1] The most compelling evidence for these enduring changes comes from studies in which animals are exposed to SSRIs either in utero or during early development – as well as a handful of studies on early postnatal human exposure too.

While SSRIs are still considered safe by prescribers and are still a recommended treatment for depression during pregnancy – there’s an accumulating body of evidence to suggest the contrary. Significant concentrations of SSRIs have been found both in the umbilical cord blood and amniotic fluid of women taking these drugs during pregnancy. [11][12]

Furthermore, the doses of these medications appear to be sufficient to have neurological effects on the developing foetus, since these babies show clear signs of anti-depressant withdrawal for up to a month after birth. [13][14] These symptoms include shivering, convulsions, and irritability. In this article, I will examine the evidence indicating that SSRIs may have substantial effects on infant health, including lasting impacts on neurological development.

Health Repercussions and Cognitive Delay

Studies examining the effects of SSRI exposure on human foetuses are limited, yet they indicate a potential for early-life complications. One study of 55 Canadian women examined the impact of SSRI exposure in late gestation. The women were taking the SSRI Paroxetine at doses between 10-60mg during the third trimester, primarily to treat anxiety or depression.

Of the 55 infants exposed to Paroxetine, 12 (about 1 in 4) suffered severe complications necessitating prolonged hospitalisations. 9 of the babies suffered from respiratory distress, 2 experienced hypoglycemia and 1 from jaundice. [2] Furthermore, 20% of the babies in the Paroxetine group were born prematurely versus only 3.7% in the control.

Most of these women continued to take Paroxetine after delivery, and even noted symptoms in their infants in response to breastfeeding including changes in alertness and irritability. Upon final analysis, the researchers identified that Paroxetine exposure in the third trimester caused a 9.5-fold increase in the risk of causing respiratory distress.

This isn’t the only study to highlight the significant risks of early life exposure to SSRIs; a 1996 study published in The New England Journal of Medicine reviewed the pregnancy outcomes of 228 women taking Fluoxetine. One third of these infants suffered some form of maladaptation, and those infants exposed to Fluoxetine during the third trimester had a 5-fold increase in risk of premature delivery. [10] Both birth weight and birth length were also negatively impacted.

While it is clear that SSRIs can have significant postnatal health effects, it is reasonable to question whether these effects have lasting repercussions for affected infants. A 2003 study published in The Journal of Pediatrics sought to address this by tracking the neurological development of 31 children exposed to SSRIs in utero, assessing them between the ages of 6 and 40 months. [3] Most of the mothers were taking Sertraline, Fluoxetine, or Paroxetine to manage major depressive disorder.

The study found that drug-exposed children scored significantly lower on psychomotor and mental development assessments using the Bayley Scales of Infant Development (BRS). However, the researchers acknowledge the possibility that other factors, such as the impact of maternal depression itself, could also contribute to these outcomes.

Changes to Serotonin Circuitry

Studies on SSRI exposure in infants consistently indicate poorer health outcomes and developmental changes early in life. However, pinpointing the specific effects on brain development remains complex. Animal studies offer valuable insights here, as they allow for direct examination of brain tissue. In one such study, rats were treated with the SSRI Citalopram during early postnatal development, then evaluated for both behavioural and neurological changes.

Compared to controls, the Citalopram-treated rats showed dramatically impaired sexual activity. Examination of brain samples from these rats found some significant changes in the serotonergic system. The two weeks of citalopram treatment had resulted in profound reductions in tryptophan hydroxylase in two key regions of the Raphe Nuclei. Tryptophan Hydroxylase is the enzyme that converts tryptophan into Hydroxytryptophan (5-HTP), which is the precursor to serotonin. [4] The Raphe Nuclei is a tiny structure in the brain stem that controls serotonin release throughout the brain.

The second identifiable change was a 60% reduction in SERT, the serotonin transporter,in the prefrontal cortex and somatosensory cortex. SERT is the primary target of SSRI treatment, as it is responsible for reabsorbing serotonin back across the synapse, thereby ending serotonin signalling. By inhibiting SERT, SSRIs interrupt this process in order to prolong the effect of Serotonin on the post-synaptic neuron.

The effect of decreased tryptophan hydroxylase would in theory hamper serotonin production, however a reduction in SERT would increase the effect of serotonin by inhibiting its reuptake – comparable to the direct effect of SSRI treatment. It’s possible that the reduction in tryptophan hydroxylase represents an adaptation to offset the decrease in SERT.

Other animal studies have similarly found that foetal exposure to SSRIs can have a lasting impact on sexual behaviour. Mice exposed to Fluoxetine throughout gestation experienced a loss of preference for sexual incentive and motivation – despite there being no significant change in testosterone or testis. [5]

In other articles I’ve presented the evidence for SSRIs impacting sexual behaviour through lasting alterations in the behaviour of the 5-HT1A serotonin receptor. These changes aren’t contingent on early life treatment but are instead an adaptation in response to chronic SSRI exposure. The 5-HT1A receptor is present on neurons throughout the cortex and limbic system, and even influences hormonal balance via the hypothalamus. [6][9] These changes present yet another pathway by which SSRIs impact sexual behaviour in a lasting manner.

Conclusion

SSRI exposure, particularly in late pregnancy, may lead to significant neonatal complications, including respiratory distress, preterm birth, and developmental delays. Troublingly, SSRIs appear to have lasting effects on neurological development, with studies in animals showing changes in brain structure and serotonin pathways that influence behaviour and development. These neurological changes may contribute to behavioural alterations in later life, such as decreased sexual motivation and preference. There is a distinct lack of long term follow up studies on infants exposed to SSRIs during gestation, making it hard to conclude whether these early behavioural effects are in fact life-long changes.