This study provides evidence that ketamine could effectively treat aspects of maternal adversity-induced depression-like phenotypes in offspring without conferring adverse consequences of direct serotonin disruption like fluoxetine. Both drugs alleviated anxiety-like behaviours in an elevated plus maze and reversed maternal adversity’s impacts on anhedonia based on sucrose preference tests. However, in a forced swim test assessing behavioural despair, fluoxetine outperformed ketamine. These findings have implications for optimizing maternal depression treatment to support healthy neurodevelopment.
Maternal adversity exposure utilizing chronic stressors mimics elements of human environmental risk factors that could act alone or interact with genetic vulnerabilities to induce perinatal depression. As predicted based on prior work, offspring demonstrated anxiety-like behaviour with reduced open arm exploration on the elevated plus maze (Tang et al. 2021; Bashiri et al. 2021) coupled with decreased sucrose preference indicating anhedonia (Dean et al. 2018; Planchez et al. 2019). Open field testing revealed no differences in center zone exploration but did suggest hyperlocomotion in the fluoxetine group.
Both ketamine and fluoxetine ameliorated anxiety-related behaviours, aligning with known anxiolytic effects (Houwing et al. 2019; Carrier and Kabbaj 2013). The mechanism may involve buffering excess stimulation of the HPA axis and downstream corticosterone release triggered by maternal stress (Bashiri et al. 2021). A rat model of inflammation-induced prenatal stress found that fluoxetine prevented epigenetic effects on corticotrophin releasing factor receptor 2, which could mitigate anxiety by potentiating serotonin signalling (Bashiri et al. 2021). In contrast, ketamine may reduce anxiety through opposing interactions with NMDA and AMPA glutamate receptors which regulate excitation/inhibition balance (Carrier and Kabbaj 2013).
Our results also demonstrate ketamine and fluoxetine's efficacy in treating anhedonia, one of depression's hallmark symptoms. This adds to existing evidence that ketamine alleviates reward processing deficits in both human and animal studies (Carrier and Kabbaj 2013; Lally et al. 2015; Lullau et al. 2023). Increased ventral striatal responses to reward cues post-ketamine infusion correlated with reduced anhedonia ratings, suggesting medium spiny neuron disinhibition. Enhancing AMPA throughput could strengthen dopaminergic encoding of value and salience (Francois et al. 2016). Unlike traditional antidepressants targeting the serotonergic system, ketamine may more directly modulate reward circuity through glutamate and dopamine interactions (Carrier and Kabbaj 2013).
In the forced swim test though, ketamine failed to impact floating time whereas fluoxetine robustly decreased immobility. Our results support previous studies showing limited effects of ketamine on despair-like behaviour in this specific assay, potentially due to stress-induced corticosterone interference (Carrier and Kabbaj 2013; Franceschelli et al. 2015). However clinical investigations demonstrate ketamine rapidly reduces suicidal ideation in treatment-resistant patients, so lack of effects in rodent forced swim may simply reflect a poor model of predictive validity for this singular dimension of depression (Wilkinson and Sanacora 2019). Patients describe the post-ketamine state as no longer feeling burdened by negative thoughts rather than a stimulated mood, so the test may not capture relevant phenomenology (Loo et al. 2016). Regardless, our findings indicate superior efficacy of fluoxetine over ketamine for mitigating behavioural despair in offspring exposed to maternal adversity.
Open field results were more difficult to interpret, with no clear effects on centre zone exploration but seemingly increased locomotors activity in the fluoxetine group over time. Hyperlocomotion could relate to other research showing adolescent and adult hyperactivity following developmental fluoxetine exposure, which authors posit reflects serotonergic excitation/inhibition imbalance in cortical and striatal circuits (Houwing et al. 2019; Rodriguez-Porcel et al. 2011). This again highlights potential unintended consequences of directly interfering in the serotonergic system during sensitive neurodevelopmental windows.
Counter to original hypotheses, ketamine did not outperform fluoxetine across all domains. While demonstrating equal effectiveness for anxiety and moderate improvements in anhedonia, fluoxetine elicited more robust antidepressant-like responses. However, it remains concerning that despite alleviating offspring behaviour, fluoxetine still crosses the placenta and acts directly on the foetal brain during vulnerable developmental periods with unpredictable echo effects that may not manifest until adolescence or adulthood (Houwing et al. 2019). Ketamine, in contrast, has not been shown to accumulate in foetal tissue or breastmilk, conferring an advantage (Deng et al. 2022).
Optimal dose and timing of exposure represent other critical considerations moving forward. Our ketamine dosage and injection schedule were selected based on common antidepressant administration. But the lacklustre forced swim test results raise questions about whether this regimen sufficiently penetrates the foetal compartments to induce sustained behavioural changes. Recent work suggests the S(+)-ketamine enantiomer confers greater potency and longer-lasting upregulation of trophic factors that may bolster neuroplasticity required for depression remission (Zhang et al. 2014; Song and Zhu 2021). Earlier initiation of treatment prior to implementing maternal stressors could also reinforce neuroprotective pathways.
Furthermore, we only examined a subset of behaviours in adult male offspring. Testing a wider range of phenotypes, including social, cognitive, sensorimotor, and self-administration assays could reveal additional domains where ketamine and fluoxetine diverge. Female offspring may also respond differently based on based on sex differences in placental functioning, epigenetic profiles, and neurotransmitter systems modulated by hormones (Bale et al. 2010; Migliore et al. 2021). Our modest sample sizes likewise limit generalizability and warrant studies with larger cohorts reflecting a spectrum of genetic and environmental variability to better translate findings to heterogeneous human populations.
Ketamine holds advantages over conventional antidepressants like fluoxetine due to the risks SSRIs pose to the developing foetal brain when crossing the placenta. However, timing, dosage, and interactions with the maternal-foetal interface could influence ketamine’s effects as well. While maternal treatment cannot replicate direct exposure, some transmission to offspring likely still occurs during pregnancy and lactation through indirect pathways.
For example, blocking NMDA receptors impairs negative feedback on CRH neurons, increasing hypothalamic CRH which then circulates to the placenta (Sandman et al. 2011). Placental CRH secretion also inhibits active transport of maternal nutrients like zinc and fatty acids to the fetus which play vital roles in neurodevelopment (Kassotaki et al. 2021). Ketamine’s antidepressant actions stem from ultimate downstream impacts on BDNF and synaptogenesis, so even minor reflective changes in levels reaching the foetus could exert actions on neuronal growth and connectivity imprinting lifelong consequences. Multi-generational studies tracking transdiagnostic outcomes are imperative.
Our future directions include testing direct foetal and early postnatal ketamine administration to model reported clinical IV administration protocols for mothers. Comparing long-term safety and efficacy to maternal exposure alone will better isolate mechanisms of transmission versus protection. Testing more chronic low-dose paradigms may provide insight on whether sustaining neurotropic factor upregulation prevents maladaptive plasticity associated with early adversity. Rational polytherapy combining ketamine with omega-3s could synergize these neuroprotective and anti-inflammatory pathways as well.