Antidepressant Mechanisms and Responses in Major Depression

Major depression is a heterogeneous disorder characterised by persistent low mood, anhedonia and cognitive impairment. Traditional antidepressants, including selective serotonin reuptake inhibitors and dual‐action agents, restore monoaminergic balance over weeks and engage downstream neurotrophic and synaptic plasticity pathways. However, a substantial proportion of patients reach only partial remission or remain treatment resistant. In response, research has focused on rapid‐acting interventions that target glutamatergic neurotransmission and neurotrophic signalling. Ketamine, an N-methyl-D-aspartate receptor antagonist, triggers immediate synaptic disinhibition, dendritic remodelling and activation of brain-derived neurotrophic factor receptor pathways, yielding swift behavioural improvements. Complementary strategies such as brief anaesthetic exposures engage similar plasticity cascades without psychotomimetic side effects. Converging evidence also implicates adult hippocampal neurogenesis, modulation of interneuron subtypes and restoration of mesolimbic circuit function in the resolution of core depressive symptoms. Together, these insights are redefining our understanding of both the cellular substrates of resilience and the diverse neurobiological responses to antidepressant treatments.

Research from Nature Portfolio

Recent studies have elucidated how subanaesthetic ketamine remodels prefrontal microcircuits by selectively suppressing somatostatin-expressing interneurons, leading to dendritic spine disinhibition and enhanced calcium transients in pyramidal neuron spines. These local changes correlate with restored frontal connectivity and rapid behavioural amelioration. Foundational work has shown that the sustained antidepressant effect of ketamine depends on activation of TrkB-mediated signalling within adult hippocampal progenitor cells, accelerating their differentiation into mature granule neurons via ERK pathway engagement and thus supporting prolonged functional recovery. Moreover, brief isoflurane anaesthesia has been found to elicit antidepressant-like behavioural effects through convergent activation of TrkB and mTOR pathways, inhibition of glycogen synthase kinase-3β and facilitation of hippocampal long-term potentiation, offering a non-psychotomimetic route to harness plasticity mechanisms comparable to those of ketamine.

Antidepressant Mechanisms and Responses in Major Depression publication trend

The graph below shows the total number of articles in antidepressant mechanisms and responses in major depression across all publications each year (not limited to Nature Index journals).

Technical terms

N-methyl-D-aspartate receptor (NMDAR): A subtype of glutamate receptor critical for synaptic plasticity and memory formation.

TrkB: A high-affinity receptor for brain-derived neurotrophic factor involved in neuronal survival, differentiation and plasticity.

mTOR: A kinase that regulates protein synthesis and synaptic growth in response to neuronal activity.

Dendritic spine: A small protrusion on a neuron's dendrite that forms the postsynaptic component of most excitatory synapses.

Neurogenesis: The birth and integration of new neurons in adult brain regions, notably the dentate gyrus of the hippocampus.

References

1. Ketamine rescues anhedonia by cell-type- and input-specific adaptations in the nucleus accumbens. Neuron (2025).
2. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology (2023).
3. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nature Communications (2020).
4. TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response. Nature Communications (2017).
5. Isoflurane produces antidepressant effects and induces TrkB signaling in rodents. Scientific Reports (2017).
6. Ketamine and selective activation of parvalbumin interneurons inhibit stress-induced dendritic spine elimination. Translational Psychiatry (2018).