Abstract

Neuronal plasticity is a critical mechanism underlying resilience and the antidepressant effects. Furthermore, there is some evidence suggesting that restricted plasticity may be an underlying factor in the pathophysiology of mood disorders. Our previous studies have shown that antidepressant drug treatment promote neuroplasticity and resilience. Beneficial effects of are not produced by the drug treatment alone, but drug treatment needs to be combined with training that guides the changes in neural networks rendered plastic by antidepressant treatment.

We have shown that many, if not all antidepressant drugs (including typical drugs SSRIs and tricyclics, but also the rapid-acting ketamine) act by directly binding to TrkB, the receptor for brain-derived neurotrophic factor (BDNF) and allosterically increasing BDNF signaling. We recently showed that psychedelic compounds LSD and psilocin directly bind to TrkB with high affinity and thereby promote plasticity and antidepressant effects, but not the hallucinogenic effects. The plasticity-promoting and antidepressant-like effects of various drugs known to have antidepressant effects are lost in mice with a mutation in TrkB that is otherwise silent but prevents drug binding to TrkB. We have also shown that the effects of antidepressants are predominantly mediated by TrkB receptors on the parvalbumin-expressing interneurons and that the activation of TrkB in these neurons reduces the expression of parvalbumin and the density of perineuronal nets, thereby reducing their inhibitory control of pyramidal neurons and promoting network activity through disinhibition.

These findings have dramatic effects of our understanding of the antidepressant drug action. First, they suggest that all antidepressants act though the same mechanism, binding to TrkB, which calls into question the role of serotonin and NMDA-type glutamate receptors in the antidepressant effects. Second, they implicate that the antidepressant-relevant plasticity-promoting effects of psychedelics can be separated from their hallucination-producing effects. Third, these studies show that antidepressants act by increasing the sensitivity of neuronal networks to environmental influences, suggesting that active engagement of the patient together with drug-promoted plasticity is beneficial and emphasizing that antidepressant drug treatment needs to be combined with supporting therapy for optimal effects.