A human translational model based on neuroplasticity for pharmacological agents potentially effective in Treatment-Resistant Depression: focus on dopaminergic system

Drugs that share the common mechanism of increasing dopaminergic neurotransmission were shown to improve symptoms in TRD patients as adjunctive treatment to SSRI (Dunlop and Nemeroff, 2007; Fawcett et al., 2016). [...]the dopaminergic system could be seen as a preferred substrate in targeting TRD patients with endogenously reduced dopaminergic transmission. [...]how the molecular and cellular mechanisms of action of ketamine translate in humans is only partially understood. Since ketamine is known to increase dopaminergic neurotransmissions in cingulate/prefrontal cortex (Kokkinou et al., 2018), we suggest that ketamine also induces neuroplasticity in the dopamine system, contributing to the delivery of antidepressant and anti-anhedonic effects in TRD patients. [...]human iPSC-derived neurons together with pharmacodynamic signals, soluble biomarkers, genetic risk profile and neuroimaging can work in parallel, complementing each other, to generate a better understanding of the therapeutic relevance of neuroactive pharmacological agents, providing an integrated translational approach for drug development. Intriguingly, ketamine-induced neuroplasticity on human dopaminergic neurons required functionally intact dopaminergic D3 receptors (D3R), since these effects were abolished by pretreatment with selective D3R antagonists (Cavalleri et al., 2018). [...]activation of D3R using D3R-preferential agonist pramipexole produced structural plasticity in dopaminergic neurons at concentration compatible with their clinical therapeutic use in TRD patients (Fawcett et al., 2016; Collo et al., 2018a).