Do Molecular Interventions (Ketamine) Re-establish Synapses in Affected Brain Structures?

Ketamine, at suitable sub-anaesthetic doses, is now recognised as the major discovery in the use of antidepressants for over half a century. This chapter provides a technical overview of what we know concerning how this drug brings about its effects. In this final chapter, it is argued that the powerful antidepressant effects of ketamine are due to its action in restoring functional synapses. Direct evidence for this is now available through the use of a radioactively labelled constituent of synapses (SV2A) in human cortex, which shows the deficit in synapse density in a participant with MDD/PTSD is offset by the enhanced density in the same participant 24 h after ketamine treatment. Following administration of ketamine in preclinical experiments, the activities of the BA25 (SCG) and the amygdala, key centres of the distributed depression network that are abnormally active in MDD, are lowered according to measurements for SCG and the amygdala. It seems highly likely that the principal role of ketamine as an antidepressant is to work on these centres so as to bring about the normalisation of amygdala activity, known to directly reflect the extent of MDD. Finally, there are several molecular mechanisms by which ketamine could work on these centres that are at present under investigation. Three of these examined in detail are action through N-methyl-D-aspartate receptors (NMDAR), hyperpolarisation-activated cyclic nucleotide-gated channels (HCN), and ‘mammalian target of rapamycin’ (mTOR).