Multistage drug effects of ketamine in the treatment of major depression.

A substantial number of patients diagnosed with major depression disorder show poor or no response to standard antidepressive drugs. Recent studies showed that ketamine promotes a rapid and sustained antidepressive effect in treatment-resistant depression. Importantly, after a single dose, such antidepressant action appears very fast, reaching maximum efficacy after 1-2 days before it slowly decays after 3-7 days. This temporal pattern is especially interesting since most effects are investigated following single, subanesthetic doses. This means that effects are observed at time points when the blood levels have long fallen below any active threshold. Mechanisms of action thus may be sought either in secondary or compensatory processes, which develop after acute systemic derangement or in molecular downstream mechanisms of action, which after initiation do not require the presence of active drug levels. We here review acute and delayed effects of subanesthetic ketamine infusion and discuss potential origins of antidepressant drug action. We will provide evidences that both acute effects on abnormal network configuration and delayed effects at the level of homeostatic synaptic plasticity may be necessary for antidepressant action. We further argue that such effects should be followed by a temporally well-defined exploitation of these transient changes by therapeutic processes, aiming at sustained changes of network configuration via psychotherapeutic or other methods.