Converging evidence indicates that the antidepressant mechanisms of subanesthetic dose racemic ketamine involve a reduction of self-reinforcing pathophysiology, which otherwise can worsen brain health and treatment outcomes. Ketamine targets neuroprogressive factors which maintain neurodegeneration and hinder neuroplasticity via several mechanisms, including facilitation of neuroprotective processes and attenuation of neurotoxicity. It also increases the capacity for neurogenesis, dendritogenesis, and synaptogenesis via upregulation of brain-derived neurotrophic factor. Furthermore, emerging evidence begins to untangle how ketamine’s acute synaptogenic effects can start a cascade that initiates a positive feedback loop with the result of a sustained enhancement of synaptic potentiation and translational activity. Attenuation of neuroprogressive factors combined with initiation of synaptogenesis may underlie improved clinical ketamine treatment outcomes. This impact may also increase patients’ benefits from further treatment modalities, while simultaneously offering a period of decreased symptom burden.