Abstract
Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine’s use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.
Highlights
Ketamine was originally used as an anesthetic drug in the 60s (Domino et al, 1965), but soon after, its widespread diffusion as a recreational drug posed a serious and continuing concern (Liao et al, 2017)
Recently Abdallah et al (2018), observed that ketamine increased glutamate-glutamine cycling in the prefrontal cortex (PFC) of major depression disorder (MDD) patients that was correlated with a rapid antidepressant effect, an effect that could be representative of an increased neurotransmission strength in the PFC
A further support of the involvement of the nucleus accumbens (NAc) in the effects of ketamine has been provided by Yao et al (2018), who have demonstrated that a single injections of a low dose of ketamine induced the impairing of long-term potentiation in the NAc; this effect was maintained for 7 days and was not associated with any alteration of basal synaptic transmission mediated by AMPARs and NMDA receptors
Summary
Ketamine was originally used as an anesthetic drug in the 60s (Domino et al, 1965), but soon after, its widespread diffusion as a recreational drug posed a serious and continuing concern (Liao et al, 2017). The lack of an adequate animal model of depression has largely hindered the research in this field In such a scenario, understanding ketamine’s mechanism of action has the potential to markedly improve the knowledge of the etiology of depression and may lead the way to selecting new, more efficacious and safer antidepressants (Harmer et al, 2017; Chaki, 2017). Among the effects that ketamine induces, it seems possible to distinguish very early effects that may be common to the stimulating actions of ketamine, and enduring effects that may be more framed in its antidepressant actions These effects may acquire relevance in depressed patients because they occur in a background of altered synaptic connectivity (Duman et al, 2019). We will discuss the relationship between ketamine and brain circuitry involved in stress and in depression therapy, with the aim of shedding light, on the etiology of depression, and on the development of potential new therapies for its treatment
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