A continuum hypothesis of psychotomimetic rapid... — Research Summary & Context

Ketamine, classical psychedelics and sleep deprivation are associated with rapid effects on depression. Interestingly, these interventions also have common psychotomimetic actions, mirroring aspects of psychosis such as an altered sense of self, perceptual distortions and distorted thinking. This raises the question whether these interventions might be acute antidepressants through the same mechanisms that underlie some of their psychotomimetic effects. That is, perhaps some symptoms of depression can be understood as occupying the opposite end of a spectrum where elements of psychosis can be found on the other side. This review aims at reviewing the evidence underlying a proposed continuum hypothesis of psychotomimetic rapid antidepressants, suggesting that a range of psychotomimetic interventions are also acute antidepressants as well as trying to explain these common features in a hierarchical predictive coding framework, where we hypothesise that these interventions share a common mechanism by increasing the flexibility of prior expectations. Neurobiological mechanisms at play and the role of different neuromodulatory systems affected by these interventions and their role in controlling the precision of prior expectations and new sensory evidence will be reviewed. The proposed hypothesis will also be discussed in relation to other existing theories of antidepressants. We also suggest a number of novel experiments to test the hypothesis and highlight research areas that could provide further insights, in the hope to better understand the acute antidepressant properties of these interventions.

J. and colleagues conclude that several interventions known for rapid antidepressant effects — principally ketamine, classical psychedelics and sleep deprivation — also share psychotomimetic properties. The authors propose a "continuum hypothesis of psychotomimetic rapid antidepressants", arguing that the commonality between these interventions is not accidental but reflects a shared tendency to reduce the influence of prior expectations (priors) across levels of the cortical hierarchy. Within a hierarchical predictive coding framework, the authors argue that diminishing the precision or strength of priors increases the relative influence of incoming sensory evidence (that is, exaggerated bottom-up prediction errors). In healthy individuals this produces excessive cognitive flexibility and perceptual/experiential disturbances characteristic of psychosis. By contrast, in people with depression — a condition the authors characterise as involving cognitive inflexibility and overly rigid priors — acutely increasing prior flexibility may rapidly alleviate core depressive cognitive features, producing antidepressant effects almost immediately.