Insomnia and inflammation: a two hit model of depression risk and prevention
Michaela Irwin, D. Piber
World Psychiatry September 7, 2018 DOI: 10.1002/wps.20556 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Randomized Peer reviewed |
|---|---|
| Topics | Depression |
| Key points | Proposes that serotonin differentially encodes responses to uncertainty: the 5-HT1A receptor provides basal emotional stability and patience, while the 5-HT2A receptor engages during crisis to relax prior assumptions across perceptual, emotional, cognitive, and philosophical levels, increasing sensitivity to context. Argues this mechanism may explain the therapeutic potential of classic psychedelics, which act on 5-HT2A. |
Abstract
tial impact of psychedelic drugs on psychiatry to that of the microscope on biology and, while this analogy may strike some as laughable, let us reflect for a moment that human research with psychedelics has been effectively moribund since the restrictive drug policy reforms of the 1960s-70s, and has only recently been revived. Classic serotonergic psychedelics – such as LSD, psilocybin and dimethyltryptamine – all possess agonist properties at the 5-HT2A receptor subtype, and 5-HT2A receptor agonism is known to be the pharmacological trigger of the “psychedelic experience”. Crucially, there is also a wealth of evidence to implicate 5-HT2A receptor signaling in processes of plasticity, such as neurogenesis, neurodevelopment, learning, extinction learning, cognitiveflexibility andenhancedenvironmental sensitivity. Added to this, the subjective quality of a psychedelic experience is highly susceptible to contextual influence, for example from the environment in which it occurs as well as from the expectations of the “tripper” and those around him or her. Moreover, the quality of an acute psychedelic experience appears to be a highly reliable predictor of subsequent long-term mental health outcomes. Another predictor of long-term psychological outcomes is the degree of increase in the complexity or “entropy” of brain activity recorded during the psychedelic experience, and this brain effect is hypothesized to be relatively unique to psychedelics, and key to an understanding of their exceptional phenomenology and therapeutic potential. Within the last 12 years, a growing body of evidence, albeit from mostly small scale pilot studies, has suggested that psychedelics, combined with contextual manipulation (such as music listening and psychological support), can offer a safe and effective treatment for a range of different psychiatric disorders. Where successful, the treatment effect appears to be rapid and enduring. Moreover, promising outcomes have not just been seen in depression, but in addiction and other disorders as well. That just one or two treatment sessions can yield therapeutic effects lasting for several months is unprecedented in modern psychiatry. Of course, incredible claims require credible evidence but, with large randomized controlled trials beginning with psilocybin for depression, the required roads are being laid. A simple and plausible model of therapeutic mechanisms of psychedelic treatments would greatly complement this ongoing clinical work. The thesis is put forward here that serotonin differentially encodes behavioral and physiological responses to uncertainty. More specifically, it is proposed that the limbic-rich inhibitory postsynaptic 5-HT1A receptor subtype provides basal control during normal conditions, via moderating emotion and anxiety, and promoting a generalized patience. On the other hand, the cortically-rich 5-HT2A receptor subtype is hypothesized to engage more during conditions of crisis, when the above-mentioned default mechanism becomes suboptimal, e.g. when an individual’s internal and/or external milieu becomes so changeable and/or inconsistent with his/her prior beliefs and behaviors that significant revisions becomemandated. Viewed through a Bayesian lens, it is proposed that the principal functional effect of 5-HT2A receptor stimulation is to relax prior assumptions or beliefs, held at multiple levels of the brain’s functional hierarchy: perceptually, emotionally, cognitively and philosophically (e.g., in terms of biases). In so doing, it opens a door to heightened sensitivity to context, an ideal pre-condition for effective change.
Comparable studies
Other theoretical and historical papers on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Mindfulness-based cognitive therapy for depression | 2006 | Theoretical or philosophical paper | |
| Psilocybin-assisted therapy of major depressive disorder using Acceptance and Commitment Therapy as a therapeutic frame | 2020 | Theoretical or philosophical paper | |
| The Yale Manual for Psilocybin-Assisted Therapy of Depression (using Acceptance and Commitment Therapy as a Therapeutic Frame) | 2020 | Theoretical or philosophical paper | |
| Neuroinflammation and neuroprogression in depression: Effects of alternative drug treatments | 2022 | Theoretical or philosophical paper | |
| Improving cognitive functioning in major depressive disorder with psychedelics: A dimensional approach | 2021 | Theoretical or philosophical paper |