A continuum hypothesis of psychotomimetic rapid antidepressants

This hypothesis article (2021) proposes that psychedelics (and sleep deprivation) are acute antidepressants that fall on a continuum of increasing the flexibility of prior expectations (top-down hierarchy). The article ends with suggestions for experiments to test this hypothesis.

Abstract

“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.“

Authors: Joost Haarsma, Catherine J. Harmer & Sandra Tamm

Summary

Introduction

Depression is a leading cause of disability. Ketamine, psychedelics and sleep deprivation are less well-established treatments that are associated with a rapid decrease in depressive symptoms.

Traditional antidepressants target the affective biases commonly seen in depression, which corrects the depressive worldview over time.

Cognitive inflexibility is a separate component of depression that interacts with the affective bias account. It is believed that traditional antidepressants only affect cognitive inflexibility indirectly, which might contribute to the reason why they take multiple weeks to have an effect.

Ketamine, classical psychedelics and sleep deprivation are associated with rapid effects on depression. These interventions share a common mechanism by increasing the flexibility of prior expectations, which could explain their acute antidepressant properties.

Ketamine, psychedelics and sleep deprivation are acute antidepressants that induce some of the symptoms of psychosis. However, there are important differences between psychotic symptoms caused by ketamine, psychedelics and sleep deprivation, compared to clinical cases of psychosis. Interestingly, psychosis has been described as an overly flexible brain, and psychotomimetic interventions may increase cognitive flexibility and therefore have acute antidepressant effects.

In the following review, we will describe various acute antidepressants and their psychotomimetic features, and then suggest a theoretical framework that can explain why these treatments are acute antidepressants.

Ketamine

Ketamine is a non-competitive open channel N-methyl-D-aspartate (NMDA) antagonist, first synthesized in 1962 by Calvin Stevens at Parke-Davis Co. It has been shown to cause an acute antidepressant effect, lasting for hours and peaking at 24 h after administration.

Ketamine administration causes a burst in glutamate via inhibition of GABA interneurons, followed by an increase in synaptic plasticity and the release of brain-derived neurotrophic factor and mTORC1 signalling.

Ketamine has been shown to have psychotomimetic effects, including alterations in perception, dissociations and hallucinations, but also to mimic the negative symptoms of schizophrenia including apathy and social withdrawal.

Psychedelics

Classical psychedelics have a long history of usage in spiritual practices, and have become popular in the West in the 1950s and 1960s. They have been shown to reduce depressive symptoms and anxiety in individuals with treatment-resistant depression.

Psychedelics exert their effects by activating pyramidal neurons in layer 5 of the cortex, which leads to increased glutamatergic activity and subsequently increased serotonergic and dopaminergic activity in the raphe nucleus and ventral tegmental area.

Psychedelics induce pronounced changes in consciousness, including changes in perceptual experiences such as brightening of colours, synaesthesia, illusory patterns, or full-blown hallucinations and a sense of derealisation.

Sleep deprivation

The antidepressant effects of sleep loss were first reported in 1818, and the first trial of sleep deprivation for depression was published in 1971. The response rate to sleep deprivation in depression is 45% – 50%.

A number of putative mechanisms have been suggested to cause the antidepressant effect of sleep deprivation, including CLOCK gene transcription and a reset of the circadian rhythm, synaptic plasticity model theory, and the glutamatergic system.

Sleep deprivation is associated with psychotic symptoms in healthy volunteers and patients with bipolar disorder, and these symptoms develop in an almost dose-dependent manner.

A theoretical framework to understand the link between psychosis and rapid antidepressants

The previous section described interventions that are both rapid antidepressants as well as psychotomimetic. The hierarchical predictive coding model is the framework we will use in this article.

Predictive coding is a solution to how the brain forms a model of its environment. It involves comparing predictions to new sensory input and updating the model over time. The brain uses a probability distribution to represent sensory input and predictions, and uses a variance to represent how certain a belief is. The precision of a prior belief is used to weight the influence of higher-level beliefs versus lower-level evidence.

Neurotransmitters such as dopamine and acetylcholine are believed to play an important role in coding the precision of sensory evidence and prior expectations.

Affective biases can be caused by the degree to which new information is given weight, and prior expectations can be given undue weight, which can lead to cognitive inflexibility, which is known to contribute to depression.

Psychosis

If the brain forms a model of the world through hierarchical inference, misallocation of precision can result in hallucinations and delusions. Psychosis is thought to be caused by aberrant changes in precision in different levels of the cortical hierarchy through different stages of psychotic illness, with weaker perceptual priors and stronger learned priors dominating perception.

Depression

There are multiple variations of the hierarchical predictive coding model of depression, but all involve an increased influence of prior expectations on cognitive as well as interoceptive processes. Understanding how these prior expectations can be altered is crucial to understanding depression and developing novel treatments. Another view puts the emphasis on aberrant interceptive predictions, which in time generate false stress responses, effectively dysregulating the hypothalamic – pituitary – adrenal (HPA)-axis, which overtime results in depression.

Other models focus on reward learning, and argue that depressed brains are characterised by a hierarchical structure of depressive beliefs, producing a consistent negative bias. This negative bias leads to oversampling the environment to confirm these negative expectations.

These models suggest that symptoms of depression can be understood as overly precise prior expectations. Making the priors more flexible might therefore be of therapeutic value.

Do psychotomimetics have antidepressant effects by decreasing precision of priors?

Sleep deprivation, classical psychedelics and ketamine have a tendency to induce symptoms of psychosis in healthy individuals, as well as acute antidepressant effects in depressed patients. It could be argued that the mechanisms for these effects are the same, through making the brain’s prior expectations more flexible.

Ketamine

Ketamine reduces the precision of prior expectations by making them more flexible and malleable, and can induce symptoms of early psychosis through reducing the precision of prior expectations in otherwise healthy individuals. Research on higher-level learning and ketamine has demonstrated similar findings, in line with a reduced precision of prior expectations. This suggests a potential link between cognitive flexibility and anhedonia.

Ketamine administration has been shown to decrease neural reactivity in the bilateral amygdalo-hippocampal complex during emotional stimulation, and increase sensitivity for rewarded items in patients with depressive disorder. Ketamine is a psychotomimetic rapid antidepressant that is thought to put the brain in a more flexible state. This flexibility may be due to ketamine’s ability to reduce the precision of prior expectation during inference, and thereby reduce cognitive biases in depression.

Psychedelics

Psychedelics have long been suggested to make the mind more flexible. This is primarily reflected in experiments related to sensory preprocessing, such as reduced mismatch negativity responses, altered binocular rivalry, and increased bottom-up signalling from the parahippocampus to the visual cortex during music listening.

Some studies explored emotional processing in relation to psychedelics, and found that the left amygdala and the right medial prefrontal cortex were less reactive to fearful faces after LSD, whereas the right amygdala was more reactive to both negative and positive stimuli after psilocybin.

Sleep deprivation

In healthy individuals, sleep deprivation leads to increased sleepiness, decreased performance in attentional tasks, greater risky decision making, lower response inhibition and cognitive control, and hyper-sensitisation of reward-related regions of the brain. However, evidence directly supporting the notion that prior expectations become more flexible is lacking.

How does the continuum hypothesis fit with existing theoretical perspectives?

Our hypothesis predicts that the interventions described above reduce the precision of prior expectations of negative and positive events, and that this underlies the acute antidepressant effects. Using reversal learning paradigms, an agent can learn to respond adaptively to fluctuations in the volatility of both losses and rewards. Ketamine, psychedelics and sleep deprivation can alter the precision of prior expectations, making the agent more receptive to upcoming rewards and losses.

The effects of ketamine, psychedelics and sleep deprivation are separable from the effects of commonly used SSRIs, in that they alter the use of information that has already been acquired.

The model suggested in this article is not a complete explanation of how psychotomimetic rapid antidepressants work, and it does not provide an explanation for how the different treatments should be understood at a molecular/neurochemical level.

In terms of neurocognitive research, the continuum hypothesis of psychotomimetic rapid antidepressants needs to be tested against other possible theories. For example, ketamine might affect interoceptive signalling, which has been hypothesised to play an important role in depression.

We have made the case that psychedelics, ketamine and sleep deprivation are psychotomimetic, as well as acute antidepressants, and that this might relate to the ability to lower the precision of prior expectations. However, psychosis might not necessarily be an antidepressant state.

The proposed hypothesis of psychotomimetic rapid antidepressants might still be informative when developing future treatments, since the combination of fast-acting antidepressants with psychotherapy may lead to additive effects.

Conclusion

We have reviewed various rapid antidepressants that have psychotomimetic properties. We suggest that this is because they diminish the brain’s priors across different levels of the cortical hierarchy, which causes an overly flexible state of mind and psychotic symptoms.