This theory-building literature review (2021) proposes a model that explains how psychedelics can reduce the negativity bias in depressed patients according to Research Domain Criteria (RDoC), a framework that investigates the underlying neurobiology of clinical symptoms across multiple levels of explanation. It is proposed that psychedelics improve depressive symptoms via a similar mechanism as the antidepressant vortioxetine, by stimulating neuroplasticity in the prefrontal cortex and the hippocampus, and decreasing negativity bias through the restoration of deficits in pattern separation.
Abstract
“The high symptomatic and biological heterogeneity of major depressive disorder (MDD) makes it very difficult to find broadly efficacious treatments that work against all symptoms. Concentrating on single core symptoms that are biologically well understood might consist of a more viable approach. The Research Domain Criteria (RDoC) framework is a trans-diagnostic dimensional approach that focuses on symptoms and their underlying neurobiology. Evidence is accumulating that psychedelics may possess antidepressant activity, and this can potentially be explained through a multi-level (psychobiological, circuitry, (sub)cellular and molecular) analysis of the cognitive systems RDoC domain. Cognitive deficits, such as negative emotional processing and negativity bias, often lead to depressive rumination. Psychedelics can increase long-term cognitive flexibility, leading to normalization of negativity bias and reduction in rumination. We propose a theoretical model that explains how psychedelics can reduce the negativity bias in depressed patients. At the psychobiological level, we hypothesize that the negativity bias in MDD is due to impaired pattern separation and that psychedelics such as psilocybin help in depression because they enhance pattern separation and hence reduce negativity bias. Pattern separation is a mnemonic process that relies on adult hippocampal neurogenesis, where similar inputs are made more distinct, which is essential for optimal encoding of contextual information. Impairment in this process may underlie the negative cognitive bias in MDD by, for example, increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes. On the (sub) cellular level, psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex. Together, these effects help restoring resilience to chronic stress and lead to modulation of the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala. Based on these observations, we propose a new translational framework to guide the development of a novel generation of therapeutics to treat the cognitive symptoms in MDD.”
Authors: Igor Magaraggia, Zilla Kuiperes & Rudy Schreiber
Notes
Sometimes we can get stuck in a thought loop. We humans have the great ability to be excited about something that happens in the future. The anticipation before going to a concert (again) can be just as great as the actual experience at the venue. This works the other way around too. If we expect to feel bad when it rains, if we dread going out that day, we sure will feel bad (without even having left the house). Or when we ascribe anxious nerves as a sign that we can’t perform that next business presentation, the chances increase for you not feeling your best.
All this to say that our patterns in our heads have a strong influence on how we feel, even before the actual events in the real world happen. Or when they happen, they can reinforce our patterns, be they negative or positive. And as you may have guessed from the title of this section, psychedelics are a way to separate thought patterns.
The current paper investigated the therapeutic process of psychedelics through a Research Domain Criteria (RDoC) framework. This takes into account the many levels at which psychedelic-assisted therapy works. It tries to combine everything from genes (which influence we spoke of last week) to the self-reported effects.
This is what the study concluded
- Psychedelic stimulate the growth of neuronal cells (in the hippocampus) and specifically lead to the growth and strengthening of dendrites (the ‘receiving antennas’ of a cell)
- This then leads to better resilience in the face of (chronic) stress, both at the level of neurons as subjectively experienced
- This then leads to an increase in cognitive flexibility, less negative bias, and thus fewer depressed symptoms
Within this framework, with the assistance of psychedelics, a depressed person is now better able to form new memories without the older (negative) memories clouding their judgment. And so breaking free from old thought patterns.
When looking at psychedelic-assisted therapy specifically, one could say that psychedelics make one more receptive to the learning of new patterns and storing new (more positive) memories and self-image. What the most effective dose, form of therapy, and substance will be for which situation is a question that many are now working on.
Summary
Journal Pre-proofs
Psychedelics may reduce the negativity bias in depressed patients by increasing long-term cognitive flexibility, which can normalize negative emotional processing and reduce rumination. This can be explained by a multi-level analysis of the cognitive systems domain of the Research Domain Criteria framework. Psychedelics stimulate hippocampal neurogenesis, synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex, which helps restoring resilience to chronic stress and modulates the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala.
Major depressive disorder is the most common mood disorder, and the current COVID-19 pandemic likely will worsen the prediction, as the virus negatively affects the psychological well-being of the general population. One of the challenges in CNS drug discovery is the diagnosis of mental health disorders based on categorical nosologies. MDD is diagnosed by five of nine different symptoms, including one of two core symptoms: depressed mood or anhedonia. Patients with MDD experience impaired cognitive function due to the disruption of neural circuitries in the prefrontal cortex, hippocampus and amygdala. Psychedelics may be a novel class of antidepressants that can improve cognitive processes in MDD by reversing impaired neuroplasticity.
Recent clinical trials have shown that serotonergic psychedelics have a high therapeutic potential for the treatment of depressive disorders, including treatment-resistant depression and MDD. The psychobiological mechanism underlying these effects remains poorly understood.
We aim to explore the use of psychedelics for the treatment of cognitive deficits, such as those observed in MDD, by identifying the key molecular, cellular and neurofunctional mechanisms that underlie the persistent therapeutic effects of psychedelics.
The cognitive model of depression considers internalized cognitive schemas that are activated by internal and external stimuli. Patients with MDD can profoundly benefit from treatments that help them deconstruct the negative schemas, thus improving their ability to think flexibly and enable them to develop new “healthier” schemas.
Current standard nosology (i.e., DSM-5) is unable to explain the biological basis of impaired cognitive flexibility in MDD. The Research Domain Criteria (RDoC) provides a dimensional framework to study this, and the cognitive symptoms of decreased ability to think and indecisiveness observed in MDD can be causally linked to these symptoms. One proposed link between depression and cognitive functions is the negativity bias, which is present in attention, information processing, and memory. Moreover, the negativity bias has been linked to behavioural, affective, somatic, and motivational symptoms of depression.
The neural mechanism that seems to underlie the negative bias involves hyperactivity of limbic structures and decreased activity in cognitive control regions that modulate it. The atrophy of neurons observed in the PFC of patients with MDD contributes to this lack of top-down modulation.
The neurotrophic hypothesis of depression proposes a role for decreased neuroplasticity in the PFC and hippocampus in the pathophysiology of the disorder. This decrease is observed as a reduction of dendritic arbors and spine density in pyramidal neurons, and a decrease in the number of newborn neurons.
Brain-derived neurotrophic factor (BDNF) signalling is involved in the processes of neurito-, spino-, and synaptogenesis and the strengthening of LTP in the hippocampus and PFC of patients with major depressive disorder (MDD). However, the levels of BDNF in the blood are lower and the epigenetic regulation is altered.
Chronic stress leads to the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which in turn leads to decreased BDNF gene expression in MDD and increased spine density and excitability of amygdalar neurons. This leads to a steady inhibition of cortical and hippocampal neuroplasticity. Adult hippocampal neurogenesis plays a critical role in encoding functions of the hippocampal circuit such as pattern separation, which is essential for optimal encoding of contextual information. Pattern separation plays an important role in the regulation of affect, and may underlie the negative cognitive bias seen in MDD by increased pattern completion of strongly encoded aversive memories and excessive deliberation on aversive outcomes.
A tripartite “translational fingerprint” for novel therapeutics that target negativity bias in MDD is proposed, consisting of increased neuroplasticity, structural changes, adult newborn cells, and improved pattern separation. This would lead to a modulation of the expression of fear and stress reactivity, executive functions and anhedonia. Pattern separation could be used to predict and monitor treatment responses in MDD patients, and could serve as a bridge between preclinical findings and human data. We hypothesize that psychedelics have long-term antidepressant effects, and provide evidence for this hypothesis at the behavioural, cognitive, neural, and cellular level.
During the first wave of psychedelic research, scientists found that psilocybin reduced symptoms of depression and anxiety in patients with life-threatening cancer. In the second wave, small randomized clinical trials were able to replicate these findings in a similar patient population.
Studies with double doses of psilocybin, administered 1 week apart in supportive settings, showed long-lasting improvements in depressive symptoms in a subpopulation of twenty patients with treatment-resistant depression. Similarly, preliminary evidence shows antidepressant properties of other serotonergic psychedelics such as the DMT and LSD. Psychedelics reduce the activity of the brain areas that regulate self-referential thinking, autobiographical memory, and reflection of one’s own emotional state, and enhance environmental sensitivity and emotional release. These effects are believed to be responsible for the long-term antidepressant effects of these drugs.
Psychedelics reduce connectivity between key areas in the brain regarding perception, which results in sensory overload and ego dissolution. This allows people to confront negative cognitive schema. Administration of hallucinogenic doses of psychedelics increased behaviors associated with cognitive flexibility, such as divergent and convergent creative thinking, suggestibility, and openness to new experiences. The cognitive model of depression suggests that an increase in cognitive flexibility might exert antidepressant effects by loosening the cognitive biases and therefore a reduction of negative affect present in MDD patients. Moreover, an increase in resting state functional connectivity between brain areas involved in processes of cognitive flexibility may be predictive of treatment response.
16 observation, changes in inferior parietal lobule activity have been associated with the reduction of attentional biases by cognitive behavioural therapy in MDD, and improvements in declarative memory have been found after long-term antidepressant treatment. Psychedelics induce a long-term stimulation of various mechanisms of neuroplasticity in the PFC and the hippocampus, including an increase in the number of newborn DG granule cells and the expansion and differentiation of neuronal stem cells. Although the exact molecular mechanism underlying the effects of psychedelics on neuroplasticity remains poorly understood, BDNF seems to play an important role.
Discussion and conclusion
Increasingly, research points to the potential use of psychedelics in the treatment of MDD. Our hypothesis is that psychedelics improve depressive symptoms by stimulating neuroplasticity in the PFC and hippocampus, which restores the deficits in pattern separation, leading to a decrease in depressive symptoms. Beyond cognition, psychedelics may influence the negative valence, positive valence and cognitive systems domains in MDD patients, and may be responsible for the disruption of the negativity bias and the reduction of deficits in negative and positive affect present in MDD.
Caveats
Several topics need further consideration to elucidate the mechanism underlying the antidepressant action of psychedelics. For example, the relationship between drug effects on BDNF and on neuroplasticity processes in the PFC and hippocampus need to be better understood. Two isoforms of the BDNF protein exist, mature and pro-BDNF, and these have opposite effects on neuroplasticity. Psychedelic drugs may affect both mature and pro-BDNF, and hence neurogenesis, differently. Future studies should investigate the effects of psychedelics on BDNF signalling and neurogenesis at all levels of analysis, and should be site-specific (e.g. hippocampus, PFC, amygdala). A better understanding of the pharmacokinetic-pharmacodynamic (PK/PD) relationships will be useful to inform dose selection in later trials.
The role of serotonin and other monoamine receptors in the psychobiological effects of psychedelics cannot be ruled out. Furthermore, the pharmacological differences between psychedelics might translate into differences in the way these drugs affect neuroplasticity and, in turn, pattern separation. Studies are needed to better understand the degree of specificity of the 5-HT2A receptor for these effects, and the role of the acute hallucinogenic experience in the long-term activation of the neuroplastic pathways proposed in this model.
The hallucinogenic experience allows for the creation of awareness and disruption of negative cognitive schemas in depressed patients, which in turn allows for an increase in cognitive flexibility and reduction in the negative bias.
A model for the long-term effects of psychedelics on neuroplasticity was proposed. However, more studies are needed to draw valid conclusions. Although we argue for a role of the acute subjective experience in the long-term antidepressant effects of psychedelics, evidence shows that subchronic administration of sub-hallucinogenic doses of LSD can have positive effects on cognitive flexibility and sustained attention. Psychedelics induce neuroplasticity even after excretion, but single hallucinogenic doses can cause temporary states of severe distress and anxiety in some patients undergoing treatment. Microdosing might provide a more steady stimulation of the biological mechanisms underlying this process, and therefore potentially increase the therapeutic effects of the treatment.
The SRI vortioxetine and psychedelics have different PK/PD profiles, and ketamine might be of interest for further research. The antidepressant effects of ketamine are similar to those of psychedelics, and the drug may stimulate cortical neuroplasticity and hippocampal neurogenesis.
The current COVID-19 pandemic has been associated with mood alterations and cognitive dysfunctions. The neurogenesis-promoting effects of psychedelic compounds might be able to reverse these changes, yet future studies are needed to understand whether COVID-related cognitive dysfunctions include deficits in pattern separation.
Acknowledgements
MDD may have cognitive dysfunctions that lead to low mood and anhedonia. Psychedelics may restore pattern separation.