Improving cognitive functioning in major depressive disorder with psychedelics: a dimensional approach
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.
Authors
- Kuiperes, Z.
- Schreiber, R.
Published
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.
Research Summary of 'Improving cognitive functioning in major depressive disorder with psychedelics: a dimensional approach'
Introduction
Magaraggia and colleagues frame major depressive disorder (MDD) as a heterogeneous syndrome in which cognitive dysfunction—particularly decreased ability to think, indecisiveness and psychomotor retardation—contributes substantially to functional impairment. The paper argues that categorical diagnostic systems such as the DSM and ICD obscure biologically meaningful targets, and that a dimensional, Research Domain Criteria (RDoC) approach focused on cognitive and valence domains may better guide therapeutic development. Structural and functional abnormalities in the prefrontal cortex (PFC), hippocampus and amygdala, together with reduced neuroplasticity and lower neurotrophic support (notably BDNF), are highlighted as core biological substrates of the cognitive deficits observed in MDD. The authors set out to explore whether serotonergic psychedelics (for example psilocybin, LSD and DMT) could constitute a novel class of therapeutics for MDD by reversing impaired neuroplasticity and improving cognitive processes. They propose a translational, dimensional framework that links drug-induced changes at molecular and cellular levels to circuit function and cognitive outcomes, in particular by targeting negativity bias and cognitive inflexibility. Pattern separation—a hippocampal-dependent mnemonic process that reduces interference between similar inputs—is introduced as a measurable cognitive construct that may bridge preclinical and clinical investigation of these mechanisms.
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Study Details
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- APA Citation
Magaraggia, I., Kuiperes, Z., & Schreiber, R. (2021). Improving cognitive functioning in major depressive disorder with psychedelics: a dimensional approach. Neurobiology of Learning and Memory, 183, 107467. https://doi.org/10.1016/j.nlm.2021.107467
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