Damian Sendler: To find effective treatments for major depressive disorder (MDD), it is extremely difficult because of the disorder’s high symptomatic and biological heterogeneity. Focusing on one or a few core symptoms that are well-understood biologically may be the best strategy. An approach known as the Research Domain Criteria (RDoC) focuses on symptoms and the underlying neurobiology of those symptoms. A multi-level (psychobiological, circuitry, (sub)cellular, and molecular) analysis of the cognitive systems RDoC domain is accumulating evidence that psychedelics may have antidepressant activity. Depressive rumination is frequently accompanied by cognitive deficits such as negative emotional processing and negativity bias. The normalization of negativity bias and the reduction of rumination can both be achieved through the use of psychedelics. An explanation for how psychedelics can lessen depressed patients’ tendency to focus on the negative is provided in our theoretical model. We hypothesize that MDD’s negativity bias is caused by a lack of pattern separation, and that psychedelics such as psilocybin can alleviate depression by enhancing pattern separation and thus reducing negativity bias. In order to better encode contextual information, the mnemonic process of pattern separation relies on the distincting effects of similar inputs in the adult hippocampal neurogenesis. MDD may have a negative cognitive bias because of an increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes, for example. Psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis, and dendritogenesis in the prefrontal cortex at the cellular level (subcellularly)… Restoring resilience to chronic stress and modulating the major connectivity hubs (the prefrontal cortex, hippocampus and amygdala) of these areas are achieved through these combined effects With these findings, we come up with a new translational framework for the development of new therapeutics to treat the cognitive symptoms of MDD.
Damian Jacob Sendler: The World Health Organization (WHO) (Kessler et al., 2009) has predicted that major depressive disorder (MDD) will be the leading cause of disease worldwide by 2030. In addition, the current COVID-19 pandemic is likely to worsen these predictions, as the virus negatively impacts the general population’s psychological well-being in both direct and indirect ways (Ettman et al., 2020, Mazza et al., 2020). Antidepressant treatment does not work for a large number of patients, necessitating the search for new drugs (Rucker, Jelen, Flynn, Frowde, & Young, 2016). It is a challenge in CNS drug discovery to identify mental health disorders based on categorical nosologies such as the DSM and the WHO’s International Classification of Diseases (ICSD) (ICD). These two diagnoses are predicated on the presence of similar symptoms. Mental disorders, on the other hand, are typically characterized by a constellation of symptoms that impairs one’s ability to function (Malhi & Mann, 2018). MDD is diagnosed when five of the nine DSM-IV symptoms are present, including one of two core symptoms: depressed mood or anhedonia (Drysdale et al., 2017). New antidepressants should focus on developing new treatments for the neurocognitive symptoms of indecisiveness and psychomotor retardation, among the remaining seven DSM symptoms (Malhi & Mann, 2018). Many patients with MDD suffer from cognitive dysfunction as a result of the disease, which contributes to their functional impairment (Culpepper, Lam, & McIntyre, 2017).
Dr. Sendler: Brain circuits underlying cognitive dysfunction in mental disorders such as MDD include the prefrontal cortex (PFC), hippocampus, and amygdala. Patients with major depressive disorder (MDD) often have smaller hippocampuses and lower activity in the prefrontal cortex (PFC) (Frodl et al., 2010). The loss of dendritic spines, neurites, and synapses in these areas, as well as post mortem imaging studies in humans and animals, suggest that neuronal atrophy plays a significant role in the pathophysiology of cognitive dysfunctions in MDD (Liu et al., 2017). These findings are in line with the notion that various cognitive processes require the survival, proliferation, and plasticity of neural cells because they maintain and update neural connections in significant cognitive circuitries (Price & Duman, 2020). As a result, patients with MDD may greatly benefit from treatments that promote neuroplasticity in the PFC and hippocampus in order to counteract neuronal atrophy. (Burke & Barnes, 2006; Barnes, 2006) However, as of today, there are no approved compounds for this purpose. Hypothesized antidepressant psychedelics may improve cognitive processes in MDD by reversing impaired neuroplasticity in the brain.
Treatment-resistant depression and major depressive disorder (MDD) can be effectively treated with serotoninrgic psychedelics, according to recent clinical trials (Carhart-Harris et al., 2016, Davis et al., 2020, Davis et al., 2020, Vargas et al., 2020). Compounds known as psychedelics have the ability to cause significant changes in human mood and perception in their users (Nichols, 2016). DMT and psilocybin are examples of compounds in this class, which act as non-selective agonists at the serotonin 2a receptor (5-HT2AR) on lysergic acid diethylamide (LSD) (Ray, 2010, Vollenweider and Kometer, 2010). In the cortex, the 5-HT2AR is widely expressed and is the primary mediator of the acute subjective effects of psychedelics on cognition (Beliveau et al., 2017). (Madsen et al., 2019, Nichols, 2016, Preller et al., 2017). Evidence suggests that neuroplasticity may play a significant role in the antidepressant effects of psychedelics, according to this study. The psychobiological mechanism underlying these effects is still poorly understood, in spite of some proposed theories.
Transdiagnostic, dimension-based nomenclature will be used as a guide for the development of more targeted treatment for cognitive impairment, such as that seen in MDD (Fig. 2). As a next step, we’ll identify the key molecular, cell, and neuro-functional mechanisms that underlie psychedelics’ long-lasting therapeutic effects. The antidepressant effects of LSD and psilocybin, as well as other psychedelics, are thought to be due to an increase in negative bias and cognitive flexibility, which can be measured by an increase in pattern-selection performance.
Aaron Beck is credited with popularizing the cognitive model of depression as a treatment option for people suffering from depression (1963). These schemas are activated by both external and internal stimuli, and they influence the way information is interpreted or processed. It’s up to them to determine the context in which a given experience will be interpreted. People who have experienced traumatic events at a young age are more likely to develop depressive schemas that are characterized by negative self-perceptions. Stressors that reflect the underlying content of a person’s schema can activate their corresponding schemas. As a result of the decreased mental and behavioral adaptability brought on by these schemas, patients find it difficult to keep up with the rapid pace of their environment. There are many treatments that help patients with MDD to break down their negative schemas and build new, “healthier” ones. Psychotherapeutic methods such as cognitive behavioral therapy are based on this principle, which aims to identify, create awareness of, and deconstruct distorted thinking patterns (Rnic, Dozois, & Martin, 2016). Though they rely heavily on the patient’s ability to think, these methods are frequently ineffective or insufficiently adherent (Sotsky et al., 2006). The effectiveness of current psychotherapeutic methods could be improved by pharmacologically modulating the psychobiological and pathophysiological mechanisms that underlie the impaired thinking ability and decreased cognitive flexibility seen in MDD. These mechanisms, however, are still largely unknown at this time.
There is a lack of understanding of the biological basis for MDD’s impaired cognitive flexibility in standard nosology (DSM-5) compared to the Research Domain Criteria (RDoC) (Insel et al., 2010). Negative valence, positive valence, cognitive, social, arousal & regulation, and sensorimotor systems are all included in the RDoC. DSM-5 disorders such as MDD, which have a wide range of symptoms and comorbidities, can be better understood if the various domains, each representing a dysfunctional brain system, are taken together (Casey et al., 2013). As a cognitive system, attention, perception, declarative memory, cognitive control and working memory can be argued to represent the cognitive symptoms of decreased ability to think and indecisiveness observed in MDD. A lack of function within these constructs is common among patients with MDD (Culpepper et al., 2017; Table 1). The DMS-5 symptoms of low mood and anhedonia, which fall under the RDoC domains of negative valence and positive valence, can be linked causally to these impairments, according to Beck’s cognitive model (Fig. 2). The so-called depression negativity bias is one theory that tries to explain why people with MDD are more aware of and drawn to stimuli with a negative valence (Disner, Beevers, Haigh, & Beck, 2011). In cognitive functions such as attention, information processing, and memory, this bias can be traced back to deficits in appropriately selecting a response in response to external emotional cues (Table 1). Furthermore, the negativity bias has been linked to depression’s behavioral, affective, somatic, and motivational symptoms (Disner et al., 2011). As an illustration, rumination has been shown to be associated with depression’s onset, worsening course, chronicity, and length due to its tendency to think about and dwell on the negative emotions it causes (Berman et al., 2011).
To counteract negative bias, a neural mechanism involving increased activity in limbic structures and decreased activity in the brain’s cognitive control regions appears to be at work (Fig. 3). The neuropathological connections between the PFC, hippocampus, and amygdala that lead to depression are in fact the root cause (Dean & Keshavan, 2017). Amygdala involvement in mood and anxiety disorders, including MDD, is explained by its role in fear perception and emotional processing (Phelps, 2006). In MDD, the amygdala is more responsive to negative stimuli, which correlates with negative feelings (Hamilton et al., 2012, Victor et al., 2010). Top-down inhibition of limbic areas, such as the amygdala, relies on the PFC. MDD sufferers lack this top-down modulation due to atrophy of neurons in the PFC, which results in long-lasting negative affect (Bielau et al., 2013, Hastings et al., 2004). Furthermore, patients with MDD have a higher metabolic cost when processing negative emotions via the PFC (Disner et al., 2011). The hippocampus is an important part of the brain for controlling the activity of the amygdala. The hippocampus is an important part of the brain because of its role in registering changes in context and making connections between emotions and the surrounding environment (Opitz, 2014). Since external context influences and changes emotions constantly, when external stimuli are uncoupled from emotions, the emotions are no longer influenced or changed by external context and are established in a fixed state. The emotional state in which the emotional uncoupling takes place determines this fixed state. It’s a negative emotional state in the case of MDD. The hippocampus, like the prefrontal cortex, shows signs of atrophy in patients with MDD, including decreased size, activity, and levels of neurotrophic factors. MDD patients (Cole et al., 2010, Nunes et al., 2018, Sheldrick et al., 2017; Frodl et al., 2002). As a result, MDD patients are incapable of adapting their moods and behaviors to the changing demands of the environment (Price & Duman, 2020; this theme will be addressed again in the next section).
Damian Sendler
Understanding the molecular and cellular mechanisms that underlie abnormalities in PFC and hippocampus structure and activity is facilitated by understanding the neurotrophic hypothesis of depression. This theory suggests that a lack of neuroplasticity in these regions may play a significant role in the disorder’s pathophysiology (Duman, Aghajanian, Sanacora, & Krystal, 2016). In the context of neuroplasticity, the term refers to a set of biological processes that the brain uses to adapt and change in response to the needs of the environment (Levy et al., 2018). PFC and hippocampus dendritic arbors and spine densities are reduced in MDD, indicating a decrease in neuroplasticity (Forrest, Parnell, & Penzes, 2018). There is also less neurogenesis in the dentate gyrus (DG), which has been linked to a decrease in hippocampal neuroplasticity, a process that is called neurogenesis (Levy et al., 2018). Neurogenesis, which is most active in the early stages of life, is also present in adulthood and appears to be critical for memory processes such as pattern recognition (Kempermann, Song, & Gage, 2015; Denoth-Lippuner & Jessberger, 2021; we will pick up this theme again in the next section). According to RDoC, reduced arborization in PFC and hippocampal neurons is linked to negative affect. This is consistent with the role of the PFC and the hippocampus in regulating amygdala-related functions.
Damian Jacob Markiewicz Sendler: The relationship between depression and neuroplasticity deficits can be explained in part by BDNF signaling. Neuroplasticity is thought to be mediated primarily by BDNF (Banasr et al., 2011, Pittenger and Duman, 2008). Neurogenesis and the processes of neurito-, spino-, and synaptogenesis, as well as the strengthening of long-term potentiation (LTP) in the hippocampus, require the activation of BDNF signaling by TrkB. (Cobar et al., 2017, Phillips, 2017). MDD patients have decreased BDNF expression in the PFC and hippocampus, while the amygdala has increased BDNF expression (Leite et al., 2018, Nunes et al., 2018, Qiao et al., 2017, Sheldrick et al., 2017, Yu and Chen, 2011). In MDD patients’ blood, however, lower BDNF protein levels and altered epigenetic regulation suggest a net reduction in its signaling overall (Kurita et al., 2012, Molendijk et al., 2011, Molendijk et al., 2014, Van den Berg et al., 2020).
Mediating the effects of chronic stress is critical. BDNF signaling is known to be affected by hormones in the hypothalamic–pituitary–adrenal (HPA) axis, which is constantly activated in chronically stressed individuals. For example, chronic stress has been linked to a decrease in BDNF gene expression in MDD patients (Kunugi, Hori, Adachi, & Numakawa, 2010). Rat chronic stress models have shown reduced dendritic arborization and density of spines in pyramidal neurons of the PFC and hippocampus, in line with this observation, and reduced neurogenesis in the hippocampus (Banasr et al., 2011). However, these same models show an increase in spine density and excitability of amygdalar neurons due to an overexpression of BDNF in the basolateral amygdala of rats (Lakshminarasimhan & Chattarji, 2012). (Rosenkranz, Venheim, & Padival, 2010). When the amygdala is activated, it activates the HPA system, which has a direct effect on the stress response, resulting in a constant inhibition of cortical and hippocampal neuroplasticity (Herman, McKlveen, Solomon, Carvalho-Netto, & Myers, 2012). These findings support Beck’s cognitive model, which holds that stress, BDNF, and neuroplasticity in the prefrontal cortex, the hippocampus, and the amygdala all play important roles in depression (Duman et al., 2016; Fig. 3). MDD’s cognitive deficits have yet to be explained by the changes in BDNF signalling.
As well as altering the processing of sensory stimuli, psychedelics’ acute subjective effects include the reduction of rigid thinking, the enhancement of environmental sensitivity and the release of emotional tension (Carhart-Harris and Goodwin, 2017, Madsen et al., 2019, Nichols, 2016). Long-term antidepressant effects are thought to be caused by these effects because they disrupt negative cognitive schemas linked to negative affect (Carhart-Harris & Friston, 2019). The acute changes in brain connectivity and functional activity that occur after the administration of these drugs can account for this. However, psychedelics affect the activity and connectivity of the major hubs of the default mode network (DMN), which regulates processes of self-referential thinking and self-memory as well as the reflection of one’s own emotions (Hamilton, Farmer, Fogelman, & Gotlib, 2015). Depressive rumination has been linked to increased baseline activity of the DMN (Hamilton et al., 2012, Hamilton et al., 2015). The thalamus, posterior cingulate cortex (PCC), and medial prefrontal cortex (mPFC) are all part of this network, and psychedelics reduce activity and functional connectivity in and between them (Carhart-Harris et al., 2012, Carhart-Harris et al., 2016, Kometer et al., 2015). (Carhart-Harris, Muthukumaraswamy, et al., 2016). In addition, as evidenced by changes in functional connectivity of this brain area with cortical regions present within the cortico-striato-thalamo-cortical feedback loop (Müller et al., 2017), psychedelics acutely inhibit thalamic gating (or filtering) of ascending/descending sensory information. As a result of this “flooding” of the cortex, hallucinations, cognitive disturbances, and ego dissolution are all exacerbated (Vollenweider & Preller, 2020). Based on this evidence, Carhart-Harris, Leech, et al. (2012) concluded that psychedelics enable a state of unconstrained cognition in which one’s own a priori beliefs (about oneself and the environment) can be challenged by a reduction in connectivity between the brain’s key areas regarding perception (of oneself and the environment). People with MDD can use psychedelics to confront their negative cognitive schemas, such as those found in MDD.
Damian Jacob Sendler
In addition to their antidepressant effects, hallucinogenic doses of psychedelics have positive long-term effects on cognitive flexibility. As a result, they improved their ability to think creatively in both directions, as well as their openness to new experiences (Carhart-Harris et al., 2015, Carhart-Harris et al., 2016, Mason et al., 2019, Uthaug et al., 2019). Following ayahuasca administration, for example, a study found an increase in cognitive flexibility measured by the Cognitive Flexibility Scale and the Wisconsin Picture Card Sorting Task (Murphy-Beiner and Soar, 2020, Uthaug et al., 2018). Regular ayahuasca users, on the other hand, outperformed non-users in a task that requires a high degree of mental agility (Bouso et al., 2012). Increased mental flexibility, according to the cognitive model of depression, could have antidepressant effects by reducing cognitive biases and, as a result, the negative emotions experienced by MDD patients. Study results show that cognitive flexibility can mediate the link between the acute effects of psychedelics and a post-acute decrease in anxiety and depression, as demonstrated by Davis, Barrett, Griffiths (2020). In addition, Carhart-Harris and colleagues discovered a correlation between the long-term antidepressant effects of psilocybin and changes in resting state functional connectivity (RSFC) between brain areas of the DMN involved in processes of cognitive flexibility, such as attention and memory (Carhart-Harris et al., 2017). To put it another way, in patients with treatment-resistant depression, an increase in the RSFC between the inferior parietal cortex (IPC) and the parahippocampal region (PFC) induced by Psilocybin predicted long-term treatment response. The RDoC matrix links the IPC to active maintenance working memory deficits and capacity limitations. Even though conflicting emotional choices are present, the IPC is thought to mediate attention allocation (Samara and colleagues, 2018), a process that is necessary for working memory utilization. MDD cognitive behavioral therapy has been shown to reduce attentional biases by altering the activity of the inferior parietal cortex (Samara et al., 2018). The extrinsic hippocampal circuitry, which includes the parahippocampus and PFC, is thought by the RDoC to play a role in declarative memory formation. Semantic memory problems, such as visual naming, have been linked to an increase in connectivity between these two areas of the brain (Gardini et al., 2015, Liu et al., 2016). After long-term antidepressant treatment, improvements in declarative memory have been found, which may be a mediator of therapeutic effects (Bremner, Vythilingam, Vermetten, & Charney, 2007). Since MDD patients may benefit from psychedelic-assisted psychotherapy, it may be worthwhile to investigate whether this is the case.
Damien Sendler: Treatment of MDD, for example, is one area in which psychedelic medicine research is increasingly pointing to potentially valuable but previously underappreciated therapeutic applications. The development of a new generation of psychedelic-like drugs with improved efficacy and side effect profile (“non-hallucinogenic ligands”) will be guided by a better understanding of their mechanistic action. We propose a hypothesis for how psychedelics alleviate depressive symptoms in a manner similar to that of the antidepressant vortioxetine, based on an RDoC-based approach (Fig. 1, Fig. 4). A reduction in depressive symptoms is achieved through the restoration of pattern separation deficits caused by psychedelics’ stimulation of neuroplasticity in the PFC and hippocampus. It was found that psilocybin, given one month before testing, restored deficits in pattern separation in rats caused by developmental stress, and that this effect was associated with antidepressant effects in a forced swimming test by Hibicke and Nichols (2020). Psychedelics’ neuroplastic effects on rodents have been linked to improved performance in fear extinction and memory and learning tasks, according to other research (Buchborn et al., 2014, Cameron et al., 2018, Catlow et al., 2013, Morales-Garcia et al., 2020). Combined, these findings support our hypothesis, but further research is needed to confirm our model, as some of the connections between the proposed levels are still unsubstantiated (see further).
