Future Directions for Clinical Psilocybin Research: The Relaxed Symptom Network

This theory-building paper (2022) makes the case for using the Network Theory of Mental Disorders as a clinical tool in psychedelic research. It is argued that Network Theory may provide deeper insights into the effects of PAP on specific symptom interactions, generate fruitful hypotheses for the clinical action of PAP, and provide a pre-emptive tool for making the most of ‘intentions’ preceding and during psychedelic experiences.

Abstract

“Recent clinical trials have demonstrated that psilocybin may have strong antidepressant effects, and may be effective in the treatment of depressive disorders when embedded in a psychotherapeutic protocol (psychedelic-assisted psychotherapy; PAP). There are now dozens of registered and ongoing clinical trials that intend to test for the efficacy of psilocybin within a psychotherapeutic protocol. Despite promising results, the mechanism(s) that may be responsible for the antidepressant effects of PAP are still hotly contested. In this paper, we provide a broad overview of the recent clinical work conducted with psychedelics on depressive disorders and summarise several theories of action of PAP. Extending on the state of the field, we argue that the “Network Theory of Mental Disorders” is a useful tool for clinical research with psychedelics. We hypothesise that, if PAP is successful, the connections between symptoms in a network will weaken, thereby rendering the patient less vulnerable to developing or relapsing into depression. We argue that application of the Network Theory may (a) provide deeper insights into the effects of PAP on specific symptom interactions, both on an interindividual and intraindividual basis, (b) generate fruitful hypotheses for the clinical action of PAP, and (c) provide a pre-emptive tool for making the most of ‘intentions’ preceding and during psychedelic experiences. These findings we hope will ultimately improve responsiveness and reduce relapse in response to this promising therapy.”

Authors: Evan Lewis-Healey, Ruben Laukkonen & Michiel van Elk

Summary

Psilocybin may have strong antidepressant effects, and may be effective in the treatment of depressive disorders when embedded in a psychotherapeutic protocol (psilocybin-assisted psychotherapy; PAP). The mechanism(s) of action of PAP remain contested, but the Network Theory of Mental Disorders may help researchers understand these effects. Psilocybin-assisted psychotherapy has seen an explosion of interest in the past decade. The application of the network theory to mental health disorders would improve response to this promising therapeutic modality.

Classic psychedelics are agonists at the 5-HT2A receptor and alter the functional organisation of the brain. Clinical trials have found extremely large effect sizes when using psilocybin to treat depressive disorders, alcohol use disorder, and obsessive-compulsive disorder. As the field of psychedelic psychiatry develops, researchers must deepen their understanding of the clinical action of psychedelics. The Network Theory of Mental Disorders can help.

The network theory is a novel way to conceptualise mental health disorders, where symptoms are connected to each other in varying strengths. Psilocybin-assisted psychotherapy (PAP) may weaken the connections between symptoms in a patient’s mental health disorder network, thereby rendering them less vulnerable to developing depression. We present evidence of the antidepressant potential of psilocybin for depressive disorders, provide an overview of the network theory of mental disorders, and outline the concrete benefits that the network theory will provide when applied to clinical psychedelic research.

Psilocybin is the most commonly used ‘classic’ psychedelic in contemporary psychedelic psychiatry due to its tolerability and relatively short-lived effects. Psilocybin-Assisted Psychotherapy (PAP) involves one to three dosing sessions with psilocybin, in the presence of a therapist who provides guidance and emotional support when needed. After the psychedelic session, a number of integration sessions are attended, with the aim of integrating any insights that may lead to positive long-term mental health outcomes.

It is beyond the scope of this paper to summarise all of the clinical research that has used PAP to treat depressive disorders. Psilocybin has been shown to be effective in treating major depressive disorder compared to escitalopram, a conventionally prescribed antidepressant. However, larger sample sizes with effective placebo-control measures are needed to determine the true magnitude of effects of PAP.

Over the past fifteen years, a variety of theories have been proposed to account for the efficacy of psilocybin, including neurochemical effects, neural effects, and extra-pharmacological effects. Although the network theory of psychopathology is a multi-level therapeutic modality, it has several hypotheses that are hypothetically contributing to PAP’s efficacy in treating depressive disorders, amongst other neuropsychiatric issues. It is important to improve clinical studies by including measures that provide insight into a patients’ clinical development.

The diagnostic perspective on mental disorders assumes that there are discrete categories of symptoms, whereas the dimensional perspective assumes that there are continuous scales of symptoms, with more severe symptomatology entailing a more severe case of depression. The latent construct perspectives within psychiatry have been considered problematic from a theoretical and a psychometric perspective, but remain hugely influential in the field of psychiatry.

The network approach proposes an alternative causal account of psychopathology, in which symptoms are causally connected to each other, and mutually reinforce each other, through psychological, biological, and societal mechanisms. In a symptom network of depression, if enough symptoms are active, then the psychopathology of depression emerges. This is because strong connections between symptoms facilitate a self-sustaining feedback loop, which causes symptoms to activate each other.

Future directions for clinical psilocybin research include research into the network theory, which explains how major depression can manifest and maintain itself, and the existence of high rates of comorbidity in specific mental health disorders. A network theory approach to the conceptualisation of mental disorders is presented in Cramer et al. (2016). They found that individuals with strong connections between symptoms of depression were more vulnerable to developing major depression, while individuals with weak connections between symptoms were less vulnerable to developing depression.

A strong connection between symptoms in Figure 1A leads to a reduced symptom activation over time, while weak connections between symptoms in Figure 1B lead to more widespread symptom activation, instantiating a global self-sustaining feedback loop, which leads to the emergence and maintenance of depression. A psychopathology network explains how an individual may become ‘stuck’ in a depressive episode. Strong connections between symptoms will indicate the vulnerability of a patient to develop a depressive episode.

The network theory and clinical research with psychedelics represent a paradigmatic shift within the field of psychiatry. They both acknowledge that mental health issues occur in a nuanced fashion with biological, psychological, and environmental factors that all contribute to the proliferation of a disorder. Researchers have found that patients who undergo the PAP protocol for treatment-resistant depression relapse back into a depressive episode after several months. They believe that the connections between symptoms in the patients’ depression network should weaken as the patient progresses through the protocol.

The PAP protocol weakens the connections in the patient’s depressive symptom network, ultimately leading to the patient becoming less vulnerable to developing a depressive episode later on. The primary hypothesis of this study is that effective PAP treatment will relax the symptom network, providing a window for deep psychological change. This hypothesis is also supported by other popular models regarding the effects of psychedelics.

We present real-world examples of how to generate psychopathology networks, and explore their utility in solving practical issues within clinical psychedelic research. Cross-sectional networks can be used to directly test the hypothesis that the connections between symptoms in a depression network will weaken as a function of successful PAP.

Researchers can generate personalised symptom networks using the experience sampling method, which allows them to more easily evaluate the difference between groups on the basis of variables such as network connectivity. Researchers can use personalised symptom networks to gain insight into the effectiveness of a psychedelic session on an intra-individual basis, and to predict the susceptibility of a patient to relapse into another depressive episode.

A personalised symptom network can be used to identify central symptoms in a depressive disorder, and can be used to guide clinicians and patients to set an intention that draws attention towards a central symptom during the psychedelic experience, potentially increasing the chances that the patient ‘breaks’ the depressive symptom network. Time-series data is advantageous over data collected through standardised score scales at discrete time points, as it allows researchers to gain a deeper insight into the specific fluctuations of symptomatology.

Data collected through digital means may be used to gain a deeper insight into the pathogenesis of depressive disorders for individual patients, and move away from the issues that plague standardised scale scores to categorise and measure mental health. The network theory approach is promising for future research on psychedelics, but it is important to consider some limitations. For example, researchers may want to consider including nodes that are antithetical to depressive symptoms in a network model of psychopathology.

Future directions for clinical psilocybin research may include the use of network theory to assess the centrality of symptoms in mental health issues.

This paper highlights the current clinical work using PAP to treat depressive disorders. The network theory may be used to tailor the intensity/frequency of psychedelic dosing, to discover whether PAP exerts its effectiveness on specific symptoms within depressive disorders, and to test theories regarding therapeutic mechanisms.

Future research in clinical psilocybin may include a meta-analysis of the efficacy of acceptance and commitment therapy for clinically relevant mental and physical health problems, a systematic review of experience sampling and ecological momentary assessment studies, and a long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.

Future directions for clinical psilocybin research include: an integrative approach to the structure of psychopathology; network analysis; and a prospective study on how symptoms in a network predict the onset of depression. Carhart-Harris, R. L., Friston, K. J., Erritzoe, D. E., Haijen, E., Kaelen, M., Watts, R., & Nutt, D. J. (2019). REBUS and the anarchic brain: toward a unified model of the brain action of psychedelics.

Future directions for clinical psylopharmacology research include: pragmatic research, real-world data and digital technologies aid the development of psychedelic medicine; a computational perspective on mood; a study of psychopathology from the network analysis perspective; and a study of comorbidity. Cuijpers, Sijbrandij, Koole, S. L., Andersson, G., Beekman, A. T., & Reynolds III, C. F. (2014). Psychotherapy for depression in adults: a meta-analysis.

Future directions for clinical psilocybin research include: a randomized clinical trial of psilocybin-assisted therapy on major depressive disorder; a personalized network modeling in psychopathology; a review of the literature on psilocybin as an anti-inflammatory agent; and a discussion of challenges and directions for psychopathological network theory and methodology.

Future directions for clinical psilocybin research include a review of recent insights into mental disorders as networks of problems, a comparison of the centrality of DSM and non-DSM symptoms of depression in a network analysis, and a meta-analysis of experimental effects of psilocybin on symptoms of anxiety and depression. Psilocybin produced substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.

Future directions for clinical psilocybin research include studies on mystical-type experiences, cancer anxiety, psilocybin treatment for anxiety, acceptance and commitment therapy, awe, a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy, and a network approach to social anxiety disorder.

Future directions for clinical psilocybin research include: a network theory of mental disorders, a study of the hidden therapist, a meta-analysis of placebo-controlled trials of psychedelic-assisted therapy, and research on the role of music in psychedelic therapy.

Future directions for clinical psilocybin research include: experience sampling research in psychopathology, validation of the ego-dissolution inventory (EDI), psychedelic psychiatry’s brave new world, combining psychedelic and mindfulness interventions, and homological scaffolds of brain functional networks.

Future research directions for clinical psilocybin include: A meta-analysis of psychedelic treatments for depressive symptoms; Validation of the Emotional Breakthrough Inventory; Effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers; and a phase 1 trial.

Future directions for clinical psilocybin research include: identifying blinding and expectancy confounds in psychedelic randomized controlled trials; evaluating acute effects of lysergic acid diethylamide in healthy subjects; and integrating theories of psychedelic drug effects. van Borkulo, Boschloo, L., Borsboom, D., Penninx, B. W., Waldorp, L. J., Schoevers, R. A., Borsboom, D., & Waldorp, L. J. (2015) found that the network structure of symptoms was associated with the course of depression.

A psychological flexibility model was used to support psychedelic assisted therapy.