More realistic forecasting of future life events after psilocybin for treatment-resistant depression

This open-label study (n=30) found that psilocybin corrected pessimism biases in depressed patients and that this change in pessimism was significantly correlated with improvement in depressive symptoms.

Abstract

“Background: Evidence suggests that classical psychedelics can promote enduring changes in personality, attitudes and optimism, as well as improvements in mental health outcomes. Aim: To investigate the effects of a composite intervention, involving psilocybin, on pessimism biases in patients with treatment-resistant depression (TRD).

Methods: Patients with TRD (n = 15) and matched, untreated non-depressed controls (n = 15) performed the Prediction Of Future Life Events (POFLE) task. The POFLE task requires participants to predict the likelihood of certain life events occurring within a 30-day period, after which the actual rate of event occurrence is reported; this gives an index of potential pessimism versus optimism bias. Psilocybin was administered in two oral dosing sessions (10 and 25 mg) one week apart. Main outcome measures were collected at baseline and one week after the second dosing session.

Results: Patients showed a significant pessimism bias at baseline [t(14) = -3.260, p = 0.006; 95% CI (-0.16, -0.03), g = 1.1] which was related to the severity of their depressive symptoms (rs = -0.55, p = 0.017). One week after psilocybin treatment, this bias was significantly decreased [t(14) = -2.714, p = 0.017; 95% CI (-0.21, -0.02), g = 0.7] and depressive symptoms were greatly improved [t(14) = 7.900, p < 0.001; 95% CI (16.17, 28.23), g = 1.9]; moreover, the magnitude of change in both variables was significantly correlated (r = -0.57, p = 0.014). Importantly, post treatment, patients became significantly more accurate at predicting the occurrence of future life events [t(14) = 1.857, p = 0.042; 95% CI (-0.01, 0.12), g = 0.6] whereas no such change was observed in the control subjects.

Conclusion: These findings suggest that psilocybin with psychological support might correct pessimism biases in TRD, enabling a more positive and accurate outlook.”

Authors: Taylor Lyons & Robin L. Carhart-Harris

Summary

Introduction

Major depressive disorder (MDD) contributes to the overall global burden of disease and 30% of patients suffer from treatment-resistant depression.

MDD patients have a negative attitude towards themselves, the environment and the future, and anticipate unfavorable outcomes when facing life events of unknown emotional impact. This is partly explained by the cognitive-bias model of depression.

MDD is associated with excessive pessimism, and increased serotonin 2A receptor signaling has been shown to increase optimism, psychological wellbeing, trait openness, and life satisfaction following just a single dose in healthy populations.

Psilocybin has been shown to alleviate depression and anxiety in patients with life-threatening cancer, and a recent feasibility study has found that it is well tolerated and associated with rapid and marked reductions in depressive symptoms.

The present study sought to investigate whether psilocybin could alleviate pessimism in TRD patients, and compared TRD patients’ data with those of healthy control subjects.

Ethical Approvals

This study received favorable opinions from NRES LondonWest London, Imperial College London, and the Medicines and Healthcare products Regulatory Agency.

Study Design and Participants

In this open-label pilot study, 15 patients with TRD were administered psilocybin in two dosing sessions: an initial safety dose (10 mg) and a subsequent treatment dose (25 mg) 1 week later.

Outcome Measures

Depressive symptoms were measured using the Beck Depression Inventory (BDI) and cognitive biases were measured using the Prediction Of Future Life Events task (POFLE). All patients completed both versions of the POFLE and were contacted 30 days after completing each version to determine which events actually occurred.

Statistical Analysis

All statistical analyses were performed using SPSS version 23.0 (IBM Corp., Armonk, NY, United States). Depressive symptoms were analyzed using the Friedman Test with Dunn’s correction for multiple post hoc comparisons.

Results

Demographics

The majority of participants were Caucasian and male with a post-secondary level of education. All patients with TRD were diagnosed with depression of at least moderate severity, with most meeting criteria for severe depression.

Depressive Symptoms

Patients with depression scored significantly higher on the BDI at baseline and showed a significant decrease in BDI scores one week after psilocybin treatment. There was no significant difference found in the controls’ baseline versus follow-up BDI scores.

Although their depressive symptoms were significantly reduced, patients’ post-treatment BDI scores remained significantly different from the controls’ follow-up values one week after psilocybin treatment.

The patients’ depressive symptoms were reduced significantly over time, and were significantly reduced even further following each dose of psilocybin. One week after both dosing sessions, the patients’ depressive symptoms were significantly reduced when compared to baseline, dosing day 1, and dosing day 2 scores.

Predicting Future Life-Events Before Psilocybin Treatment

Before testing the specific hypotheses of this study, some description of the prediction and event occurrence data is warranted. The patients predicted a negative future that was not borne out by their experience.

Control subjects predicted more desirable life events than patients at baseline, and reported the occurrence of more desirable events within the ensuing 30 days. Patients predicted less desirable events than controls, but there was no significant difference found between patients and controls.

Although there were more desirable than undesirable life events occurring within the ensuing 30-day period, patients predicted significantly less desirable life events than the control subjects, which is consistent with an unrealistic pessimism bias in the patients prior to receipt of psilocybin.

Predicting Future Life-Events After Psilocybin-Treatment (Second 30-Day Period)

In contrast to their pre-treatment pessimism, post-treatment patients gave significantly higher probability estimates for desirable than undesirable life events, and reported a higher percentage of desirable events actually occurring within this 30-day period.

Control subjects predicted more desirable life events than undesirable events, and reported the occurrence of more desirable events than undesirable events within the ensuing 30 days. There were no significant between-groups differences in the rates at which desirable and undesirable events actually occurred.

After treatment with psilocybin, TRD patients made more accurate predictions of future life events, in line with healthy control subjects.

Accuracy of Forecasts

We examined whether there were any changes in participants’ forecasts between baseline and the post-treatment repeat phase. Patients were significantly more accurate in their predictions post-treatment.

The accuracy of the non-treated healthy control subjects was 0.72, SD = 0.12, and there were no significant between-groups differences found at baseline or the follow-up.

Assessing the Presence of a Pessimism Bias in the TRD Patients

Before testing specific hypotheses, some description of the computation of bias is warranted. Bias scores can range from -1 to 1, with a score of 0 indicating neither an optimism nor pessimism bias.

The mean amount of bias shown by patients at baseline was significantly lower than zero, indicating a suspected pessimism bias. Following psilocybin treatment, this pessimism bias was significantly reduced to such an extent that the mean score was no longer significantly different from zero.

Patients were significantly more pessimistic than controls at baseline, but this bias was alleviated to control levels following psilocybin treatment.

Relationship Between Cognitive Biases and Depressive Symptoms

We investigated whether baseline pessimism was related to depressive symptoms. We found that greater pessimism was associated with more severe depressive symptoms.

The magnitude of change in scores between baseline and the follow-up was significantly higher for the patients than the control subjects. The decrease in BDI score was significantly related to the decrease in pessimism for the patients.

Discussion

A study was conducted to investigate the effects of psilocybin on pessimism bias in patients with TRD. The results indicated that the psychologically supportive administration of psilocybin remediates negative cognitive biases characteristic of severe depression.

Depressive Symptoms, Biases and Accuracy of Predictions

Researchers found that psilocybin treatment alleviated depressive symptoms in patients with recurrent MDD, and that the effects persisted for 6 months. Moreover, psilocybin treatment also increased trait openness, optimism and quality of life in patients suffering from depression reactive to advanced-stage cancer.

Here we found that patients with treatment-resistant depression were unrealistically pessimistic about the likelihood of positive life events befalling them prior to psilocybin treatment. This finding is consistent with classic depression research demonstrating that depressed patients present with excessively negative perspectives that are disproportionate to their true life circumstances.

One week after psilocybin treatment, patients’ pessimism was alleviated and they no longer showed any cognitive biases. This finding is in line with previous research that has shown sustained increases in optimism following psilocybin treatment in patients suffering from depression and anxiety reactive to advanced-stage cancer.

The lack of cognitive bias in controls found here is in contrast to previous research suggesting that healthy individuals have a tendency towards an optimism bias. This unrealistic optimism may have drawbacks, such as underestimating risks and failing to adopt preventative and/or protective measures.

Although optimism is conducive to positive mental health, an accurate perception of reality is most important for mental health, and entertaining worst-case scenarios may help one’s ability to cope with negative outcomes, through contingency plans and preparedness.

The neurobiology of optimism versus pessimism is poorly understood, but serotonergic mechanisms are involved in mood states and cognitive styles. Psychedelics have been shown to temporarily deconstruct the default-mode network, which is associated with cognitive biases.

The ruminative network (DMN) in the brain is associated with psilocybin-induced ruminative thought, self-reflection and introspection. A functional imaging paradigm that incorporates the actual forecasting of future life events (prospection) might be interesting to explore in this context.

Methodological Strengths

The results reported here extend previous research demonstrating increased optimism following psychedelic drug use by analyzing the effects of psilocybin on the prediction of one’s personal future. This study is the first to analyze psychedelic-induced changes in cognitive biases in patients with TRD.

Limitations

This study was part of an open-label clinical trial with a small sample size. It is possible that a natural decline of depressive symptoms contributed to the findings, and that some drug-unrelated factor(s) contributed to the changes in cognitive bias observed here.

The specificity of our main results requires careful consideration, as well as the question of causality. It is unclear whether the reported changes in cognitive bias were selective for these outcomes or rather an epiphenomenon of the treatment’s core effects on depressive symptoms.

Conclusion

In conclusion, this study found that psilocybin with psychological support alleviated pessimism bias in patients with TRD. Further controlled studies are warranted to better determine the causality, reliability, specificity and durability of these findings.