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Background Psilocybin is being investigated as a treatment for a myriad of disorders, including treatment-resistant depression. The main focus has been on positive effects, with little attention paid to negative outcomes, especially in clinical settings. Quantitative methodology limits further exploration of such events and can also miss improvements not captured on rating scales. Aims To highlight potential adverse events of psilocybin and underline limits of quantitative methodology, calling for process evaluations alongside clinical trials. Case presentation This is a case of a participant in a phase 2b clinical trial of psilocybin for treatment-resistant depression who presented with increased suicidal ideation and a prolonged period of severely restricted eating following administration, leading to a period of destabilisation and a need for support. Despite the difficulties encountered and the participant's limited improvement on rating scales, she found the experience to have been helpful and led her to make changes to her life which she found beneficial. She described her experience in a written account to the authors. Method The case was summarised and the written account was thematically analysed and synthesised into a logic model. Conclusions Psilocybin could lead to temporary worsening of suicidal ideation and instigate prolonged adverse events that outlast its acute effects. Paradoxically, it could simultaneously lead to an improvement in functional outcomes which is not clear on depression rating scales. This calls for a qualitative exploration of serious adverse events and participant accounts to deepen our understanding of the psilocybin experience and its different outcomes.

Background Autonomic nervous system (ANS) dysregulation might be relevant to the pathophysiology of fatigue and cognitive impairment in depression and perhaps should be considered when making prescribing decisions. Aims To determine the relationship of self-reported ANS symptoms with fatigue, cognition and prescribed medication in people with a diagnosis of depression, in comparators without depression but with other mental health, neurodevelopmental or neurodegenerative disorders (active controls) and in healthy controls. Method Cross-sectional analysis of an opportunistic sample from England. Self-reported data were collected on demographics, diagnosis, medication, ANS symptoms (Composite Autonomic Symptom Scale-31, COMPASS-31) and fatigue (Visual Analogue Scale for Fatigue, VAS-F). A subsample completed cognitive tests (THINC-it), including the subjective Perceived Deficits Questionnaire five-item version (PDQ-5). Spearman's correlation and mediation models were used to explore the relationship between COMPASS-31, VAS-F and PDQ-5 scores. Results Data were obtained for 3345 participants, 22% with depression. The depression group had significantly (P < 0.01) more severe autonomic dysregulation as measured by COMPASS-31 scores (median 30) than active (median 23) and healthy controls (median 10). The depression group had significantly higher symptom severity (P < 0.01) than both control groups on the VAS-F and PDQ-5. Overall, there was a significantly positive correlation (P < 0.01) between COMPASS-31, VAS-F scores (Spearman's rho rs = 0.44) and PDQ-5 scores (rs = 0.56). COMPASS-31 scores mediated greater symptom severity on the VAS-F and PDQ-5 for those with depression. COMPASS-31 scores remained significantly different between the depression group and both control groups independently of medication. Conclusions People with a diagnosis of depression report worse fatigue and cognition than active and healthy comparators; this appears to be mediated by ANS dysregulation.

Background Individuals with treatment-resistant depression (TRD) experience a high burden of illness. Current guidelines recommend a stepped care approach for treating depression, but the extent to which best-practice care pathways are adhered to is unclear. Aims To explore the extent and nature of ‘treatment gaps’ (non-adherence to stepped care pathways) experienced by a sample of patients with established TRD (non-response to two or more adequate treatments in the current depressive episode) across three cities in the UK. Method Five treatment gaps were considered and compared with guidelines, in a cross-sectional retrospective analysis: delay to receiving treatment, lack of access to psychological therapies, delays to medication changes, delays to adjunctive (pharmacological augmentation) treatment and lack of access to secondary care. We additionally explored participant characteristics associated with the extent of treatment gaps experienced. Results Of 178 patients with TRD, 47% had been in the current depressive episode for >1 year before initiating antidepressants; 53% had received adequate psychological therapy. A total of 47 and 51% had remained on an unsuccessful first and second antidepressant trial respectively for >16 weeks, and 24 and 27% for >1 year before medication switch, respectively. Further, 54% had tried three or more antidepressant medications within their episode, and only 11% had received adjunctive treatment. Conclusions There appears to be a considerable difference between treatment guidelines for depression and the reality of care received by people with TRD. Future research examining representative samples of patients could determine recommendations for optimising care pathways, and ultimately outcomes, for individuals with this illness.

BackgroundChildhood maltreatment is one of the strongest predictors of adulthood depression and alterations to circulating levels of inflammatory markers is one putative mechanism mediating risk or resilience.AimsTo determine the effects of childhood maltreatment on circulating levels of 41 inflammatory markers in healthy individuals and those with a major depressive disorder (MDD) diagnosis.MethodWe investigated the association of childhood maltreatment with levels of 41 inflammatory markers in two groups, 164 patients with MDD and 301 controls, using multiplex electrochemiluminescence methods applied to blood serum.ResultsChildhood maltreatment was not associated with altered inflammatory markers in either group after multiple testing correction. Body mass index (BMI) exerted strong effects on interleukin-6 and C-reactive protein levels in those with MDD.ConclusionsChildhood maltreatment did not exert effects on inflammatory marker levels in either the participants with MDD or the control group in our study. Our results instead highlight the more pertinent influence of BMI.Declaration of interestD.A.C. and H.W. work for Eli Lilly Inc. R.N. has received speaker fees from Sunovion, Jansen and Lundbeck. G.B. has received consultancy fees and funding from Eli Lilly. R.H.M.-W. has received consultancy fees or has a financial relationship with AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Ferrer, Janssen-Cilag, Lundbeck, MyTomorrows, Otsuka, Pfizer, Pulse, Roche, Servier, SPIMACO and Sunovian. I.M.A. has received consultancy fees or has a financial relationship with Alkermes, Lundbeck, Lundbeck/Otsuka, and Servier. S.W. has sat on an advisory board for Sunovion, Allergan and has received speaker fees from Astra Zeneca. A.H.Y. has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. A.J.C. has received honoraria for speaking from Astra Zeneca, honoraria for consulting with Allergan, Livanova and Lundbeck and research grant support from Lundbeck.

Background. Depressed patients show deficits on neuropsychological tests. However, the basis of these impairments and their relationship with mood disturbance remains unclear. Methods. This paper reviews the literature regarding the relationship between mood disturbance and neuropsychological impairment in depression and the evidence for serotonergic and hypothalamic–pituitary–adrenal (HPA) axis involvement in these two domains. Results. Mood disturbance and neuropsychological impairment both occur in depression, but have no clear relationship in time or degree. Impairment of post-synaptic 5-HT1A receptor function may result in the symptom of low mood in depression. Depressed patients demonstrate abnormalities in the functional control of the HPA axis with a resultant hypercortisolaemia, which may impair neuropsychological function. These processes may be related given the extensive interactions between the serotonergic system and the HPA axis. Conclusions. We argue that there is a neurobiological cause of impaired neuropsychological function in depression. The complex relationship between neuropsychological function and mood may be a result of interactions between the serotonergic system and the HPA axis, particularly in the hippocampus with involvement of serotonergic 5-HT1A and glucocorticoid receptors. A primary dysfunction in these receptors will produce a lowering of mood and neuropsychological impairment respectively. Either dysfunction will result in a secondary impairment of the alternate system. Thus, the affective and psychological changes of depressive illness are likely to have complex relationships in time and severity to one another and the illness as a whole may result from a range of primary aetio-pathologies. [ABSTRACT FROM AUTHOR]