Medical Research Council.

RationaleRecent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.ObjectivesHere, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.MethodsTwenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.ResultsTreatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.ConclusionsAlthough limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.Electronic supplementary materialThe online version of this article (10.1007/s00213-017-4771-x) contains supplementary material, which is available to authorized users.

a b s t r a c tThe classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called 'psychoneurotic' disorders sometimes benefited considerably from their tendency to 'loosen' otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low. Since 2006, there have been several pilot trials and randomised controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders. These have provided encouraging results that provide initial evidence of safety and efficacy, however the regulatory and legal hurdles to licensing psychedelics as medicines are formidable. This paper summarises clinical trials using psychedelics pre and post prohibition, discusses the methodological challenges of performing good quality trials in this area and considers a strategic approach to the legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry.

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Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49–16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.

Unipolar mood disorders, including major depressive disorder and persistent depressive disorder (dysthymia), confer high rates of disability and mortality and a very high socioeconomic burden. Current treatment is suboptimal in most cases and there is little of note in the pharmaceutical development pipeline. The psychedelic drugs, including lysergic acid diethylamide and psilocybin, were used extensively in the treatment of mood disorders, and other psychiatric conditions, before their prohibition in the late 1960s. They are relatively safe when used in medically controlled environments, with no reported risk of dependence. Here, we present a systematic review of published clinical treatment studies using psychedelics in patients with broadly defined UMD, and consider their place in psychiatry. Whilst all of the included studies have methodological shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement after treatment with psychedelics. A recently completed pilot study in the UK favours the use of psilocybin with psychological support in treatment resistant depressive disorder. The evidence overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their use in unipolar mood disorders and other non-psychotic mental health conditions.

Genome-wide single nucleotide polymorphism (SNP) data from 936 bipolar disorder (BD) individuals and 940 psychiatrically healthy comparison individuals of North European descent were analyzed for copy number variation (CNV). Using multiple CNV calling algorithms, and validating using in vitro molecular analyses, we identified CNVs implicating several candidate genes that encode synaptic proteins, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5, as well as the neuronal splicing regulator RBFOX1 (A2BP1), and neuronal cell adhesion molecule CHL1. We have also identified recurrent CNVs on 15q13.3 and 16p11.2-regions previously reported as risk loci for neuropsychiatric disorders. In addition, we performed CNV analysis of individuals from 215 BD trios and identified de novo CNVs involving the NRXN1 and DRD5 genes. Our study provides further evidence of the occasional involvement of genomic mutations in the etiology of BD, however, there is no evidence of an increased burden of CNVs in BD. Further, the identification of CNVs at multiple members of the neurexin gene family in BD individuals, supports the role of synaptic disruption in the etiology of BD.

BackgroundThe increasingly large sample size requirements of modern adult mental health research suggests the need for a data collection and diagnostic application that can be used across a broad range of clinical and research populations.AimsTo develop a data collection and diagnostic application that can be used across a broad range of clinical and research settings.MethodWe expanded and redeveloped the OPCRIT system into a broadly applicable diagnostic and data-collection package and carried out an interrater reliability study of this new tool.ResultsOPCRIT+ performed well in an interrater reliability study with relatively inexperienced clinicians, giving a combined, weighted kappa of 0.70 for diagnostic reliability.ConclusionsOPCRIT+ showed good overall interrater reliability scores for diagnoses. It is now incorporated in the electronic patient record of the Maudsley and associated hospitals. OPCRIT+ can be downloaded free of charge at .