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A proof-of concept randomized controlled trial to show that the antidepressant effect of psilocybin does not require a psychedelic experience: study protocol
- M. I. Husain, D. M. Blumberger, D. J. Castle, S. M. Kloiber, A. Ortiz, J. D. Rosenblat, B. H. Mulsant
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S557
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Introduction
During the last decade there has been a resurgence of interest on the use of psychedelics as novel treatments for mental disorders, including treatment-resistant depression (TRD). Psilocybin, the chemical component of “magic mushrooms”, has been administered with psychotherapy in randomized clinical trials (RCTs) showing large and sustained antidepressant effects. As the use of psilocybin expands, it is becoming more important to understand whether psilocybin’s psychedelic effects are required for psilocybin’s antidepressant effects. Psilocybin’s psychedelic effects are known to be dependent on serotonin 2A receptor (5-HT2AR) activation. Given the safety concerns associated with psilocybin’s psychedelic effects, all studies have used it in conjunction with at least 12 hours of intensive psychotherapy. This makes psilocybin-assisted psychotherapy (PAP) highly resource intensive and impedes scalability given limited resources and access to trained therapists in most jurisdictions. Studies in healthy volunteers have shown that psilocybin’s psychedelic effects are blocked by 5-HT2AR antagonists like risperidone and ketanserin. In a pre-clinical study using a mouse model of depression, administration of ketanserin followed by psilocybin had the same antidepressant effect as psilocybin alone. We propose to conduct the first study to test in humans whether the antidepressant effects of psilocybin are attenuated by 5-HT2AR blockade from risperidone.
ObjectivesAim 1: To evaluate the feasibility and tolerability of administering psilocybin with risperidone in adults with TRD by evaluating recruitment, retention, tolerability, and safety.
Aim 2: To evaluate psychedelic effects (measured with the 5-Dimensional Altered States of Consciousness Rating Scale) in the three groups.
Aim 3: To evaluate antidepressant effects (measured with the Montgomery Asberg Depression Rating Scale; MADRS) in the three groups. .
MethodsA three-arm, 4-week, double blind, proof-of-concept RCT for patients with a DSM-5 major depressive episode that has failed to respond to at least two adequate trials of antidepressants. Participants will be randomized to: 1) psilocybin 25 mg plus risperidone 1 mg; 2) psilocybin 25 mg plus placebo; 3) placebo plus risperidone 1 mg. All participants will receive 12 hours of manualized psychotherapy.
ResultsEthics approval for the proposed study has been obtained. We will present preliminary feasibility data at the meeting in March.
ConclusionsIf the study demonstrates that psilocybin’s psychedelic effects are not necessary for psilocybin’s antidepressant effects, the combination of psilocybin and a 5-HT2AR antagonist, such as risperidone, could increase acceptability and access to the use of psilocybin to treat MDD and related conditions.
Disclosure of InterestNone Declared
Depression, comorbidities and the TNF-α system
- H. Himmerich, S. Fulda, J. Linseisen, H. Seiler, G. Wolfram, S. Himmerich, K. Gedrich, S. Kloiber, S. Lucae, M. Ising, M. Uhr, F. Holsboer, T. Pollmächer
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- European Psychiatry / Volume 23 / Issue 6 / September 2008
- Published online by Cambridge University Press:
- 16 April 2020, pp. 421-429
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Depression has frequently been reported to be associated with other physical diseases and changes in the cytokine system. We aimed to investigate associations between a medical history of depression, its comorbidities and cytokine plasma levels in the Bavarian Nutrition Survey II (BVS II) study sample and in patients suffering from an acute depressive episode.
The BVS II is a representative study of the Bavarian population aged 13–80 years. The disease history of its 1050 participants was assessed through face-to-face interviews. A sub-sample of 568 subjects and 62 additional acutely depressed inpatients of the Max Planck Institute of Psychiatry participated in anthropometric measurements and blood sampling. Tumor necrosis factor-α (TNF-α) and soluble TNF receptor (sTNF-R) p55 and sTNF-R p75 plasma levels were measured using enzyme-linked immunosorbent assays.
A history of depression was associated with a higher incidence of high blood pressure, peptic ulcer, dyslipoproteinemia, osteoporosis, allergic skin rash, atopic eczema and thyroid disease.
Within the BVS II sample, participants with a history of depression differed from subjects who had never had depression with regard to sTNF-R p55 and sTNF-R p75 levels even when controlling for age, BMI and smoking status. Acutely depressed inpatients showed even higher levels of sTNF-R p55 and sTNF-R p75 than subjects in the normal population. TNF-α levels were also significantly elevated in acutely depressed patients.
These results confirm earlier studies regarding the comorbidities of depression and support the hypothesis that activation of the TNF-α system may contribute to the development of a depressive disorder.
Genetic Relationship Between Depression and Body Mass Index
- M. Rivera, A.E. Locke, T. Corre, D. Czamara, C. Wolf, A. Ching-Lopez, Y. Milaneschi, S. Kloiber, D.I. Boomsma, B. Müller-Myhsok, B.W.J.H. Penninx, M. Preisig, A.E. Farmer, C.M. Lewis, G. Breen, P. McGuffin
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- European Psychiatry / Volume 30 / Issue S1 / March 2015
- Published online by Cambridge University Press:
- 15 April 2020, p. 1
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Introduction
Depression and obesity are highly prevalent major public health problems that frequently co-occur. Shared aetiological factors have been found between depression and obesity. The role of the fat mass and obesity associated (FTO) gene in body mass index (BMI) and obesity has been confirmed in many independent studies. Recently, we reported the first study implicating FTO in the association between depression and obesity.
ObjectivesWe aimed to confirm these findings by investigating the FTO rs9939609 polymorphism in a meta-analysis of 13,701 individuals.
MethodsThe sample consists of 6,902 depressed cases and 6,799 controls from five studies (Radiant, PsyCoLaus, GSK, MARS and NESDA/NTR). Common inclusion criteria were information available on a lifetime DSM-IV diagnosis of major depressive disorder (MDD), BMI and genotype data. Linear regression models for quantitative traits assuming an additive genetic model were performed to test for association and interaction between rs9939609, BMI and depression. Fixed and random-effects meta-analyses were performed.
ResultsFixed-effects meta-analyses support a significant association between rs9939609 polymorphism and BMI (whole-sample: ß=0.07, p=1.29×10-12, depressive-cases: ß=0.12, p=6.92×10-12). No association was found in controls (ß=0.02, p=0.15). Meta-analyses further support a significant interaction between FTO, BMI and depression (fixed-effects: ß=0.13, p=3.087×10-7; random-effects: ß=0.12, p=0.027), wherein depressed carriers of the risk allele have an additional increase of 2.2% in BMI.
ConclusionsThis meta-analysis demonstrates a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. Depression-related alterations in key biological processes may interact with the rs9939609 FTO risk allele to increase obesity risk.
Gene–PUFA interactions and obesity risk
- C. Jourdan, S. Kloiber, A. Nieters, H. Seiler, H. Himmerich, M. A. Kohli, S. Lucae, G. Wolfram, C. Gieger, H.-E. Wichmann, J. Linseisen
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- Journal:
- British Journal of Nutrition / Volume 106 / Issue 8 / 28 October 2011
- Published online by Cambridge University Press:
- 18 May 2011, pp. 1263-1272
- Print publication:
- 28 October 2011
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Although there are indications for modulatory effects of PUFA on associations between SNP and obesity risk, scientific evidence in human subjects is still scarce. The present analyses investigated interaction effects between SNP in candidate genes for obesity and PUFA in erythrocyte membranes on obesity risk. Within the second Bavarian Food Consumption Survey (cross-sectional, population-based), 568 adults provided blood samples. Fatty acid composition of erythrocyte membranes was analysed by means of GC. Genotyping was performed for twenty-one genes, including cytokines, adipokines, neurotransmitters and transcription factors. In addition, plasma IL-6 concentrations were analysed. For the statistical analysis, a logistic regression model assuming additive genetic effects was chosen. About 20 % of the study participants were classified as obese (BMI ≥ 30 kg/m2). Several significant gene–PUFA interactions were found, indicating regulatory effects of PUFA by gene variants of IL-2, IL-6, IL-18, TNF receptor family member 1B and 21, leptin receptor and adiponectin on obesity risk. After stratification by genotype, the strongest effects were found for rs2069779 (IL-2) and all tested PUFA as well as for rs1800795 (IL-6) and linoleic or arachidonic acid. The obesity risk of minor allele carriers significantly decreased with increasing fatty acid content. The genetic PUFA–IL-6 interaction was also reflected in plasma IL-6 concentrations. If replicated in a prospective study with sufficient statistical power, the results would indicate a beneficial effect of high PUFA supply for a substantial proportion of the population with respect to obesity risk.