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Welcome to Psylo's Neuroscience Newsletter - August Edition!
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Clinical Trials of Antidepressants
A recent study by Namiot et al., published in Translational Psychiatry, systematically analyzed 10,606 global clinical trials on depression, offering key insights into the landscape of antidepressant development. Here are some of the highlights from the study:
1. Ketamine was the most extensively researched drug in clinical trials of depression, with 137 registered trials. Other commonly researched drugs include sertraline, duloxetine, fluoxetine, and venlafaxine.
- *If you're interested in the history of antidepressant drug development, check out our previous article on the topic.
2. A total of 663 unique agents were identified in depression trials. Of these:
- 74.5% were already approved drugs
- 23.2% were investigational drugs
- 1.8% had been withdrawn
- 0.3% were nutraceuticals
- 0.2% were illicit substances
3. Most drugs being trialled were FDA-approved drugs - 19 were specifically approved for major depressive disorder, while 217 were approved for other indications.
- 💡 Non-U.S. databases included a wider range of alternative treatments, such as probiotics and nutritional supplements.
4. The drugs being investigated were categorized into 34 groups. The largest categories were 'antidepressive agents' and 'nutrients, amino acids, and chemical elements.'
- 💡 Notably, less than 5% of 'antidepressive agents' were investigational drugs - most were already approved for use.
5. The study identified 26 investigational antidepressive agents, with 16 different drug targets.
The most common were:
- Buprenorphine (opioid partial agonist)
- Saredutant (NK2 tachykinin receptor antagonist)
- Seltorexant (orexin OX2 receptor antagonist)
6. The study includes a comprehensive table of 40 drugs approved for depression (FDA and EMA), including:
- SSRIs/SNRIs (12)
- TCAs (8)
- Atypical Antipsychotics (7)
- MAOIs (4)
- GABA-A PAMs (2)
- NMDA antagonists (2)
- + agomelatine (melatonin agonist; approved by the EMA and TGA but not the FDA)
7. Notably, only five drugs have been approved for treatment-resistant depression:
- Fluoxetine (SSRI)
- Esketamine (NMDA antagonist)
- Isocarboxazid (MAO inhibitor)
- Tranylcypromine (MAO inhibitor)
- Olanzapine (Atypical antipsychotic)
This study sheds light on the current landscape of antidepressant development, particularly the emphasis on repurposing existing drugs and exploring new drug targets for depression. For more details, be sure to check out the full paper.
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Clinical Research
- Machine learning predicts brain age from 5-HT2A | 5-HT2A receptor binding predicted brain age in healthy individuals, and combining it with gray matter volume data improved the prediction accuracy; a PET and MRI study of 209 participants. Geroscience.
- Psychedelics vs. escitalopram for depression | This meta-analysis compared the effectiveness of oral psychedelics and escitalopram in treating depression. It found that placebo responses were lower in psychedelic trials, potentially overestimating their effects. High-dose psilocybin was more effective than both placebo and escitalopram, but its effect size was smaller than previously reported after adjusting for placebo differences. BMJ
- 5-HT4 agonist lowers depression risk | Prucalopride, a 5-HT4 receptor agonist, significantly reduced the incidence of depression compared to other anti-constipation drugs in an emulated target trial using electronic health records (N=~8,500 in each cohort). Br J Psychiatry
- Effect of SSRIs on brain 5-HT4 receptors | After 8 weeks of SSRI treatment, 5-HT4R binding in the neostriatum was reduced by 9%, and this change was associated with improvements in verbal memory but not overall clinical depressive symptoms – a longitudinal brain imaging study of 90 patients with MDD treated with escitalopram. Biol Psychiatry
- Comparing R-MDMA and S-MDMA in Humans | S-MDMA showed stronger stimulant effects than R-MDMA and racemic MDMA, and both R-MDMA and S-MDMA had different pharmacokinetic profiles but neither demonstrated significantly more psychedelic-like effects - a randomized, double-blind, placebo-controlled crossover trial of 24 healthy participants. Neuropsychopharmacology.
- Psychological protocols in psilocybin therapy for depression | This Bayesian meta-analysis of 10 clinical trials with 515 adults assessed the impact of different psychological protocols on the efficacy of psilocybin therapy for depression. Different psychological support approaches did not significantly impact the efficacy of psilocybin-assisted therapy for treating depression. Front Psychiatry
- 5-HT1A receptor methylation and childhood abuse in depression | Childhood abuse was associated with increased gray matter volume (GMV) in several brain regions, while serotonin 1A receptor methylation was linked to GMV in the orbitofrontal cortex - a cross-sectional study of 50 individuals with Major Depressive Disorder, including 18 with a history of childhood abuse. J Affect Disord
- Psychedelic public health and equity concerns | Fewer than 10% of public health programs engage with psychedelics, with only a small proportion addressing equity and Indigenous contributions – an analysis of webpage content from 228 public health programs and 59 psychedelic research centers. Soc Sci Med
- [Case study] SSRI discontinuation for psilocybin and alcohol relapse | Stopping SSRIs before psilocybin treatment was linked to a heavy relapse in alcohol use, despite ongoing naltrexone treatment, in a patient with major depression and alcohol use disorder. J Clin Psychiatry
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Preclinical Research
- Predicting hallucinogenic potential using AI models | Machine learning models accurately predicted the hallucinogenic potential of molecules by evaluating their interaction with 5HT2A receptors; a computational study using SVC and random forest models with in vitro and in vivo data sets. ACS Chem Neurosci
- Psilocybin facilitates fear extinction | Psilocybin enhanced fear extinction, extinction retention, and reduced fear renewal in mice, with these effects mediated by 5-HT2A and 5-HT1A receptors and dependent on dose and timing. ACS Chem Neurosci
- Brain gene expression measurement with noninvasive ultrasound | The REMIS method allows non-invasive monitoring of brain activity in mice by detecting gene expression using ultrasound to open the blood-brain barrier and release protein markers. Sci Adv
- Methamphetamine suppresses head-twitch response in mice | Methamphetamine dose-dependently suppressed HTR in younger mice, with the effect reversed by a 5-HT1A antagonist. Behav Pharmacol
- 5-HT2A receptor involvement in alcohol use and optimism | Rats deemed ‘optimistic’ consumed less alcohol than 'pessimistic' rats, and intake was linked to reduced 5-HT2A receptor binding in the nucleus accumbens. Prog Neuropsychopharmacol Biol Psychiatry
- Cardiac effects of amphetamine-related hallucinogens on | Amphetamine-related hallucinogenic drugs had opposing effects on cardiac contractile force of ex vivo human atrial tissue, with DOI and DOM (5-HT2A agonists) reducing contractile force and mephedrone increasing it through noradrenaline release. Int J Mol Sci
- Target Genes of S-ketamine for Depression | S-ketamine modulates the expression of key genes (TGM2, HSP90AB1, ADORA3) and signaling pathways, potentially alleviating depression; a bioinformatics and network pharmacology study predicting therapeutic targets (N=228 genes). J Psychopharmacol
- Serotonin 5-HT2A receptor's role in bladder pain | 5-HT2A receptor activation increases bladder afferent neuron sensitivity, contributing to bladder overactivity and pain, and blocking the receptor reduces these symptoms in a rat model of cystitis. Eur J Pharmacol
- 5-HT2A receptor impacts bladder control | The 5-HT2A/2C receptor agonist improved bladder function in spinal cord-injured rats, by inhibiting L-type voltage-gated calcium channels. CNS Neurosci Ther
- 5-HT1B receptors modulate aggression in mice | Activation of the DRN→vHip pathway inhibited reactive aggression through 5-HT1B receptors in socially isolated mice, suggesting that these receptors suppress aggressive behavior. Eur J Pharmacol
- Stress effects on 5-HT1A receptor binding | Stress caused cerebrometabolic activation in key brain regions, but minimally affected the binding of radioligand [18F]F13640 to 5-HT1A receptors in rats, supporting the use of this radiopharmaceutical for psychiatric imaging studies. Nucl Med Biol
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Reviews and Commentaries
- Opportunities for use of neuroimaging in de-risking drug development and improving clinical outcomes in psychiatry: an industry perspective | This review discusses how neuroimaging modalities like PET, EEG, and MRI can be leveraged in psychiatric drug development to improve precision in dosing, patient selection, and clinical outcomes, ultimately enhancing drug efficacy and success rates. Neuropsychopharmacology
- Mind over matter: The microbial mindscapes of psychedelics and the gut-brain axis | This review explores the potential role of gut microbiota in modulating the effects of psychedelics on behavior, suggesting that the gut-brain axis may influence how psychedelics promote positive mental shifts, and calls for future research incorporating microbiome considerations into psychedelic therapies. Pharmacol Res
- The effect of antidepressant treatment on blood BDNF levels in depressed patients: a review and methodological recommendations for assessment of BDNF in blood | This review examines the impact of antidepressant treatments on blood brain-derived neurotrophic factor (BDNF) levels in patients with major depressive disorder (MDD), concluding that while antidepressants raise blood BDNF levels, BDNF is not a reliable biomarker for depression severity or treatment outcome. Eur Neuropsychopharmacol
- Comparison between single-dose and two-dose psilocybin administration in the treatment of major depression: a systematic review and meta-analysis of current clinical trials | This review and meta-analysis examine the therapeutic effects of single-dose and two-dose psilocybin treatments for major depressive disorder (MDD) and treatment-resistant depression (TRD), finding that both dosing strategies significantly reduce depressive symptoms, with two-dose treatments sometimes yielding longer lasting effects. Brain Sci
- Systematic insights into the relationship between the microbiota-gut-brain axis and stroke with the focus on tryptophan metabolism | This review explores the intricate connection between the microbiota-gut-brain axis, particularly tryptophan metabolism, and stroke, discussing how this metabolic pathway may influence stroke progression and offer potential therapeutic targets. Metabolites
- Functional unblinding in pivotal studies and the future of psychedelic medicine | This commentary discusses the challenge of functional unblinding in psychedelic drug trials and explores potential criteria for addressing this issue while still allowing approval of novel, effective treatments for unmet clinical needs. J Clin Psychiatry
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Clinical Trials Update
A round-up of the latest registered clinical trials investigating psychedelics:
- Lysergic acid diethylamide (LSD) | Biomarker for Depression, Anxiety (N=10) | Salivary Oxytocin as a Biomarker in Psychedelic Assisted Psychotherapy. Investigating the reactivity of salivary oxytocin during a single LSD intake as part of Psychedelic Assisted Psychotherapy treatment for anxiety disorders or depression - NCT06557239
- Psilocybin as CYB003 | Major Depressive Disorder (N=220) | A Study of a Psilocybin Analog (CYB003) in Humans With Major Depressive Disorder (APPROACH) [Phase 3] - NCT06564818
- Psilocybin Microdosing +/- Meditation | Healthy Volunteers: Feasibility, Acceptability, Safety and Tolerability (N=24) | Optimizing Microdosing and Meditation (OMM) - NCT06560658
- MDMA-assisted Therapy | Pathological Narcissism (N=12) | MDMA-Assisted Therapy for Pathological Narcissism - NCT06565494
- Ketamine +/- Psychotherapy | Major Depressive Disorder (N=70) | Ketamine-Assisted Psychotherapy (KAP) Compared to Ketamine Alone for the Treatment of Depression - NCT06559826
- (2R,6R)-Hydroxynorketamine (RR-HNK) | Obsessive-Compulsive Disorder (N=45) | Pilot Study of RR-HNK in OCD - NCT06575075
- Novel Virtual Reality Program (DeepDream) vs Psychedelics | Healthy Volunteers: Subjective Experiences (N=15) | Psychedelic Virtual Reality - NCT06581263
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Dr William Jorgensen, Psylo's Director of Medicinal Chemistry, will be presenting at the ASCEPT Drug Discovery SIG student & ECR symposium on September 11. Register here.
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Josh Ismin (CEO) and Dr William Jorgensen (Director of Medicinal Chemistry) will be representing Psylo at the NSW Health Commercialisation Training Program Showcase in Sydney on September 16.
This special event will celebrate a decade of NSW Health’s achievements in driving bio, med, and health commercialisation.
Come meet the team at our Founder Pod and discover how Psylo is shaping the future of mental health treatment.
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Sam met with the Biagon Inc. team in person to discuss founder-led biotech, psychedelics and 5-HT2A, and our work at Psylo. |
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Sam Banister (Psylo), Ryan Field (Kernel), Jacob Robinson (Motif Neurotech) and Sam Tabone (Focalpoint Partners) proposed a panel discussion for SXSW 2025 on the future of mental health and precision neuromedicine.
Panel description: 🧠 Dive into the world of cutting-edge neuroscience, brain imaging and diagnostics, bioelectronic medicine and psychedelic-inspired therapeutics. Join us in unpacking these new avenues in neuro and what it means for patients!
Voting for the panel has closed, and we’re eagerly awaiting the outcome.
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