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21st November 2022
The use of a single dose of psilocybin leads to a significant improvement in symptoms among patients with treatment-resistant major depression according to the findings of a study by an international team of researchers.
Treatment-resistant depression (TRD) is a subset of major depressive disorder which does not respond to traditional and first-line therapeutic options. The estimate of TRD varies although according to a 2021 US study, among 8.9 million adults treated for major depression, 2.8 million (30.9%) had TRD. Psilocybin is the major psychoactive alkaloid of some species of mushrooms distributed worldwide and a known hallucinogen. Interest in the use of psilocybin to help with the depression and anxiety associated with advanced stage cancer, revealed a positive trend toward improved mood and anxiety. More recently, two doses of the hallucinogen given to patients with major depression in the context of supportive psychotherapy, suggested that psilocybin combined with therapy is efficacious in the treatment of major depressive disorder. To date, only a single, open-label feasibility trial has examined the value of psilocybin for the treatment of patients with treatment-resistant depression, offering support for its safety and efficacy and serving as the basis for further trials.
Consequently, in the present study, researchers recruited adults with TRD across 22 sites in 10 countries randomised them 1:1:1 to a single dose of psilocybin (10 mg, 25 mg) or 1 mg which served as a control. The treatment was given with a support session lasting6 to 8 hours and participants followed up for 12 weeks. The primary endpoint was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score which ranges from 0 to 60 with higher scores reflecting more severe depression. The researchers examined the change in scores for the 10 and 25 mg doses compared to the 1 mg dose. Secondary outcomes included a response, defined as a > 50% decrease from baseline to week 3 in the MADRS score and a sustained response, i.e., continuing from week 3 to 12.
Psilocybin and treatment response
A total of 233 individuals with a mean age of 39.8 years (52% female) were included and randomised to each arm of the study (ranging from 75 to 79 participants). At baseline, 68% of the entire cohort had a MADRS score indicating severe depression.
The reduction in MADRS scores were -6.6 (95% CI -10.2 to -2.9) for the 25 mg dose (p < 0.001 vs 1 mg dose) and -2.5 (95% CI -6.2 to 1.2) for the 10 mg dose (p = 0.18 vs 1 mg dose).
At 3 weeks, a response was also more likely in those given 25 mg compared to 1 mg (Odds ratio, OR = 2.9, 95% CI 1.2 – 6.6) but this was not significant for the 10 mg dose (OR = 1.2, 95% CI 0.5 – 3.01). However, the response to treatment was not sustained at 12 weeks for either dose.
Adverse effects included headaches (24%) and nausea (22%) and were much more common in the 25 mg dose group, although suicidal ideation or behaviour or self-injury was seen in each of the groups.
The authors concluded that psilocybin given as a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects, prompting the need for further studies of the treatment.
Goodwin GM et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Eng J Med 2022
6th January 2022
A potential biomarker which indicates the presence of major depression and its response to treatment could become a useful diagnostic tool and create a platform for personalised medicine. This was the conclusion of a proof-of-concept study by a team led by researchers from Signant Health, Boston, USA.
Depression is the commonest mental illness worldwide and the incidence has increased by 49.8% from 1990 to 2017, affecting some 25.8 million people. Moreover, the incidence of major depression also appears to be on the increase, with a US study in 2021 indicating that number of US adults with major depression aged 18-34 years increased from 34.6 to 47.5% between 2010 and 2018. Although treatment of depression with antidepressant drugs has become widespread, some evidence from a real-world study suggests that only a third of patients achieve remission with the antidepressant, citalopram. A potential biomarker that not only identified those with major depression but also enabled tracking of a patient’s response to treatment could therefore be invaluable to clinicians.
Studies suggest that the cyclic adenosine monophosphate (cAMP) cascade is down regulated in major depression but up regulated by antidepressant treatment. Moreover, G protein coupled receptors and their attendant G proteins and effectors, such as adenylyl cyclase, are involved in the generation of cAMP. Many neurotransmitter receptors, G proteins, and signalling effectors such as second-messenger-generating enzymes are present in lipid rafts and one particular protein, G-s alpha (GSA), appears to be the target of antidepressants, which facilitate the activation of adenylyl cyclase by making GSA more available.
In the present study, researchers hypothesised that antidepressant treatment increases the concentration of GSA, enabling it to exit from the lipid raft and stimulating the enzyme, adenylyl cyclase. They used blood platelets to determine adenylyl cyclase activity based on its response to prostaglandin E1 (PGE1) stimulation, which served as their potential biomarker by measuring of the extent of GSA-adenylyl cyclase coupling in both patients with major depression and healthy controls. The level of depression was assessed using the Hamilton rating scale for depression (HamD) and included patients were required to have a score > 15 at the initial visit.
Using samples from 41 individuals with major depression and 44 healthy controls, baseline measurement revealed a significantly lower PGE1 activation in those with depression compared to controls (p = 0.02), suggesting that there was less GSA available. A total of 19 depressed individuals (6 men and 13 women) with a mean age of 50.6 years and a mean baseline HamD score of 20.4 consented to having a course of antidepressant therapy. After 6 weeks of treatment, there were 11 responders (HamD scores > 50% improvement from baseline) whose platelet samples demonstrated a significant increase in PGE1 stimulated adenylyl cyclase compared to non-responders (p = 0.05). In fact, treatment responders showed a 62% increase in mean PGE1 stimulation compared to baseline, compared to -4.6% decrease for non-responders.
The authors concluded that the translocation of GSA from lipid rafts, as reflected by an increased PGE1 stimulated adenylyl cyclase, after treatment with antidepressants, could be used as a potential biomarker for both major depression and patients response to therapy and called for future studies to determine the utility of this biomarker.
Targum SD et al. A novel peripheral biomarker for depression and antidepressant response Mol Psychiatry (2022).