depression: psilocybin seems to help a lot

 A small randomized controlled trial found that psilocybin was an effective therapy for patients with major depressive disorders; and it worked quite rapidly, unlike the standard meds (see depression psilocybin helps jamapsych2020 in dropbox, or doi:10.1001/jamapsychiatry.2020.3285) 

 

Details: 

-- the study was performed in the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center, from 2017-2019 

-- adults aged 21 to 75yo with a major depressive disorder (MDD); not on antidepressants; and no history of psychotic disorder, serious suicide attempt or hospitalization, were recruited through fliers, print advertisements, Internet forums, social media, and the study website

    -- 870 individuals were screened

-- 27 people were randomized to an immediate treatment group (n=15) or a delayed treatment group (n=12)

    -- the delayed treatment group was to control for spontaneous improvement, with a delay of eight weeks to getting the treatment

-- patient were randomized based on age, sex, depression severity at screening by the GRID-Hamilton Depression Rating Scale (GRID-HAMD) score 

    --the GRID-HAMD is a version of the Hamilton Depression Reading Scale and has high reliability and validity 

    --a score of 0-7=no depression, 8-16= mild depression, 17-23=moderate depression, >23 = severe depression

    --enrollment in this study required a score of at least 17

-- mean age 40, 67% women, 92% white, 58% with a bachelor's degree and 17% master's degree, 46% married, 63% employed full-time/17% part-time/21% unemployed 

-- time with depression 22 years, time in current major depressive episode 24 months

-- lifetime psychedelic use: 0.8% 

-- mean GRID-HAMD score 22.8 

-- Intervention: two sessions with psilocybin: first session 20 mg/70kg dose, second session 30 mg/70 kg dose, in the context of supported supportive psychotherapy (approximately 11 hours) 

    -- during the infusion sessions, “inward reflection” music was played from an eight-hour playlist, which, buried in the supplements, turns out to be basically classical music and not the Grateful Dead or Jimi Hendrix (ie, no Purple Haze). Participants were instructed to wear eye shades and headphones [not kidding!!!] 

 

-- primary outcome: depression severity by GRID-HAMD at baseline, and at one and four weeks after the intervention 

-- secondary outcome: Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR), assessed more frequently (range 0-27, the higher the score the worse the depression)

Results: 

-- 24 of 27 (89%) completed the intervention and the post-session assessments 

-- mean GRID-HAMD (baseline 22.8) 

    -- at one week: 8.0 

    -- at four weeks: 8.5 

-- in the delayed treatment group, at a comparable time of five and eight weeks after randomization (but prior to starting the meds) 

    -- at week 5: 23.8 

    -- at week eight: 23.5 

-- the differences in the intervention group, vs the delayed treatment group 4 weeks after the intervention, was statistically significant at p<0.001 [ie, very unlikely that this dramatic decrease was related to spontaneous depression remission]

 

-- overall: 67% of participants at week one and 71% at week four had a clinically significant response with at least a 50% reduction in the GRID-HAMD score 

    -- and, 58% at week one and 54% at week four were in remission of their depression  (GRID-HAMD score <8) 

 

-- mean QIDS-SR scores: 

    -- by day one after psilocybin session 1: decrease from 16.7 to 6.3, p<0.001 [!!!]

    -- this decrease remained through week four after session 2, with a score 6.0, similarly p<0.001 

-- Other outcomes measured for depression and anxiety showed a similar pattern of dramatic and statistically significant results: the Beck Depression Inventory II, the Patient Health Questionnaire-9, and the Hamilton Anxiety Reading Scale

-- and, suicidal ideation was low at baseline but strongly trended lower with treatment 

 

-- and, there were very high scores for the psilocybin sessions for creating experiences that were personally meaningful, spiritually significant, psychologically challenging, but psychologically insightful. the presence of these experiences correlated with depression response

 

-- no serious adverse events. there was a transient increase in blood pressure (diastolic blood pressure >100mmHg) during session 1, no intervention was needed 

    -- there was also mild to moderate transient headaches in 33% 

    -- there were lots of emotional effects during the psilocybin sessions, especially feeling like crying, sadness, emotional or physical suffering, etc., etc. see their eTable 8. But these only lasted during the sessions 

        -- there were very few longer-lasting effects after the sessions, other than headache in 29% 

 

Commentary: 

-- depression is the number one cause of disability in the US, with a relative risk of all-cause mortality being 1.7 times that of the general population 

-- approximate 10% of the adult population in the US has been diagnosed with MDD in the past 12 months, with an economic burden annually of $210 billion 

-- there are many meds used now for MDD (SSRIs, SNRIs, etc), with reasonable effectiveness, though 30 to 50% of patients do not respond fully and 10 to 30% are treatment-resistant (so, the average treatment effects are only a bit larger than that of placebo). These medications typically increase levels of serotonin and norepinephrine 

-- ketamine infusions have been shown to be rapidly effective in reducing depressive symptoms, but these last from days to only about two weeks after an infusion 

-- psilocybin, a hallucinogen, has a combined effect on serotonergic and glutamatergic receptors, with some preliminary evidence that it helps with depression in some with cancer as well as patients with treatment-resistant depression. And it seems to have a lower addiction potential and fewer toxic effects vs ketamine 

-- studies in patients and healthy volunteers have found that the intensity of the mystical-type experiences after psilocybin is associated with favorable anti-depressant outcomes, and that mystical/psychologically insightful experiences predict positive therapeutic effects. This was also found in the above study 

-- the effect size of psilocybin was about 2.5 times greater than that found by psychotherapy and more than four times greater than that found in psychopharmacological depression treatment 

 

Limitations: 

-- there was likely a strong selection bias in which patients wanted to go to Center for Psychedelic and Consciousness Research for depression treatment...  and get a hallucinogen

-- though this was a randomized controlled trial, it is problematic to compare outcomes in those randomized to immediate therapy with 11 hours of supportive therapy sessions and 2 infusions of psilocybin to those serving as a control who were still waiting to have these treatments  (ie, was it the psilocybin or the huge amounts of attention the group got)

-- also, this was a small study without much patient diversity, limiting our ability to generalize its results 

 

So, pretty interesting: 

-- these novel drugs (psilocybin and ketamine) do seem to have some efficacy in treating MDD, including treatment-resistant MDD. 

-- The preliminary data suggest that the pretty profound benefit appears to be in a large percentage of patients treated 

-- and, unlike SSRIs and the older antidepressants, the benefit seems to be really rapid (and it sometimes is a challenge to get very depressed patients to take their SSRIs regularly, especially since there is no likely benefit for 3 to 4 weeks, and perhaps months with the typically necessary up-titration of meds, changing the meds, or adding additional meds)

    -- of course, the other effective treatment for patients with drug-resistant depression that also has a rapid action is electroconvulsive therapy . with its own issues (memory, etc)

-- from this small study, it seems that the beneficial effects of psilocybin, though similar to ketamine, lasted at least four weeks, with 71% showing a clinically significant response at their four-week follow-up (much longer than ketamine)

-- but this needs to be assessed by larger studies in more diverse populations...

geoff

 

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