Psilocybin in Treatment-Resistant Major Depression

The Wayback Machine - http://web.archive.org/web/20260629215225/https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2846478 Close Original Investigation Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial Efficacy and Safety of Psilocybin in Treatment-Resistant Major DepressionVisual Abstract.Figure 1. CONSORT Flow DiagramIMP indicates investigational medicinal product; SAE, severe adverse event.aThe number of initial contacts is the total number of people expressing interest at both trial centers. Because recruitment was conducted autonomously at both trial centers without exchange of personal information between centers, people who contacted both trial centers are potentially counted twice.bPrescreening consisted of a multistep process, starting with (1) an initial email contact, through which first relevant data on the inclusion and exclusion criteria were collected and (2) a prescreening call via video or phone. Individuals who did not report back after initial contact or were only prescreened in terms of data provided via email are counted as prescreened.cPatients were randomized to 4 trial arms determining their dosing scheme for the first and second IMP dose from the beginning. Both trial centers randomized 72 participants in the trial.dMajor time deviations in visit scheduling were regarded as an intercurrent event impacting the interpretation of the clinical outcome of interest when the time deviation was more than 3 weeks. Two of those 3 participants still underwent the whole trial/received both IMP administrations.eWhile receiving treatment refers to the estimand strategy of while-on-treatment according to the ICH E9 harmonized guideline on statistical principles for clinical trials (ICH E9(R1)).fAll randomized patients are included in the safety analysis set. Of those 144 patients, 143 received at least 1 IMP administration (1 person in the arm receiving psilocybin, 25 mg, was excluded due to high blood pressure the morning of the first dose).Figure 2. Line Graph Depicting Mean Change From Baseline on the Hamilton Depression Rating Scale (HAMD17) Total ScoreDosings occurred at week 0 (dose 1) and week 6 (dose 2) after assessment of the primary end point, indicated by the dashed vertical lines.

Total scores on the HAMD17 range from 0 to 52 with higher scores indicating more severe depressive symptoms. Bars represent 95% CIs. At week 6, the left number refers to the number of participants at assessment of the primary end point, and the right number refers to the number of participants who received the second investigational medicinal product (IMP) administration. Provided model statistics are based on a mixed-effects linear regression model for treatment phase 1 with the HAMD17 total score as outcomes, including treatment (nicotinamide vs psilocybin, 5 mg vs 25 mg), time (baseline, week 1, week 6), treatment × time interactions, and center as a covariate (fixed effects) and participant-specific intercepts (random effects). Reported P values are nominal uncorrected P values at a 1-sided α level of .03.aIn the nicotinamide group, in total 44 participants received a second IMP administration, 2 with major time deviations as an intercurrent event (and, therefore, not included in the while-receiving-treatment population for the second treatment phase). Table 1. Demographic and Clinical Characteristics at Trial Entry and Baseline by Treatment Group at Primary End PointaCharacteristicNicotinamide + psilocybin, 25 mg (n = 48)Psilocybin, 5 mg + psilocybin, 25 mg (n = 48)Psilocybin, 25 mg + psilocybin, 25 mg or 5 mg (n = 48)Overall (N = 144)Age, mean (SD), y42.63 (10.86)41.77 (11.25)43.42 (10.55)42.60 (10.83)Age, median (range), y40 (27-62)39 (25-63)44 (26-64)41 (25-64)Sex, No. (%)

Female20 (42)18 (38)21 (44)59 (41) Male28 (58)30 (62)27 (56)85 (59)Race, No. (%) Asian001 (2)1 (0.7) Black0000 Multiracial01 (2)1 (2)2 (1.4) White48 (100)47 (98)46 (96)141 (98)Level of education, No. (%) Lower than high school3 (6)3 (6)1 (2)7 (5) High school16 (33)10 (21)8 (17)34 (24) Professional degree6 (13)7 (15)7 (15)20 (14) Graduate10 (21)11 (23)11 (23)32 (22) Postgraduate13 (27)17 (35)21 (44)51 (35)IQ (WST)b Mean (SD)109.28 (9.06)111.28 (8.37)115.13 (9.01)111.92 (9.09) Median (range)107 (95-139)110 (90-129)114 (93-133)110 (90-139)Body mass indexb,c Mean (SD)25.48 (4.62)23.22 (3.07)24.99 (4.61)24.58 (4.26) Median (range)25.13 (17.99-34.58)22.82 (17.63-31.41)25.20 (17.93-38.53)24.31 (17.63-38.53)Psychedelic naive, No. (%)

41 (85)41 (85)46 (96)128 (89)Psychiatric historyDuration since first MDD diagnosis, y Mean (SD)13.45 (9.47)14.32 (10.38)13.79 (9.26)13.86 (9.65) Median (range)10.59 (1.16-36.47)12.30 (1.25-48.73)12.52 (2.05-40.77)12.05 (1.16-48.73)No. of MDD episodes Mean (SD)6.03 (8.02)5.21 (6.57)7.39 (11.56)6.25 (9.04) Median (range)3 (1-40)3 (1-30)3.5 (1-50)3 (1-50)No. of previous psychiatric hospitalizations Mean (SD)2.17 (2.70)2.27 (2.10)1.98 (1.88)2.14 (2.24) Median (range)1 (0-16)2 (0-8)2 (0-8)2 (0-16)No. of previous antidepressant agents tried (lifetime) Mean (SD)5.38 (2.97)6.04 (3.27)4.88 (2.06)5.43 (2.83) Median (range)5 (2-16)5 (2-19)4 (2-11)5 (2-19)No.

of augmentative agents tried (lifetime) Mean (SD)1.25 (1.66)0.92 (1.66)1.31 (1.98)1.16 (1.77) Median (range)1 (0-8)0 (0-9)1 (0-11)1 (0-11)Withdrawn from antidepressant medication at trial entry, No. (%)d17 (35)21 (44)25 (52)63 (44)Withdrawn from any psychotropic medication at trial entry, No. (%)d19 (40)23 (48)28 (58)70 (49)Any current psychiatric comorbidity, No. (%)e37 (77)37 (77)38 (79)112 (78)Depression severity at baselineHAMD17 total score Mean (SD)22.06 (3.59)22.40 (4.85)21.83 (5.10)22.10 (4.53) Median (range)22 (15-30)21 (14-34)21 (11-33)21 (11-34) Mild: 8-16, No. (%)f2 (4)3 (6)7 (15)12 (8) Moderate: 17-24, No. (%)33 (69)30 (63)28 (58)91 (63) Severe: ≥25, No. (%)

13 (27)15 (31)13 (27)41 (28)BDI-IIg Mean (SD)33.60 (9.77)33.33 (8.73)32.60 (9.21)33.18 (9.19) Median (range)32.5 (11-55)32.5 (17-52)34.0 (15-58)33 (11-58) Minimal to mild: 11-19, No. (%)3 (6)2 (4)4 (8)9 (6) Moderate: 20-28, No. (%)10 (21)14 (29)13 (27)37 (26) Severe: ≥29, No. (%)35 (73)32 (67)31 (65)98 (68)CGI severity Mean (SD)5.98 (0.56)5.83 (0.66)6.06 (0.67)5.96 (0.64) Median (range)6 (5-7)6 (5-7)6 (5-8)6 (5-8) Moderately, No. (%)8 (17)15 (31)8 (17)31 (22) Markedly, No. (%)33 (69)26 (54)30 (63)89 (62) Severely to extremely severe, No. (%)

7 (15)7 (15)10 (21)24 (17)GAF Mean (SD)50.65 (7.71)51.38 (7.72)50.75 (8.04)50.92 (7.78) Median (range)55 (30-66)55 (35-65)55 (31-65)55 (30-66)Suicidality at trial entry (CSSRS)hSuicidal ideation in the past 6 mo, No. (%) Wish to be dead37 (77)35 (73)33 (69)105 (73) Nonspecific active suicidal thoughts21 (44)20 (42)20 (42)61 (42) Active suicidal ideation with any method without intent to act15 (31)10 (21)13 (27)38 (26) Active suicidal ideation with some intent to act, without specific plan2 (4)1 (2)2 (4)5 (3) Active suicidal ideation with specific plan and intent01 (2)2 (4)3 (2)Suicidal behaviors, No. (%)i Suicidal behaviors (lifetime)12 (25)6 (13)12 (25)30 (21) Suicidal behaviors (past year)1 (2)1 (2)3 (6)5 (3)Table 2. Primary and Secondary Efficacy Results of the Hamilton Depression Rating Scale (HAMD17) and Beck Depression Inventory II (BDI-II) (While-Receiving-Treatment Population) Treatment Phase IaEnd points: treatment phase 1Psilocybin, 25 mgPsilocybin, 5 mgNicotinamideHAMD17, No.47b48b47bPrimary end point Response at week 6 No./total No.

of participants (%)8/47 (17.0)6/48 (12.5)5/47 (10.6) Odds ratio vs nicotinamide (95% CI)1.73 (0.53 to 6.23); P = .19c1.14 (0.31 to 4.29)NA Odds ratio vs 5 mg (95% CI)1.52 (0.47 to 4.85); P = .24dNANASecondary end points Response at week 1 No./total No. of participants (%)16/47 (34.0)5/48 (10.4)3/47 (6.4) Odds ratio vs nicotinamide (95% CI)7.60 (2.29 to 34.75)1.68 (0.39 to 8.63)NA Odds ratio vs 5 mg (95% CI)4.51 (1.49 to 13.69)NANATotal score at week 6, mean (SD)15.9 (6.58)18.9 (7.04)20.4 (6.01)Change from baseline at week 6 (SD)6.06 (7.93)3.46 (5.82)1.51 (5.36) Estimated average change from baseline at week 6 (95% CI)−3.68 (−4.66 to −2.70) Estimated difference at week 6 vs nicotinamide (95% CI)−4.60 (−7.01 to −2.18); P <.001d−1.50 (−3.91 to 0.90)NA

Estimated difference at week 6 vs 5 mg (95% CI)−3.09 (−5.50 to −0.69); P = .02dNANATotal score at week 1, mean (SD)14.8 (7.01)18.6 (7.12)19.7 (5.18)Change from baseline at week 1, mean (SD)7.15 (7.76)3.81 (6.02)2.30 (4.24) Estimated average change from baseline at week 1 (95% CI)−4.42 (−5.40 to −3.44) Estimated difference at week 1 vs nicotinamide (95% CI)−4.89 (−7.31 to −2.48)−1.07 (−3.47 to 1.34)NA Estimated difference at week 1 vs 5 mg (95% CI)−3.83 (−6.23 to −1.42)NANARemission at week 1, No./total No. (%)7/47 (14.9)4/48 (8.3)1/47 (2.1)Remission at week 6, No./total No. (%)5/47 (10.6)0/48 (0)1/47 (2.1)BDI-II, No.47b48b47bResponse at week 6 No./total No. of participants (%)11/47 (23.4)3/48 (6.3)5/47 (10.6) Odds ratio vs nicotinamide (95% CI)2.64 (0.87 to 9.05); P = .049d0.57 (0.11 to 2.48)NA Odds ratio vs 5 mg (95% CI)4.61 (1.19 to 17.83); P = .01dNANAResponse at week 1 No./total No.

of participants (%)13/47 (27.7)9/48 (18.8)4/47 (8.5) Odds ratio vs nicotinamide (95% CI)4.29 (1.36 to 16.46)2.49 (0.74 to 9.86)NA Odds ratio vs 5 mg (95% CI)1.72 (0.65 to 4.58)NANAResponse at day 1 No./total No. of participants (%)18/47 (38.3)11/48 (22.9)5/47 (10.6) Odds ratio vs nicotinamide (95% CI)5.13 (1.76 to 17.47)2.64 (0.85 to 9.31)NA Odds ratio vs 5 mg (95% CI)1.94 (0.77 to 4.89)NANATotal score at week 6 (SD)24.7 (11.3)29.6 (11.4)32.0 (11.6)Change from baseline at week 6 (SD)8.02 (12.2)3.36 (8.02)1.40 (9.66) Estimated average change from baseline week 6 (95% CI)−4.22 (−5.69 to −2.75) Estimated difference at week 6 vs nicotinamide (95% CI)−7.21 (−11.86 to −2.56); P <.001d−2.05 (−6.67 to 2.58)NA Estimated difference at week

6 vs 5 mg (95% CI)−5.16 (−9.79 to −0.52); P = .007dNANATotal score at week 1, mean (SD)23.5 (12.6)27.6 (12.7)30.1 (11.9)Change from baseline at week 1, mean (SD)9.27 (10.9)5.50 (9.75)3.44 (9.16) Estimated average change from baseline at week 1 (95% CI)−6.10 (−7.59 to −4.62) Estimated difference at week 1 vs nicotinamide (95% CI)−6.92 (−11.61 to −2.23)−2.36 (−7.01 to 2.30)NA Estimated difference at week 1 vs 5 mg (95% CI)−4.56 (−9.23 to 0.11)NANATotal score at day 1, mean (SD)21.2 (12.9)24.7 (12.0)27.4 (12.1)Change from baseline at day 1, mean (SD)11.6 (9.09)8.64 (8.31)6.09 (8.69) Estimated average change from baseline at day 1 (95% CI)−8.94 (−10.42 to −7.46) Estimated difference at day 1 vs nicotinamide (95% CI)−5.84 (−10.51 to −1.17)−2.47 (−7.15 to 2.20)NA Estimated difference at day 1 vs 5 mg (95% CI)−3.37 (−8.02 to 1.28)NANARemission at day 1, No./total No. (%)