Amanda Downey, MD

🚨🍄 Major new preprint alert 🍄🚨 I think these will be important results. They are not going make me popular with my #psychedelic in-group, please do not shoot the messenger! The premise of this pre-registered meta analysis (osf.io/preprints/psya…) is that it is biased to compare open-label trials to blind trials, it is only fair to compare open-label trials to other open-label trials. In the first case the open-label trials would gain an unfair advantage by benefitting from effects related to knowing the treatment. Therefore, we compared the efficacy of psychedelic-assisted therapy (PAT), which is open-label regardless of formal blinding to open-label traditional antidepressants (tAD; such as SSRIs/SNRIs where binded trials are very close to be truly blind) for the treatment of major depression. We tested 3 prior hypothesis (MCID: minimum clinically important difference, which we set to be 3-points on Hamilton depression scale; differences smaller than this are clinically meaningless): 1. At the primary endpoint, the estimated mean difference between PAT and open-label tAD will exceed the MCID, favoring PAT. 2. At the primary endpoint, the estimated mean difference between blinded and open-label tAD trials will exceed the MCID, favoring open-label administration. 3. At the primary endpoint, the estimated mean difference between blinded and open-label PAT trials will not exceed the MCID. In contrast with our prior hypothesis, we did not find PAT to be more effective than open-label tADs (H1). Not only was the difference not clinically meaningful, but practically there was no difference at all (~0.3 HAMD units). This finding means that tAD administered knowingly to patients, which is the case in real-life medical practice, is as effective as PAT. This result was robust across variations in study selection, including when we removed PAT trials on treatment-resistant depression. The improvement from baseline to endpoint was ~12 HAMD points for both treatments. We also assessed the impact of blinding in both PAT and tAD trials. We found that for tAD (H2), but not for PAT (H3), open label is associated with better outcomes than blinded treatment. However, even in the case of tAD, the difference was much lower than the MCID. How come hypothesis 1 failed, i.e. that PAT is no ore effective than open-label tADs, given that tAD trials are famous for small drug-placebo difference (~2.4 HAMD units), while PAT trials reported large effects (~7.3 large effects)? Well, there are two major factors: 1. As we show, open-label tAD is approximately ~1.2 HAMD units more effective than blinded treatment (H2). This effect can be interpreted as the influence of knowing one’s treatment assignment, such as positive expectancy. 2. A recent meta-analysis of depression trials found that relative to tAD trials, the placebo response is 4.0 HAMD points lower in psychedelic trials (Hsu et al., 2024). This suppressed placebo response leads to an inflated between-arm difference, as the treatment arm is measured against a lower floor. The sum of these two effects is 1.2 + 4.0 = 5.2 HAMD units which equals the difference of the reported between-arm effects (7.3 - 2.4 ~ 5), explaining why hypothesis 1 failed. The suppressed placebo response in PAT trials is likely attributable to the ‘know-cebo’ effect, i.e. the disappointment when patients realize they are in the control group. In PAT trials, this placebo suppression accounts for 4.0 / 7.3 ~ 55% of the total between-arm effect. In other words, ~55% of PAT’s between-arm effect is not explained by improvement in the treatment arm, but rather by the lack of improvement in the placebo arm. In summary, we found that for the treatment of depression, PAT is no more effective than open-label SSRIs/SNRIs. Our results for psychedelics are twofold: PAT demonstrated a robust and large therapeutic effects (~12 HAMD units), which justifies optimism. On the other hand, PAT’s lack of superiority compared to SSRIs/SNRIs under equal-unblinding conditions highlights the influence of blinding integrity and presents a sobering reality check for psychedelic medicine. In collaboration with @QuantPsychiatry and Hannah Barnett 🙏🫂 👆should be of interest to @MattBurkeMD @igoreckert @bita137 @Brainclinics @bruce_lambert @thelablab @IoanaA_Cristea @GregFonzo @MFPL6 @fredemag @n_sepeda @chchatham @LGHemkens @HolBjo @NaudetFlorian @NathanHuneke @RecoveryDoctor @iainjordan @GlynLewis9 @HengartnerMP @shayla__love @f_hieronymus @And_Cipriani @FlamelingJop @JD_Rosenblat @RickZeifman @AVoineskos @LukeJelen @TehseenNoorani @a_lisinski @PloederlM @ElliotMarseille @KingFranklinIV @JulesEvans11 @EikoFried @ExistWell @singletonion @_fernando_rosas @vincepsy @hartogsohn @MichielElk @JacobSAday @BWe1ss @sdpnayak @Colloca_Luana @JeremyHowick @mattbagg @TheBorisLab @BenColagiuri

📢 Exciting news! The AED Medical Care Standards Committee has just released "The AED Guide to Selecting Pharmacologic Treatments for Patients with #EatingDisorders." Want to read more? aedweb.org/resources/publ… #MedicalCare #Pharmacology #HealthGuidelines