Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-Responders with Treatment-Resistant Depression (ASCERTAIN-TRD) PDF

Molecular Psychiatry www.nature.com/mp ARTICLE OPEN Comparative effectiveness research trial for antidepressant...

Molecular Psychiatry www.nature.com/mp ARTICLE OPEN Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial ✉ George I. Papakostas1 , Madhukar H. Trivedi 2, Richard C. Shelton 3, Dan V. Iosifescu4, Michael E. Thase5, Manish K. Jha 2, 6 Sanjay J. Mathew , Charles DeBattista7, Mehmet E. Dokucu8, Olga Brawman-Mintzer9, Glenn W. Currier10, William Vaughn McCall 11, Mandana Modirrousta12, Matthew Macaluso3,13, Alexander Bystritsky14, Fidel Vila Rodriguez 15, Erik B. Nelson16, Albert S. Yeung1, Anna Feeney1, Leslie C. MacGregor1, Thomas Carmody2 and Maurizio Fava1 © The Author(s) 2024 Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine 1234567890();,: XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = −17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = −14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = −13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = −37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = −42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = −34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression. Trial registration: ClinicalTrials.gov, NCT02977299 Molecular Psychiatry (2024) 29:2287–2295; https://doi.org/10.1038/s41380-024-02468-x INTRODUCTION controlled studies of TRD patients: switching to an antidepressant MDD is a serious, debilitating, life-shortening illness that affects of a different class and augmenting the antidepressant with many persons of all ages and backgrounds. A particularly critical atypical antipsychotics. Despite both augmentation with atypical decision in everyday practice is choosing what to do next when antipsychotic agents and switching to a different antidepressant patients with MDD present after antidepressant treatments have class having well-established efficacy, strikingly, there has never failed to produce a clinical response, and a large evidence gap been a direct comparison of them for TRD. exists with respect to this common clinical scenario [1–8]. There To date, aside from the atypical antipsychotic agents, electro- are many augmentation and switch options to choose from for convulsive therapy (ECT) and esketamine, repetitive transcranial patients with TRD, each of these with varying degrees of evidence magnetic stimulation (rTMS) represents the only other modality [9, 10]. As discussed in a review on the integrative management of approved for use in MDD patients who have not responded to TRD , the authors conclude that two pharmacotherapeutic antidepressant therapy [12, 13]. rTMS has been extensively studied options have accrued the most evidence for efficacy from well- for MDD (29 randomized clinical trials (RCTs) ), as well as in 1 Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 2University of Texas Southwestern Medical Center, Dallas, TX, USA. 3University of Alabama at Birmingham, Birmingham, AL, USA. 4Nathan Kline Institute for Psychiatric Research and New York University School of Medicine, New York, NY, USA. 5Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA. 6Baylor College of Medicine, Houston, TX, USA. 7Stanford University School of Medicine, Stanford, CA, USA. 8 Dartmouth Geisel School of Medicine, Lebanon, NH, USA. 9Medical University of South Carolina, Charleston, SC, USA. 10Morsani College of Medicine, University of South Florida, Tampa, FL, USA. 11Medical College of Georgia, Augusta, GA, USA. 12University of Manitoba, Winnipeg, MB, Canada. 13University of Kansas School of Medicine, Wichita, KS, USA. 14 Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, LA, USA. 15University of British Columbia, Vancouver, BC, Canada. 16University of Cincinnati Academic Health Center, Cincinnati, OH, USA. ✉email: [email protected] Received: 6 September 2023 Revised: 23 January 2024 Accepted: 29 January 2024 Published online: 7 March 2024  G.I. Papakostas et al. 2288 TRD specifically (18 RCTs ), including as augmentation, with an treatment arms is included in the supplementary material (Supplementary evidence-base greater than for almost any other intervention for Methods 1b). Serious adverse events were defined as per the FDA (https:// TRD save for the atypical antipsychotic agents (21 RCTs ). The www.fda.gov/safety/reporting-serious-problems-fda/what-serious-adverse- results of a meta-analysis showed rTMS to be efficacious in MDD event). and in TRD, with equivalent efficacy when delivered as mono- therapy or augmentation. There is also accumulating Statistical analysis evidence for the durability of the antidepressant effect of rTMS The study primary outcome was defined as the change in MADRS scores in clinical practice. (MGH CTNI-administered). All efficacy analyses were conducted on the In summary, TRD remains a significant challenge for clinicians modified intent-to-treat dataset (MITT), where all patients with any post- baseline data were included. All tests were two-sided. Because two and patients alike, and further research is needed to help improve different augmentation arms were each compared with switching, we used both the standard of care and the outcome for patients with TRD. a Bonferroni corrected alpha of 0.025, and no interim analyses were A critical evidence gap exists with respect to whether pharmaco- planned or conducted. Since the objective of the original request for logical or non-pharmacological augmentation is superior to proposals by PCORI was to compare augmentation versus switching, no antidepressant switch, or vice-versa. An additional evidence gap formal planning for the comparison between the augmentation groups exists with regards to our limited knowledge as to which US Food was made, therefore justifying an alpha of 0.025 rather than 0.016. and Drug Administration (FDA)-approved augmentation versus Analyses were conducted using SAS V9.4. For the MADRS analyses, mixed- switch strategies to employ. Our proposal was designed to effects models with repeated measures (MMRM) were conducted with address these evidence gaps by comparing two FDA-approved treatment group (augment versus switch) as the between-subjects factor, treatments for patients with TRD, namely augmentation with time as the within-subjects factor, and a group by time interaction term. The baseline measurement of the MADRS was included as a covariate and atypical antipsychotics versus augmentation with repetitive not as a predictor. Site and site by treatment group interactions were transcranial magnetic stimulation (rTMS), with one of the examined and retained in the model only if a significant improvement in commonly used strategies for TRD: switching to the serotonin- model fit (based on the Schwarz’s Bayesian Criterion) resulted. The linearity norepinephrine reuptake inhibitors (SNRI) venlafaxine extended assumption was examined by a change-over-time graph by subject and by release (XR) or duloxetine. testing if the model goodness of fit could be significantly increased by inclusion of a time-squared term or the transformation ln (week+1). The assumptions of normality and homogeneity of variance and the presence METHODS of outliers were examined by reference to the distribution of model This was a multi-site, eight-week, randomized rater-blinded trial comparing residuals. Determination of a significant treatment effect was based on the three treatment arms for MDD patients with TRD who are currently on model treatment group effect or treatment group by time interaction. ongoing, stable and adequate antidepressant therapy (ADT): a) aripiprazole The self-rated SDQ was analyzed in an identical manner to the MADRS. SAS augmentation, b) rTMS augmentation, and c) switching to venlafaxine XR Proc Mixed was used to perform the analyses. Sensitivity analyses were (or duloxetine for patients who had received venlafaxine during their performed for the MADRS to examine the effect of excluding participants current major depressive episode) (clinicaltrials/gov: NCT02977299). This randomized to venlafaxine/duloxetine with rTMS randomizations were trial was conducted according to the U.S. FDA guidelines and the paused due to COVID. Declaration of Helsinki. IRB-approved written informed consent was Under the MMRM approach, assuming a small-to-medium effect size of obtained from all patients before any protocol-specified procedures were f = 0.12 (based on Cohen’s f for analysis of variance where f = 0.10 is a carried out (IRB approval was site specific). Subjects were enrolled across small effect ) and a total of seven remote assessment observations 17 sites in the United States and Canada, where treatment assignment was (baseline, and visits 1–6), each treatment arm will require N = 170, for a performed and patients followed clinically. total sample size of 510 patients powered at 80%. Since randomized patients with no post-baseline severity measurements were not included in the analysis, we assumed a loss of 20%. Therefore, the sample size was Key inclusion and exclusion criteria increased by 20% to 639 with the goal of obtaining 510 randomized A subject was considered to be eligible for inclusion only if all inclusion subjects with one post-baseline assessment. criteria were met. Subjects were a) women and men ages 18–80, b) with Logistic regression models were fit with MADRS remission (an exit MDD, of at least 12 weeks duration, c) who had a Montgomery-Asberg MADRS of 10 or less) and response (50% or more baseline to exit Depression Rating Scale (MADRS ) score of at least 20 at screening and improvement) as the dependent variables, and terms for treatment group baseline, and d) who met criteria for TRD during the current major and baseline MADRS and as covariates along with site as a covariate if depressive episode, documented in the MGH Antidepressant Treatment needed. Rates and NNT were reported. NNT for a binary outcome for History Questionnaire (ATRQ). TRD was defined as being non- treatments A versus B represents the number of participants who must be responders during the current episode (less than 50% of symptom treated with A in order to have one more response/remission than if the improvement) to two or more depression treatment trials of adequate same number of participants were treated with B. dose and duration, as defined by the MGH ATRQ. In addition, included subjects had documented non-response to their current antidepressant. Patients found eligible during site screening were scheduled for a remote RESULTS assessment by clinicians at MGH CTNI for confirmation of study eligibility. Additional detail regarding inclusion and exclusion criteria is included in A total of 278 eligible participants were randomized to treatment the Supplementary Material (Supplementary Methods 1a). during the course of the trial. This was far less than the projected 639. Main reasons for this included a delay in study startup, slow recruitment (aripiprazole and venlafaxine XR/duloxetine were Randomized phase chosen due to their popularity so as to render study results more At baseline, MGH CTNI as well as site clinicians administered the MADRS, and eligible patients were randomized 1:1:1 in an open-label fashion to generalizable, but this also meant that many potential subjects one of the three study interventions. Randomization was performed within had already received treatment with these two agents during their site with a computer number generating sequence conducted at the study current depressive episode), as well as the COVID pandemic. Of data coordinating center, and using randomly varied blocks of 3, 6, or 9. these 278 subjects, 260 (95.2%) had at least one post-baseline Post-baseline visits occurred at weeks 1, 2, 3, 4, 6 and 8. At the beginning MADRS score and were eligible for the MITT analysis of the of each post-baseline visit, MADRS was performed by an MGH CTNI rater primary outcome. Participants were enrolled from 07/13/2017 to blinded to treatment assignment, and the score was then provided to the 12/22/2021, with the study allowed to continue for the initially site clinician who would record side-effects and adjust medications as planned duration (no early stop). Altogether, 235 (90.3%) of needed per the guidelines below. Site clinicians did not complete the 260 subjects in the MITT analysis completed the 8-week randomized MADRS post-baseline as they were unblinded as to treatment assignment. The self-rated symptoms of depression questionnaire (SDQ ) was trial. Disposition of study participants is shown in Fig. 1, and baseline administered at each site visit. Additional detail regarding each of the clinical and demographic factors of randomized participants Molecular Psychiatry (2024) 29:2287 – 2295  G.I. Papakostas et al. 2289 shown in Table 1. Baseline antidepressants by group are shown in continue enrolling in the medication treatment arms but not the Supplementary Table 1. See Supplementary Material (Supplemen- rTMS arm (the study had been halted from 3/16/2020 due to tary Tables 2–6) for reports of adverse events and serious adverse COVID19). The rationale for this was to minimize the chances of events according to the treatment groups. There were no drug or COVID spreading to patients and staff, since rTMS required many rTMS-related serious adverse events during the course of the trial. in-person visits (please see rTMS methods section). All three arms Maximum doses were as follows: aripiprazole mean (SD) 9.0 (4.1) of the study were re-initiated 3/1/2021. An analysis comparing mg, median 10 mg, minimum 2 mg, maximum 20 mg, venlafaxine rTMS to venlafaxine on the study primary outcome excluding mean (SD) 190.7 (66.7) mg, median 225 mg, minimum 38 mg, venlafaxine subjects randomized during this period is reported in maximum 375 mg, duloxetine mean (SD) 97.5 (25.4) mg, median the supplemental section of this manuscript (Supplementary 105 mg, minimum 60 mg, maximum 120 mg. Only one subject Table 7), and is in line with main results. required treatment with benztropine for aripiprazole-related For all MMRM analyses, examination of model residuals akathisia. indicated the residuals were normally distributed and no One significant change in the protocol had to occur due to the observations should be classified as outliers. For all models the COVID pandemic. Specifically, on 8/17/2020, an amendment spatial powers correlated errors covariance structure produced the previously approved by the sponsor was put into effect to best fitting model. Screened (n=537) Failed Screening Visit (N=251) Withdrew Consent (n= 19) Lost to Follow-up (N=22) Inclusion/Exclusion Criteria (N=206)* Other (N=1) Reason not Recorded (N=3) Passed Screening Visit (N=286) Failed Baseline Visit (N=8) Withdrew Consent (N=1) Inclusion/Exclusion Criteria (N=5) No post-baseline MADRS (N=18) Reason not Recorded (N=2) Randomized (n=278) Aripiprazole (N=1) rTMS (N=14) Venlafaxine/Duloxene (N=3) MITT (n=260) Aripiprazole (N=92) rTMS (N=70) Venlafaxine/Duloxene (N=98, 74 Venlafaxine, 24 Duloxene) Disconnued (n=9) Disconnued (N=9) Disconnued (n=7) AEs (N=1) Noncompliance (N=1) AEs (N=2) Noncompliance (N=2) Lost to Follow-up (N=3) Lost to Follow-up (N=2) Lost to Follow-up (N=1) Withdrew Consent (N=3) Withdrew Consent (N=4) Withdrew Consent (N=4) Terminated by Sponsor Terminated by Sponsor (N=1) Other (N=1) (N=2) Other (N=1) Completed (n=83) Completed (N=61) Completed (n=91) Fig. 1 CONSORT flow diagram. AE Adverse events, MITT Modified intent-to-treat, MADRS Montgomery Asberg Depression Rating Scale, rTMS repetitive transcranial magnetic stimulation. *Five most frequently cited reasons for not meeting Inclusion/Exclusion Criteria: Criteria for treatment resistant depression not met during current episode (n = 54, 26.2%) Did not pass CNTI remote assessment (n = 45, 21.8%). Criteria for current antidepressant not met (n = 30, 14.6%). Current episode less than 12 weeks duration (n = 21, 10.2%). History of bipolar disorder or psychosis (n = 20, 9.7%). Molecular Psychiatry (2024) 29:2287 – 2295  G.I. Papakostas et al. 2290 Table 1. Baseline demographic and clinical factors of randomized participants. Variable All N (%) Aripiprazole augmentation N (%) rTMS augmentation N (%) Venlafaxine XR/Duloxetine Switch N (%) Female 196 (70.5) 69 (74.1) 58 (69.0) 69 (68.3) White 203 (74.3) 66 (72.5) 65 (80.2) 72 (71.2) African 41 (15.0) 15 (16.4) 7 (8.6) 19 (18.8) American Race/Other 29 (10.6) 10 (10.9) 9 (11.1) 10 (9.9) Hispanic ethnicity 29 (10.5) 9 (9.6) 6 (7.1) 14 (14.2) Variable All mean (SD) Aripiprazole augmentation mean TMS augmentation mean Venlafaxine XR/Duloxetine (SD) (SD) switch mean (SD) Age (years) 45.6 (15.3) 47.0 (16.1) 43.8 (14.5) 45.6 (15.3) Number of failed 2.85 (1.0) 2.94 (1.1) 2.82 (1.0) 2.80 (0.9) trials Median = 3 Median = 3 Median = 2.5 Median = 3 25th 25th 25th 25th percentile = 2 percentile = 2 percentile = 2 percentile = 2 75th 75th 75th 75th percentile = 3 percentile = 3 percentile = 3 percentile = 3 Minimum = 2 Minimum = 2 Minimum = 2 Minimum = 2 Maximum = 8 Maximum = 8 Maximum = 6 Maximum = 6 MADRS total score 32.6 (6.3) 33.1 (6.0) 33.1 (6.0) 33.0 (6.0) Median = 32 Median = 33 Median = 33 Median = 32 25th 25th percentile = 29 25th percentile = 29 25th percentile = 28 percentile = 28 75th percentile = 37 75th percentile = 38 75th percentile = 38 75th Minimum = 20 Minimum = 21 Minimum = 21 percentile = 37 Maximum = 46 Maximum = 45 Maximum = 46 Minimum = 20 Maximum = 46 SDQ total score 156.1 (25.4) 155.2 (22.8) 155.9 (26.1) 156.9 (27.1) Median = 154 Median = 155 Median = 155 Median = 153 25th 25th 25th 25th percentile = 138 percentile = 138 percentile = 138 percentile = 140 75th 75th 75th 75th percentile = 174 percentile = 169 percentile = 175 percentile = 177 Minimum = 95 Minimum = 113 Minimum = 95 Minimum = 96 Maximum = 223 Maximum = 205 Maximum = 222 Maximum = 223 MADRS Montgomery Asberg Depression Rating Scale, rTMS Repetitive Transcranial Magnetic Stimulation, SD standard deviation, SDQ Symptoms of Depression Questionnaire. Change in MADRS scores: aripiprazole augmentation versus slopes for MADRS scores for rTMS augmentation versus switching switch to venlafaxine XR/duloxetine to venlafaxine XR/duloxetine were −8.95 (1.1) versus −6.26 (0.7). A A plot of change over time for each participant showed the graphic depiction of the outcome is shown in Fig. 2. change was non-linear. Examination of the goodness of fit statistic indicated that use of the log(time+1) transformation produced Change in SDQ scores: Aripiprazole augmentation versus the best fitting model. Neither the treatment group main effect switch to venlafaxine XR/duloxetine (p = 0.069) nor week by treatment group interaction effect A plot of change over time for each participant showed a (p = 0.708) were significant. Model estimated mean (SE) change deviation from linearity. Examination of the goodness of fit from baseline to week 8 in MADRS scores for aripiprazole statistic indicated that use of log(time+1) transformation pro- augmentation versus switching to venlafaxine XR/duloxetine were duced the best fitting model. The treatment group main effect −14.9 (1.1) versus −13.18 (1.1). Mean (SE) slopes for MADRS scores was significant at the pre-specified level of alpha=0.025 for aripiprazole augmentation versus switching to venlafaxine XR/ (p = 0.003), while the week by treatment group interaction effect duloxetine were −5.85 (1.1) versus −6.26 (0.8). A graphic was not significant (p = 0.172). Model estimated mean (SE) change depiction of the outcome is shown in Fig. 2. in SDQ scores for aripiprazole augmentation versus switching to venlafaxine XR/duloxetine were −37.79 (2.9) versus −32.88 (2.8). Change in MADRS scores: rTMS augmentation versus switch to Mean (SE) slopes for SDQ scores for aripiprazole augmentation venlafaxine XR/duloxetine versus switching to venlafaxine XR/duloxetine were −9.80 (3.1) A plot of change over time for each participant showed a non- versus −14.07 (2.2). A graphic depiction of the outcome is shown linear change. Examination of the goodness of fit statistic in Fig. 3. indicated that use of the log(time+1) transformation produced the best fitting model. The treatment group interaction effect was Change in SDQ scores: rTMS augmentation versus switch to not significant (p = 0.234), but the week by treatment group effect venlafaxine XR/duloxetine was significant at the pre-specified level of alpha=0.025 A plot of change over time for each participant showed a slight (p = 0.015). Model estimated mean (SE) level for MADRS scores deviation from linearity. Examination of the goodness of fit for rTMS augmentation versus switching to venlafaxine XR/ statistic indicated that use of time without transformation duloxetine were −17.39 (1.3) versus −13.22 (1.1). Mean (SE) produced the best fitting model. The treatment group main Molecular Psychiatry (2024) 29:2287 – 2295  G.I. Papakostas et al. 2291 Fig. 2 Model adjusted change in MADRS scores. MADRS Montgomery Asberg Depression Rating Scale, rTMS Repetitive Transcranial Magnetic Stimulation. Alpha = 0.025. Fig. 3 Model adjusted change in SDQ scores. SDQ Symptoms of Depression Questionnaire, rTMS Repetitive Transcranial Magnetic Stimulation. Alpha = 0.025. effect (p = 0.031) and the week by treatment group interaction DISCUSSION effect (p = 0.832) were not significant. Model estimated mean The present study is the first randomized effectiveness study to (SE) change in SDQ scores for rTMS augmentation versus compare augmentation versus switching in a general outpatient switching to venlafaxine XR/duloxetine were −42.96 (3.6) versus population with TRD. Results of our study show a greater −34.45 (3.0). Mean (SE) slopes for SDQ scores for rTMS reduction in depressive symptoms following rTMS augmentation augmentation versus switching to venlafaxine XR/duloxetine than switching to venlafaxine XR/duloxetine. The magnitude of were −3.07 (0.7) versus −2.93 (0.4). A graphic depiction of the the difference in efficacy expressed in mean MADRS reduction outcome is shown in Fig. 3. was 4.17 points. Although our study was not designed or powered to detect a statistically significant difference in response MADRS response and remission or remission rates between the two groups, the NNT for response For all logistic regression models, it was found that site effects did and remission was, approximately, 7 and 11 respectively. Taken not significantly improve the fit of the model and so were together, these results are informative for clinical practice in TRD, removed from the model leaving treatment group and baseline and support rTMS augmentation over switching for this patient MADRS as predictors. MADRS response (50% or greater reduction population. Future studies comparing rTMS augmentation with in symptoms from baseline to exit visit) and remission (total score other treatment strategies specifically for MDD patient popula- less than 10 at the exit visit) was not significantly different tions not included in our trial (i.e. adolescents, elderly) are between aripiprazole augmentation versus venlafaxine XR/dulox- warranted. Finally, it is worth noting emphasizing in the etine switch subjects (model estimated response rate = 0.381 and discussion that the superiority of adjunctive rTMS to an 0.358, number needed to treat (NNT) = 44, p = 0.743; model antidepressant switch in TRD patients contrasts with the estimated remission rate = 0.253 and 0.249, NNT = 250.0, comparatively more modest efficacy of rTMS monotherapy for p = 0.946, respectively). MADRS response and remission was not TRD as shown in the meta-analysis of 24 RCTs by Lam et al. significantly different at the pre-specified alpha = 0.025 level (pooled response of 25%, pooled remission of 9%). The present between rTMS augmentation versus venlafaxine XR/duloxetine findings are consistent with the literature suggesting a switch subjects (model estimated response rate = 0.522 and 0.358, larger effect with rTMS as adjunctive (rather than mono-) therapy NNT = 7, p = 0.038; model estimated remission rate = 0.342 and (e.g., as suggested by the meta-analysis of 7 RCTs as augmenta- 0.249, NNT = 11, p = 0.203, respectively). A graphic depiction of tion which found a pooled response rate of 46%, an OR of 5.12 these outcomes is shown in Fig. 4. and an SMD of 0.86. Molecular Psychiatry (2024) 29:2287 – 2295  G.I. Papakostas et al. 2292 Fig. 4 MADRS response and remission rates comparing different study arms. A MADRS response rates (%); B MADRS remission rates (%). MADRS Montgomery-Asberg Depression Rating Scale (MADRS), rTMS Repetitive Transcranial Magnetic Stimulation; y-axis = % response/ remission, x-axis = study arms. Our study was also the first to compare augmenting with an attribute more expectancy as compared with a new drug. Instead, we atypical antipsychotic agent versus switching to venlafaxine/dulox- chose to employ raters blinded to treatment assignment for etine in TRD. In contrast to the VA Augmentation and Switching the assessment of the study primary outcome measure. Second, Treatments for Improving Depression Outcomes (VAST-D) study we chose to limit drug treatment arms to a finite number of agents no statistically significant difference in efficacy between these two (aripiprazole, venlafaxine XR, duloxetine) as opposed to classes of treatments was found on the primary outcome measure (MADRS, agents. Whether our findings extend to other approved atypical p = 0.069). However, similar to VAST-D, aripiprazole augmentation antipsychotic agents (quetiapine, brexpiprazole, cariprazine) or was found superior to switching to venlafaxine XR/duloxetine on a antidepressants for MDD is a matter of speculation. The same patient-rated scale (SDQ). Therefore, it is quite possible that a argument can be made for ECT, ketamine, esketamine, or significant, treatment effect could have been detected on the “accelerated” protocols of rTMS which are gaining in popularity. MADRS, as was in the SDQ, if we had been able to enroll the 639 Third, whether our findings extend to specific sub-populations that participants indicated by the power analysis in ASCERTAIN (which were excluded in ASCERTAIN, such as adolescents or the elderly, involved a sample size just 16% of that of VAST-D). Differences in remains unknown. Future studies for this purpose are warranted. study design such as population (predominant male veteran-based Fourth, the number of participants in the rTMS arm is lower as versus general adult outpatient), disease stage (failure of at least one randomization to this arm was interrupted early in the COVID-19 antidepressant versus TRD), or switch agent (bupropion versus pandemic due to restrictions imposed on the in-person visits venlafaxine/duloxetine) may have also contributed to differences in necessary for this treatment arm. However, findings excluding study results. In light of the extensive literature focusing on the use of venlafaxine subjects randomized during this period remain statisti- aripiprazole augmentation in MDD, and advantage over switching on cally significant for rTMS. Furthermore, a greater number of patient-rated symptoms, our study lends further support regarding individuals in the rTMS arm did not have any post-baseline MADRS the usefulness of this strategy for TRD. and may be related to unwillingness in some subpopulations to In summary, despite the modest effect size favoring aripiprazole accept rTMS, which in turn may account for some differences in race augmentation over switching in ASCERTAIN, and given clinical and age distribution between the three groups. The limitation of the challenges and adverse outcomes associated with TRD, the sum of statistical method applied (which is standard in clinical trials in the findings of ASCERTAIN and VAST-D continue to support the field) is that differential early attrition can introduce bias. However, to importance of augmenting with atypical antipsychotics versus include these subjects would mean imputing data, and imputed data switching for these patients. Rates of response (18.5%–46.6%) and is not real data. Nevertheless, we concede that our results apply more remission (7.4%–36.8%) with aripiprazole augmentation in prior to subjects willing to commit to the requirements of rTMS. Finally, studies [25–29] are similar to those observed in this study (38.1% variations in treatment effect by site may be present but could not be and 25.3%, respectively). Similarly, the rates of response (35.8%) and adequately tested given the number of sites and the size of the study. remission (24.9%) with switch to venlafaxine XR/duloxetine in In conclusion, results of the current trial demonstrate the ASCERTAIN is similar to those observed in the level 2 of Sequenced superiority of rTMS augmentation over switching to venlafax- Treatment Alternatives to Relieve Depression , where individuals ine XR/duloxetine in TRD on clinician-rated symptoms of with MDD were switched to venlafaxine after inadequate improve- depression, with a moderate-to-large effect size. In addition, ment on treatment with citalopram (28.2% and 25.0%, respectively). similar to VAST-D, a statistically significant advantage was found Several limitations of our study are worth mentioning. First, this for aripiprazole augmentation versus switching on patient-rated was an open label trial where subjects were not blinded to treatment symptoms of depression. These findings are informative for assignment. Blinding to treatment assignment when comparing clinical practice in TRD and warrant future studies in select sub- augmentation versus switching is logistically very complicated, populations such as adolescents or the elderly. challenging and costly, since either matching drug-placebo pills must be created for multiple marketed antidepressants and dose levels or a lead-in with a single antidepressant must be employed DATA AVAILABILITY which can increase sample size requirements by as much as four-fold GIP and TC had full access to all the data in the study and takes responsibility for the (Salloum et al., 2020). The same limitation applies to rTMS, which integrity of the data and the accuracy of the data analysis. TC conducted and is was not blinded to the patient, and to which the patient might responsible for the data analysis. Molecular Psychiatry (2024) 29:2287 – 2295  G.I. Papakostas et al. 2293 REFERENCES 25. Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, et al. 1. Patkar AA, Pae CU. Atypical Antipsychotic Augmentation Strategies in the Con- The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive text of Guideline-based Care for the Treatment of Major Depressive Disorder. CNS Disorder: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. J Drugs. 2013;27:29–37. https://doi.org/10.1007/s40263-012-0031-0. Clin Psychiatry. 2007;68:6122. 2. Bschor T, Baethge C. No evidence for switching the antidepressant: systematic 26. Fava M, Mischoulon D, Iosifescu D, Witte J, Pencina M, Flynn M, et al. A Double- review and meta-analysis of RCTs of a common therapeutic strategy. Acta Psy- Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant chiatr Scand. 2010;121:174–9. https://doi.org/10.1111/j.1600-0447.2009.01458.x. Therapy among Depressed Outpatients with Inadequate Response to Prior 3. Connolly KR, Thase ME. If at First You Don’t Succeed. Drugs. 2011;71:43–64. Antidepressant Therapy (ADAPT-A Study). Psychother Psychosom. 2012;81:87–97. https://doi.org/10.2165/11587620-000000000-00000. https://doi.org/10.1159/000332050. 4. Rush AJ, Warden D, Wisniewski SR, Fava M, Trivedi MH, Gaynes BN, et al. STAR*D. 27. Berman RM, Fava M, Thase ME, Trivedi MH, Swanink R, McQuade RD, et al. Ari- CNS Drugs. 2009;23:627–47. https://doi.org/10.2165/00023210-200923080-00001. piprazole augmentation in major depressive disorder: a double-blind, placebo- 5. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of Antidepressants controlled study in patients with inadequate response to antidepressants. CNS With Atypical Antipsychotic Medications for Treatment-Resistant Major Depres- Spectr. 2009;14:197–206. https://doi.org/10.1017/s109285290002021. sive Disorder: A Meta-Analysis. J Clin Psychiatry. 2007;68:1677. 28. Lenze EJ, Mulsant BH, Blumberger DM, Karp JF, Newcomer JW, Anderson SJ, et al. 6. Souery D, Papakostas GI, Trivedi MH. Treatment-Resistant Depression. J Clin Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripi- Psychiatry. 2006;67:21622. prazole for treatment-resistant depression in late life: a randomized placebo- 7. Fava M. Management of Nonresponse and Intolerance: Switching Strategies. J controlled trial. Lancet Lond Engl. 2015;386:2404–12. https://doi.org/10.1016/ Clin Psychiatry. 2000;61:11095. S0140-6736(15)00308-6. 8. Nelson JC. Treatment of Antidepressant Nonresponders: Augmentation or 29. Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, et al. Switch? J Clin Psychiatry 1998;59:21357. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive 9. Papakostas GI. Managing Partial Response or Nonresponse: Switching, Aug- disorder: a second multicenter, randomized, double-blind, placebo-controlled mentation, and Combination Strategies for Major Depressive Disorder. J Clin study. J Clin Psychopharmacol. 2008;28:156–65. https://doi.org/10.1097/JCP. Psychiatry. 2009;70:11183. https://doi.org/10.4088/JCP.8133su1c.03. 0b013e31816774f9. 10. Papakostas GI, Ionescu DF. Towards new mechanisms: an update on therapeutics 30. Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, et al. for treatment-resistant major depressive disorder. Mol Psychiatry. 2015;20:1142–50. Bupropion-SR, Sertraline, or Venlafaxine-XR after Failure of SSRIs for Depression. https://doi.org/10.1038/mp.2015.92. N Engl J Med. 2006;354:1231–42. https://doi.org/10.1056/NEJMoa052963. 11. Carvalho AF, Berk M, Hyphantis TN, McIntyre RS. The Integrative Management of 31. Salloum NC, Fava M, Ball S, Papakostas GI. Success and efficiency of phase 2/3 Treatment-Resistant Depression: A Comprehensive Review and Perspectives. adjunctive trials for MDD funded by industry: a systematic review. Mol Psychiatry. Psychother Psychosom. 2014;83:70–88. https://doi.org/10.1159/000357500. 2020;25:1967–74. https://doi.org/10.1038/s41380-020-0646-3. 12. O’Reardon JP, Solvason HB, Janicak PG, Sampsom S, Isenberg KE, Nahas Z, et al. 32. Caulfield KA, Fleischmann HH, George MS, McTeague LM. A transdiagnostic Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment review of safety, efficacy, and parameter space in accelerated transcranial mag- of Major Depression: A Multisite Randomized Controlled Trial. Biol Psychiatry. netic stimulation. J Psychiatr Res. 2022;152:384–96. https://doi.org/10.1016/ 2007;62:1208–16. https://doi.org/10.1016/j.biopsych.2007.01.018. j.jpsychires.2022.06.038. 13. Levkovitz Y, Isserles M, Padberg F, Lisanby SH, Bystritsky A, Xia G, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a pro- spective multicenter randomized controlled trial. World Psychiatry. 2015;14:64–73. AUTHOR CONTRIBUTIONS https://doi.org/10.1002/wps.20199. The listed authors made contributions in each of these 4 areas: 1. Conception and 14. Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remission design or data analysis and interpretation. 2. Drafting of the manuscript or revision and drop-out rates following high-frequency repetitive transcranial magnetic for important intellectual content. 3. Approving the final version of the manuscript stimulation (rTMS) for treating major depression: a systematic review and meta- that is to be published. 4. Accountability for all aspects of the work and the ability to analysis of randomized, double-blind and sham-controlled trials. Psychol Med. identify the contributions of each coauthor and ensure the integrity of their 2014;44:225–39. https://doi.org/10.1017/S0033291713000512. contributions. 15. Brunoni AR, Fraguas R, Fregni F. Pharmacological and combined interventions for the acute depressive episode: focus on efficacy and tolerability. Ther Clin Risk Manag. 2009;5:897–910. https://doi.org/10.2147/TCRM.S5751. 16. Dunner DL, Aaronson ST, Sackeim HA, Janicak PG, Carpenter LL, Boyadjis T, et al. FUNDING A Multisite, Naturalistic, Observational Study of Transcranial Magnetic Stimulation This study was funded by PCORI under contract TRD-1511-33227. PCORI had for Patients With Pharmacoresistant Major Depressive Disorder: Durability of oversight but played no active role in the study (including design and conduct of the Benefit Over a 1-Year Follow-Up Period. J Clin Psychiatry. 2014;75:12379. https:// study; collection, management, analysis, and interpretation of the data; preparation, doi.org/10.4088/JCP.13m08977. review, or approval of the manuscript; and decision to submit the manuscript for 17. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to publication). change. Br J Psychiatry. 1979;134:382–9. https://doi.org/10.1192/bjp.134.4.382. 18. Chandler GM, Iosifescu DV, Pollack MH, Targum SD, Fava M. Validation of the mas- sachusetts general hospital Antidepressant Treatment History Questionnaire (ATRQ). COMPETING INTERESTS CNS Neurosci Ther. 2010;16:322–5. https://doi.org/10.1111/j.1755-5949.2009.00102.x. GIP has served as a consultant for Abbott Laboratories, Acadia Pharmaceuticals, Inc*, 19. Pedrelli P, Blais MA, Alpert JE, Shelton RC, Walker RSW, Fava M. Reliability and Alkermes, Inc, Almatica*, Alphasigma USA*, Inc, AstraZeneca PLC, Arrivo Bioventures- validity of the Symptoms of Depression Questionnaire (SDQ). CNS Spectr. Sirtsei Phamaceuticals, Avanir Pharmaceuticals, Axsome Therapeutics*, Boehringer 2014;19:535. https://doi.org/10.1017/S1092852914000406. Ingelheim, Boston Pharmaceuticals, Inc.*, Brainsway Ltd, Bristol-Myers Squibb 20. Kraemer HC, Kupfer DJ. Size of treatment effects and their importance to clinical Company, Cala Health*, Cephalon Inc., Dey Pharma, L.P., Eleusis health solutions research and practice. Biol Psychiatry. 2006;59:990–6. https://doi.org/10.1016/ ltd*, Eli Lilly Co., Genentech, Inc*, Genomind, Inc*, GlaxoSmithKline, Evotec AG, H. j.biopsych.2005.09.014. Lundbeck A/S, Inflabloc Pharmaceuticals, Janssen Global Services LLC*, Jazz 21. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Routledge; Pharmaceuticals, Johnson & Johnson Companies*, Merck*, Methylation Sciences 1988. https://doi.org/10.4324/9780203771587. Inc, Monopteros Therapeutics*, Mylan Inc*, Neurocenria, Novartis Pharma AG, One 22. Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial magnetic sti- Carbon Therapeutics, Inc*, Osmotica Pharmaceutical Corp.*, Otsuka Pharmaceuticals, mulation for treatment-resistant depression: a systematic review and metanalysis. PAMLAB LLC, Pfizer Inc., Pierre Fabre Laboratories, Praxis Precision Medicines*, Ridge Can J Psychiatry. 2008;53:621–31. https://doi.org/10.1177/070674370805300909. Diagnostics (formerly known as Precision Human Biolaboratories), Sage Therapeu- 23. Liu B, Zhang Y, Zhang L, Li L. Repetitive transcranial magnetic stimulation as an tics*, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Taisho Pharmaceutical Co, augmentative strategy for treatment-resistant depression, a meta-analysis of ran- Ltd*, Takeda Pharmaceutical Company LTD, Theracos, Inc., and Wyeth, Inc. GIP has domized, double-blind and sham-controlled study. BMC Psychiatry. 2014;14:342. received honoraria (for lectures or consultancy) from Abbott Laboratories, Abbvie, https://doi.org/10.1186/s12888-014-0342-4. Acadia Pharmaceuticals Inc, Alkermes Inc, Alphasigma USA Inc, Asopharma America 24. Mohamed S, Johnson GR, Chen P, Hicks PB, Davis LL, Yoon J, et al. Effect of Cntral Y Caribe, Astra Zeneca PLC, Avanir Pharmaceuticals, Boehringer Ingelheim, Antidepressant Switching vs Augmentation on Remission Among Patients With Bristol-Myers Squibb Company, Brainsway Ltd, Cephalon Inc., Dey Pharma, L.P., Eli Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST- Lilly Co., Evotec AG, Forest Pharmaceuticals, GlaxoSmithKline, Inflabloc Pharmaceu- D Randomized Clinical Trial. JAMA. 2017;318:132–45. https://doi.org/10.1001/ ticals, Grunbiotics Pty LTD, Hypera S.A., Jazz Pharmaceuticals, H. Lundbeck A/S, jama.2017.8036. Medichem Pharmaceuticals, Inc, Meiji Seika Pharma Co. Ltd, Novartis Pharma AG, Molecular Psychiatry (2024) 29:2287 – 2295  G.I. Papakostas et al. 2294 Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pharma Trade SAS, Pierre Fabre served as a consultant to Allergan, Alkermes, Almatica Pharma, Axsome Therapeutics, Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, BioXcel Therapeutics, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Takeda Pharmaceutical Company LTD, Theracos, Inc., Titan Pharmaceuticals, and Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Wyeth Inc. GIP has received research support (paid to hospital) from Alphasigma USA, Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Inc, AstraZeneca PLC, Beckley Psytech, Bristol-Myers Squibb Company, Cala Health, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Forest Pharmaceuticals, the National Institute of Mental Health, Mylan Inc, Health, Sunovion and Worldwide Clinical Trials. He has received research support Neuralstem, Inc*, PAMLAB LLC, PCORI, Pfizer Inc., Johnson & Johnson Companies, from Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Therapeutics, and VistaGen Therapeutics. CDB: Grant support: Compass, Otsuka, Pharmaceuticals, Tal Medical, and Theracos, Inc. GIP has served (not currently) on the Beckley, Relmada, Janssen, Sage. Consultant: Corcept, Sage, Alkermes, Pfizer, AbbVie, speaker’s bureau for BristolMyersSquibb Co and Pfizer, Inc.* Asterisk denotes MED: In 2008, MED received a one-time consulting honorarium from Neuronetics Inc. consulting activity undertaken on behalf of Massachusetts General Hospital. MHT has In 2012, MED attended a speaker training symposium invited and organized by provided consulting services to ACADIA Pharmaceuticals, Akili Interactive, Allergan, Neuronetics. Inc but has not participated in any speaker bureau activities. From Alkermes Inc., Alto Neuroscience Inc, Applied Clinical Intelligence, LLC, Axsome 2015–2021, Neuronetics Inc. donated TMS treatment supplies to a Northwestern Therapeutics, Biogen MA Inc, Boegringer Ingelheim, Cerebral Inc., Circular Genomics University funded clinical TMS trial for cancer survivors (25 patients) in which MED Inc., Compass Pathfinder Limited, GH Research, GreenLight VitalSign6 Inc, Global was the principal investigator. OB-M: Lifetime. OB-M has received contract research Medical Education, Heading Health, Health Care Global Village, Janssen Pharmaceu- grants from AgeneBio, Pfizer, Green Valley Pharmaceuticals, Avanir, Axsome tical, Jazz Pharmaceutical, Legion Health, Lilly USA, Lundbeck Research USA, therapeutics, Takeda, DoD CDMRP, VA HSR&D, USC ATRI (NIA/NIH), UCSD ADCS Medavante, Medscape LLC, Merck Sharp & Dohme Corp., Mind Medicine Inc., (NIA/NIH), Lundbeck, Janssen, Shire pharmaceuticals, Eli Lilly, Biovail, UCB Pharma, Mitsubishi Tanabe Pharma Development America, Myriad Neuroscience, Naki Health Bristol-Meyers Squibb, Sanofi Aventis, AstraZeneca, Forest pharmaceuticals, Novartis, Ltd, Navitor, Neurocrine Biosciences Inc., Neuronetics, Noema Pharma AG, Orexo US Merk, Bristol-Meyers Squibb, Wyeth-Ayerst. Consultant fees Janssen, Pfizer, AstraZe- Inc., Otsuka America Pharmaceutical Inc, Pamlab, Perception Neuroscience Holdings, neca, Forest. Speaker’s Bureaus for Pfizer, Janssen, AstraZeneca, Forest. 12 Months. Pfizer, PGxHealth, Pharmerit International, Phoenix Marketing Solutions, Policy OB-M has received research grants from AgeneBio, Green Valley Pharmaceuticals, Analysis Inc., Praxis Precision Medicines Inc, Rexahn Pharmaceuticals, Ridge Avanir, DoDCDMRP, VA HSR&D, USC ATRI (NIA/NIH), UCSD ADCS (NIA/NIH), Axsome Diagnostics, Roche TCRC, SAGE Therapeutics, Shire US, Signant Health, SK Life, Therapeutics. GWC: none. WVM: Lifetime. WVM has received contract research grants Sparian Biosciences, Sunovian Pharmaceuticals, Tal Medical, Targacept, The Baldwin from Vistagen, Merck, MECTA, Neurosync, Cephalon, Corcept, Sealy, Sanofi, Bristol- Group, Titan Pharmaceuticals, Takeda Pharmaceuticals Inc, WebMD. He has received Meyers Squibb, Glaxo, Somaxon, Neuronetics, Cephalon, Sepracor, Takeda, Searle, grant/research funding from NIMH, NIDA, NCATS, American Foundation for Suicide and Wyeth-Ayerst. Consultant fees from Idorsia, and royalties from Wolters Kluwer. Prevention, Patient-Centered Outcomes Research Institute (PCORI), and Blue Cross Speaker’s Bureaus for Pfizer, Wyeth-Ayerst, Sepracor, GSK 12 Months. WVM has Blue Shield of Texas. Additionally, he has received editorial compensation from received contract research grants from Vistagen, consultant fees from Idorsia, and Engage Health Media, and Oxford University Press. RCS: Research Support: NIH, roylaties from Wolters Kluwer. MModirrousta: none. MMacaluso: D.O. has conducted PCORI, American Foundation for Suicide Prevention, Acadia Pharmaceuticals, clinical trials research as principal investigator for the following pharmaceutical Alkermes, Inc., Allergan, Plc, Alto Pharmaceuticals, Avanir Pharmaceuticals, Inc., companies over the last twelve months: 1. AssureRx/Myriad 2. Avanir 3. Boehringer- Boehringer Ingelheim, Denovo Biopharma, Genomind, InMune Bio, Intra-cellular Ingelheim 4. Electrocore 5. Janssen 6. Liva Nova 7. Merck 8. Neurocrine 9. Novartis 10. Therapies, Janssen Pharmaceuticals, LivaNova PLC, Navitor Pharmaceuticals, Neuro- Otsuka All clinical trial and study contracts were with and payments made to the crine Biosciences, Neurorx, Novartis Pharmaceuticals, Otsuka Pharmacetical Com- University of Alabama at Birmingham. From April 2019 to June of 2020, Dr Macaluso pany, Sunovion Pharmaceuticals, Takeda Pharmaceuticals. Consulting: Acadia was a member of the speaker bureau for Janssen pharmaceuticals (Spravato/ Pharmaceuticals, Allergan, Plc, Alphasigma USA, Inc., Boehringer Ingelheim, Cerecor, esketamine). MMacaluso serves as a consultant for Nusachi labs and PharmaTher. Inc., Denovo Biopharma, Janssen Pharmaceuticals, Myriad Neuroscience, Neurorx, MMacaluso has received royalties from Springer Nature for textbooks published. AB Novartis AG, Otsuka Pharmaceuticals, Seelos Therapeutics, Inc., Sunovion Pharma- has previously received grant support from BMS, Wyeth and Brainsway. FVR receives ceuticals, Takeda Pharmaceuticals. DVI: In the last ten years, DVI has received research support from CIHR, Brain Canada, Michael Smith Foundation for Health consulting honoraria from Alkermes, Allergan, Axsome, Biogen, Boehringer Ingel- Research, Vancouver Coastal Health Research Institute, and Weston Brain Institute for heim, Centers for Psychiatric Excellence, Clexio, Jazz, Lundbeck, Otsuka, Precision investigator-initiated research. Philanthropic support from Seedlings Foundation. In- Neuroscience, Relmada, Sage, Sunovion; he has received research support (through kind equipment support for this investigator-initiated trial from MagVenture. He has his academic institutions) from Alkermes, Astra Zeneca, Brainsway, Litecure, Neosync, received honoraria for participation in an advisory board for Allergan. EBN: none. ASY: Otsuka, Roche, Shire. MET: Disclosure Information (Past 24 Months) Grant Support: none. AF: None. LCM: None. TC has been a consultant for Alkermes. MF: Reports Acadia, Inc.; Allergan, Inc.; AssureRx Health; Axsome Therapeutics Inc.; BioHaven, Inc.; 3-year disclosures as below - Research Support: Acadia Pharmaceuticals; Aditum Bio Intracellular, Inc.; Johnson & Johnson; Otsuka Pharmaceutical Company, Ltd.; Patient- Management Company, LLC; Allergan, Alkermes, Inc.; Altimate Health Corporation; Centered Outcomes Research Institute (PCORI); Takeda Pharmaceutical Company, Alto Neuroscience, Inc.; Ancora Bio, Inc.; Angelini S.p.A; Aptinyx; Arbor Pharmaceu- Ltd. Advisory/Consultant: Acadia, Inc.; Akili, Inc.; Alkermes PLC; Allergan, Inc.; Axsome ticals LLC; Avanir Pharmaceuticals Inc.; Axsome; Benckiser Pharmaceuticals, Inc.; Therapeutics, Inc.; BioHaven, Inc.; Bocemtium Consulting, S.L.; Boehringer Ingelheim BioClinica, Inc.; Biogen; BioHaven; BioShin Limited; Cambridge Science Corporation; International; CatalYm GmbH; Clexio Biosciences; Gerson Lehrman Group, Inc.; H. Centrexion Therapeutics Corporation; Cerecor; Cybin IRL Limited; Eliem Therapeutics Lundbeck, A/S; Jazz Pharmaceuticals; Janssen; Johnson & Johnson; Luye Pharma LTD; Gate Neurosciences, Inc.; GenOmind, LLC; Gentelon, LLC; Happify; Johnson & Group, Ltd.; Merck & Company, Inc.; Otsuka Pharmaceutical Company, Ltd.; Pfizer, Inc.; Johnson; Lundbeck Inc.; Marinus Pharmaceuticals; Methylation Sciences, Inc.; Sage Pharmaceuticals; Seelos Pharmaceuticals; Sunovion Pharmaceuticals, Inc.; Millennium Pharmaceutics, Inc.; Minerva Neurosciences; Neuralstem; Neurocrine Takeda Pharmaceutical Company, Ltd. CE Speakers Bureau: None. Stockholder Biosciences, Inc.; NeuroRX Inc.; Novaremed; Novartis; Otsuka; Pfizer; Premiere (privately held): None. Stockholder (publicly traded): None. Royalties: American Research International; Praxis Precision Medicines; Protagenic Therapeutics, Inc.; Psychiatric Foundation; Guilford Publications; Herald House; Kluwer-Wolters; W.W. Relmada Therapeutics. Inc.; Reckitt; Shenox Pharmaceuticals; Stanley Medical Norton & Company, Inc. Spouse’s Employment: Peloton Advantage, which does Research Institute (SMRI); Taisho; Takeda; University of Michigan; Vistagen; business with most major pharmaceutical companies. MKJ: Lifetime (same as 36 WinSanTor, Inc.; Xenon Pharmaceuticals, Inc.; National Institute of Drug Abuse months). MKJ has received contract research grants from Acadia Pharmaceuticals, (NIDA); National Institutes of Health (NIH); National Institute of Mental Health (NIMH); Neurocrine Bioscience, Navitor/Supernus and Janssen Research & Development, and PCORI. MF has not done any personal consulting. Any consulting he has done educational grant to serve as Section Editor of the Psychiatry & Behavioral Health has been on behalf of Massachusetts General Hospital, except for Sensorium Learning Network, consultant fees from Eleusis Therapeutics US, Inc, Janssen Global Therapeutics. Speaking/Publishing: Lecture given at Global Medical Education, Inc. Services, Janssen Scientific Affairs, Worldwide Clinical Trials/Eliem and Inversargo, and Mood Disorders Summit, November 2020. Stock/Other Financial Options: Equity Guidepoint Global, and honoraria from North American Center for Continuing Holdings: Compellis; Neuromity; Psy Therapeutics; Sensorium Therapeutics Royalty/ Medical Education, Medscape/WebMD, Clinical Care Options, and Global Medical patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), Education. 12 Months. MKJ has received contract research grants from Neurocrine licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, Bioscience, Navitor/Supernus and Janssen Research & Development, educational US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), Network, consultant fees from Eleusis Therapeutics US, Inc, Janssen Global Services, licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Janssen Scientific Affairs, Worldwide Clinical Trials/Eliem, and Guidepoint Global, and Treatment with Folate (US_9546401, US_9540691). Copyright for the MGH Cognitive honoraria from North American Center for Continuing Medical Education, Medscape/ & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), WebMD, Clinical Care Options, and Global Medical Education. SJM is supported Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation- through the use of resources and facilities at the Michael E. Debakey VA Medical Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire Center, Houston, Texas and receives support from The Menninger Clinic. SJM has (SDQ), and SAFER; Belvior; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Molecular Psychiatry (2024) 29:2287 – 2295  G.I. Papakostas et al. 2295 Scientific Publishing Co. Pte.Ltd. **All lifetime disclosures can be viewed online by Open Access This article is licensed under a Creative Commons navigating to: https://mghcme.org/faculty >MF, MD>View Bio>View Disclosures Here. 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