OBJECTIVE:Ketamine rapidly reduces suicidal ideation in major depressive disorder (MDD), but its effects are transient. Preclinical and clinical studies suggest that ketamine's antidepressant and antisuicidal effects may be partly mediated by mu-opioid receptor (MOR) modulation. The authors investigated the efficacy and safety of low-dose sublingual buprenorphine, a partial MOR agonist, as a follow-on treatment to prolong the effects of intravenous ketamine. METHODS:This was a randomized, double-blind, placebo-controlled trial conducted at a single outpatient center in the United States. Adults with MDD and a total score ≥6 on the Scale for Suicide Ideation (SSI) were randomly assigned in a 1:1 ratio to receive either sublingual buprenorphine (0.2 to 0.8 mg/day) or a matched placebo for 4 weeks, beginning 48 hours after a single open-label intravenous ketamine infusion (0.5 mg/kg over 40 minutes). The primary outcome was the change in SSI total score, assessed weekly from day 1 through day 31. RESULTS:From November 2020 to March 2025, 50 participants (68% female) received ketamine, of whom 45 completed at least 1 week of follow-on treatment. Both groups showed significant reductions in SSI total scores, with greater improvement in the buprenorphine group (mean change, -11.6, SD=5.8; N=23) than the placebo group (mean change, -6.3, SD=7; N=22) (Glass delta=0.76, 95% CI=0.11, 1.39). Mixed-effects modeling showed a significant time-by-treatment interaction (p<0.001). Depression scores did not differ significantly between groups. No serious treatment-related adverse events occurred. CONCLUSIONS:This randomized controlled trial provides the first evidence that a pharmacological intervention, buprenorphine, significantly sustains and enhances the antisuicidal effects of ketamine in MDD. These findings offer a potentially scalable and safe therapeutic option for a population at risk of suicide.

OBJECTIVE:Anxious depression is a negative prognostic factor linked to worse outcomes in major depressive disorder (MDD). However, its role in treatment-resistant depression (TRD) remains unclear. This secondary analysis of the ASCERTAIN-TRD trial investigates the role of anxious depression as a predictor or moderator of treatment response. METHODS:A Hamilton Depression Rating Scale Anxiety and Somatization Subscale score of at least 7 identified subjects with the anxious depressive subtype. Treatment response was evaluated based on changes in Montgomery-Asberg Depression Rating Scale scores using mixed-effects models with repeated measures and included additional terms accounting for the presence or absence of anxious depression. Two hundred fifty-three patients, who had at least one post-baseline Montgomery-Asberg Depression Rating Scale and Hamilton Depression Rating Scale score were included in the analysis. Of them, 182 subjects presented anxious and 71 nonanxious depression. RESULTS:Treatment outcomes were similar across the three treatment groups regardless of anxious MDD status ( P -value > 0.5 for all comparisons) suggesting that anxious depression was not a significant predictor or moderator of treatment outcome. CONCLUSION:These findings indicate that anxious depression alone may be prognostic rather than predictive. These findings may be a useful guidance for clinicians, suggesting that standard TRD treatments remain applicable in the anxious MDD subtype.

Major depressive disorder (MDD) is a severe and debilitating illness. Despite the available treatments, clinical outcomes remain suboptimal, and hence, it is crucial to identify predictive factors for response. This is a secondary analysis investigating the relationship between treatment preference and response to treatment in the antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) trial (NCT02977299) comparing three treatment arms [aripiprazole augmentation, repetitive transcranial magnetic stimulation (rTMS) augmentation, switching to venlafaxine XR or duloxetine] in MDD patients with treatment-resistant depression (TRD) who are currently on ongoing, stable, and adequate antidepressant therapy. Patient treatment preferences were recorded in the study entry. In total, 278 subjects were randomly assigned to one of three treatment groups: aripiprazole ( n  = 92), rTMS ( n  = 70), or venlafaxine/duloxetine ( n  = 98). Of these 278 subjects, 256 (92.1%) had at least one postbaseline Montgomery-Asberg Depression Rating Scale (MADRS) score and a recorded treatment preference and were included in this secondary analysis. In the total population, participants' preferences did not affect their response to treatment, and the change in MADRS score was similar among patients who received their preferred treatment, had no preference, or received treatment against their preference ( P  = 0.49). These results indicate that patient preference is not a significant factor that predisposes to optimal treatment outcomes.

Subjective cognitive impairment is a key symptom of major depressive disorder (MDD). Improvement of cognitive function in patients with treatment-resistant depression (TRD) is an important treatment outcome. This study compared the impact of augmenting antidepressants with aripiprazole or repetitive transcranial magnetic stimulation (rTMS) versus switching to venlafaxine (or duloxetine for those not eligible to receive venlafaxine) on cognition in TRD patients. In a pre-defined secondary analysis of a multi-site, open-label trial, patients with TRD were randomly assigned to aripiprazole augmentation, rTMS augmentation, or switching to venlafaxine XR/duloxetine in 1:1:1 ratio and they were treated for 8 weeks. Cognition was assessed using the Cognitive and Physical Functioning Questionnaire (CPFQ). A mixed-effects model with repeated measures was conducted. Among the 258 randomized subjects with at least one post-baseline CPFQ assessment (aripiprazole n = 91; rTMS = 70;venlfaxine XR/duloxetine = 97), neither aripiprazole nor rTMS demonstrated significant differences compared to the venlafaxine XR/duloxetine switch group in cognitive outcome as measured by CPFQ scale (p > 0.025). The mean (SE) change in CPFQ scores from baseline to Week 8 was -8.04 (0.77) (aripiprazole augmentation) versus -6.70 (0.75) (venlafaxine XR/duloxetine switch), and - 8.81 (0.64) (rTMS augmentation) versus -6.72 (0.55) (venlafaxine XR/duloxetine switch). Hedge's g values were 0.21 for aripiprazole augmentation versus switching to venlafaxine XR/duloxetine and 0.33 for rTMS augmentation versus switching to venlafaxine XR/duloxetine. Although rTMS augmentation did not reach a statistically significant difference in subjective cognitive improvement, it showed a larger effect size compared to aripiprazole augmentation. Our findings signal that rTMS augmentation may offer a well-tolerated strategy for improving cognition in TRD.

Objective: This study compared the effects of augmenting antidepressants with aripiprazole or repetitive transcranial magnetic stimulation (rTMS) versus switching to venlafaxine XR/duloxetine on quality of life (QoL) among patients with treatment resistant depression (TRD). Methods: In a predefined secondary analysis of a multisite, open-label, effectiveness trial, patients with TRD were randomly assigned to aripiprazole augmentation, rTMS augmentation, or switching to venlafaxine XR/duloxetine in a 1:1:1 ratio, and they were treated for 8 weeks. TRD was defined as an inadequate response to 2 or more antidepressant trials of adequate dose and duration, as defined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. QoL was predefined as a key secondary end point for this study and assessed using the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF). A mixed-effects model with repeated measures was applied. This study was conducted from July 13, 2017, to December 22, 2021. Results: Among 258 randomized participants with at least 1 postbaseline Q-LES-Q-SF measurement, augmentation with aripiprazole demonstrated statistically significant superiority over switching on the Q-LES-Q-SF (P=.002), while rTMS did not (P=.326). At end point, changes from baseline in the Q-LES-Q-SF scores were 10.61 (SE=1.0) for aripiprazole augmentation, 11.59 (SE=1.1) for rTMS augmentation, and 8.68 (SE=0.9) for venlafaxine XR/duloxetine switch. Conclusion: Augmentation with aripiprazole, but not rTMS, improved QoL significantly versus venlafaxine XR/duloxetine switch in TRD patients. However, a much smaller than expected sample size for the rTMS group may explain the lack of statistical significance rendering the latter finding of indeterminate nature. Trial Registration: ClinicalTrials.gov identifier: NCT02977299.

Objective: This study compared the effects of augmenting antidepressants with aripiprazole or repetitive transcranial magnetic stimulation (rTMS) versus switching tovenlafaxine XR/duloxetine on quality of life (QoL) among patients with treatment resistant depression (TRD). Methods: In a predefined secondary analysis of a multisite, open-label, effectiveness trial, patients with TRD were randomly assigned to aripiprazole augmentation, rTMS augmentation, or switching to venlafaxine XR/duloxetine in a 1:1:1 ratio, and they were treated for 8 weeks. TRD was defined as an inadequate response to 2 or more antidepressant trials of adequate dose and duration, as defined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. QoL was predefined as a key secondary end point for this study and assessed using the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF). A mixed-effects model with repeated measures was applied. This study was conducted from July 13, 2017, to December 22, 2021. Results: Among 258 randomized participants with at least 1 postbaseline Q-LES-Q-SF measurement, augmentation with aripiprazole demonstrated statistically significant superiority over switching on the Q-LES-Q-SF (P = .002), while rTMS did not (P = .326). At end point, changes from baseline in the Q-LES-Q-SF scores were 10.61 (SE = 1.0) for aripiprazole augmentation, 11.59 (SE = 1.1) for rTMS augmentation, and 8.68 (SE =0.9) for venlafaxine XR/duloxetine switch. Conclusion: Augmentation with aripiprazole, but not rTMS, improved QoL significantly versus venlafaxine XR/ duloxetine switch in TRD patients. However, a much smaller than expected sample size for the rTMS group may explain the lack of statistical significance rendering the latter finding of indeterminate nature. Trial Registration: ClinicalTrials.gov identifier: NCT02977299.

Objective: To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression. Methods: For treatment-resistant depression, 233 participants received a single dose of 25, 10, or 1 mg of COMP360 psilocybin (a proprietary, pharmaceutical-grade synthesized psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.) with psychological support. The resulting psychedelic experience (Five- Dimensional Altered States of Consciousness questionnaire [5D-ASC] and Emotional Breakthrough Inventory EBI]) were measured. These proximal variables and outcome 3 weeks post-administration (change in Mont-gomery-& Aring;sberg Depression Rating Scale [MADRS]) were explored using correlation analysis. Results: The mean intensity of psychedelic effects was dose-related, but distributions of scores for different doses overlapped considerably. Depression response correlated with select aspects of the psychedelic experience overall and for individual doses. At the 25 mg dose, 5D-ASC dimensions Oceanic Boundlessness (Pearson cor-relation coefficient r = 0.508) and Visual Restructuralization (r = 0.516), and EBI (r = 0 & sdot;637) were the variables with the strongest correlation to the Week 3 change from Baseline in MADRS score. Limitations: The existence of correlation does not establish causation and exploratory findings require further replication, preferably in larger independent samples. Conclusions: The intensity of psychedelic experience overlaps widely across doses and mitigates the risk of unblinding to dose. Correlations between psychedelic experience and outcome suggest specificity in psilocybin's mechanism of action. Quality and intensity of psychedelic experience may be a measure of pharmacodynamic effect and reveal an effective dose response phenomenon for single oral doses

Background The subgenual cingulate cortex (SGC) has been identified as a key structure within multiple neural circuits whose dysfunction is implicated in the neurobiology of depression. Deep brain stimulation in the SGC is thought to reduce and normalize local metabolism, causing normalization of circuit behavior and an improvement in depressive symptoms. We hypothesized that nonablative stereotactic radiosurgery (SRS) to the SGC would reduce local metabolism and reduce the severity of depression in patients with treatment-resistant bipolar depression. Methods Under the FDA's Humanitarian Device Exemption program, patients were screened for inclusion and exclusion criteria. Three volunteers meeting the criteria provided informed consent. Bilateral SGC targets were irradiated to a maximum dose of 75 Gy in one fraction. Subjects were followed for one year following the procedure with mood assessments (Hamilton Depression Rating Scale (HDRS), Clinical Global Impression-Improvement, Clinical Global Impression-Severity, and Young Mania Rating Scale), neurocognitive testing (Delis-Kaplan Executive Function System, Wechsler Adult Intelligence Scale III digit span, and California Verbal Learning Test II), and imaging. Further imaging was completed approximately two years after the procedure. Clinical improvement was defined as a ≥50% reduction in HDRS. Results Two of the three subjects showed clinical improvement in depressive symptoms during the follow-up period, while one subject showed no change in symptom severity. One of three subjects was hospitalized for the emergence of an episode of psychotic mania after discontinuing antipsychotic medications against medical advice but promptly recovered with the reinstitution of an antipsychotic. Sequential assessments did not reveal impairment in any cognitive domain assessed. For one of the three subjects, MRI imaging showed evidence of edema at 12 months post-SRS, which resolved at 22 months post-procedure. In a second of three patients, there was evidence of local edema at the target site at long-term follow-up. All imaging changes were asymptomatic. Conclusion Radiosurgical targeting of the SGC may be a noninvasive strategy for the reduction of severe depression in treatment-resistant bipolar disorder. Two out of three patients showed clinical improvement. While these results are promising, further study, including improvements in target selection and dosing considerations, is needed.

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 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

Psychotropics continue to be among the most commonly prescribed medications in clinical practice. There are over 380 million outpatient psychotropic prescriptions in the US every year Greenblatt et al. (2018). The majority of these prescriptions are for antidepressants (58%) followed by anxiolytics (22%), hypnotics (14%) and antipsychotics (5%). Since the last edition of this Black Book in 2016, a large number many new psychotropics have been approved by the FDA and are now in clinical use. Over the past several years, there has been a paradigm shift in antidepressant development. Historically, antidepressants have been oral agents which generally take 4–8 weeks to achieve maximum benefit at therapeutic doses. Two antidepressants have been approved that have been demonstrated efficacy in improving symptoms of major depression in hours or days as opposed to months. One of these, esketamine (Spravato), is the S enantiomer of ketamine which has been used as an anesthetic and for pain management since the 1960’s. While IV ketamine has long been demonstrated to be rapidly effective for treatment resistant depression, IV use require regular visits to a clinic and is generally not covered by insurance. Esketamine (Spravato) is an intranasal preparation which is typically administered twice weekly for 4 weeks, one weekly for 3 weeks, and then every week or two thereafter. Esketamine, like ketamine, is a schedule 3 drug that require a REMs registration of patients and providers and carries some risk of abuse. Like ketamine, the most common symptoms include nausea, dissociation, and increases in blood pressure and heart rate. Thus, patients have to be observed for at least two hours in the clinic after each administration and cannot drive to or from the clinic for each visit. In addition, since ketamine and S ketamine can be habituating, it is important to adhere to the guidelines for frequency and duration of dosing.

Background: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints.Methods: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. Results: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. Limitations: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. Conclusions: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.

We previously reported the rapid OCD symptom reduction of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, vs saline infusions in a proof-of-concept crossover trial (n=15) in unmedicated adults with OCD. Building on this initial finding, we evaluated the efficacy of ketamine in a larger group of unmedicated OCD patients with improved control conditions (active placebo control condition).

Major depressive disorder (MDD) is a mental health disorder that can cause disability and functional impairment that standard-of-care (SOC) antidepressant therapies (ADTs) can take weeks to treat. Zuranolone is a neuroactive steroid and positive allosteric modulator of synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors approved as an oral, once-daily, 14-day treatment course in adults with postpartum depression and under investigation in adults with MDD. The phase 3 CORAL Study (NCT04476030) evaluated the efficacy and safety of zuranolone 50 mg co-initiated with SOC ADT (zuranolone+ADT) vs placebo co-initiated with SOC ADT (placebo+ADT) in adults with MDD. Patients were randomized 1:1 to once-daily, blinded zuranolone+ADT or placebo+ADT for 14 days, then continued open-label SOC ADT for 28 more days. The primary endpoint was change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day 3. Among 425 patients in the full analysis set, CFB in HAMD-17 total score at Day 3 was significantly improved with zuranolone+ADT vs placebo+ADT (least squares mean [standard error], −8.9 [0.39] vs −7.0 [0.38]; p = 0.0004). The majority of patients receiving zuranolone+ADT that experienced treatment-emergent adverse events (TEAEs) reported mild or moderate events. The most common TEAEs present in ≥10% of patients in either zuranolone+ADT or placebo+ADT groups were somnolence, dizziness, headache, and nausea. These results demonstrate that zuranolone+ADT provided more rapid improvement in depressive symptoms compared with placebo+ADT in patients with MDD, with a safety profile consistent with previous studies. Clinical trial registration: ClinicalTrials.gov identifier: NCT04476030.

OBJECTIVE:Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression.METHODS:Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment.RESULTS:At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group.CONCLUSIONS:SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

Background: Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices. Methods: We retrospectively analyzed 9016 depression patients who received KIT between 2016 and 2020 at one of 178 community practices across the United States. Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). The induction phase of KIT was defined to be a series of 4-8 infusions administered over 7 to 28 days. Results: Among the 537 patients who underwent induction and had sufficient data, 53.6% of patients showed a response (>= 50% reduction in PHQ-9 score) at 14-31 days post-induction and 28.9% remitted (PHQ-9 score drop to < 5). The effect size was d = 1.5. Among patients with baseline suicidal ideation (SI), 73.0% exhibited a reduction in SI. A subset (8.4%) of patients experienced an increase in depressive symptoms after induction while 6.0% of patients reported increased SI. The response rate was uniform across 4 levels of baseline depression severity. However, more severe illness was weakly correlated with a greater drop in scores while remission status was weakly inversely correlated with depression severity. Kaplan-Meier analyses showed that a patient who responds to KIT induction has approximately 80% probability of sustaining response at 4 weeks and approximately 60% probability at 8 weeks, even without maintenance infusions. Conclusion: KIT can elicit a robust antidepressant response in community clinics; however, a small percentage of patients worsened.

Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression (DSM-IV-TR MDD) and to assess whether the use of concomitant oral benzodiazepines differentially affected treatment response to ketamine versus midazolam. Methods: This trial ran from December 2015 to December 2016. Subjects who were taking oral benzodiazepines (n = 44) were compared to those who were not (n = 55). A significant treatment-by-benzodiazepine effect could be interpreted as a possible moderator of differential treatment response to ketamine versus midazolam. Benzodiazepine use was examined as both a binary and a continuous predictor, to assess the impact of dosage. Results: Benzodiazepine users did not differ from non-users on the original study's primary outcome measure, score on the 6-item Hamilton Depression Rating Scale (HDRS-6), at baseline, but the former had more severe anxiety. When oral benzodiazepine use was modeled as a binary predictor, benzodiazepine use did not impact differential treatment response. However, when benzodiazepine dosage was considered, there was a significant impact of benzodiazepine use on differential treatment response. Oral benzodiazepines significantly impacted HDRS-6 (P = .018) and Clinical Global Impressions-Severity of Illness scale (CGI-S; P = .008) scores at day 1 (24 hours post treatment); effects were nonsignificant for all day 3 outcomes. Among ketamine subjects, higher doses of benzodiazepines were associated with less improvement in depression scores at day 1. Conclusions: Concomitant oral benzodiazepines at higher doses may attenuate the antidepressant effects of IV ketamine at day 1 but not day 3 post-infusion. Trial Registration: ClinicalTrials.gov identifier: NCT01920555.

BACKGROUND Psilocybin is being studied for use in treatment-resistant depression. METHODS In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at 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. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).