Update on the assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form-2 (ATHF-SF2).

All definitions of treatment-resistant depression (TRD) require that patients have experienced insufficient benefit from one or more adequate antidepressant trials. Thus, identifying "failed, adequate trials" is key to the assessment of TRD. The Antidepressant Treatment History Form (ATHF) was one of the first and most widely used instruments that provided objective criteria in making these assessments. The original ATHF was updated in 2018 to the ATHF-SF, changing to a checklist format for scoring, and including specific pharmacotherapy, brain stimulation, and psychotherapy interventions as potentially adequate antidepressant treatments. The ATHF-SF2, presented here, is based on the consensus of the ATHF workgroup about the novel interventions introduced since the last revision and which should/should not be considered effective treatments for major depressive episodes. This document describes the rationale for these choices and, for each intervention, the minimal criteria for determining the adequacy of treatment administration. The Supplementary Material that accompanies this article provide the Scoring Checklist, Data Collection Forms (current episode and composite of previous episodes), and Instruction Manual for the ATHF-SF2.

A Pilot Study of High-Frequency Transcranial Magnetic Stimulation for Bipolar Depression.

Objective: Repetitive transcranial magnetic stimulation (rTMS) is a standard treatment approach for major depressive disorder. There is growing clinical experience to support the use of high-frequency left-sided rTMS in bipolar depression. This study collected open-label safety and effectiveness data in a sample of patients with bipolar depression.Methods: Thirty-one adults (13 male/ 18 female; mean age: 42.2 [14.3] years) with bipolar (I or II) depression verified by DSM-5 criteria were recruited at Sheppard Pratt and Mayo Clinic between August 2017 and February 2020 for rTMS. Standardized treatment protocols employed 6 weeks of 10-Hz rTMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4-second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥50% or score <10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.Results: The majority of patients with bipolar depression reached response (n = 27; 87.1%) and remission (n = 23; 74.2%). Older age and concurrent treatment with lithium were associated with higher MADRS scores throughout the treatment course (0.1 ± 0.05, P =.05; 4.05 ± 1.27, P = .003, respectively). Concurrent treatment with lamotrigine was associated with lower MADRS scores (-3.48 ± 1.26, P = .01). Treatment with rTMS was safe and well tolerated. There were no completed suicides, induced manic episodes, or other serious adverse events.Conclusion: Although preliminary, the present findings are encouraging regarding the safety and effectiveness of 10-Hz rTMS for bipolar depression.Trial Registration: ClinicalTrials.gov identifier: NCT02640950.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

When to hold and when to fold: Early prediction of nonresponse to transcranial magnetic stimulation in major depressive disorder.

BACKGROUND: Determining when to recommend a change in treatment regimen due to insufficient improvement is a common challenge in therapeutics. METHODS: In a sample of 7215 patients with major depressive disorder treated with transcranial magnetic stimulation (TMS) and with PHQ-9 scores before, during and after the course, 3 groups were identified based on number of acute course sessions: exactly 36 sessions (N = 3591), more than 36 sessions (N = 975), and less than 36 sessions (N = 2649). Two techniques were used to determine thresholds for percentage change in PHQ-9 scores at assessments after 10, 20, and 30 sessions that optimized prediction of endpoint response status: the Youden index and fixing the false positive rate at 10%. Positive and negative predictive values were calculated to assess the accuracy of identifying final nonresponders and responders, respectively. RESULTS: There was greater accuracy in predicting final response than nonresponse, especially in the groups that had at least 36 sessions. Substantial proportions of patients with low levels of early improvement were classified as responders at the end of treatment. LIMITATIONS: The findings should be validated with clinician ratings using a more comprehensive depression severity scale. CONCLUSIONS: Manifesting clinical improvement early in the TMS course is strongly predictive of final status as a responder, while lack of early improvement is a relatively poor indicator of final nonresponse status. The predictive value of lack of early symptomatic improvement is too low to make reliable recommendations regarding changes in treatment regimen.

New evidence for flexible psilocybin dosing in patients with treatment-resistant depression.

Psilocybin has demonstrated efficacy for treating depression; however, psychiatrically complex patients have been excluded from trials. A recent clinical trial by Rosenblat at al.1 demonstrates feasibility of a flexible dosing schedule of psilocybin in individuals with severely treatment-resistant depression (TRD), including those with co-morbid conditions or bipolar II disorder (BPII), potentially expanding the current treatment paradigm.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: II. Sensitivity to treatment effects.

OBJECTIVE: Characteristics of difficult-to-treat depression (DTD), including infrequent symptom remission and poor durability of benefit, compel reconsideration of the outcome metrics historically used to gauge the effectiveness of antidepressant interventions. METHODS: Self-report and clinician assessments of depression symptom severity were obtained regularly over a 2-year period in a difficult-to-treat depression registry sample receiving treatment as usual (TAU), with or without vagus nerve stimulation (VNS). Alternative outcome metrics for characterizing symptom change were compared in effect size and discriminating power in distinguishing the vagus nerve stimulation + treatment as usual and treatment as usual treatment groups. We expected metrics based on remission status to produce weaker between-group separation than those based on the classifications of partial response or response and metrics that integrate information over time to produce greater separation than those based on single endpoint assessment. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination in separating the treatment groups than metrics based on partial response or response classifications. Metrics that integrated information over the 2-year observation period had stronger performance characteristics than those based on symptom scores at single endpoint assessment. For both the clinician-rated and self-report depression ratings, the metrics with the strongest performance characteristics were the median percentage change in symptom scores over the observation period and the proportion of the observation period in partial response or better. CONCLUSION: In difficult-to-treat depression, integrative symptom severity-based and time-based measures are sensitive and informative outcomes for assessing between-group treatment effects, while metrics based on remission status are not.

Efficacy and safety of zuranolone co-initiated with an antidepressant in adults with major depressive disorder: results from the phase 3 CORAL study.

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.

Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Controlled Trial.

Importance: Bipolar II disorder (BDII) is a debilitating condition frequently associated with difficult-to-treat depressive episodes. Psilocybin has evidence for rapid-acting antidepressant effects but has not been investigated in bipolar depression. Objective: To establish the safety and efficacy of psilocybin in patients with BDII in a current depressive episode. Design, Setting, and Participants: This was a 12-week, open-label nonrandomized controlled trial conducted at Sheppard Pratt Hospital. Participants aged 18 to 65 years with BDII, a current depressive episode longer than 3 months, and documented insufficient benefit with at least 2 pharmacologic treatments during the current episode were invited to participate. Of 70 approached, 19 met inclusion criteria and were enrolled. The trial was conducted between April 14, 2021, and January 5, 2023. Interventions: A single dose of synthetic psilocybin, 25 mg, was administered. Psychotropic medications were discontinued at least 2 weeks prior to dosing. Therapists met with patients for 3 sessions during pretreatment, during the 8-hour dosing day, and for 3 integration sessions posttreatment. Main Outcomes and Measures: The primary outcome measure was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Secondary measures included MADRS scores 12 weeks posttreatment, the self-rated Quick Inventory of Depression Symptoms-Self Rating (QIDS-SR), and the self-rated Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), each completed at baseline and all subsequent visits. Safety measures included the Columbia Suicide Severity Rating Scale (CSSRS) and the Young Mania Rating Scale (YMRS) completed at each visit. Results: Of the 15 participants in this study (6 male and 9 female; mean [SD] age, 37.8 [11.6] years), all had lower scores at week 3, with a mean (SD) change of -24.00 (9.23) points on the MADRS, (Cohen d = 4.08; 95% CI, -29.11 to -18.89; P < .001). Repeat measures analysis of variance showed lower MADRS scores at all tested posttreatment time points, including the end point (Cohen d = 3.39; 95% CI, -33.19 to -16.95; adjusted P < .001). At week 3, 12 participants met the response criterion (50% decrease in MADRS), and 11 met remission criterion (MADRS score ≤10). At the study end point, 12 patients met both response and remission criteria. QIDS-SR scores and Q-LES-Q-SF scores demonstrated similar improvements. YMRS and CSSRS scores did not change significantly at posttreatment compared to baseline. Conclusions and Relevance: The findings in this open-label nonrandomized controlled trial suggest efficacy and safety of psilocybin with psychotherapy in BDII depression and supports further study of psychedelics in this population.

Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported.Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s).Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146]).Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.Trial Registration: ClinicalTrials.gov identifier: NCT03864614.

Dosing transcranial magnetic stimulation in major depressive disorder: Relations between number of treatment sessions and effectiveness in a large patient registry.

BACKGROUND: The number of sessions in an acute TMS course for major depressive disorder (MDD) is greater than in the earlier randomized controlled trials. OBJECTIVE: To compare clinical outcomes in groups that received differing numbers of TMS sessions. METHODS: From a registry sample (N = 13,732), data were extracted for 7215 patients treated for MDD with PHQ-9 assessments before and after their TMS course. Groups were defined by number of acute course treatment sessions: 1-19 (N = 658), 20-29 (N = 616), 30-35 (N = 1375), 36 (N = 3591), 37-41 (N = 626), or >41 (N = 349) and compared in clinical outcomes at endpoint and at fixed intervals (after 10, 20, 30, and 36 sessions). The impact of additional treatments beyond 36 sessions was also examined. RESULTS: Groups that received fewer than 30 sessions had inferior endpoint outcomes than all other groups. PHQ-9 symptom reduction was greatest in the group that ended treatment at 36 sessions. The extended treatment groups (>36 sessions) differed from all other groups by manifesting less antidepressant response early in the course and had a slower but steady rate of improvement over time. Extending treatment beyond 36 sessions was associated with further improvement without evidence of a plateau. CONCLUSIONS: In real-world practice, there are strong relations between the number of TMS sessions in a course and the magnitude of symptom reduction. Courses with less than 30 sessions are associated with diminished benefit. Patients with longer than standard courses typically show less initial improvement and a more gradual trajectory, but meaningful benefit accrues with treatment beyond 36 sessions.

Assessing potential of psilocybin for depressive disorders.

INTRODUCTION: There has been increasing interest in the role psilocybin may play in the treatment of depressive disorders. Several clinical trials have shown psilocybin to have efficacy in reducing symptoms of depression. AREASCOVERED: We discuss the current understanding of psilocybin's therapeutic mechanism of action and review existing clinical data investigating psilocybin as a novel therapeutic agent for the treatment of depression. EXPERT OPINION: There is still much unknown regarding the risks of psilocybin treatment. When weighing the known risks and benefits of psilocybin treatment against those found in existing standards of care, among patients with depression, patients with treatment-resistant depression (TRD) may be the most suitable candidates for psilocybin treatment at this time.

Psychedelics, With a Focus on Psilocybin: Issues for the Clinician.

There has been a burgeoning interest in psychedelics among the public, state legislatures, psychiatrists and other clinical providers, and within the research community. Increasing numbers of studies evaluating psychedelics for depression, anxiety, posttraumatic stress disorder, and substance use disorders have been conducted or are underway. While discussing psychedelics in general, the focus of this paper is on psilocybin and its mechanism, how it exerts a psychedelic effect, dosing, and a review of the treatment studies of psilocybin, which were primarily for treatment-resistant depression and cancer-related anxiety. Future directions and potential limitations of studying and regulating psilocybin and other psychedelics are also discussed.

Psilocybin therapy for treatment resistant depression: prediction of clinical outcome by natural language processing.

RATIONALE: Therapeutic administration of psychedelics has shown significant potential in historical accounts and recent clinical trials in the treatment of depression and other mood disorders. A recent randomized double-blind phase-IIb study demonstrated the safety and efficacy of COMP360, COMPASS Pathways' proprietary synthetic formulation of psilocybin, in participants with treatment-resistant depression. OBJECTIVE: While the phase-IIb results are promising, the treatment works for a portion of the population and early prediction of outcome is a key objective as it would allow early identification of those likely to require alternative treatment. METHODS: Transcripts were made from audio recordings of the psychological support session between participant and therapist 1 day post COMP360 administration. A zero-shot machine learning classifier based on the BART large language model was used to compute two-dimensional sentiment (valence and arousal) for the participant and therapist from the transcript. These scores, combined with the Emotional Breakthrough Index (EBI) and treatment arm were used to predict treatment outcome as measured by MADRS scores. (Code and data are available at https://github.com/compasspathways/Sentiment2D .) RESULTS: Two multinomial logistic regression models were fit to predict responder status at week 3 and through week 12. Cross-validation of these models resulted in 85% and 88% accuracy and AUC values of 88% and 85%. CONCLUSIONS: A machine learning algorithm using NLP and EBI accurately predicts long-term patient response, allowing rapid prognostication of personalized response to psilocybin treatment and insight into therapeutic model optimization. Further research is required to understand if language data from earlier stages in the therapeutic process hold similar predictive power.

Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life.

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.

The Anxiolytic and Antidepressant Effects of Transcranial Magnetic Stimulation in Patients With Anxious Depression.

Objective: To determine the extent that treatment with transcranial magnetic stimulation (TMS) in diverse clinical settings has anxiolytic and antidepressant effects in patients with major depressive disorder (MDD) and moderate-to-severe anxiety symptoms and to contrast anxious and nonanxious depression subgroups in antidepressant effects.Methods: Within the NeuroStar Advanced Therapy System Clinical Outcomes Registry, 1,820 patients were identified with a diagnosis of MDD (using ICD-9, ICD-10, or DSM-IV) who completed the Patient Health Questionnaire-9 (PHQ-9) and Global Anxiety Disoder-7 scale (GAD-7) at baseline and following at least 1 TMS treatment between May 2016 and January 2021. Anxious depression was defined as a baseline GAD-7 score of 10 or greater (n = 1,514) and nonanxious depression by GAD-7 scores below this threshold (n = 306). Intent-to-treat and Completer samples were defined for patients treated with any TMS protocol and for the subgroup treated only with high-frequency left dorsolateral prefrontal cortex stimulation.Results: Patients with anxious depression showed clinically meaningful anxiolytic and antidepressant effects, averaging approximately 50% or greater reductions in both GAD-7 and PHQ-9 scores following TMS in all samples. The anxious and nonanxious depression groups had equivalent absolute improvement in PHQ-9 scores (P values ≥ .29). However, the anxious group had higher scores both at baseline and following TMS resulting in significantly lower categorical rates of response (P values < .02) and remission (P values < .001) in depressive symptoms. Among those with anxious depression, the change in anxiety and depression symptoms strongly covaried (r1512 = 0.75, P < .001).Conclusions: Routine TMS delivered in diverse clinical settings results in marked anxiolytic and antidepressant effects in patients with anxious depression. The extent of improvement in anxiety and depression symptoms strongly covaries.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: I. Association with change in quality of life.

BACKGROUND: In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. METHODS: Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores. CONCLUSIONS: Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

Optimizing outcomes in psilocybin therapy: Considerations in participant evaluation and preparation.

Recent studies have demonstrated the promise of psilocybin therapies in creating positive changes for those with poor mental health across multiple diagnostic categories, including major depressive disorder (MDD), end-of-life anxiety, and obsessive-compulsive disorder (OCD). While there may be a large population that is eligible to participate in psilocybin therapy based on psychiatric diagnosis and medical clearance, little attention has been given to intrapersonal and interpersonal factors that might influence patient's readiness (i.e., eligibility and capacity) for psychedelic interventions. This paper proposes that readiness assessment includes both intrapersonal and interpersonal factors in order to improve safety, patient care, and treatment outcomes. While at the present time a reliable and valid instrument has not been developed, we propose that three specific areas of focus - patient presentation, therapeutic alliance, and patient safety - may be used to establish a patient's readiness for psilocybin therapy, thus increasing therapy optimization and personalization.

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

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.).