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.

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.

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.

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.

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.

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.

Comparative efficacy, cognitive effects and acceptability of electroconvulsive therapies for the treatment of depression: protocol for a systematic review and network meta-analysis.

INTRODUCTION: There have been important advances in the use of electroconvulsive therapy (ECT) to treat major depressive episodes. These include variations to the type of stimulus the brain regions stimulated, and the stimulus parameters (eg, stimulus duration/pulse width). Our aim is to investigate ECT types using a network meta-analysis (NMA) approach and report on comparative treatment efficacy, cognitive side effects and acceptability. METHOD: We will conduct a systematic review to identify randomised controlled trials that compared two or more ECT protocols to treat depression. This will be done using the following databases: Embase, MEDLINE PubMed, Web of Science, Scopus, PsycINFO, Cochrane CENTRAL and will be supplemented by personal contacts with researchers in the field. All authors will be contacted to provide missing information. Primary outcomes will be symptom severity on a validated continuous clinician-rated scale of depression, cognitive functioning measured using anterograde verbal recall, and acceptability calculated using all-cause drop-outs. Secondary outcomes will include response and remission rates, autobiographical memory following a course of ECT, and anterograde visuospatial recall.Bayesian random effects hierarchical models will compare ECT types. Additional meta-regressions may be conducted to determine the impact of effect modifiers and patient-specific prognostic factors if sufficient data are available. DISCUSSION: This NMA will facilitate clinician decision making and allow more sophisticated selection of ECT type according to the balance of efficacy, cognitive side effects and acceptability. ETHICS: This systematic review and NMA does not require research ethics approval as it will use published aggregate data and will not collect nor disclose individually identifiable participant data. PROSPERO REGISTRATION NUMBER: CRD42022357098.

Comparison of clinical outcomes with left unilateral and sequential bilateral Transcranial Magnetic Stimulation (TMS) treatment of major depressive disorder in a large patient registry.

BACKGROUND: It has been suggested that sequential bilateral (SBL) TMS, combining high frequency, left dorsolateral prefrontal cortex (DLPFC) stimulation and low frequency, right DLPFC stimulation, is more effective than unilateral TMS. OBJECTIVE: To contrast treatment outcomes of left unilateral (LUL) and SBL protocols. METHODS: Registry data were collected at 111 practice sites. Of 10,099 patients, 3,871 comprised a modified intent-to-treat (mITT) sample, defined as a primary MDD diagnosis, age ≥18, and PHQ-9 completion before TMS and at least one PHQ-9 assessment after baseline. The mITT sample received high frequency (10 Hz) LUL TMS exclusively (N = 3,327) or SBL TMS in at least 90% of sessions (N = 544). Completers (N = 3,049) were responders or had received ≥20 sessions and had an end of acute treatment PHQ-9 assessment. To control for site effects, a Matched sample (N = 653) included Completers at sites that used both protocols. To control for selection bias, the SBL group was also compared to a Restricted LUL group, drawn from sites where no patient switched to SBL after substantial exposure to LUL TMS. Secondary analyses were conducted on CGI-S ratings. RESULTS: The LUL group had superior outcomes compared to the SBL group for multiple PHQ-9 and CGI-S continuous and categorical measures in the mITT, Completer and Matched samples, including in the specified primary analyses. However, outcome differences were not observed when comparing the Restricted LUL and SBL groups. Within SBL protocols, the LUL-RUL order had superior outcomes compared to the RUL-LUL order in all CGI-S, but not PHQ-9, measures. CONCLUSIONS: While limited by the naturalistic design, there was no evidence that SBL TMS was superior to LUL TMS. The sequential order of RUL TMS followed by LUL TMS may have reduced efficacy compared to LUL TMS followed by RUL TMS.

Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Adaptive current-flow models of ECT: Explaining individual static impedance, dynamic impedance, and brain current density.

BACKGROUND: Improvements in electroconvulsive therapy (ECT) outcomes have followed refinement in device electrical output and electrode montage. The physical properties of the ECT stimulus, together with those of the patient's head, determine the impedances measured by the device and govern current delivery to the brain and ECT outcomes. OBJECTIVE: However, the precise relations among physical properties of the stimulus, patient head anatomy, and patient-specific impedance to the passage of current are long-standing questions in ECT research and practice. To this end, we develop a computational framework based on diverse clinical data sets. METHODS: We developed anatomical MRI-derived models of transcranial electrical stimulation (tES) that included changes in tissue conductivity due to local electrical current flow. These "adaptive" models simulate ECT both during therapeutic stimulation using high current (∼1 A) and when dynamic impedance is measured, as well as prior to stimulation when low current (∼1 mA) is used to measure static impedance. We modeled two scalp layers: a superficial scalp layer with adaptive conductivity that increases with electric field up to a subject-specific maximum (σSS¯), and a deep scalp layer with a subject-specific fixed conductivity (σDS). RESULTS: We demonstrated that variation in these scalp parameters may explain clinical data on subject-specific static impedance and dynamic impedance, their imperfect correlation across subjects, their relationships to seizure threshold, and the role of head anatomy. Adaptive tES models demonstrated that current flow changes local tissue conductivity which in turn shapes current delivery to the brain in a manner not accounted for in fixed tissue conductivity models. CONCLUSIONS: Our predictions that variation in individual skin properties, rather than other aspects of anatomy, largely govern the relationship between static impedance, dynamic impedance, and ECT current delivery to the brain, themselves depend on assumptions about tissue properties. Broadly, our novel modeling pipeline opens the door to explore how adaptive-scalp conductivity may impact transcutaneous electrical stimulation (tES).

Vagus Nerve Stimulation in Patients Receiving Maintenance Therapy With Electroconvulsive Therapy: A Series of 10 Cases.

OBJECTIVES: Electroconvulsive therapy (ECT) is a mainstay in both acute and long-term management of difficult-to-treat depression. However, frequent acute courses of ECT or prolonged maintenance ECT treatment may increase adverse-effect burden and/or reduce patient acceptability. Therefore, we investigated the effectiveness of adjunctive vagus nerve stimulation (VNS) therapy as an alternative strategy for long-term maintenance treatment in ECT-responsive patients. METHODS: This retrospective chart review identified maintenance ECT patients with unipolar (n = 5) and bipolar depression (n = 5) from 2 large hospital systems who had a history of ECT response, but the patients had significant residual incapacitating symptoms or increasing concerns regarding the burden associated with ECT and opted to receive adjunctive VNS therapy. The patients were followed for 2 years after VNS implantation. Response and remission were defined as Clinical Global Impression-Severity scale scores of ≤2 and 1, respectively, obtained at 1- and 2-year postimplantation compared with just before VNS implantation. RESULTS: One-year postimplantation, 6 of 10 had responded of which 5 met remission criteria. All 10 patients benefited from adjunctive VNS therapy with either fewer hospitalizations and/or ECT sessions. Seven of 10 stopped maintenance ECT by the end of year 1; an additional patient stopped maintenance ECT by year 2. No patients required an acute course of ECT during the 2-year follow-up. There was a statistically significant reduction (P < 0.0001) in mean (SD) Clinical Global Impression-Severity scale scores between baseline (5.4 [0.51]) and the 1-year postimplantation (2.1 [1.37]) time points, and between baseline and the 2-year postimplantation (2.3 [1.16]) time points, whereas no difference existed between the 1- and 2-year postimplantation time points. CONCLUSIONS: Vagus nerve stimulation therapy may be a useful maintenance strategy in patients with difficult-to-treat depression receiving maintenance ECT.

The Effects of Focal Electrically Administered Seizure Therapy Compared With Ultrabrief Pulse Right Unilateral Electroconvulsive Therapy on Suicidal Ideation: A 2-Site Clinical Trial.

BACKGROUND: Preliminary data suggest that focal electrically administered seizure therapy (FEAST) has antidepressant effects and less adverse cognitive effects than traditional forms of electroconvulsive therapy (ECT). This study compared the impact of FEAST and ultrabrief pulse, right unilateral (UB-RUL) ECT on suicidal ideation. METHODS: At 2 sites, patients in a major depressive episode were treated openly with FEAST or UB-RUL ECT, depending on their preference. The primary outcome measure was scores on the Beck Scale for Suicide Ideation (SSI). Scores on the suicide item of the Hamilton Rating Scale for Depression (HRSD-SI) provided a secondary outcome measure. RESULTS: Thirty-nine patients were included in the intent-to-treat sample (FEAST, n = 20; UB-RUL ECT, n = 19). Scores on both the SSI and HRSD-SI were equivalently reduced with both interventions. Both responders and nonresponders to the interventions showed substantial reductions in SSI and HRSD-SI scores, although the magnitude of improvement was greater among treatment responders. CONCLUSIONS: Although limited by the open-label, nonrandomized design, FEAST showed comparable effects on suicidal ideation when compared with routine use of UB-RUL ECT. These results are encouraging and support the need for further research and a noninferiority trial.

Is There Evidence That Stimulus Parameters and Electrode Placement Affect the Cognitive Side Effects of Electroconvulsive Therapy in Patients With Schizophrenia and Schizoaffective Disorder?: A Systematic Review.

ABSTRACT: Seventy percent of patients with treatment-resistant schizophrenia do not respond to clozapine. Electroconvulsive therapy (ECT) can potentially offer significant benefit in clozapine-resistant patients. However, cognitive side effects can occur with ECT and are a function of stimulus parameters and electrode placements. Thus, the objective of this article is to systematically review published clinical trials related to the effect of ECT stimulus parameters and electrode placements on cognitive side effects. We performed a systematic review of the literature up to July of 2020 for clinical studies published in English or German examining the effect of ECT stimulus parameters and/or electrode placement on cognitive side effects in patients with schizophrenia or schizoaffective disorder. The literature search generated 3 randomized, double-blind, clinical trials, 1 randomized, nonblinded trial, and 1 retrospective study. There are mixed findings regarding whether pulse width and stimulus dose impact on cognitive side effects. One study showed less cognitive side effect for right unilateral (RUL) than bitemporal (BT) electrode placement, and 2 studies showed a cognitive advantage for bifrontal (BF) compared with BT ECT. Only 1 retrospective study measured global cognition and showed post-ECT cognitive improvement with all treatment modalities using Montreal Cognitive Assessment in comparison to pre-ECT Montreal Cognitive Assessment scores. Current data are limited, but evolving. The evidence suggests that RUL or BF ECT have more favorable cognitive outcomes than BT ECT. Definitive larger clinical trials are needed to optimize parameter and electrode placement selection to minimize adverse cognitive effects.