Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties.

Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight - at times, bordering on the mystical - one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of 'non-psychedelic/subjective psychedelics', or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence - both clinical and preclinical - surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question.

Change in neurocognitive functioning in patients with treatment-resistant depression with serial intravenous ketamine infusions: The Bio-K multicenter trial.

This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03-1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (ß =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD. Trial Registration: ClinicalTrials.gov: NCT03156504.

Metabolomic signatures of intravenous racemic ketamine associated remission in treatment-resistant depression: A pilot hypothesis generating study.

In this pilot study (N = 9), we highlight new insights gained on ketamine's mechanism of action where we have mapped biochemical processes that are affected within 40 min of intravenous ketamine exposure. Targeting acylcarnitines, we demonstrated rapid utilization of short-chain acylcarnitines within 40 min of ketamine treatment followed by restoration within 24 h; this change in short chain acylcarnitine with rapid-acting antidepressant treatment is consistent with previous work identifying similar change but at 8-weeks with slower-acting SSRI treatment. Using a non-targeted metabolomics platform, we defined broader effects of ketamine on lipid metabolism and identified changes in triglyceride that correlate with ketamine response. This study provides novel insights into ketamine's action and highlighting a possible role for mitochondrial function and energy metabolism in ketamine's mechanism of action.

A Characterization of the Clinical Global Impression Scale Thresholds in the Treatment of Adolescent Depression Across Multiple Rating Scales.

Introduction: The Clinical Global Impressions-Improvement (CGI-I) scale is widely used in clinical research to assess symptoms and functioning in the context of treatment. The correlates of the CGI-I with efficacy scales for adolescent major depressive disorder are poorly understood. This study focused on benchmarking CGI-I scores with changes in the Children's Depression Rating Scale-Revised (CDRS-R) and the Quick Inventory of Depressive Symptomatology-Adolescent (17-item) Self-Report (QIDS-A17-SR). Methods: We examined three datasets with the clinician-rated CDRS-R to ascertain equivalent percent changes in total scores and CGI-I ratings. Exploratory analyses examined corresponding percentage changes in the QIDS-A17-SR and the CGI-I ratings. The CGI-I was the reference scale for nonparametric equipercentile linking with the Equate package in R. Results: CGI-I scores of 1 mapped to ≥78%-95% change in CDRS-R scores at 4-6 weeks across three datasets. CGI-I scores of 2 mapped to 56%-94% change in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 3 mapped to 30%-68% changes in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 4 mapped to a range of 29%-44% at 4-6 weeks across three studies. There was no significant difference (p ≥ 0.6) between treatment groups in both the Treatment of Adolescents with Depression and Treatment of Resistant Depression in Adolescents studies, for each CGI-I score ( = 1, or = 2 or = 3, or ≥4), associated mapping of total depression severity score, or associated percent change from baseline for corresponding follow-up visits. There was no significant sex difference (p > 0.2) in CGI-I linkages to CDRS-R total or percentage changes. Conclusions: These findings establish clear relationships among CGI-I scores and the CDRS-R and the QIDS-A17-SR. These benchmarks have utility for clinical trial study design, inter-rater reliability training, and clinical implementation.

A preliminary study of the association of increased anterior cingulate gamma-aminobutyric acid with remission of depression after ketamine administration.

Gamma-aminobutyric acid (GABA) and glutamate neurotransmission have been implicated in the pathophysiology of depression and mechanistically linked to ketamine's antidepressant response. Seven patients with treatment-resistant depression enrolled in an open-label, feasibility trial of a single IV 40-min ketamine infusion during a functional MR spectroscopy (fMRS) scan utilizing a novel frequency adjusting MEGA-PRESS sequence. Next-day treatment remission and reduction in the MADRS scores correlated with anterior cingulate cortex peak GABA levels. These novel findings provide further insights into the underlying neurobiological mechanisms of ketamine and, if confirmed in larger studies, would be encouraging for further development of GABAergic biomarker associated with ketamine response.

Accelerated TMS for Depression: A systematic review and meta-analysis.

Repetitive transcranial magnetic stimulation (TMS) is now widely available for the clinical treatment of depression, but the associated financial and time burdens are problematic for patients. Accelerated TMS (aTMS) protocols address these burdens and attempt to increase the efficiency of standard TMS. This systematic review and meta-analysis aimed to examine accelerated TMS studies for depressive disorders in accordance with PRISMA guidelines. Inclusion criteria consisted of studies with full text publications available in English describing more than one session of TMS (repetitive or theta burst stimulation) per day. Studies describing accelerated TMS protocols for conditions other than depression or alternative neuromodulation methods, preclinical studies, and neurophysiology studies regarding transcranial stimulation were excluded. Eighteen articles describing eleven distinct studies (seven publications described overlapping samples) met eligibility criteria. A Hedges' g effect size and confidence intervals were calculated. The summary analysis of three suitable randomized control trials revealed a cumulative effect size of 0.39 (95% CI 0.005-0.779). A separate analysis including open-label trials and active arms of suitable RCTs revealed a g of 1.27 (95% CI 0.902-1.637). Overall, the meta-analysis suggested that aTMS improves depressive symptom severity. In general, study methodologies were acceptable, but future efforts could enhance sham techniques and blinding.

High-frequency repetitive TMS for suicidal ideation in adolescents with depression.

BACKGROUND: This exploratory study sought to examine the effect of an acute course of high-frequency repetitive TMS on suicidal ideation in adolescents. METHODS: Data were pooled from 3 prior protocols providing a 30-session course of open-label TMS treatment for adolescents with treatment-resistant depression. All participants (n = 19) were outpatients taking antidepressant medication, with TMS provided as adjunctive treatment. Suicidality was assessed at baseline, after 10 treatments, after 20 treatments, and after 30 treatments. Outcome measures of suicidal ideation included the Columbia Suicide Severity Rating Scale (C-SSRS) "Intensity of Ideation" subscale and Item 13 "Suicidality" on the Children's Depression Rating Scale, Revised (CDRS-R). RESULTS: The predicted odds of suicidal ideation (CDRS-R Item 13 and C-SSRS Intensity of Ideation subscale) significantly decreased over 6 weeks of acute TMS treatment without adjustments for illness (depression) severity. However, the magnitude of the decrease in the predicted odds of suicidal ideation across 6 weeks of treatment was attenuated and rendered non-significant in subsequent analyses that adjusted for illness (depression) severity. LIMITATIONS: This was an exploratory study with a small sample size and no sham control. Regulatory and ethical barriers constrained enrollment of adolescents with severe suicidality. CONCLUSIONS: The present findings suggest that open-label TMS mitigated suicidal ideation in adolescents through the treatment and improvement of depressive symptom severity. Although caution is warranted in the interpretation of these results, the findings can inform the design and execution of future interventional trials targeting suicidal ideation in adolescents.