Background The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses. Methods This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment. Results The analysis showed that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, baseline pain intensity, and ethnicity. Additionally, there was negligible correlation between postoperative pain intensity and depression severity. Limitations This post hoc analysis was conducted on a small sample, and the findings need to be confirmed by prospective controlled studies. Conclusions Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

Rapidly acting therapeutics like 3,4-methylenedioxymethamphetamine (MDMA) are promising treatments for disorders such as posttraumatic stress disorder (PTSD). However, understanding who benefits most and the underlying neural mechanisms remains a critical gap. Stratifying individuals by neural circuit profiles could help differentiate neural, behavioral, and affective responses to MDMA, enabling personalized treatment strategies. To investigate whether baseline stratification of individuals based on negative affect circuit profiles, particularly in response to nonconscious threat stimuli, can differentiate acute responses to MDMA. This randomized clinical trial, implementing a double-blinded, within-participant, placebo- and baseline-controlled design, was conducted at Stanford University School of Medicine between November 2, 2021, and November 9, 2022, for wave 1 data collection. Participants had used MDMA on at least 2 prior occasions, but not in the past 6 months, and had subthreshold PTSD symptoms and early life trauma but no current psychiatric disorders. Data were analyzed from March 1, 2023, to January 1, 2024. Participants completed 4 visits: 1 baseline session followed by 1 placebo session and 2 MDMA sessions in a randomized order, totaling 64 visits. Baseline functional magnetic resonance imaging (fMRI) assessed the negative affect circuit using a nonconscious threat processing task (NTN). Primary outcomes included activity and connectivity of amygdala and subgenual anterior cingulate cortex (sgACC) defining the negative affect circuit. Secondary outcomes were behavioral measures of implicit threat bias, likability of threat expressions, and affective assessments. Sixteen participants (10 [63%] female; mean [SD] age, 40.8 [7.6] years) were stratified into subgroups with high and low levels of NTN activity in the amygdala (NTNA+ [n = 8] and NTNA− [n = 8], respectively), based on a median split of baseline nonconscious threat-evoked fMRI responses. Following administration of the 120 mg of MDMA vs placebo, the NTNA+ subgroup showed significant reductions in amygdala (contrast estimate [CE], −1.43; 95% CI, −2.60 to −0.27; Cohen d, −1.22; P = .02) and sgACC activity (CE, −1.48; 95% CI, −2.42 to −0.54; Cohen d, −1.56; P = .004), increased sgACC-amygdala connectivity (CE, 0.65; 95% CI, 0.02-1.28; Cohen d, 1.02; P = .04), and increased likability of threat expressions (CE, 14.38; 95% CI, 1.46-27.29; Cohen d, 0.86; P = .03) compared with the NTNA− subgroup. In this randomized clinical trial of MDMA’s acute profiles, 120 mg of MDMA acutely normalized negative affect circuit reactivity in participants stratified by heightened amygdala reactivity at baseline, demonstrating the potential of neuroimaging to identify prospective biomarkers and guide personalized MDMA-based therapies. ClinicalTrials.gov Identifier: NCT04060108

Importance:Rapidly acting therapeutics like 3,4-methylenedioxymethamphetamine (MDMA) are promising treatments for disorders such as posttraumatic stress disorder (PTSD). However, understanding who benefits most and the underlying neural mechanisms remains a critical gap. Stratifying individuals by neural circuit profiles could help differentiate neural, behavioral, and affective responses to MDMA, enabling personalized treatment strategies. Objective:To investigate whether baseline stratification of individuals based on negative affect circuit profiles, particularly in response to nonconscious threat stimuli, can differentiate acute responses to MDMA. Design, Setting, and Participants:This randomized clinical trial, implementing a double-blinded, within-participant, placebo- and baseline-controlled design, was conducted at Stanford University School of Medicine between November 2, 2021, and November 9, 2022, for wave 1 data collection. Participants had used MDMA on at least 2 prior occasions, but not in the past 6 months, and had subthreshold PTSD symptoms and early life trauma but no current psychiatric disorders. Data were analyzed from March 1, 2023, to January 1, 2024. Interventions:Participants completed 4 visits: 1 baseline session followed by 1 placebo session and 2 MDMA sessions in a randomized order, totaling 64 visits. Baseline functional magnetic resonance imaging (fMRI) assessed the negative affect circuit using a nonconscious threat processing task (NTN). Main Outcomes and Measures:Primary outcomes included activity and connectivity of amygdala and subgenual anterior cingulate cortex (sgACC) defining the negative affect circuit. Secondary outcomes were behavioral measures of implicit threat bias, likability of threat expressions, and affective assessments. Results:Sixteen participants (10 [63%] female; mean [SD] age, 40.8 [7.6] years) were stratified into subgroups with high and low levels of NTN activity in the amygdala (NTNA+ [n = 8] and NTNA- [n = 8], respectively), based on a median split of baseline nonconscious threat-evoked fMRI responses. Following administration of the 120 mg of MDMA vs placebo, the NTNA+ subgroup showed significant reductions in amygdala (contrast estimate [CE], -1.43; 95% CI, -2.60 to -0.27; Cohen d, -1.22; P = .02) and sgACC activity (CE, -1.48; 95% CI, -2.42 to -0.54; Cohen d, -1.56; P = .004), increased sgACC-amygdala connectivity (CE, 0.65; 95% CI, 0.02-1.28; Cohen d, 1.02; P = .04), and increased likability of threat expressions (CE, 14.38; 95% CI, 1.46-27.29; Cohen d, 0.86; P = .03) compared with the NTNA- subgroup. Conclusions and Relevance:In this randomized clinical trial of MDMA's acute profiles, 120 mg of MDMA acutely normalized negative affect circuit reactivity in participants stratified by heightened amygdala reactivity at baseline, demonstrating the potential of neuroimaging to identify prospective biomarkers and guide personalized MDMA-based therapies. Trial Registration:ClinicalTrials.gov Identifier: NCT04060108.

Back to table of contents Previous article Next article Letters to the EditorFull AccessReduction in Trauma-Related Symptoms After Anesthetic-Induced Intra-Operative DreamingLaura M. Hack, M.D., Ph.D., Pilleriin Sikka, Ph.D., Kelly Zhou, D.N.P., C.R.N.A., Makoto Kawai, M.D., Harrison S. Chow, M.D., Boris Heifets, M.D., Ph.D.Laura M. Hack, M.D., Ph.D., Pilleriin Sikka, Ph.D., Kelly Zhou, D.N.P., C.R.N.A., Makoto Kawai, M.D., Harrison S. Chow, M.D., Boris Heifets, M.D., Ph.D.Published Online:13 Mar 2024https://doi.org/10.1176/appi.ajp.20230698AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the editor: While dreaming during anesthesia is common (1), it is not known whether this phenomenon differs from normal dreaming or has post-surgical benefits. We present two cases of female patients who experienced rapid and sustained reduction of posttraumatic stress disorder (PTSD) symptoms immediately following anesthetic-based EEG-guided intraoperative dream induction. Both patients underwent surgeries and received propofol/opioid-based anesthetics. Upon finishing the surgery but before emergence, we maintained a pre-emergent anesthetic state characterized by specific frontal cortical activity for several minutes: reduced alpha power and enhanced beta power (2). Based on previous findings showing that dreaming during anesthesia is associated with more high-frequency frontal power before emergence (3) or as compared to connected consciousness (1), we believe this cortical activity reflects dreaming while being sedated. Patients were interviewed immediately upon emergence, and both reported having had vivid dreams.Both patients were identified as part of a quality-improvement program to enhance recovery after surgery, which includes informing patients of the possibility of dreaming without priming content, minimizing likelihood of emergence agitation through use of intravenous rather than inhalational anesthesia, minimal sensory input during gradual anesthetic emergence (4), and assessment for intraoperative awareness and dreaming immediately on emergence using a modified Brice Questionnaire (5). After identification, both patients provided informed consent for retrospective psychiatric diagnostic interviews. Patients were not identified preoperatively. Anesthetic adjustments, assessment, and diagnostic interviews adhere to established standards of care, received approval from the IRB, or fall under IRB exemption (IRB exempt protocols #54043, #59783, #65538, #67245; informed consent provided on IRB protocol #67399).Patient 1, a 57-year-old White female with no current alcohol, tobacco, or drug use and noncontributory medical history except invasive ductal carcinoma of the right breast, presented for a right breast lumpectomy and axillary lymph node biopsy. She was not taking psychiatric medications at the time of surgery. She endorsed one nightmare per week about her son, who had died by suicide in 2017. She recalled two "euphoric" intra-operative dreams: in one, she experienced her son's birth, originally traumatic, as deeply joyful; in a second, she spent time with her adult son and experienced cathartic relief. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) indicated a diagnosis of PTSD pre-operatively. One-month post-surgery, she no longer met criteria for PTSD, and by 1 year, she had remitted. Self-report scales indicated improvement in depression, anxiety, and sleep (Figure 1). The patient reported that she has not had a nightmare "in over 18 months" and that her experience during surgery "saved her life."FIGURE 1. Retrospective symptom ratings after dreaming associated with anesthesiaaaDiagnostic interviews for PTSD were performed at 38 and 324 days (patient 1) and 25 days (patient 2) after the surgical encounter. From left to right, symptom scales for PTSD (Clinician-Administered PTSD Scale [CAPS-5], depression (Patient Health Questionnaire, eight items [PHQ-8]), Generalized Anxiety Disorder, seven items [GAD-7]), and sleep quality (Pittsburgh Sleep Quality Index [PSQI]). Retrospective ratings are indicated by open symbols, current ratings are indicated by closed symbols. Day of surgery indicated on x-axis, orange line. Remission threshold for each scale indicated on y-axis, dashed red line.Patient 2, a 72-year-old White female with no reported alcohol, tobacco, or drug use and noncontributory medical history except hyperparathyroidism, presented for parathyroidectomy. She was taking fluoxetine for anxiety and depression at the time of surgery. She reported occasional nightmares about her son in the month pre-surgery, who died in 2000 from alcohol poisoning during a college fraternity hazing. Intra-operatively, she dreamed about being with her late son and other family members and described the dream as "very positive." CAPS-5 assessment indicated that she met criteria for PTSD in the month pre-surgery but not in the month post-surgery, and self-report scales for anxiety and depression showed improvement (Figure 1). She denied nightmares in the month post-surgery.Anesthetic-induced prolonged dream states may serve as an emotion regulation function. Patients experiencing fear memory elements (i.e., dreaming about their sons) on a background of anesthetic-induced low arousal may have contributed to fear extinction (6). We recently presented a case of resolution of acute stress disorder (2) after anesthetic-induced intra-operative dreaming. These collected cases suggest that anesthetic-induced intra-operative dreaming may be therapeutic in both recent onset and long-standing trauma disorders and have a rapid and durable effect. This preliminary evidence justifies an open-label study of deliberate induction of dreaming with anesthesia in PTSD.Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Calif. (Hack, Kawai, Heifets); Sierra Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), VA Palo Alto Health Care System, Palo Alto, Calif. (Hack, Kawai); Department of Psychology, Stanford University, Stanford, Calif. (Sikka); Department of Psychology, University of Turku, Turku, Finland (Sikka); Department of Cognitive Neuroscience and Philosophy, University of Skövde, Skövde, Sweden (Sikka); Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, Calif. (Sikka, Zhou, Chow, Heifets).Send correspondence to Dr. Heifets ([email protected]).Dr. Hack and Dr. Sikka are equal first authors.Dr. Chow and Dr. Heifets are equal senior authors.The authors report no financial relationships with commercial interests.References1. Casey CP, Tanabe S, Farahbakhsh Z, et al.: Distinct EEG signatures differentiate unconsciousness and disconnection during anaesthesia and sleep. Br J Anaesth 2022; 128:1006–1018Crossref, Medline, Google Scholar2. Chow HS, Hack LM, Kawai M, et al.: Anesthetic-induced intraoperative dream associated with remission of a psychiatric disorder: a case report. A A Pract 2022; 16:e01613Medline, Google Scholar3. Leslie K, Sleigh J, Paech MJ, et al.: Dreaming and electroencephalographic changes during anesthesia maintained with propofol or desflurane. Anesthesiology 2009; 111:547–555Crossref, Medline, Google Scholar4. Tolly B, Waly A, Peterson G, et al.: Adult emergence agitation: a veteran-focused narrative review. Anesth Analg 2021; 132:353–364Crossref, Medline, Google Scholar5. Brice DD, Hetherington RR, Utting JE: A simple study of awareness and dreaming during anaesthesia. Br J Anaesth 1970; 42:535–542Crossref, Medline, Google Scholar6. Levin R, Nielsen TA: Disturbed dreaming, posttraumatic stress disorder, and affect distress: a review and neurocognitive model. Psychol Bull. 2007; 133:482–528Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byNone Metrics KeywordsPosttraumatic Stress Disorder (PTSD)PsychopharmacologyPDF download History Received 5 September 2023 Revised 12 December 2023 Accepted 3 January 2024 Published online 13 March 2024

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or ‘biotypes’ to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry. Personalized brain circuit measures quantified using a new imaging technology in 801 patients with depression and anxiety identify six biotypes with unique symptoms, behaviors and responses to different types of treatment.

Numerous studies have demonstrated that inflammation has effects on neurotransmitter systems and neurocircuits in the brain and thereby can affect behavior. Moreover, studies have reliably demonstrated reproducible relationships between inflammatory markers and psychiatric disorders. The goal of this project was to review the literature to determine which specific symptoms across disorders are most reliably associated with inflammation and its effects on the brain. The clinical subgroup of the NSAS Challenge Workshop on Brain Immune Interactions focused on reviewing a range of symptoms including anhedonia, fatigue, appetite, sleep, anxiety, pain, cognition, suicidality, and irritability. PubMed searched for these symptoms and for immune dysregulation: ("Inflammatory" OR "Inflammation" OR "Inflammat*" OR "Cytokine*" OR "Interleukin" OR "C-reactive Protein" OR "CRP" OR "IL-6" OR "Interleukin 6" OR "immune" OR "Immun*" OR "nucleophiles" OR "lymphocytes" OR "immunogenetics" OR "white blood cell" OR "WBC" OR "neutrophil*"). There has been a recent surge of reports with past-five-years accounting for over a third of publications on these topics. Multiple meta-analyses have also been published related to these searches for psychiatric disorders including 3 on anhedonia, 5 on fatigue, 2 on appetite, 9 on sleep, 29 on anxiety, 5 on pain, 17 on cognition, 20 on suicidality, an 0 on irritability. Detailed results of the review of these findings from the workshop (01-05JUN2023) will be presented. Identification of transdiagnostic symptoms reliably associated with inflammation will help further elucidate inflammatory phenotypes that can be used as outcome variables in future studies, especially clinical trials using anti-inflammatory treatments of psychiatric disorders.

BackgroundWithin the perioperative period, depression-related diagnoses are associated with postoperative complications. We developed a perioperative depression screening programme to assess disease prevalence and feasibility for intervention.MethodsAdult patients in multiple surgical departments at a single academic centre were screened for depression via the electronic health record patient portal or preoperative anaesthesia clinic before surgery, using the Patient Health Questionnaire (PHQ)-2 and -8. We utilised a broad method, screening all patients, and a focused method, only screening patients with a history of depression. Logistic regression was used to identify characteristics associated with clinically significant depression (PHQ-8 ≥10). Symptomatic patients were administered a brief psychoeducational intervention and referred for mental health services.ResultsA total of 3735 patients were identified by the broad and focused screens, of whom 2940 (79%) returned PHQ-2 data and were included in analysis. The broad screen (N=1216) found 46 (4%) patients who reported symptoms of moderate or greater severity. The focused screen (N=1724) found 242 (14%) patients with symptoms of moderate or greater severity and over all higher rates of depression across the symptom severity scale. Using the total screened pool, logistic regression identified a history of depression as the strongest associated patient characteristic variable but this did not capture most cases. Finally, we found that 66% of patients who were contacted about mental health services accepted referrals or sought outside care.ConclusionsAt least 4% of preoperative patients have clinically significant symptoms of depression, most of whom do not have a chart history of depression.

Background:The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses. Methods:This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment. Results:In the placebo arm, baseline opioid use was associated with a 10-point increase (95% CI: 0.81-19.4) in MADRS scores across all post-treatment time points, indicating worse depression in this subgroup. In an alternative model using percent change in MADRS scores, the difference between opioid users and non-users was 38.4% (95% CI: 8.59-68.2), with opioid users experiencing less improvement. For ketamine-treated participants, baseline opioid use did not significantly impact MADRS scores or the percent change in MADRS scores. Pain intensity was not a significant predictor of MADRS outcomes, and the correlation between post-treatment MADRS scores and pain intensity was negligible (R=0.12). Limitations:This analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies. Conclusions:Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

We present the case of Mr. B, who was part of a NIMH-funded, longitudinal, observational study (2013 to 2016) that recruited unmedicated participants who were experiencing a range of palpable symptoms related to states of negative affect and who were assessed on multiple objective measures. A feedback report was generated based on Mr. B's multimodal measurements. One of the authors, LMW, along with Mr. B's psychotherapist, discussed the results with Mr. B in a feedback session. Mr. B's objective testing profile was consistent with a history of trauma, allowing him for the first time to be comfortable with revealing to his therapist that he experienced early-life trauma. Mr. B's case highlights several known advantages of integrating objective data into psychiatric encounters, including reducing stigma, motivating patients to pursue treatment, and improving clinical outcomes by aiding in identification of the right treatment, which is the ultimate goal of precision psychiatry. [ Psychiatr Ann . 2024;54(4):e113–e118.]

BackgroundRepetitive transcranial magnetic stimulation (TMS) is now widely accepted as an effective non-pharmacologic treatment for treatment-resistant depression. However, whether repeated acute TMS courses can recapture the antidepressant effects of the initial acute course is still an open question, especially in the Veteran population. We present here a retrospective analysis of a specialty clinic within the Veteran Affairs Hospital System to help address this question.AimsFollowing an acute treatment course of TMS, we sought to determine the treatment response of a subsequent TMS course. We hypothesized that those who responded to an initial acute TMS course would respond in a similar manner to a subsequent treatment course.Methods116 cases referred for evaluation for TMS between September 2017 to April 2021 were reviewed. 63 Veterans completed at least one acute course of TMS and 12 completed at least two courses and met inclusion criteria for this review. 6 met criteria for treatment response in the first course, while the other 6 were initial treatment nonresponders. Symptoms were evaluated via self-reported scales at baseline and weekly throughout treatment. Clinical response to subsequent treatment (>50% symptom reduction as measured by the PHQ-9) was compared to initial treatment response.ResultsOf the initial treatment responders (n = 6), all six responded to a second acute course, with an 85.3% symptom reduction. Of the initial treatment nonresponders (n = 6), three responded to a second acute course. No adverse events were reported in those who completed a second course, and the Veterans tolerated the treatment well.ConclusionsOur findings support the growing understanding that a second acute TMS treatment course for treatment-resistant depression is safe, well-tolerated, and effective in initial responders and some non-responders. Despite multiple confounders in a naturalistic setting, robust initial treatment response was sustained in a second acute course. Low power limits generalizability, and larger powered, prospective studies are needed.

ImportanceCognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or “biotype”) of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes.ObjectiveTo undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities.Design, Setting, and ParticipantsThis secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023.Main Outcomes and MeasuresPretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging.ResultsA total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = −0.25; 95% CI, −0.39 to −0.11;P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex:d = −0.78; 95% CI, −1.28 to −0.27;P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%];P = .04) and cognitive impairments persisted regardless of symptom change, remaining at least 0.2 standard deviations below the healthy mean. The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse.Conclusions and RelevanceOur findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction.Trial RegistrationClinicalTrials.gov Identifier:NCT00693849

3,4-Methylenedioxymethamphetamine (MDMA), a serotonin releaser, reduces interpersonal defensiveness but is also thought to open a “critical period” in the brain in which alterations in consciousness may enhance a therapeutic process. However, the relationship between MDMA-induced effects on brain connectomes and these altered states has not been directly examined.

Abstract While the precision effort using transcranial magnetic stimulation (TMS) in major depressive disorder (MDD) has mostly focused on more precise targeting, less progress has occurred in patient stratification. This chapter focuses on dysfunctions in large scale neural networks measured using functional magnetic resonance imaging (MRI) as a means of identifying baseline predictors of TMS response and subtyping depressed individuals. Illustrating this approach, the chapter describes an innovative, large (target n = 100), pragmatic mechanistic TMS study embedded within the national Veterans Administration (VA) TMS Clinical Program involving 4 VA sites and standardized treatment parameters and neuroimaging protocols. The chapter concludes with a description of the promises and pitfalls of big data approaches for patient stratification in TMS in MDD.

Importance:Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes. Objective:To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities. Design, Setting, and Participants:This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023. Main Outcomes and Measures:Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging. Results:A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = -0.25; 95% CI, -0.39 to -0.11; P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d = -0.78; 95% CI, -1.28 to -0.27; P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P = .04) and cognitive impairments persisted regardless of symptom change (executive function: ηp2 = 0.241; P < .001; response inhibition: ηp2 = 0.750; P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse. Conclusions and Relevance:Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction. Trial Registration:ClinicalTrials.gov Identifier: NCT00693849.

Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain’s affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals.

3,4-Methylenedioxymethamphetamine (MDMA) has been shown to reduce interpersonal defensiveness, but the neural mechanisms by which it promotes enhanced trust and openness are not well understood.

Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. Here we present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (ClinicalTrials.gov, NCT03861988 ). Adult patients (N = 40) with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg kg−1) or placebo (saline) during usual anesthesia. All participants, investigators and direct-patient-care staff were masked to treatment allocation. The primary outcome was depression severity measured by the Montgomery–Åsberg Depression Rating Scale at 1, 2 and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (−5.82, 95% confidence interval −13.3 to 1.64, P = 0.13). Of all participants, 36.8% guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in patients with moderate-to-severe depression using surgical anesthesia. Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment to minimize participant-expectancy bias. In this clinical trial, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder.