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Background: Misophonia is a complex condition characterized by extreme emotional distress in response to specific sounds or specific visual stimuli. Despite a growing body of clinical and neuroscientific literature, the etiology of this condition remains unclear. Hyperarousal, that is, a state of heightened alertness and disinhibition, as a core feature of misophonia is supported by behavioral and neuroimaging literature and might represent a viable clinical target for the development of both behavioral and pharmacological interventions. The aim of this study was to investigate how hyperarousal might be linked to neurocognitive processes associated with vigilance and stimulus discrimination in youth with misophonia., Methods: We compared 72 children and adolescents with misophonia (13.74 ± 2.44 years) (64 % female) and 89 children and adolescents with anxiety (12.35 ± 2.57 years) (58.4 % female) on behavioral and signal detection performance of the immediate memory task (IMT). Anxiety patients were used as a clinical control group to distinguish attentional processes specific for misophonia., Results: Both groups demonstrated similar behavioral performance, including response rate and reaction time. However, misophonia was associated with elevated stimulus discrimination (d prime), which in turn was positively correlated with the severity of misophonia trigger reports., Conclusions: Our findings are in line with previous cognitive and neuroimaging studies, and support an arousal-based model of misophonia, where individuals with misophonia experience a state of heightened vigilance, being more aware of stimuli in the environment. Our findings provide a neurocognitive basis for future study of neurochemical imaging that might further progress towards clinical targets., Competing Interests: Declaration of competing interest N. Murphy has received grants/research support from NIMH (1R21MH119441-01A1); REAM Misophonia Research Fund (The REAM Foundation - YR01); Caroline Wiess Law Fund for Research in Molecular Medicine, and has previously received research support as a subinvestigator for clinical research for Neurocrine Biosciences Inc. M. Cervin receives research support from the Swedish Research Council for Health, Working Life and Welfare, the Lindhaga Foundation, Stiftelsen Clas Grochinskys Minnesfond, the Crown Princess Lovisa's Association, Region Skåne, and Skåne University Hospital's Foundations and Donations; and financial compensation from Springer for editorial work outside of the submitted work. Dr. Guzick receives grant support from the REAM Foundation/Misophonia Research Fund as well as the Texas Higher Education Coordinating Board. Dr. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He is a consultant for Brainsway and Biohaven Pharmaceuticals. He owns stock less than $5000 in NView (for distribution of the Y-BOCS and CY-BOCS) and Limbix. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, Routledge, and Jessica Kingsley., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Drug development in psychiatry has been hampered by the lack of reliable ways to determine the neurobiological effects of the assets tested, difficulties in identifying patient subsets more amenable to benefit from a given asset, and issues with executing trials in a manner that would convincingly provide answers. An emerging idea in many companies is to validate tools to address changes in neural circuits by pharmacological tools as a key piece in quantifying the effects of our drugs. Here, we review past, present, and emerging approaches to capture the outcome of the modulation of brain circuits. The field is now ripe for implementing these approaches in drug development., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Ketamine is an effective intervention for treatment-resistant depression (TRD), including late-in-life (LL-TRD). The proposed mechanism of antidepressant effects of ketamine is a glutamatergic surge, which can be measured by electroencephalogram (EEG) gamma oscillations. Yet, non-linear EEG biomarkers of ketamine effects such as neural complexity are needed to capture broader systemic effects, represent the level of organization of synaptic communication, and elucidate mechanisms of action for treatment responders. In a secondary analysis of a randomized control trial, we investigated two EEG neural complexity markers (Lempel-Ziv complexity [LZC] and multiscale entropy [MSE]) of rapid (baseline to 240 min) and post-rapid ketamine (24 h and 7 days) effects after one 40-min infusion of IV ketamine or midazolam (active control) in 33 military veterans with LL-TRD. We also studied the relationship between complexity and Montgomery-Åsberg Depression Rating Scale score change at 7 days post-infusion. We found that LZC and MSE both increased 30 min post-infusion, with effects not localized to a single timescale for MSE. Post-rapid effects of reduced complexity with ketamine were observed for MSE. No relationship was observed between complexity and reduction in depressive symptoms. Our findings support the hypothesis that a single sub-anesthetic ketamine infusion has time-varying effects on system-wide contributions to the evoked glutamatergic surge in LL-TRD. Further, changes to complexity were observable outside the time-window previously shown for effects on gamma oscillations. These preliminary results have clinical implications in providing a functional marker of ketamine that is non-linear, amplitude-independent, and represents larger dynamic properties, providing strong advantages over linear measures in highlighting ketamine's effects., (© 2023. The Author(s).)

Background: Misophonia is characterized by intense emotional reactions to specific sounds or visual stimuli and typically onsets during childhood. An obstacle for research and clinical practice is that no comprehensively evaluated measures for pediatric misophonia exist., Methods: In a sample of 102 youth meeting the proposed diagnostic criteria of misophonia, we evaluated the child and parent-proxy versions of the self-reported Misophonia Assessment Questionnaire (MAQ; assessing broad aspects of misophonia) and the child version of the Amsterdam Misophonia Scale (A-MISO-S; assessing misophonia severity). Confirmatory and exploratory factor analysis were used to examine factor structures of the measures. Further, child-parent agreement on the MAQ and associations between both measures and misophonia-related impairment, quality of life, and misophonia-related school interference were examined to evaluate aspects of convergent validity., Results: For both youth- and parent-ratings, four MAQ factors emerged: pessimism, distress, interference, and non-recognition. A-MISO-S showed a unidimensional structure, but the item 'effort to resist' did not load significantly onto the unidimensional factor. Good child-parent agreement on the MAQ scales were found and both MAQ and A-MISO-S were moderately to strongly associated with misophonia-related impairment, quality of life (inverse association), and misophonia-related school interference., Limitations: MAQ and A-MISO-S assess sensitivity to auditory but not visual stimuli, the sample size was modest, and repeated assessments were not conducted., Conclusions: The combination of MAQ and A-MISO-S shows promise as a multidimensional assessment approach for pediatric misophonia. Future evaluations should include known-groups validity, screening performance, and sensitivity to change in symptom severity., Competing Interests: Declaration of competing interest None, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: There is little information on the clinical presentation, functional impact, and psychiatric characteristics of misophonia in youth, an increasingly recognized syndrome characterized by high emotional reactivity to certain sounds and associated visual stimuli., Method: One-hundred-two youth (8-17 years-old) with misophonia and their parents were recruited and compared with 94 youth with anxiety disorders. Participants completed validated assessments of misophonia severity, quality of life, as well as psychiatric symptoms and diagnoses., Results: The most common misophonia triggers included eating (96 %), breathing (84 %), throat sounds (66 %), and tapping (54 %). Annoyance/irritation, verbal aggression, avoidance behavior, and family impact were nearly universal. Misophonia severity was associated with internalizing symptoms, child-reported externalizing behaviors, and poorer quality of life. High rates of comorbidity with internalizing and neurodevelopmental disorders were found. Quality of life and externalizing behaviors were not significantly different between misophonia and anxiety samples; internalizing symptoms and autism characteristics were significantly higher among youth with anxiety disorders., Limitations: This self-selected sample was characterized by limited multicultural diversity., Conclusions: This study presents misophonia as a highly impairing psychiatric syndrome. Future interdisciplinary work should clarify the mechanisms of misophonia, establish evidence-based treatments, and extend these findings to randomly sampled and more culturally diverse populations., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Drs. Guzick, Storch, Lewin, and Lijffijt receive grant support from the Ream Foundation. Dr. Guzick also receives grant funding from the Texas Higher Education Coordinating Board unrelated to this study. Dr. Lijffijt has served as principal investigator for studies funded by NeuroRx and VistaGen Therapeutics. Dr. Goodman has received donated devices from Medtronic and is a consultant for Biohaven Pharmaceuticals. Dr. Lewin has unrelated grant support from the Centers for Disease Control and Prevention and Tourette Association of America. He receives editorial and/or publishing honorarium from Springer and Elsevier. He is on the Scientific Advisory Board for the International OCD Foundation and is a Tourette Centers of Excellence Director. He may receive travel compensation for service to the American Psychological Commission on Accreditation or Board of Directors for the American Board of Clinical Child and Adolescent Psychiatry. Dr. Storch discloses the following relationships: consultant for Biohaven Pharmaceuticals; Book royalties from Elsevier, Springer, American Psychological Association, Wiley, Oxford, Kingsley, and Guilford; Stock valued at less than $5000 from NView; Research support from NIH, IOCDF, Ream Foundation, and Texas Higher Education Coordinating Board., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The goal of this study was to replicate previous findings of three distinct treatment response pathways associated with repeated intravenous (IV) ketamine infusions among patients with major depressive disorder (MDD)., Methods: We conducted growth mixture modeling to estimate latent classes of change in depression (Quick Inventory of Depressive Symptomatology-Self Report, QIDS-SR) across six treatment visits in 298 patients with MDD treated with IV ketamine in an outpatient community clinic. Mean age was 40.36 and patients were primarily male (58.4 %). The sample had relatively severe depression (QIDS-SR = 16.61) at pre-treatment and the majority had not responded to at least two prior medications., Results: Best-fit indices indicated three trajectory groups to optimally demonstrate non-linear, quadratic changes in depressive symptoms during ketamine treatment. Two groups had severe depression at baseline but diverged into a group of modest improvement over the treatment course (n = 78) and a group of patients with rapid improvement (n = 103). A third group had moderate depression at baseline with moderate improvement during the treatment course (n = 117). Additional planned trajectory comparisons showed that suicidality at entry was higher in the high depression groups and that change in suicidality severity followed that of depression., Limitations: This was a retrospective analysis of a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples., Conclusions: This replication study in an independent community-based ketamine clinic sample revealed similar response trajectories, with only about a third of depressed patients benefitting substantially from an acute induction course of ketamine infusions., Competing Interests: Conflict of Interest Drs. Averill, Lijffijt, Mathew, O'Brien, Swann and Tamman are supported through the use of resources and facilities at the Michael E. Debakey VA Medical Center, Houston, Texas. Dr. Averill has served as a consultant, speaker and/or advisory board member for Guidepoint, Transcend Terapeutics, Source Research Foundation, Reason for Hope, Beond, and Ampelis. Dr. Lijffijt receives support from BrainsWay and Ceruvia Lifesciences. Dr. Mathew has served as a consultant to Allergan, Alkermes, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, Sunovion and Worldwide Clinical Trials. Dr. Mathew has received research support from Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, and VistaGen Therapeutics. Drs. Mathew, Lee, and Murphy receive support from The Menninger Clinic. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: The late positive potential (LPP) could be a marker of emotion dysregulation in youth with pediatric bipolar disorder (PBD). However, the neuroanatomical correlates of the LPP are still not clarified., Objective: To provide cortical and deep gray matter correlates of the LPP in youth, specifically, youth with PBD., Methods: Twenty-four 7 to 17 years-old children with PBD and 28 healthy controls (HC) underwent cortical thickness and deep gray matter volumes measurements through magnetic resonance imaging and LPP measurement elicited by passively viewing emotional faces through electroencephalography. T-tests compared group differences in LPP, cortical thickness, and deep gray matter volumes. Linear regressions tested the relationship between LPP amplitude and cortical thickness/deep gray matter volumes., Results: PBD had a more pronounced LPP amplitude for happy faces and a thinner cortex in prefrontal areas than HC. While considering both groups, a higher LPP amplitude was associated with a thicker cortex across occipital and frontal lobes, and with a smaller right globus pallidus volume. In addition, a higher LPP amplitude for happy faces was associated with smaller left caudate and left globus pallidus volumes across both groups. Finally, the LPP amplitude correlated negatively with right precentral gyrus thickness across youth with PBD, but positively across HC., Conclusion: Neural correlates of LPP in youth included fronto-occipital areas that have been associated also with emotion processing and control. The opposite relationship between BPD and HC of LPP amplitude and right precentral gyrus thickness might explain the inefficacy of the emotional control system in PBD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Misophonia is a complex disorder characterized by a heightened reaction to certain sounds and associated stimuli. While there is no uniformly accepted treatment to date, different intervention approaches are being investigated. Individual's perceptions of different misophonia treatment methods may affect compliance and satisfaction with treatment options. We sought to gather data on patient perceptions of currently available misophonia treatments., Methods: Using an online survey, we collected data about treatment preferences, treatment usage, and diagnosis history from parents of children with misophonia (N = 141) and adults with misophonia (N = 252)., Results: Most respondents were not satisfied with misophonia treatments that they or their children had previously received. Audiologic interventions including active and passive noise cancelling and lifestyle modifications were rated as most appropriate for treatment of misophonia by both parent and adult respondents., Limitations: Because of the descriptive nature of this study, we chose to use a completer-only approach to ensure the data reflect the true responses of participants, though this did result in a meaningful proportion of missing data. Participants were selected through convenience sampling and responses were self-reported. Individuals with more severe misophonia symptoms may be more likely to participate and complete a research survey., Conclusions: Most interventions are considered inappropriate by parents of youth with misophonia and by adults with misophonia. This should be interpreted in the light of a general lack of misophonia-specific interventions. Findings suggest dissatisfaction with currently available treatments and an opportunity for development of effective treatment strategies corresponding to participants' preferences. Deeper understanding of treatment preferences has the potential to guide future treatment development., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Evidence supporting specific therapies for late-life treatment-resistant depression (LL-TRD) is necessary. This study used Bayesian adaptive randomization to determine the optimal dose for the probability of treatment response (≥50% improvement from baseline on the Montgomery-Åsberg Depression Rating Scale) 7 days after a 40 min intravenous (IV) infusion of ketamine 0.1 mg/kg (KET 0.1), 0.25 mg/kg (KET 0.25), or 0.5 mg/kg (KET 0.5), compared to midazolam 0.03 mg/kg (MID) as an active placebo. The goal of this study was to identify the best dose to carry forward into a larger clinical trial. Response durability at day 28, safety and tolerability, and effects on cortical excitation/inhibition (E/I) ratio using resting electroencephalography gamma and alpha power, were also determined. Thirty-three medication-free US military veterans (mean age 62; range: 55-72; 10 female) with LL-TRD were randomized double-blind. The trial was terminated when dose superiority was established. All interventions were safe and well-tolerated. Pre-specified decision rules terminated KET 0.1 (N = 4) and KET 0.25 (N = 5) for inferiority. Posterior probability was 0.89 that day-seven treatment response was superior for KET 0.5 (N = 11; response rate = 70%) compared to MID (N = 13; response rate = 46%). Persistent treatment response at day 28 was superior for KET 0.5 (response rate = 82%) compared to MID (response rate = 37%). KET 0.5 had high posterior probability of increased frontal gamma power (posterior probability = 0.99) and decreased posterior alpha power (0.89) during infusion, suggesting an acute increase in E/I ratio. These results suggest that 0.5 mg/kg is an effective initial IV ketamine dose in LL-TRD, although further studies in individuals older than 75 are required., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: Converging evidence from structural and functional magnetic resonance imaging (MRI) studies points to amygdala alteration as crucial in the development of paediatric bipolar disorder (pBP). The high number of recent studies prompted us to comprehensively evaluate findings. We aimed to systematically review structural and functional MRI studies investigating the amygdala in patients with pBP and in youth at high-risk (HR) for developing pBP., Methods: We searched PubMed from any time to 25 September 2020 using: 'amygdala AND (MRI OR magnetic resonance imaging) AND bipolar AND (pediatr* OR child OR children OR childhood OR adolescent OR adolescents OR adolescence OR young OR familial OR at-risk OR sibling* OR offspring OR high risk)'. In this review, we adhered to the PRISMA statement., Results: Amygdala hyperactivity to emotional stimuli is the most commonly reported finding in youth with pBP and HR compared to healthy peers (HC), whereas findings from structural MRI studies are inconsistent., Conclusions: Hyperactivation of the amygdala might be an endophenotype of pBP.

Clinical Trial Registration: Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.

Background: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization., Methods: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores., Results: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4., Conclusion: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD., (© 2021 Wiley Periodicals LLC.)

Background: The N-methyl-D-aspartate receptor antagonist ketamine is potentially effective in treatment resistant depression. However, its antidepressant efficacy is highly variable, and there is little information about predictors of response., Methods: We employed growth mixture modeling (GMM) analysis to examine specific response trajectories to intravenous (IV) ketamine (three infusions; mean dose 0.63 mg/kg, SD 0.28, range 0.30 - 2.98 mg/kg over 40 min) in 328 depressed adult outpatients referred to a community clinic. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) assessed depression severity at baseline and before each infusion, up to three infusions for four total observations., Results: GMM revealed three QIDS-SR response trajectories. There were two groups of severely depressed patients, with contrasting responses to ketamine. One group (n=135, baseline QIDS-SR=18.8) had a robust antidepressant response (final QIDS-SR=7.3); the other group (n=97, QIDS-SR=19.8) was less responsive (final QIDS-SR=15.6). A third group (n=96) was less severely depressed at baseline (QIDS-SR=11.7), with intermediate antidepressant response (final QIDS-SR=6.6). Comparisons of demographic and clinical characteristics between groups with severe baseline depression revealed higher childhood physical abuse in the group with robust ketamine response (p=0.01)., Limitations: This was a retrospective analysis on a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. Information pertaining to traumatic events occurring after childhood and pre-existing or concurrent medical conditions that may have affected outcomes was not available., Conclusions: Overall, ketamine's effect in patients with severe baseline depression and history of childhood maltreatment may be consistent with ketamine-induced blockade of behavioral sensitization., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-D-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.

Susceptibility to combined depressive and manic syndromes correlates strongly with arousal-related symptoms including impulsivity, anxiety and agitation. This relationship to a driven, "mixed" activation-depression state, generated by a life-long process, was described in classical times. Course of illness in mixed states includes increased episode frequency, duration, earlier onset, and association with addiction- and trauma/stress-related disorders. Mixed episodes have catecholamine and hypothalamic-pituitary-adrenocortical activity increased beyond nonmixed states of similar symptom severity. These properties resemble behavioral sensitization, where salient, survival-related stimuli (traumatic or rewarding) can generate persistently exaggerated responses with disrupted arousal and reward, with potential for suicide and other severe consequences., Competing Interests: Disclosure A.C. Swann: Grant support from American Foundation for Suicide Prevention, National Institutes of Health; Veterans Administration Cooperative Studies Program; Department of Defense. M. Lijffijt: Grant support from National Institutes of Health; Department of Defense., (Published by Elsevier Inc.)

Interest in the coexistence of manic and depressive symptoms fostered hypotheses on neurobiological underpinnings of mixed states. Neurobiological properties of mixed states, however, have not been comprehensively described. The authors searched databases for articles on neurobiological markers related to mixed states. Results showed that mixed states are characterized by elevated central and peripheral monoamine levels, greater alterations in hypothalamic-pituitary-adrenal axis, increased inflammation, and greater circadian rhythms dysfunction than nonmixed forms. Furthermore, the magnitude of pathophysiologic alterations in mixed states exceeds those associated with nonmixed mania or depression and suggest that hyperactivation and hyperarousal are core features of mixed states., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Treatment guidelines for mixed states of depression or (hypo)mania focus almost exclusively on psychopharmacologic intervention without tapping into the benefits of psychotherapy. The authors highlight the complex clinical picture and illness course of mixed states, and discuss the benefit of taking a patient-centered approach to treatment incorporating techniques from a variety of evidence-based psychotherapies. A careful assessment of suicide risk as well as interventions designed specifically for anxiety are also recommended., Competing Interests: Disclosure The authors have nothing to disclose related to this work. Drs B. O’Brien, A.C. Swann, S.J. Mathew and M. Lijffijt are supported by the use of resources and facilities at the Michael E. Debakey VA Medical Center, Houston, Texas., (Published by Elsevier Inc.)

Suicide is the leading cause of injury mortality in the United States and the second-leading cause of death in people aged 10-34 years. While many long-term risk factors are known, the short-term prediction of suicidal behavior remains elusive. Many characteristics of suicidal behavior cut across diagnoses, but suicide is increased in recurrent psychiatric disorders, addictive disorders, and trauma-related disorders. Suicide results from the interaction of short-term and long-term behavioral regulation. The shorter the time-course of the mechanism, the closer it is to actual suicidal behavior, and the harder it is to prevent. We will discuss the manner in which impulsivity, a major determinant of short-term suicide risk, interacts with longer-term risk factors, especially sensitization to addictive or traumatic stimuli. Impulsivity predisposes to sensitization; in turn, impulsivity is a prominent component of sensitized behavior. Impulsivity can be described as a general pattern of behavior ("trait" impulsivity), as responses that are not conformed to their context (action-impulsivity), or as inability to delay reward or to take future consequences into account (choice-impulsivity). Each of these contributes to suicidal behavior. The neural mechanisms of impulsivity and sensitization are analogous, and sensitization can produce rapidly fluctuating patterns of impulsive behavior, arousal, and anhedonia. In order to recognize and prevent suicidal behavior, it is necessary to identify factors associated with susceptibility to bouts of impulsive behavior in people at elevated long-term risk.

Background: Individuals with post-traumatic stress disorder (PTSD) have a heightened sensitivity to subsequent stressors, addictive drugs, and symptom recurrence, a form of behavioral sensitization. N-methyl-D-aspartate receptors (NMDARs) are involved in the establishment and activation of sensitized behavior. Objective: We describe a protocol of a randomized placebo-controlled Phase 1b proof-of-mechanism trial to examine target engagement, safety, tolerability, and possible efficacy of the NMDAR antagonist lanicemine in individuals with symptoms of PTSD (Clinician Administered PTSD Scale [CAPS-5] score ≥ 25) and evidence of behavioral sensitization measured as enhanced anxiety-potentiated startle (APS; T-score ≥ 2.8). Methods: Subjects (n = 24; age range 21-65) receive three 60-min intravenous infusions of placebo or 100 mg lanicemine over 5 non-consecutive days. Primary endpoint is change in APS from pre-treatment baseline to after the third infusion. NMDAR engagement is probed with resting state EEG gamma band power, 40 Hz auditory steady state response, the mismatch negativity amplitude, and P50 sensory gating. Change in CAPS-5 scores is an exploratory clinical endpoint. Bayesian statistical methods will evaluate endpoints to determine suitability of this agent for further study. Conclusion: In contrast to traditional early-phase trials that use symptom severity to track treatment efficacy, this study tracks engagement of the study drug on expression of behavioral sensitization, a functional mechanism likely to cut across disorders. This experimental therapeutics design is consistent with recent NIMH-industry collaborative studies, and could serve as a template for testing novel pharmacological agents in psychiatry. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03166501., (Copyright © 2019 Lijffijt, Green, Balderston, Iqbal, Atkinson, Vo-Le, Vo-Le, O’Brien, Grillon, Swann and Mathew.)

Childhood maltreatment is associated with a poor treatment response to conventional antidepressants and increased risk for treatment-resistant depression (TRD). The N-methyl-D-aspartate receptor (NDMAR) antagonist ketamine has been shown to rapidly improve symptoms of depression in patients with TRD. It is unknown if childhood maltreatment could influence ketamine's treatment response. We examined the relationship between childhood maltreatment using the Childhood Trauma Questionnaire (CTQ) and treatment response using the Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR) in TRD patients receiving intravenous ketamine at a community outpatient clinic. We evaluated treatment response after a single infusion (n = 115) and a course of repeated infusions (n = 63). Repeated measures general linear models and Bayes factor (BF) showed significant decreases in QIDS-SR after the first and second infusions, which plateaued after the third infusion. Clinically significant childhood sexual abuse, physical abuse, and cumulative clinically significant maltreatment on multiple domains (maltreatment load) were associated with better treatment response to a single and repeated infusions. After repeated infusions, higher load was also associated with a higher remission rate. In contrast to conventional antidepressants, ketamine could be more effective in TRD patients with more childhood trauma burden, perhaps due to ketamine's proposed ability to block trauma-associated behavioral sensitization., Competing Interests: O’Brien, Swann and Allison Wells report no financial relationships with commercial interests. Marijn Lijffijt served as principal investigator for a trial funded by NeuroRx and has received research support from VistaGen Therapeutics. Mathew has served as consultant to Alkermes, Allergan, Bracket, Clexio Biosciences, Intracellular Therapies, Janssen, Perception Neurosciences, and Sage Therapeutics. He has served as co-investigator for clinical trials funded by NeuroRx and Janssen, and has received research support from Biohaven Pharmaceuticals and VistaGen Therapeutics.

More than eleven million U.S. Veterans are at least 65 years of age, an age group of which almost 20% suffers from clinically significant depressive symptoms. Available pharmacological treatments are suboptimal for patients, including veterans, with late-life depression. Ketamine has emerged as a potentially promising rapid-acting therapy for treatment-resistant depression (TRD). However, few studies have examined the safety, tolerability and efficacy of ketamine therapy for older adults with late-life TRD (LL-TRD). This study uses an adaptive randomization design to test the safety, tolerability, efficacy, and durability of three distinct, single sub-anesthetic doses of intravenous (IV) ketamine versus a single dose of active placebo (midazolam) in older depressed veterans. As the study progresses, Bayesian adaptive randomization recalibrates randomization ratios to allocate more participants to conditions demonstrating greater promise and fewer participants to conditions with less promise. Secondary analyses explore clinical and biological moderating and mediating factors of rapid treatment response. Results are expected to inform both the viability of ketamine treatment and optimal dosing strategies for patients with LL-TRD.

Background: We studied emotional information processing in youth with pediatric bipolar disorder (pBD) using the late positive potential (LPP), assessing automatic allocation of attentional resources to emotionally salient stimuli, and the occipital P1, assessing early sensory processing., Methods: Participants were 20 youth with pBD and 26 healthy controls (HC). Participants passively viewed faces with a fearful, neutral or happy expressions. Group differences were tested with general linear models. P1 was included to examine modulating effects on LPP. We calculated Bayes factor (BF) values to express strength of evidence for choosing one hypothesis over another., Results: A significant emotion by group interaction for LPP amplitude was associated with a larger amplitude for happy faces for pBD than HC (F[1,40] = 6.04, p = .018); this was not modulated by P1 amplitude or latency. P1 amplitude did not differ between groups, although P1 peaked earlier for HC (F[1,40] = 5.45, p = .025). BF for LPP was 2.93, suggesting moderate evidence favoring H 1 . BF for P1 latency of 14.58 suggests strong evidence favoring H 1 ., Limitations: Inclusion of children and adolescents prohibited careful control for neurodevelopmental effects., Conclusions: Larger LPP amplitude for happy faces without change in P1 suggests enhanced automatic allocation of attentional resources to positive information in pBD. Delayed P1 latency in pBD suggests slower early processing of emotional information., (Copyright © 2019. Published by Elsevier B.V.)

Immediate and long-term mechanisms interact in the regulation of action. We will examine neurobiology and practical clinical consequences of these interactions. Long-term regulation of immediate behavioural control is based on analogous responses to highly rewarding or stressful stimuli: (i) impulsivity is a failure of the balance between activation and inhibition in the immediate regulation of action. (ii) Sensitization is a persistently exaggerated behavioural or physiological response to highly salient stimuli, such as addictive stimuli or inescapable stress. Sensitization can generalize across classes of stimuli. (iii) Impulsivity, possibly related to poor modulation of catecholaminergic and glutamatergic functions, may facilitate development of long-term sensitized responses to stressful or addictive stimuli. In turn, impulsivity is prominent in sensitized behaviour. (iv) While impulsivity and sensitization are general components of behaviour, their interactions are prominent in the course of bipolar disorder, emphasizing roles of substance-use, recurrent course and stressors. (v) Suicide is a complex and severe behaviour that exemplifies the manner in which impulsivity facilitates behavioural sensitization and is, in turn, increased by it, leading to inherently unpredictable behaviour. (vi) Interactions between impulsivity and sensitization can provide targets for complementary preventive and treatment strategies for severe immediate and long-term behavioural disorders. Progress along these lines will be facilitated by predictors of susceptibility to behavioural sensitization. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.

We tested whether enhanced stimulus orienting operationalized as N1 and P2 auditory evoked potentials to increasing loudness (50-90 dB clicks) could be associated with trait impulsivity (Barratt Impulsiveness Scale, BIS-11), impulsive action (commission error on the Immediate Memory Task), or impulsive choice (immediate responses on temporal discounting tasks). We measured N1 and P2 loudness sensitivity in a passive listening task as linear intensity-sensitivity slopes in 36 men with antisocial personality disorder with a history of conviction for criminal conduct and 16 healthy control men. Across all subjects, regression analyses revealed that a steeper P2 slope predicted higher IMT commission error/correct detection ratio, and lower stimulus discriminability (A-prime). These associations were also found within both groups. These relationships suggest an association between enhanced early stimulus orienting (P2), impulsive action (response inhibition), and impaired signal-noise discriminability (A-prime).

Deficits in both empathy and cognition have been reported widely in patients with schizophrenia. However, little is known about how these deficits interact among such patients. In the present study, we used pain portraying pictures preceding a color-word Stroop task to investigate the effect of empathetic pain observation on cognition among patients with schizophrenia. Twenty patients with schizophrenia and twenty healthy controls were included. The control group showed increased Stroop facilitation and decreased interference during the empathetic pain condition compared with the non-empathetic condition. Although patients with schizophrenia exhibited deficits in cognition, they demonstrated a similar empathy effect to controls on Stroop facilitation, but a somewhat larger empathy effect on Stroop interference (a more decreased effect). In particular, the groups did not differ in either automatic or controlled processing during the non-empathetic condition, suggesting general rather than specific cognitive deficits in schizophrenia. Together, we interpret our findings in terms of two opposing effects of empathy on cognition in schizophrenia, with possible neuromodulatory mechanism. Whereas prior studies showed empathy to be impaired, our outcomes indicate that at least some components of empathetic pain processing are preserved in such patients.

Impulsivity and sensation seeking are stimulus-oriented traits. Because they differ in degree of intention and planning, they may have distinct neurophysiological mechanisms. Impulsivity is prominent in bipolar disorder, and may be related to pre-attentional information filtering and stimulus-orientation. We investigated specificity of relationships between impulsivity and sensitivity to stimulus intensity in bipolar disorder and controls, using intensity-sensitivity of auditory evoked potentials. Seventy-six subjects (37 healthy controls, 39 with bipolar disorder) were administered an intensity-sensitivity paradigm. Additional measures included Barratt Impulsiveness Scale (BIS-11) and Eysenck Impulsivity and Venturesomeness scores. State-dependent rapid-response impulsivity was measured using the Immediate Memory Task. Intensity-sensitivities of the auditory evoked P1N1, N1P2, P1, N1, and P2 potentials were assessed as the slope of amplitude relative to loudness. Analyses used general linear models (GLM) with impulsivity-related measures as dependent variables and age, gender, education, and diagnosis as dependent variables. BIS-11 total, motor, and attentional impulsivity scores correlated positively with pre-attentional N1 and P1N1 intensity-sensitivity slopes in bipolar disorder, but not in controls. BIS-11 nonplanning and Eysenck Venturesomeness scores did not correlate with intensity-sensitivity. Intensity-sensitivity slopes did not correlate with rapid-response impulsivity. Correlations between N1 or P1N1 slopes and BIS-11 scores in bipolar disorder were not affected by age, education, WAIS, treatment, symptoms, or gender. Trait impulsivity in bipolar disorder may be related to poorly modulated stimulus-driven late pre-attentional responses to stimuli, potentially resulting in exaggerated responses to intense stimuli even before conscious awareness. Components of trait impulsivity are physiologically heterogenous relative to intensity-sensitivity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)