Neural Circuitry-Related Biomarkers for Drug Development in Psychiatry: An Industry Perspective.

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.

Alterations in attentional processing in youth with misophonia: A phenotypical cross-comparison with anxiety patients.

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.

Measuring misophonia in youth: A psychometric evaluation of child and parent measures.

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).

Neural complexity EEG biomarkers of rapid and post-rapid ketamine effects in late-life treatment-resistant depression: a randomized control trial.

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.

Neuroanatomical Correlates of the Late Positive Potential in Youth with Pediatric Bipolar Disorder.

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.

Clinical characteristics, impairment, and psychiatric morbidity in 102 youth with misophonia.

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.

Replication of distinct trajectories of antidepressant response to intravenous ketamine.

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.

Identification of an optimal dose of intravenous ketamine for late-life treatment-resistant depression: a Bayesian adaptive randomization trial.

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.

Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial.

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.

Amygdala structure and function in paediatric bipolar disorder and high-risk youth: A systematic review of magnetic resonance imaging findings.

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.

Does mismatch negativity have utility for NMDA receptor drug development in depression?

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.

Distinct trajectories of antidepressant response to intravenous ketamine.

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.

Temporal Structure of Mixed States: Does Sensitization Link Life Course to Episodes?

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.

The Neurobiology of Mixed States.

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.

A Proof-of-Mechanism Study to Test Effects of the NMDA Receptor Antagonist Lanicemine on Behavioral Sensitization in Individuals With Symptoms of PTSD.

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. 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.

The Impact of Childhood Maltreatment on Intravenous Ketamine Outcomes for Adult Patients with Treatment-Resistant Depression.

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.

Bayesian adaptive randomization trial of intravenous ketamine for veterans with late-life, treatment-resistant depression.

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.

Early and late cortical reactivity to passively viewed emotional faces in pediatric bipolar disorder.

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.

Interactions of immediate and long-term action regulation in the course and complications of bipolar disorder.

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.