Enhancing Cognitive Restructuring with Concurrent Repetitive Transcranial Magnetic Stimulation: A Transdiagnostic Randomized Controlled Trial.

INTRODUCTION: Emotional dysregulation constitutes a serious public health problem in need of novel transdiagnostic treatments. OBJECTIVE: To this aim, we developed and tested a one-time intervention that integrates behavioral skills training with concurrent repetitive transcranial magnetic stimulation (rTMS). METHODS: Forty-six adults who met criteria for at least one DSM-5 disorder and self-reported low use of cognitive restructuring (CR) were enrolled in a randomized, double-blind, sham-controlled trial that used a between-subjects design. Participants were taught CR and underwent active rTMS applied at 10 Hz over the right (n = 17) or left (n = 14) dorsolateral prefrontal cortex (dlPFC) or sham rTMS (n = 15) while practicing reframing and emotional distancing in response to autobiographical stressors. RESULTS: Those who received active left or active right as opposed to sham rTMS exhibited enhanced regulation (ds = 0.21-0.62) as measured by psychophysiological indices during the intervention (higher high-frequency heart rate variability, lower regulation duration). Those who received active rTMS over the left dlPFC also self-reported reduced distress throughout the intervention (d = 0.30), higher likelihood to use CR, and lower daily distress during the week following the intervention. The procedures were acceptable and feasible with few side effects. CONCLUSIONS: These findings show that engaging frontal circuits simultaneously with cognitive skills training and rTMS may be clinically feasible, well-tolerated and may show promise for the treatment of transdiagnostic emotional dysregulation. Larger follow-up studies are needed to confirm the efficacy of this novel therapeutic approach.

Ketamine for treatment of mood disorders and suicidality: A narrative review of recent progress.

BACKGROUND: Mood disorders are a leading cause of morbidity. Many patients experience treatment-resistant depression (TRD), and suicide rates are rising. Faster-acting and more effective antidepressant medications are needed. Four decades of research has transformed the use of ketamine from an anesthetic to an outpatient treatment for major depressive disorder (MDD). Ketamine is a N-methyl-d-aspartate (NMDA) receptor antagonist and has been shown to rapidly improve mood symptoms and suicidal ideation by targeting the glutamate system directly. METHODS: We used the PubMed database to identify relevant articles published until September 1, 2020. We focused on meta-analyses, randomized controlled trials, and original observational studies. We included relevant studies for depression, MDD, TRD, bipolar disorder, anxiety, posttraumatic stress disorder (PTSD), suicide, ketamine, and esketamine. RESULTS: Both racemic ketamine and esketamine have been shown to rapidly treat depression and suicidality. There is evidence that ketamine can be helpful for anxiety and PTSD; however, more research is needed. Intranasal esketamine has been FDA approved to treat depression. CONCLUSIONS: This narrative review describes the evolution of ketamine to treat mood disorders and suicidality. We provide the evidence supporting recent developments using esketamine as well as unresolved issues in the field, such as dosing and safety.

Switching to Intranasal Esketamine Maintains the Antidepressant Response to Intravenous Racemic Ketamine Administration: A Case Series of 10 Patients.

PURPOSE: This study aims to assess the efficacy and safety of intranasal (IN) esketamine as maintenance antidepressant therapy in patients who have demonstrated clinical improvement with off-label intravenous (IV) racemic ketamine for treatment-resistant depression (TRD). METHODS: This is a retrospective case series of 10 consecutive outpatients with TRD who all had a clinically meaningful response when treated with IV racemic ketamine and were then switched to IN esketamine for maintenance therapy. Patient outcomes were assessed with the Montgomery-Åsberg Depression Rating Scale, Patient Health Questionnaire 9, and Clinical Global Impression of Improvement scale at each visit. Adverse effects were assessed at each treatment. FINDINGS: Results indicated that 9 patients either maintained the benefit or showed greater improvement when transitioned to IN esketamine for antidepressant maintenance therapy. One patient had worsening of depression due to an acute psychosocial stressor but still improved from baseline IV racemic ketamine treatment. Six patients returned to work or pursued employment, and 4 patients with suicidal ideation remitted during IV racemic ketamine treatment and had no recurrence of suicidality with IN esketamine. No serious adverse reactions or tolerability issues were observed. IMPLICATIONS: This case series reports the outcomes of 10 severely ill patients with TRD who had a clinically meaningful response to IV racemic ketamine and demonstrated a maintenance of effect or continued improvement when transitioned to IN esketamine. Although this finding needs to be replicated in larger, controlled studies, this report provides promising results for patients who have safely and effectively switched to Food and Drug Administration-approved IN esketamine after receiving acute or maintenance depression treatment with off-label IV racemic ketamine.

Resilience as a translational endpoint in the treatment of PTSD.

Resilience is a neurobiological entity that shapes an individual's response to trauma. Resilience has been implicated as the principal mediator in the development of mental illness following exposure to trauma. Although animal models have traditionally defined resilience as molecular and behavioral changes in stress responsive circuits following trauma, this concept needs to be further clarified for both research and clinical use. Here, we analyze the construct of resilience from a translational perspective and review optimal measurement methods and models. We also seek to distinguish between resilience, stress vulnerability, and posttraumatic growth. We propose that resilience can be quantified as a multifactorial determinant of physiological parameters, epigenetic modulators, and neurobiological candidate markers. This multifactorial definition can determine PTSD risk before and after trauma exposure. From this perspective, we propose the use of an 'R Factor' analogous to Spearman's g factor for intelligence to denote these multifactorial determinants. In addition, we also propose a novel concept called 'resilience reserve', analogous to Stern's cognitive reserve, to summarize the sum total of physiological processes that protect and compensate for the effect of trauma. We propose the development and application of challenge tasks to measure 'resilience reserve' and guide the assessment and monitoring of 'R Factor' as a biomarker for PTSD.

Efficacy and safety of ketamine in the management of anxiety and anxiety spectrum disorders: a review of the literature.

Anxiety disorders are among the most prevalent psychiatric conditions. Despite many proven pharmacological and non-pharmacological treatments available, high rates of partial response and low rates of long-term remission remain. Ketamine has been receiving increasing attention as an interventional treatment modality in psychiatry, especially among refractory conditions, including major depressive disorder. There is limited yet growing evidence to support the use of ketamine in anxiety disorders. In this review of the literature, we present case reports, case series, and controlled trials demonstrating proof-of-concept for its potential role in the treatment of anxiety and anxiety spectrum disorders. Its unique mechanism of action, rapid onset, and high rate of response have driven its use in clinical practice. Ketamine is generally well tolerated by patients and has a limited side effect profile; however, the effects of long-term use are unknown. While there is a growing body of research and increasing clinical experience to suggest ketamine may have clinical applications in the treatment of refractory anxiety disorders, further research to determine long-term safety and tolerability is indicated.

Updates on Preclinical and Translational Neuroscience of Mood Disorders: A Brief Historical Focus on Ketamine for the Clinician.

BACKGROUND: The development of new-generation antidepressants comes at a time of great clinical need when the global burden of depression, suicide, and other psychiatric conditions continues to increase. Our current treatment armamentarium is limited by the time delay needed for antidepressant effects and the significant number of patients who do not show an adequate response to antidepressants. The past 2 decades of psychiatric research has revealed that ketamine, known to be used only as an anesthetic and drug of abuse and to produce experimental models of psychosis, is effective at subanesthetic doses to ameliorate clinical depression. METHODS: We performed a systematic search of PubMed/MEDLINE indexed reports to identify clinical and translational research done with ketamine for purposes of treating depression. RESULTS: We will first present the rationale for investigating ketamine and other N-methyl-D-aspartate receptor antagonists as a novel class of glutamate system targeting antidepressants. We will summarize putative molecular pathways underlying mood disorders and outline a brief history of investigation into ketamine as a treatment for depression. Recent clinical/translational evidence of ketamine's rapid-acting antidepressant mechanism will be critically reviewed in detail. CONCLUSIONS: At the end of this review, we will opine on the role of ketamine and derivatives in clinical practice.

Allopregnanolone Levels Are Inversely Associated with Self-Reported Pain Symptoms in U.S. Iraq and Afghanistan-Era Veterans: Implications for Biomarkers and Therapeutics.

BACKGROUND AND OBJECTIVES: Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. METHODS: The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. RESULTS: Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann­Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P = 0.0028], chest pain [P = 0.032], and aggregate total pain (sum of all four pain items) [P = 0.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P = 0.001]. CONCLUSIONS: These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.

Cortical control of affective networks.

Transcranial magnetic stimulation and deep brain stimulation have emerged as therapeutic modalities for treatment refractory depression; however, little remains known regarding the circuitry that mediates the therapeutic effect of these approaches. Here we show that direct optogenetic stimulation of prefrontal cortex (PFC) descending projection neurons in mice engineered to express Chr2 in layer V pyramidal neurons (Thy1-Chr2 mice) models an antidepressant-like effect in mice subjected to a forced-swim test. Furthermore, we show that this PFC stimulation induces a long-lasting suppression of anxiety-like behavior (but not conditioned social avoidance) in socially stressed Thy1-Chr2 mice: an effect that is observed >10 d after the last stimulation. Finally, we use optogenetic stimulation and multicircuit recording techniques concurrently in Thy1-Chr2 mice to demonstrate that activation of cortical projection neurons entrains neural oscillatory activity and drives synchrony across limbic brain areas that regulate affect. Importantly, these neural oscillatory changes directly correlate with the temporally precise activation and suppression of limbic unit activity. Together, our findings show that the direct activation of cortical projection systems is sufficient to modulate activity across networks underlying affective regulation. They also suggest that optogenetic stimulation of cortical projection systems may serve as a viable therapeutic strategy for treating affective disorders.

A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression.

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials. Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710.

Enrichment using speech latencies improves treatment effect size in a clinical trial of bipolar depression.

Clinical trials in depression lack objective measures. Speech latencies are an objective measure of psychomotor slowing with face validity and empirical support. 'Turn latency' is the response time between speakers. Retrospective analysis was carried-out on the utility of turn latencies as an enrichment tool in a clinical trial of bipolar I depression. Speech data was obtained from 274 participants during 1,352 Montgomery-Åsberg Depression Rating Scale (MADRS) recordings in a randomized, placebo controlled, 6-week clinical trial of SEP-4199 (200 mg or 400 mg). Post-randomization turn latencies were compared between patients with moderate to severe depression and patients whose depression had remitted. A cutoff was determined and applied to turn latencies pre-randomization to classify individuals into two groups: Speech Latencies Slow (SL-Slow) and Speech Latencies Normal (SL-Normal). At week 6, SL-Slow (N = 172) showed significant separation in MADRS scores between placebo and treatment arms. SL-Normal (N = 102) showed larger MADRS improvements and no significant separation between placebo and treatment arms. Excluding SL-Normal increased primary outcome effect size by 52 % and 100 % for the treatment arms. Turn latencies are an objective measure available from standard clinical assessments and may assess the severity of symptoms more accurately and screen out placebo responders.

Estimating heterogeneity of treatment effect in psychiatric clinical trials.

Currently, placebo-controlled clinical trials report mean change and effect sizes, which masks information about heterogeneity of treatment effects (HTE). Here, we present a method to estimate HTE and evaluate the null hypothesis (H0) that a drug has equal benefit for all participants (HTE=0). We developed measure termed 'estimated heterogeneity of treatment effect' or eHTE, which estimates variability in drug response by comparing distributions between study arms. This approach was tested across numerous large placebo-controlled clinical trials. In contrast with variance-based methods which have not identified heterogeneity in psychiatric trials, reproducible instances of treatment heterogeneity were found. For example, heterogeneous response was found in a trial of venlafaxine for depression (peHTE=0.034), and two trials of dasotraline for binge eating disorder (Phase 2, peHTE=0.002; Phase 3, 4mg peHTE=0.011; Phase 3, 6mg peHTE=0.003). Significant response heterogeneity was detected in other datasets as well, often despite no difference in variance between placebo and drug arms. The implications of eHTE as a clinical trial outcomes independent from central tendency of the group is considered and the important of the eHTE method and results for drug developers, providers, and patients is discussed.

Evaluating speech latencies during structured psychiatric interviews as an automated objective measure of psychomotor slowing.

We sought to derive an objective measure of psychomotor slowing from speech analytics during a psychiatric interview to avoid potential burden of dedicated neurophysiological testing. Speech latency, which reflects response time between speakers, shows promise from the literature. Speech data was obtained from 274 subjects with a diagnosis of bipolar I depression enrolled in a randomized, doubleblind, 6-week phase 2 clinical trial. Audio recordings of structured Montgomery-Åsberg Depression Rating Scale (MADRS) interviews at 6 time points were examined (k = 1,352). We evaluated speech latencies, and other aspects of speech, for temporal stability, convergent validity, sensitivity/responsivity to clinical change, and generalization across seven socio-linguistically diverse countries. Speech latency was minimally associated with demographic features, and explained nearly a third of the variance in depression (categorically defined). Speech latency significantly decreased as depression symptoms improved over time, explaining nearly 20 % of variance in depression remission. Classification for differentiating people with versus without concurrent depression was high (AUCs > 0.85) both cross-sectionally and longitudinally. Results replicated across countries. Other speech features offered modest incremental contribution. Neurophysiological speech parameters with face validity can be derived from psychiatric interviews without the added patient burden of additional testing.

Discovery and Model-Informed Drug Development of a Controlled-Release Formulation of Nonracemic Amisulpride that Reduces Plasma Exposure but Achieves Pharmacodynamic Bioequivalence in the Brain.

Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II.

A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy.

BACKGROUND: Ulotaront (SEP-363856) is a novel agonist at trace amine-associated receptor 1 and serotonin 5-HT1A receptors in clinical development for the treatment of schizophrenia. Previous studies demonstrated ulotaront suppresses rapid eye movement (REM) sleep in both rodents and healthy volunteers. We assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cataplexy and alertness in subjects with narcolepsy-cataplexy. METHODS: In a multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, ulotaront was evaluated in 16 adults with narcolepsy-cataplexy. Two oral doses of ulotaront (25 mg and 50 mg) were administered daily for 2 weeks and compared with matching placebo (6-treatment sequence, 3-period, 3-treatment). RESULTS: Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared to placebo. A sustained 2-week administration of both doses of ulotaront reduced the mean number of short-onset REM periods (SOREMPs) during daytime multiple sleep latency test (MSLT) compared to placebo. Although cataplexy events decreased from the overall mean baseline during the 2-week treatment period, neither dose of ulotaront statistically separated from placebo (p = 0.76, 25 mg; p = 0.82, 50 mg), and no significant improvement in patient and clinician measures of sleepiness from baseline to end of the 2-week treatment period occurred in any treatment group. CONCLUSIONS: Acute and sustained treatment with ulotaront reduced nighttime REM duration and daytime SOREMPs, respectively. The effect of ulotaront on suppression of REM did not demonstrate a statistical or clinically meaningful effect in narcolepsy-cataplexy. REGISTRATION: ClinicalTrials.gov identifier: NCT05015673.

Enhancing cognitive restructuring with concurrent fMRI-guided neurostimulation for emotional dysregulation-A randomized controlled trial.

BACKGROUND: Transdiagnostic clinical emotional dysregulation is a key component of many mental health disorders and offers an avenue to address multiple disorders with one transdiagnostic treatment. In the current study, we pilot an intervention that combines a one-time teaching and practice of cognitive restructuring (CR) with repetitive transcranial magnetic stimulation (rTMS), targeted based on functional magnetic resonance imaging (fMRI). METHODS: Thirty-seven clinical adults who self-reported high emotional dysregulation were enrolled in this randomized, double-blind, placebo-controlled trial. fMRI was collected as participants were reminded of lifetime stressors and asked to downregulate their distress using CR tactics. fMRI BOLD data were analyzed to identify the cluster of voxels within the left dorsolateral prefrontal cortex (dlPFC) with the highest activation when participants attempted to downregulate, versus passively remember, distressing memories. Participants underwent active or sham rTMS (10 Hz) over the left dlPFC target while practicing CR following emotional induction using recent autobiographical stressors. RESULTS: Receiving active versus sham rTMS led to significantly higher high frequency heart rate variability during regulation, lower regulation duration during the intervention, and higher likelihood to use CR during the week following the intervention. There were no differences between conditions when administering neurostimulation alone without the CR skill and compared to sham. Participants in the sham versus active condition experienced less distress the week after the intervention. There were no differences between conditions at the one-month follow up. CONCLUSION: This study demonstrated that combining active rTMS with emotion regulation training for one session significantly enhances emotion regulation and augments the impact of training for as long as a week. These findings are a promising step towards a combined intervention for transdiagnostic emotion dysregulation.