Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder.

Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these episodes can vary widely between individuals, significantly impacting quality of life. Individuals with BD spend almost half their lives experiencing mood symptoms, especially depression, as well as associated clinical dimensions such as anhedonia, fatigue, suicidality, anxiety, and neurovegetative symptoms. Persistent mood symptoms have been associated with premature mortality, accelerated aging, and elevated prevalence of treatment-resistant depression. Recent efforts have expanded our understanding of the neurobiology of BD and the downstream targets that may help track clinical outcomes and drug development. However, as a polygenic disorder, the neurobiology of BD is complex and involves biological changes in several organelles and downstream targets (pre-, post-, and extra-synaptic), including mitochondrial dysfunction, oxidative stress, altered monoaminergic and glutamatergic systems, lower neurotrophic factor levels, and changes in immune-inflammatory systems. The field has thus moved toward identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction. Diverse pharmacological and non-pharmacological approaches targeting neurobiological pathways other than neurotransmission have also been tested in mood disorders. This article reviews different neurobiological targets and pathophysiological findings in non-canonical pathways in BD that may offer opportunities to support drug development and identify new, clinically relevant biological mechanisms. These include: neuroinflammation; mitochondrial function; calcium channels; oxidative stress; the glycogen synthase kinase-3 (GSK3) pathway; protein kinase C (PKC); brain-derived neurotrophic factor (BDNF); histone deacetylase (HDAC); and the purinergic signaling pathway.

Immune targets for therapeutic development in depression: towards precision medicine.

Over the past two decades, compelling evidence has emerged indicating that immune mechanisms can contribute to the pathogenesis of major depressive disorder (MDD) and that drugs with primary immune targets can improve depressive symptoms. Patients with MDD are heterogeneous with respect to symptoms, treatment responses and biological correlates. Defining a narrower patient group based on biology could increase the treatment response rates in certain subgroups: a major advance in clinical psychiatry. For example, patients with MDD and elevated pro-inflammatory biomarkers are less likely to respond to conventional antidepressant drugs, but novel immune-based therapeutics could potentially address their unmet clinical needs. This article outlines a framework for developing drugs targeting a novel patient subtype within MDD and reviews the current state of neuroimmune drug development for mood disorders. We discuss evidence for a causal role of immune mechanisms in the pathogenesis of depression, together with targets under investigation in randomized controlled trials, biomarker evidence elucidating the link to neural mechanisms, biological and phenotypic patient selection strategies, and the unmet clinical need among patients with MDD.

Comparison of Long-Term Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant in Younger Versus Older Patients With Treatment-Resistant Depression: Post-Hoc Analysis of SUSTAIN-2, a Long-Term Open-Label Phase 3 Safety and Efficacy Study.

BACKGROUND: Older, compared with younger, patients with treatment-resistant depression (TRD) typically have lower response and remission rates with poorer tolerability to antidepressant treatment. This post-hoc analysis compared outcomes following treatment with esketamine nasal spray (ESK) between younger (18-64 years) and older (≥65 years) patients with TRD. METHODS: SUSTAIN-2, an up to 1-year open-label safety and efficacy study of ESK plus an oral antidepressant, included patients with TRD either directly enrolled (≥18-year) or transferred from a phase 3 double-blind study, TRANSFORM-3 (≥65-year). Patients were treated in two phases: 4-week induction and 48-week optimization/maintenance. RESULTS: Younger (n = 624) and older (n = 178) patients had similar baseline characteristics except for hypertension history (21.5% versus 48.3%, respectively). Patients (younger versus older) had similar mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores and mean (SD) reductions in MADRS total scores for induction (-18.0 [7.19] versus -18.1 [9.37]; p = 0.492 [t = 0.69, df = 701]) and optimization/maintenance (week 12) (-19.9 [7.03] versus -22.2 [9.50]; p = 0.265 [t = -1.12, df = 3470]) phases. Treatment-emergent adverse events (TEAEs) reported in younger versus older patients, respectively, were: induction, 86.1% versus 74.8%; optimization/maintenance, 86.8% versus 81.0%; serious TEAEs: induction, 2.2% versus 1.9%; optimization/maintenance, 6.7% versus 4.8%; TEAEs of increased blood pressure: induction, 6.9% versus 6.5%; optimization/maintenance, 7.1% versus 9.5%; and falls: induction, 0.3% versus 0.6%; optimization/maintenance, 0.2% versus 0.8%. Cognitive tests did not show clinically meaningful differences between the age groups. CONCLUSIONS: Although limited by the open-label design of SUSTAIN-2, this post-hoc analysis showed generally comparable improvement in depression between ESK-treated younger and older adult patients with TRD, with consistent safety outcomes.

Building brain capital.

Brains are indispensable drivers of human progress. Why not invest more heavily in them? We seek to place Brain Capital at the center of a new narrative to fuel economic and societal recovery and resilience.

Comments to Drs. Bahji, Vazquez, and Zarate.

In the absence of head-to-head studies directly comparing the efficacy of intranasal esketamine to that of intravenous ketamine, valid conclusions regarding comparative efficacy cannot be made based on the existing data from trials using markedly differing study designs and patient populations.

Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II).

BACKGROUND: Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. METHODS: This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. RESULTS: Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. CONCLUSION: This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.

Bag-1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience.

Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress-related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 over-expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 over-expression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.

Publisher Correction: ASPI: a public-private partnership to develop treatments for autism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I).

OBJECTIVE: To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. METHODS: This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate. RESULTS: Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence. CONCLUSIONS: These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03039192.

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3.

BACKGROUND: Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment. METHODS: This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset. RESULTS: For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks. CONCLUSIONS: Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (<55 years).

Harnessing digital technology to predict, diagnose, monitor, and develop treatments for brain disorders.

Digital technologies-including smartphones, wearables, and social media data-show great potential for helping to alleviate suffering from brain disorders such as Parkinson's disease, Alzheimer's disease, depression, and schizophrenia. However, as researchers, technology developers, disease-focused groups, and others forge forward to take advantage of the tremendous opportunities in this domain, it is important to avoid hype and overpromising, and to ensure that this work is done rigorously and collaboratively. In June 2018, the National Academies of Sciences, Engineering, and Medicine's Forum on Neuroscience and Nervous System Disorders hosted a workshop that brought together a wide range of experts and stakeholders. The workshop provided an opportunity to take stock of the rapidly-evolving landscape and discuss how to work together to address both scientific and practical challenges, so that the potential of digital technologies can be translated into meaningful contributions toward the health of individuals and society. Workshop presentations and discussions focused on four key challenges: transforming data into insight, navigating regulatory pathways, designing user-centered tools, and building partnerships across a complex ecosystem. This article highlights the many issues, challenges, and opportunities discussed by individual participants at the workshop.

Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1).

BACKGROUND: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression. METHODS: This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested. RESULTS: Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache. CONCLUSIONS: Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02417064.

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Importance: Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. Objective: To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. Design, Setting, and Participants: In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Interventions: Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Main Outcomes and Measures: Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Results: Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo. Conclusions and Relevance: For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo. Trial Registration: ClinicalTrials.gov identifier: NCT02493868.