Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression.

Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABAA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.

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.

Explainable drug side effect prediction via biologically informed graph neural network.

Early detection of potential side effects (SE) is a critical and challenging task for drug discovery and patient care. In-vitro or in-vivo approach to detect potential SEs is not scalable for many drug candidates during the preclinical stage. Recent advances in explainable machine learning may facilitate detecting potential SEs of new drugs before market release and elucidating the critical mechanism of biological actions. Here, we leverage multi-modal interactions among molecules to develop a biologically informed graph-based SE prediction model, called HHAN-DSI. HHAN-DSI predicted frequent and even uncommon SEs of the unseen drug with higher or comparable accuracy against benchmark methods. When applying HHAN-DSI to the central nervous system, the organs with the largest number of SEs, the model revealed diverse psychiatric medications' previously unknown but probable SEs, together with the potential mechanisms of actions through a network of genes, biological functions, drugs, and SEs.

The Role of the Gut Microbiome in Bipolar Disorder and its Common Medical Comorbidities.

Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with significant psychosocial and medical disease burden. Much difficulty has been encountered in developing novel therapeutics and objective biomarkers for clinical use in this population. In that regard, gut-microbial homeostasis appears to modulate several key pathways relevant to a variety of psychiatric, metabolic, and inflammatory disorders. Microbial impact on immune, endocrine, endocannabinoid, kynurenine, and other pathways are discussed throughout this review. Emphasis is placed on this system's relevance to current pharmacology, diet, and comorbid illness in bipolar disorder. Despite the high level of optimism promoted in many reviews on this topic, substantial obstacles exist before any microbiome-related findings can provide meaningful clinical utility. Beyond a comprehensive overview of pathophysiology, this review hopes to highlight several key areas where progress is needed. As well, novel microbiome-associated suggestions are presented for future research.

Processing speed - A potential candidate cognitive endophenotype for bipolar disorder.

Background: Bipolar disorder (BD) is a chronic multifactorial disorder that presents with cognitive impairment as one of its main features, in patients as well as in their first-degree relatives. However, the profile of cognitive dysfunction in BD patients and their relatives is not yet well defined. Various neurocognitive deficits have been proposed as endophenotypes for BD. In the present study, we explored the susceptibility to neurocognitive deficits in BD patients and their siblings compared to healthy controls. Method: A sample consisting of patients diagnosed with BD (N=37), their unaffected siblings (N=30) and a healthy control group (N=39) was assessed using the Brief Assessment of Cognition for Affective Disorders (BAC-A) battery of tests in various cognitive domains: memory, processing speed, working memory, reasoning and problem solving, and affective processing. Results: Compared to healthy controls, BD patients and their unaffected siblings showed deficits in attention and motor speed, or processing speed as measured by the Symbol coding task (p = 0.008), as well as a similar degree of impairment (p = 1.000). Limitations: The lack of statistically significant findings in the other cognitive domains could be related to differences in task difficulty. Most patients were taking psychotropic medication with varying effects on cognition and being treated as outpatients, implying a currently higher level of functioning, which may limit extrapolation of the sample to the general population of BD patients. Conclusions: These results support the view of considering processing speed as an endophenotype for bipolar disorder.

Incidence rate of psychiatric disorders in 2020: The pivotal role played by SARS-CoV-2 infection.

IMPORTANCE: The Coronavirus Disease (COVID-19) pandemic has significantly impacted mental health outcomes. While the frequency of anxiety and depressive symptoms has increased in the whole population, the relationship between COVID-19 and new psychiatric diagnoses remains unclear. OBJECTIVE: To compare the population incidence rate of emergence of de novo psychiatric disorders in 2020 compared to the previous years, and to compare the incidence rate of new psychiatric disorder diagnoses between people with vs without COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This study utilized administrative claims data from the Clinformatics® Data Mart database, licensed from Optum®. The study is a cross-sectional analysis that compared the incidence rate of new psychiatric disorders in 2020 vs. 2018 and 2019 in the entire insured population database. Subsequently, the incidence of new psychiatric disorders in people with vs. without COVID-19 during 2020 was analyzed. EXPOSURE: The exposures included diagnosis and severity of COVID-19 infection. MAIN OUTCOMES MEASURES: The dependent variables of interest were the incidence rates of new psychiatric disorders, specifically schizophrenia spectrum disorders, mood disorders, anxiety disorders, and obsessive-compulsive disorder. RESULTS: The population studied included 10,463,672 US adults (mean age 52.83, 52% female) who were unique people for the year of 2020. Incidence of newly diagnosed psychiatric disorders per 1,000 individuals in the 2020 whole population were 28.81 (CI: 28.71, 28.92) for anxiety disorders, 1.04 (CI: 1.02, 1.06) for schizophrenia disorders, 0.42 (CI: 0.41, 0.43) for OCD and 28.85 (CI: 28.75, 28.95) for mood disorders. These rates were not significantly higher than 2018 or 2019. When comparing incidence rates between COVID-19 vs. non-COVID-19 populations in 2020, the rates were significantly higher in the COVID-19 population: 46.89 (CI: 46.24, 47.53) for anxiety, 49.31 (CI: 48.66, 49.97) for mood disorders, 0.57 (CI: 0.50, 0.65) for OCD, and 3.52 (CI: 3.34, 3.70) for schizophrenia. COVID-19 severity was significantly associated with new diagnoses of schizophrenia, anxiety and mood disorders in multivariate analyses. CONCLUSIONS: Compared to 2018 and 2019, in 2020 there was no increased incidence of new psychiatric disorders in the general population based on insurance claims data. Importantly, people with COVID-19 were more likely to be diagnosed with a new psychiatric disorder, most notably disorders with psychosis, indicating a potential association between COVID-19 and mental/brain health.

Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis.

(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [-0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility.

Lithium increases cortical and subcortical volumes in subjects with bipolar disorder.

Bipolar disorder (BD) is a highly variable and burdensome disease for patients and caregivers. A BD diagnosis almost triples the likelihood of developing dementia as the disease progresses. Neurocognitive reserve appears to be one of the most important influences on lifelong functional outcomes and quality of life in BD. Though several prior studies have assessed the effects of lithium on regional gray and white matter volumes in this population, representative cohorts are typically middle-aged, have a more severe pathology, and are not as commonly assessed in the depressive phase (which represents the majority of most patients' lifespans outside of remission). Here we have shown that positive adaptations with lithium can be observed throughout the brain after only six weeks of monotherapy at low-therapeutic serum levels. Importantly, these results remove some confounders seen in prior studies (patients were treatment free at time of enrollment and mostly treatment naïve). This cohort also includes underrepresented demographics in the literature (young adult patients, mostly bipolar II, and exclusively in the depressed phase). These findings bolster the extensive body of evidence in support of long-term lithium therapy in BD, furthering the possibility of its expanded use to wider demographics.

The role of lithium treatment on comorbid anxiety symptoms in patients with bipolar depression.

BACKGROUND: Comorbid anxiety is pervasive and carries an immense psychosocial burden for patients with bipolar disorder. Despite this, trials reporting anxiety-related outcomes in this population are uncommon, particularly with regards to monotherapies. METHODS: Patients (n = 31) with both bipolar I or II disorder in current depressive episodes were enrolled in a six-week, open-label, single-center trial assessing the efficacy of lithium monotherapy in treating symptoms depression and comorbid anxiety. Patients were mostly medication-free and lithium-naïve at baseline. RESULTS: Significant improvements in depression (HAMD) and anxiety (HAM-A) were observed at the six-week endpoint, with remission and response rates greater than 50%. There was a positive correlation between endpoint HAM-A scores and HAM-D scores, r = 0.80, (p < 0.01). Improvements were realized at low serum lithium concentrations (0.49 ± 0.20 mEq/L). LIMITATIONS: Lack of placebo control and small sample size warrants validation in larger randomized studies. CONCLUSIONS: Taken in the context of prior evidence, lithium may have an important role in treating comorbid anxiety in bipolar disorder, both as adjunct and monotherapy. Lower doses of lithium may provide equivalent efficacy and enhance tolerability and compliance.

Analysis of COVID-19 Infection and Mortality Among Patients With Psychiatric Disorders, 2020.

Importance: People with major psychiatric disorders are more likely to have comorbidities associated with worse outcomes of COVID-19. This fact alone could determine greater vulnerability of people with major psychiatric disorders to COVID-19. Objective: To assess the odds of testing positive for and mortality from COVID-19 among and between patients with schizophrenia, mood disorders, anxiety disorders and a reference group in a large national database. Design, Setting, and Participants: This cross-sectional study used an electronic health record data set aggregated from many national sources in the United States and licensed from Optum with current and historical data on patients tested for COVID-19 in 2020. Three psychiatric cohorts (patients with schizophrenia, mood disorders, or anxiety disorders) were compared with a reference group with no major psychiatric conditions. Statistical analysis was performed from March to April 2021. Exposure: The exposures observed include lab-confirmed positivity for COVID-19 and mortality. Main Outcomes and Measures: The odds of testing positive for COVID-19 in 2020 and the odds of death from COVID-19 were measured. Results: The population studied included 2 535 098 unique persons, 3350 with schizophrenia, 26 610 with mood disorders, and 18 550 with anxiety disorders. The mean (SD) age was 44 (23) years; 233 519 were non-Hispanic African American, 1 583 440 were non-Hispanic Caucasian; and 1 580 703 (62%) were female. The schizophrenia cohort (positivity rate: 9.86%; adjusted OR, 0.90 [95% CI, 0.84-0.97]) and the mood disorder cohort (positivity rate: 9.86%; adjusted OR, 0.93 [95% CI, 0.87-0.99]) had a significantly lower rate of positivity than the anxiety disorder cohort (positivity rate: 11.17%; adjusted OR, 1.05 [95% CI, 0.98-1.12) which was closer to the reference group (11.91%). After fully adjusting for demographic factors and comorbid conditions, patients with schizophrenia were nearly 4 times more likely to die from the disease than the reference group (OR, 3.74; 95% CI, 2.66-5.24). The mood disorders COVID-19 cohort had a 2.76 times greater odds of mortality than the reference group (OR, 2.76; 95% CI, 2.00-3.81), and the anxiety disorders cohort had a 2.39 times greater odds of mortality than the reference group (OR, 2.39; 95% CI, 1.68-3.27). Conclusions and Relevance: By examining a large database while controlling for multiple confounding factors such as age, race and ethnicity, and comorbid medical conditions, the present study found that patients with schizophrenia had much increased odds of mortality by COVID-19.

Inflammatory signaling mechanisms in bipolar disorder.

Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with a high individual and societal burden. While not all patients display overt markers of elevated inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease, and likely explains the elevated rates of comorbid inflammatory illnesses seen in this population. While individual systems have been intensely studied and targeted, a relative paucity of attention has been given to the interconnecting role of inflammatory signals therein. This review presents an updated overview of some of the most prominent pathophysiologic mechanisms in bipolar disorder, from mitochondrial, endoplasmic reticular, and calcium homeostasis, to purinergic, kynurenic, and hormonal/neurotransmitter signaling, showing inflammation to act as a powerful nexus between these systems. Several areas with a high degree of mechanistic convergence within this paradigm are highlighted to present promising future targets for therapeutic development and screening.

Pharmacogenomics of Lithium Response in Bipolar Disorder.

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium's therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium's exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

Cognitive outcomes of the bipolar depression electrical treatment trial (BETTER): a randomized, double-blind, sham-controlled study.

Bipolar depression is associated with marked cognitive deficits. Pharmacological treatments for this condition are limited and may aggravate depressive and cognitive symptoms. Therefore, therapeutic interventions that preserve adequate cognitive functioning are necessary. Our previous results demonstrated significant clinical efficacy of transcranial direct current stimulation (tDCS) in the Bipolar Depression Electrical Treatment Trial (BETTER). Here, cognitive outcomes of this study are reported. We randomized 59 patients with bipolar disorder I or II in an acute depressive episode to receive active (12 2 mA, 30-min, anodal-left, cathodal-right prefrontal cortex tDCS sessions) or sham tDCS. Patients were on stable pharmacological regimen for at least 2 weeks. A battery of 12 neuropsychological assessments in five cognitive domains (attention and processing speed, memory, language, inhibitory control, and working memory and executive function) was performed at baseline, after two weeks and at endpoint (week 6). No significant differences between groups over 6 weeks of treatment were observed for any cognitive outcomes. Moreover, no decrease in cognitive performance was observed. Our findings warrant further replication in larger studies. Trial Registration: clinicaltrials.gov Identifier: NCT02152878.

The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response.

Dysfunction in a wide array of systems-including the immune, monoaminergic, and glutamatergic systems-is implicated in the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway. This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD (23 F, ages 18-65) received a single ketamine infusion (0.5 mg/kg) over 40 min. KYN pathway analytes-including plasma concentrations of indoleamine 2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)-were assessed at baseline (pre-infusion), 230 min, day 1, and day 3 post-ketamine. General linear models with restricted maximum likelihood estimation and robust sandwich variance estimators were implemented. A repeated effect of time was used to model the covariance of the residuals with an unstructured matrix. After controlling for age, sex, and body mass index (BMI), post-ketamine IDO levels were significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA levels at days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/KYN was observed at day 1. In addition, baseline levels of proinflammatory cytokines and behavioral measures predicted KYN pathway changes post ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.

Intracellular Signaling Cascades in Bipolar Disorder.

Bipolar spectrum disorders carry a significant public health burden. Disproportionately high rates of suicide, incarceration, and comorbid medical conditions necessitate an extraordinary focus on understanding the intricacies of this disease. Elucidating granular, intracellular details seems to be a necessary preamble to advancing promising therapeutic opportunities. In this chapter, we review a wide range of intracellular mechanisms including mitochondrial energetics, calcium signaling, neuroinflammation, the microbiome, neurotransmitter metabolism, glycogen synthase kinase 3-beta (GSK3ß), protein kinase C (PKC) and diacylglycerol (DAG), and neurotrophins (especially BDNF), as well as the glutamatergic, dopaminergic, purinergic, and neurohormonal systems. Owing to the relative lack of understanding and effective therapeutic options compared to the rest of the spectrum, special attention is paid in the chapter to the latest developments in bipolar depression. Likewise, from a therapeutic standpoint, special attention should be paid to the pervasive mechanistic actions of lithium as a means of amalgamating numerous, disparate cascades into a digestible cognitive topology.

A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression.

BACKGROUND: Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression. METHODS: After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. RESULTS: Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. CONCLUSIONS: In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.ClinicalTrials.gov identifier: NCT02484456.

Psychotic and affective symptoms of early-onset bipolar disorder: an observational study of patients in first manic episode

Objective: Presence of psychotic symptoms seems to be a commonplace in early-onset bipolar disorder (BD). However, few studies have examined their occurrence in adolescent-onset BD. We sought to investigate the frequency of affective and psychotic symptoms observed during the first manic episode in adolescents. Methods: Forty-nine adolescents with bipolar I disorder (DSM-IV criteria) were admitted to a psychiatric hospital during their first acute manic episode. Assessment for current psychiatric diagnosis was performed by direct clinical interview and the DSM-IV version of the Diagnostic Interview for Children and Adolescents (DICA). Results: Teenage inpatients with BD consistently exhibited typical manic features, such as euphoria, grandiosity, and psychomotor agitation. In addition, disorganization and psychotic symptoms were present in 82 and 55% of the total sample, respectively. There was no significant difference in symptoms between early- and late-adolescent subgroups. Remarkably, most patients (76%) reported previous depressive episode(s); of these, 47% had prominent psychotic features in the prior depressive period. Conclusion: These findings suggest that disorganization and psychotic symptoms during the first manic episode are salient features in adolescent-onset BD, and that psychotic depression frequently may precede psychotic mania. Nevertheless, differential diagnosis with schizophrenia should be routinely ruled out in cases of early-onset first psychotic episode.