Effects of ketamine on metabolic parameters in depressive disorders: A systematic review.

BACKGROUND: Persons with Major Depressive Disorder (MDD), notably treatment-resistant depression (TRD), are differentially affected by type 2 diabetes mellitus and associated morbidity. Ketamine is highly efficacious in the treatment of adults living with MDD, notably TRD. Herein, we sought to determine the effect of ketamine on metabolic parameters in animal stress paradigms and human studies. METHODS: We performed a comprehensive search on PubMed, OVID, and Scopus databases for primary research articles from inception to May 5, 2024. Study screening and data extraction were performed by two reviewers (S.W. and G.H.L.). Both preclinical and clinical studies were included in this review. RESULTS: Results from the preclinical studies indicate that in experimental diabetic conditions, ketamine does not disrupt glucose-insulin homeostasis. Within adults with MDD, ketamine is associated with GLUT3 transporter upregulation and differentially affects metabolomic signatures. In adults with TRD, ketamine induces increased brain glucose uptake in the prefrontal cortex. Available evidence suggests that ketamine does not adversely affect metabolic parameters. LIMITATIONS: There are a paucity of clinical studies evaluating the effects of ketamine on glucose-insulin homeostasis in adults with MDD. CONCLUSIONS: Our results indicate that ketamine is not associated with significant and/or persistent disruptions in metabolic parameters. Available evidence indicates that ketamine does not adversely affect glucose-insulin homeostasis. These results underscore ketamine's efficacy and safety as an antidepressant treatment that is not associated with metabolic disturbances commonly reported with current augmentation therapies.

Electroencephalography (EEG) spectral signatures of selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs) and vortioxetine in major depressive disorder: A systematic review.

BACKGROUND: Converging evidence suggests electroencephalography (EEG) methods may elucidate alterations in global structural and functional connectivity that underlie the pathophysiology of depressive disorders. Extant literature suggests SSRIs and SNRIs may broadly induce alterations to EEG-measured neural activity. Herein, this systematic review comprehensively evaluates changes to EEG spectral signatures associated with vortioxetine and each FDA-approved agent within the SSRI and SNRI class. METHODS: We conducted a systematic review of studies investigating changes to EEG spectral signatures associated with SSRI, SNRI, and/or vortioxetine treatment in persons with MDD. Database search occurred from database inception to May 3, 2024. RESULTS: Our search yielded 15 studies investigating overall spectral signature changes associated with SSRI- and/or SNRI-treatment. The existing literature presents with mixed findings. Notwithstanding, we did observe a pattern in which the SSRI and SNRI agents reproducibly affect EEG spectral signatures. We observed overlapping yet distinct spectral patterns for each agent within- and between-drug classes of SSRIs and SNRIs. Changes in resting/wake EEG were also observed. LIMITATIONS: The findings from our systematic review are mixed. Heterogeneity exists with sample size, composition, dosing of antidepressants, duration of antidepressant exposure, as well as the type of EEG devices used. DISCUSSIONS: Our findings provide support to the notion that although SSRIs, SNRIs and vortioxetine block reuptake of the serotonin transporter; they are different in their profile of pharmacology as evidenced by differential EEG signatures. EEG changes associated with SSRIs, SNRIs and vortioxetine are also highly replicated findings across mixed studies and populations.

Association between rumination, suicidal ideation and suicide attempts in persons with depressive and other mood disorders and healthy controls: A systematic review and meta-analysis.

INTRODUCTION: Suicidal ideation and behaviors are a leading cause of disability worldwide. Approximately 90 % of suicide completers have a diagnosable mood disorder. Extant literature reports rumination mediates functional impairment across mood disorders. Herein, we report the association between rumination and suicidality amongst persons with psychiatric disorders and healthy controls. METHODS: Our systematic review and meta-analysis included relevant articles retrieved from Web of Science, OVID and PubMed from inception to March 20, 2024. Random effects model was used to calculate the correlation between rumination, suicidal ideation and attempt. RESULTS: A total of 27 eligible studies were included in our systematic review and meta-analysis. Rumination (r = 0.25 [95 % CI: -0.03, 0.49]), reflection (r = 0.15 [-0.71, 0.83]) and brooding (r = 0.13 [-0.58, 0.73]) were nonsignificantly correlated with suicidal ideation in mood disorders. Suicide attempt history was significantly associated with greater odds of rumination in persons with depressive disorders (OR = 1.13 [0.42, 3.02]). In healthy controls, rumination (r = 0.30 [0.21, 0.38]), reflection (r = 0.23 [0.13, 0.32]) and brooding (r = 0.24 [0.12, 0.36]) were significantly correlated with suicidal ideation. Rumination also predicted lifetime history of suicide attempts in healthy controls (OR = 1.70 [1.16, 2.49]). LIMITATIONS: There were inadequate sample sizes of persons with different mood and psychiatric disorders which may have underpowered our ability to detect clinically meaningful associations. DISCUSSION: Our study reports a transdiagnostic association between measures of rumination and suicidality. Future research vistas should parse the neurobiological substrates subserving rumination and identify targeted therapies and their association with general cognition and treatment response.

Association between cognitive functioning, suicidal ideation and suicide attempts in major depressive disorder, bipolar disorder, schizophrenia and related disorders: A systematic review and meta-analysis.

INTRODUCTION: Treatable mental disorders, such as psychotic, major depressive disorder (MDD), and bipolar disorder (BD), contribute to a substantial portion of suicide risk, often accompanied by neurocognitive deficits. We report the association between cognitive function and suicidal ideation/suicide attempts (SI/SA) in individuals with schizoaffective disorder, BD, and MDD. METHODS: A systematic search was conducted on PubMed, Ovid and Scopus databases for primary studies published from inception to April 2024. Eligible articles that reported on the effect size of association between cognition and SI/SA were pooled using a random effects model. RESULTS: A total of 41 studies were included for analysis. There was a negative association between executive functioning and SI/SA in schizoaffective disorder (SA: Corr = -0·78, 95 % CI [-1·00, 0·98]; SI: Corr = -0·06, 95 % CI [-0·85, 0·82]) and MDD (SA: Corr = -0·227, 95 % CI [-0·419, -0·017]; SI: Corr = -0·14, 95 % CI [-0·33, 0·06]). Results were mixed for BD, with a significant positive association between SA and global executive functioning (Corr = 0·08, 95 % CI [0·01, 0·15]) and negative association with emotion inhibition. Mixed results were observed for processing speed, attention, and learning and memory, transdiagnostically. LIMITATIONS: There is heterogeneity across sample compositions and cognitive measures. We did not have detailed information on individuals with respect to demographics and comorbidities. CONCLUSIONS: We observed a transdiagnostic association between measures of cognitive functions and aspects of suicidality. The interplay of cognitive disturbances, particularly in reward-based functioning, may underlie suicidality in individuals with mental disorders. Disturbances in impulse control, planning, and working memory may contribute to self-injurious behavior and suicide.

Subjective and objective measures of cognitive function are correlated in persons with Post-COVID-19 Condition: a secondary analysis of a Randomized Controlled Trial.

BACKGROUND: It remains unclear whether subjective and objective measures of cognitive function in Post COVID-19 Condition (PCC) are correlated. The extent of correlation has mechanistic and clinical implications. METHODS: This post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial contains baseline data of subjective and objective measures of cognition in a rigorously characterized cohort living with PCC. Herein, we evaluated the association between subjective and objective condition function, as measured by the Perceived Deficits Questionnaire, 20-item (PDQ-20) and the Digit Symbol Substitution Test (DSST) and Trails Making Test (TMT)-A/B, respectively. RESULTS: A total of 152 participants comprised the baseline sample. Due to missing data, our statistical analyses included 150 for self-reported PDQ-20, 147 individuals for combined DSST-measured cognitive function (composite z-score of the Pen/Paper plus Online CogState Version, NcombinedDSST), 71 for in-person DSST-measured cognitive function (Pen/Paper Version), 70 for TMT-A-measured cognitive function, and 70 for TMT-B-measured cognitive function. After adjusting for age, sex, and education, PDQ-20 was significantly correlated with pen-and-paper DSST (ß = -0.003, p = 0.002) and TMT-B (ß = 0.003, p = 0.008) scores, but not with TMT-A scores (ß = -0.001, p = 0.751). CONCLUSIONS: Overall, a statistically significant correlation was observed between subjective and objective cognitive functions. Clinicians providing care for individuals with PCC who have subjective cognitive function complaints may consider taking a measurement-based approach to cognition at the point of care that focuses exclusively on patient-reported measures.

A replication study using the World Health Organization pharmacovigilance database (VigiBase®) to evaluate whether an association between ketamine and esketamine and alcohol and substance misuse exists.

BACKGROUND AND OBJECTIVES: Ketamine and esketamine are increasingly prescribed in the treatment of resistant mood disorders and persons at risk of suicide. Ketamine is a drug of misuse with increasing non-therapeutic use in the general population. Herein, our aim was to determine whether ketamine and/or esketamine are disproportionately associated with reports of substance and/or alcohol misuse. METHODS: Replicating a similar analysis recently conducted using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, we identified cases of "alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder (SUD), substance abuse, drug dependence, drug use disorder and drug abuse" in association with ketamine and esketamine reported to the World Health Organization Pharmacovigilance Database (WHO VigiBase). We searched the database from inception to January 2024. The reporting odds ratio (ROR) of each of the aforementioned parameters was calculated; acetaminophen was used as the control. The numerator of the equation represents the number of cases (n) and the denominator represents the total cases of psychiatric disorders (N). Significance was obtained when the lower limit of the 95 % confidence (CI) > 1.0. RESULTS: The RORs for ketamine was increased for most parameters (i.e., alcohol abuse (3.24), substance dependence (12.48), substance use disorder (170.44), substance abuse (2.94), drug dependence (2.88), drug use disorder (11.54) and drug abuse (2.85), respectively). With respect to esketamine, the RORs were observed to be different from ketamine insofar as we observed a reduction in the RORs for three parameters (i.e., substance abuse (0.41), drug dependence (0.083) and drug abuse (0.052), respectively). The IC025 values were significant for ketamine in cases of alcohol abuse (0.35), substance dependence (0.50), substance use disorder (2.77), substance abuse (0.83), drug dependence (0.97), drug use disorder (1.95) and drug abuse (0.94). Additionally, oxycontin showed significant IC025 values for substance use disorder (0.0014), substance abuse (0.042), and drug dependence (0.17). CONCLUSION: Esketamine was not associated with an increased ROR for any parameter of alcohol and/or substance use disorder. Mixed results were observed with ketamine with some RORs increased and others decreased. Estimating RORs using a pharmacovigilance database does not establish causation in the case of elevated RORs and cannot be assumed to be a therapeutic effect when lower RORs were observed.

Relationship between anhedonia and psychosocial functioning in post-COVID-19 condition: a post-hoc analysis.

BACKGROUND: Post-COVID-19 condition (PCC), also known as "long COVID," is characterized by persistent symptoms, negatively affecting the well-being of individuals with PCC. Anhedonia (i.e. reduced capacity for pleasure) and compromised psychosocial functioning are notable symptoms in those with PCC. We aimed to provide insights to understand the effects of anhedonia and impaired psychosocial functioning of individuals with PCC. METHODS: This post-hoc analysis used data from an 8-week, double-blind, randomized, placebo-controlled trial which evaluated vortioxetine for cognitive deficits in individuals with PCC (Clinicaltrials.gov Identifier: NCT05047952). A total of 147 eligible participants were randomly assigned to receive vortioxetine or matching placebo over eight weeks of double-blind treatment. Our study investigated the relationship between anhedonia, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS), and psychosocial functioning, measured with the Post-COVID Functional Status (PCFS) scale. The analysis was conducted using a generalized linear model, with adjustments for relevant covariates such as age, sex, education, suspected versus confirmed COVID diagnosis, MDD diagnosis, and alcohol consumption. RESULTS: Of the 147 participants, 143 participants had available baseline data for analysis. We observed that baseline PCFS score was statistically significantly positively correlated to baseline SHAPS score (ß = 0.070, p = 0.045, 95% CI). DISCUSSIONS: Our analysis revealed a significant relationship between measures of anhedonia and psychosocial functioning in adults with PCC. Strategies that aim to improve patient-reported outcomes with PCC need to prioritize the prevention and treatment of hedonic disturbances in patients experiencing PCC.

Preclinical and clinical efficacy of kappa opioid receptor antagonists for depression: A systematic review.

BACKGROUND: Approximately 30 % of persons with Major Depressive Disorder (MDD) inadequately respond to conventional antidepressants. Kappa opioid receptor (KOR) antagonists, aticaprant and navacaprant, are in development as treatments for MDD. Herein, we aim to comprehensively evaluate the safety, efficacy and pharmacology of aticaprant and navacaprant for MDD. METHODS: We performed a systematic review of primary research investigating aticaprant and navacaprant on PubMed, OVID, and Scopus databases from inception to April 2024. Studies that reported on the pharmacological profile and/or safety and efficacy of aticaprant and navacaprant were included. RESULTS: Navacaprant monotherapy and aticaprant adjunctive therapy are in development for MDD. Navacaprant exhibits 300-fold selectivity for the KOR compared to the mu-opioid receptor, while aticaprant exhibits 30-fold selectivity. At clinically-relevant doses, navacaprant and aticaprant occupy 87-95 % and 73-94 % of KORs, respectively. Clinical trials of the foregoing agents (navacaprant as monotherapy and actiprant as adjunctive therapy) reported significant improvement in depressive symptoms and may clinically benefit measures of anhedonia. Both agents appear well-tolerated, with most adverse events mild and no known safety concerns. LIMITATIONS: Aticaprant and navacaprant treatment for MDD are in early stages of clinical trials and results from Phase 3 pivotal trials are not yet available. CONCLUSIONS: Kappa opioid receptor antagonists may serve as mechanistically-novel treatments for MDD and persons who inadequately respond to index conventional antidepressants. Anhedonia is debilitating and insufficiently treated with conventional antidepressants. Future research vistas should establish the efficacy and safety of KORAs in phase 3 studies in both acute and maintenance paradigms.

Impact of vortioxetine on depressive symptoms moderated by symptoms of anxiety in persons with post-COVID-19 condition: A secondary analysis.

OBJECTIVE: Recovery from a COVID-19 infection can lead to post-COVID-19 condition (PCC), which causes a multitude of debilitating symptoms that negatively affect an individual's health-related quality of life, including depressive and anxiety symptoms. We aim to examine the mediatory effects of anxiety on depressive symptoms in persons with PCC receiving vortioxetine. METHODS: We performed a post-hoc analysis of a randomized, double-blinded, placebo-controlled clinical trial investigating vortioxetine treatment on cognitive functioning in persons with PCC. Anxiety and depressive symptoms were measured by the 7-Item Generalized Anxiety Disorder (GAD-7) Scale and the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR-16), respectively. RESULTS: Based on data of 147 participants, GAD-7 scores were significantly positively associated with QIDS-SR-16 scores (ß=0.038, 95 % CI [0.029,0.047], p < 0.001). After adjusting for covariates, a significant group (χ2=176.786, p < 0.001), time (χ2=8.914, p = 0.003), and treatment x time x GAD-7 score interaction (χ2=236.483, p < 0.001) effect was observed. Vortioxetine-treated participants had a significant difference in overall change in depressive symptoms (mean difference=-3.15, SEM=0.642, 95 % CI [-4.40,-1.89], p < 0.001). CONCLUSION: Anxiety symptoms were significantly associated with depressive symptoms in persons with PCC. Antidepressant efficacy on ameliorating depressive symptoms is dependent on improving anxiety symptoms, underscoring significant implications in improving treatment efficacy and patient quality of life.

Comparing suicide completion rates in bipolar I versus bipolar II disorder: A systematic review and meta-analysis.

BACKGROUND: Bipolar disorder (BD) has a high disease burden and the highest mortality risk in BD comes from suicide. Bipolar disorder type II (BD-II) has been described as a milder form of bipolar disorder; however, extant literature is inconsistent with this description and instead describe illness burden and notably suicidality comparable to persons with bipolar I disorder (BD-I). Towards quantifying the hazard of BD-II, herein we aim via systematic review and meta-analysis to evaluate the rates of completed suicide in BD-I and BD-II. METHOD: We conducted a literature search on PubMed, OVID (Embase, Medline) and PsychINFO databases from inception to June 30th, 2023, according to PRISMA guidelines. Articles were selected based on the predetermined eligibility criteria. A meta-analysis was performed, comparing the risk of completed suicide between individuals diagnosed with BD-I to BD-II. RESULTS: Four out of eight studies reported higher suicide completion rates in persons living with BD-II when compared to persons living with BD-I; however, two of the studies reported non-significance. Two studies reported significantly higher suicide completion rates for BD-I than BD-II. The pooled odds ratio of BD-II suicide rates to BD-I was 1.00 [95 % CI = 0.75, 1.34]. LIMITATIONS: The overarching limitation is the small number of studies and heterogeneity of studies that report on suicide completion in BD-I and BD-II. CONCLUSION: Our study underscores the severity of BD-II, with a risk for suicide not dissimilar from BD-I. The greater propensity to depression, comorbidity and rapid-cycling course reported in BD-II are contributing factors to the significant mortality hazard in BD-II.

Association between fatigue and depressive symptoms in persons with post-COVID-19 condition: a post hoc analysis.

OBJECTIVE: Post-COVID-19 Condition (PCC) is a prevalent, persistent and debilitating phenomenon occurring three or more months after resolution of acute COVID-19 infection. Fatigue and depressive symptoms are commonly reported in PCC. We aimed to further characterize PCC by assessing the relationship between fatigue and depressive symptom severity in adults with PCC. METHODS: A post hoc analysis was conducted on data retrieved from a randomized, double-blinded, placebo-controlled study evaluating vortioxetine for cognitive deficits in persons with PCC. We sought to determine the relationship between baseline fatigue [i.e. Fatigue Severity Scale (FSS) total score] and baseline depressive symptom severity [i.e. 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR-16) total score] in adults with PCC. RESULTS: The statistical analysis included baseline data from 142 participants. After adjusting for age, sex, education, employment status, history of major depressive disorder (MDD) diagnosis, self-reported physical activity, history of documented acute SARS-CoV-2 infection and body mass index (BMI), baseline FSS was significantly correlated with baseline QIDS-SR-16 (ß = 0.825, p = .001). CONCLUSION: In our sample, baseline measures of fatigue and depressive symptoms are correlated in persons living with PCC. Individuals presenting with PCC and fatigue should be screened for the presence and severity of depressive symptoms. Guideline-concordant care should be prescribed for individuals experiencing clinically significant depressive symptoms. Fatigue and depressive symptom severity scores were not pre-specified as primary objectives of the study. Multiple confounding factors (i.e. disturbance in sleep, anthropometrics and cognitive impairment) were not collected nor adjusted for in the analysis herein. TRIAL REGISTRATION: Unrestricted Research Grant from H. Lundbeck A/S, Copenhagen, Denmark. ClinicalTrials.gov Identifier: NCT05047952.

The association between ketamine and esketamine and suicidality: reports to the Food And Drug Administration Adverse Event Reporting System (FAERS).

INTRODUCTION: Replicated evidence indicates that ketamine and esketamine reduce measures of suicidality in persons with treatment-resistant depression (TRD). It remains uncertain whether individuals experience worsening of preexisting suicidality with either agent. RESEARCH DESIGN AND METHODS: The Food and Drug Administration Adverse Event Reporting System (FAERS) database was searched from 1970 and 2019 to 30 September 2023 for reports of suicidal ideation, depression suicidal, suicidal behavior, suicidal attempt, and completed suicide in association with ketamine and esketamine exposure, respectively. We present reporting odds ratios (ROR) significance was determined when the lower limit of the 95% confidence interval (CI) exceeded 1.0. Lithium was used as the control agent. RESULTS: Observed a higher ROR for suicidal ideation (ROR 7.58, 95% CI 6.34-9.07) and depression suicidal (ROR 14.19, 95% CI 1.80-112.07) with esketamine. Significantly lower RORs were observed for suicide attempt with ketamine (ROR 0.15, 95% CI 0.11-0.21) and esketamine (ROR 0.57, 95% CI 0.48-0.67). CONCLUSIONS: Mixed RORs across aspects of suicidality were observed with ketamine and esketamine. Limitations of the FAERS database prevent any determination of causal effects new onset suicidality to either agent. The lower RORs for suicide attempt with ketamine and esketamine is noted but cannot be interpreted as a direct therapeutic effect.

Sex Differences in Outcomes after Endovascular Thrombectomy for Patients with Acute Ischemic Stroke.

INTRODUCTION: Endovascular thrombectomy (EVT) is the standard of care for patients with large-vessel occlusion acute ischemic stroke (AIS). There may be differing recanalization effectiveness based on patients' sex, and understanding such variations can improve patient outcomes by adjusting for differences. We aimed to assess the sex differences in outcome after EVT for patients with AIS. METHODS: We retrospectively analyzed 250 consecutive AIS patients who underwent EVT from July 2019 to February 2022 across two large comprehensive tertiary care stroke centers in China. Outcomes of male patients were compared to females, where poor outcome was defined as a modified Rankin score (mRS) of 3-6 at 90 days. RESULTS: Male patients had higher rates of symptomatic intracranial hemorrhage (sICH) (12.50% vs. 4.05%, p = 0.042) and higher hospitalization costs (114,541.08 vs. 105,790.27 RMB, p = 0.024). Male patients also had a longer median onset-to-needle time (ONT) (146.00 [104.00, 202.00] versus 120.00 [99.25, 144.75], p = 0.026). However, there were no differences in hospitalization length (p = 0.251), 90-day favorable outcome (p = 0.952), and 90-day mortality (p = 0.931) between the sexes. CONCLUSION: Female patients had lower hospitalization costs and sICH rates than males after EVT for AIS. Identifying such differences and implementing measures, including adaptations to workflow optimization, would help to reduce the ONT and last known normal-to-puncture time seen in males to improve patient outcomes. Despite such variations, favorable outcomes and mortality are similar in female and male AIS patients.

The psychological factors mediating/moderating the association between body-image disturbance and depression: A systematic review.

Available evidence demonstrates that individuals with body-image disturbance (BID) are prone to suffer from depression. This systematic review provides, to our knowledge, the first synthesis of the psychological mechanism of the association between BID and depression. We conducted a thorough search of online databases, including PubMed, Web of Science, and PsycINFO, for articles published up until February 2024. The final analysis comprised a total of 23 studies that focused on the mediating or moderating effects of psychological factors between depression and BID. This review identifies self-esteem and social support as both mediators and moderators of the relationship between BID and depression, while perceived stress acted only as a mediator. High self-esteem and strong social support as well as low levels of perceived stress may help individuals experience lower levels of BID, thereby contributing to a decreased likelihood of depression. Interventions aimed at increasing self-esteem, developing strong support, and decreasing perceived stress may hold promise to reduce the risk of depression in those with BID.

Association between dual orexin receptor antagonists (DORAs) and suicidality: reports to the United States Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: Package inserts for the FDA-approved dual orexin receptor antagonists (DORAs) suvorexant, lemborexant and daridorexant state that suicide risk should be monitored. It remains unknown whether suicidality is attributed to DORAs. We aim to evaluate suicidality associated with DORAs reported to the FDA Adverse Event Reporting System (FAERS). METHODS: The reporting odds ratio (ROR) was determined with trazodone as the control. Significant disproportionate reporting was determined when 95% confidence intervals (CIs) did not encompass 1.0. We used information components (ICs) to calculate the lower limit of the 95% CI (IC025). IC was significantly increased when the IC025 ≥0. RESULTS: Suvorexant (0.025 ROR), lemborexant (0.019 ROR) and daridorexant (0.002 ROR) were significantly associated with lower odds of reported completed suicides compared to trazodone (p < 0.05). There was no significantly increased RORs for the DORAs regarding suicidal ideation, depression suicidal, suicidal behavior and suicide attempts. Nonsignificant associations between all parameters of suicidality were observed for each DORA using IC025. CONCLUSION: We did not find a significant association between any parameter of suicidality captured in the FAERS for each DORA. All persons treated for insomnia pharmacologically/non-pharmacologically should be evaluated for emergence/worsening of any suicidality aspect.

The role of KCNQ channel activators in management of major depressive disorder.

Depression, a complex disorder with significant treatment challenges, necessitates innovative therapeutic approaches to address its multifaceted nature and enhance treatment outcomes. The modulation of KCNQ potassium (K+) channels, pivotal regulators of neuronal excitability and neurotransmitter release, is a promising innovative therapeutic target in psychiatry. Widely expressed across various tissues, including the nervous and cardiovascular systems, KCNQ channels play a crucial role in modulating membrane potential and regulating neuronal activity. Recent preclinical evidence suggests that KCNQ channels, particularly KCNQ3, contribute to the regulation of neuronal excitability within the reward circuitry, offering a potential target for alleviating depressive symptoms, notably anhedonia. Studies using animal models demonstrate that interventions targeting KCNQ channels can restore dopaminergic firing balance and mitigate depressive symptoms. Human studies investigating the effects of KCNQ channel activators, such as ezogabine, have shown promising results in alleviating depressive symptoms and anhedonia. The aforementioned observations underscore the therapeutic potential of KCNQ channel modulation in depression management and highlight the need and justification for phase 2 and phase 3 dose-finding studies as well as studies prespecifying symptomatic targets in depression including anhedonia.

Risk of VMAT2 inhibitors on suicidality and parkinsonism: report utilizing the United States Food and Drug Administration adverse event reporting system.

Prescription of vesicular monoamine transporter 2 (VMAT2) inhibitors, valbenazine, deutetrabenazine, and tetrabenazine, is becoming increasingly common in persons treated with antipsychotics. Reported suicidality and parkinsonism are safety concerns with VMAT2 inhibitors. Herein, we aim to evaluate the aforementioned safety outcomes using the FDA Adverse Event Reporting System. Reporting odds ratios (RORs) and lower limits of 95% confidence intervals of information components (IC025) were calculated to quantify VMAT2 inhibitor-associated adverse events. Acetaminophen was the reference agent. Suicidal ideation was significantly associated with VMAT2 inhibitors, with RORs ranging from 2.38 to 10.67 and IC025 ranging from 0.73 to 2.39. Increased odds of suicidal behavior was observed with tetrabenazine (ROR 3.011, IC025 0.0087), but not deutetrabenazine or valbenazine. Decreased odds of suicide attempts and completed suicide were observed with VMAT2 inhibitors, with RORs ranging from 0.011 to 0.10 (all IC025 < 0). Increased odds of parkinsonism were reported for all VMAT2 inhibitors, with RORs and IC025 ranging from 19.49 to 25.37 and 1.66 to 2.93, respectively. The mixed results with VMAT2 inhibitor-associated suicidality and parkinsonism do not establish causal relationships. The parameters of suicidality may be explained by underlying psychiatric disorders.

The association between ketamine and esketamine with alcohol and substance misuse: Reports to the Food and Drug Administration adverse event reporting system (FAERS).

INTRODUCTION: Ketamine and esketamine have been proven to be effective in treating adults with treatment resistant depression (TRD). Preliminary evidence indicates that, when combined with behavioral and psychological interventions, both agents may offer benefits for individuals with substance use disorder (SUD) and alcohol use disorder (AUD). Notwithstanding, concerns have been raised as to whether either or both agents are associated with abuse and/or gateway activity. METHODS: Herein, we evaluate disproportionate reporting expressed as reporting odds ratios (ROR) for esketamine and ketamine. The outcomes of interest include alcohol problem, alcoholism, alcohol abuse, substance dependence, SUD, substance abuse, drug dependence, drug use disorder and drug abuse as codified by the Medical Dictionary for Regulatory Activities (MedDRA) within the FAERS. The IC025 values were significant for ketamine in cases of alcohol abuse (0.28), substance dependence (1.88), substance use disorder (0.996), substance abuse (0.61), drug dependence (0.56), drug use disorder (1.17) and drug abuse (1.22). Additionally, oxycontin showed significant IC025 values for substance dependence (0.067), substance use disorder (0.094), substance abuse (0.035), and drug dependence (0.27). RESULTS: We observed significant increases in the reporting odds ratios (RORs) for ketamine with respect to various outcomes: alcohol abuse (ROR 2.84, 95 % CI 1.53-5.28; p = 0.0010), substance dependence (ROR 18.72, 95 % CI 8.49-41.30; p ≤ 0.0001), SUD (ROR 11.40, 95 % CI 4.24-30.65; p ≤ 0.0001), substance abuse (ROR 2.29, 95 % CI 1.73-3.04; p ≤ 0.0001), drug dependence (ROR 1.99, 95 % CI 1.64-2.42; p ≤ 0.0001), drug use disorder (ROR 4.50, 2.94-6.88; p ≤ 0.0001) and drug abuse (ROR 3.72, 3.36-4.12; p ≤ 0.0001). For esketamine, we observed that the ROR was significantly reduced for substance abuse (ROR 0.37, 95 % CI 0.22-0.63; p = 0.0003), drug dependence (ROR 0.13, 95 % CI 0.076-0.23; p ≤ 0.0001) and drug abuse (ROR 0.048, 95 % CI 0.030-0.078; p ≤ 0.0001). To our knowledge, this is the first report of spontaneous adverse events related to these outcomes of interest in the FAERS. CONCLUSION: Mixed RORs were observed across aspects of SUD and AUD for both ketamine and esketamine. Due to limitations in the FAERS, establishing causal links between new onset alcohol and substance misuse with either agent remains inconclusive. Possible beneficial effects on measures of SUD and AUD were observed. It is currently unclear, but possible, whether both agents have differential ameliorative effects across dimensions of SUD and AUD, which is a focus of ongoing research.