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.

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.

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.

National trends and correlates of treatment resistance in major depressive episode and associated suicidal ideation and behaviors among adults in the United States.

OBJECTIVE: To examine recent 12-year trends in prevalence of suicidal ideation and behaviors (SIBs) among US adults experiencing a past-year treatment-resistant depression (TRD). METHODS: Using data from the National Survey of Drug Use and Health, we estimated the annual percentage of individuals aged ≥18 with TRD who reported past-year SIBs, and estimated linear trends adjusting for potentially confounding factors from 2009 to 2020. RESULTS: Of estimated 237.5 million US adults, 7.1 % met diagnostic criteria for a past-year major depressive episode (MDE) between 2009 and 2020. Of these, 9.7 % met criteria for TRD. The proportion reporting past-year suicidal ideation in TRD ranged from 39.5 % (95 % confidence interval [CI], 32.1-47.3 %) in 2009-2010 to 43.4 % (95 % CI, 36.7-503 %) in 2019-2020, with an average annual percent change (AAPC) of 1.3 % (95 % CI, -0.7 % to 3.3 %). The prevalence of past-year suicide attempts in TRD was 7.3 % across the study period (AAPC, 0.1 %; 95 % CI, -4.3 % to 4.7 %). Past-year SIBs were significantly associated with an increased likelihood of meeting criteria for TRD among adults with MDE (adjusted odds ratio [AOR], 1.53; 95 % CI, 1.35-1.75 for suicidal ideation; AOR, 2.17; 95 % CI, 1.79-2.62 for suicide attempts). No significant differences were observed between 2019 and 2020, reflecting the COVID-19 pandemic. CONCLUSION: Among individuals with TRD, proportions of SIBs are high. These findings underscore an urgent need for suicide prevention efforts in this high-risk population, including preventive services across diverse settings and accessibility to evidence-based pharmacological and non-pharmacological interventions.

Association Between the Time Spent on and Sources of the News of Russo-Ukrainian War and Psychological Distress Among Individuals in Poland and Ukraine: The Mediating Effect of Rumination.

Background: The Russo-Ukrainian War has resulted in massive social, economic, and psychological burdens worldwide. This study aimed to investigate the associations between time spent on the war-related news and psychological distress, including depression, anxiety, and post-traumatic stress disorder (PTSD) and the mediating effects of rumination on the associations in people residing in Poland and Ukraine. Methods: This cross-sectional study recruited 1438 internet users in Poland and Ukraine, and collected data on levels of rumination, psychological distress, and the amount of time spent on and sources of the news of the Russo-Ukrainian War. Structural equation modeling with bootstrapping methods was used to evaluate the mediation effect. Multivariate linear regression was used to identify predictive effect of the source of the war-related news on psychological distress and rumination. Results: The results showed a mediating effect of rumination on the association between the amount of time spent on the war-related news and psychological distress among participants in Poland (ß = 0.16, p < 0.001) and Ukraine (ß = 0.15, p < 0.001). Approaching the news from television was associated with rumination (ß = 0.607, p < 0.001) and PTSD symptoms in Poland (ß = 2.475, p = 0.009), while approaching news from the internet was associated with rumination in Poland (ß = 0.616, p = 0.001). Conclusion: The study identified the mediating effect of rumination and the associations of approaching the war-related news from television and the internet with mental health.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Effects of cannabidiol and Δ9-tetrahydrocannabinol on cytochrome P450 enzymes: a systematic review.

Due to legal, political, and cultural changes, the use of cannabis has rapidly increased in recent years. Research has demonstrated that the cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) inhibit and induce cytochrome P450 (CYP450) enzymes. The objective of this review is to evaluate the effect of CBD and THC on the activity of CYP450 enzymes and the implications for drug-drug interactions (DDIs) with psychotropic agents that are CYP substrates. A systematic search was conducted using PubMed, Scopus, Scientific Electronic Library Online (SciELO) and PsychINFO. Search terms included 'cannabidiol', 'tetrahydrocannabinol', and 'cytochrome P450'. A total of seven studies evaluating the interaction of THC and CBD with CYP450 enzymes and psychotropic drugs were included. Both preclinical and clinical studies were included. Results from the included studies indicate that both CBD and THC inhibit several CYP450 enzymes including, but not limited to, CYP1A2, CYP3C19, and CYP2B6. While there are a few known CYP450 enzymes that are induced by THC and CBD, the induction of CYP450 enzymes is an understudied area of research and lacks clinical data. The inhibitory effects observed by CBD and THC on CYP450 enzymes vary in magnitude and may decrease the metabolism of psychotropic agents, cause changes in plasma levels of psychotropic medications, and increase adverse effects. Our findings clearly present interactions between THC and CBD and several CYP450 enzymes, providing clinicians evidence of a high risk of DDIs for patients who consume both cannabis and psychotropic medication. However, more clinical research is necessary before results are applied to clinical settings.

Effects of anhedonia on health-related quality of life and functional outcomes in major depressive disorder: A systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous group of mood disorders. A prominent symptom domain is anhedonia narrowly defined as a loss of interest and ability to experience pleasure. Anhedonia is associated with depressive symptom severity, MDD prognosis, and suicidality. We perform a systematic review and meta-analysis of extant literature investigating the effects of anhedonia on health-related quality of life (HRQoL) and functional outcomes in persons with MDD. METHODS: A literature search was conducted on PubMed, OVID databases, and SCOPUS for published articles from inception to November 2023, reporting on anhedonia and patient-reported outcomes in persons with MDD. The reported correlation coefficients between anhedonia and self-reported measures of both HRQoL and functional outcomes were pooled using a random effects model. RESULTS: We identified 20 studies that investigated anhedonia with HRQoL and/or functional outcomes in MDD. Anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS) scores had a statistically significant correlation with patient-reported HRQoL (r = -0.41 [95 % CI = -0.60, -0.18]) and functional impairment (r = 0.39 [95 % CI = 0.22, 0.54]). LIMITATIONS: These preliminary results primarily investigate correlations with consummatory anhedonia and do not distinguish differences in anticipatory anhedonia, reward valuation or reward learning; therefore, these results require replication. CONCLUSIONS: Persons with MDD experiencing symptoms of anhedonia are more likely to have worse prognosis including physical, psychological, and social functioning deficits. Anhedonia serves as an important predictor and target for future therapeutic and preventative tools in persons with MDD.

Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder.

INTRODUCTION: Cariprazine treats acute manic and depressive episodes in bipolar I disorder (BP-I), but its efficacy in preventing relapse of mood episode remains unknown. METHODS: In this phase 3b, double-blind, placebo-controlled study, patients with BP-I with acute manic or depressive episodes (each with/without mixed features), were treated with cariprazine 3.0 mg/day during a 16-week open-label treatment period; those who achieved stable remission within 8 weeks and remained stable for at least another 8 weeks were randomized to receive cariprazine 1.5 or 3.0 mg per day or placebo in the double-blind treatment period for up to 39 weeks. The primary efficacy endpoint was time to relapse of any mood episode. Adverse events (AEs) were assessed. RESULTS: Patients (440/896) enrolled in the open-label treatment period achieved stability criteria and were randomized to receive cariprazine 3.0 mg/day (n = 148), cariprazine 1.5 mg/day (n = 147), or placebo (n = 145) in the double-blind treatment period. Relapse rates were 17.9%, 16.8%, and 19.7% in the cariprazine 3.0 mg/day, cariprazine 1.5 mg/day, and placebo groups, respectively. Neither dose of cariprazine was more effective than placebo on the primary outcome (3.0 mg/day: HR = 0.89, [95% CI: 0.5, 1.5]; 1.5 mg/day: HR = 0.83, 95% CI [0.5, 1.4]). The most frequently reported AEs (≥5%) were akathisia, headache, insomnia, and nausea in the open-label treatment period and increased weight and insomnia in the double-blind treatment period. In the open-label and double-blind treatment periods, 7.5% and 1.6% of patients experienced an AE leading to discontinuation. CONCLUSION: Cariprazine was not superior to placebo in the prevention of relapses in this study. Relapse rates were unusually low in the placebo group. Cariprazine was well-tolerated.

Relative associations of behavioral and physiological risks for cardiometabolic disease with cognition in bipolar disorder during mid and later-life: findings from the UK biobank.

BACKGROUND: Cardiometabolic disease risk factors are disproportionately prevalent in bipolar disorder (BD) and are associated with cognitive impairment. It is, however, unknown which health risk factors for cardiometabolic disease are relevant to cognition in BD. This study aimed to identify the cardiometabolic disease risk factors that are the most important correlates of cognitive impairment in BD; and to examine whether the nature of the relationships vary between mid and later life. METHODS: Data from the UK Biobank were available for 966 participants with BD, aged between 40 and 69 years. Individual cardiometabolic disease risk factors were initially regressed onto a global cognition score in separate models for the following risk factor domains; (1) health risk behaviors (physical activity, sedentary behavior, smoking, and sleep) and (2) physiological risk factors, stratified into (2a) anthropometric and clinical risk (handgrip strength, body composition, and blood pressure), and (2b) cardiometabolic disease risk biomarkers (CRP, lipid profile, and HbA1c). A final combined multivariate regression model for global cognition was then fitted, including only the predictor variables that were significantly associated with cognition in the previous models. RESULTS: In the final combined model, lower mentally active and higher passive sedentary behavior, higher levels of physical activity, inadequate sleep duration, higher systolic and lower diastolic blood pressure, and lower handgrip strength were associated with worse global cognition. CONCLUSIONS: Health risk behaviors, as well as blood pressure and muscular strength, are associated with cognitive function in BD, whereas other traditional physiological cardiometabolic disease risk factors are not.

Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review.

BACKGROUND: Electrophysiologic measures provide an opportunity to inform mechanistic models and possibly biomarker prediction of response. Serotonergic psychedelics (SPs) (i.e., psilocybin, lysergic acid diethylamide (LSD)) and ketamine represent new investigational and established treatments in mood disorders respectively. There is a need to better characterize the mechanism of action of these agents. METHODS: We conducted a systematic review investigating the spectral signatures of psilocybin, LSD, and ketamine in persons with major depressive disorder (MDD), treatment-resistant depression (TRD), and healthy controls. RESULTS: Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD. LIMITATIONS: The studies included in our review were heterogeneous in their patient population, exposure, dosing of treatment and devices used to evaluate EEG and MEG signatures. Our results were extracted entirely from persons who were either healthy volunteers or persons with MDD or TRD. CONCLUSIONS: Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.

Impact of elevated body mass index (BMI) on cognitive functioning and inflammation in persons with post-COVID-19 condition: a secondary analysis.

BACKGROUND: Individuals who have recovered from the acute stage of SARS-CoV-2 infection may be at risk of developing post-COVID-19 condition (PCC), characterised by a spectrum of persisting, non-specific, and functionally impairing symptoms across multiple organ systems. Obesity has been implicated as a risk factor for PCC, mediated by chronic systemic inflammation. The foregoing has also been separately reported to mediate cognitive dysfunction in PCC. METHODS: This is a post-hoc analysis of a randomised, double-blinded, placebo-controlled clinical trial evaluating vortioxetine treatment for cognitive impairments in persons with PCC who received vortioxetine or placebo for eight weeks. This analysis comprises baseline data, examining the impact of BMI on cognitive functioning measured by the Digit Symbol Substitution Test (DSST) and Trails Making Tests (TMT)-A/B, as well as inflammation, via serum c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RESULTS: Complete data from 70 participants were statistically analysed and adjusted for age and sex. BMI was negatively correlated with performance on the DSST (ß = -0.003, p = 0.047), TMT-A (ß = -0.006, p = 0.025), and TMT-B (ß = -0.006, p = 0.002). BMI was positively correlated with serum CRP (unstandardized ß = 0.193, standardized ß = 0.612, p < 0.001) and ESR (ß = 0.039, p < 0.001) levels. CONCLUSION: We observed a significant negative correlation between BMI and cognitive functioning, and a significant positive correlation between BMI and inflammation in persons with PCC, suggesting a bidirectional interplay between BMI, PCC, and cognitive function; individuals with an elevated BMI may be at a greater risk of developing PCC and/or presenting with greater cognitive deficits mediated by chronic systemic inflammation.

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, N combinedDSST ), 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.

Greater Role of Cognitive Impairment Over Fatigue in Post-COVID-19 Quality of Life: A Post-Hoc Analysis of a Randomized Controlled Trial.

Background: Post COVID-19 Condition (PCC) is a common and debilitating condition with significant reports of fatigue and psychosocial impairment globally. The extent to which cognitive symptoms and fatigue contribute to reduced quality of life in affected individuals remains clear. Methods: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial that evaluated the effect of vortioxetine on cognitive function in adults with PCC. The post-hoc analysis herein aimed to determine the overall effect of baseline cognitive function [as measured by the Digit Symbol Substitution Test (DSST)] and baseline fatigue severity [as measured by the Fatigue Severity Scale (FSS)] on baseline health-related quality of life (HRQoL) [as measured by the 5-item World Health Organisation Well-Being Index (WHO-5)]. Results: A total of 200 participants were enrolled in the primary trial. Due to missing baseline data, our statistical analysis included baseline measures of 147 individuals. Our generalized linear model analysis revealed a significant positive correlation between DSST-measured objective cognitive function and self-reported WHO-5-measured HRQoL (ß = 0.069, 95% CI [0.006, 0.131], p = 0.032). In contrast, our analysis revealed a significant negative correlation between FSS and WHO-5 scores (ß = -0.016, 95% CI [-0.021, -0.011], p < 0.001). The beta-coefficient ratio (ß DSST / ß FSS = 0.069 / 0.016) is calculated as 4.313. Conclusions: Overall, we observed that increased cognitive function was associated with increased HRQoL at baseline in adults with PCC. Moreover, we observed that increased severity of fatigue symptoms was associated with decreased HRQoL at baseline in adults with PCC. Furthermore, we observed that an improvement in cognitive function would have a four-fold greater impact on HRQoL than the effect generated by improvement in fatigue.

Number needed to treat (NNT) for ketamine and esketamine in adults with treatment-resistant depression: A systematic review and meta-analysis.

BACKGROUND: Ketamine has been established as efficacious in adults living with Treatment-resistant Depression (TRD). Toward providing a quantifiable estimate of the clinical meaningfulness of the therapeutic benefit of ketamine, herein, we conduct a systematic review that aims to report the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH). METHODS: This systematic review searched Embase, Medline/Pubmed, PsycINFO and ClinicalTrials.gov from inception up to October 15th 2023, for placebo-controlled, Randomized Controlled Trials (RCTs) assessing racemic ketamine or esketamine therapy for unipolar TRD. We calculated NNT and NNH for ketamine treatments over various time points. RESULTS: A total of 21 studies with 2042 participants were included. Racemic ketamine treatments had pooled NNTs for response of 7 at 4 h, 3 from one day to one week and 9 for studies at four weeks. Esketamine treatment was found to have a similar efficacy with an NNT of 2 at one day and 11 at four weeks. NNH values indicated low risk for ketamine treatments. LIMITATIONS: Limitations in the data used include the possibility of functional unblinding and selective reporting bias. Moreover, the meta-analysis may have been limited in its precision by including low threshold definitions of treatment resistance (≥ 1 failed antidepressant) and low-dose ketamine treatments. CONCLUSION: Herein, we determined that the NNT for ketamine treatment in adults living with TRD across different intervals of observation was <10. We conclude that the NNTs observed herein are highly clinically meaningful in this difficult to treat disorder.

Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Efficacy, safety, and tolerability of xanomeline for schizophrenia spectrum disorders: a systematic review.

INTRODUCTION: We systematically reviewed extant studies evaluating the efficacy and tolerability of xanomeline and xanomeline-trospium (KarXT) for treatment of adults with schizophrenia. METHODS: In accordance with PRISMA guidelines, articles were systematically searched for in databases and clinical trial registries. RESULTS: A total of 4 preclinical trials and 3 randomized controlled trials (RCTs) were included in this review. A 4-week RCT observed a difference of 24.0 points (SD 21.0) in the Positive and Negative Syndrome Scale (PANSS) total score between xanomeline and placebo groups (p = 0.039). A 5-week RCT observed PANSS total score changes from baseline to week 5, including -17.4 and -5.9 points in KarXT and placebo groups, respectively (LSMD -11.6 points; 95% CI -16.1 to -7.1; p < 0.001; d = 0.75). Another 5-week RCT observed PANSS total score changes from baseline to week 5, including -21.2 (SE 1.7) and -11.6 (SE 1.6) points in KarXT and placebo groups, respectively (LSMD -9.6; 95% CI -13.9 to -5.2; p < 0.0001; d = 0.61). Side effects include constipation, nausea, vomiting, dyspepsia, and dry mouth. CONCLUSION: KarXT offers an innovative non-D2 blocking approach, representing a promising treatment avenue for schizophrenia.