Efficacy, safety, and tolerability of ulotaront (SEP-363856, a trace amine-associated receptor 1 agonist) for the treatment of schizophrenia and other mental disorders: a systematic review of preclinical and clinical trials.

INTRODUCTION: Schizophrenia is a mental illness that can disrupt emotions, perceptions, and cognition and reduce quality of life. The classical approach to treat schizophrenia is to use typical and atypical antipsychotics; however, limitations include low efficacy in mitigating negative symptoms and cognitive dysfunctions and a range of adverse effects. Evidence has accumulated on trace amine-associated receptor 1 (TAAR1) as a novel therapeutic target for treating schizophrenia. This systematic review investigates the available evidence on a TAAR1 agonist, ulotaront, as a treatment for schizophrenia. METHODS: A systematic search was conducted on PubMed/MEDLINE and Ovid databases for English-published articles from inception to 18 December 2022. The literature focusing on the association between ulotaront and schizophrenia was evaluated based on an inclusion/exclusion criterion. Selected studies were assessed for the risk of bias, using the Cochrane Collaboration tool, and summarized in a table to generate discussion topics. RESULTS: Three clinical, two comparative, and five preclinical studies examining ulotaront's pharmacology, tolerability and safety, and/or efficacy were identified. Results indicate that ulotaront has a differing adverse effect profile from other antipsychotics, may mitigate metabolic-related adverse effects commonly associated with antipsychotics, and may be effective for treating positive and negative symptoms. CONCLUSIONS: Findings from the available literature present ulotaront as a potential and promising alternative treatment method for schizophrenia. Despite this, our results were limited due to the lack of clinical trials on ulotaront's long-term efficacy and mechanisms of action. Future research should focus on these limitations to elucidate ulotaront's efficacy and safety for the treatment of schizophrenia and other mental disorders with similar pathophysiology.

Brain-Derived Neurotrophic Factor (BDNF) as a biomarker of treatment response in patients with Treatment Resistant Depression (TRD): A systematic review & meta-analysis.

Multiple lines of evidence have implicated brain-derived neurotrophic factor (BDNF) in treatment-resistant depression (TRD). The aim of this synthesis was to determine the impact of TRD treatments on peripheral BDNF levels, and ascertain whether these changes are associated with antidepressant effects. Thirty-six articles involving 1198 patients with TRD were included herein. Electroconvulsive therapy (ECT), ketamine, and repetitive transcranial magnetic stimulation (rTMS) were the most common TRD treatments investigated. Serum BDNF levels significantly increased in six, two, four and one studies following ECT, ketamine, rTMS and atypical antipsychotics, respectively. The estimated mean baseline serum BDNF concentration in TRD patients ± 95% CI was 15.5 ± 4.34 ng/mL. Peripheral BDNF levels significantly increased overall (Hedges' g ± 95% CI = 0.336 ± 0.302; p < 0.05), but no association with depressive symptoms was found (p ≥ 0.05). These results demonstrate that peripheral measurements of total BDNF (i.e., mature and percursor forms of BDNF) are inadequate predictors of treatment response in TRD patients, and other considerations suggest that this would still apply to separable measurements of mature BDNF and its precursor.

Lumateperone for the Treatment of Adults With Schizophrenia: a Systematic Review.

PURPOSE OF REVIEW: Lumateperone (LUM) is the U.S. Food and Drug Administration approved atypical antipsychotic agent for adults with schizophrenia (SCZ) and bipolar depression (for both bipolar I and bipolar II disorder as as monotherapy or as adjunctive treatment to lithium or valproate). LUM simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. The foregoing pleiotropic mechanism of action is predictive of therapeutic benefits across multiple domains of psychopathology in SCZ (i.e., positive, negative, cognitive, and prosocial symptoms). Herein, the overarching aim is to synthesize the extant literature reporting on the efficacy, safety, and tolerability of LUM in adults with SCZ. RECENT FINDINGS: Four clinical studies (i.e., three RCTs and one open-label trial) were included in this synthesis. Overall, LUM significantly reduced the severity of SCZ compared with placebo. The open label study provided the real-world effectiveness of shifting stable patients with SCZ to LUM from other atypical antipsychotics. With respect to safety and tolerability profile, LUM demonstrated placebo-level rates of weight gain, metabolic shift, prolactin elevation, extrapyramidal side effects (EPS), and akathisia across short term trials (i.e., 4-6 weeks). Taken together, our results indicate that LUM significantly improves symptoms severity in adults with SCZ. LUM also exhibits a favorable tolerability and safety profile with placebo level rates of weight gain, metabolic disruption, akathisia, extrapyramidal side effects (excluding akathisia), and prolactin elevation. Lumateperone should be conceptualized as a first-line treatment strategy for adults with SCZ.

Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis.

Ketamine is a promising therapeutic option in treatment-resistant depression (TRD). The acute efficacy of ketamine in TRD has been demonstrated in replicated randomised-controlled trials (RCTs), but the generalizability of RCT data to real-world practice is limited. To this end, we conducted a systematic review (Search date: 25/12/2021; 1482 records identified) and meta-analysis of studies evaluating the real-world clinical effectiveness of ketamine in TRD patients. Four overlapping syntheses (Total n = 2665 patients; k = 79 studies) and 32 meta-regressions (Total n = 2050; k = 37) were conducted. All results suggest that the mean antidepressant effect is substantial (mean ± 95% CI, % responded = 45 ± 10%; p< 0.0001, % remitted = 30 ± 5.9%; p< 0.0001, Hedges g of symptomatological improvement = 1.44 ± 0.609; p < 0.0001), but the effect varies considerably among patients. The more treatment-resistant cases were found to remit less often (p < 0.01), but no such effect on response was evident (p > 0.05). Meta-regressions also confirmed that the therapeutic effect does not significantly decline with repeated treatments (p > 0.05). These results demonstrate that even the most treatment-resistant patients may benefit from ketamine, and that mid-to-long term treatment is effective in many patients.

Olanzapine and samidorphan combination treatment: A systematic review.

INTRODUCTION: The overarching aim of this review is to synthesize the efficacy, tolerability, and weight-mitigation effects of the olanzapine/samidorphan (OLZ/SAM) combination treatment in adults with schizophrenia and bipolar disorder-I. METHODS: A systematic search of PubMed, Web of Science, Embase, and The Cochrane Library was conducted on August 15th, 2021. Studies were included if they investigated the use of OLZ/SAM treatment in patients with schizophrenia or bipolar disorder-I, and reported the clinical outcomes: efficacy, change in weight or waist circumference, tolerability, pharmacokinetics, or change in metabolic parameters. A narrative synthesis was undertaken of the data. RESULTS: Eight studies met the inclusion criteria. All identified studies were conducted in adults with schizophrenia. Compared to OLZ-monotherapy, OLZ/SAM was associated with decreased odds of developing clinically significant (>10%) weight gain (OR=0.50, 95% CI:0.31,0.80; p= 0.003) and increase in waist circumference (risk difference = -17.1% 95% CI:-26.3,-7.8) from baseline measurements respectively. In another study, OLZ was 2.7 times more associated with clinically significant weight gain as compared to OLZ/SAM (OR=2.73, 95% CI:1.11, 6.67; p = 0.023). The clinical efficacy of OLZ/SAM remained similar to OLZ with improved tolerability in both short- and long-term studies with no significantly altered pharmacokinetic properties of the constituent agents. CONCLUSION: OLZ/SAM-treatment is associated with mitigated weight-gain liability when compared to OLZ-monotherapy in adults with schizophrenia. Additional studies are needed to ascertain patient acceptability, appropriate selection and sequencing of OLZ/SAM in the treatment algorithms for adults with schizophrenia (and BD-I), as well as to determine cost-effectiveness and long-term metabolic effects.

Trace amine-associated receptor 1 (TAAR1): Potential application in mood disorders: A systematic review.

There is a need for innovation with respect to therapeutics in psychiatry. Available evidence indicates that the trace amine-associated receptor 1 (TAAR1) agonist SEP-363856 is promising, as it improves measures of cognitive and reward function in schizophrenia. Hedonic and cognitive impairments are transdiagnostic and constitute major burdens in mood disorders. Herein, we systematically review the behavioural and genetic literature documenting the role of TAAR1 in reward and cognitive function, and propose a mechanistic model of TAAR1's functions in the brain. Notably, TAAR1 activity confers antidepressant-like effects, enhances attention and response inhibition, and reduces compulsive reward seeking without impairing normal function. Further characterization of the responsible mechanisms suggests ion-homeostatic, metabolic, neurotrophic, and anti-inflammatory enhancements in the limbic system. Multiple lines of evidence establish the viability of TAAR1 as a biological target for the treatment of mood disorders. Furthermore, the evidence suggests a role for TAAR1 in reward and cognitive function, which is attributed to a cascade of events that are relevant to the cellular integrity and function of the central nervous system.

Impact of SARS-CoV-2 Infection on Cognitive Function: A Systematic Review.

The prevalence and etiology of COVID-19's impact on brain health and cognitive function is poorly characterized. With mounting reports of delirium, systemic inflammation, and evidence of neurotropism, a statement on cognitive impairment among COVID-19 cases is needed. A substantial literature has demonstrated that inflammation can severely disrupt brain function, suggesting an immune response, a cytokine storm, as a possible cause of neurocognitive impairments. In this light, the aim of the present study was to summarize the available knowledge of the impact of COVID-19 on cognition (i.e., herein, we broadly define cognition reflecting the reporting on this topic in the literature) during the acute and recovery phases of the disease, in hospitalized patients and outpatients with confirmed COVID-19 status. A systematic review of the literature identified six studies which document the prevalence of cognitive impairment, and one which quantifies deficits after recovery. Pooling the samples of the included studies (total sample n = 644) at three standards of quality produced conservative estimates of cognitive impairment ranging from 43.0 to 66.8% prevalence in hospitalized COVID-19 patients only, as no studies which report on outpatients met criteria for inclusion in the main synthesis. The most common impairment reported was delirium and frequent reports of elevated inflammatory markers suggest etiology. Other studies have demonstrated that the disease involves marked increases in IL-6, TNFα, and IL-1ß; cytokines known to have a profound impact on working memory and attention. Impairment of these cognitive functions is a characteristic aspect of delirium, which suggests these cytokines as key mediators in the etiology of COVID-19 induced cognitive impairments. Researchers are encouraged to assay inflammatory markers to determine the potential role of inflammation in mediating the disturbance of cognitive function in individuals affected by COVID-19.