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.

Changes in insulin resistance following antidepressant treatment mediate response in major depressive disorder.

BACKGROUND: Insulin resistance (IR) is a potential predictor of antidepressant treatment response. AIMS: We assess changes in IR after antidepressant treatment and whether these changes have any effect on treatment response. Also, to see whether changes in IR mediates relationship between C-reactive protein (CRP) and antidepressant efficacy. METHODS: This is a secondary analysis of an 8-week, open-label clinical trial with 95 adults experiencing a major depressive episode. Response to vortioxetine was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). Generalized estimating equation models were utilized for this intent-to-treat analysis. RESULTS: When adjusted for age, sex, and body mass index, there was a significant increase in IR following treatment in the overall sample (p = 0.035). This finding was detected in treatment non-responders (p = 0.019), whereas it was not observed in responders (p = 0.329). Mediation analysis revealed that change in IR during treatment was responsible for change in MADRS as well as the relationship between baseline CRP and treatment response. CONCLUSIONS: Exacerbation of IR during antidepressant treatment mediated non-response. Conversely in treatment responders IR reduced. Like previous studies, baseline CRP moderated treatment response. This relationship was also mediated by changes in IR. These findings further elucidate the role of IR in terms of antidepressant response as well as potentially explain inflammation's relationship with the latter.

The abuse liability of ketamine: A scoping review of preclinical and clinical studies.

While ketamine has been used clinically over the past decades, it has only been recently shown to be a promising therapy for treatment-resistant depression (TRD). However, ketamine and related dissociative agents may also be misused recreationally, creating significant concerns for abuse liability when prescribed for depression. Although the abuse potential of ketamine is widely recognized, there is limited evidence on the differential abuse liability of ketamine enantiomers, (S)-ketamine and (R)-ketamine. The current scoping review aims to summarize the extant literature on the abuse liability of (R,S)-ketamine and the enantiomers. A systematic search was conducted on the Embase, Medline, and APA PsycInfo databases from 1947 to July 29, 2021. Clinical and preclinical studies that assessed the abuse potential of (R,S)-ketamine, (S)-ketamine, and (R)-ketamine were screened and assessed for eligibility by two independent reviewers. A total of 65 eligible studies were identified; 55 were preclinical studies and 10 were clinical studies. Only 4 preclinical studies evaluated the abuse liability of ketamine enantiomers. Available preclinical evidence suggests that (R,S)-ketamine and (S)-ketamine have greater risk for abuse compared to (R)-ketamine. (R)-ketamine, at the antidepressant-relevant doses in rodents, appears to be safe with minimal liability for abuse. Although the abuse potential of (R,S)-ketamine is well-established in animals, limited clinical studies indicate that single or repeated ketamine administrations in professionally controlled settings did not result in misuse, dependence, diversion and/or gateway activity in patients with TRD. However, most clinical studies were retrospective and did not systematically evaluate the abuse liability of ketamine via validated psychological scales/questionnaires. Future randomized controlled trials are warranted to ascertain the abuse liability of racemic, (S)- and (R)-ketamine in TRD population, especially among patients with comorbid substance use disorders.

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.

The efficacy and safety of adjunctive intranasal esketamine treatment in major depressive disorder: a systematic review and meta-analysis.

INTRODUCTION: Intranasal (IN) esketamine represents an innovative treatment for individuals with treatment resistant depression and depression with suicidal ideation and behavior. Herein, we synthesize extant long-term studies (≥ 4 weeks) regarding this treatment. RESEARCH DESIGN AND METHODS: The interventional studies of IN esketamine in patients with depression having a study period of at least four weeks were included for our synthesis. A meta-analysis was undertaken for the efficacy and safety parameters of adjunctive IN esketamine vs IN placebo with an oral antidepressant. The data excluded from meta-analysis were synthesized narratively. RESULTS: After pooling data from seven randomized controlled trials, treatment with adjunctive IN esketamine vs IN placebo was safe overall, and more effective at decreasing depressive symptoms (d = -0.239; 95%CI = -0.335,-0.142;p < 0.0001), with higher response (RR = 1.221; 95% CI = 1.055,1.428; p = 0.017) and remission (RR = 1.366; 95% CI = 1.182,1.578; p < 0.0001) rates. The year-long trials showed that treatment with adjunctive IN esketamine led to lower relapse rates with no considerable long-term side effects. CONCLUSION: Intranasal esketamine was demonstrated to be safe, well tolerated, and rapidly effective in individuals with treatment resistant depression, suicidal ideation, and suicidal behavior.

Pharmacogenomics of ketamine: A systematic review.

Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Predictors of antidepressant response and adverse effects to ketamine remain poorly understood due to contradictory results. The objective of the systematic review herein is to identify and evaluate the extant literature assessing pharmacogenomic predictors of ketamine clinical benefits and adverse effects. Electronic databases were searched from inception to July 2021 to identify relevant articles. Twelve articles involving 1,219 participants with TRD, 75 who underwent elective surgeries and received ketamine as an anesthetic, 49 with pain, and 68 healthy participants met the inclusion criteria and enrolled to this review. While identified articles reported mixed results, three predictors emerged: 1) Val66Met (rs6265) brain derived neurotrophic factor (BDNF; Met allele) was associated with reduced antidepressant and anti-suicidal effects, 2) CYP2B6*6 (e.g., CYB2B6 metabolizer) was associated with more severe dissociative effects and 3) NET allelic (rs28386840) variant were associated with greater cardiovascular complications (e.g., moderate to severe treatment emergent hypertension). Several important limitations were identified, most notably the small sample sizes and heterogeneity of study design and results. Taken together, preliminary evidence suggests the potential for pharmacogenomic testing to inform clinical practices; however, further research is needed to better determine genetic variants of greatest importance and the clinical validity of pharmacogenomics to help guide ketamine treatment planning.